Homeonews N 17 2013

Transcription

Homeonews N 17 2013

HOMEONEWS
Edición N° 17
Año 2013
Director: Farm. Fernando Estevez Castillo
DISTRIBUCION GRATUITA
PARA PROFESIONALES DE LA SALUD
Homeonews
Edición N° 17 – Año 2013
Edición n° 17
Año 2013
Registro de la Propiedad Intelectual n°: 505276
Director: Fernando Oscar Estevez Castillo
Propietario: Fernando Oscar Estevez Castillo
E.Mail: festevez_castillo@hotmail.com ó
festevezcastillo@yahoo.com.ar
Director: Fernando Estevez Castillo
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INDICE
1- Editorial, pág. 5.
2- Fitoterapia:
Extractos vegetales de Psidium guajava, Mangífera y Mentha sp. Inhiben el
crecimiento de especies presentes en la placa bacteriana; pág. 6.
3- Alopatía:
Aumento del riesgo de deterioro cognitivo en pacientes diabéticos tratados
con metformina, pág. 18.
4- Homeopatía:
Tratamiento homeopático del síndrome premenstrual: una serie de casos,
pág. 29.
5- Nutrición:
Los efectos del consumo de escaramujo sobre los marcadores de riesgo de
diabetes tipo 2 y enfermedad cardiovascular: investigación cruzada,
randomizada, a doble ciego, en personas obesas, pág. 38.
6- Notas de interés:
-Curso superior de Medicina Naturista para Profesionales de la Salud de la
Asociación Argentina de Médicos Naturistas; pág. 50.
-Jornada de Actualización en Fitoterapia, Colegio de Farmacéuticos de la
Provincia de Santa Fe 1° Circ.; pág. 51.
-I Jornadas Nacionales de Fitomedicina y Promoción de la Fitomedicina
Veterinaria; pág. 52.
7- Recursos humanos:
-Toxicidad en las empresas; pág. 54.
.
8- Novedades:
-Nuevos productos: AVENA+KARITE; pág. 60.
9- Cursos:
-Cursos de la Asociación Argentina de Fitomedicina, pág. 61.
10- Formulario de suscripción, pág. 63.
Homeonews
Foto de tapa: Mentha piperita L. (Lamiaceae).
Las opiniones vertidas en los artículos firmados son responsabilidad de sus autores.
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EDITORIAL
Estimados colegas del equipo de salud:
Tarde pero seguro, dice el refrán!!!.
Un año ha pasado desde el último número de Homeonews, pero nuevamente
llego a Uds., con esta nueva edición, y con mucho material, para poder cumplir
con las expectativas, de la gran cantidad de lectores de la Revista, que día a
día, me lo solicitaban, a través de correos electrónicos.
En esta edición, podrán encontrar un trabajo de FITOTERAPIA sobre la
inhibición del crecimiento de especies presentes en la placa bacteriana,
mediante extractos vegetales de Psidium guajava, Mangífera y Mentha
sp.; en ALOPATÍA, el aumento del riesgo de deterioro cognitivo en
pacientes diabéticos tratados con metformina. En el Capítulo de
HOMEOPATÍA, el tratamiento homeopático del síndrome premenstrual.
Pasando a NUTRICIÓN, una investigación sobre los efectos del consumo de
escaramujo sobre los marcadores de riesgo de diabetes tipo 2 y
enfermedad cardiovascular, en personas obesas. En NOTAS DE INTERES,
las detalles de tres actividades: el Curso Superior de Medicina Naturista, de
la Asociación Argentina de Médicos Naturistas; la Jornada de Actualización
en Fitoterapia, realizada en el Colegio de Farmacéuticos de la Provincia de
Santa Fe 1° Circ., y las I° Jornadas Nacionales de Fitomedicina y
Promoción de la Fitomedicina Veterinaria, realizadas en San Miguel de
Tucumán. Con respecto a NOVEDADES, Laboratorios Dr. Madaus presentó
un nuevo producto, llamado AVENA+KARITE y en CURSOS, muy buenas
posibilidades para capacitarse durante el año. A partir de este número, se
incorpora una nueva sección, llamada RECURSOS HUMANOS, donde volcaré
experiencias y conocimientos de especialistas en la materia, dado que esta
temática se está convirtiendo en el principal desafío que enfrentan las
organizaciones, que es el mejoramiento contínuo del personal que las integran,
para poder cumplir sus objetivos. Por tal motivo, para comenzar, vamos a
plantear, el tema: la “Toxicidad en las Empresas”.
Nos despedimos hasta el próximo número, esperando que no se haga rogar
tanto!!, pero no quiero dejar pasar la oportunidad, para desearles a TODOS,
un FELIZ Y PROSPERO AÑO NUEVO.
Farm. Fernando Estévez Castillo
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FITOTERAPIA
EXTRACTOS VEGETALES DE PSIDIUM GUAJAVA, MANGIFERA Y
MENTHA SP. INHIBEN EL CRECIMIENTO DE ESPECIES PRESENTES EN
LA PLACA BACTERIANA
Wan Nordini Hasnor WI1*, Fathilah AR2 and Rahim ZHA2
1
Faculty of Pharmacy, Universiti Teknologi MARA (Bertam Campus), Penang, Malaysia
Faculty of Dentistry, Department of Oral Biology, University of Malaya, 50603 Kuala
Lumpur, Malaysia
2
[Altern Integ Med 2013, 2:1 (http://dx.doi.org/10.4172/2327-5162.1000102)]
RESUMEN
Recientemente el uso de gárgaras ha ganado popularidad. Ya sea en base
alcohólica o a partir de extractos vegetales, el principal propósito de la
utilización de gárgaras, es prevenir la acumulación de la placa o el mal olor
bucal, que habitualmente es provocado por el crecimiento de la placa
bacteriana oral.
En este estudio, fue ensayado el efecto antimicrobiano de Psidium guajava,
Mangifera sp y Mentha sp, vs especies simples de la placa, tales como
Streptococcus sanguinis y Streptococcus mitis. La placa fue dejada crecer
sobre las perlas de vidrio recubiertas de saliva, en el Modelo Artificial de Boca
de Nordini (NAM), que representa la cavidad bucal, durante 24 horas. La saliva
formaría la película experimental sobre las perlas de vidrio.
Los resultados obtenidos mostraron que la placa de Streptococcus mitis
desplegó una adherencia máxima (11,53%) comparada con Streptococcus
sanguinis (1,83%), sobre la película experimental no tratada. Cuando se
aplicaron los extractos acuosos vegetales acuosos, la adherencia bacteriana
fue significativamente reducida a 1,54% (Streptococcus mitis) y 0,21%
(Streptococcus sanguinis). Este resultado indica que ciertos extractos vegetales
seleccionados, pueden ser utilizados para inhibir el crecimiento de la placa
bacteriana.
Palabras clave: extractos vegetales, placa bacteriana, Streptococcus mitis,
Streptococcus sanguinis, adherencia bacteriana 2.
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ARTICULO ORIGINAL
Introduction
Psidium guajava (guava), Mangifera sp. (mango) and Mentha sp (mint) have a
long history of traditional uses [1,2] much of which has been validated by
scientific research. The guava leaves extract which comes from the family
Myrtaceae, was reported to be very effective in inhibiting the growth of
Staphylococcus aureus [3] while the guava bark methanolic extract showed a
positive antibacterial activity against Bacillus subtilis, Staphylococcus aureus,
Escherichia coli and Pseudomonas aeruginosa [4]. In addition, the leaves were
also reported to have an anti-adherence effect towards the oral bacteria,
especially the early colonizers of dental plaque [5,6]. Mangifera sp. or popularly
known as mango, comes from the family Anacardiaceae. The mango tree is not
only grown naturally, but is also cultivated mainly in tropical and subtropical
regions. The decoction of the leaves functions as antihelmintic and also can be
used to gargle in the prevention of halitosis [1]. It was also reported that an
ethanolic extract of mango seed kernel possessed an antimicrobial activity
against food-borne pathogenic bacteria [7]. In the fourteenth century, mint
(Mentha sp.) which comes from the family Labiatae, was used for whitening the
teeth, and its distilled oil is still used to flavour tooth-pastes and chewing gum.
Streptococcus sanguinis (Strep. sanguinis) or previously known as
Streptococcus sanguis [8] which belongs to the mitis-group [9], is one of the
early colonizers of dental plaque [5,10]. Once a tooth erupts into the oral cavity,
Strep. sanguinis colonizes its surface. The colonization of Strep. sanguinis to
the tooth surfaces begins at the age of nine months in infants and their
population was shown to increase with the age of the infants [11,12].
Streptococcus mitis (Strep. mitis) is a common species in the mouth and
frequently predominates with Strep. sanguinis during the initial colonization of
the tooth surface [10]. Strep. mitis is commonly found on the soft tissues of the
cheeks, lips and the ventral surface of the tongue as they tend to adhere to nonkeratinized mucosa in the mouth [9]. In an oral cavity, these microbes tend to
grow in the form of biofilm. They are arranged in micro colonies and surrounded
by protective matrix [13] consisting of extracellular 3 polymers that form a thick,
continuous, hydrated, charged layer around the cells [14,15].
The matrix protects the biofilm from host defences [14], desiccation and the
action of antimicrobial agents [16]. Throughout the years, many researchers
have attempted to study the mechanism of action of plant extracts as
antibacterial agents [5,17-23]. However, their research involved mainly
microbes growing under the planktonic state, which refers to the bacteria that
live as floating organisms in the test tube or flask cultures in the laboratory.
Under such condition, the microbes may not best represent those found in
dental plaque. Investigation of oral biofilm in vivo however is often made difficult
by its heterogeneity, limited access, the existence of variable and uncontrollable
oral environments as well as ethical problems [24]. Therefore, there is a need to
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investigate the effect of the chosen plant extracts on the single- species oral
biofilm in vitro.
Material and Methods
Preparation of plant extracts
Leaves of mango (Mangifera sp.) (Figure 1) were obtained from Puchong,
Selangor and leaves of guava (Psidium sp.) (Figure 2) were obtained from Kota
Bharu, Kelantan. Leaves of mint (Mentha sp.) (Figure 3) grown in Cameron
Highlands, Pahang were purchased from the local market in Kuala Lumpur. The
leaves were oven-dried at 60°C for 48 hours until no changes in the weight
were observed. The dried leaves were then grounded into powder and used in
the preparation of the aqueous extract. One hundred gram of powdered
samples prepared from the leaves of Mangifera sp., Mentha sp. and Psidium
sp. were weighed and put into a large beaker. One thousand ml of deionised
distilled water was added and the mixture was allowed to boil until the final
volume became one tenth (1:10) of the original. The debris was then filtered out
using filter paper (Whatman No.1, diameter 24 cm) with the aid of a suction
pump (SPARMAX, Taiwan). One ml of the clear crude extracts was dispensed
into micro centrifuge tubes (1 ml/tube) and dried using the speed vacuum
concentrator (HETO) until no further changes in weight were observed. The
dried extracts were then stored at -20°C until further use [25]. Prior to use, all
three extracts were diluted with sterile deionised distilled water and mixed to a
final concentration of 0.5 mg/ml. All three extracts were combined together
before used in the experiment.
NAM model
The Nordini’s Artificial Mouth (NAM) model was used in the study to represent
the oral cavity. The model was developed according to the method described
earlier [26]. Basically, the model consists of a glass chamber, glass beads,
saliva reservoir, bacterial reservoir and peristaltic pump (Figure 4).
Preparation of the glass beads as substratum
In the study, the glass beads (3 mm diameter) were used to represent the tooth
enamel onto which the experimental pellicle and single-species biofilm will
develop. The glass beads were cleaned and sterilized by autoclaving at 121°C
(15 p.s.i) for 20 minutes. The sterilized glass beads were kept in a sterilized
bottle before use.
