- Journal of SOPI

Transcription

- Journal of SOPI

F
E
NC
A
MACOVIG
R
A
IL
H
P
(INDIA)
JOURNAL OF PHARMACOVIGILANCE & DRUG SAFETY
• VOLUME 9 • NUMBER 1 •
SOCIETY O
JANUARY - MARCH, 2010
NUMBER 1
VOLUME 7
JANUARY - MARCH, 2010
• PAGES 1-52
Journal of Pharmacovigilance & Drug Safety
(Official Publication of Society of Pharmacovigilance, India)
Volume 7, No 1, 2010
Society of Pharmacovigilance (India)
Patron:
Prof. K.C. Singhal
Treasurer:
Dr. Govind Mohan
President:
Prof. R.K.Goyal
Vice President
Prof. Meera Desai
Secy. International Affairs Co-ordinator Asia Pacific
Dr. S. Ziaur Rahman
Prof. J.F. Knight
Secretary:
Dr. Sandeep Agarwal
Editor - in - Chief
Dr. Anurag Tomar
Executive Committee
Dr. R.N. Acharya (Jamnagar)
Dr. Priti Baijal (Delhi)
Dr. Pramod Mediratta (Delhi)
Dr. G.P. Rauniar (Nepal)
Dr. Surendra K. Goyal (Sirsa)
Dr. Arunabha Ray (Delhi)
Dr. Y.P. Singla (Sirsa)
Prof. D.D. Santani (Ahmedabad)
Organizing Secretary
Immediate Past President
Dr. H.S. Rehan (Delhi)
Dr. K.K. Sharma (Delhi)
Editorial Board
Editor-in-Chief Dr. Anurag Tomar
Dr. B.R. Madan (Jaipur)
Dr. R.K. Goyal (Vadodara)
Dr. M.C. Sharma (Jaipur)
Dr. Sandhya Kamat (Mumbai)
Dr. S.K. Tripathi (Kolkata)
Dr. Urmila Thatte (Mumbai)
Dr. V.N. Sharma (Jaipur)
Dr. Shobha Kulshresthra (Jaipur)
Dr. Pramil Tiwari (SAS Nagar)
Dr. Sagun Desai (Karamsad)
Dr. Naresh Khanna (Delhi)
Dr. R. Balaraman (Vadodara)
International Advisory Board
Dr.
Dr.
Dr.
Dr.
Ralph Edwards (Sweden)
G.P. Velo (Italy)
P. Subish, (Nepal)
John Autian (USA)
Dr.
Dr.
Dr.
Dr.
Sten Olsson (Sweden)
R.H.B. Meyboon (Sweden)
Chris J.VanBoxtel (Holland)
Abha Agarwal (U.S.A.)
Journal of Pharmacovigilance & Drug Safety (ISSN 0972-8899) is published by the Society of Pharmacovigilance, India (SOPI).
Journal is provided free of charge to Life members. For institutional library annual subscription is Rs. 2000/- and for individuals Rs.
500/- per annum. Loose issues will not be sold. Manuscripts and illustration for publication should be sent to Dr. Anurag Tomar,
Editor-in Chief, Journal of Pharmacovigilance & Drug Safety, NIMS City Centre, 4 Govind Marg, Jaipur - 302004 India. Email
sopijaipur@rediffmail.com Please refer to instruction for Authors, for additional information concerning preparation of
manuscripts for publication.
FOR YOUR KIND ATTENTION
?
The Views expressed by the authors do not necessarily reflect those of the sponsor or publisher. Although
every care has been taken to ensure technical accuracy, no responsibility is accepted for errors of omissions.
?
The claims of the manufacturers and efficacy of the products advertised in the journal are the responsibility
of the advertiser. The journal does not own any responsibility for the guarantee of the products advertised
January - March, 2010 Volume 7 : Number 1
Particulars
Page
From the Desk of the Editor
Contents.....
John Autian Oration-2009
1-6
BRUCE HUGMAN
Pharmacogenomics: The Future of Pharmacovigilance
7-8
SANTANU K. TRIPATHI
Cholesterol Lowering Potential Of Seabuckthorn
9-13
IMRAN ZAFAR, M. FAHIM
Off Label Drug Treatment and Related Problem in Children
14-17
CHETAN MEHNDIRATTA, SYED ZIAUR RAHMAN, PIPASHA BISWAS
Nanobiotechnology Today: Focus on Nanoparticles
18-26
ANSHUL KUMAR, IMRAN ZAFAR
A Retrospective Comparison of Buprenorphine & Pentazocine as
an Analgesic in AMI at Pravara Rural Hospital.
27-31
RAHUL KUNKULOL, PRONOB K SANYAL,
KAILAS R. GADEKAR, Y GRIDHAR REDDY
Biosafety Issues In Laboratories: A Review
32-37
AMIT JAIN, ZAHRA HASHEMI
Pharmacovigilance of Homeopathy - Questioning its Efficacy
38-42
DINESH K. JAIN, RAJ K. ARYA
Risks and Recall of Medicines Pharmacovigilance Perspective
ADITI NIGAM, ETHIRAJ DHANARAJ, PRAMIL TIWARI
Events
NEWS & CONFERENCE ANNOUNCEMENTS
43-52
In the modern era of clinical application of knowledge of pharmacology, it is a big dilemma in
choosing between the good and the best drug. In making a decision for treatment planning clinician
must consider the additional features of local and systemic issues, patient's economic status as well as
potential adverse effect of the drug.
There are large number of drug trial going on world wide to observe the effect of a particular drug or a
molecule. However, the scenario has changed drastically in last 20 years. What it was with the
western/ developed world is now shifting over to developing world.
India is set to grab clinical trial business, making the subcontinent world's preferred destination for
clinical trials. The big reason being low cost of trial along with friendly drug control system with
competent work force and patient availability. Indian investigators and clinical trial research
professionals have already demonstrated their medical and scientific skills in various global clinical
trials. It is time now to capitalize on this opportunity. Indian investigators and research professionals
can prove their ability and show to the world and register their presence now as well as for future.
Clinical trials can provide answers related to the use or not to use a therapeutic agent that can benefit
millions of patients in India and worldwide contributing to global drug research and development
programme.
It takes a huge amount of money to bring one drug to market through a series of procedure, but the
success rate is variable. Therefore, we clinicians, researchers, pharmacologists and all the people
related should have drug safety as our primary concern. And that concern can only be translated to
human welfare if we are documenting the good as well adverse effect of a particular drug, whether
new or old. The journal here provides a platform to document all the drug related events.
With the request to all the members and readers to kindly document and submit their articles in the
journal. I thank the members of editorial board in helping me to come out with another issue of the
esteemed journal.
Dr. Anurag Tomar
MBBS, MD (Pediatrics)
Editor in Chief
J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 1-6)
BRUCE HUGMAN
PO. Box 246 Amphur Muang, Chiang, Rai Thailand 57000
The Front Line
he didn't. What did the pharmacist say? Take one tablet
three times a day after meals. I have been to that hospital. It
is inundated with patients: the wards are overflowing and
the corridors are heaving with queues of people waiting for
attention. Everyone on the staff is doing their best, but the
odds against the delivery of universally effective
healthcare are depressingly large. Lives are saved, bodies
are repaired, wounds are stitched, disease is treated but, I
suspect, it is a lottery, the risks of which the wealthy and
educated would never tolerate. Today, I am not concerned
with the political, economic and financial issues of
healthcare, urgent and enormous though those are; no, I
want to remind us that this is life as it is experienced at the
front line, as it is for so many people, in so many countries,
where there are healthcare services at all.
I want to take you on a journey to the front line, the front
line where patients are sick or at risk and where doctors and
nurses, pharmacists and traditional healers are struggling
to make people well; the front line where, like in a battle or
the aftermath of a natural disaster, the priorities and needs
are urgent and vivid. I want to see what we can learn from
the messy and dramatic reality of the front line, and how
what we learn there might influence our thinking and
practice in pharmacovigilance and patient safety.
Signposts For The Journey
On this journey to the front line, I shall pause to consider a
number of questions, including:
F
Why treatment often fails to be as safe as it should be,
and what can be done
F
Why status differentials compromise many aspects of
patient safety
F
Why HCPs are less committed than we would wish to
reporting ADRs
F
Why we should pay attention to Honda worldwide and
to Mrs Gupta and the millions of street traders in India
F
Why listening at the front line is critical for success
F
Why we in PV need to be well-known and trusted
Neglected At Hospital
Well Documented Problems
I started with an anecdote which raises deep concerns for
me, but that is not a good enough basis on which to develop
a serious professional argument. I must at least refer to the
research which tells us that there really are widespread
problems at the front line. You know it already: the
prevalence of adverse reactions and the morbidity and
mortality associated with them; the frequency of medical
and medication errors; staggeringly low levels of patient
compliance around the world (WHO estimates that 50%
may be near the mark in many places); dangerously
irrational prescribing of antibiotics; the incursion of substandard and counterfeit medicines, among the major
headline issues. All of this is extensively and dramatically
documented in the literature: at the heart of healthcare there
are radical, dangerous problems and deficiencies, which
have proved extremely difficult to moderate or remedy.
Many of these fall within our areas of interest and
responsibility.
Let us start with a very low-level anecdote. I am the
guardian of a lovely piece of land in the north of Thailand. I
am not the owner, because foreigners are not allowed to
own land in Thailand, but I care for it as if it were my own,
and have replanted what was a bare hillside with thousands
of trees. For many years now, the serious daily work has
been done by farmworker, Mr Tom, originally from a poor
hill-tribe village on the border with Burma. He is neither
clever nor literate, but he is loyal and hard-working.
Recently he had some trouble with his left leg swelling and
went to the busy government hospital in the local market
town. When he returned I asked him what had happened.
The doctor had given him some pills, he told me, showing
me a small plastic bag with his name on it. What was the
problem? I asked. The doctor didn't say. What will the pills
do? The doctor didn't say. Did he ask to see you again? No
How, then, do our concerns about PV and patient safety
relate to the front line, this place of human drama and
frequent failure?
What Went Wrong?
Let me return to the story of my farmworker, Mr Tom. The
problems and failures are illuminating. First, the
characteristics of the actors
1
The doctor was under extreme pressure of time
8F
The doctor did not feel any need to explain anything to
8F
the patient, and so The doctor dealt with the patient as
an object on a rapidly moving production line
The patient was deferential and undemanding
8F
The pharmacist dispensed the pills and nothing
8F
more What were the risks of a consultation of this
kind?
Under such pressure of time, both diagnostic and
8F
medication errors are more likely
The patient had no understanding of the cause of the
8F
symptoms and therefore how to remedy or prevent
them with or without drugs in the future
The patient did not know what drugs he was
8F
prescribed, how they worked, what effects they would
have nor what risks they carried
There was no secondary patient information about the
8F
medicine, which was dispensed in a plastic bag from
bulk supplies. (Even if there had been printed material
this patient could not have read it in any case.)
The patient left the consultation essentially untouched
8F
personally, emotionally, intellectually, and with no
new knowledge about his body, the disease or about
medicines
What are the chances of an ADR experienced by this
patient being recognised and reported by anyone? What are
the chances of this patient becoming a more intelligent,
critical and rational user of medicines? Before I am
finished, I shall make some suggestions as to how we can
begin to address some of these problems, but first I want to
take our analysis a bit further.
The Social And Professional Context
What are some of the social and professional
characteristics which support and intensify some of the
problems we've identified? India, like many Asian
countries, has what the sociologists call a High Power
Distance Indicator. This describes the distance, and the
differences in personal freedom to act between the
powerful, wealthy and educated from those who are
relatively powerless, poor and educated to only basic
levels, if at all. Though things are changing, status remains
an important dimension of social identity, and deference to
those of higher status an almost instinctive response for
many. As India's great democracy progresses, these
influences may diminish further, but they are embedded in
the culture (and in religion), as they are in China and my
homeland, Thailand, and many other places. They are by
no means absent in developed countries. These values have
a profound influence on every aspect of life, including
bureaucracy, education and healthcare. Even in relatively
egalitarian societies, there is a tendency for bureaucrats,
educators and healthcare professionals to assume that they
know best and that they do not need to consult their
constituents about their wishes, needs and priorities. It's
evident, for example, in classrooms and lecture halls round
the world where the fruitless and boring transmission of
information masquerades under the label of education.
True education is the development of dynamic and critical
minds, where there is no fear of debate, questioning, or
critical argument
even if the target is the most
distinguished professor in the entire universe. Some of
India's dramatic economic and social development has
come from the liberating effect of this process the creation
of dynamic, entrepreneurial, risk-taking modern thinkers.
But this has, as yet, affected only a minority, mostly from
the privileged middle classes, and there are also many
sectors which lag far behind and not just here. Status
arrogance and paternalism, as well as authoritarianism, of
course, corrupt systems and communications in many parts
of the world by hi-jacking them for their own purposes and
professional protectionism is a good example of the
process. The maintenance of disabling power differentials
compromises the growth and maturity of those who are
kept in dependence; it is a very real form of oppression.
Inequality and injustice are also rooted in differentials in
knowledge and access to information. Knowledge IS
power, and it may be exercised generously or oppressively.
Patients who know little about disease and therapeutics are
gravely disadvantaged when faced with the decisions or
opinions of status superiors. We can all experience this
when we are reliant on experts to solve even our domestic
problems plumbers, electricians, mechanics, relationships
with whom can be very complex when it comes to issues a
good deal less important than life and death (though I have
to say that life and death are real issues with the work of
some of the electricians I have had the misfortune to
employ). As long as doctors assume that they have all the
answers, and patients adopt attitudes of uncritical
deference, we shall never have safe and effective
healthcare. As long as bureaucratic systems are developed
at the centre and imposed on the rest of the world by people
who believe they know best, the systems will never deliver
the fruits of their good intentions.
J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1
2
who believe they know best, the systems will never deliver
the fruits of their good intentions.
Long And Complex Forms: What Use Are They?
I take as a very simple example of this ADR report forms in
many parts of the world. Why do so many systems fail to
deliver frequent and useful information about the risks of
drugs, in some kind of credible ratio to the actual use of
drugs? If we revisit the front line we observed earlier, here
are the some of the reasons we can extrapolate for low
levels of response to ADR reporting:
F
No time
F
No commitment or knowledge
No motivation
F
How can we address these profound obstacles?
and patient safety concerns. Does Honda's Greenwing
brand really deserve so much more attention, creativity,
energy and marketing talent than the health and welfare of
the people of India or any other country? Yet, as you know,
our vital work gets a millionth part of the exposure of the
most modest commercial product. (There are exceptions,
and the Indian oral contraceptive campaign is one of the
but they are rare.) Walking down the streets of any town, I
am unlikely pass a patient safety shop and if I did, its
windows would be shuttered, its doors would be closed,
and there might be a very small notice by the door saying
something incomprehensible like, 'Pharmacovigilance
Centre'. Gosh! Can't you just see the population queuing to
get some? Before this excursion into retail marketing, my
question was, What can we do to overcome some of the
enormous obstacles of ignorance, low motivation and lack
of enthusiasm for what we do?
Tripping Over Honda
Vivid Presence And High Profile
Rather early one morning recently (well, rather early for
me), I was walking through the centre of the market town
where I live in northern Thailand, at a time when the shops
were opening up and the business of the day was getting
going. I had to step off the sidewalk to avoid a bunch of new
motorcycles parked where I should have been able to walk.
I looked up, and on the broad terrace in front of the shop,
workers were hauling out great elevated display stands,
inclined platforms and big, colourful posters on stands;
others were wheeling out more motorbikes to join the herd
on the sidewalk. The terraces was being swept and washed,
and the waiting bikes being buffed and polished till they
sparkled in the sun.
We first have to ensure that pharmacovigilance and patient
safety are vividly on the map in every healthcare
curriculum, on the agendas of every hospital and clinic, in
the minds of every healthcare professional and every
journalist, citizen and patient. That's a great project for
every medical, nursing and pharmacy school for the
education of the nation's children and for the public
relations departments which every PV centre should have.
OK, that's a radical, long-term goal, but we need to be
actively engaged in pursuing it now, everywhere
remembering that scientists, bureaucrats and academics
are not always the best people to do it. There's a lot to be
learnt from street stalls and traders whose colourful
creativity is evident everywhere in India: if we had some of
Mrs Gupta's marketing skills, there wouldn't be a passing
citizen who didn't end up going home with something
useful from our shop which they didn't set out to acquire,
but which they are pleased to have.
Everyday life in the world of business, in this case of
Honda: they were putting their goods on display to the best
possible advantage, to catch the attention of as many
potential customers as possible.
The Great Marketing Enterprise
Now this is a very low-level anecdote from a sleepy old
man in a provincial town: BUT what I observed there, and
have reported to you, is one small example of a vast,
universal human enterprise happening every day in every
part of the world in every great city and every tiny
community: people with something to sell, or a message to
promote, are actively and creatively and ingeniously
finding ways to get noticed.
Of course, it's a vast human enterprise which, generally
speaking, does not include much in the way of healthcare
offers and messages, and even fewer pharmacovigilance
Ask And Listen Or Go Extinct
But for the other problems? The answer is simple: we must
ask the people we want to involve, and listen to what they
say. That is the core practice of every successful
commercial enterprise in the world: they constantly
research the tastes, needs, wants, attitudes and behaviour of
their customers and potential customers; they ask and they
listen. They are successful because what they manufacture,
print or broadcast is tailored accurately to the known needs
and tastes of the market. They can bring
3
innovations to market (which the public didn't realise it
wanted) because they know so much about the tastes and
habits of the market that they can anticipate what will be
acceptable and popular. Companies who don't have this
knowledge of their market simply disappear.
Bureaucracies don't disappear, however blind they are to
the tastes, habits and behaviour of their audiences. They
just tend to plough on doing what they've always done
because that's what they're paid to do. No matter that the
outcomes are poor and the customers are disillusioned. To
those officials who say to me (as they often do) that patient
safety and the serious business of healthcare has nothing to
learn from the bustling and vulgar world of commerce, I
say: think again; are traders not communicating messages
and trying to influence people's behaviour, just as we
should be trying to do? Do they not have a genius for
getting noticed, just as we should be? We're talking about
provoking change, and that needs energy and imagination
and a willingness to take risks.
What Can We Do To Help You Report ADRs?
If we want healthcare professionals to report ADRs, we
have to ask them (after we've convinced then that PV is
important): what is the maximum effort you are prepared to
make to tell us about ADRs in your practice? Some will say,
'No time. Can't do.' Others might say: 'I'm willing to put a
date and a patient reference on a pre-printed, pre-paid,
addressed postcard which takes me no more than twenty
seconds. You can then follow that up and do the work.'
Now, we're getting somewhere! Yes, more work for the PV
centre following up initial contact, but what is preferable
more work or no reports? The system has to be resourced to
do the job as it is specified at the front line. Instead of a
long, complicated, demanding form (and I've seen many
which are an insult to a busy professional) this postcard
solution offers us a very efficient, quick mechanism where
the barrier to co-operation is very low. (There might be a
comparable electronic solution as well, of course.) I'm not
saying this is the best or only answer, but it is an answer,
and it's a great deal better than much of what currently
passes for a credible system in many places.
Stodge From The Centre
Most ADR forms are devised at the centre, by scientists and
officials who know what they want in elaborate and
comprehensive detail, but without any serious thought (if
any thought) about the effect it will have at the front line let
alone asking for the opinion of the people at the front
line. What we should be trying to do in co-opting the help
of busy professionals, is finding the overlap between the
maximum they are willing to do and the absolute minimum
we require to operate the system.
Reciprocity
This principle of engagement and reciprocal
communication applies across the board in all our
immediate concerns, and across the whole of healthcare.
Without it, patient safety is at risk at every point along the
way. Transmission only, the method of centralised
bureaucracies, top-down institutions and unhelpful
professionals, doesn't work. Patients who are dealt with as
bundles of symptoms to be medicated will not enjoy the
quality of life and health of those who are seen as whole
people in the complex context of family and social life;
patients who learn nothing about their disease and their
medication can never become mature citizens, taking
responsibility for their own bodies and health and those of
their children, families and communities; patients who are
uncritical and undemanding in the face of professional
confidence, or assertiveness or arrogance will remain
helpless and dependent; patients who are not given full and
intelligible information about their medicines, may not
take them, may not take them properly, may be seriously
harmed by them. We only have to know that there is one
patient in the world swallowing their suppositories (as
there certainly is), and one nurse giving an intra-thecal
injection of an intravenous fluid (as there certainly is), to
know that communication of all kinds is central to safe and
effective therapy.
Compassion And Support
But there are much bigger issues too. Health is not just
about an absence of disease or of troubling symptoms, nor
is it about the medication of every element of discomfort
that we poor human beings are subject to. It has a far wider
role in the creation of a dynamic and healthy society.
Healthcare is the front line where we see the suffering of
human beings, caused by disease, accidents, impossible
work conditions, insanitary living conditions, hunger,
poverty, domestic abuse, addiction, irresponsible
behaviour, ignorance and criminal activity too. We cannot
respond to these vast and intractable problems in any
radical way, but we have a duty to treat those who suffer
from them with empathy and attention, and to make sure
that what we do is not just short-term patching up for return
to the battle front. When our patients leave us, they should
4
have not only their pills, but a small measure of confidence,
optimism and belief in themselves. They should feel that
they have been taken seriously and that even the experts
may be able to learn from them. They should feel a little
better able to cope with their burdens in one way or another.
They should feel a similar sense of familiarity and
confidence in relation to us, the pharmacovigilance and
patient safety professionals and, more to the point, should
feel able to trust us and our commitment to the best possible
solutions for everyone. Remember Honda? Think of the
public profile and accessibility of most regulatory and
pharmacovigilance authorities! Invisible!
What Should We Be Doing?
What Do Patients Want?
So, where does all this high-flown stuff leave us? What's
the relevance to pharmacovigilance and patient safety? It is
this: beyond the science- the data management, the signal
detection, the causality assessment, the risk management before all of that, we must be out at the front line seeing,
experiencing and understanding what exactly is going on,
what is driving people, what their beliefs and behaviour
are. We must be out and about asking people what they
want, how they could collaborate with us, what their
problems are, how WE can help THEM. Research shows
us that in the list of patient priorities, effective treatment is
always at the top, but very close, wherever the question has
been investigated, come effective explanation and
communication. And in those countries where healthcare is
at increasing risk of challenge in the courts, it is the
healthcare professionals and institutions which do not
communicate with their patients, which do not seem to care
about them, which are most likely to be sued. Patients do
not sue doctors they like.
Attention Heals
And if we are talking about effectiveness, we must at least
acknowledge in passing the immense amount of research
there has been on placebo: patients, in many disease
categories, respond positively to attention, concern and
kindness, with and without medicines. If we are blind to the
psychological and spiritual dimensions of therapy, or our
systems ensure that they are neglected, we are missing out
on a very powerful resource. And, in terms of public
feelings about a regulatory authority, especially in a crisis,
we know that reactions will be more rational and moderate
if the authority is known and trusted and seen to be
positively committed to communication and the interests
of the people. We need to be talking to patients about their