Preparation of sterile saliva
Undiluted sterile saliva was prepared according to the method described by De
Jong and Van der Hoeven [27]. Approximately 25 ml of stimulated whole saliva
(SWS) was collected everyday from a single volunteer to minimize any
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variations that may arise. The volunteer was asked to chew on a sugar-free
gum to stimulate saliva production. The collection of SWS was done using icechilled test tubes. The aggregation of protein in the SWS samples was
minimized by adding 1,4-Dithio- D,L-threitol (DTT) to a concentration of 2.5 mM.
Upon the addition of DTT, the saliva was stirred slowly for 10 mins before it was
centrifuged at 864g for 30 mins. The supernatant obtained was then filtersterilized through a disposable 0.2 µm (Supor Membrane) low protein-binding
filter (Acrodisc Syringe Filters, Pall Corp, USA) into sterile test tubes. The
sterile SWS was then stored at -20°C. Prior to use, the SWS was thawed and
centrifuged once again to remove any precipitate.
Preparation of bacterial suspension
The stock culture of oral bacteria (Strep. mitis and Strept. Sanguinis) were
obtained from the Department of Oral Biology, Faculty of Dentistry, University of
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Malaya. The stock which was kept at -80°C was thawed at room temperature.
Each of the thawed stock culture was then inoculated into sterilized BHI broth
(1:100 v/v) and incubated at 37°C for 18-24 hours. The bacterial suspension
was adjusted spectrophotometrically at 550 nm to 0.144 absorbance which is
equivalent to108 cells/ml [5]. This procedure is important to standardize the
number of cells in the suspension to be used in the study.
The development of experimental pellicle and single-species biofilm in
NAM model
Experimental pellicle: negative-control: The development of experimental
pellicle and single-species biofilm (Strep. sanguinis and Strep. mitis) in NAM
model was carried out according to the method described by Wan Nordini
Hasnor et al. [28]. Ten glass beads were placed in the glass chamber to
represent the tooth in the mouth. The glass chamber was then placed in water
bath which serves as an incubator to maintain temperature that mimics the
human body temperature.
A sterilized saliva reservoir with a capacity of 50 ml was connected to a
peristaltic pump and the NAM model via sterilized rubber tubing. Sterilized
saliva was pumped into the NAM model for two minutes at a flow rate of 0.3
ml/min to coat the glass beads. This was followed by a flow of sterile distilled
water to rinse off the excess saliva that remains on the glass beads. The
experimental pellicle was now ready to receive bacterial inoculum. Bacterial
reservoir which consisted of single-species inoculum (Strep. sanguinis and
Strep. mitis) (108 CFU/ml) was pumped into the model at a rate of 0.3 ml/min
and was allowed to form on the glass beads for 24 hours to form a 24 hours
biofilm.
Treated experimental pellicle: The steps in the above step i.e. experimental
pellicle: negative-control was repeated. After rinsing off the excess saliva on the
glass beads with sterile distilled water, a 50 ml aqueous solution consisted of
mixture plant extracts (0.5 mg/ml) was allowed to flow into the NAM model for
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two minutes at a rate of 0.3 ml/min. This was followed by a flow of sterile
distilled water once again to rinse off the excess extracts on the glass beads.
Subsequently, the bacterial inoculum (108 CFU/ml) was pumped into the model
over a period of 24 hours to allow for the formation of a 24 hours single-species
biofilm on the glass beads. This procedure was repeated by using 0.12%
chlorhexidine (CHX) in place of the plant extracts to serve as a positive-control.
The experiment was carried out in triplicates.
The harvesting of the single-species biofilm on the glass beads and
determination of bacterial population
The procedures employed in the harvesting of the single-species biofilm were
carried out according to the chart in figure 5. After 24 hours, each of the six
glass beads with the biofilm formed on them was carefully taken out and placed
in the respective micro centrifuge tubes (1.5 ml) containing 1.0 ml of phosphateDirector: Fernando Estevez Castillo
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buffered saline (PBS). Each of the tubes was sonicated (10 seconds) and
vortexed (1 minute) to dislodge any attached bacteria on the glass bead. Each
of the tube subsequently containing the bacterial suspension. Out of the six
tubes, three were chosen for serial dilution while the other three were kept as
reserve. Six serial dilutions of the bacterial suspensions were carried out for
each of the tubes. The first serial dilution was referred to as tube 1 (T1) and the
sixth serial dilution as tube 6 (T6). A 100 µL of each of the serially diluted
bacterial suspensions (T1 to T6) was pipetted out and plated on three separate
Brain Heart Infusion (BHI) agars. The plates were incubated aerobically at 37°C
for 18-24 hours. From the plated results, the plates with the Colony Forming
Unit (CFU) number between 30-300 were used in the determination of adhered
bacteria [29]. In this study, the fourth serial dilution tube (T4) was found to
correspond to this CFU numbers.
Preparation of samples for scanning electron microscope (SEM) viewing
The preparation of samples for SEM viewing was carried out according to the
method described by Lagacé et al. [30]. The glass beads with the biofilm
formed on them were fixed in glutaraldehyde (4%) in glass vials for one hour at
room temperature. The glutaraldehyde was discarded and the glass beads were
rinsed once with distilled water. The washed glass beads were then fixed in
osmium tetraoxide (1%) and left overnight (14 hours) in tightly capped vials at
4°C in the refrigerator. On the next day, the vials were taken out from
refrigerator and left for 30 minutes at room temperature. The osmium tetraoxide
(1%) was gently pipetted out and the samples were washed with distilled water
for 15 minutes. The dehydration process was carried out by treating the
samples with the ascending percentages of ethanol (10%-100%). The samples
were immersed in the different concentrations of ethanol for 15 minutes. The
samples were then immersed in 100% ethanol twice to ensure that most of the
water in the samples was eliminated. Gradual displacement of ethanol with
acetone was then carried out (20 minutes each) using the following ratios (v/v):
Ethanol: Acetone 3:1 1:1 1:3 Following that, the samples were immersed in
100% acetone for four times, 20 minutes each time, followed by Critical Point
Dessication (CPD) process. The samples were then mounted on metal stubs
and coated with gold. After gold-coating process, the samples were ready for
SEM viewing.
Statistical Analysis
All data obtained in the study were analysed using t test of SPSS software. The
values were expressed as mean ± SD.
Results
From 100% bacterial inoculum pumped into the model, a single-species biofilm
of Strep. mitis showed the maximum adherence (11.53%) on the untreated
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experimental pellicle over a period of 24 hours, whereas only 1.83% of Strep.
sanguinis adhered (Figure 6).
The differences in the adherence capacity of these bacteria in the formation of
the single-species biofilms were statistically significant (p<0.05). When the
experimental pellicle was treated with plant extracts, the populations were
significantly reduced for both streptococci. On the experimental pellicle treated
with 0.12% chlorhexidine (CHX), it was observed that there was no adherence
of Strep. sanguinis, while Strep. mitis showed slight adherence at 1.13%. The
population of Strep. sanguinis on the experimental pellicle treated with CHX
was observed to be significantly less than their populations on the experimental
pellicle treated with plant extracts (p<0.05). The population of Strep. mitis
adhering on the experimental pellicle treated with CHX and plant extracts
however showed no difference (p>0.05). This result was further confirmed by
SEM viewing (Figures 7 and 8). It was clearly shown that population of Strep.
sanguinis showed a moderate number of cells on the untreated experimental
pellicle (Figure 7a). The cells tended to clump to each other. However, the
population of Strep. sanguinis was decreased on the experimental pellicle
treated with plant extracts (Figure 7b). The cells were also arranged in colonies
of short chain consisted of two to three cells. On the experimental pellicle
treated with 0.12% CHX, no cells were detected on the glass beads (Figure 7c).
The population of Strep. mitis showed a large number of cocci cells when they
were allowed to grow on the untreated experimental pellicle (Figure 8a). The
cells were clumped together. The numbers of cells were much reduced when
the experimental pellicle was treated with plant extracts. Similar to Strep.
sanguinis, the cells of Strep. mitis were also arranged in chains of colonies
consisting of four to seven cells per chain (Figure 8b). On the experimental
pellicle treated with 0.12% CHX, the number of cells adhered were almost
similar to the cells that adhered on the experimental pellicle treated with plant
extracts. However, only short chains were observed which consisted of two to
four cells per chain (Figure 8c).
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Discussion
Currently, there is an increasing interest to investigate the effect of natural
compounds, especially plants extracts, on the residence of the oral cavity. Many
of the investigations have been focused on the ability of the compound to either
promote the growth of beneficial organisms or inhibit the growth and
metabolism of oral bacteria associated with certain diseases. It has been
reported that Morus alba [21], Andrographis paniculata and Chinese black tea
[31], cranberry [32] and Mikania sp. [33] exhibited potentially useful antibacterial
properties towards some oral pathogens. An alkaloid extract sanguinarine
obtained from the plant Sanguinaria canadensis (bloodroot) is one example of
natural based antimicrobials. The combined usage of mouthrinse and dentifrice
containing sanguinarine has been shown to demonstrate the antiplaque effect
[34-37] and also can be used to cure gingivitis [36,37].
Our study has shown that the extract of the leaves of Psidium sp., Mentha
sp. and Mangifera sp. exhibited antimicrobial activities. The selection of these
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plants was based on findings that their extracts exhibited antimicrobial activities
against oral microbes grown under the planktonic state [5]. The planktonic state
refers to the condition where the bacteria were allowed to grow as suspension
in the test tubes. It has been demonstrated in their studies that pre-treatment of
experimental pellicle on saliva-coated glass beads with either P. guajava or
Piper betle can significantly disrupt the adhesion of the early plaque colonizers
to the pellicle. This subsequently will interfere with the initial stage of biofilm
development. Similar observations have also been reported by Percival et al.
[38] who strongly acknowledged the importance of the salivary pellicle during
the initial stages of biofilm formation. The property of the pellicle can be altered
in the presence of certain plant extracts. In a study carried out by Prashant et al.
[39], positive antimicrobial activity of mango chewing stick was detected against
oral Streptococci. The many positive antimicrobial activities on oral bacteria
exhibited by plant extracts provide great support in the promotion of such
extracts as oral healthcare agents. Their use may help to moderate the
development of dental plaque so that its texture is always thin and porous.
Besides, mouthwash sold in pharmacy stores or local supermarkets are either
contains many chemicals or alcohol-based which may cause unwanted side
effects to the consumers. On the untreated experimental pellicle, the adhesion
affinity of the single-species biofilm of Strep. mitis is the highest (11.53%)
compared to those of Strep. sanguinis (1.83%). The data obtained in this study
however contradicted the findings reported by Fathilah [40] who reported that
Strep. mitis and Strep. sanguinis, both showed almost similar percentage of
adhesion affinities (22%). The discrepancy in the results obtained in this study
and Fathilah [40] might have been due to the state of cells used in the
experiment. In our study, the bacteria cells and the nutrients were continuously
supplied to the growth system of the artificial mouth (NAM) model. On the
contrary in the planktonic state, bacteria cells were grown under a static phase
[40]. In a condition when there was no flow of nutrients involved, the cells in the
planktonic state may have the ability to adhere at a greater extent than cells
growing in a continuous system [41]. Under this state, cells were more exposed
to the clearing effect of the flowing liquid. Significant differences with respect to
the growth of cells while under the planktonic and biofilm condition have also
been reported by Black et al. [42] and Ceri et al. [43].