attitudes and behaviour; teaching them about drug safety
and rational use; identifying and reducing the most
common risks - interactions, counterefeit medicines, noncompliance; sharing of medicines; poor storage conditions
and so on; finding effective ways of discovering
information about the real, front line situation and planning
our response. And it is the doctors, nurses, pharmacists,
pharmacist assistants and technicians, and traditional
healers, who need to be our committed eyes and ears,
seeded throughout the nation. They need to be the ones who
are driving our work, shaping our policies and systems,
telling us what needs to be done at the front line.
What Are The Priorities In Pharmacovigilance?
Healthcare, in all its modern and traditional manifestations
is a remarkable if variably successful enterprise, with some
great, enduring achievements to its credit. The success of
pharmacovigilance is less easy to assess, with its object as
the prevention of harm, which is difficult to measure,
though the absence of major disasters like thalidomide
might suggest a measure of success. But there are those
who are inclined to judge PV by such crude measures as the
number of drug withdrawals prompted by ADR reporting
systems. This, it can certainly be argued, seems more like a
measure of failure in many cases, when useful drugs are
taken off the market because their risks cannot be
satisfactorily managed. Here we enter the complex area of
risk communication and a further area of challenges for us.
Some of the principles we have already discussed will be
pertinent here too. Over the years, there has been no
shortage of communications about the risks of particular
drugs in the form of label changes, boxed warnings, email
alerts, bulletins, Dear Doctor letters and many other
methods. What has become clear in some dramatic cases is
that these communications have had little or no influence
on rescribing behaviour. (This has also been the case in
relation to antibiotic prescribing.)
Why Is Risk Communication Currently
So Unsatisfactory?
What, then, have been the failures here?
The high level answer is simple: regulatory authorities in
many parts of the world have simply not found effective
ways of communicating urgent and important messages to
their healthcare professionals in ways which influence
their behaviour. Now I have no panacea solutions to this.
5
Various communications activities have differential effects
in the Tome country and in different parts of the world, but
we have very little direct evidence of what works well, how
and why. Our evidence of failure is rather unsatisfactory,
too, because it usually comes from prescribing or
dispensing statistics which, inevitably, follow a long time
behind the mistakes. What we do know is that
communications become more effective, for any audience
at all, the nearer they approach the one-to-one end of the
spectrum: the more personal and individual the contact, the
greater the impact will be.
Ineffective Routines
Dear Doctor letters are an elaborate, time-consuming and
expensive mechanism for communicating new
information about risk to a mass audience, but there is little
evidence that they have much effect. Yet, regulatory
authorities require companies to produce them, year after
year. Many of them are lengthy, complex documents
which, I suspect, busy healthcare professionals don't get
round to reading, or won't remember if they do. What we
have to do is to ask them what would be useful and effective
for them, and then seek feedback and test the results time
and time again. A similar kind of empty, administrative
routine has driven the production of some patient
information leaflets in countries where these have been
mandatory. The PIL for Viagra, one of the most successful
and popular drugs in the history of the world, is a ridiculous
document (here it is) printed in tiny, condensed type on a
very odd shape of paper, full of complex and obscure
information. I ask you: in the heat of the moment, on the
way to the bedroom, WHO IS GOING TO READ THIS?
That is a perfect symbol of the failure of imagination of
those who sit and make decisions a million miles from the
front line. Did the regulators who approved this PIL think,
for a moment, of the situation of the patient who has just
been prescribed or just bought Viagra? We know, only too
well, that doctors and pharmacists are often not reliable
communicators of thoughtful risk and safety information,
so does the regulator assume that the PIL is an effective
fallback resource for all kinds and conditions of patients?
Does the regulator imagine that, as the patient lights the
candles and turns on the soft music that he'll be sitting
down reading this impenetrable document? I doubt that
such a regulator and the company which produces the
document think about anything at all except technical and
legal matters which are important to them in their dimly lit
offices. They have no empathy for the end-user, no concept
at all of what things look like at the front line. These kinds
of narrow-minded bureaucrats are the enemy within:
they are as dangerous to patient safety as defective
drugs. Against them and their obstructionism and shortsightedness we must be ever vigilant, ready to sweep
them away when we have opportunity. Do not ever
imagine that bureaucratic or administrative routines are
ever the real answer to front line social problems.
So What's Better?
Having raised the issue with such strength, I shall at
least offer you some thoughts about remedies, but only
briefly, because this takes us away from the main theme
of the material. Verbal or printed information about risk
and safe use must focus on the top few priorities: IF
YOU READ NOTHING ELSE, READ THIS. Great
progress has been made in improving patient
information in some countries by talking to patients and
to patient groups about what information they want and
is useful to them. They have also generated good ideas
about various forms in which patients need the
information and can make use of it as opposed to the one
size fits all philosophy of regulation. If we remember
that up to half the population in even advanced countries
may not be able to read or make sense of printed health
information, we have some measure of the huge
challenge, and of the absurdity of over-reliance on
printed information. My message then, evident, I hope,
throughout this journey, is this: we must not only look
outwards to the real, complex world, but must be out in
the midst of the real world, gathering reliable evidence
about what people are thinking, saying and doing;
communicating, engaging, listening. It is the doctors,
nurses, pharmacists, pharmacist assistants and
technicians, and traditional healers, who need to be our
committed eyes and ears, seeded throughout the nation.
They, along with citizens and patients, need to be the
ones who are driving our work, shaping our policies and
systems, telling us what needs to be done at the front
line, and how our work can have the maximum positive
impact on the health of the nation. Whatever we are
doing, we must think about the front line; and after
we've thought about it, we must go out and find out what
is happening there, ask and observe, question and
investigate. Then we can hope to be told about and to
find solutions which fit with reality and will change how
people think and behave. It's the revolution of shifting
from top-down to bottom-up, from transmission to
interaction, from the centre to the front line, and it can
change our world for the better, beyond recognition.
6
ORIGINAL ARTICLE
Pharmacogenomics - The Future of Pharmacovigilance
SANTANU K TRIPATHI
Department of Pharmacology, Burdwan Medical College, Burdwan 713104
Ethical Concerns
Drugs are the indispensable companion of human life. Drugs
prolong life, protect and promote health, prevent diseases but
they also hurt and harm. Adverse drug reactions (ADRs) are
the unfortunate legacy of pharmacotherapy.
PGx studies however pose some unique ethical dilemma.
How to ensure that PGx information / data of a given patient
will not be misused or used for purposes other than
optimizing treatment for the given patient? Should a PGx
study require prior ethics committee approval? Should
informed consent be obtained for PGx testing? Labeling as
'non-responder' or 'ADR-prone' may lead to insurance and
workplace discrimination that
ADRs are mainly of two types: Type A that are augmented
pharmacological effects, and Type B that are bizarre. The
Type B or idiosyncratic ADRs have hitherto been considered
non-preventable. Recent developments in molecular
genetics revealed that many of the Type B ADRs could be
predicted and hence avoided through individualizing drug
therapy based on genetic information.
may result in erosion of self-image and vulnerability to
psychological instability. How to ensure maintenance of
patient privacy and confidentiality? How to deal with
unfavorable polymorphism association with some ethnic
minority? - Pharmacological apartheid!
Drug responses, desired or adverse, are in general considered
as a gene-by-environment phenotype. Traditionally, severe
uncommon ADRs triggered exploration of pharmacogenetic
phenotypes, using a forward genetic, phenotype-to-genotype
approach (Pharmacogenetics). With successful sequencing
of the entire human genome by The Human Genome Project
and associated phenomenal technological advances in
genomics, a reverse genetic, genotype-to-phenotype
approach, has been feasible (Pharmacogenomics). This
makes the ADR risk anticipation more precise. Safer
treatment strategies can be planned through a tailored
approach. Pharmacogenomics (PGx) aims at developing
rational means to optimize drug therapy, with respect to the
patients' genotype, and thus ensuring maximum efficacy
with minimal adverse effects. Such approaches promise the
advent of personalized medicine in which drugs and drug
combinations are optimized for each individual's unique
genetic makeup. Through in-depth genome-wide analysis of
the determinants of drug responses PGx holds the promise
for being exploited as a pharmacovigilance tool for riskstratification.
Direct-to-Consumer (DTC) Advertising and PGx Tests
DTC advertising for PGx tests is likely to affect the demand
for genetic technologies in clinical practice. Genelex
advertises testing for three important drug metabolizing
enzymes (CYP2D6, CYP2C19, and CYP2C9) at $250/each
or $650 for all three. (www.healthanddna.com, accessed
July 31, 2003). Regulators need to pay particular attention
to DTC advertising for PGx based tests since there is
widespread debate over the wisdom of such marketing
strategy.
Regulatory Challenges
Regulatory processes should be able to guide the
development and approval of PGx-based drugs and
diagnostics that will be safe and effective for public use as
well as “least burdensome” to industry sponsors. Labeling
is one way to encourage providers to use PGx-based tests.
The FDA criteria for PGx drug label include safety (the
seriousness of the adverse event), effectiveness (the
consequences of not responding), incidence of clinical
outcome, variability in the clearance of the drug, how well
adverse events can be managed, need to educate providers
and third-party payers, and feasibility of accessing and
using the test. Application of PGx-based therapies in
clinical settings will typically require the availability to the
provider, through the drug label, of the information about
genetic variation and of an accurate and valid genotyping
test. FDA's gatekeeping function specifies if the test is
required or suggested. FDA advocated the use of PGx to
increase post-marketing safety, and approved trastuzumab
Pre-Prescription Genotyping and PGx Testing Technologies
Conventional PGx tests involving techniques like Southern
blot, polymerase chain reaction (PCR) or restriction frequent
length polymorphism (RELP) analysis are run on one-gene /
one-test basis. This means for the 70 variant alleles of the
CYP2D6 locus, 70 genetic tests are to be performed. The
newer technology DNA chip microarray permits
simultaneous testing of all or as many alleles as wished.
7
Tripathi : Pharmacogenomics The Future of Pharmacovigilance
(Herceptin®) and the associated tests for HER2/neu overexpression in breast cancer (the first PGx prescription) in a
bid to regulate PGx-based drugs and diagnostics in
combination. Only women with HER2/neu over-expressing
breast tumors, as confirmed by a genetic test, may benefit
from use of Herceptin. Accordingly, Herceptin labeling
specifies the tests that are approved for guiding prescribing
decisions. In contrast, the label for Atomoxetine
(Strattera®), used to treat ADHD, notes that a test for
genetic mutations is available but it does not specify that the
test is required, it is only suggested or recommended.
Off- Label Use of PGx Drugs
Testing for thiopurine methyltransferase (TPMT) enzyme
mutations prior to prescribing 6-mercaptopurine (6MP) for
patients with ALL is one of the most evolved and best
understood applications of PGx, but 6MP, approved for
oncology, is
increasingly being used off-label for other disease areas. It
has been particularly challenging for FDA to regulate offlabel use.
PGx-Guided Drug Rescue
Drugs withdrawn from the market because of serious
adverse events (SAEs) might be rescued by identifying
genetic associations that accurately predict the occurrence
of the ADR and that could be tested for before prescribing.
Practical barriers to drug rescue include lack of real
examples difficulties with retrospective analysis fears of
litigation expired or near-expired drug patents the
possibility that providers would still not use the drug in
clinical practice because of worries about safety based on
the initial drug indication.
Industry Concerns
The industry has been worried about premature regulatory
constraints and desires clear guidelines and transparency
from regulators. An economic disincentive for industry in
developing PGx based drugs and diagnostics is the
decreased likelihood for blockbuster drugs.
Physicians Inform Thyself
The physician's checklist for applying PGx in reducing
ADRs include the following:
F
Check if the intended drug is metabolized by a
polymorphic drug metabolizing enzyme.
F
Study if the prevalence of a deficient variant is
high in the patient population being treated.
F
Consider alternative drugs that are not subject to
polymorphic drug metabolizing enzymes.
F
If no alternative, prescribe but counsel patient to
carefully monitor for possible ADRs.
F
Remember ADR problems are compounded if
multiple drugs metabolized by the same polymorphic drug
metabolizing enzymes are used.
F
Circumstances permitting, consider genotyping
beforehand
to reduce possibility of ADR, or afterwards
to ascertain if genetic variance is indeed the cause of the
ADR.
More Cost-Effectiveness Analysis Needed
A review of the literature revealed that only 11 costeffectiveness of PGx tests had been published as of July
2004. To make such analyses useful they need to be
conducted prior to widespread implementation of PGx tests,
but the catch-22 is that the data to evaluate them are often
lacking or proprietary.
Implications for public health programmes
Elucidation of population and cross-ethnic differences in
pharmacogenetics traits will pave the path for more
successful disease control, containment and eradication
programmes with drugs and vaccines. Appropriate policy
decisions can be arrived at national level towards reducing
some ADRs known to occur more frequently and / or more
seriously in a given population.
Epilogue
ADRs have a multigenic and multifactorial aetiology, akin
to that observed with complex diseases. Genetic factors may
play a major role in the pathogenesis of many ADRs, and
pre-prescription testing may allow us to prevent or at least
minimise the ADRs, as has been shown for abacavir
hypersensitivity. PGx has been one of the most immediate
and important applications of the Human Genome Project.
PGx advocates for prescribing decisions based on genetic
test results besides optimizing success in drug development
(DD). Interest in PGx and personalized medicine is
accelerating because of ongoing concerns about ADRs and
the high failure rates in DD. The future prospect of
personalised medicine in the context of PGx and
pharmacovigilance seems to be bright and encouraging, yet
highly challenging. It is the need of the hour that all the stake
holders e.g., industry, regulators, care providers and the
people at large, analyze the opportunities and challenges in
achieving efficient, science-based risk management in the
area of PGx. Demonstration of the clinical utility of PGxbased tests is going to be crucial before they can be
recommended for use in clinical practice. Large multicentre studies are urgently needed to identify and collect
samples from well phenotyped patients with ADRs, which
will serve as a resource to establish individual susceptibility
to the ADRs. With the advances in technologies
(genotyping, proteomic, metabonomic, informatics and
statistical), PGx, in the wider context of a systems biology
approach has the potential to help in predicting the toxicity
of drugs and through this bring us closer to the concept of
personalised medicine.
8
Cholesterol lowering potential of Seabuckthorn
ORIGINAL ARTICLE
IMRAN ZAFAR, M. FAHIM1,
Institute of Pharmacy, NIMS University Rajasthan, Jaipur - 303 121
1
V.P.Chest Institute, University of Delhi, Delhi - 110 007
ABSTRACT
The present study was designed to investigate the effect of Seabuckthorn on lipid profile, its antioxidant potency and its effect on
haemodynamic changes and baroreceptor mediated blood pressure regulatory mechanism in hypercholesterolemic rats. For
induction of hypercholesterolemia rats were fed with fructose in drinking water and in vivo experiment had done to investigate the
heamodynamic as well as biochemical profile of seabuckthorn.it is a natural product and investigations carried out so far do not
report any apparent toxic effect. Based upon the results of the present study, it is recommended that seabuckthorn pulp oil may be
supplemented with normal diet for providing protection against hypercholesterolemia. The fall in blood pressure of animals
having a normal lipid profile suggests that it may have a hypotensive effect. Hence, its use as a lipid lowering agent needs to be
carefully monitored especially in people with cardiac problems. Conclusive evidence shows that baroreceptor modulation of heart
rate is impaired in animals and patients with atherosclerosis. It has been suggested that oxygen free radicals produced in
atherosclerosis may contribute to baroreceptor dysfunction.Seabuckthorn prevented development of hypertension and reduced
insulin resistance in chronically fructose fed rats and reduced vascular superoxide anion production through lowering the NAD
(P) H oxidase activity in hypertensive rats.
Key words- Hypercholestrolemia, Hypertension, Atherosclerosis, Baroreceptor Dysfunction, Free Radicals
Introduction
including carotenoids, tocopherols, sterols, flavonoids,
lipids, ascorbic acid, tannins, etc.; many of them possess
biological and therapeutic activity. Flavanoids such as
leucocyanidin, catechin, flavonol and flavones lower
cholesterol, prevent inflammation and vitamin C
degradation and probably control formation of
atherosclerotic plaques6. In addition, the sterols and stanols
present in seabuckthorn reduce the absorption of
cholesterol. Together, these effects may be beneficial in
hypercholesterolemia and ultimately atherosclerosis. 7,8.To
the best of our knowledge, no study has reported the effect
of Seabuckthorn pulp oil on lipid profile and baroreflexes
in hypercholesterolemia. Hence, the present study was
planned to investigate the effect of SBT on serum lipid
profile and baroreflex sensitivity in experimentally
induced hypercholesterolemia in rats.
Cardiovascular disease (CVD) encompasses a number of
different diseases including coronary heart disease, stroke
and peripheral vascular disease. However, the underlying
pathology for all of these disorders is atherosclerosis1. A
number of risk factors for CVD have been described, such
as hypercholesterolemia (HC)2. hypertension3, smoking,
diabetes and obesity4. Till date, there have been many
studies on mechanisms by which high levels of LDLcholesterol affect biology of blood vessels and cause
atherosclerotic lesion formation. Arterial baroreceptors are
known to regulate absolute blood pressure and ultimately
help in maintaining adequate circulation to brain and other
organs. Baroreflex contributes importantly to neural
circulatory control. Abnormalities in arterial baroreflex
function have been linked to adverse cardiovascular
outcomes5. Functional (neural) mechanisms, in addition to
structural vascular changes, contribute importantly to
altered baroreflex responses in normal and
pathophysiological states. Presently available lipid
lowering agents are mainly synthetic drugs, which have
many side effects. Natural compounds with fewer side
effects are being looked into as an alternative therapy.
Seabuckthorn contains a series of chemical compounds
Methods
Healthy male Wistar albino rats, weighing between 250300 g, were obtained from the animal house of VPCI. They
were housed in cages in groups of four rats per cage and
were kept in room temperature maintained at 25±2°C with
a 12-h light/dark cycle. Experiments were performed
according to the guidelines of the Committee for the
Purpose of Control and Supervision of Experiments on
9
Imran Zafar : Cholesterol lowering potential of Seabuckthorn
Animals (CPCSEA), India. The Institutional Animal
Ethical Committee, Vallabhbhai Patel Chest Institute
(VPCI), University of Delhi, New Delhi, India, approved
this study.
Preparation of Seabuckthorn Pulp Oil
We procured SBT pulp oil from DIPAS (Defense Institute
of Physiological and Allied Sciences). Fruits of
seabuckthorn were collected from hilly regions of western
Himalayas, India and dried J Pharmcovig Drug Safety
2009 (April June) 6(1) : 3-7under shade. The extraction
was carried out using fruit by deseeding and crushing the
berries. The pulp was centrifuged to obtain SBT pulp oil.
Plan of Study
Hypercholesterolemia was induced by feeding rats with
10% fructose for 3 weeks in drinking water. SBT pulp oil
was given in a dose of 2ml/kg body weight orally. Study
was conducted in 20 rats, which were randomly divided
into following groups.
Control Group(I) -Rats fed with normal pellet diet: Rats
of this group were maintained on normal balanced diet and
water for 3 weeks.
Hypercholestrolemic Group(II)- Rats fed with 10%
fructose: For induction of hypercholesterolemia, rats were
maintained on normal pellet and 10% fructose in drinking
water for 3 weeks.
Fructose+Seabuckthorn Group(III)- Rats given 10%
fructose and seabuckthorn pulp oil: rats of this group were
maintained on normal pellet and 10% fructose in drinking
water and seabuckthorn pulp oil for 3 weeks. Seabuckthorn
pulp oil (2ml/kg/day) is administered through oral route
with the help of oral feeding needle.
Seabuckthorn Group (IV)-Rats fed with normal pellet
diet along with seabuckthorn: In order to study the effect of
seabuckthorn on normal rats, seabuckthorn was
administered in the dose of 2ml/kg/day, orally with the help
of oral feeding needle for 3 weeks.
Biochemical Determinations
After completion of experiment, under deep anesthesia
blood samples were collected by direct heart puncture after
opening the chest of the animal. Blood was allowed to clot
and then centrifuged for 10 min at 5000 rpm, to obtain the
serum. Serum sample was transferred into dry and clean
vials and stored at -20°C for biochemical analysis at a later
date and determined by commercially available
spectrophotometric assay kits (Monozymes, India), as per
the manufacturer procedure given.
Arterial Blood Pressure and Heart Rate
Rat was anesthetized with urethane dissolved in distilled
water and injected intraperitoneally (i.p.) at a dose of
1gm/kg body weight. Disappearance of pedal reflexes
indicated adequate anesthesia. Rat was placed on a small
table and secured by tying the limbs. A middle incision was
given in the neck region; retracting the pretracheal muscle
exposed trachea and a transverse incision was given in
between two rings. A cannula was introduced into the
opening to allow free breathing without obstruction. Body
temperature of the rat was maintained at 37-38 oC. Femoral
artery of one side was exposed and a polyethylene catheter
filled with heparin solution (500 IU/ml, v/v) was inserted
in the artery through a small incision for recording arterial
blood pressure (ABP). The catheter was attached to 23gauge needle connected via three-way stopcock to a
pressure transducer (Statham-P23D). Femoral vein of the
other limb was cannulated for injecting drugs (Ashraf et al.,
2005). Prior to recording ABP, catheter was flushed with
heparinized saline solution (500 IU/ml, v/v) to prevent
formation of any blood clot, which might interfere with
normal recording of ABP. The pressure recording system
was calibrated with the help of a mercury manometer
before each experiment. Arterial blood pressure was
measured after 20 min of stabilization period. Systolic,
diastolic, mean arterial pressures and heart rate were
displayed and recorded on Power Lab data-acquisition
system (4SP, AD Instruments, Australia) with a
computerized analysis programme.
Measurement Of Baroreflex Sensitivity (BRS)
BRS was measured by administering 20µg/ml/kg
phenylephrine (vasoconstrictor) and sodium nitroprusside
(vasodilator) through venous catheter. The resultant
changes in heart rate at corresponding rise or fall in SBP
were measured at different time intervals (every 2 sec). The
relationship between increase in SBP evoked by
phenylephrine and associated bradycardia or decrease in
SBP evoked by sodium nitroprusside and associated
tachycardia was assessed by regression analysis for
individual animal. The regression coefficient (slope of
regression line), expressed as beats per minute per mm of
mercury (beats/min/mmHg) was taken as an index of
baroreflex sensitivity.
Statistical Analysis
The data are presented as mean ± SEM. Statistical analysis
was done by analysis of variance (ANOVA) followed by
10
tukeys multiple comparison method. P value for statistical
significance was set at 5% i.e., p< 0.05.
Results
No significant difference in the diet intake and body weight
was observed among the various groups.
Haemodynamic Profile
Effect of seabuckthorn on arterial blood pressure and heart
rate
along with fructose in drinking water showed significant
(P<0.05) fall in total cholesterol, triglycerides, LDL-C and
significant (P<0.05) increase in HDL-C level compared
with hypercholesterolemic group. Following treatment of
rats with seabuckthorn on normal diet for 3 weeks,
hypercholesterolemic rats showed significant (P<0.05)
decrease in total cholesterol, triglycerides, LDC-L, and
significantly (P<0.05) increased HDL-C level compared
with hypercholesterolemic group. These are followings
data shown in Table-2
Rats fed with fructose showed rise in systolic blood
pressure, diastolic blood pressure, mean arterial pressure,
and heart rate compared with control rats. Treatment of rats
with seabuckthorn along with fructose prevented the rise in
systolic blood pressure, diastolic blood pressure, mean