When the experimental pellicle was treated with plant extracts, it was clearly
shown in the results that the number of adhering cells in the single-species
biofilm was reduced. This is because the binding of bacterial cells to the
acquired pellicle in the mouth or to the experimental pellicle in vitro is much
influenced by the adherence capacity of the pellicle. Once the experimental
pellicle was altered by plant extracts or any other antimicrobial agent, it will
affect the binding affinity of the bacteria. Our results are consistent with the
study carried out by Oliveira et al. [44], which confirmed the antimicrobial effects
of plant’s components to the single-species oral biofilm. Throughout the studies,
CHX was chosen as a positive-control as it is the most widely used
chemotherapeutic agent and known for its ability to inhibit plaque and gingivitis
[44-48]. CHX has been vastly used in the prevention of dental caries especially
in patients following radiation therapy who often have difficulty in performing
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tooth brushing [49,50]. The mechanism of action of CHX has been associated
with its effect on pellicle formation [51], bacterial adherence mechanisms as
well as modification of the bacterial cell wall properties which ultimately will
cause lysis of the cell [52]. From SEM results, we are suggesting that the
mechanism of action of mixed-plant extracts used in this study might be towards
the formation of experimental pellicle. Once this pellicle was disrupted, the
pioneer bacteria in the oral cavity like Strep. mitis and Strep. sanguinis could
not adhere to the tooth surfaces. However, further study need to be done to
investigate more on this matter.
Conclusions
The plant extract applied to the saliva-coated glass beads appeared to have
altered the experimental pellicle and subsequently reduced the adhesion affinity
of the bacteria in the biofilms. This may suggest that the extracts of the plants
have potential as anti-plaque agents.
Acknowledgement
This study was supported by Vote F0145/2005A, R&D IRPA No 09-02-03- 0197
EA197 & Kuok Foundation Bhd. 13.
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ALOPATIA
AUMENTO DEL RIESGO DE DETERIORO COGNITIVO EN PACIENTES
DIABETICOS TRATADOS CON METFORMINA
Eileen M. Moore, PHD1,2; Alastair G. Mander, MBBS2; David Ames, MD1,3; Mark
A. Kotowicz, MBBS2,4,5; Ross P. Carne, MD2,4; Henry Brodaty, MD6,7; Michael
Woodward, MD8; Karyn Boundy, MD9; Kathryn A. Ellis, PHD1,3,10; Ashley I.
Bush, PHD10,11; Noel G. Faux, PHD10; Ralph Martins, PHD12,13; Cassandra
Szoeke, PHD3,14; Christopher Rowe, MD 15; David A. Watters, MBCHM2,4; The
AIBL Investigators*
1
The University of Melbourne, Department of Psychiatry, Parkville, Victoria, Australia; 2Barwon Health,
Geelong, Victoria, Australia; the 3National Ageing Research Institute, Parkville, Victoria, Australia; the
4
Deakin University School of Medicine, Waurn Ponds, Victoria, Australia; the 5North West Academic
Centre, The University of Melbourne, Sunshine, Victoria, Australia; the 6Centre for Healthy Brain Ageing,
University of New South Wales, School of Psychiatry, Sydney, Australia; 7Aged Care Psychiatry, Prince of
Wales Hospital, Randwick, New South Wales, Australia; 8Austin Health, Heidelberg Repatriation Hospital,
Heidelberg, Victoria, Australia; 9The Queen Elizabeth Hospital, Woodville South, South Australia, Australia;
the 10Mental Health Research Institute, The University of Melbourne, Parkville, Victoria, Australia;
the 11Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia; the 12Centre of
Excellence for Alzheimer’s Disease Research & Care, School of Exercise, Biomedical and Health Sciences,
Edith Cowan University, Joondalup, Western Australia, Australia; the 13Sir James McCusker Alzheimer’s
Disease Research Unit (Hollywood Private Hospital), Neurosciences Unit, Health Department of Western
Australia, Perth,Western Australia, Australia; 14Preventative Health Flagship, Commonwealth Scientific
and Industrial Research Organisation (CSIRO), Parkville, Victoria, Australia; and the 15Austin PET Centre, Austin
Hospital, Heidelberg, Victoria, Australia; *A complete list of the AIBL Investigators can be found at www.aibl.csiro.au.
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[Diabetes Care 36:2981-2987, 2013]
RESUMEN
Objetivo: Investigar las asociaciones de metformina, vitamina B12 sérica,
suplementos de calcio y deterioro cognitivo, en pacientes con diabetes.
Diseño de la investigación y Métodos: Los participantes fueron reclutados de
los estudios clínicos “Primary Research in Memory” (PRIME), de los estudios
de envejecimiento “Australian Imaging, Biomarkers and Lifestyle” (AIBL), y de la
Región Barwon del sudeste de Australia. Se incluyeron pacientes con
enfermedad de Alzheimer (AD) (n = 480) o deterioro cognitivo leve (n = 187) y
otros cognitivamente intactos (n = 687); y fueron excluidos los que tuvieron un
ACV, o enfermedades neurodegenerativas diferentes al AD. Los análisis de los
subgrupos se realizaron para los participantes que tenían diabetes tipo 2 (n =
104) o intolerancia a la glucosa (n = 22).
Resultados: Los sujetos con diabetes (n = 126) tuvieron una peor perfomance
cognitiva con respecto a aquellos que no tenían (n = 1,228; razón de
posibilidades ajustada 1.51 [95% CI 1.03–2.21]). Entre los pacientes con
diabetes la peor perfomance cognitiva fue asociada con el uso de metformina
(2.23 [1.05–4.75]). Después de ajustar por edad, sexo, nivel de educación,
historia de depresión, vitamina B12 sérica y uso de metformina, los
participantes con diabetes, quienes estaban tomando suplementos de calcio,
tuvieron la mejor perfomance cognitiva (0.41 [0.19–0.92]).
Conclusión: el uso de metformina fue asociado con la perfomance de
deterioro cognitivo. La vitamina B12 y los suplementos de calcio, pueden
mejorar la deficiencia de vitamina B12 inducida por metformina y fueron
asociados con los mejores resultados cognitivos. Los estudios prospectivos
podrán garantizar la evaluación de los efectos benéficos de la vitamina B12 y el
calcio sobre la cognición, en personas ancianas con diabetes que están
medicados con metformina.
Introduction
In 2010, more than 346 million people had diabetes worldwide. Recent studies
from the U.K. (1) and Italy (2) reported that the adult prevalence of diabetes was
approximately 4.2%. In the U.S., the prevalence of diabetes in the adult
population may be as high as 14% when undiagnosed cases are included (3).
The prevalence of diabetes may be higher in some developing nations: in the
developing region of southern China it was reported to be 21.7% in 2010 (4).
The prevalence of diabetes is more than 20% in some Pacific Island nations,
reaching 47% in 22- to 64-year-old American Samoans (5).
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In diabetes, hyperglycemia activates the cellular signaling protein kinase C,
which induces production of the vasoconstrictor protein endothelin-1. Excess
intracellular glucose is converted to sorbitol by the enzyme aldose reductase.
When intracellular levels of glucose are high, this process exhausts the energy
substrate NADPH, resulting in oxidative stress. High intracellular sorbitol levels
cause osmotic stress and cell death. These biochemical changes in
hyperglycemia are a proposed mechanism for macrovascular and
microvascular complications and neuropathy (6–8). Diabetes is associated with
a faster rate of cognitive decline in those with mild cognitive impairment (MCI)
(9) and an increased risk for developing Alzheimer disease (AD) (10).
Approximately 90% of patients with diabetes have type 2 diabetes (1). The
biguanide metformin is a first-line treatment for type 2 diabetes, increasing
glucose uptake in muscle while reducing liver gluconeogenesis (the synthesis of
glucose from amino acids). These effects are mediated by activation of the
celular signaling protein AMP–activated protein kinase (11).
Metformin first became available in the U.K. in 1958 and entered the Canadian
market in 1971, but it has been available in the U.S. only since 1995. In a
survey of 65,000 U.S. war veterans (12), metformin use among those with
diabetes increased from 29% in 2000 to 63% in 2005. Among 242 Australian
veterans who had diabetes, metformin was used by 75% in 2005 but decreased
to 57% in 2009 (13). The rate of vitamin B12 deficiency among patients who are
taking metformin is reported to approach 30% (14–16). A drug interaction
between metformin and the cubilin receptor inhibits the uptake of vitamin B12
from the distal ileum, lowering serum vitamin B12 levels. In a longterm,
randomized, placebo-controlled trial, metformin therapy in type 2 diabetes was
associated with a 19% reduction in serum vitamin B12 concentrations
compared with placebo (17). In a case-control study, Wile and Toth (18)
reported that metformin use was associated with reduced vitamin B12 levels
and more severe peripheral neuropathy in patients with diabetes.
In a prospective trial, calcium supplements were reported to reverse the drug
interaction that causes vitamin B12 deficiency induced by metformin (19). The
clinical significance of alleviating metformin induced vitamin B12 malabsorption
by calcium supplementation has not been previously investigated. By correcting
vitamin B12 levels in patients with diabetes who use metformin, calcium
supplements may help to preserve cognitive function. In addition, neuronal
signaling in memory and learning involves a calcium-mediated process, so
calcium supplementation may also have a direct effect on the brain. Calcium
dysregulation is the subject of one proposed theory for age-related cognitive
changes and AD (20). The risks and potential benefits of calcium
supplementation on cognition and for alleviating vitamin B12 malabsorption
merit further investigation. The amyloid plaques seen in the brains of patients
with AD are formed by aggregation of Ab peptides. In cell cultures, Chen and
colleagues (21) reported that activation of AMP–activated protein kinase by
metformin increased the expression of b-secretase, an enzyme that increases
the formation of Ab peptides.
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One recent case-control study that included 14,172 participants 65 years of age
or older reported that taking metformin over the long term increased the risk of
AD (odds ratio [OR] 1.71 [95% CI 1.12–2.60]) (22). Recent studies of murine
models of diabetes indicate that metformin may attenuate irregularities in
phosphorylation of tau proteins (23) or may facilitate neuroneogenesis (24) and
so may be of benefit to those with AD. In 25,393 patients older than 50 years
with type 2 diabetes, metformin was reported to reduce the risk of dementia by
24% (hazard ratio 0.76 [95% CI 0.58–0.98]) (25). The purpose of our study was
to investigate the associations of metformin, serum vitamin B12 levels, and
cognition in a sample of patients with diabetes.
Research, designs and methods
Participants and settings
Participants were recruited from two prospective studies: the Prospective
Research in Memory (PRIME) clinics study and the Australian Imaging,
Biomarkers and Lifestyle (AIBL) study of aging. Only data and biochemical
measurements pertaining to baseline visits were included in this analysis. The
PRIME study recruited 970 participants from 9 sites in Australia, including 3
each in Victoria and New South Wales and 1 each in Queensland, Western
Australia, and South Australia. The AIBL study of aging recruited 1,112
participants in Victoria (60%) and Western Australia (40%). The study cohorts
and methods of the PRIME and AIBL studies are described elsewhere (26,27).
A further 862 participants who resided in the Barwon region of southeastern
Australia between 2001 and 2011 also were recruited through the Cognitive,
Dementia and Memory Services clinic at the McKellar Centre, a rehabilitation
and aged-care facility. Patients with AD who were seen at a geriatrician’s
private practice during the same period also were recruited (n = 935).
Study design
Participants in the PRIME study were recruited during routine patient care. AIBL
participants volunteered after an advertisement on television in late 2006. The
Mini-Mental State Examination (MMSE) was used to assess cognitive ability.
Subjects were assessed at scheduled visits during the PRIME and AIBL studies
or ad hoc during routine patient care. All participants with serum vitamin B12
measurements taken within 6 months of cognitive assessment were included.
Participants without serum measurements taken within 6 months of cognitive
assessment (n = 1,015) were excluded. The data from records pertaining to
subjects who were recruited from more than one source (n = 566) were merged.
Of the remaining participants, there were 121 with stroke and 566 with
diagnoses other than AD, such as frontotemporal dementia, Parkinson disease,
dementia with Lewy bodies, or mixed dementias. Participants with other
neurodegenerative diseases were excluded to limit confounders. A further 291
participants were excluded because they had incomplete medical histories;
information that was missing included dates of birth, medication use, and
comorbid conditions. A subgroup analysis was performed with participants who
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had diabetes (n = 104) or impaired glucose tolerance (n = 22). Patientswith type
1 diabeteswere not specifically excluded, but there were none with serum
vitamin B12 measurements taken within 6 months of cognitive assessment.
Ethical approval
Institutional review was performed at each study host site. Reviewing
committees included the Barwon Health Human Research Ethics Committee
(HREC) (Victoria), Austin Health HREC (Victoria), St. Vincent’s Hospital
Governance Review Unit (Victoria), Hunter New England HREC (New
SouthWales), Northern Hospital Network HREC (New South Wales), Northern
Sydney Central Coast HREC (New South Wales), Metro North Health Service
District HREC (Queensland), South Metropolitan Area Health Service HREC
(Western Australia), and The Queen Elizabeth Hospital Ethics of Human
Research Committee (South Australia).
Statistical analyses
An ordinal logistic regression model was formed with categories of cognitive
performance as the response variable and diabetes as a predictor. Categories
were ordered by cognitive performance, including “most impaired” (MMSE ,18;
n = 137), “mildly impaired” (MMSE 18–23; n = 240), “minimally impaired”
(MMSE 24–27; n = 295), and “not impaired” (MMSE 28–30; n = 682). The
model was adjusted for age, sex, level of education, and depression because
these factors were previously reported to affect MMSE testing (28,29).
A subgroup analysis of only patients with diabetes was then performed. The
response variable was cognitive performance. Categories were “most impaired”
(MMSE ,18; n = 39), “mildly impaired” (MMSE 18–23; n = 40), “minimally
impaired” (MMSE 24–27; n = 32), and “not impaired” (MMSE 28–30; n = 15).
The effect of metformin on the cognitive performance of patients with diabetes
was investigated in this model, which then was adjusted for serum vitamin B12
measurements and use of calcium supplements to investigate any possible
interactions. There was insufficient information on use of other antidiabetic
drugs, the duration of metformin use, and markers for socioeconomic status,
diet, or exercise to investigate these variables.
Results
There were 1,354 participants included in this analysis (Fig. 1).
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Participants were 51–99 years old (mean age 6 SD 73.8 6 8.3 years); females
outnumbered males (59.5 vs. 40.5%). Just more than half of the participants
(50.4%) scored 28–30 on the MMSE and so were considered not impaired;
21.8% were minimally impaired (MMSE 24–27), 17.7% were mildly impaired
(MMSE 18–23), and 10.1% scored less than 18 on the MMSE (most impaired).
Participants with diabetes were marginally older than participants without
diabetes (75.5 vs. 73.6 years; P = 0.013). The number of males was
proportionally larger among participants with diabetes (46.8 vs. 39.9%), but this
difference was not statistically significant. Prevalence of depression was similar
between participants with diabetes and those without diabetes (31.7 vs. 27.3%;
P = 1.000). The proportion of participants with a tertiary level of education was
higher among participants without diabetes than participants with diabetes (39.3
vs. 22.2%; P , 0.001). The number of participants who scored below 28 on the
MMSE was proportionally higher among participants with diabetes than those
without diabetes (69.0 vs. 47.6%; P = 1.000). After adjusting for age, sex,
education, and depression, participants with type 2 diabetes had worse
cognitive performance than participants without diabetes (adjusted OR 1.51
[95% CI 1.03–2.21]). Cognitive performance was better in younger participants,
those without depression, and those with a higher level of education. The
adjusted ORs for each predictor are shown in Table 1. Among participants with
diabetes, cognitive performance was worse in patients who were taking
metformin (adjusted OR 2.23 [95% CI 1.05–4.75]).
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MMSE scores were lower in participants with diabetes who used metformin
(mean score 6 SD 22.8 +/- 5.5) than in those who did not use metformin (24.7
+/- 4.4). Participants with diabetes who had vitamin B12 levels ,250 rmol/L also
[1.12–4.66]). MMSE scores were lower among those with serum vitamin B12
,250 rmol/L (22.9 6 4.7) than those with higher levels (25.0 6 4.7). Each 1-year
increase in age was associated with an 8% increased risk of impaired cognitive
performance (OR 1.08 [95% CI 1.03–1.13]). A secondary or tertiary level of
education was the strongest predictor of better cognitive performance in
patients with diabetes. The adjusted ORs for each variable are shown in Table
2.
Conclusions
In our series, patients with diabetes who were taking metformin had worse
cognitive performance than participants who were not taking metformin. Our
observations agree with those previously reported by Imfeld and colleagues
(22), in particular that patients who are taking metformin may be at an increased
risk for cognitive impairment.
This association was weakened after adjusting for serum vitamin B12 levels;
thus any effect metformin has on cognitive performance may be at least partially
mediated by altering serum vitamin B12 levels. Alternatively, patients who are
prescribedmetformin may haveworse glycemic control or diabetes-related
complications than patients with diabetes who are not prescribed metformin, so
there remains the potential for confounding, despite restricting the analysis to
only patients with diabetes. However, because metformin is a first-line
pharmacotherapy for the treatment of type 2 diabetes, this would seem unlikely
(30).
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There was insufficient information regarding the duration of metformin use, the
severity of diabetes (e.g., HbA1c levels), duration of diabetes, or use of other
antidiabetic drugs to enable us to investigate these effects in our study,
particularly because these findings were based on a small sample. We
recommend a larger study to examine the effect of dose and duration of
metformin use, and the effects of other antidiabetic agents using a battery of
cognitive assessments and following participants over a number of years.
Calcium supplements have previously been reported to reverse vitamin B12
deficiency induced bymetformin. In this study, patients with diabetes who used
calcium supplements were less likely to be cognitively impaired. However,
calcium supplements have been reported to be associated with an increased
risk for myocardial infarction in postmenopausal women and in patients with
chronic kidney disease (31–34). In contrast, a recent meta-analysis indicates
that supplementation with both vitamin D and calcium is associated with a
reduction in mortality compared with vitamin D supplementation alone (35).
Because this population already has increased cardiovascular risk (36), the
safety of calcium supplementation in patients with diabetes treated
withmetformin would need to be established before such interventions could be
recommended.
Patients with diabetes are at an increased risk for AD (10). In diabetes, amylin
aggregation destroys the b-cells of the pancreas (37). By the same mechanism,
a protein misfolding disorder may be related to aggregation of amyloid plaques.
Metformin is a widely prescribed first-line monotherapy for type 2 diabetes but is
associated with vitamin B12 deficiency and peripheral neuropathy. A casecontrol study of more than 14,000 patients reported that long-term metformin
use was associated with an increased risk for AD in those $65 years old (22).
Metformin at pharmacological doses was reported to increase the expression of
b-secretase in cell culture; this may be a possible disease mechanism (21).
Alternatively, metformin also impairs absorption of vitamin B12 via a drug
interaction that occurs at the distal ileum. Low serum vitamin B12 levels are
associated with AD and other neurodegenerative diseases (38).
Cognitive performance of patients with diabetes was measured using the
MMSE. TheMMSEmay be inadequate for detecting differences between higher
functioning adults (39). The MMSE is sensitive to age, depression, and level of
education, so allmodels were adjusted for these factors. Most of our subjects
were assessed during routine clinical care by clinicians who use the MMSE as
part of their standard assessment. In Australia, documentation of cognitive
impairment using an MMSE score and improvement while receiving therapy is
required to obtain subsidized antidementia therapies (40). More comprehensive
assessment tools may be preferable for use in future investigations of cognitive
impairment in at-risk populations such as those we have studied.
Increased monitoring of cognitive ability in patients with diabetes who use
metformin is warranted, particularly among older adults (aged older than 50
years).
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Vitamin B12 supplements are inexpensive and may improve the cognitive
outcomes of patients with diabetes. Adequately powered, prospective,
controlled trials are warranted to investigate further the association between
diabetes, cognitive decline, and the effect of metformin therapy, as well as the
possible amelioration using vitamin B12 and/or calcium supplementation.
Acknowledgments
The PRIME study was funded by Janssen Australia. This study received support from the
National Health and Medical Research Council via the Dementia Collaborative Research
Centres program (DCRC2). The AIBL study currently receives funding from the Science
Industry Endowment fund.
Pfizer International contributed financial support to assist with analysis of blood samples and to
further the AIBL research program. Core funding for the AIBL study was provided by the
Commonwealth Scientific and Industrial Research Organisation (CSIRO), which was
supplemented by in-kind contributions from the study partners: The University of Melbourne,
Neurosciences Australia Ltd., Edith Cowan University, Mental Health Research Institute,
Alzheimer’s Australia, National Ageing Research Institute, Austin Health, University of Western
Australia, CogState Ltd., Macquarie University, Hollywood Private Hospital, and Sir Charles
Gardner Hospital.
A.I.B. is a shareholder in Cogstate Ltd., Prana Biotechnology Ltd., Mesoblast Pty Ltd., and
Eucalyptus Pty Ltd. A.I.B. is a former consultant for Prana Biotechnology Ltd., has received
speaker fees from Amgen, and is supported by an Australia Fellowship from the National Health
andMedical Research Council (NHMRC).
N.G.F. is supported by an NHMRC training fellowship. C.S. is supported in part by a research
fellowship funded by Alzheimer’s Australia. No other potential conflicts of interest relevant to this
article were reported. Alzheimer’s Australia (Victoria and Western Australia) assisted with
promotion of the study and screening of telephone calls from volunteers. Other than initial
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promotion of the study and screening of volunteer calls by Alzheimer’s Australia, the study
sponsors did not have any role in the study design; the collection, analysis, or interpretation of
data; thewriting of the article; or the decision to submit the article for publication.
E.M.M. reviewed the literature, collected biochemical measurements from study host sites,
analyzed and interpreted the data, and drafted the manuscript. A.G.M., M.A.K., R.P.C., and
D.A.W. interpreted the data and reviewed the manuscript. D.A. interpreted the data and
reviewed the manuscript, collected the PRIME data and managed the PRIME study database,
and collected the AIBL data and managed the AIBL database. H.B., M.W., and K.B. interpreted
the data and reviewed the manuscript and collected the PRIME data and managed the PRIME
study database. K.A.E., A.I.B., N.G.F., R.M., C.S., and C.R. interpreted the data and reviewed
the manuscript and collected the AIBL data and managed the AIBL database. E.M.M. is the
guarantor of this work and, as such, had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data analysis. This study was
presented at the 2012 Smart Geelong Network Research of the Year Awards, Victoria,
Australia, 26 October 2012, for which it was awarded the Population Health Researcher of the
Year Award.
The investigators thank the participants and clinicians who contributed to collection of the data
at the nine study sites: Prince of Wales Hospital (Marika Donkin, Kim Burns, Katrin Seeher);
The Queen Elizabeth Hospital (Shelley Casey, Trish Steventon); St George’s Hospital (Maree
Mastwyk, Alissa Westphal, Nicola Lautenschlager, Olga Yastrubetskaya, Marilyn Kemp,
Edmond Chiu, Jennifer Ames); Austin Health Repatriation Hospital (Irene Tan, Henry Zeimer,
Leonie Johnston); Hornsby Ku-Ring-Gai Hospital (Sue Kurrle, Roseanne Hogarth, Judith Allan);
Fremantle Hospital (Roger Clarnette, Janice Guy, Denae Clark); The Prince Charles Hospital
(Chris Davis, Mary Wyatt, Katrina Brosnan,MargaretMorton); Rankin Park Hospital (John Ward,
Jeanette Gatgens); and Geelong Private Hospital (Bernadine Charles). The investigators also
thank the following clinicians, who referred patients with AD and/or MCI to the study: Brian
Chambers (The University of Melbourne), Edmond Chiu (The University of Melbourne), Roger
Clarnette (Fremantle Hospital), David Darby (Mental Health Research Institute), Mary Davison
(Glencairn Consulting Suites),
John Drago (Warrigal House), Peter Drysdale (Delmont Memory Clinic), Jacqui Gilbert (Royal
Melbourne Hospital), Kwang Lim (The University of Melbourne),Nicola Lautenschlager (The
University of Melbourne), Dina LoGiudice (The University of Melbourne), Peter McCardle (The
University of Melbourne), Steve McFarlane (Delmont Memory Clinic), John Merory (Diamond
Valley Specialist Centre), Daniel O’Connor (Kingston Centre), Christopher Rowe (Austin
Health), Ron Scholes (Donvale General Physicians), Mathew Samuel (Fremantle Mental Health
Services), and Darshan Trivedi (Rockingham General Hospital).