arterial pressure, and heart rate compared with
hypercholesterolemic rats. Treatment of rats with
seabuckthorn on normal diet for 3 weeks prevented the rise
in systolic blood pressure, diastolic blood pressure, mean
arterial pressure, and heart rate compared with
hypercholesterolemic rats. These are followings data
shown in Table-1.
Effect of seabuckthorn on the arterial baroreceptor
mediated blood pressure regulatory mechanism
Baroreflex sensitivity was measured as a ratio of
bradycardia response to rise in arterial pressure by
phenylephrine or as a ratio of tachycardia response to fall in
arterial pressure by sodium nitroprusside. Rats given
fructose showed significant (P<0.05) decrease in
Lipid Profile
baroreflex sensitivity compared to the control rats.
Treatment with seabuckthorn along with the fructose
showed significant (P<0.05) restoration of baroreflex
sensitivity compared with hypercholesterolemic group.
Rats treated with seabuckthorn and maintained on normal
diet did not show any change in baroreflex sensitivity
compared with control group. These are followings data
shown in Table-3.
Effect of Seabuckthorn on serum lipid profile
Rats given fructose (10%) in drinking water developed
hypercholesterolemia marked by significant (P<0.05)
increase in total cholesterol, triglycerides, LDL-C, and a
significant (P<0.05) decrease in the level of HDL-C
compared with control rats. Treatment with seabuckthorn
11
Lipid profile
Discussion
Hypercholesterolemia, which is characterized by high
levels of lipoprotein containing cholesterol in blood, is
generally accepted as a major risk factor for the
development of atherosclerosis and subsequent
myocardial ischemia 9 .Wistar rat as a model of
hypercholesterolemia has been chosen for the present
study as it shows increase in serum cholesterol due to
feeding of fructose rich diet. Rats can develop
hypercholesterolemia after feeding the fructose rich diet
for a long period of time. But rats have shown functional
changes in vascular responsiveness even with a relatively
small elevation of plasma cholesterol levels10. So, it has
been suggested that, rat may be a good model for studying
vascular functions during hypercholesterolemia prior to
the development of atherosclerotic lesions 11 .
In the present study, fructose rich diet feeding for 3 weeks
caused a significant increase in serum TC, LDL-C, TG
with a significant decrease in HDL-C in rats. Seabuckthorn
treatment along with fructose diet in rats (preventive
effect) showed significant reduction in serum TC, LDL-C,
TG with a significant increase in HDL-C compared with
hypercholesterolemic rats. After treatment with
Seabuckthorn along with normal diet for 3 weeks in
hypercholesterolemic rats (therapeutic effect) showed
further reduction in serum TC, LDL-C, TG with a
significant increase in HDL-C compared with
hypercholesterolemic rats.
Haemodynamic profile
In this study, hypercholesterolemic rats show significant
rise in SBP, DBP, MAP and HR. Another important
finding is that Seabuckthorn treatment along with fructose
feeding in rats (preventive) completely prevented the rise
12
in SBP, DBP, MAP and HR compared with
hypercholesterolemic group. However, hypotensive effect
was observed in rats treated with Seabuckthorn and fed
with normal diet. Taken together, the present data suggest
that Seabuckthorn attenuated the development of
hypertension in hypercholesterolemic rats probably
through its antioxidative properties.
Baroreflex sensitivity
Results of the present study showed that the bradycardia
response to phenylephrine (PE) and the tachycardia
response to sodium nitroprusside (SNP) were attenuated in
hypercholesterolemic animals. The linear regression
analysis of the reflex changes in HR in response to changes
in SBP indicated a decreased baroreflex sensitivity in
hypercholesterolemic rats compared with normal rats. The
present work have shown that Seabuckthorn treatment
along with fructose feeding in rats improved the baroreflex
sensitivity to depressor and pressor responses to SNP and
PE, respectively. Further, rats treated with Seabuckthorn
and maintained on normal diet did not show any change in
baroreflex sensitivity. Seabuckthorn has shown
antioxidant activity in our study as well as in other studies11.
This may explain its beneficial effect on the baroreflex
sensitivity in hypercholesterolemic rats as decreased
baroreflex sensitivity has been correlated with oxidative
stress 12 .
References
1. Naseem, K.M., The role of nitric oxide in
cardiovascular diseases .2005 Mol Aspects Med., 26,
33-65.
2. Creager, M.A., Impaired vasodilation of forearm
resistance vessels in hypercholesterolemic humans. J Clin
Invest.1990, 86,1, 228-234.
3. Panza JA, Quyyumi AA, Brush JE Jr and Epstein SE.
Abnormal endothelium-dependent vascular relaxation in
patients with essential hypertension. N Engl J Med. 1990
323,1, 22-27.
4. Jousilahti P, Vartiainen E, Tuomilehto J and Puska P.
Sex, age, cardiovascular risk factors, coronary heart
disease: a prospective follow-up study of 14786
middle-aged men, women in Finland. Circulation
1999, 99,9, 1165-1172.
5. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A,
Schwartz PJ. Baroreflex sensitivity and heart-rate
variability in prediction of total cardiac mortality after
myocardial infarction. ATRAMI (Autonomic Tone
and Reflexes After Myocardial Infarction)
Investigators. Lancet.1998. 14;351,9101,478-84.
6. Ross R. The pathogenesis of atherosclerosisan update.
N Engl J Med.1986, 314:,488 500.
7. Vallance P, Collier J and Moncanda S. Effect of
endothelium derived nitric oxide on peripheral
arteriolar tone in man. Lancet.1989, 344; 997-1000.
8. Davis, P.F.. Vascular cell interaction with special
reference to the pathogenesis of atherosclerosis. Lab
invest. 1986, 55, 2-24.
9. Saini HK, Arneja AS and Dhalla NS. Role of
cholesterol in cardiovascular dysfunction. Can J
Cardiol. 2004. 1: 20,3, 333-346.
10. O' Rourke and Docherty JR. Effects of a highcholesterol diet on vascular and endothelial function in
rat aorta. Pharmacology 1998, 56,1-6.
11. S. Geetha, M. Sai ram, Virendra singh, G. Ilavazhagon
and R.C. Sawhney. Effect of seabuckthorn on sodium
nitroprusside induced cytotoxicity in Murine
Macrophages. Biomed pharcother, 2002, 56 , 463-467
12. Girouard, H., Denault, C., Chulak, C. and Champlain,
J.D. Treatment by N-acetylcysteine and melatonin
increases cardiac baroreflex and improves antioxidant
reserve. Am J Hypertens. 2004, 17, 947-954
13
Off Label Drug Treatment and Related Problem in Children
ORIGINAL ARTICLE
CHETAN MEHNDIRATTA, SYED ZIAUR RAHMAN, PIPASHA BISWAS1
Department of Pharmacology, Jawaharlal Nehru Medical College, AMU, Aligarh - 202002,
1
Symogen UK Marlow, Buckinghamshire SL7 1JW, United Kingdom.
Introduction
Special Characteristics of Paediatric Pharmacovigilance
In pediatrics, majority of medications are off label because
of the scarcity of pediatric cases in clinical trials. The
routine procedure for determining the dosage, indications,
route and contraindications depends on the adult clinical
trials. Because of the difference in drug pharmacokinetics
and pharmacodynamics in the pediatric and adult
population the above mentioned method for pediatric
prescription is very inadequate and incomplete. This has
caused a lot of disasters in the past e.g. solvent, which was
used to make sulfanilamide palatable caused renal failure,
grey baby syndrome by chloramphenicol and thalidomide
disaster. The role of pharmacovigilance and
pharmacoepidemiology lies in the fact that post marketing
studies are the single most evidence based method to
substantiate the safety signals in pediatric population. The
benefit-risk ratio of a given drug has to be assessed and the
decisions should be based on sound knowledge and
observations. Ideally the drugs, which have pediatric
labeling information should be prescribed and in
medications which do not have any details in pediatric
population the use should be judged by the seriousness of
the condition and other available treatment modalities.
When a drug or medical device is used to treat a disease or
condition not listed on its label, or used in such a way that's
not outlined in the label, it's said to be used off-label. This
off-label use is also sometimes referred to as extra-label
use, nonapproved use or unapproved use. A response
which is noxious, and unintended and which occurs at
doses normally used in man for the prophylaxis, diagnosis,
or therapy of disease as for the modification of
physiological function excluding failure to accomplish the
intended purpose (WHO Technical Report Series, 498,
1972), while, Edwards IR, et al defined ADR as “An
appreciably harmful or unpleasant reaction, resulting from
an intervention related to the use of a medicinal product,
which predicts hazard from future administration and
warrants prevention or specific treatment, alteration of
dosage regimen, or withdrawal of the product.
The conduct of pharmacovigilance for medicines for
paediatric use requires special attention. Childhood
diseases and disorders may be qualitatively and
quantitatively different from their adult equivalents.
Chronic conditions may require chronic treatment and
hence the susceptibility to adverse drug reactions (ADRs)
may change throughout the patient's life-time according to
age and the stage of growth and development. Irrespective
of the duration of treatment, growth and development
during childhood reflect many underlying processes which
may result in ADRs not seen in the adult population. Also,
the associated rapid changes in body mass present
additional challenges in identifying and selecting the
optimal dosing regimen. Particular problems associated
with the lack of reliable data in paediatric populations
include:
F Lack of clinical trials in the paediatric population limits
the safety data available;
F Lack of kinetics data or dose-finding studies may lead to
under or over-dosing in some age groups;
F Under-dosing may result in lack of benefit or
development of resistance;
F Over-dosing may result in an increase of Type A
reactions;
F Lack of appropriate formulations may lead to incorrect
dosing, use of products of less controlled quality or
inappropriately high local concentrations leading to
local adverse reactions;
F Routinely available safety data may not adequately
capture events arising in the paediatric population.
F Safety data in the paediatric population cannot
necessarily be extrapolated from data in adults because
certain ADRs may only be seen in the paediatric
population depending on the maturation of organ
systems (e.g. kidney, liver, blood-brain-barrier),
metabolism, growth and development. In particular:
F The pharmacokinetics and pharmacodynamics of a
14
Chetan Mehndiratta: Off Label Drug Treatment and Related Problem in Children
compound may be different in the paediatric population
compared with adults and the former may be particularly
vulnerable to adverse drug reactions (ADRs) or have
different drug interaction profiles;
F
The paediatric population may be more susceptible to
ADRs from specific excipients;
F
Different adverse events may be relevant for different
paediatric age groups and specific
F
Pharmacovigilance tailored accordingly. In utero
exposure may represent an additional risk factor;
F
Due to maturation, growth and development the
paediatric population may be susceptible to drug
induced growth and developmental disorders, as well
as to delayed ADRs not seen in adults. Long term
follow-up data may be necessary to detect such
effects;
F
Drug-induced “programming” may occur i.e.
permanent effects may result from a drug exposure at a
sensitive point in development ('critical window'),
often in fetal or neonatal life;
F
Certain ADRs may only be seen in the paediatric
population, irrespective of effects on growth and
development. The problems are accentuated when the
drugs involved are not authorized for paediatric use
F
Unlicensed medicines or medicines used 'off-label'
may have inadequate product information to support
safe paediatric use;
F
Underreporting of adverse reactions occurs in relation
to unlicensed or 'off-label' use.
F
In addition, children may be unable to communicate
adverse events clearly to their carers/ health care
professionals or may not be aware of the adverse
events as such.
F
Premature babies may be at a much higher risk (for
example due to slow elimination of xenobiotics,
distribution barriers, physiological regulatory
functions and “imprinting”) and therefore need
enhanced pharmacovigilance.
Background
The paediatric population is defined in the European Union
as those persons aged between 0 and 16 years. Many
medicines are prescribed to the paediatric population on an
unlicensed or 'off-label' basis, because they have not been
adequately tested and/or formulated and authorized for use
in appropriate paediatric age groups. Rather they have been
tested and formulated for adults. This varies according to
the setting in which the medicines are prescribed. Whereas
only 10-20% of medicines prescribed for children by
general practitioners have not been licensed for use in
children, this number rises to about 45% of medicines used
in general paediatric wards and over 90% of those used in
neonatal intensive care. Doctors prescribing such
medicines for children have to take responsibility for this
unlicensed (off-label) use. They may prescribe adult
formulations, or use licensed medicines in an unlicensed
way (for example crushed in drinks to enable children to
take them). Because a child's body does not behave like
that of a small adult, it is not possible to make a simple
extrapolation from the adult data.
For some medicines, this lack of information or
appropriate formulations may expose children to side
effects, over-dosing or under-dosing (lack of efficacy).
Why are so few medicines specifically licensed for use in
children? Until 10-15 years ago there was widespread
reluctance to conduct studies of medicines on children due
to ethical reasons. However, there has been a significant
shift in opinion in recent years, such that the lack of trials
and the dearth of information is now seen as the chief
ethical concern. There are also practical difficulties that
may make clinical studies on children more complex and
expensive than those on adults. Finally, the pharmaceutical
industry chooses what medicines to develop, test and
market. The potential return often is not sufficient to justify
investment in R&D of medicines specifically for children.
Concerns over children's medicines surfaced in the UK in
the late 1990s. In 2000 the Council of Health Ministers
decided that the European Commission would address this
issue. The resulting new EU Regulation on Medicinal
Products for Paediatric Use should enter into force in the
UK before the end of 2006.
Age Classification
Children are a heterogonous group. Within the paediatric
population, (0 to 18), there are different sub-groups and
international guidelines separate them into five groups:
1.
2.
3.
4.
5.
Preterm newborn infants;
Term newborn infants 0-27 days;
Infants 28 days 23 months;
Children 2 - 11 years and;
Adolescents between 12 and 16/18 years.
15
Chetan Mehndiratta : Off Label Drug Treatment and Related Problem in Children
Aim and Objectives
1. To study the use of drugs (mostly Antibiotics) in
pediatric patients.
2. Effect of off label drug use in the vulnerable
population group with particular reference to pediatric
off label use.
3. To see how the pediatric age group patients are
treated in a well equipped urban settings hospital.
4. To identify the safety risk in pediatric population
from off label drug use.
5. To see the awareness among the practicing
physicians about pediatric use of drugs.
Methods
In the present cohort study, prescriptions of paediatric
patients were reviewed and examined in a Out patient
Department, Child Welfare Clinic, Maternity Home,
Defense Colony, New Delhi. All prescriptions were
audited for any off-label drug prescriptions as per available
evidence based information.
Results
In the following clinical setup, off-label paediatric
prescriptions were monitored. Out patient Department, Child
Welfare Clinic, Maternity Home, Defense Colony, New
Delhi Patient profile: Middle class Delhi population living in
Pucca housing with proper sanitation facilities. Drugs and
ADR reported for the month of October & November 2008
from patients reporting to OPD of the health care set up.
Drug used: Cotrimoxazole Pediatric tablets 100mg
sulfomethoxazole + 20mg trimethoprim SS [single strength]
200mg sulfomethoxazole + 40mg trimethoprim. Total no of
patients treated with this combination in month of October &
November 2008 were 75.
-
-
-
-
-
-
16
Chetan Mehndiratta : Off Label Drug Treatment and Related Problem in Children
-
-
-
-
-
Discussion
The harm from off label and unlicensed medicines use in
children is scarce. There is however sufficient evidence
that harm actually occurs and is underreported.This
supports measures to improve information on medicines
used in children. This also supports setting up
prospective monitoring of ADR's in children, including
for children in the community, in order to obtain an
objective picture of the risks and benefits of paediatric
medicines.
FPaediatric clinical trials remain challenging for
physicians, clinical pharmacologists, regulators and
industry due to numerous specifics of this highly
vulnerable population.
FNew measures to avoid or minimise pain and distress in
the paediatric population during clinical trials have to be
developed.
FNew methodological approaches for clinical trials in the
paediatric exist, but have to be further explored.
FPharmacovigilance in the paediatric population requires
specific tools and considerations to appropriately detect
adverse reactions and in particular address long-term
safety risks.
Note: The study is a part of a project report for the partial
approval of Certificate Course in Pharmacovigilance and
Pharmacoepidemiology, during (September December,
2008), Symogen India Pvt. Ltd., New Delhi,
References
1.PDCO opinions on PIPs and waivers are transforme into
EMEA decisions within the timeframe laid down by the
Paediatric Regulation (Regulation (EC) No 1901/2006, as
``amended). The decions can be found on the EME A
website:http/www.emea.europa.eu/htms/human/paeditri
cs/decisins.html
2. The document on procedural advice for validation of
new Marketing authorization applications forextensions
/variations and compliance check with an agreed PIP is
published in the Medicines for children section of the
EMEA website.
3. More information about the PDCO and the Paediatric
Regulation is available in the 'Medicines for children'
section of the EMEA website.
4. This press release, together with other information on
the work of the EMEA, can be found on the EMEA
website: http://www.emea.europa.eu
5. Conroy S, Choonara I, Impicciatore P, et al. Survey of
unlicensed and off-label drug use in paediatric wards in
European countries. BMJ 2000;320:7982.
6. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse
reactions to unlicensed and off-label drugs on paediatric
wards. Acta Paediatr 1999;88:9658
7. Straand J, Rokstad K, Heggedal U. Drug prescribing for
children in general practice. A report from More &
Romsdal Prescription Study. Acta Paediatr 1998;87:
21824.
8. Rylance G,Woods C, Cullen R, Rylance M. Use of
drugs by children. BMJ 1988;297:4457.
9. Bonati M, Choonara I, Hoppu K, Pons G, Seyberth
H.Closing the gap in drug therapy. Lancet 1999;353:
1625.
10.Van den Anker J, Choonara I. ENDIC European
Network for Drug Investigation in Children. Pediatric
and Perinatal Drug Therapy 1999;3:1516.
11.Wikipedia,the free encyclopedia:Off Label Use in
Pediatric, can be found on Website: http//en.
wikipedia.org /off label use. b
17
Nanobiotechnology Today: Focus on Nanoparticles
ANSHUL KUMAR, IMRAN ZAFAR
Institute of Pharmacy NIMS University Rajasthan , Jaipur - 303 121
ABSTRACT
Nanobiotechnology is the branch of nanotechnology with biological and biochemical applications or uses. Nanobiotechnology
often studies existing elements of nature in order to fabricate new devices These include bottom-up and molecular self-assembly,
biological effects of naked nanoparticles and nano-safety, drug encapsulation and nanotherapeutics, and novel nanoparticles for
use in microscopy, imaging and diagnostics. This review highlights recent nanoparticle research is currently an area of intense
scientific research, due to a wide variety of potential applications in biomedical, optical, and electronic fields.
History
pottery. The object was then placed to a kiln and heated to
about 600°C in a reducing atmosphere.
Although generally nanoparticles are considered an
invention of modern science, they actually have a very long
history. Specifically, nanoparticles were used by artisans as
far back as in the 9th century Mesopotamia for generating a
glittering effect on the surface of pot.
Lustre technique shows that craftsmen had a rather
sophisticated empirical knowledge of materials. The
technique originates in the Islamic world. As Muslims
were not allowed to use gold in artistic representations,
they had to find a way to create a similar effect without
using real gold. The solution they found was using lustre.
Even these days pottery from the Middle Ages and
Renaissance often retain a distinct gold or copper colored
metallic glitter. This so called lustre is caused by a metallic
film that was applied to the transparent surface of a glazing.
The lustre can still be visible if the film has resisted
atmospheric oxidation and other weathering.
Michael Faraday provided the first description, in
scientific terms, of the optical properties of nanometerscale metals in his classic 1857 paper "Experimental
relations of gold (and other metals) to light." Much of the
modern day studies of these objects have been conducted at
the ESRF laboratory. Several techniques were used to
characterizes the chemical and physical properties of these
lustre, such as Rutherford Backscattering Spectrometry
(RBS), optical absorption in the visible-ultraviolet region,
electron microscopy (TEM and SEM)
The lustre originates within the film itself, which contains
silver and copper nanoparticles, dispersed homogeneously
in the glassy matrix of the ceramic glaze. These
nanoparticles were created by the artisans by adding
copper and silver salts and oxides together with vinegar,
ochre, and clay, on the surface of previously-glazed
Figure 1 : Silicon nanopowder Nanodiamonds, TEM Image
18
Kumar A : Nanobiotechnology today: focus on Nanoparticles
Properties
Classification
Nanoparticles are of great scientific interest as they are
effectively a bridge between bulk materials and atomic or
molecular structures. A bulk material should have constant
physical properties regardless of its size, but at the nanoscale this is often not the case. Size-dependent properties
are observed such as quantum confinement in
semiconductor particles, surface plasmon resonance in
some metal particles and superparamagnetism in magnetic
materials. The properties of materials change as their size
approaches the nanoscale and as the percentage of atoms at
the surface of a material becomes significant. For bulk
materials larger than one micrometre the percentage of
atoms at the surface is minuscule relative to the total number
of atoms of the material. The interesting and sometimes
unexpected properties of nanoparticles are partly due to the
aspects of the surface of the material dominating the
properties in lieu of the bulk properties. Nanoparticles
exhibit a number of special properties relative to bulk
material. For example, the bending of bulk copper (wire,
ribbon, etc.) occurs with movement of copper
atoms/clusters at about the 50 nm scale. Copper
nanoparticles smaller than 50 nm are considered super hard
materials that do not exhibit the same malleability and
ductility as bulk copper. The change in properties is not
always desirable. Ferroelectric materials smaller than 10
nm can switch their magnetisation direction using room
temperature thermal energy, thus making them useless for
memory storage. Suspensions of nanoparticles are possible
because the interaction of the particle surface with the
solvent is strong enough to overcome differences in density,
which usually result in a material either sinking or floating
in a liquid. Nanoparticles often have unexpected visible
properties because they are small enough to confine their
electrons and produce quantum effects. For example gold
nanoparticles appear deep red to black in solution. The large
surface area to volume ratio also reduces the incipient
melting temperature of nanoparticles. Moreover
nanoparticles have been found to impart some extra
properties to various day to day products. Like the presence
of titanium dioxide nanoparticles impart what we call as the
self-cleaning effect, and the size being nanorange, the
particles can't be seen. Nano Zinc Oxide particles have been
found to have superior UV blocking properties compared to
its bulk substitute. This is one of the reasons why it is often
used in the sunscreen lotions. These nanoparticles are hard,
and impart their properties to the polymer (plastic).
Nanoparticles have also been attached to textile fibers in
At the small end of the size range, nanoparticles are often
referred to as clusters. Nanospheres, nanorods, and
nanocups are just a few of the shapes that have been grown.
Metal, dielectric, and semiconductor nanoparticles have
been formed, as well as hybrid structures (e.g., core-shell
nanoparticles). Nanoparticles made of semiconducting
material may also be labeled quantum dots if they are small
enough (typically sub 10 nm) that quantization of
electronic energy levels occurs. Such nanoscale particles
are used in biomedical applications as drug carriers or
imaging agents. Semi-solid and soft nanoparticles have
been manufactured. A prototype nanoparticle of semi-solid
nature is the liposome. Various types of liposome
nanoparticles are currently used clinically as delivery
systems for anticancer drugs and vaccines.
Characterization
Nanoparticle characterization is necessary to establish
understanding and control of nanoparticle synthesis and
applications. Characterization is done by using a variety of
different techniques, mainly drawn from materials science.
Common techniques are electron microscopy [TEM,
SEM], atomic force microscopy [AFM], dynamic light
scattering [DLS], x-ray photoelectron spectroscopy [XPS],
powder x-ray diffractometry [XRD], Fourier transform
infrared spectroscopy [FTIR], Matrix-Assisted LaserDesorption Time-of-flight mass spectrometry [MALDITOF], and Ultraviolet-visible spectroscopy. Whilst the
theory has been known for over a century (see Robert
Brown), the technology for Nanoparticle tracking analysis
(NTA) allows direct tracking of the Brownian motion and
this method therefore allows the sizing of individual
nanoparticles in solution.
Fabrication of Nanoparticles
There are several methods for creating nanoparticles;
attrition and pyrolysis are common methods. In attrition,
macro or micro scale particles are ground in a ball mill, a
planetary ball mill, or other size reducing mechanism. The
resulting particles are air classified to recover
nanoparticles.
In pyrolysis, a vaporous precursor (liquid or gas) is forced
through an orifice at high pressure and burned. The
resulting solid (a version of soot) is air classified to recover
oxide particles from by-product gases. Pyrolysis often
results in aggregates and agglomerates rather than
19
singleton primary particles. A thermal plasma can also
deliver the energy necessary to cause evaporation of small
micrometre size particles. The thermal plasma
temperatures are in the order of 10000 K, so that solid
powder easily evaporates. Nanoparticles are formed upon
cooling while exiting the plasma region. The main types of
the thermal plasmas torches used to produce nanoparticles
are dc plasma jet, dc arc plasma and radio frequency (RF)
induction plasmas. In the arc plasma reactors, the energy
necessary for evaporation and reaction is provided by an
electric arc which forms between the anode and the
cathode. For example, silica sand can be vaporized with an
arc plasma at atmospheric pressure. The resulting mixture
of plasma gas and silica vapour can be rapidly cooled by
quenching with oxygen, thus ensuring the quality of the
fumed silica produced. The working frequency is typically
between 200 kHz and 40 MHz. Laboratory units run at
power levels in the order of 30-50 kW while the large scale
industrial units have been tested at power levels up to 1
MW. As the residence time of the injected feed droplets in
the plasma is very short it is important that the droplet sizes
are small enough in order to obtain complete evaporation.
The RF plasma method has been used to synthesize
different nanoparticle materials, for example synthesis of
various ceramic nanoparticles such as oxides,
carbours/carbides and nitrides of Ti and Si.
Inert-gas aggregation is frequently used to make
nanoparticles from metals with low melting points. The
metal is vaporized in a vacuum chamber and then super
cooled with an inert gas stream. The super cooled metal
vapor condenses in to nanometer-sized particles, which
can be entrained in the inert gas stream and deposited on a
substrate or studied in situ.
Nanoparticle Morphology
Nanostars of Vanadium (IV) oxide
Scientists have taken to naming their particles after the real
world shapes that they might represent. Nanospheres,
nanoreefs, nanoboxes and more have appeared in the
literature. These morphologies sometimes arise
spontaneously as an effect of a templating or directing agent
present in the synthesis such as micellular emulsions or
anodized alumina pores, or from the innate crystallographic
growth patterns of the materials themselves. Some of these
morphologies may serve a purpose, such as long carbon
nanotubes being used to bridge an electrical junction, or just
a scientific curiosity like the stars shown at left.
J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1)
20
Cluster Physics
In physics, the term clusters(Physics) denotes small,
multiatom particles. As a rule of thumb, any particle of
somewhere between 3 and 3*10^7 atoms is considered a
cluster. Two-atom particles are sometimes considered
clusters as well. The term can also refer to the organization
of protons and neutrons within nuclei.
Cluster science was born in the 1980s. One purpose of the
research was to study the gradual development of
collective phenomena which characterize a bulk solid.
These are for example the color of a body, its electrical
conductivity, its ability to absorb or reflect light, and
magnetic phenomena such as Ferro-, ferri-, or
antiferromagnetism. These are typical collective
phenomena which only develop in an aggregate of a large
number of atoms.
It was found that collective phenomena break down for
very small cluster sizes. It turned out, for example, that
small clusters of a ferromagnetic material are superparamagnetic rather than ferromagnetic. Paramagnetism is
not a collective phenomenon, which means that the
ferromagnetism of the macrostate was not conserved by
going into the nanostate. The question then was asked for
example “How many atoms do we need in order to obtain
the collective metallic or magnetic properties of a solid”?
Soon after the first cluster sources had been developed in
1980, an ever larger community of cluster scientists was
involved in such studies. This development led to the
discovery of fullerenes in 1986 and carbon nanotubes a few
years later.
Powder (Substance)
A powder is a dry, bulk solid composed of a large number
of very fine particles that may flow freely when shaken or
tilted. Powders are a special sub-class of granular
materials, although the terms powder and granular are
sometimes used to distinguish separate classes of material.
In particular, powders refer to those granular materials that
have the finer grain sizes, and that therefore have a greater
tendency to form clumps when flowing. Granulars refers
to the coarser granular materials that do not tend to form
clumps except when wet.
Mechanical properties
Typically, a powder can be compacted or loosened into a
vastly larger range of bulk densities than can a coarser
granular material. When deposited by sprinkling, a powder
may be very light and fluffy. When vibrated or compressed
it may become very dense and even lose its ability to flow.
The bulk density of coarse sand, on the other hand, does not
vary over an appreciable range.
The clumping behavior of a powder arises because of the
molecular Van der Waals force that causes individual
grains to cling to one another. Only when the grains are
very small and lightweight does the Van der Waals force
become predominant, causing the material clump like a
powder.
Many other powder behaviors are common to all granular
materials. These include segregation, stratification,
jamming and unjamming, fragility, loss of kinetic energy,
frictional shearing, compaction and Reynolds' dilatancy.
Nanocrystal
Fahlman, B. D. has described a nanocrystal as any
nanomaterial with at least one dimension ¡ 100nm and that
is single crystalline. More properly, any material with a
dimension of less than 1 micrometre, i.e., 1000
nanometers, should be referred to as a nanoparticle, not a
nanocrystal. For example, any particle which exhibits
regions of crystallinity should be termed nanoparticle or
nanocluster based on dimensions. These materials are of
huge technological interest since many of their electrical
and thermodynamic properties show strong size
dependence and can therefore be controlled through
careful manufacturing processes.
Crystalline nanoparticles are also of interest because they
often provide single-domain crystalline systems that can
be studied to provide information that can help explain the
behaviour of macroscopic samples of similar materials,
without the complicating presence of grain boundaries and
other defects. Semiconductor nanocrystals in the sub10nm size range are often referred to as quantum dots.
Crystalline nanoparticles made with zeolite are used as a
filter to turn crude oil onto diesel fuel at an ExxonMobil oil
refinery in Louisiana, a method cheaper than the
conventional way.
A layer of crystalline nanoparticles is used in a new type of
solar panel named SolarPly made by Nanosolar. It is
cheaper than other solar panels, more flexible, and claims
12% efficiency. The term NanoCrystal is a registered
trademark of Elan Pharma International Limited (Ireland)
used in relation to Elan's proprietary milling process and
nanoparticulate drug formulations.
Nanoparticle photovoltaic cell Generally, solar cells on the
market today do not produce much electricity from
ultraviolet light, instead it is either filtered out or absorbed
by the cell, heating the cell. That heat is wasted energy and
21
could even lead to damage to the cell. By diluting particles
of silicon in alcohol, covering a solar cell with it and letting
the alcohol evaporate to leave the nanoparticles of silicon
on the cell has been increased the cell power output by 67%
in the ultraviolet range and about 10% in the visible range
.
On the other hand, titanium dioxide and zinc oxide become
transparent at the nanoscale, however are able to absorb
and reflect UV light.
Safety Issues
Nanoparticles present possible dangers, both medically
and environmentally. Most of these are due to the high
surface to volume ratio, which can make the particles very
reactive or catalytic. Hey are also able to pass through cell
membranes in organisms, and their interactions with
biological systems are relatively unknown.
However, free nanoparticles in the environment quickly
tend to agglomerate and thus leave the nano-regime, and
nature itself presents many nanoparticles to which
organisms on earth may have evolved immunity (such as
salt particulates from ocean aerosols, terpenes from plants,
or dust from volcanic eruptions). A fuller analysis is
provided in the article on nanotechnology.
According to the San Francisco Chronicle, "Animal
studies have shown that some nanoparticles can penetrate
cells and tissues, move through the body and brain and
cause biochemical damage they also have shown to cause a
risk factor in men for testicular cancer. But whether
cosmetics and sunscreens containing nanomaterials pose
health risks remains largely unknown, pending completion
of long-range studies recently begun by the FDA and other
agencies." Diesel nanoparticles have been found to
damage the cardiovascular system in a mouse model.
Uses of Nanobiotechnology
Since its inception, Strem Chemicals has focused on
offering unique organometallic compounds for both
academic and industrial research purposes. Close
relationships with leading researchers in the field have
enabled Strem to stay abreast of the latest scientific
advances in and regularly add novel chemicals to our
product portfolio. Most recently, Strem has embraced the
emerging area of nanotechnology and formed
collaboration with the Max-Planck-Institut fuer
Kohlenforschung. A series of nanomaterials, including
metal nanoclusters, metal nanocolloids (organosols and
hydrosols), metal nanopowders, metal nanoparticles, and
magnetic fluids are now available from Strem. Below is a
discussion of potential applications of these nanomaterials
in the medical/pharmaceutical market.
Biosensors and Biolabels
Using Biosensors and biolabels to understand living cells
Nanotechnology has the potential to increase our ability to
understand the fundamental working of living cells. Many
potential applications for metal nanomaterials as
biosensors and biolabels are under investigation. They
have found use in cellular studies, enhanced spectroscopic
techniques, biochips, and protein and enzyme analysis.
Using Fluorescent Nanoparticles for Cell Labeling and
Magnetic Nanoparticles as Sensors. Multi-calor labeling
of both fixed and living cells with fluorescent
nanoparticles conjugated with biological ligands that
specifically bind against certain cellular targets enables the
recording of diffusion pathways in receptor cells. Uptake
of nanoparticles into the vesicular compartments around
the nucleus of cells can be used to label the cells so that
their pathway and fate can be followed. The nanoparticles
exhibit reduced photobleaching as compared to traditional
dyes and are passed on to daughter cells during cell
division, therefore allowing for much longer term
observation. Magnetic nanoparticles can also act as sensors
for assessing how external stresses affect changes in
intracellular biochemistry and gene expression. How
Colloidal Gold Nanoparticles and Colloidal Gold
Biofunctionalized Nanomodules Are Used to Monitor
Cells Colloidal gold nanoparticles have been found to
strongly enhance the native signals of chemical
constituents in cells. Surface Enhanced Raman
Spectroscopy (SERS) relies on this signal magnification
and serves as a tool for ultra-sensitive monitoring of the
intracellular distribution of these chemicals. Colloidal gold
biofunctionalized nanomodules also have potential for use
in enzyme multi-sensors. Gold nanoparticles coated with
proteins have been used to detect conformation changes in
the attached proteins via observation of calor changes in the
solution. Overview Medical use of nanomaterials
Nanomedicine seeks to deliver a valuable set of research
tools and clinically helpful devices in the near future. The
National Nanotechnology Initiative expects new commercial
applications in the pharmaceutical industry that may include
advanced drug delivery systems, new therapies, and in vivo
imaging. Neuro-electronic interfaces and other
nanoelectronics-based sensors are another active goal of
research. Further down the line, the speculative field of
molecular nanotechnology believes that cell repair machines
could revolutionize medicine and the medical field.
Nanomedicine is a large industry, with nanomedicine sales
reaching 6.8 billion dollars in 2004, and with over 200
companies and 38 products worldwide, a minimum of 3.8
billion dollars in nanotechnology R&D is being invested
every year. As the nanomedicine industry continues to
grow, it is expected to have a significant impact on the
economy.
Antigen Detection
Linkers
Protective Layer
Fluorescent signaling
Biocompatibility
Shape recognition
Figure 2. Diagram showing how nanotechnology methods can improve our understanding of living cells.
22
Medical Use of Nanomaterials
Drug Delivery
Nanomedical approaches to drug delivery center on
developing nanoscale particles or molecules to improve
the bioavailability of a drug. Bioavailability refers to the
presence of drug molecules where they are needed in the
body and where they will do the most good In vivo imaging
is another area where tools and devices are being
developed. Using nanoparticle contrast agents, images
such as ultrasound and MRI have a favorable distribution
and improved contrast. The new methods of
nanoengineered materials that are being developed might
be effective in treating illnesses and diseases such as
cancer. Drug delivery systems, lipid- or polymer-based
nanoparticles, can be designed to improve the
pharmacological and therapeutic properties of drugs. The
strength of drug delivery systems is their ability to alter the
pharmacokinetics and biodistribution of the drug.
Nanoparticles have unusual properties that can be used to
improve drug delivery. Where larger particles would have
been cleared from the body, cells take up these
nanoparticles because of their size. Complex drug delivery
mechanisms are being developed, including the ability to
get drugs through cell membranes and into cell cytoplasm.
If a drug is cleared too quickly from the body, this could
force a patient to use high doses, but with drug delivery
systems clearance can be reduced by altering the
pharmacokinetics of the drug.
Cancer
The small size of nanoparticles endows them with
properties that can be very useful in oncology, particularly
in imaging. Quantum dots (nanoparticles with quantum
confinement properties, such as size-tunable light
emission), when used in conjunction with MRI (magnetic
resonance imaging), can produce exceptional images of
tumor sites. These nanoparticles are much brighter than
organic dyes and only need one light source for excitation.
This means that the use of fluorescent quantum dots could
produce a higher contrast image and at a lower cost than
todays organic dyes used as contrast media. The downside,
however, is that quantum dots are usually made of quite
toxic elements. Another nanoproperty, high surface area to
volume ratio, allows many functional groups to be attached
to a nanoparticle, which can seek out and bind to certain
tumor cells. Additionally, the small size of nanoparticles
(10 to 100 nanometers), allows them to preferentially
accumulate at tumor sites (because tumors lack an effective
lymphatic drainage system). A very exciting research
question is how to make these imaging nanoparticles do
more things for cancer. For instance, is it possible to
manufacture multifunctional nanoparticles that would
detect, image, and then proceed to treat a tumor? This
question is under vigorous investigation; the answer to
which could shape the future of cancer treatment. A
promising new cancer treatment that may one day replace
radiation and chemotherapy is edging closer to human
trials. Kanzius RF therapy attaches microscopic
nanoparticles to cancer cells and then "cooks" tumors
inside the body with radio waves that heat only the
nanoparticles and the adjacent (cancerous) cells. Sensor
test chips containing thousands of nanowires, able to detect
proteins and other biomarkers left behind by cancer cells,
could enable the detection and diagnosis of cancer in the
early stages from a few drops of a patient's blood.
Nanoparticles of cadmium selenide (quantum dots) glow
Molecular Imaging & Therapy
Improved
Imaging
Localized
Therapy
Cancer
Diagnosed
Targeting
Medication
Homing on
Tumor
Killing
Cancer
Cells
Figure 3. A schematic illustration showing how nanoparticles or other cancer drugs might be used to treat cancer.
23
when exposed to ultraviolet light. When injected, they seep
into cancer tumors. The surgeon can see the glowing tumor,
and use it as a guide for more accurate tumor removal. In
photodynamic therapy, a particle is placed within the body
and is illuminated with light from the outside. The light gets
absorbed by the particle and if the particle is metal, energy
from the light will heat the particle and surrounding tissue.
Light may also be used to produce high energy oxygen
molecules which will chemically react
with and destroy most organic molecules that are next to
them (like tumors). This therapy is appealing for many
reasons. It does not leave a “toxic trail” of reactive
molecules throughout the body (chemotherapy) because it
is directed where only the light is shined and the particles
exist. Photodynamic therapy has potential for a
noninvasive procedure for dealing with diseases, growths,
and tumors.
Surgery
At Rice University, a flesh welder is used to fuse two pieces
of chicken meat into a single piece. The two pieces of
chicken are placed together touching. A greenish liquid
containing gold-coated nanoshells is dribbled along the
seam. An infrared laser is traced along the seam, causing
the two sides to weld together. This could solve the
difficulties and blood leaks caused when the surgeon tries
to restitch the arteries he/she has cut during a kidney or
heart transplant. The flesh welder could meld the artery into
a perfect seal.
Visualization
Tracking movement can help determine how well drugs are
being distributed or how substances are metabolized. It is
difficult to track a small group of cells throughout the body
so scientists used to dye the cells. These dyes needed to be
excited by light
of a certain wavelength in order for them to light up. While
different color dyes absorb different frequencies of light,
there was a need for as many light sources as cells. A way
around this problem is with luminescent tags. These tags
are quantum dots attached to proteins that penetrate cell
walls. The dots can be random in size, can be made of bioinert material, and they demonstrate the nanoscale property
that color is size-dependent. As a result, sizes are selected
so that the frequency of light used to make a group of
quantum dots fluoresce is an even multiple of the frequency
required to make another group incandesce. Then both
groups can be lit with a single light source.
Nanoparticle Targeting
It is greatly observed that nanoparticles are promising tools
for the advancement of drug delivery, medical imaging,
and as diagnostic sensors. However, the biodistribution of
these nanoparticles is mostly unknown due to the difficulty
in targeting specific organs in the body. Current research in
the excretory systems of mice, however, shows the ability
of gold composites to h
selectively target certain organs based on their size and
charge. These composites are encapsulated by a dendrimer
and assigned a specific charge and size. Positively-charged
gold nanoparticles were found to enter the kidneys while
negatively-charged gold nanoparticles remained in the
liver and spleen. It is suggested that the positive surface
charge of the nanoparticle decreases the rate of
osponization of nanoparticles in the liver, thus affecting the
excretory pathway. Even at a relatively small size of 5nm,
though, these particles can become compartmentalized in
the peripheral tissues, and will therefore accumulate in the
body over time. While advancement of research proves
that targeting and distribution can be augmented by
nanoparticles, the dangers of nanotoxicity become an
important next step in further understanding of their
medical uses.
Diagnostics
How Nanotechnology Methods Can Improve Medical
Diagnostics Early detection of disease remains a primary
goal of the medical community. Nanotechnology holds
great promise for enabling the achievement of this goal.
Nanoparticles in particular have exhibited tremendous
potential for detecting fragments of viruses, pre-cancerous
cells, disease markers, and indicators of radiation damage.
Gold coatings have made it possible to use toxic cobalt
nanoparticles for biomedical applications. Gold coated
ferromagnetic nanoparticles tagged with HIV antibodies
may be able to detect virus particles left after completion of
conventional drug therapy. Metal nanoparticles in the form
of dendrimers have also been functionalized with different
biomolecules to detect specific proteins, antibodies, and
other disease indicators. Fluorescent markers can also be
attached to the dendrimers.
Early Cancer Detection Using Superparamagnetic Iron
Oxide (USPIO) Particles and Magnetic Resonance
Imaging (MRI) Biomolecule coated ultra small
superparamagnetic iron oxide (USPIO) particles injected
in the blood stream recognize target molecular markers
24
Figure 4. Diagram showing how nanoparticles can be used to detect diseased cells
present inside cells and induce a specific signal for
detection by magnetic resonance imaging (MRI). This
technology may allow for detection of individual cancer
cells months or years earlier than traditional diagnostic
tools, which require the presence of hundreds of cancer
cells. How Biobarcode Amplification Assays (BCA) Use
Nanoparticles in Disease Detection. A nanoparticle-based
biobarcode amplification assay (BCA) utilizes gold
nanoparticles and magnetic microparticles attached to
large numbers of DNA strands and antibodies for a specific
disease marker. The marker binds to the nano- and
microparticles forming a complex that is separated from
the sample using a magnetic field. Heating the complexes
releases the DNA barcodes, which emit an amplified signal
due to their large numbers. This BCA technology has been
applied to the detection of markers forAlzheimer's disease
and is being investigated for numerous others.Targeted
Drug DeliveryHow Nanotechnology Can Improve
Targeted Drug Delivery Methods Targeted drug delivery
systems can convey drugs more effectively and/or more
conveniently, increase patient compliance, extend the
product life cycle, provide product differentiation, and
reduce health care costs. Drug delivery systems that rely on
nanomaterials also allow for targeted delivery of
compounds characterized by low oral bioavailability due
to poor water solubility, permeability and/or instability and
provide for longer sustained and controlled release
profiles. These technologies can increase the potency of
traditional small molecule drugs in addition to potentially
providing a mechanism for treating previously incurable
diseases. Using Magnetic Nanoparticles Targeted Drug
Delivery - What This 'Tag and Drag' Process Involves. The
use of magnetic nanoparticles in targeted drug delivery
systems is under investigation by several research groups.
Therapeutic drug molecules have been immobilized on the
surface of magnetic nanoparticles or nanocrystals and
directed to a specific target tissue using a magnetic field
gradient. The drug is released by applying a radio
frequency (RF) pulse. Gold coated iron, nickel and cobalt
ferromagnetic nanoparticles have been employed in this
“tag and drag” approach. In hypothermal treatment,
magnetic nanoparticles are directed to diseased tissue
containing heat sensitive tumors. An AC magnetic field is
applied such that the nanoparticles become heated,
causing destruction of the cancerous cells. More effective
radiation therapy for tumor treatment can also be expected
using metallic nanoparticles instead of, for example,
magnetite. The nanoparticles allow the application of
higher dosages of radiation at the tumor while sparing
normal tissue. Other Applications for Nanomaterials in the
Medical and Pharmaceutical Sector. Numerous other
potential applications exist in the medical and
pharmaceutical field for nanomaterials from Strem. Areas
currently under investigation include gene therapy,
antibacterial/ antimicrobial agents for burn and wound
dressings, repair of damaged retinas, artificial tissues,
prosthetics, enhancing signals for magnetic resonance
imaging examinations, and as radio frequency controlled
switching of complex biochemical processes. List of
Nanomaterials that Strem Can Supply to All Types of
Industry: A listing of specific metal nanoclusters, metal
nanocolloids (organosols and hydrosols), metal
nanopowders, metal nanoparticles, and magnetic fluids
offered by Strem is available upon request or via our
website. Application sheets discussing the potential use of
these products in the medical and pharmaceutical, defense
and security, chemical, automotive, and energy fields, and
as magnetic fluids, can also be obtained from Strem. More
information is also available in the form of a reference
sheet listing literature source materials.
25
Result and Decision:
In nanotechnology, a particle is defined as a small object that
behaves as a whole unit in terms of its transport and
properties. It is further classified according to size: In terms
of diameter, fine particles cover a range between 100 and
2500 nanometers, while ultrafine particles, on the other
hand, are sized between 1 and 100 nanometers. Similarly to
ultrafine particles, nanoparticles are sized between 1 and 100
nanometers, though the size limitation can be restricted to
two dimensions. Nanoparticles may or may not exhibit sizerelated intensive properties that differ significantly from
those observed in fine particles or bulk materials.
Nanoclusters have at least one dimension between 1 and 10
nanometers and a narrow size distribution. Nanopowders are
agglomerates of ultrafine particles, nanoparticles, or
nanoclusters. Nanometer sized single crystals, or singledomain ultrafine particles, are often referred to as
nanocrystals.
References
1. Fahlman, B. D. Materials Chemistry; Springer: Mount
Pleasant, MI, 2007; 1, 282-283.
2. See for example US TM Reg. Nos. 2386089 / 2492925
and EU CTM Reg. No. 000885079
3. Faraday, Michael (1857). "Experimental relations of
gold (and other metals) to light". Phil. Trans. Roy.
Soc. London 147:145181. doi:10.1098/rstl.1857
4. Buffat, Ph.; Burrel, J.-P. (1976), "Size effect on the
melting temperature of gold particles", Physical
ReviewA13(6):22872298,doi:10.1103/PhysRevA.13.2
287,http://link.aps.org/abstract/PRA/v13/p2287
5. Yugang Sun and Younan XI a Science 298 (2002)
2176. doi:10.1126/science.1077229
6. Catherine Murphy, Science 298 (2002) 2139.doi:
10.1126/science.1080007
7. Anisa Mnyusiwalla, Abdallah S Daar and Peter A
Singer 2003 Nanotechnology 14 R9-R13
doi:10.1088/0957-4484/14/3/201
8. Ying, Jackie. Nanostructure Materials. New York:
Academic Press, 2001.