References
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diabetes in the UK: 1996-2005. J Epidemiol Community Health 2009;63:332–336
2. Monesi L, Baviera M, Marzona I, Avanzini F, Monesi G, Nobili A, et al. Prevalence, incidence and
mortality of diagnosed diabetes: evidence from an Italian population based study. Diabet Med
2012;29:385–392
3. Boyle JP, Thompson TJ,Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of
diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes
prevalence. Popul Health Metr 2010;8:
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4. Zhang YH, Ma WJ, Thomas GN, et al. Diabetes and pre-diabetes as determined by glycated
haemoglobin A1c and glucose levels in a developing southern Chinese population. PLoS One
2012;7:e37260
5. Maga A, de Courten M, Dan L, et al. American Samoa NCD Risk Factors STEPS Report. Suva, Fiji,
Department of Health, World Health Organization, 2007
6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412
7. Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of
retinopathy in type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156–163
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8. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of
diabetes on the development and progression of long-term complications in insulin-dependent diabetes
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9. Ravona-Springer R, Luo X, Schmeidler J, et al. Diabetes is associated with increased rate of cognitive
decline in questionably demented elderly. Dement Geriatr Cogn Disord 2010;29:68–74
10. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity,
diabetes, and related disorders. Biol Psychiatry 2009;67:505–512
11. Zhou G, Myers R, Li Y, et al. Role of AMP activated protein kinase in mechanism of metformin action. J
Clin Invest 2001;108:1167–1174
12. Huizinga MM, Roumie CL, Elasy TA, et al. Changing incident diabetes regimens: a Veterans
Administration cohort study from 2000 to 2005. Diabetes Care 2007;30:e85
13. Proust-Lima C, Amieva H, Dartigues JF, Jacqmin-Gadda H. Sensitivity of four psychometric tests to
measure cognitive changes in brain aging-population-based studies. Am J Epidemiol 2007;165:344–350
14. Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term
metformin therapy. BMJ 1971;2:685–687
15. Andrès E, Vidal-Alaball J, Federici L, Loukili NH, Zimmer J, Kaltenbach G. Clinical aspects of
cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with
special focus on oral cobalamin therapy. Eur J Intern Med 2007;18:456–462
16. Stowers JM, Smith OA. Vitamin B 12 and metformin. BMJ 1971;3:246–247
17. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes
and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181–c2187
18. Wile DJ, Toth C. Association ofmetformin, elevated homocysteine, and methylmalonic acid levels and
clinically worsened diabetic peripheral neuropathy. Diabetes Care 2010;33:156–161
19. BaumanWA, ShawS, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses
vitamin B12 malabsorption induced bymetformin. Diabetes Care 2000; 23:1227–1231
20. Oliveira AM, BadingH. Calcium signaling in cognition and aging-dependent cognitive decline.
Biofactors 2011;37:168–174
21. Chen Y, Zhou K, Wang R, et al. Antidiabetic drug metformin (GlucophageR) increases biogenesis of
Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A 2009;
106:3907–3912
22. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s
disease: a population based case-control study. J Am Geriatr Soc 2012;60:916–921
23. Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer’s disease-like neuropathology in obese,
leptin-resistant mice. Pharmacol Biochem Behav 2012;101:564–574
24. Wang J, Gallagher D, DeVito LM, et al. Metformin activates an atypical PKC-CBP pathway to promote
neurogenesis and enhance spatial memory formation. Cell Stem Cell 2012;11:23–35
25. Hsu CC,Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and
reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011;24:485–493
26. Brodaty H, Woodward M, Boundy K, Ames D, Balshaw R; PRIME Study Group Patients in Australian
Memory Clinics: baseline characteristics and predictors of decline at six months. Int Psychogeriatr
2011;23:1086–1096
27. Ellis KA, Bush AI, Darby D, et al. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of
aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of
Alzheimer’s disease. Int Psychogeriatr 2009;21:672–687
28. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State
Examination by age and educational level. JAMA 1993;269: 2386–2391
29. Iverson GL. Interpretation of Mini-Mental State Examination scores in community dwelling elderly and
geriatric neuropsychiatry patients. Int J Geriatr Psychiatry 1998;13:661–666
30. Colagiuri S,Dickinson S,Girgis S,Colagiuri R. National Evidence Based Guideline for Blood Glucose
Control in Type 2 Diabetes.
Canberra, Diabetes Australia and the NHMRC, 2009
31. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium
supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the
Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPICHeidelberg). Heart 2012;98:920–925
32. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction
and cardiovascular events: meta-analysis. BMJ 2010;341:c3691–c3699
33. Bollanc MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D
and risk of cardiovascular events: reanalysis of theWomen’s Health Initiative limited access dataset and
meta-analysis. BMJ 2011;342:d2040–d2048
34. West SL, Swan VJ, Jamal SA. Effects of calcium on cardiovascular events in patients with kidney
disease and in a healthy population. Clin J Am Soc Nephrol 2010; 5(Suppl. 1):S41–S47
35. Rejnmark L, Avenell A, Masud T, et al. Vitamin D with calcium reduces mortality: patient level pooled
analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab 2012;97:2670–2681
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36. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO
Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44(Suppl. 2):S14–S21
37. Hayden MR, Tyagi SC, Kerklo MM, Nicolls MR. Type 2 diabetes mellitus as a conformational disease.
JOP 2005;6:287–302
38. Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. Cognitive impairment and vitamin B12:
a review. Int Psychogeriatr 2012;24:1–16
39. Lawrence de Koning AB, Werstuck GH, Zhou J, Austin RC.Hyperhomocysteinemia and its role in the
development of atherosclerosis. Clin Biochem 2003;36:431–441
40. Ames D, Flynn E. Dementia services: an Australian view. In Dementia. Burns A, Levy R, Eds. London,
Chapman and Hall Medical, 1994, p. 611–621
HOMEOPATIA
TRATAMIENTO HOMEOPATICO DEL SINDROME PREMENSTRUAL: UNA
SERIE DE CASOS
Karine Danno*, Aurélie Colas, Laurence Terzan and Marie-France Bordet
Laboratoires Boiron, 20 rue de la Libération, F-69110 Sainte-Foy-les-Lyon,
France
[Homeopathy: (2013) 102;59-65]
RESUMEN
Objetivo: Estudio observacional prospectivo para describir el manejo
homeopático del síndrome premenstrual (PMS) por un grupo de médicos
franceses.
Métodos:
Mujeres con síndrome premenstrual (PMS) fueron tratadas con homeopatía
individualizada. La intensidad de los 10 síntomas clínicos de PMS fueron
determinados individualmente, a la inclusión, a los 3 y a los 6 meses de
seguimiento: ausente=0, leve=1, moderado=2, severo=3. El puntaje Total de
Síntomas (rango: 0 a 30) fue calculado y comparado para cada paciente, a la
inclusión y durante el seguimiento. El impacto de los PMS sobre las actividades
cotidianas (calidad de vida, QoL), fue comparado a la inclusión y durante el
seguimiento, como: ninguno, leve, moderado, severo, muy severo.
Resultados: Veintitrés mujeres recibieron solamente tratamiento homeopático
(edad promedio: 39.7 años). Folliculinum (87%) fue el medicamento
homeopático más prescripto, seguido por Lachesis mutus (52.2%). Los
síntomas premenstruales (PMS) más comunes (moderado o severo) a la
inclusión fueron: irritabilidad, agresión y tensión (87%), mastodinia (78.2%),
aumento de peso y distensión abdominal (73.9%); al seguimiento: irritabilidad,
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30
agresión y tensión (39.1%), aumento de peso y distensión abdominal (26.1%) y
mastodinia (17.4%). El puntaje global promedio para la intensidad de síntomas,
fue 13.7 a la inclusión y 6.3 al seguimiento. El descenso (7.4) fue
estadísticamente significativo (p < 0.0001). Veintiún mujeres reportaron que su
calidad de vida (QoL), también mejoró significativamente (91.3%; p < 0.0001).
Conclusiones: El tratamiento homeopático fue bien tolerado y pareció tener
un impacto positivo sobre los síntomas premenstruales (PMS). Folliculinum fue
el medicamento homeopático más prescripto. Sería necesario un ensayo
randomizado controlado contra placebo para investigar la eficacia de los
medicamentos homeopáticos individuales sobre los síntomas premenstruales
(PMS).
Palabras clave: Homeopatía; estudio observacional; síndrome premenstrual;
Folliculinum; salud femenina; manejo de los síntomas.
ARTICULO ORIGINAL
Introduction
Premenstrual syndrome (PMS) is a common condition, affecting 3-5% of
women of childbearing age,1 and encompasses a broad range of somatic, mood
and behavioural symptoms that appear during the luteal phase of the menstrual
cycle (MC) and disappear when menstruation begins. Numerous symptoms
have been described in daily diary recordings of patients and several symptombased tools for the diagnosis of PMS and the more severe form of the condition,
known as premenstrual dysphoric disorder (PMDD), have been proposed.2-7
The social burden of PMS is high and the repeated cyclic nature of symptoms
can cause significant impairments in personal/family relationships and everyday
life8. Symptoms ofPMS are severe enough towarrant treatment in 20-25%of
women.9 Treatment strategies are based on either suppression of the hormonal
cycle leading to ovulation or treatment of individual symptoms that cause the
most distress to patients.10 The systematic review of the Cochrane Database
2009 by Brown et al.1 supports the efficacy of selective serotonin reuptake
inhibitors in patients with severe PMS, and a second review of the Cochrane
Database 2009 by Lopez et al. showed possible efficacy of combined oral
contraceptives containing drospirenone (plus ethinyl estradiol 20 mg).11
However, side-effects including nausea, insomnia, intermenstrual bleeding,
asthenia, breast pain and decreased libido have been reported with these
treatments and often result in treatment withdrawal.1,11 Many women are now
turning to therapies outside of conventional medicine such as homeopathy,
acupuncture and cognitive-behavioural therapy in order to relieve their PMS
symptoms.12 Several recent studies and literature reviews report the efficacy of
a number of herbal, vitamin,
fatty acid and mineral-based remedies in women with PMS.12-16
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31
We carried out this observational study in women with PMS in order to describe
the homeopathic management of PMS by a group of general practitioners (GPs)
and gynaecologists with experience in homeopathy and to assess the effect of
homeopathic treatments in relieving PMS symptoms and improving quality of
life (QoL).
Materials and Methods
This prospective, observational study was carried out between September 2008
and April 2010 in seven centres in France. Seven GPs and gynaecologists with
experience and expertise in prescribing homeopathic medicines participated in
the study. These doctors had all received specific training in homeopathy during
their Masters degree.