9. Keya Davidson. "FDA urged to limit nanoparticle use
in cosmetics and sun screens Francisco Chronicle.20
April 2007.
10. http://www.bloomberg.com/apps/news?pid=
Washington story&sid=aBt.yLf.Yf Oo study -Pollution
Particles Lead to Higher Heart Attack Risk (Update1)
11. http://www.autobloggreen.com/2007/08/21/siliconnanoparticle -film-can-increase-solar-cell
performance/
12. http://www.nano.dtu.dk/upload/centre/nanodtu/nano
eknologiske_horisonter / supplerende% 20
under visningsmateriale /kap1/ nanoscience % 20and
% 20 nanotechnologies % 20 opportunities % 20 and
% 20 uncertainties.pdf
26
A Retrospective Comparison of Buprenorphine
& Pentazocine as an Analgesic in AMI at
Pravara Rural Hospital.
ORIGINAL ARTICLE
RAHUL KUNKULOL, PRONOB K SANYAL, KAILAS R. GADEKAR, Y GRIDHAR REDDY1
Department of Pharmacology, Prosthodontics and Biochemistry YCMM and RDF'S, Ahmednagar, Pin: 414 003.
Dept. of Orthodontics, NIMS University Rajasthan, Jaipur 303121
1
ABSTRACT
The study aimed to compare Pentazocine and Buprenorphine as an analgesic in the treatment of acute myocardial infarction in
terms of morbidity, mortality, and outcome and to find out differences if any in the ultimate prognosis. This was a retrospective
study. For the study, patients suffering from AMI admitted in ICCU of Pravara Rural Hospital from 1999 2009were chosen.
Pentazocine was used in the treatment of AMI from 1999 2002 in this institution (n-117). From 2003 2009Buprenorphine was
used instead of Pentazocine for the treatment of pain of AMI (n-123). Patients were grouped as 1) Pentazocine treated 2)
Buprenorphine treated and following parameters were studied, ECG, Morbidity and mortality, infract size and clinical status at
discharge.ECG parameters, regression of infract went in favor of Buprenorphine, The morbidity profile in terms of arrhythmias,
CCF and shock was significantly less in Buprenorphine treated group. Mortality in Pentazocine treated group was significantly
higher as well as extension of infract was notable in this group. All in all in the present study Buprenorphine unequivocally came out
as the better drug in the emergency treatment of AMI.
Key words: AMI, ECG, Pentazocine, Buprenorphine
Introduction
choice. Due to unavailability of Morphine, as Morphine
comes under restricted drugs and has narcotic code other
analgesics preferred are Pentazocine, Buprenorphine,
Meperidine. Pentazocine acts as a weak antagonist or a
partial agonist at mu receptor while it is agonist at Kappa.
Buprenorphine is described as mixed agonist antagonist
acting mainly as partial agonist at mu receptors with some
antagonistic activity at Kappa. Buprenorphine is 25-50
times more potent than Morphine.
In the emergency department, the goals for the management
of patient with suspected AMI include control of cardiac
pain. Parenterally administrated narcotic analgesics are a
critically important part of therapy to control cardiac pain
for the patients with acute myocardial ischemic syndromes.
These agents are very effective and when used with
appropriate caution and monitoring are also generally safe.
They not only relieve sensation of pain but also relieve the
effective and physiologic reaction to pain and thus reduce
patient anxiety. The haemodynamic effects of these agents
are quite different in patients with active pain during the
period of acute ischemia or in patients that are
haemodynamically unstable. Haemodynamic studies
during these acute setting however are extremely difficult
to perform because the patients acute distress mandates
rapid administration of analgesic agent prior to the
institution of invasive monitoring. With these cautions
relating to data interpretation in mind, it is still possible to
make certain recommendations regarding the use of
analgesic therapy in AMI. Although a wide verity of
analgesics has been used in the treatment of pain associated
with AMI including Meperidine, Pentazocine,
Buprenorphine and Morphine, the last remained the drug of
In view of the aforementioned pharmacological actions of
Buprenorphine and Pentazocine more particularly so in the
setting of acute myocardial infarction, it was thought
Prudent to evaluate the use of Pentazocine and
Buprenorphine in the treatment of acute myocardial
infarction.
Aims and Objective
To study and compare the outcome of use of Pentazocine
and Buprenorphine in patients suffering from AMI.To
evaluate results in terms of various parameters of AMI in
patients treated with Pentazocine and Buprenorphine.To
find out differences if any in the ultimate prognosis of acute
myocardial infarction in terms of morbidity and mortality
in patients treated with Pentazocine and Buprenorphine.
27
Kunkulol et al: A Retrospective Comparison Of Buprenorphine & Pentazocine As An Analgesic In AMI At Pravara Rural Hospital
Methods
This was a retrospective study. Patients suffering from
AMI admitted in ICCU of Pravara Rural Hospital from
1999 2005 were chosen. Pentazocine was used in the
treatment of AMI from 1999, 2002 in this institution (N117). From 2002-2005 Buprenorphine was used instead of
Pentazocine for the treatment of pain of AMI (N-123).
The patients who have suffered from acute attack of
myocardial infarction and are on same other concomitant
therapy were grouped as under:
1. Pentazocine treated
2. Buprenorphine treated
4. Mortality-Mortality was recorded in numbers
i)
ii)
iii)
iv)
Within 24 hrs
24-48 hrs
48-72 hrs
72 hrs and beyond after administration of opioid
5. Clinical status at the time of discharge from the
hospital were noted which includes;
1) Normal
2) Poor
3) Death
Statistical analysis was done by using ‘Z’ test.
p<0.05 was considered to be statistically significant.
Following parameters were studied,
1. ECG parameters recorded after administration of
opioid-ECG changes during the course of treatment
were recorded at 6 hrs, 12 hrs, and 24 hrs after
administration of opioid and at discharge as persistent,
extension and regression of infract and were compared
between both the groups.
2. Serum enzymes studies after administration of opioids
included LDH, CPK, and GOT.
3. Morbidity - i.e. important complications / treatment
complications in pentazocine and Buprenorphine
treated patients of AMI were noted
a. Arrhythmias
b. Congestive heart failure
c. Cardiogenic shock
Results
All the patients included in the study received the same
other concomitant therapy and the only difference in the
therapy for the two groups was the use of either
Pentazocine or Buprenorphine, the results obtained in this
study can very well be attributed to the use of two opioid.
Comparison of ECG parameters in Pentazocine and
Buprenorphine treated patients of acute myocardial
infarction (values recorded within 24 hrs of administration
of Opioid) and ST elevation or depression pattern showed
highly significant difference (P < 0.01) in favor of
Buprenorphine treated patients than that of Pentazocine
treated patients. (Table no. 1&2)
Table 1: Comparison of ECG parameters in Pentazocine and Buprenorphine treated patients of acute
myocardial infarction (values recorded within 24 hrs of administration of Opioids).
28
Table 2:- ST elevation or depression pattern in Pentazocine and Buprenorphine treated patients of acute
myocardial infarction (values recorded within 24 hrs of administration of Opioids).
Figure 1:- Comparison of ECG changes in Pentazocine and Buprenorphine treated patients of acute
myocardial infarction
Pentazocine (n = 117) Buprenorphine (n=123) For all the above three graphs after applying the 'Z' test of difference
between two proportions there was a significant difference in favour of Buprenorphine in comparison with Pentazocine.
Table 3:- Complication/s/treatment complication/s in Pentazocine and Buprenorphine treated patients of acute
myocardial infarction
Figure 2:-Comparison of mortality in Pentazocine and Buprenorphine treated patients of AMI
29
Figure 3. Clinical status at discharge in Pentazocine and Buprenorphine treated patients of AMI
Pentazocine (n = 117) Buprenorphine (n=123)
Note: - For the above table after applying the 'Z' test of difference between two proportions, there was a
significant difference in favor of Buprenorphine in all complications in both the groups i.e. in between
Pentazocine and Buprenorphine for Table no.5,6,7.
Discussion
On comparison of ECG changes in Buprenorphine treated
and Pentazocine treated patients at 6 hours, 12 hours, 24
hours and at discharge, the observations reveled persistent
ECG changes, extension of infract, and regression patterns
which were statistically highly significant (P< 0.01) in
favor of Buprenorphine treated patients as compare to
Pentazocine treated patients at 6 hours, 12 hours, 24 hours
and at discharge (Figure 1 Graph 3a, 3b, 3c). The
complication/s/ treatment complication/s were observed
in 40(34.18%) Pentazocine treated patients while in 17
(13.82%) Buprenorphine treated patients (Table no. 3). On
comparison of mortality in Pentazocine and
Buprenorphine treated patients, mortality count was 24
(20.52%) in Pentazocine treated patients out of which 09
died within 24 hours, and remaining 15 patients died in 24
48 hours. The mortality count with Buprenorphine treated
patients was 05 (4.08%) and the death of all these 05
patients occurred after 72 hours of administration of these
drugs. The mortality with Pentazocine treated patients was
statically highly significant (P < 0.01) as compared to the
Buprenorphine treated patients (Figure 2). The study of
clinical status of patients at discharge revealed that 77% of
Buprenorphine treated patients and only 39.31% of
Pentazocine treated patients became normal, while the
clinical status of 40.17% of Pentazocine treated patients
and 18.69% of Buprenorphine treated patients was poor at
discharge. This study revealed that the clinical status at
discharge was statically highly significant (P < 0.01) in
favor of Buprenorphine treated patients (Figure 3).The
various parameters which we studied yielded statistically
significant or highly significant results in favor of
Buprenorphine over Pentazocine.
Most of the deleterious changes with Pentazocine which
either resulted into morbidity and or mortality or heralded
the onset of the same occurred during the first 24 hours of
administration of Pentazocine. The unequivocal results in
favor of Buprenorphine implicitly points towards
Pentazocine as the not unlikely cause for the harmful
events in the patients of AMI. Furthermore most of the
events or the significant changes in the parameter studied
were in the first 24 hours after administration of
Pentazocine, where as the occurrence of the same, the same
time frame with Buprenorphine was minimal and
insignificant. For those who critically evaluate, we have
some additional advantages of Buprenorphine which
would definitely satisfy them, these are provided by the
studies of Keith J et al on opioids receptors and myocardial
protection which reported :
FThe recent studies of Schultz et al which suggested that
delta opioid receptors in the intact rat heart mediate
cardio protective effects of ischemic preconditioning
and opioids.
FThe reduction in binding affinity of kappa receptor was
correlated with reduction in vulnerability of ventricles to
fibrillate and incidence of ventricular fibrillation.
FPentazocine binds to kappa receptors and acts as an
agonist at kappa sites. It stimulates K3 receptor and
causes sedation and supraspinal analgesia, while K1
stimulation causes spinal analgesia thus the binding to
kappa receptor is increased.
FThese data allowed speculation that the cardioprotective
effects of both ischemic preconditioning and opioids was
in some way related to activity of delta receptors and
in versely to activity of kappa receptor.
30
Kunkulol et al: A retrospective comparison of Buprenorphine & Pentazocine as an analgesic in AMI at Pravara Rural Hospital
F Additionally Xia and coworkers proposed that
activation of kappa receptors may be a contributing
factors for arrhythmia induced by myocardial ischemia
and reperfusion.
F In an in vivo rat model of AMI, opioid receptor
stimulation has been observed to result in a reduction in
infarct size similar to ischemic preconditioning and
was due to involvement of myocardial ATP Sensitive
potassium channel (KATP). Further it was suggested that
opening of KATP channel may be an endogenous
protective mechanism in humans also.
F Opening of KATP channel is differentially involved in
antinociceptive effects of some opioids including
Buprenorphine, Morphine as Pentazocine, Fentanyl or
Levorphanol.
F On the basis of analysis of these in vivo data, it was
speculated that and Methadone but not in others such
Buprenorphine posses previously unrecognized
beneficial cardioprotective effects in patients including
those undergoing by pass surgery and those
experiencing an AMI.
F Importantly data from antinociceptive studies
indicated that differences have existed between opioids
for antinociception with Buprenorphine having
greatest cardioprotective potential while in contrast
Pentazocine having least or no cardioprotective
potential.
F Further it has been reported that Buprenorphine at
doses that induce antinociception also provides
protection against myocardial ischemia.
With such a plethora of advantages of Buprenorphine over
Pentazocine it can be safely argued and concluded that the
observations of the present study singling out
unequivocally Buprenorphine as by far the better drug
between the two studied for used in AMI can not be
perchance.
Conclusion
All in all in the present study Buprenorphine Unequi vocally came out as the better drug in the emergency
treatment of AMI.
In view of these results Buprenorphine is recommended
for the treatment of pain in all types of AMI and especially
in those with compromised cardiac functions.
31
References
1. Avery GS: Drug treatment: 2nd edition: 325 - 6, 1213:
1980.
2. Carl P and Crawford ME: Long term treatment with
epidural opioids: Anaesthesia:1986, 41: 32.
3. Buprenex package insert (Norwich Eaton
Resolution, 1985/6.
US),
4. Elimauer S, Different opioids in patients at
cardiovascular risk, Anaesthesist, 1994, 43(11), 7439.
5. Elliot M, “Harrison's Principles of Internal
Medicine”, 243. Acute myocardial infarction, 2001,
15th edition.
6. Kaplan JA, editor cardiac anaesthesia, Cardiovascular
Pharmacology, 1983, 2, 65 69.
7. Martindales, The complete drug references, 1999, 32nd
Ed.,P22.
8. Lee's Synopsis of anaesthesia, 1999, 12th edition:
ch.26.
9. Keith J, Opioid receptors and myocardial protection,
Clin. Drug. Invest. 1998. 15 (5), 445 54.
10. Mitaka C, Comparison of Haemodynamic effects of
Morphine, Buprenorphine and Pentazocine on ICU
patients, Bull Tokyo Med Dent. Univ., 1985, 32 (2);
31- 9.
11. Oranto Joseph, Cardiovascular emergencies, 1986,
9, 145.
12. Rabinov M, A double blind comparison of the relative
efficacy, side effects, and cost of Buprenorphine in
Patients after cardiac surgery: Aust N Z J Surgery: 57
(4): 227- 31.
13. Richard C, 39 Acute myocardial infarction, Braunwald
E, Heart diseases, 1988, 1215 - 25, 4th Ed.
14. Terry R and Pasternek G: Opioid analgesics and
antagonists, Goodman Gilman's The Pharmacological
basis of Therapeutics, 1996, 9th ed., 546- 48.
Biosafety Issues In Laboratories: A Review
REVIEW ARTICLE
AMIT JAIN, ZAHRA HASHEMI1
Nidaan Diagnostic and Research Center, Aligarh-202001
Centre for Safety & Rational Use of Indian Systems of Medicine, Ibn Sînâ Academy, Aligarh-202001
1
In spite of vigorous awareness campaigns about the
transmission of various infections by blood or parentral
routes, there seems to be little or negligible change in the
perception not only among the laymen but also the
healthcare workers and paramedical staff. Since the advent
of AIDS epidemic extra ordinary efforts had gained
momentum regarding the biosafety and prevention of
laboratory acquired infections all over the world but now
they seem to be again vaining .The lack of proper
infrastructure, low levels of awareness and certain degree
of complacency among laboratory staff all seem to be
contributing factors. Biosafety infractions are common,
including inadequate laboratory location, lack of biosafety
protocols, and dangerous disposal practices. In one of the
studies Ninety-four percent of respondents stated that
continuing education regarding biosafety in laboratory
safety would be useful 1.This article is an effort to quickly
refresh all the facts that a healthcare personnel already had
read or know regarding the biosafety in laboratories.
potentially infected materials must be aware of potential
hazards, and must be trained and proficient in the practices
and techniques required to handle such material safely.
Each laboratory should develop or adopt a biosafety or
operations manual that identifies the hazards that will or
may be encountered, and that specifies practices and
procedures designed to minimize or eliminate exposures to
these hazards. Laboratory personnel, safety practices, and
techniques must be supplemented by appropriate facility
design and engineering features, safety equipment, and
management practices
Safety Equipment (Primary Barriers)
Safety equipment includes biological safety cabinets
(BSCs), enclosed containers, and other engineering
controls designed to remove or minimize exposures to
hazardous biological materials. The biological safety
cabinet (BSC) is the principal device used to provide
containment of infectious splashes or aerosols generated
by many microbiological procedures 3, 4. Three types of
biological safety cabinets (Class I, II, III) used in
microbiological laboratories. Open-fronted Class I and
Class II biological safety cabinets are primary barriers
which offer significant levels of protection to laboratory
personnel and to the environment when used with good
microbiological techniques. The Class II biological safety
cabinet also provides protection from external
contamination of the materials (e.g., cell cultures,
microbiological stocks) being manipulated inside the
cabinet. The gas-tight Class III biological safety cabinet
provides the highest attainable level of protection to
personnel and the environment. An example of another
primary barrier is the safety centrifuge cup, an enclosed
container designed to prevent aerosols from being released
during centrifugation. It must be used when handling
infectious agents that can be transmitted through the
aerosol route of exposure. Safety equipment also may
include items for personal protection, such as gloves, coats,
gowns, shoe covers, boots, respirators, face shields, safety
glasses, or goggles. Personal protective equipment is often
used in combination with biological safety cabinets,
however in some situations in which it is impractical
Biosafety in a laboratory set up may be considered under
following three heads:
-
Universal work precautions -- Guidelines in relation to
blood, body fluids etc.
Effective use of disinfection and sterilization
Safe disposal of hospital waste.
I. Universal Work Precautions:
Universal precautions refer to precautions consistently
applied to all patients regardless of their blood borne
infection status 2. Blood and body fluids of all the patients
are taken to be positive for HIV, HBV, and HCV and other
blood borne pathogens. All instruments and equipment that
have come in contact with blood are considered to be
potentially contaminated and must be properly handled,
cleaned sterilized and safely disposed off. Universal
precautions took the place of and eliminated the need for
the isolation category "Blood and Body Fluid Precautions"
in the 1983 CDC Guidelines for Isolation Precautions in
Hospitals. The most important element of it is strict
adherence to standard microbiological practices and
techniques. Persons working with infectious agents or
32
Jain A: Biosafety Issues in Laboratories: A Review
to work in biological safety cabinets, personal protective
equipment may form the primary barrier between
personnel and the infectious materials.
Secondary barriers such as hand washing sinks and waste
decontamination facilities must be available to reduce
potential environmental contamination.
Biosafety Levels: Four biosafety levels (BSLs) are
described, which consist of combinations of laboratory
practices and techniques, safety equipment, and laboratory
facilities. Each combination is specifically appropriate for
the operations performed, the documented or suspected
routes of transmission of the infectious agents, and the
laboratory function or activity.
Biosafety Level 3 practices, safety equipment, and facility
design and construction are applicable to clinical,
diagnostic, teaching, research, or production facilities in
which work is done with indigenous or exotic agents with a
potential for respiratory transmission, and which may
cause serious and potentially lethal infection,
Mycobacterium tuberculosis, St. Louis encephalitis virus,
and Coxiella burnetii are representative of the
microorganisms assigned to this level. Primary hazards to
personnel working with these agents relate to auto
inoculation, ingestion, and exposure to infectious aerosols.
design and construction are appropriate for undergraduate
and secondary educational training and teaching
laboratories, and for other laboratories in which work is
done with defined and characterized strains of viable
microorganisms not known to consistently cause disease in
healthy adult humans. Biosafety Level 1 represents a basic
level of containment that relies on standard
microbiological practices with no special primary or
secondary barriers recommended, other than a sink for
hand washing.
Biosafety Level 2 practices, equipment, and facility design
and construction are applicable to clinical, diagnostic,
teaching, and other laboratories in which work is done with
the broad spectrum of indigenous moderate-risk agents
that are present in the community and associated with
human disease of varying severity. With good
microbiological techniques, these agents can be used
safely in activities conducted on the open bench, provided
the potential for producing splashes or aerosols is low.
Hepatitis B virus, HIV, the salmonellae, and Toxoplasma
spp. and recent H1N1 influenza virus, are representative of
microorganisms assigned to this containment level. For
those performing rapid immunoassay tests for influenza,
splash protection is required. For those performing more
complex procedures (e.g., direct or indirect fluorescent
antibody tests [DFA, IFA], culture, molecular assays), a
Class II biosafety cabinet (BSC) in a biosafety level-2
(BSL-2) laboratory is required. .Biosafety level-3 (BSL-3)
practices are no longer required for H1N1 viral isolation5
Biosafety Level 2 is appropriate when work is done with
any human-derived blood, body fluids, tissues, or primary
human cell lines where the presence of an infectious agent
may be unknown. (Laboratory personnel working with
human-derived materials should refer to the OSHA Blood
borne Pathogen Standard 6 for specific required
precautions.)
design and construction are applicable for work with
dangerous and exotic agents that pose a high individual risk
of life-threatening disease, which may be transmitted via
the aerosol route and for which there is no available
vaccine or therapy. Viruses such as Marburg or CongoCrimean hemorrhagic fever are manipulated at Biosafety
Level 4. The laboratory worker's complete isolation from
aerosolized infectious materials is accomplished primarily
by working in a Class III BSC or in a full-body, air-supplied
positive-pressure personnel suit. The Biosafety Level 4
facility itself is generally a separate building or completely
isolated zone with complex, specialized ventilation
requirements and waste management systems to prevent
release of viable agents to the environment. Except in
extraordinary circumstances (e.g., suspected hemorrhagic
fever), the initial processing of clinical specimens and
serological identification of isolates can be done safely at
Biosafety Level 2, the recommended level for work with
blood borne pathogens such as hepatitis B virus and HIV.
The containment elements described in Biosafety Level 2
are consistent with the OSHA standard, "Occupational
Exposure to Blood borne Pathogens" 7, 8 from the
Occupational Safety and Health Administration. This
requires the use of specific precautions with all clinical
specimens of blood or other potentially infectious material
(Universal or Standard Precautions).9 Additionally, other
recommendations specific for clinical laboratories may be
obtained from the National Committee for Clinical
10
Laboratory Standards.
Biosafety Level 2 focuses on the prevention of
percutaneous and mucous membrane exposures to clinical
material. Primary barriers such as biological safety
33
cabinets (Class I or II) should be used when performing
procedures that might cause splashing, spraying, or
splattering of droplets. Biological safety cabinets also
should be used for the initial processing of clinical
specimens when the nature of the test requested or other
information suggests the likely presence of an agent readily
transmissible by infectious aerosols
I. General Bio-Safety Guidelines For Laboratory
Workers
1) Access to laboratory should be limited at the discretion
of laboratory- in charge when experiments are in
progress. The door should have a symbol of
'BIOHAZARD - NO ADMITANCE'. Laboratories
should be well ventilated so as to ensure that the
personnel do not breathe in contaminated air.
2) Eating, drinking, smoking and application of
cosmetics are prohibited in the laboratory Sandals and
open style shoes do not afford proper foot protection
and are not to be used. Contact lenses especially the
soft ones should not be worn.
3) Laboratory and work tables should be scrupulously
cleaned with liquid detergents and disinfectants.
Laboratory work surface should be decontaminated
once a day after completion of day's activity and
immediately after spill of viable material with
disinfectant.
.4) Biological safety cabinets and other primary
containment devices e.g. centrifuge safety caps should
be used whenever handing hazardous specimens and
when it is likely to produce aerosols or infectious
droplets.
5) Blood and other specimen containers should be
labeled with a warning sign. The outside of the
specimen container should be cleaned with sodium
hypochlorite solution in case of visible contamination.
6) Gloves should be worn while dealing with blood
specimens, blood-soiled items, body fluids,
excretions, secretions, surface materials and objects
exposed to them.
7) Gowns/laboratory coats must be worn while working
with potentially infective materials and removed
before leaving the laboratory.
8) Hands should be washed immediately after contact
with blood and before leaving the laboratory.
9) Mechanical pipetting devices should be used. Mouth
should be followed to minimize the creation of aerosols.
10) Accidental wounds from sharp instruments should be
avoided. Extreme caution is warranted when handing
needles and sharps to avoid auto inoculation. Needles
should be promptly placed in a puncture resistant
container immediately after decontamination.
11) Paper work should not be done on potentially
contaminated surface.
12) All potentially contaminated materials and wastes
from the laboratory should be disposed after
decontamination preferably by autoclaving. A label
with a globally accepted biological hazard sign should