Patients
Physicians recruited the first women who presented at their surgery for the main
reason of PMS, with symptoms present for >3 months, and if they were
prescribed homeopathic treatment at the time of consultation. In these cases,
the study was proposed to the women and if they agreed to participate the
physicians completed the study documents according to the oral declarations
made by the women concerning symptoms and QoL. No specific criteria were
used for the diagnosis of PMS as it was an observational study based on the
procedures used in daily clinical practice; the clinical symptoms of PMS were
not prompted by the physician and the diagnosis was made by the physicians
solely on the basis of the symptoms declared spontaneously by the patients.
Thus, the symptoms reported by the women were not prompted by the clinical
diagnosis established by the physician. The diagnosis depended on the
competence of the physician to identify PMS. Women were not included in the
study if they had: any known neoplastic gynaecological pathology,
hysterectomy, continuous progestative treatment (implant, vaginal ring,
intrauterine device, pill) or combined oral contraceptives (oestrogen and a
progestogen).Womenwere also excluded if they did not comply with treatment,
if there was a change in their hormone status (introduction of an oestrogen
and/or progestogen, amenorrhoea, pregnancy), if they underwent a
hysterectomy and/or bilateral oophorectomy during the study period, or if they
withdrew consent or were lost to follow-up. All patients were required to attend
an inclusion consultation and a follow-up consultation, usually between 3 and 6
months later. All women gave their informed consent to participate. Physicians
were remunerated for participation in the study, but no patient received any
payment or other incentive.
Therapy
All women were prescribed homeopathic medication by their physician (GP or
gynaecologist) who recorded the treatment prescribed on the study documents.
The choice of treatment, dosage and treatment duration were left to the
discretion of the treating physician and were individualized for each patient.
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32
Assessment of clinical progress
All patients were followed for a period of 3-6months after initiation of treatment.
As mentioned above, the intensity of symptoms and impact of PMS on QoL
were recorded by the physicians according to oral declarations made by the
women at inclusion and at the follow-up visit. The intensity of 10 clinical
symptoms of PMS (mastodynia; irritability e aggression e tension; feeling
depressed; asthenia; weight gain and abdominal bloating; feeling of bearing
down; heaviness of lower limbs; back pain; headaches; skin manifestations)
was scored individually at inclusion and at follow-up, as follows: symptom
absent = 0, mild in intensity = 1, moderate in intensity = 2, severe in intensity =
3. The global score for the 10 symptoms was then determined by adding up the
individual scores to give a final score ranging from 0 to 30. The global symptom
score was then compared for each patient at inclusion and at the 3-6 month
follow-up. Evolution of symptom intensity was rated as: aggravation (change
from absent to mild, mild to moderate, moderate to severe); stable (no change);
or improvement (change in intensity from severe to moderate, moderate to mild
or mild to absent). The impact of PMS symptoms on daily activities was
assessed by the women as: none, mild, moderate, severe, very severe.
Evolution of impact on daily activities was rated as: improvement (change from
very severe to severe, severe to moderate, moderate to mild or mild to none);
stable (no change); or aggravation (change from none to mild, mild to moderate,
moderate to severe, or severe to very severe).
Statistical analysis
The following tests were used to compare the data collected at inclusion and at
follow-up: Student’s t test or Wilcoxon test (ShapiroeWilk) for quantitative data,
or generalized equations of estimation for qualitative data. Alpha risk was fixed
at 5%. p Values were calculated using a GEE (generalized estimating
equations) model. All statistical analyses were carried out using SAS software.
Results
Study population
A total of 34 women with PMS were recruited during the study period. Five were
excluded from the final analysis for the following reasons: wrongly included in
the study (receiving oestrogen and/or progestogen treatment), n = 2; premature
withdrawal, n = 1; poor compliance, n = 1; lost to follow-up, n = 1. Six further
patients were excluded since they did not receive homeopathic treatment
exclusively. Thus, the final population analyzed consisted of 23 women (mean
age 39.7 years, range: 19e56). The clinical symptoms of PMS in these women
at inclusion are shown in Table 1.
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33
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34
D: dose GR: granules
One dose consists of 200 globules and corresponds to approximately 10 granules. MD: missing data
Homeopathic medicines prescribed
The homeopathic treatments and dosages prescribed to the 23 women are
summarized in Table 1. The most frequently prescribed homeopathic medicine
was Folliculinum (20/23; 87%), mainly 15c and 30c, followed by Lachesis mutus
15c and 30c (12/23; 52.2%). One patient took Folliculinum only, six patients
(26.1%) took two different medicines, 12 patients (52.2%) took three or four
different medicines and four (17.4%) took five or six. Folliculinum was
associated with Lachesis mutus in nine patients (39.1%), with Lycopodium
clavatum in three (13.0%), with Nux vomica in three (13.0%), with Lac caninum
in four (17.4%), with Natrum muriaticum in three (13.0%), with Cyclamen
europaeum in three (13.0%), with Histaminum in three (13.0%) and with
Progesteronum in three (13.0%). Prescription of Folliculinum
was not
associated with any particular symptom. Concerning the dosage, Folliculinum is
prescribed twice during the MC when oestrogen secretions are maximal: once
before ovulation (around the 8th day of the MC) and then around the 20th day
of the MC (oestrogenic peak). Other homeopathic medicines were also
prescribed cyclically.
PMS symptoms at inclusion
The symptoms of PMS at inclusion are shown in Table 1. The most frequent
clinical symptoms (moderate or severe) of PMS at inclusion were: irritability,
aggression and tension in 20 (87%) women, mastodynia in 18 (78.2%) and
weight gain and abdominal bloating in 17 (73.9%). The mean global score for
symptom intensity at inclusion was 13.7.
Effects of homeopathic treatment at follow-up
The most frequent clinical symptoms (moderate or severe) at follow-up were:
irritability, aggression and tension in nine women (39.1%), weight gain and
abdominal bloating in six (26.1%) and mastodynia in four (17.4%). The mean
global score for symptom intensity at follow up was 6.3. The mean decrease in
global score from inclusion (-7.4) was statistically significant (p < 0.0001). All
patients reported an improvement in their symptoms at the end of the study,
particularly irritability, aggression and tension, and mastodynia, which were the
most common clinical symptoms at inclusion. The difference in results between
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35
inclusion and follow-up was statistically significant for all symptoms except back
pain (Table 2). QoL also improved significantly at follow-up in 21 of the 23
women (91.3%; p < 0.0001) (Figure 1). In the two women who did not report an
improvement in QoL, the distress caused by PMS remained unchanged in one
(patient 17) and had become worse in one (patient 10).
Mean follow-up time for the 23 patients was 19 weeks (131.0 +/- 48.1 days),
corresponding to five MCs. The mínimum duration was 76 days (2.5 months),
the median was 122 days and the maximum was 269 days (9 months).
Homeopathic treatment was well tolerated and compliance with treatment was
good.
Discussion
The results of this study support those of previous randomized placebocontrolled trials (RCTs) where homeopathic medicines appeared to be effective
at reducing PMS symptoms.17,18 In the 23 women in our study, there was a
significant decrease in intensity of all symptoms except back pain at the 3-6
month follow-up and 21 women (91.3%) reported that PMS was no longer a
significant problem in their daily life. The most frequently prescribed remedy
was Folliculinum, mainly 15c and 30c, but also 9c, 7c and 12c. Folliculinum is a
homeopathic medicament made from oestrone, a synthetic form of oestrogen.
One of the physiological mechanisms proposed for PMS is a hormonal
imbalance between oestrogen and progesterone.19,20 In the absence of official
recommendations on the management of PMS there has been much interest in
complementary therapies for the treatment of PMS symptoms over the past
decade. Whelan et al. identified 62 herbs, vitamins and minerals for which
claims of efficacy in PMS have been made.13 However, only calcium appeared
to have good quality evidence to support its use in PMS, while chasteberry and
vitamin B6 may be effective.13 Data in the literature also support the possible
efficacy of polyunsaturated (essential) fatty acids in PMS.14,16 Hypericum
perforatum has been shown to improve the physical and behavioural symptoms
of PMS but has no effect on mood- and pain-related symptoms compared to
placebo.15 In an RCT carried out in France in 1995, Lapaisant reported that
Folliculinum was more effective at reducing mastodynia in women with PMS
than placebo.17 The efficacy of homeopathic treatment at reducing the
symptoms of PMS was confirmed in another placebo-controlled RCT carried out
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36
in Israel by Yakir et al.18 Most studies performed to date are not RCTs and do
not measure the effect of treatment on the severity of individual PMS
symptoms. Furthermore, most studies on homeopathic treatment in PMS are
short in duration and have an inadequate sample size. Indeed, only 19 patients
completed the RCT carried out by Yakir et al. (11 treatment vs. 8 placebo)18
while the RCT of Lapaisant included only 36 patients (21 homeopathy vs. 15
placebo).17 More RCTs are required to take these factors into account and to
consider the heterogeneity of this syndrome. Our study has several important
limitations. First, like previous studies, the population treated with homeopathy
alone was small and comprised only 23 women. Second, the study was
observational in design and was based on the daily clinical practices and
diagnosis established by practitioners. No formal criteria, as described in the
literature,2-7 were used to diagnose PMS and the inclusion of patients therefore
depended on the competence of the physicians to establish a correct diagnosis.
For this reason, and the fact that there was no comparator arm, we cannot
conclude further on the efficacy of homeopathic treatment for PMS but simply
present the patients as a series of cases. Indeed, previous data in the literature
show that over 20% of patients submitted to placebo treatment in PMS studies
have a major improvement in their symptoms.17,18,21 Third, the seven centres
involved in this study did not recruit a similar number of women [range: 1-6] and
a posible centre effect was not taken into account in the analysis of the results.
Fourth, we did not use daily rating forms to record symptoms due to the long
study period and because the study was observational in design. This is the
most widely accepted tool to measure patient outcome.4 Assessment of
symptom intensity was subjective and was reported after patient self-rating.
However, as our objective was simply to describe the symptoms reported by the
patients on which the doctor based his/her diagnosis and not to attribute them
to the luteal or follicular phase of the MC we considered that patient selfreporting was adequate for the current study since patients would report those
symptoms that were most important to them, either in intensity or impact. We
also chose not to record the presence of any major psychiatric comorbidities or
other conditions with symptoms that are exacerbated by the MC for a similar
reason. Finally, each symptom was given the same weighting and no individual
symptom was considered to be more important than another.
Conclusions
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This observational study confirms the place of homeopathic medicines in the
management of women with PMS. The most frequently prescribed homeopathic
medicines were Folliculinum and Lachesis mutus. In this study of homeopathy
in daily practice, PMS symptoms and QoL were improved by homeopathic
treatment. Most therapies ultimately originate from practice experience but
should be supported by the results of RCTs conducted to investigate the
efficacy of individual homeopathic medicines as a treatment for PMS.
Conflict of interest statement
All authors are employees of Laboratoires Boiron, France.
Acknowledgements
The authors thank Newmed Publishing Services for writing this manuscript.
Manuscript production was funded by Laboratories Boiron.
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20 Smith MA, Youngkin EQ. Managing the premenstrual syndrome. Clin Pharm 1986; 5: 788-797.
21 Freeman EW, Rickels K. Characteristics of placebo responses in medical treatment of premenstrual
syndrome. Am J Psychiatry 1999; 156: 1403-1408.
NUTRICION
LOS EFECTOS DEL CONSUMO DE ESCARAMUJO SOBRE LOS
MARCADORES DE RIESGO DE DIABETES TIPO 2 Y ENFERMEDAD
CARDIOVASCULAR: INVESTIGACION CRUZADA, RANDOMIZADA, A
DOBLE CIEGO EN PERSONAS OBESAS.
U Andersson1, K Berger1, A Hogberg2, M Landin-Olsson3 and C Holm1
1
2
Department of Experimental Medical Science, Lund University, Lund, Sweden; Corporate
3
Affairs, Orkla ASA, Oslo, Norway and Department of Clinical Sciences, Lund University, Lund,
Sweden.