be applied.
13) Effective use of sterilization and disinfection.
II. Effective Use of Sterilization and Disinfection:
Disinfection is a process which reduces the number of
pathogenic microorganisms, but not necessarily bacterial
spores from inanimate objects or skin, to a level which is
not harmful to health. Sterilization is a process which
destroys all micro-organisms including bacterial spores.
The level of decontamination should be such that there is
not risk for infection when using the equipment.
Classification of infection risk from equipment or
environment into three categories and suggested levels of
decontamination.
Low Risk: Items in contact with normal and intact skin, or
the inanimate environment not in contact with the patient
(e.g. walls, floors, ceilings, furniture, sinks and drains).
Cleaning and drying is usually adequate except when there
is spill of blood/body fluids.
Intermediate Risk: Equipment which does not penetrate
the skin or enter sterile areas of the body but is in contact
with mucous membranes or non-intact skin, or other items
contaminated with virulent or transmissible organisms
(e.g. respiratory equipment gastro-intestinal endoscopes,
vaginal instruments, thermometers). High level
disinfection is usually adequate.
High Risk: Items penetrating sterile tissues, including
body cavities and the vascular system (e.g. surgical
instruments, intra-uterine devices, vascular catheters,
syringes and needles etc.) Decontamination followed by
cleaning and sterilization is required. High level
disinfection may sometimes be appropriate if sterilization
is not possible.
34
Environmental Cleaning: Floors, surfaces, sinks and
drains should be cleaned with warm water and detergent
Routine use of disinfectants is unnecessary. If there is
spillage of blood, body fluids or sputum, disinfection
before cleaning is recommended in high risk areas or
following spillage from a known infected patient the
surface is cleaned using freshly prepared 0.5 - 1% sodium
hypo chlorite solution 11 Gloves should be worn. Release of
chlorine gas from disinfection of large spillage can be
hazardous to staff. If spillage is immediately removed
general disinfection of the room is not necessary though
cleaning will suffice.
Disinfection: Most of the disinfectants used in health care
settings in this country, if used in proper concentration and
for suitable period of time are effective against HIV. Either
thermal or chemical processes are used for disinfection.
Thermal disinfection is preferred whenever possible12. It is
generally more reliable, leaves no residue, is more easily
controlled and is non-toxic. Organic matter (serum, blood
pus or faecal matter) interferes with the antimicrobial
efficiency of either method. The larger the number of
microbes present the longer it takes to disinfect. Boiling
(100oC) for 20-30 minutes (holding time) is a very simple
and reliable method for the inactivation of all microorganisms including hepatitis B, HIV and mycobacterium.
Carefully done, it is a high-level disinfection procedure
.The main use of chemical disinfectants is for heat labile
equipments where single use is not cost effective.
III. Safe Disposal of Laboratory Wastes :
Laboratory wastes are potential hazards. Infectious waste
can transmit numerous diseases in the community and put
those who handle waste and live on its proximity, at risk.
Besides, the increasing use of disposables in health care is
also posing an additional burden on the waste management
facility. It is extremely important that the recycling of these
items is prevented. Only a small percentage (<10%) of the
waste generated in health care settings are infectious while
another 5% is non-infectious but hazardous. The most
practical approach to the management of biomedical waste
is to identify and segregate infectious waste, for which
some special precautions appear prudent. This will
drastically reduce the cost of the disposal methods in health
care settings.
Setting up of Biomedical Waste Facility.
Every hospital, nursing home, veterinary institution ,
animal-house, blood banks, research institutes generating
35
biomedical wastes should install an appropriate
biomedical waste facility in the premises or should set up a
common facility in accordance with the directions given by
the appropriate authority. Every hospital should have a
waste management programme. It helps in determining
both the type and quantity of waste being generated in the
hospital including the laboratory and determines the
feasible methods of disposal.
Containing Waste at Generation Point
At the generation point i.e. the laboratory waste is managed
in the following was
F Collection
F Segregation and weighing
F Storage
Waste segregation is the key to any waste management
scheme. It consists of placing different types of waste in
different containers or colour-coded bags at the site of
generation. This helps in reducing the bulk of infectious
waste and contains spread of infection to general waste.
Proper segregation should identify waste according to
source and type of disposal / disinfection. Waste should be
segregated into different categories at the site of generation
i.e. in the laboratory and weighed separately at the time the
waste is being disposed. Solid Non infectious waste is
collected in black bags and disposed as household waste.
Infectious waste must be separated at the point of
generation itself and should be decontaminated prior to its
storage, transport and disposal. Solid infectious waste is
disposed as follows:
Sharps
a) Needles and syringe nozzle-shredded in needledestroyer (if available): if not available
decontaminated as in b)
b) Scalpel blades / lancets / broken glass-should be put in
separate container with bleach, transferred to
plastic/cardboard boxes, sealed to prevent spillage and
transported to incinerator.
Glass wares should be disinfected, cleaned and sterilized.
Culture plates with viable culture should be autoclaved in
plastic autoclave bags, media are removed and collected in
yellow bags and disposed of by incineration/ microwaving/hot air oven. The plates can be reused after
sterilization. Swabs should be chemically disinfected
followed by incineration. Disposable items include single
are often recycled and have the risk of being reused
illegally, these should be disinfected by dipping in freshly
prepared 1% Sodium hypochlorite for 30 minutes to 1 hour.
Bins which can be used for this purpose are a set of twin
bins, one inside the otherwise the inner one being
perforated and easily extractable. This minimizes contact
when the contents are being removed.
Disposable items like to gloves, syringes etc. should be
shredded cut or mutilated before disposal followed by deep
burial or properly accounted before disposal. Extreme care
should be taken while handing the needles.
Packing, Storage and Transport
All segregated and disinfected waste should be packed in
proper containers and color-coded bags (Table1), with red
labels mentioning details of biomedical waste and
biohazard signs. All containers used for storage of such
waste shall be provided with a properly covered lid.
Such containers should be inaccessible to scavengers and
protected against insects, birds, animals and rain.
There should not be any spillage during handing and transit
of such waste. The waste sharps, after pre-treatment should
be broken before packing in the container. The waste
should-be transported in vehicles authorized for this
purpose only. No such waste should be stored in the place
where it is generated for a period of more than two days.
Treatment and Disposal
Disposal methods: Disposal may be done by Municipal
Corporation and or Sanitary landfill.
If incinerator is not available, deep burial in controlled
landfill sites is recommended. Decontamination should be
carried out before burial.
Incineration (Temprature = 750oC): Incinerator burns /
reduces the infectious waste to ashes and therefore
favoured by hospitals. It may be of two types-common or
individual. There are some disadvantages like
pollution/incomplete melting of needle. Hospitals with
more than 30 beds or 1000 patients per month should have
an incinerator. Plastics cannot be incinerated.
36
Guidelines for Waste Disposal 13
All biomedical wastes should be treated and disposed of strictly
in accordance with the options mentioned in the Table 1.
Waste which cannot be incinerated, (plastics) should be
pretreated by disinfectant and disposed of in an environmentally
sound manner. Waste should not be dumped discharged or
disposed in any place other than a site identified for the purpose.
All precautions and personal safety measures should be taken
(including provision of protective clothing, masks, gloves,
gumboots, goggles, etc. as may be necessary). Hepatitis B
vaccine is recommended for affording protection to all personnel
engaged in handling biomedical waste, or being exposed to such
wastes against infection from handing or exposure.
References
1. Assessment of laboratory and biosafety practices associated
with bacterial culture in veterinary clinics J. Scott Weese,
DVM, DVSc, DACVIM; John F. Prescott, VetMB, PhD.
Journal of the American Veterinary Medical Association. 1,
2009,234, No. 3,352-358. 10.2460/javma.234.3.352
2. CDC update: Universal precautions for preventing
transmission of human immunodeficiency virus, hepatitis B
virus and other blood borne pathogens in health care
settings. MMWR 1988; 377-388.
3. Centers for Disease Control and Prevention. Primary
containment for biohazards: selection, installation and use
of biological safety cabinets. Washington, DC: U.S.
Government Printing Office, 2000.
All treatment and disposal facilities should be located at
specified area away from the general service area of the hospital,
public places and residential areas. When the treatment option is
burial, the pits should be located at sites away from agricultural
land, residential areas, ground-and sale water sources. There
should be no leakage from the pits in to surrounding areas. All
plastics should be disinfected, shredded and disposed o in an
environmentally friendly manner. Recycling of disposables e.g.
syringes, needles, gloves, transfusion bags etc. should be
prevented. All liquid waste should be disinfected and flushed in
the sinks at the point of generation.
5. Interim Biosafety Guidance for All Individuals handling
Clinical Specimens or Isolates containing 2009-H1N1
Influenza A Virus (Novel H1N1), including Vaccine Strains.
www.cdc.gov/h1n1flu/specimencollection.htmn
Biomedical waste should not be disposed of on open land and
municipal dustbins. Untreated liquid waste should not be let into
sewers.
7. U.S. Department of Labor, Occupational Safety and Health
Administration. 1991. (2)
Maintenance of Records.
Separate records for classification of waste and their regular
disposal should be maintained in the laboratory. The waste
disposal programme should be supervised and monitored
regularly.
IV. Implementation of Bio-Safety Practices in Lab
Although guidelines regarding universal precautions and other
bio-safety practices are available since long, strict
implementation is not in practice in healthcare settings in India
even in the capital city. With increase in the prevalence of HIV
infection, there is a definite need that the health care workers
take bio-safety practices seriously. For effective compliance, the
laboratory managers should ensure adequate supply of personal
protective equipments, availability of materials for hand
washing, disinfectants and set up an effective waste disposal
programme for disposal of biomedical wastes. Training
regarding need of and national guidelines of bio-safety practices
is extremely important and should be provided at regular
intervals for different levels of health care workers. Guidelines
for bio-safety should be provided which may be modified from
time to time according to requirement
4. Kruse, R.H., Puckett, W.H., and Richardson, J.H. Biological
safety cabinetry. Clin Microbiol Rev 1991; 4:207-41.
6. U.S. Department of Labor, Occupational Safety and Health
Administration. 1991. Occupational Exposure to Blood
borne Pathogens, Final Rule. Fed. Register 56:6417564182.
8. Richmond, J.Y. 1994. "HIV Biosafety: Guidelines and
Regulations." In (G. Schochetman, J. R. George, Eds.),
AIDS Testing, Edition 2 (pp. 346-360). Springer-Verlag
New York, Inc.
9. Centers for Disease Control. 1988. Update: Universal
Precautions for Prevention of Transmission of Human
Immunodeficiency Virus, Hepatitis B Virus and Other
Blood borne Pathogens in Healthcare Settings. MMWR,
37:377-382, 387, 388.
10. National Committee for Clinical Laboratory Standards
(NCCLS). 1997. Protection of laboratory workers from
instrument biohazards and infectious disease transmitted by
blood, body fluids, and tissue. Approved guideline. 1977,
NCCLS Doc. M29-A (ISBN1-56238-339-6.
11. WHO Biosafety manual 2nd edition, 1993 World health
organization.
12. Interim Biosafety Guidance for All Individuals handling
Clinical Specimens or Isolates containing 2009-H1N1
Influenza A Virus (Novel H1N1), including Vaccine Strains
CDC 2009. www.cdc.gov/h1n1flu/guidelines_labworkers
13. WHO managing Medical Waste in developing countries.
1994 World health organization, Geneva.
37
Pharmacovigilance of Homeopathy Questioning its Efficacy
ORIGINAL ARTICLE
DINESH K. JAIN, RAJ K. ARYA
Department of Pharmacology, G.R. Medical College, Gwalior -474001
ABSTRACT
Creation of knowledge is a continuous process in the history of mankind. In primitive period treatment was associated with
appeasing the sprits. The idea of a God or Gods was later conceived to intervene and protect him from the evil spirits. Before the
advent of science based approaches, repeated attempts were made to construct systems of therapeutics. One of these was
allopathy. The favoured remedies include blood letting, emetics and purgative which was responsible for death of many patients.
Hahnemann introduced the practice of Homeopathy in the early 19th century in reaction against allopathy. After review of all
Homeopathic principles on the basis of present medical knowledge, it has been found that they are illogical, irrational and not in
accordance with the knowledge of available criteria's of scientific therapeutic system. Government of India is ready to prohibit
use of such drugs which are therapeutically ineffective, then it is the duty of pharmacologists to inform to government about
ineffectiveness of Homeopathic drugs.
(Key Words: Hahnemann, Homeopathy, Adverse Effects, Therapeutically Ineffective, Drugs And Cosmetics Act.)
Creation of Knowledge is a Continuous Process
the context of present knowledge. If we follow the concepts
that developed knowledge opposes, it is quite irrational.
"Medicineman, primitive healers, has no connection with the
knowledge of medicine, pharmacy, or even surgery. It is
associated with appeasing the spirits. When the medicineman
amputates a finger, trephines a skull, cauterizes a scalp, cuts
the prepuce from a male child, sucks the blood or pus from a
wound, or opens a vein for blood letting, he does so without
any intention of counteracting a pathological condition on a
rational basis. His purpose is to permit the egress of an evil
spirit from the body, and for this purpose alone he employs a
surgical procedure. The idea that disease is a punitive
measure dispensed by the gods for violation of religious
principles was a later conception. Man's concept of spirits
antedated his belief in benevolent deities or gods. The idea of
a God or Gods was later conceived to intervene and protect
him from the evil spirits."1
"The great Greek physician Hippocrates (460-377 BC) has
been called the father of modern medicine. He denied the
intervention of deities and demons in the development of
disease."3
Before Hippocrates it was presumed that all diseases are
due to supernatural influences. It was Hippocrates who first
of all opposed supernatural influences in the development
of diseases. He presented revolutionary concept which
made him father of modern medical science.
"Before the advent of science based approaches, repeated
attempts were made to construct systems of therapeutics
many of which produced even worse results than pure
empiricism. One of these was allopathy, espoused by
James Gregory (1735-1821). The favoured remedies
include blood letting, emetics and purgatives, which were
used until the dominant symptoms of the disease were
suppressed. Many patients died from such treatment and it
was in reaction against it that Hahnemann introduced the
practice of Homeopathy in the early 19th Century."4
"Superstition and development of knowledge are two
contradictory concepts in a society. The concepts and beliefs
that are prevalent in society, if genuine, based on logic and
reason, need no reformation and thus would continue to be
practiced. But this does not hold true. On the basis of
evolved knowledge, change in the society is a normal
practice of healthy community"2
Present Status of Homeopathy
Creation of knowledge is a continuous process. The history
of knowledge is closely associated with the history of human
being. Beliefs, traditions and concepts of our forefathers
should be changed if they are found unsuitable in
Samuel Hahnemann of Germany (1755-1843) developed a
new system of therapeutics - Homeopathy. It entered India
during 1810-1839 and now it has become a part of Indian
culture.
38
Jain D: Pharmacovigilance of Homeopathy - Questioning its Efficacy
India has the highest number of Homeopaths.
"Homeopathy reached its peak of popularity in the early
nineteenth century. Today there is a resurgence of the
popularity of this old medical practice. There are about
3000 recognized practitioners in the U.S. who practice
Homeopathy. In the US there are at least five schools and
training centers for Homeopathy. In France, 16 percent of
the population uses Homeopathic drug products on a
regular basis. In England, 45 percent of conventional
physicians refer patients to Homeopathic practitioners. In
Russia, at least 20 percent of the medical care is
Homeopathic. Homeopathy has a strong following in
Belgium, Germany, Netherlands, Italy and South America.
Homeopathy traditionally has had a strong following in
poorer countries. India has 100,000 prescribers of
Homeopathic medicine."5 This indicates Homeopathy is
becoming popular throughout the world.
What is Homeopathy ?
"The guiding principles of Homeopathy are like cures like
and activity can be enhanced by dilution."6 "Like cures
like" means symptoms of disease can be reproduced in a
healthy body by a drug then this drug is effective in that
disease. Similar symptoms in the remedy remove similar
symptoms in the disease.
The second important principle of Homeopathy is "dilution
potentiates the potency." According to Hahnemann, effect
of drugs is potentiated by dilution even to the extent that an
effective dose may not contain a single molecule of drug.
Hahnemann recommended 30th potency dilution in which
one molecule of drug would be in a volume of a sphere of
literally astronomical circumference.
Other important principles of Homeopathy are"7,8,9,10 (1)
Knowledge regarding etiology, pathology and nature of
disease is not important. (2) Name and diagnosis of disease
are not necessary. (3) Removal of symptoms means total
cure, no symptoms indicate no disease. (4) Bacteria or other
microbial agents, and any other external factors are not
responsible for development of disease. According to
Homeopathy, dirty food and dirty water cannot be held
responsible for any disease. (5) Hahnemann rejected the
examination of blood, urine and other investigations for
diagnosis and treatment of diseases. (6) If symptoms of
disease are changed then drug should be changed (7)
Medicines can show nothing curative besides their
tendency for produce morbid symptoms in healthy persons.
(8) Jealousy, lack of love, disturbed piece, selfishness,
unfairness, unjustified attitude, non religious thought are
the causative factors in the development of psora which is
the basis of all diseases. (9) Homeopathy opposes external
application of lotion and ointment in skin diseases (10) It
opposes injections & vaccinations. (11) To know study of
effectiveness of a drug, it should not be given to patients.
(12) Homeopathy condemns the principle of removal of
external manifestations of disease by an external means
whatsoever (13) Parts of body or organs from the body can
be removed and yet man will exist. (14) This pathy says
"God warned that he should be followed otherwise men will
suffer from tuberculosis and fever". (15) When the
treatment of infant is concerned, Hahmenn advised drug
administration to the nursing mother.
Pharmacovigilance & Duty of Pharmacologist
"World Health Organization defines pharmacovigilance is
the science & activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other
possible drug related problems. Recently its concerns have
been widened to include herbals, traditional &
complementary medicines, blood products, biological
medical devices & vaccines (W.H.O. 2002). Appreciating
the importance and benefits of pharmacovigilance, Central
Drugs Standards Control Organization (CDSCO), Ministry
of Health and Family Welfare, Govt. of India launched the
National Pharmacovigilance Programme (NPP) in
November 2004"11
Safety and efficacy are two major concerns about any drug.
Pharmacokinetic, pharmacodynamic and efficacy study of
drugs of modern medical science are possible because drugs
of modern medical science are known single chemical
molecules. Whereas these studies of substances of
alternative and complementary medicines are not possible
because effective single chemical molecules are not known.
Unfortunately, when this term pharmacovigilance is
mentioned, there is still a confusion on this topic.
Pharmacologists and other medical specialists think that
pharmacovigilance is concerned only with side effects,
untoward effects and toxic effects. It is absolutely wrong.
Efficacy should be the first step of pharmacovigilance.
When alternative and complementary medicines are
included in pharmacovigilance, evaluation of efficacy
should be the first concern because efficacy of these
systems are doubtful. It is rightly mentioned in the most
standard text book of medicine "Complementary and
alternative medical (CAM) practices include Acupuncture,
Ayurvedic Medicine, Dance Therapy, Massage, Meditation,
Naturopathy, Siddha Medicine, Unani
39
Medicine, Yoga, Homeopathy etc. None the less, over the
past few decades thousands of studies have been performed
of various CAM approaches including hundreds of trials
involving herbal, Acupuncture, or Homeopathy. To date
however, no single approach has been proven effective in
convincing way. (If they had, the practice would no longer
be considered CAM. Several factors contribute to the lack
of convincing evidence. The vast majority of CAM studies
have been seriously flawed by lack of appropriate controls,
bias on the part of the investigators, small sample sizes,
reliance on highly subjective and non-validated measures of
benefit, and by in appropriate statistical tests."12
Actually efficacy is included in adverse reactions but
pharmacologists are ignoring this fact. Analysis of efficacy
of drugs is a part of study of adverse reaction. "An adverse
drug reaction is defined as any response to a drug that is
noxious and unintended and that occurs at doses used in
man for the prophylaxis, diagnosis or therapy of disease or
for modification of physiological function (WHO)"13
Unintended action of drug means that action of drug which
is not planned or not intended to happen. If a drug has no
therapeutic effect then therapeutic dose can not be
determined and such action will be unintended. Therefore
absence of efficacy is also a type of adverse reaction of drug.
A substance is being given to a patient for treatment and if
this substance has no therapeutic effect then absence of
such effect becomes part of adverse reaction because
absence of therapeutic effect is harmful to patient and such
absence is unintended action of drug.
Study of efficacy is a part of study of adverse reaction as
described in this definition. "Adverse drug reaction or an
adverse reaction means a response to a medicine in the
humans or animals, which is noxious and unintended,
including lack of efficacy, and which occurs at any dosage
and can also result from an overdose, misuse or abuse of a
medicine."14
Therefore it is the duty of pharmacologists to study and
discuss efficacy of substances used in alternative and
complementary systems of medicine first. Pharmacologists
are talking of side effects and toxic effects of substances of
CAM without discussing efficacy. "Review articles of
pharmacovigilance of ayurvedic and unani medicines are
being publishing in journals without raising questions on
efficacy of these systems.15.16 It is giving wrong massage to
medical scientists, society and government that substances
of CAM are therapeutically effective.
Analysis of Homeopathic Principles
Drug is a substance used in the prevention, diagnosis,
treatment or cure of disease in man or animal. Criteria of a
drug in all type of therapeutic systems should be the same.
Estimation of therapeutic utility of drugs in modern
medical science or in alternative and complementary
systems of medicine is based on common principles of
medical science. Modern medical science is based on
logical, controlled clinical trials, accurate experimentation
with full knowledge of pathogenesis of disease and
pharmacokinetic and pharmacodynamic study of drugs.
Samuel Hahnemann (1755-1843), a German physician,
formulated Homeopathy's basic principles in the late
eighteenth century. In those days modern scientific
medicine was in infancy, that's why Hahnemann had
limitations due to lack of medical knowledge at that time.
Today we have vast and developed medical knowledge.
Hahnemann's principles of Homeopathy can be analysed
on its basis. "Hahnemann had two erroneous principles.
Firstly, that like cures like; and secondly that the actions of
drugs are potentiated by dilution. "Hahnemann's first
principle was a sweeping generalization based on the fact
that a large dose of cinchona bark induced in him a malarial
paroxysm; the reason for this occurrence being that he had
previously suffered from malaria and the gastric irritation
excited the paroxysm."17
The main constituent of cinchona bark is quinine. "Oral
administration of quinine often results in nausea, vomiting
and epigastric pain."18 Relapse of malaria may occur by
acute gastrointestinal problem or any intercurrent malady.
Hahnemann had taken cinchona after symptomatic cure of
malaria. Gastrointestinal problem created by cinchona
could be responsible for recurrence of malarial paroxysm.
If first principle of Homeopathy is true then quinine should
produce rigors in healthy body but "the effect of quinine on
normal body temperature is negligible."19 It shows first
principle of Hahnemann was wrong.
"His second principle was based on the fact that trituration
of mercury increased its pharmacological actions. This
effect was due to oxidation of the mercury first to
mercurous and, later, to mercuric oxide."20 Hahnemann
wrongly thought that potentiated effect was due to dilute
mercury. He did not understand that after trituration &
dilution mercury modified in to other compounds. Actually
"elemental mercury can not react with biologically
40
important molecules."21 "Cases are recorded where
individuals have swallowed a pound or two of the liquid
metal (perfectly pure) without any harmful effect."22 Now it
is clear that it was not dilution and trituration which
increased potency of mercury. It was actually conversion
of mercury in to mercuric oxide which was responsible for
increased potency. "For therapeutic effect, plasma
concentration of lithium in mania should range from .9 to
1.4 mEq/L. Concentration higher than 1.5 mEq/L is
associated with an increased incidence of side effects,
while those about 2 mEq/AL may result in serious
toxicity."23 Increased concentration of lithium causes more
potent effect on body which also proves that second
principle of Homeopathy, dilution increases potency was
wrong. "After review of all Homeopathic principles on the
basis of present medical knowledge, it has been found that
they are illogical, irrational and not in accordance with the
knowledge of available criterias of scientific therapeutic
system."24 This fact can be understood very easily when we
analyse principles of Homeopathy.
Opinion of Standard Medical Text
Books & Journals
"Hahnemann's system of Homeopathy rapidly drifted in to
absurdities. From 1829 onward he recommended the
administration of all drugs at the thirtieth potency which
corresponds to a concentration of 1 pat in 1060 parts".25 "The
claims of Homeopathy are, however difficult to understand
in the light of present concept of diseases, nor can they be
substantiated by various scientific methods applied to the
study of modern medicine."26
"Pharmacologists generally feel that in the absence of
conclusive evidence from empirical studies that
Homeopathic medicines can reproducibly be shown to
differ from placebo in clinical studies conducted according
to modern scientific standards, there is no point in
discussing the hypotheses of Homeopathy."27
"Homeopathy so far as it follows the principles of its
founder, has no place for medical sciences such as
chemistry, anatomy, physiology, pathology. Attempts have
been made by many scientists to interpret such result in
terms of modern science of physiology but they have not
been convincing. The patients of Homeopath died of the
28
disease"
29
"Medical Journal Lancet declares that Homeopathic drug
are not better than a placebo. Swiss scientists compared the
result of more than 100 trials of Homeopathic medicines
with the same number of trials of conventional medicines
in a range of conditions. They found that Homeopathy had
no more than placebo effect. An editorial written in the
Lancet titled "The end of Homeopathy" demands that
doctors recognize the absence of real curative powers in
Homeopathic medicine. The editorial also says. "It is more
surprising that the debate continue after 150 years of
unfavorable finding."
"World Health Organization (WHO) said that do not
depend on Homeopathy for the treatment of HIV, TB and
malaria. Research scholars of young science network from
U.K. and Africa wrote to WHO to prevent Homeopathic
treatment in TB, diarrhea, influenza, malaria, HIV. They
also said, there is no evidence that Homeopathy is effective
in these ailments and when Homeopathy is used in place of
modern medical science, for these diseases, death is
certain. They also said that world should understand
danger of Homeopathic treatment."30
Conclusion
Rules of Homeopathy and the concepts of modern medical
science are contradictory to each other. Either modern
medical science is correct or Homeopathy is accurate. Both
Homeopathy and modern medical science can not be
correct. Either modern medical science should be banned
or Homeopathy should be discarded. If we are saying that
both are correct, this indicates our inefficiency and in
capabilities to reach a definite conclusion. If we are
accepting contradictions in the field of knowledge then it is
the crime against humanity and science.
Actually Hahnemann concluded wrong conclusions on the
basis of wrong analysis due to lack of knowledge. There
were no knowledge of human physiology, pathology,
pathogenesis of diseases, investigations, biochemistry,
pharmaceutical chemistry, genetics, physics, clinical trials,
diagnosis of diseases at the time of Hahnemann, that's why
he had limitations. He formulated unscientific and illogical
hypothesis which can be proved wrong today.
Homeopathic drugs do not have any effect on human body,
neither therapeutic effect nor any side effect because it is
used in such dilutions which contain no any drug molecule.
The main drawback of Homeopathy is that it interferes
application of modern medical science which makes
curable disease incurable and fatal.
41
These are the facts which I am putting in front of the
scientific fraternity to take further action regarding
applicability of Homeopathy. Govt. is ready to ban all
drugs which have no therapeutic utility. Then it is our duty
to take appropriate steps to peruse Government of India to
prohibit use of Homeopathic drugs which have no
therapeutic utility.
"According to drug and cosmetics act 1940, section26A, if
the Central Government is satisfied that any drug does not
have the therapeutic value claimed or purported to be
claimed for it, then, that Government may, by notification
in the official Gazatte, prohibit the manufacture, sale or
distribution of such drug or cosmetic."31
References
1. Gordon BL.Medicine throughout antiquity.
Philadelphia : F.A. Davis Company; 1949: 110-111.
2. Jain D.K. :Homeopathy an Illusion Delhi : Peacock
Books; 2009, p. IX,X
3. Coleman J. Abnormal Psychology and modern life.
Bombay : Taraporewala and Sons; 1976, 27.
4. Rang HP, Dale MM, Ritter JM, Moore PK.
Pharmacology. Sthed. New York : Churchil
Livingstone; 2003, 3.
5. Jain D.K. Homeopathy an Illusion Delhi : Peacock
Books; 2009, p. IX,X.
6. Rang HP, Dale MM, Ritter JM, Moore PK.
Pharmacology. Sthed. New York : Churchil
Livingstone; 2003, 3.
7. Hahnemann S. Organon of medicine (English). 6th ed.
New Delhi : B Jain Publishers (P) Ltd., 1993.
8. Hahnemann S. Organon of medicine (Hindi). New
Delhi : B. Jain Publishers (P) Ltd.; 1996.
9. Kent JT. Lectures on Homeopathic Philosophy. New
Delhi : B Jain Publishers (P) Ltd.; 1993.
11. Adithan C. National Pharmacovigilance programme.
Indian J. Pharmacol 2005; 37: 347.
12. Strauss SE. Complementary and alternative Medicine.
In : Kasper LD, Braun Wald E, Fauci SA, Hauser SL,
Longo DL, Jameson JL, editors. Harrison's principles
of internal medicine. 16th ed. New York : McGraw Hill;
2005; Vol. 1, 66-69.
13. Satoskar RS, Bhandarkar SD, Ainapure SS.
Pharmacology & Pharmacotherapeutic. 18th ed.
Mumbai : Popular Prakashan; 2003, 36.
14. Yadav S. Status of adverse drug reaction monitoring
and pharmacovigilance in selected countries. Indian J.
Pharmacol. 2008; 40: Supplement: 54.
15. Thatte V, Bhalerao S.
Pharmacovigilance of
ayurvedic medicines in India. Indian J. Pharmacol.
2008; 40: Supplement. : 510.
16. Rahman SZ, Khan RA, Latif A. Importance of
Pharmacovigilance in Unani system of medicine.
Indian J. Pharmacol 2008; 40: Supplement : 517.
17. Satoskar RS, Bhandarkar SD, Ainapure SS.
Pharmacology & Pharmacotherapeutic. 18th ed.
Mumbai : Popular Prakashan; 2003, p. 655.
18. Krantz CJ, Carr CJ. The pharmacological principles of
medical practice. 6th ed. Baltimore : Williams and
Wilkins; 1965: 158.
19. Modell W, Schield H, Wilson A. Applied
pharmacology. American editon. Toronto : W.B.
Saunders Company; 1976, 9.
20. Klaassen CD. Heavy metals and heavy metal
antagonists. In Gilman AG, Goodman L, Gilman A,
editors. Goodman & Gilman's pharmacological basis
of therapeutics. 6th ed. Newyork : Macmillan; 1980;
1623.
21. Modi NJ. Textbook of medical jursiprudence and
toxicology. 9th ed. Bombay : N.M. Tripathi
Publishers; 1975 : 551.
22. Colasanti BK. Antidepressant therapy. In Craig C,
Stitzel R, editors. Modern pharmacology. 2nd ed. USA
: Little Brown; 1986, 544.
23. Jain DK. Homeopathy an illusion, Delhi : Peacock
Books; 2009.
24. Laurence DR, Bennett PN, Brown MJ. Clinical
pharmacology. 8th ed. New York : Churchill
Livingstone; 1997: 13-14.
25. Paranjpe AS. A history of pharmacology. Poona :
Maharastra Medical Journal; 1962; 679-681.
26. Boseley S. Some questions about Homeopathy. The
Hindu. Delhi, 27.8.05, p. 20.
27. Raj Express Gwalior 25.8.2009.
28. The Drugs and Cosmetic Act 1940, Govt. of India.
42
Risks and Recall of Medicines
Pharmacovigilance Perspective
REVIEW ARTICLE
ADITI NIGAM, ETHIRAJ DHANARAJ, PRAMIL TIWARI
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, SAS Nagar-16006
ABSTRACT
Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. Rare ADRs can easily go undetected in clinical
trials and thereby pose a major threat to the patient population. Pharmacovigilance assumes a potentially important role in
identifying ADRs, leading to generation of drug alerts. When the risks outweigh the benefits, the medicine in question is recalled
from the market. Delay in withdrawal may occur due to inability to establish cause and effect relationship between the drug and the
ADR. This may be attributed to confounding by indication (Rosigltazone) and also drug versus class effect (COX-II inhibitors).
The removal of a medicine from the market upon establishment of safety risks looks plausible enough, but requires careful thought
over the huge magnitude of patients already exposed to its harms. The safety based medicine recalls do not follow a uniform
pattern all over the world. This can be partly attributed to the heterogeneity of treatment effects in which a few segments of the
population are more susceptible to adverse effects due to genetic predisposition or metabolic factors. The safety profile noted in
Introduction
drug behavior in more diverse populations. As soon as it is
established that risks outweigh the benefit, the concerned
medicines are removed from the market. That sounds
plausible enough but is a serious issue considering the
effects on the huge number of patients on the particular
medicine therapy prior to withdrawal. For example
Dexfenfluramine was withdrawn owing to
cardiopulmonary toxicity; the patients exposed in clinical
trial were 1200. However, the estimated patients exposed
prior to withdrawal were 23,000,000 [1]. Drug recalls may
occur as a consequence of risks reported with their use. The
following examples illustrate this: 1) Cerivastatin was first
approved by US-FDA as a lipid-lowering drug in June 1997
and withdrawn in August 2001. By the year 2000, a total of
549 cases of rhabdomyolysis associated with cerivastatin
use had been reported to WHO-Uppsala Monitoring
Centre. Consequently, a safety alert was issued regarding
an association between cerivastatin, myopathy and
rhabdomyolysis. In August 2001, the manufacturer
voluntarily withdrew cerivastatin from the market on the
grounds of an increased risk of rhabdomyolysis [2]. 2)
Nomifensine (an antidepressant) had been available in
Germany since 1976 and had been prescribed to an
estimated ten million patients prior to its marketing in the
U.S. in July, 1985. Initial labeling for the product reflected
a variety of long-recognized hypersensitivity reactions,
including fever, liver injury, hemolytic anemia and
eosinophilia, that were apparently all readily reversible. At
the time of marketing approval, US-FDA was aware of
Adverse drug reactions (ADRs) are a significant cause of
morbidity and mortality. Before a medicine is marketed,
the experience on its safety and efficacy is limited to its use
in clinical trials. The conditions under which patients were
studied during the clinical trials do not necessarily reflect
the way the medicines are used in the hospital or in general
practice. The information about rare but serious ADRs,
chronic toxicity, use in special groups (e.g. pregnant and
lactating women, children, elderly etc.,) and drug
interactions are often incomplete or not available initially.
No drug which is pharmacologically active is entirely
without hazard. The hazard may be insignificant or may be
acceptable in relation to the drugs therapeutic action.
Furthermore, not all hazards can be known before a drug is
marketed. Pharmacovigilance is, therefore, an important
post-marketing tool in ensuring the safety of medicines.
This review focuses on risks and safety based medicine
recalls.
Risks Involved in Using Medicines
The profiling of a new drug is incomplete at the time of
approval, especially with respect to its safety data. Safety
signals for drugs may arise at different stages of drug
development including clinical trials. Nevertheless, these
trials being relatively short, with small sample sizes
designed to prove efficacy rather than detect safety, and
studied in selected populations, often do not reflect the
43
Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective
US-FDA was aware of reports of less than twenty
hemolytic anemia cases, all non-fatal; however, in 1985,
when other country adverse reaction reports showed the
hemolytic anemia might be fatal, labeling was revised to
reflect the potential seriousness of the reaction. Due to an
increase in serious hemolytic anemia cases seen in Europe,
marketing of nomifensine was reconsidered by the
manufacturer, who announced a worldwide withdrawal of
the drug in January 1986 [3]. Some medicines continue to
remain in the market despite reported adverse effects. This
is understandable because: 1) they may be the only
available options for a few sets of the patients for example,
felbamate (anti-epileptic). 2) Drug remains on the market
until better options become available in terms of safety and
efficacy. For example, terfenadine (approved in 1985) was
found to cause cardiac arrhythmias but it continued to be on
the market till the arrival of the newer analogue
fexofenadine in 1997. 3) Drugs do not pose much of a
safety risk on their own but the same is magnified upon
combination with other drugs which may turn out to be
dangerous as in the case of mibefradil. 4) Improper use of a
drug may also lead to its withdrawal as in the case of the
bromfenac. 5) Withdrawal may also become the last option
to choose if all other risk management techniques fail as
was observed in the case of the heartburn treatment
cisapride. Its label was changed several times in 1998, but
the US-FDA found that the percentage of patients
inappropriately exposed to the drug was unchanged.
Delay in Withdrawal
Pergolide was approved in 1988 in US as an adjunctive
therapy with levodopa in Parkinson's disease, and finally
was withdrawn from the market in 2007 because of
valvular heart disease. It appears that there was a delay in
the recognition of the role of pergolide in producing
valvular heart disease. The first step in reporting a safety
issue is the diagnosis of medical event. This was not
accomplished easily in this case as cardiac monitoring
generally was not indicated with pergolide. Even when a
cardiac abnormality became clinically apparent, the
diagnosis of the specific abnormality was still difficult.
Finally, after the abnormality is diagnosed and to be
reported to the regulatory as a drug related adverse event,
the physicians must have a suspicion that the event was
secondary to exposure to a drug. In this case, the diagnosis
of the valvular heart disease and attribution to pergolide
were problematic. Pergolide (an antiparkinson drug) was
withdrawn in US and Canada but is still used in UK,
Europe and Singapore with safety alerts in place.
Confounding by Indication
Rosiglitazone, an antidiabetic agent, was approved in May
1999 in US but was found to cause or exacerbate
congestive heart failure in some patients. As diabetes
mellitus is a well known risk factor for cardiovascular
disease, and the patient received the drug for glycemic
control; so it is difficult to determine whether the ADR was
caused by rosiglitazone, or was an expected manifestation
of the patient's underlying disease. The question to be
answered in evaluating the reports is whether there is
something being experienced by the patients using the drug
that is out of line with what is expected, not only with the
drug, but with the underlying disease. To attribute an ADR
to a drug, establishing the causal relationship between the
drug and the symptoms experienced needs to be
established. US-FDA urging led to revised labels of the
influenza drugs, Tamiflu (Oseltamivir, Roche) and
Zanamivir (Relenza, GSK). Both Roche and GSK revised
the warnings and precautions section of Tamiflu and
Relenza labels to inform doctors of certain
“neuropsychiatric events” associated with the use of the
drugs “in patients with influenza”, that “in some cases
resulted in label outcomes” [4,5]. The safety alert issued by
US-FDA, as well as the revised labels, acknowledged that
the contribution of the drugs to the neuropsychiatric events
“has not been established”. The impetus for the requested
labeling changes was studies of patients in Japan who took
Ta m i f l u a n d r e p o r t e d e x p e r i e n c i n g c e r t a i n
neuropsychiatric events, such as delirium, delusions and
hallucinations. US-FDA regulators conceded, however,
delirium and other such neuropsychiatric events can be
complications of influenza itself.
Drug Effect versus Class Effect
Rofecoxib was approved in May 1999 in US as an antiinflammatory drug but withdrawn due to increased risk of
myocardial infarction or stroke. Another drug of the same
class Valdecoxib approved in November 2001 was
withdrawn due to risk of toxic epidermal necrolysis.
Interestingly, other drugs of the same class Etoricoxib and
Celecoxib continue to remain in the market. Statins is
another class of drugs which shows varied responses.
Cerivastatin approved in June 1997 as a lipid lowering drug
was withdrawn in August 2001 due to increased risk of
rhabdomyolysis. However, Simvastatin approved in
December 1991 and Atorvastatin approved in December
1996 continue to be widely used. It is difficult to determine
whether the events are directly related to the use of the drugs,
44
an underlying medical condition, or other risk factors, a
combination of these factors or other unexplored factors.
Safety Based Medicine Recall
Pattern between Countries
Drugs withdrawn from market in various countries on
account of safety are shown in Table 1. Comparing the drug
withdrawal and availability pattern between countries
shows drugs withdrawn in one country to be in use at other
places. For example, 1) Aprotinin (an antihaemorrhagic) is
withdrawn in UK and Europe, subject to restricted use in
USA, Canada, Australia and Singapore, and freely
available in India; 2) Tegaserod (indicated for irritable
bowel syndrome) is withdrawn in US but is available in
India; 3) Nefazodone (an antidepressant) is withdrawn in
Canada and Singapore, but is in use in Europe and USA
along with safety alert. The difference in medicine
withdrawal pattern among various countries can be partly
attributed to the heterogeneity of treatment effects and
differences in indication approval policies by the
regulatory agencies. For example Pappas et. al. studied 13
antimicrobial compounds approved by both the US-FDA
and EMEA and found significant differences in the
indications for most antimicrobial agents [14]. For
example, Linezolid has a US indication for vancomycin
resistant Enterococcus faecium infections, but no similar
indication in Europe and Micafungin is indicated for
pediatric use in Europe but not in the US. This may be due
to the altered performance of a medicine in relation to the
racial, genetic or other environmental factors in a
population. For example, patients who have no thiopurineS-methyltransferase (TPMT) activity, a normal dose of
mercaptopurine results in an accumulation of the active
compound, placing the patient at increased risk for the
myelosuppressive effects [15]. More recently, the
relationship of warfarin dose requirements with the
CYP450, 2C9 and VKORC1 gene polymorphisms have
led to a consideration in a labeling change by the US-FDA
[16]. There are differences among countries in the
occurrence of ADRs and other drug-related problems. This
may be due to differences in diseases and prescribing
practices, genetics, diet, traditions of the people, drugs
manufacturing processes used which influence
pharmaceutical quality and composition, drug distribution
and use including indications, dose and availability.
Drug Safety Reviews and Signal Generation
Pharmacovigilance networks have been developed by the
drug regulatory agencies to monitor any adverse drug
reactions. Labelling changes are made quicker in order to
respond to new or emerging safety information of an
approved drug. Examining the appearance of labelling
changes, black box warning and withdrawals is a
reasonable way to seek-out the most important new ADRs.
Signals can arise from post-marketing data and other
sources, such as preclinical data and events associated with
other products in the same pharmacologic class. At the time
of approval, clinical data are available on limited number
of patients treated for relatively short periods. Once a
product is marketed, large number of patients may be
exposed, including patients with co-morbid illnesses,
patients using concomitant medications, and patients with
chronic exposure. Such signals assist the development of
alerts by pooling the data. The country-wise current drug
safety reviews are shown in Table 2. Some selected
examples are discussed.
Tumor Necrosis Factor-Alfa Antagonists:
Serious Skin Reactions
Tumor Necrosis Factor-alfa (TNF-á) antagonists
infliximab (approved in 1998), etanercept (approved in
2000) and adalimumab (approved in 2002) are indicated
for rheumatoid arthritis. The reported ADRs are erythema
multiforme, Stevens Johnson syndrome and toxic
epidermal necrosis. Among the three drugs, Infliximab
accounted for a greater number of serious dermatological
reactions [19]. A total of 3821 ADRs to Infliximab were
reported to MHRA during the period July 1963 to August
2009, out of which, 491 were fatal ADRs [20].
Epoetin Alfa: Increased Risk of
Death in Cancer Patients
Erythropoiesis-stimulating agent (ESA) Epoetin alfa was
approved (1999) by US-FDA to treat anemia caused by
chemotherapy in cancer patients. The potential risks
identified were thromboembolic disease, promotion of
tumor growth and decreased survival in these patients. The
new labelling by US-FDA now stipulates that epoetin alfa
should not be used in patients receiving potentially
curative treatments and removed the indication for ESA in
breast cancer or head and neck cancer patient. ESA is
approved for use only after a patient's hemoglobin levels
fall below 10 g/dL. ESA labeling in the US contrasts starkly
with that in Europe where the European regulatory agency
recommends blood transfusions instead of ESA use
[21,22].
45
Conclusion
There is nothing as an absolutely 'safe' drug. Although the
benefits of a drug to a significant proportion of the intended
patients may be clear, a major crisis can arise when a few
dozen people out of perhaps hundreds of thousands
receiving the drug suffer or die as a result of taking it. Thus,
even when a drug is known to provide significant benefits
to a substantial portion of the treated population, a
relatively infrequent occurrence of harm may give rise to
demands for drug to be restricted in use or withdrawn
completely. The drug control authorities make judgments
on behalf of populations rather than individuals, usually on
the basis of uncertain and incomplete information. Such
action may leave individuals or groups of individuals
significantly disadvantaged. Despite stringent regulatory
norms, harmful drugs pave their way into the market,
compromising public health. Hence, measures to check
this must be rigorously adhered. Additionally, regular and
systematic reporting of adverse effects by healthcare
professionals should be encouraged. The safety warnings
issued should be incorporated into prescribing practices.
The public needs to be informed regarding the prudent use
of medicines and the available information regarding both
the benefits and the risks should be disseminated to
communicate the safety concerns that arise from time to
time. Medicine information should be pooled between
various nations to gain a better perspective of the
medicine's profile. All the available evidence should be
impartially evaluated and appropriate medicine safety
measures should be formulated. Assessment of risks and
benefits should be done without any bias as the generated
evidence forms the basis of the next decisive action. Thus,
continuous medicine safety monitoring through
pharmacovigilance is essential to safeguard against the
adverse effects of medicines.
Table 1: Drugs Withdrawn from Market in Various Countries (2000 onwards)
Country / Drug
Year
Withdrawn
Indication
Reason for Withdrawal
USA [6,7]
Efalizumab
Chronic plaque psoriasis
2009
Progressive multifocal
leukoencephalopathy
Tegaserod
Irritable Bowel Syndrome
2007
Cardiovascular Risk
Pergolide
Anti-Parkinson
2007
Valvular Disease
Valdecoxib
Analgesic
2005
Cardiovascular Risk and Adverse
skin effects
Rofecoxib
Analgesic
2004
Myocardial Infarction or stroke
Levomethadyl
Opiate dependence
2003
Fatal Arrhythmia
Europe
[8]
Sibutramine
Anti-obesity
2010
Increased risk of cardiovascular
events
Efalizumab
2009
leukoencephalopathy
Rimonabant
Anti-obesity
2009
Psychiatric Disorders
Lumiracoxib
Analgesic
2007
Hepatotoxicity
Aprotinin
Reducing peri-operative blood
loss
2007
Increased Mortality
Carisoprodol
Acute lower back pain
2007
Psychomotor Impairment
Clobutinol
Cough Suppressant
2007
QT Prolongation
46
Country / Drug
Year
Withdrawn
2007
2005
Indication
Reason for Withdrawal
Veralipride
Valdecoxib
Hot flushes a/w menopuase
Analgesic
Parecoxib
Rofecoxib
Analgesic
Analgesic
Efalizumab
United Kingdom [9]
2009
Rimonabant
Lumiracoxib
Aprotinin
Valdecoxib
Anti-obesity
Analgesic
Reducing peri-operative blood loss
Analgesic
2008
2007
2007
2005
Rofecoxib
Analgesic
2004
leukoencephalopathy
Psychiatric Disorders
Hepatotoxicity
Increased Mortality
Serious skin rash and
thromboembolic events
Increased thromboembolic events
2007
2004
Hepatotoxicity
leukoencephalopathy
Valvular Disease
Hepatotoxicity
Increased risk of suicidal
behaviour
2005
2004
Depression & Tardive dyskinesia
Increased ThromboembolicEvents
Increased Thromboembolic Events
Australia [10]
Lumiracoxib
Rofecoxib
Analgesic
Analgesic
Canada [11]
Efalizumab
2009
Pergolide
Lumiracoxib
Valdecoxib
Anti-Parkinson
Analgesic
Analgesic
2007
2007
2005
Rofecoxib
Nefazodone
Analgesic
Antidepressant
2004
2003
Singapore [12]
Efalizumab
2009
Nimesulide
Valdecoxib
Analgesic
Analgesic
2007
2005
Rofecoxib
Analgesic
2004
Nefazodone
Cerivastatin
Phenylpropanola
mine
Cisapride
Antidepressant
Lipid-lowering
Decongestant and Appetite
suppressant
Gastroesophageal Reflux
2004
2001
2000
leukoencephalopathy
Hepatotoxicity
Increased thromboembolic
Events
Hepatic Failure
Rhabdomyolysis
Risk of Hemorrhagic Stroke
2000
QT Prolongation
Lactic Acidosis
Cardiac Arrhythmias
Cardiac Arrhythmias
India [13]
Valdecoxib
Analgesic
2005
Rofecoxib
Phenformin
Terfenadine
Astemizole
Analgesic
Antihyperglycemic
Antihistaminic
Antihistaminic
2004
2003
2003
2003
47
Table 2: Country-Wise Current Drug Safety Reviews
Date
Drug
Aug 13, 2008 Natalizumab
Indication
Europe [8]
Relapsing-remitting multiple
sclerosis