[European Journal of Clinical Nutritition (2012) 66, 585-590]
RESUMEN
Antecedentes/Objetivos: en estudios realizados en ratones, el polvo de
escaramujo (rosa canina), ha podido mostrar que previene y revierte la
obesidad inducida por dietas ricas en grasas y la intolerancia a la glucosa, así
como también reducir los niveles de colesterol en plasma. El objetivo de este
estudio fue investigar si la ingesta de polvo de escaramujo, durante 6 semanas,
ejerce efectos metabólicos benéficos en individuos obesos.
Sujetos/Métodos: Un total de 31 individuos obesos con tolerancia a la glucosa
normal o alterada, fueron incluidos en un estudio cruzado, randomizado, a
doble ciego, en el cual se evaluaron los efectos de la ingesta diaria, durante 6
semanas, de una bebida en base a polvo de escaramujo, comparado con una
bebida control. Fueron evaluados en los sujetos: peso corporal, tolerancia a la
glucosa, presión sanguínea y marcadores de inflamación.
Resultados: En comparación con el control, el consumo durante 6 semanas de
la bebida en base a polvo de escaramujo, dio como resultado una reducción
significativa de: la presión sistólica (-3.4%; P=0.021), colesterol plasmático
total (-4.9%; P=0.0018), (LDL) cholesterol (-6.0%; P=0.012) y la relación
LDL/HDL (-6.5%; P=0.041). El puntaje de la evaluación de riesgo de Reynolds
para enfermedad cardiovascular, se redujo en el grupo de escaramujo
comparado con el grupo control (-17%; P=0.007). El peso corporal, la presión
diastólica, la tolerancia a la glucosa, los niveles plasmáticos de HDL colesterol,
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triglicéridos, incretinas y los marcadores de inflamación, no difieren entre los
dos grupos.
Conclusión: el consumo diario de 40 g de polvo de escarmujo durante 6
semanas puede reducir significativamente el riesgo cardiovascular en personas
obesas a través de la reducción de la presión sistólica y los niveles plasmáticos
de colesterol.
Palabras clave: Colesterol; presión sanguínea; tolerancia a la glucosa; peso
corporal; inflamación.
ARTICULO ORIGINAL
Introduction
The incidence and prevalence rates of type 2 diabetes mellitus (T2DM) is
increasing dramatically all over the world.1 Current estimates predict that 439
million people worldwide will be affected by 2030,1 and this figure does not take
into account the large number of people in prediabetic states, that is, glucose
intolerance accompanied or not by obesity. Obesity is a very strong risk factor
for the development of T2DM and approximately 90% of people diagnosed with
T2DM are either overweight or obese. The mechanisms whereby obesity leads
to the development of T2DM are poorly understood, but dysfunction of the
expanding adipose tissue, leading to ectopic lipid deposition, and low-grade
inflammation are believed to be key events linking obesity to T2DM.2,3 An
inflammatory reaction may also be triggered via changes in the gut microbiota
resulting in endotoxemia.4 Besides hyperglycemia, T2DM is characterized by
elevated levels of circulating lipids and hyperlipidemia is causally linked to the
cardiovascular complications of T2DM.5 Owing to the pathophysiological role of
lipids in the development of both T2DM and its complications, diabetes care is
strongly focused on the strict regulation of the plasma levels of both glucose
and lipids. It has been estimated that the development of diabetes to a large
extent is preventable by adopting a healthy diet and increasing physical activity
(International Diabetes Federation, http://www.idf.org/prevention). Thus, there is
an urgent need for the identification and development of foods with documented
effects on the prevention of development of obesity, T2DM, and associated
diseases and complications. Rose hip is the pseudofruit of the rose plant.6 The
fruit is rich in antioxidants, such as ascorbic acid, phenolic compounds and
carotenoids. It has been used in traditional medicine for almost a century for its
high content of ascorbic acid. During the last decade, the anti-inflammatory
properties of rose hip have been documented in several studies and it has been
used successfully to ameliorate symptoms in patients suffering from
osteoarthritis, rheumatoid arthritis and lower-back pain.7-11 Recently, two
independent studies, performed in two different strains of mice, demonstrated
that rose hip exerts anti-obese and anti-diabetic effects. Ninomiya et al.12
reported that the administration of an acetone extract of fruits and seeds from
dog rose (Rosa canina) prevented body-weight gain in mice fed with a normal
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chow diet. At least some of the effects could be ascribed to trans-tiliroside, a
constituent of the extract, as administration of this reduced body-weight gain
and improved glucose tolerance. In the other study, performed in our laboratory,
the high-fat fed C57BL/6J mouse model, simulating human obesity and insulin
resistance, was used to demonstrate that the administration of rose hip powder
was able to both prevent and reverse diet-induced obesity and glucose
intolerance.13 In both studies, it was ruled out that decreased food intake
accounted for the effects. Furthermore, in both studies rose hip administration
was also shown to exert lipid-lowering effects. The aim of the present study was
to investigate whether the beneficial metabolic effects observed in response to
rose hip intake in mice could be reproduced in a human study. To this end, we
performed a randomized, double-blind, cross-over study in which either a rose
hip drink or a control drink was administered for 6 weeks to obese individuals
with or without glucose intolerance. Primary endpoints were body weight,
glucose tolerance, and fasting levels of glucose and insulin. Secondary
endpoints were plasma total cholesterol, plasma low density lipoprotein (LDL)
cholesterol, blood pressure and markers of inflammation.
Subjects and Methods
Participants
The study was carried out in the period April 2009 to February 2010 at the
Department of Clinical Sciences, Lund University Hospital. Study participants
were recruited from the registry of obese patients at the Endocrinology Clinic.
The patients of this registry had previously participated in a time-limited weight
reduction program at the clinic. Despite poor results in terms of weight
reduction, they were not interested in gastric bypass surgery, but had
expressed their interest in forthcoming weight reduction programs and food
intervention studies. Inclusion criteria were body mass index430, willingness to
participate in the study, comply with the daily intake of the drinks and the
recommended energy intake during the course of the study. Exclusion criteria
were diabetes, previous or ongoing insulin treatment, abnormal thyroid, liver or
kidney status, known gastro-intestinal disorder, pregnancy and suspected
allergy to ingredients of the control and test drinks. A total of 34 subjects,
randomly selected from the registry, were assessed for eligibility
(Supplementary Figure 1) and 31 of these (23 women and 9 men; age range
33-- 75, mean age 56, mean body mass index 35) signed the written consent
and entered as participants in the study. Seven of the participants had impaired
glucose tolerance, based on the results of the oral glucose tolerance test, nine
were on hypertensive therapy and eight were on lipid-lowering medication with
statins. There were no reported changes in medication during the study.
Baseline characteristics of the participants at the start of the study were similar
between individuals receiving control first and rose hip second, and individuals
receiving rose hip first and control second, except for a
significantly higher body weight in the group that was randomized to start
with the rose hip drink (Table 1).
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41
Study control
The study design was that of a randomized, double-blind, cross-over study with
a 6-week treatment period and a 2-week wash-out period (Supplementary
Figure 1). The participants were randomly assigned to start with either the
control or the test drink. In addition to the consumption of the control or test
drink (5 dl per day), the participants were instructed to restrict their caloric
intake to 75% of resting metabolic rate x 1.3, where resting metabolic rate was
calculated according to the equation provided by World Health Organization.
Examples of daily menus, adhering to the national guidelines of macro- and
micronutrient intake, were provided. The participants visited the clinic every 2
weeks to obtain test drinks for the following 2 weeks, measure body weight,
give blood samples and report adverse effects. Intake was confirmed by
questions to the participants at each visit at the clinic. At the start and end of
each period a meal-based glucose tolerance test was performed. Participants
visited the clinic on a total of nine occasions. Medical supervision and biological
sampling took place at Lund University Hospital, Lund, under the responsibility
of M.L-O. The study was approved by the Ethics Committee, Lund, Sweden
(Dnr 2009/11) and was in accordance with the Helsinki Declaration of 1975, as
revised in 1983.
Control and test drink
The fruit from rose hip (Rosa canina) was imported from Chile. In a twostep
procedure, seeds were removed and the remainder of the fruit was ground and
mixed with apple juice, citric acid solution and sugar in a mixing tank with
stirring. The mixture was preheated with a heat exchanger to 55°C and
degassed before heating to 92°C. After 95 s the mixture was cooled to 20°C
and stored in an aseptic tank until packaged in 500 ml aseptic Tetra Brik
packages (Tetra Pak, Lund, Sweden). The control, consisting of apple juice,
white grape juice, citric acid solution and sugar, was produced with the same
procedure. Test drinks were analyzed at Eurofins (Lidkoping, Sweden) for
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content of raw protein, raw fat, water, sucrose, fructose, glucose, total fiber,
insoluble fiber and soluble fiber. The recipe and results of analyses of the drinks
are shown in Table 2. The drinks were designed to have equal amounts of
simple sugars and the analysis of the final products showed a difference of
<10%.
Meal-based tolerance test
Glucose tolerance was assessed by measuring plasma glucose at 0, 30, 60, 90
and 120 min, and plasma insulin at 0 and 30 min following the ingestion of a
carbohydrate-rich breakfast. Participants came to the clinic at 0800 hours in
fasting condition and had a breakfast corresponding to 521 kcal and 100 g
carbohydrates, of which 38 g were disaccharides (26 sucrose) and 20.5 g
monosaccharides. Blood samples were drawn in two separate tubes, one with
Trasylol (aprotinin, Bayer AG, Leverkusen, Germany) and one with DPP-4
inhibitor, and centrifuged (4 1C) immediately after sampling. Plasma was frozen
on dry ice and stored at _80 1C until analysis. Body weight and blood pressure
Body weight was measured using an electronic body weight scale (Tanita,
Tanita Europe BV, Amsterdam, The Netherlands), which was calibrated
regularly. Blood pressure was measured using a mercury sphygmomanometer
in the sitting position after 5 min resting. The mean of three consecutive
measurements was recorded.
Laboratory analyses
Except for GLP-I, GIP, adiponectin and PAI-I, all blood and plasma analyses
were conducted at the accredited clinical chemistry laboratory at Lund
University Hospital. C-reactive protein (CRP) was measured using a
highsensitivity assay. PAI-I was analyzed using a high-sensitivity assay
available at the accredited blood coagulation laboratory at Lund University
Hospital, Malmo. GLP-I and GIP was analyzed using Luminex Technology
(LX200, Luminex Corporation, Austin, TX, USA). Adiponectin was analyzed with
ELISA (Millipore Corporation, Billerica, MA, USA).
Statistical analyses
All data are shown as means (95% confidence intervals) with s.e.m. To
determine the differences in the measured variables following intake of the
control and rose hip drink, paired t-tests were used when the data was
Gaussian distributed according to D’agostino and Pearson ómnibus normality
test. When not normally distributed, Wilcoxon matched-pairs signed rank test
was used. Statistical analyses were performed using GraphPad Prism 5
(GraphPad Software, San Diego, CA, USA) and the statistical software package
SPSS for Windows (SPSS Inc., Chicago, IL, USA). P<0.05 was considered
significant.
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Results
Dietary intake and adverse effects
43
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44
Both drinks were tolerated well by the participants, but mild gastrointestinal
problems were reported in both the groups, more frequently in the rose hip
group (11 compared with 2 in the control group). Loose stools and flatulence
was the most commonly reported adverse effect (eight in the rose hip group,
one in the control group), but obstipation was also reported (three in the rose
hip group, one in the control group).
Body weight and glucose tolerance
The sequence of the drink did not influence the outcome, so data for each drink
were pooled and referred to as control group and rose hip group, respectively.