Acute bacterial sinusitis, acute
exacerbation of chronic
bronchitis and communityacquired pneumonia
Acute or chronic complicated
pyelonephritis
Jul 24, 2008
Moxifloxacin
Jul 24, 2008
Norfloxacin
Jul 1, 2008
Erythropoietin
Chronic renal failure and
Anaemia with non-myeloid
tumours
Jun 26, 2008
Etoricoxib
Rheumatoid arthritis and
ankylosing spondylitis
Jun 26, 2008
Ergot derived
Dopamine agonists
(Cabergoline, Pergolide,
Bromocriptine,
Lisuride)
Jun 17,2008 Inhaled Insulin
T1 or T 2 Diabetes mellitus
(Exubera)
Combination therapy for HIV
Apr 4, 2008 Abacavir
infection
Mar 20, 2008 Bortezomib
Multiple Myeloma
Parkinson’s disease
Feb 14, 2008 Telbivudine
Chronic Hepatitis B
Jan 24, 2008
T2 Diabetes mellitus
Rosiglitazone
Jun 2, 2009
Mycophenolate mofetil
May 26, 2009
Erlotinib
Feb 9, 2009
Bevacizumab
Feb 2, 2009
Toremifene
United Kingdom [9]
Prophylaxis of acute transplant
rejection
Non small
cell lung cancer
Off-label intravitreal use (CAN
WE REMOVE?)
Hormone dependent metastatic
breast cancer in postmenopausal
women
48
Safety Issue
leukoencephalopathy
Fatal Liver Injury
Greater risks than benefits in
urinary infections and
pyelonephritis
Increased risk of tumour
progression, venous
thromboembolism and
shorter overall survival in
cancer patients
Cardiovascular side effects
Risk of Fibrosis, particularly
Cardiac fibrosis
Lung Cancer
Heart Attack
Cardiac and Pulmonary
Side effects
Risk of peripheral
Neuropathy
Increased cardiovascular risk
in patients with ischemic
heart disease and/or
peripheral arterial disease
Pure red cell aplasia
GI perforation
Severe eye inflammation and
sterile endophthalmitis
Dose related prolongation of
the QTc interval
Date
Jan 6, 2009
Drug
Temsirolimus
Indication
Advanced renal-cell carcinoma
Nov 7, 2008
Rituximab
Non-Hodgkin’s lymphoma and
Rheumatoid Arthritis
Oct 2, 2008
Etoricoxib
Sep 9, 2008
Cabergoline
Rheumatoid arthritis and
ankylosing spondylitis
Sep 5, 2008
Methylnaltrexone
Opioid induced constipation
Aug 15, 2008 Natalizumab
Multiple Sclerosis
Aug 5, 2008
Lenalidomide
Jul 21, 2008
Pergolide
Transfusion dependent
anemia due to myelodysplastic
syndromes (MDS)
Jul 16, 2008
Adalimumab
Jul 10, 2008
Deferasirox
Jun 18, 2008
Inhaled Insulin
(Exubera)
Apr 30, 2008 Tenofovir
Feb 20, 2008 Modafinil
Feb 18, 2008 Mycophenolate mofetil
Rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis,
Crohn’s disease and psoriasis
Transfusional he
mosiderosis
T1 or T2 Diabetes mellitus
Glioblastoma multiforme
Obstructive sleep apnea/hypopnea syndrome (OSAHS), and
shift work sleep disorder (SWSD)
Prophylaxis of acute transplant
rejection
Feb 15, 2008 Telbivudine
Chronic Hepatitis B
Feb 11, 2008 Alemtuzumab
Remission consolidation in
B-Cell Chronic Lymphocytic
Leukemia
Acute bacterial sinusitis, acute
exacerbation of chronic
bronchitis and communityacquired pneumonia
Dermatophytosis, chronic
mucocutaneous, cutaneous, and
oropharyngeal candidosis
Feb 11, 2008 Moxifloxacin
Feb 1, 2008
Ketoconazole
49
Safety Issue
Severe hypersensitivity
reactions during infusion
Progressive
multifocal
leukoencephalopathy
Not to be used if BP over
140/90
Fibrotic Cardiac
Valvulopathy
Use when response to
usual laxative treatment
not sufficient
Progressive
multifocal
leukoencephalopathy
Teratogenicity
Fibrotic Cardiac
Valvulopathy
Hepatosplenic T-cell
lymphoma
Liver failure,GI haemorrhage
and ulceration, and
renal tubulopathy
Primary lung malignancy
Impaired renal function
psychiatric symptoms
Progressive
multifocal
leukoencephalopathy
Risk of Peripheral
Neuropathy
Fatal infectious complications
Serious hepatic reactions
and bullous skin reactions
Risk of hepatotoxicity
Date
Drug
Indication
Safety Issue
USA [17,18]
Oct 16, 2009
Iron Dextran injection
Sep 25, 2009 Sitagliptin
Sep 25, 2009 Deferasirox
Iron deficient state not amenable
to oral iron therapy
Anaphylactic-type reactions
including fatalities
T2 Diabetes mellitus
Acute pancreatitis
Transfusional he
mosiderosis
Increased adverse events
including acute renal failure,
GI haemorrhages and death
Sep 16, 2009 Natalizumab
Relapsing-remitting multiple
sclerosis
leukoencephalopathy
Sep 3, 2009
Prophylaxis of organ rejection
Pure red cell aplasia
Mycophenolate mofetil
Aug 31, 2009 Tumour Necrosis Factor Juvenile idiopathic arthritis,
(TNF) Blockers
rheumatoid arthritis, psoriatic
arthritis, plaque psoriasis,
Crohn’s disease, and ankylosing
spondylitis
Increased risk of lymphoma,
leukaemia and new-onset
psoriasis
Aug 28, 2009 Leukotriene inhibitors
(Montelukast,
Zafirlukast and
Zileuton)
Prophylaxis and chronic
treatment of asthma
Neuropsychiatric events
Aug 27, 2009 Etravirine
HIV-1 strains resistant to nonSevere skin reactions like
nucleoside reverse transcriptase
Stevens-Johnson syndrome,
inhibitor) and other antiretrovirals toxic epidermal necrolysis
and erythema multiforme
Aug 24, 2009 Orlistat
Obesity management
Serious liver injury including
liver failure
Jul 1, 2009
Insulin Glargine
Diabetes Mellitus
Possible risk for cancer in
patients with diabetes
Jun 4, 2009
Proplythiouracil
Hyperthyroidism due to Graves’
disease
Serious liver injury, including
liver failure and death
Erlotinib
Non small
GI perforation
May 8, 2009
cell lung cancer
Mar 24, 2009 Mycophenolate mofetil
Prophylaxis of organ rejection
Increased susceptibility to
infection and possible
development of lymphoma
and other neoplasms
Feb 26, 2009 Metoclopramide
GI disorders
Tardive dyskinesia on long
term or high dose
50
Date
Drug
Indication
Safety Issue
Feb 23, 2009 Zonisamide
Partial seizures
Metabolic Acidosis
Feb 4, 2009
Reduction of mortality
Serious bleeding events and
mortality in patients with
sepsis
Drotrecogin
in severe sepsis
Jan 16, 2009
Local anaesthetics
Relieving pain from
mammography and other medical
tests
Cardiac arrhythmias and Fatal
strokes
Jan 15, 2009
Atomoxetine
Attention-Deficit Hyperactivity
Disorder
Hepatotoxicity
Jan 2, 2009
Varenicli ne and
Buproprion
Smoking Cessation Aids
Suicidal Ideation and
Behaviour
Nov 24, 2008 Phenytoin and
Fosphenytoin Sodium
Tonic-clonic (grand mal) and
complex-partial seizures
Serious skin reactions
(Stevens-Johnson syndrome
and toxic epidermal
necrolysis)
Nov 12, 2008 Bisphosphonates
Osteoporosis, Paget’s disease and
bone metastases
Serious atrial fibrillation
events
Oct 7, 2008
Bronchospasm associated with
chronic obstructive pulmonary
disease
Increased risk of stroke
Sep 26, 2008 Epoetin Alpha
Anemia in chronic renal failure
patients,zidovudine-treated HIVinfected patients and cancer
patients
Increased mortality in patients
after acute ischemic stroke
Sep 23, 2008 Duloxetine
Major depressive disorder and
Diabetic peripheral neuropathic
pain
Urinary retention
Tiotropium Bromide
Sep 4, 2008
Tumour Necrosis Factor Juvenile idiopathic arthritis (JIA),
(TNF) Blockers
rheumatoid arthritis, psoriatic
arthritis, plaque psoriasis,
Crohn’s disease, and ankylosing
spondylitis
Jul 7, 2008
SSRI and SNRI
antidepressants
Major depressive Disorder
Birth defects (Persistent
pulmonary hypertension of
the newborn)
Jun 23, 2008
Minocycline
Adult periodontitis
Thyroid disorders
51
Risk of Histoplasmosis and
other invasive fungal
infections
References
[Online]. [cited 2010 Mar 15]; Available form :
URL:http://www.hsa.gov.sg/publish/hsaportal/en/heal
th_products_regulation/safety_information/productsa
fety_alerts.html
1. Turning Adverse Drug Events into Better Patient Care.
[Online]. [cited 2009 Mar 10]; Available from:
URL:http:/ cme.medscape.com/viewarticle/569872_4
2. WHO Policy Perspectives on Medicines and 13. Central Drugs Standard Control Organization,
Ministry of Health and Family Welfare, Government of
Pharmacovigilance: Ensuring the Safe Use of
India:
Drugs Banned in India. [Online]. [cited 2010
Medicines. [Online]. 2004 [cited 2009 Mar 10];
M
a
r
1 5 ] ; Av a i l a b l e f r o m : U R L :
Available from: URL: http://www.who.int/
http://www.cdsco.nic.in
/html/Drugsbanned. html
medicinedocs/collect/edmweb/pdf/s6164e/s6164e.pdf
3. US FDA: The Clinical Impact of Adverse Event 14. Pappas G, Ierodiakonou V, Falagas ME. Lost in
translation: differences in antimicrobial indication
Reporting. [Online]. 2008 [cited 2009 Mar 11];
approval
policies between the United States and
vcAvailablefrom:URL:http://www.fda.gov/MEDwatch
Europe.
Clin
Ther 2009;31:1595-1603.
/articles/medcont/postmkt.htm
4. Safety Information: Tamiflu (Oseltamivir phosphate). 15. Przekop PR Jr, Tulgan H, Przekop AA and Glantz M.
Adverse Drug Reaction to Methotrexate:
[ O n l i n e ] . [ c i t e d 2 0 1 0 A p r 0 4 ] ; Av a i l a b l e
Pharmacogenetic
Origin. J Am Osteopath Assoc
from:URL:http://www.fda.gov/Safety/MedWatch/Safe
2006;106:706-7.
tyInformation/S afetyAlertsforHuman
MedicalProducts/ ucm095044.htm
16. Alfirevic A and Pirmohamed M. Pharmacogenetics of
adverse drug reactions. FOCUS – Quarterly bulletin of
5. Safety Information: Relenza (Zanamivir). [Online].
Pharmacovigilance
2007;50:1-6.
[ c i t e d 2 0 1 0 A p r 0 4 ] ; Av a i l a b l e f r o m :
URL:http://www.fda.gov/Safety/MedWatch/SafetyInfo 17. Potential Signals of Serious Risks/New Safety
rmation/SafetyAlertsforHumanMedicalProducts/ucm0
Information Identified from the Adverse Event
94982.htm
Reporting System (AERS), Quarterly Reports.
[Online]. [cited 2009 Jan 15]; Available from:
6. US FDA: CDER Report to the Nation: 2004 Drug Safety
URL:http://www.fda.gov/cder/aers/potential_signals/
and Quality. [Online]. 2005 [cited 2009 Mar 11];
default.html
AvailablefromURL:http://www.fda.gov/cder/reports/rt
n/2004/rtn 2004-4.htm#Index
18. US FDA Medical Product Safety Information.
[Online]. [cited 2009 Mar 15]; Available from: URL:
7. US FDA: CDER 2007 Update: Drug Recalls and Safetyhttp://www.fda.
Gov/medwatch/SAFETY.htm
Based Withdrawals. [Online]. 2008 [cited 2009 Mar 11];
Available from: URL: http://www.fda.gov/ 19. Adverse Drug Reaction news, 2008 . [Online]. [Cited
CDER/reports/rtn/2007/2007update.pdf
2 0 0 9 M a r 1 5 ] ; Av a i l a b l e f r o m : U R L
http://www.hsa.gov.sg/
publish/hsaportal/en/health_
8. European Medicines Agency: Human Medicines products_regulation/safety_information/adrbulletin.ht
Product Safety Announcements. [Online]. [cited 2010
ml
Mar 15]; Available From:URL:http://ww.emea.europa
20. MHRA: Download Drug Analysis Prints (DAPs) – I.
.europa.eu/htms/human/drugalert/drug alert.htm
[Online]. [cited 2009 Mar 15]; Available from :
9. Medicines and Healthcare products Regulatory Agency:
URL:http:// www.mhra.gov.uk/ home/groups/
Safety warnings, alerts and recalls. [Online]. [cited 2010
public/documents/sentineldocuments/dap_126959701
Mar 15]; Available from: URL: http://www.mhra.gov.
1676.pdf
uk/ Safetyinform ation/ Safetywarningsalert
21. Latest FDA Labeling Changes for Erythropoiesissandrecalls/ index.htm
Stimulating Agents. [Online]. [cited 2009 Mar 15];
10. Australian Government Department of Health and
Available from: URL:http://www.medscape.com/view
Ageing Therapeutic Goods Administration: Product
article/578365.
Recalls. [Online]. [cited 2010 Mar 15]; Available from:
22. US FDA Early Communication about an Ongoing
URL:http://www.tga.gov.au/recalls/index.htm
Safety Review: Epoetin alfa. [Online]. 2008 [cited
11. Health Canada: Advisories, Warnings and Recalls for
2009 Mar 15]; Available from:URL: http://www.
Health Professionals. [Online]. [cited 2010 Mar 15];
Fda.gov/cder/drug/e arly_comm/epoetin_alfa.html
Available from: URL:http://www.hc-sc.gc.ca/dhpmps/medeff/ advisories-avis/prof/index-eng.php
12. Singapore Government Health Sciences Authority:
Product Safety Alerts (for healthcare professionals).
52
JOURNAL OF PHARMACOVIGILANCE & DRUG SAFETY
Annual Subscription Form
JOURNAL OFFICE :
For Office Use
Dr. Anurag Tomar,
Editor in Chief,
NIMS City Center, 4, Govind Marg,
Jaipur-302004, India
Email : sopijaipur@rediffmail.com
anurag@nimsr.com
Ref: No.
Cash/Cheque/ DD for Rs.
Cheque/DD No.
Receipt No. & Date
Name ……………………………………………………………………………………………………………………………………………………….....................
Address ……………………………………………………………………………………………………………………………………………………....................
.....................………………………………………………………………………………………………………………………………………………………………
City …………….....................…………………………………………………………….. State …………………………………………………………………
Pin ……………………………………………Phone ( R) ……………………………………………….. (O) ……………………………............................
Mobile ………………………………………………………………. Email ……………………………………………………………………………....................
Designation ………………………………………………………….Qualification…………………………………………………………………....................
I am enclosing a DD No/ At par Cheque No.…………………………….dated…………………………drawn on …………………....................
Favoring “Editor, SOPI” Payable at Jaipur-302004 for Rs…………………………………………………………………………...................………
Subscribe
Today
Original research articles, reviews, update articles; brief communications & rare case
documentation pertaining to Pharmacovigilance & Therapeutics are invited for
publication. Any News/ Conference calendar etc., useful for
the members of the society will be published free:
Annual Subscription Fee
Individual
Institutions
Rs. 500/Rs. 2,000/-
Payment through Demand Draft/ at par cheque in favour of “Editor, SOPI” Payable at Jaipur-302004. SUBSCRIPTION RATE
includes postal charges under certificate of posting by surface mail within India. Airmail charges would be extra, at rates applicable
from time to time.
Contacts
5
.
Address for sending the membership form:Research
; Pin-281 406
E-mail : govindmohanagra@yahoo.com
Treasurer
INSTRUCTIONS TO AUTHORS
Aims and Scope: The Journal of Pharmacovigilance & Drug
Safety (JPDS) is an official, and peer reviewed journal of Society
of Pharmacovigilance, India (SOPI), that aims to encourage the
practice and research in rational drug usage, drug safety and
Pharmacovigilance. The journal invites submission of original
research articles, reviews, commentaries and case reports on
rational drug usage, therapeutic drug monitoring, drug safety,
Pharmacovigilance, pharmacoepidemiology, drug surveillance,
community medicine, community pharmacy, National or
International drug policies and related issues. Journal will not
consider basic drug research in animals unless they have direct
relevance to the above-mentioned topics.
Submission of Manuscript: Manuscripts are reviewed for
possible publication with the understanding that they have not
been published, submitted, or accepted for publication
elsewhere. They will be reviewed for scientific content, technical
importance and significance by two independent reviewers of
repute. The authors may suggest reviewers, but it is not
mandatory and editor has a right not to accept it.
The Journal will entertain research papers for publication under
the following categories:
Original research article
Short Communication
Reviews (including Mini reviews)
Commentary
Case reports on drug safety
Original research article should be a comprehensive description
of significant findings, whereas, short communication shall be
limited to 1500 words. Review articles updating current topics
will be entertained normally by invitation. A commentary on any
specific field covered shall be limited to 500 words without any
figure or table.
Three copies of manuscripts are required to be submitted along
with CD containing the electronic version using Microsoft
word or any other word-processing software. The manuscript
should be sent at following address:
Dr. Anurag Tomar
Editor-in-Chief, JPVDS
NIMS City Centre,
4, Govind Marg, Jaipur - 302 004
sopijaipur@rediffmail.com, anurag@nimsr.com
Preparation of the Manuscript
The manuscript should contain following sections:
Abstract: The abstract should state the purpose of the study or
investigation, basic procedures (selection of study subjects or
laboratory animals; observational and analytic methods), main
findings (giving specific data and their statistical significance, if
possible), and the principal conclusions.
The abstract should be self explanatory (limited to 200 words in
one paragraph) suitable for reproduction without change.
Abstract should have three sections (a) Objective (not more than
3 lines (b) Methods and Results, (c) Conclusions (not more than
3-4 lines).
Introduction: It should provide background information
providing rationale of the study giving pertinent reference.
Introduction should always end with objective of the
study/article.
Methods: One should describe selection of the observational or
experimental subjects (Patients including controls) clearly. The
age, sex and other important characteristics of the subjects
should be identified. The definition and relevance of race and
ethnicity should be ambiguous. Authors should be particularly
careful about using these categories. One should given the
methods, apparatus (The manufacturer's name and address in
parentheses), and procedures in sufficient detail to allow other
workers reduce the results. Give references to established
methods including statistical methods. All drugs and chemicals
used, including generic name(s) dose(s) and route(s) of
administration.
Results: Present your results concisely and in logical sequence
in the text, tables and illustrations. Tables and figures should be
devised in such a manner that the findings are accurately
conveyed. The same data should not be used for more than one
figure or table. Interpretation of the data should be given in the
discussion only.
Discussion: The discussion must interpret the results and relate
them to existing knowledge on the topic in as lucid a manner as
possible, avoiding repetition or duplication of information. It
should not be unnecessarily lengthy.
Include the implications of the findings and their limitations,
including implications for future research. Relate the
observations to other relevant studies. It should always end with
concluding remarks.Link the conclusions with the goals of the
study but avoid unqualified statements and conclusions not
completely supported by the data. In particular, authors should
avoid making statements on economic benefits and costs unless
their manuscript includes economic data and analyses. Avoid
claming priority and alluding to work that has not been
completed. State new hypotheses when warranted, but clearly
table them as such. Recommendations, when appropriate, may
be included.
References: References should be numbered consecutively in
the order in which they are first mentioned in the text. Identify
references in text, tables and legends by Arabic numerals in
parentheses. References cited only in tables or in legends to
figures should be numbered in accordance with the sequence
established by the first identification in the text of the particular
table or figure
Standard journal article: List the first six authors followed by
et al.
Vega KJ, Pina I, Krevsky B. Heart transplantation is associated
with an increased risk for Pancreatobiliary disease. Ann Intern
Med 1996 124(11):980-3.
More than six authors: Parkin DM, Clayton D, Black RJ,
Masuyer E, Friedl HP Ivanow E, et al. Childhood leukaemia in
Europe after Chernobyl:5 year follow-up. Br J Cancer 1996;
73:1006-12.
Organization as author: The Cardiac Society of Australia and
New Zealand. Clinical exercise stress testing. Safety and
performance guidelines. Med J Aust 1996;164:284-4.
Books and other Monographs:Personal author(s): Ringsven
MK, Bond D. Gerontology and leadership skills for nurses. 2nd
ed. Albany (NY): Delmar Publishers; 1996
Chapter in a book: Philips SJ, Whisnant JP. Hypertension and
stroke. In: Laragh JH, renner BM, editors. Hypertension:
Pathophysiology, diagnosis and management. 2nd ed. New York:
Raven Press; 1995.p.
Tables and Figure: These should be given in the end after
references section consecutively, and provided with caption.
Footnotes should be identified by lower case lettrs and cited in
the tables as italicized
superscripts. All tables should be cited in the text. Figure should
be kept to the inimum, colored figure, halftone figure will be
charged @ Rs 200 per figure.
Acknowledgements:The author shouldacknowledgement
advice from colleagues,financial/technical assistance, gifts etc.
after obtaining consent from the people whose assistance is
acknowledged. Any other footnotes may be given here.
Proofs and Reprints : Accepted paper's proofs will be sent to the
corresponding author for verification against the original and
appropriate corrections made. It will be mandatory to purchase at
least 50 reprints. An order form for reprints will be sent with
proofs. Please return the reprint order form with a cheque of Rs.
1000/- (India) in favour of “Editor-in-Chief, Journal of
Pharmacovigilance and Drug Safety.” Reprints will be posted
within 15 days after printing the journal.
Issue to Consider before submitting a Manuscript
Redundant or Duplicate Publication
Redundant or duplicate publication is publication of a paper that
overlaps substantially with one already published.
Readers of primary source periodicals deserve to be able to trust
that what they are reading is original unless there is a clear
statement that the article is being republished by the choice of the
author and editor. The bases of this position are international
copyright laws, ethical conduct, and cost-effective use of
resources.
Most journals do not wish to receive papers on work that has
already been reported in large part in a published article or is
contained in another paper that has been submitted or accepted
for publication elsewhere, in print or in electronic media. This
policy does not preclude the journal from considering a paper
that has been rejected by another journal, or a complete report
that follows publication of a preliminary report such as an
abstract or poster displayed for colleagues at a professional
meeting. Nor does it prevent journals from considering a paper
that has been presented at a scientific meeting but not published
in full or that is being considered for publication in a proceedings
or similar format. Press reports of scheduled meetings will not
usually be regarded as breaches of this rule, but such reports
should not be amplified by additional data or copies of tables and
illustrations.
When submitting a paper, an author should always make a full
statement to the editor about all submissions and previous reports
that might be regarded as redundant or duplicate publication of
the same or very similar work. The author should alert the editor
if the work includes subjects about whom a previous report has
been published. Any such work should be referred to and
referenced in the new paper. Copies of such material should be
included with the submitted paper to help the editor decide how
to deal with the matter.
If redundant or duplicate publication is attempted or occurs
without such notification, authors should expect editorial action
to be taken. At the least, prompt rejection of the submitted
manuscript should be expected. If the editor was not aware of the
violations and the article has already been published, then a
notice of redundant or duplicate publication will probably be
published with or without the author's explanation or approval.
Preliminary release, usually to public media, of scientific
information described in a paper that has been accepted but not
yet published violates the policies of many journals. In a few
cases, and only by arrangement with the editor, preliminary
release of data may be acceptable- for example, if there is a
public health emergency.
Requirements for the submission of manuscript
Double-space all parts of manuscripts.
Begin each section or component on a new page.
Review the sequence: title page, abstract and key words, text,
acknowledgements, references, tables (each on separate page),
and legends.
Illustration (uncounted prints) should be no large than 203x254
mm (8x10 in.).
Include permission to reproduce previously published material
or to use illustrations that may identify human subjects.
Enclose transfer-of-copyright and other forms.
Submit the required number of paper copies.
Keep copies of everything submitted.
EVENTS
10th Annual Conference of Society
of Pharmacovigilance (India)
: Pre-conference workshop on 26th November, 2010
Conference on 27th & 28th November, 2010
Venue : Lady Hardinge Medical College, New Delhi - 110 001
Theme : Rational Use of Medicines: An Integrated Approach
Conference Secretariat: Dr. H.S. Rehan, Organizing Secretary SOPI - 2010
Date
Professor and Head, Department of Pharmacology,
Lady Hardinge Medical College and Assoc. Hospitals,
New Delhi- 110 001, India.
Tel: 011-23741723, 011-23408151
Mob: 09811694040, 09999903031
E-mail: isrpt2008@gmail.com, harmeetrehan@hotmail.com
Website: www.isrpt.co.in
43rd Annual Conference of
Indian Pharmacological Society
Date : From 13th to 16th December, 2010
Venue : Hyderabad
Theme : Pharmacology & Translational Research
Conference Secretariat: Dr. B. Dinesh Kumar, Organizing Secretary - IPS - 2010
Food and Drug Toxicology Research Center (FDTRC)
National Institute of Nutrition ( ICMR), Tarnaka,
Hyderabad- 500 007
Tel: +91(40) 2719 7322
Email : ipsnin@rediffmail.com, dkips156@gmail.com
5th Federation of Asian and Oceanian Neuroscience
Societies (FAONS) Congress - 2010
XXVIII Annual Meeting of Indian Academy of Neurosciences
Date : From 25th to 28th November, 2010
Venue : Lucknow
Theme : Emerging Trends in Basic and Clinical Neuroscience
Conference Secretariat: Dr. Vinay K. Khanna, Organizing Secretary - IAN 2010
Dr. Prahlad K. Seth
President, FAONS
Secretary (HQ)
Indian Academy of Neurosciences,
c/o IITR, Lucknow,
Tel: +91-522-2628227
Email : faons2010@gmail.com
Tariffs For Advertisers
Cover
Inner
Quarterly
Annually
Last Page(color)
Rs. 35,000
Rs. 1,10,000
Inside back cover(color)
Rs. 25,000
Rs. 90,000
Inner Front (color)
Rs. 25,000
Rs. 90,000
Inner Full Page (color)
Rs. 20,000
Rs. 72,000
Full Page (B&W)
Rs. 15,000
Rs. 55,000
Half Page (color)
Rs. 12,000
Rs. 40,000
Half Page (B&W)
Rs. 10,000
Rs. 36,000
Payment through Cheque/Demand Draft in favour of
“Editor SOPI” Payable at Jaipur -302004
Advertising material be sent through Registered Post to:
Dr. Anurag Tomar,
Editor in Chief,
NIMS City Center, 4 Govind Marg,
Jaipur - 302 004, India
Email: sopijaipur@rediffmail.com
anurag@nimsr.com
The Journal is circulated to all the Life members of Society of Pharmacovigiliance,
India (SOPI), Institutions of Pharmacoviglance, Medical and Pharmacy Colleges in
the country & Pharmaceutical industries etc.
Subscribe
Today
Original research articles, reviews, update articles; brief communications & rare case
documentation pertaining to Pharmacovigilance & Therapeutics are invited for
publication. Any News/ Conference calendar etc., useful for
the members of the society will be published free:
Annual Subscription Fee
Individual
Institutions
Rs. 500/Rs. 2,000/-
Payment through Demand Draft/ at par cheque in favour of “Editor, SOPI” Payable at Jaipur-302004. SUBSCRIPTION RATE
includes postal charges under certificate of posting by surface mail within India. Airmail charges would be extra, at rates applicable
from time to time.

- Journal of SOPI

Transcription

Similar documents

Call 1-888-4PPA-NOW

Optical properties of MgxZn1-xO nanoparticles

Reporting Form - Yellow Card Scheme

Safety Planning When Substance Abuse is Present

O - KOCW

iauzah ac ir

NEVADA Medicaid Coverage of Medications for the Treatment of

Your competent partner for research in children`s medicines

Non-Dependence Producing Drugs in the Treatment of Addictions

top 10 homeopathics - Learn Homeopathy Now

Developing a Pharmacovigilance Culture