Daily intake of the rose hip drink was found to have no effect on body weight
and body mass index (Table 3). Furthermore, no effects were observed on
HbA1c or fasting levels of plasma glucose and insulin (Table 3), indicating that
rose hip intake had no effects on glucose tolerance or insulin sensitivity.
Possible effects on glucose tolerance were further assessed in meal-based
glucose tolerance tests. These showed no significant differences between the
groups with regard to plasma glucose levels (Supplementary Figure 2) or
plasma insulin levels (Supplementary Table 1). Also, there were no differences
with regard to the incretin response, assessed by the measurement of plasma
levels of GLP-I and GIP at 0 and 30min (Supplementary Table 1).
Plasma lipids and blood pressure
Intake of the rose hip drink was found to result in a small but significant
reduction in plasma levels of total cholesterol (-4.9%; P<0.0018), as well as LDL
cholesterol (-6.0%; P=0.012), compared the intake of the control drink (Figure
1). Plasma high-density lipoprotein (HDL) cholesterol, on the other hand, was
not altered (Figure 1). The changes in cholesterol parameters were reflected in
a decrease in the LDL/HDL ratio (-6.5%; P=0.041) in the rose hip group (Figure
1). Exclusion of the eight participants who were on statin treatment in the
analyses resulted in more pronounced cholesterol-lowering effects of rose hip,
that is, a reduction of total cholesterol by 5.5% (P=0.0039; n=19) and a
reduction of LDL cholesterol by 8.6% (P=0.0057; n=19). In contrast to
cholesterol, no differences in plasma triglyceride levels were found between the
rose hip and the control group (Table 3). Intake of rose hip was found to
significantly lower systolic blood pressure, with no effect on diastolic blood
pressure (Figure 2). Systolic blood pressure was significantly lower than that in
the control group even when the eight participants who were on
antihypertensive treatment were excluded from the analyses (-3.7%; P=0.04,
n=20). Applying the algorithm of the Reynolds risk assessment score14,15 to the
data demonstrated a significant reduction (17%, P=0.0075, n=25) in 10-year
risk of cardiovascular disease (Figure 3).
Inflammatory markers
In order to assess the possible effects of rose hip intake on lowgrade
inflammation, we measured the plasma levels of CRP and PAI-I, two markers
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of inflammation, and adiponectin, an adipokine with anti-inflammatory
properties. There were no significant differences between the groups for any of
these markers (Table 3).
Discussion
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To the best of our knowledge, this is the first study in humans investigating the
metabolic effects of dietary administration of rose hip. Daily consumption of rose
hip was found to significantly decrease plasma cholesterol and systolic blood
pressure in obese, non-diabetic individuals, whereas no effects on body weight,
glucose tolerance and markers of inflammation were observed. The reduction in
plasma cholesterol and systolic blood pressure was estimated to lower the risk
of developing cardiovascular disease by 17%, using the algorithm for Reynolds
risk assessment score. The magnitude of the lowering of plasma levels of LDL
cholesterol in the rose hip group, that is 6.0% compared with the control, was
within the range from 6 to 15% that has been reported in the few long-term
studies performed on cholesterollowering effects of single foods16-19 and
accords very well with the 5% reduction considered realistic in real-world
situations when dietary saturated fat levels are low.20 The observed decrease
in LDL cholesterol in the rose hip group is below the minimum of 8-9% required
to see a reduction in total mortality, although it is estimated to reduce the
incidence of coronary heart disease by 14.5%.21 With the exception of two
individuals who had slightly elevated cholesterol levels, the participants of the
present study had normal plasma cholesterol levels. Thus, the full potency of
rose hip to lower plasma cholesterol may not have been revealed and a followup study in hyperlipidemic individuals seems warranted. Cholesterol-lowering
properties of rose hip have previously been demonstrated in a study performed
in high-fat diet fed C57BL/6J mice.13 In that study, the reduction in total plasma
cholesterol was shown to involve a reduction in both LDL cholesterol and HDL
cholesterol with a larger effect on LDL cholesterol, resulting in a decreased
LDL/HDL ratio. In the present study, a very similar profile of the cholesterollowering effects was observed, with a significant reduction in LDL cholesterol
and LDL/HDL ratio, and a smaller, in this case non-significant, lowering of HDL
cholesterol. In a previous human study where a rose hip drink was administered
daily to hypercholesterolemic subjects for 6 weeks as a control to intake of the
same drink supplemented with Lactobacillus plantarum 299v, no cholesterollowering effects were observed by rose hip alone.22 The reason for the
discrepancy compared with the present study is not known, but it should be
pointed out that besides differences in the characteristics of subjects, the dose
of rose hip was only about 25% of that employed in the present study. In
another study where 5 g of a standardized rose hip powder (Hyben Vital) was
administered daily for 3 months to patients with osteoarthritis, total cholesterol
was reduced by 8.5%, indicating that lower doses of rose hip may also promote
lowering of plasma cholesterol if administered for longer periods.23 It should be
pointed out, however, that besides differences in dose and length of
administration, also the preparation of rose hip differs between studies, making
comparisons difficult. For instance, the powder used by Rein et al.23 contains
both the seeds and shells of the rose hip plant, whereas only the shells were
used in our study. The fact that the cholesterol-lowering effects were exerted by
both of these preparations may indicate that the shells rather than the seeds
account for the cholesterol-lowering properties of rose hip. The mechanism
whereby rose hip is capable of reducing plasma cholesterol is unknown. In the
study performed in C57BL/6J mice, the reduction in plasma cholesterol was
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47
accompanied by reduced levels of hepatic cholesterol, but the expression of
SREBP-2 and HMG-CoA reductase was unaltered, indicating that cholesterol
biosynthesis was unaffected.13 It is possible that the high fiber content of rose
hip impairs the enterohepatic circulation of bile acids by preventing their reabsorption, thereby promoting increased synthesis of bile acids from
cholesterol, that is, a mechanism of action similar to that of the cholesterollowering drug cholestyramin. The observed decrease in systolic blood pressure
(4mmHg) was close to the median reduction observed in 27 pharmacological
trials estimated to result in decreases of the incidence of coronary heart disease
and stroke by 415% and 25%, respectively.24 In a previous study, no decrease
in blood pressure in smokers was observed by daily intake of rose hip for 6
weeks, whereas intake of the same rose hip drink supplemented by
Lactobacillus plantarum resulted in a significant reduction of systolic blood
pressure.25 The dose of rose hip employed was about 25% of the dose in the
present study, which may explain why no effects were observed. The
mechanism whereby rose hip lowers systolic blood pressure is unknown. As for
the cholesterol-lowering effects, it could be speculated that the high fiber
content of rose hip at least partially accounts for the effect. Consumption of the
rose hip drink corresponded to a daily intake of 31 g of fiber. Two metaanalyses have concluded that an increase in fiber intake of 10-15 g per day for
8 weeks was associated with a decrease in systolic blood pressure of 12mmHg.26,27 Thus, the reduction of 4mmHg in the present study is likely to be
a result of the high fiber intake, although it may very well be that other bioactive
components than fiber contribute to the blood pressure-lowering effects of rose
hip. Daily intake of rose hip had no effects on body weight or glucose tolerance.
This is in contrast to two previous studies performed in mice, where dietary
intake of rose hip potently inhibited body-weight gain and also significantly
improved glucose tolerance.12,13 The reason for this discrepancy is not known,
but two obvious differences relate to the dose administered and the metabolic
status of the study population. Although the daily intake of rose hip powder in
the current study was high compared with previous studies in humans (40 vs 5
g8,11,23,28), it was much lower than that in the study in C57BL/6J mice, where
rose hip accounted for 30% of the daily food intake. The fact that the
participants of the current study, in contrast to the mouse studies, were on an
energy-restricted diet throughout the study could have obscured effects on body
weight and future studies in a large number of overweight, or even lean,
individuals on a nonrestricted diet would be of interest. Also, the present study,
designed to represent a first proof-of-concept study of posible metabolic effects
of rose hip in humans, was performed in obese individuals with no diabetes and
with only a few glucose intolerant participants. This is in contrast to the high-fat
fed C57BL/6J mouse model, where obesity is accompanied by glucose
intolerance. Several previous studies have demonstrated that the dietary
administration of rose hip to individuals with osteoarthritis and rheumatoid
arthritis exerts anti-inflammatory effects.7,8,11,29 Obesity and its associated
diseases are considered to be states of lowgrade inflammation. However, we
were unable to detect any significant differences with regard to two markers of
systemic inflammation, that is, CRP and PAI-I, or with regard to adiponectin, an
adipokine with anti-inflammatory as well as insulin-sensitizing effects. Possibly
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the most obvious explanation for the lack of effect on these markers is that the
low inflammatory tonus of our participants, shown by levels of CRP and PAI-I
within the normal range, makes it difficult to demonstrate anti-inflammatory
actions, at least as effects on these markers of inflammation. Although the
mechanisms whereby rose hip lowers systolic blood pressure and plasma
cholesterol levels remain unresolved, the findings of this study may have
important health implications. The current study could be the starting point for
exploring rose hip as a constituent of food portfolios aimed at reducing
cholesterol and blood pressure, and thereby decrease the risk of coronary heart
disease and mortality. Efficient food portfolios are urgently needed and they
represent an attractive alternative to statin treatment for people that, because of
muscle pain and increases in liver and muscle enzymes, do not tolerate statins,
as well as for people at risk of developing diabetes, as statins recently were
shown to increase the risk of diabetes.30 Food portfolios designed to lower
plasma cholesterol typically contain soy, nuts or almonds, viscous fiber and
plant sterols.20,31 It would be of interest to explore the potential additive and
synergistic effects of rose hip in such portfolios. Follow-up studies of dietary
treatment with rose hip should not only be performed in hyperlipidemic and
hypertensive individuals in order to study its potency in lowering cholesterol and
blood pressure in more detail, but also in diabetic individuals in order to further
explore its possible antidiabetic effects.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We thank Margit Bergstrom, Bertil Nilsson, Birgitta Danielsson and Sara
Larsson for the excellent technical assistance. The authors’ responsibilities
were as follows: UA, MLO, AH and CH designed the study; UA and KB
conducted research; AH was responsible for the production of control and test
drinks; UA, KB and MLO analyzed data; CH wrote the paper; UA and CH had
primary responsibility for final content of the paper. All authors read and
approved the final manuscript. This study was supported by Lund University
Antidiabetic Food Center, a VINNOVA VINN Excellence Center, the FuncFood
PhD program at Lund University, the Swedish Research Council (grant 11284
to C.H.), the Swedish Diabetes Association and A. Påhlsson Foundation.
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29 Chrubasik JE, Roufogalis BD, Chrubasik S. Evidence of effectiveness of herbal antiinflammatory drugs
in the treatment of painful osteoarthritis and chronic low back pain. Phytother Res 2007; 21, 675 -- 683.
30 Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al. Statins and risk of incident
diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375, 735 -- 742.
31 Jenkins DJ, Kendall CW, Faulkner DA, Nguyen T, Kemp T, Marchie A et al. Assessment of the longerterm effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. Am J Clin Nutr
2006; 83, 582-591.
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NOTAS DE INTERES
CURSO SUPERIOR DE MEDICINA NATURISTA PARA PROFESIONALES
DE LA SALUD
ASOCIACION ARGENTINA DE MEDICOS NATURISTAS
El 24 de abril, tuvo lugar en el Auditorio de la Asociación Argentina de Médicos
Naturistas, la clase: “"Preparaciones farmacéuticas Fitoterápicas y
Homeopáticas", perteneciente al Curso Superior de Medicina Naturista,
dictada por el Farm. Fernando Estévez Castillo.
La presentación estuvo a cargo de la Dra. Elba Albertinazzi, Presidente de la
Asociación Argentina de Médicos Naturistas, quién destacó la importancia del
conocimiento de estos tipos de medicamentos, como así también sus distintas
presentaciones, como herramientas terapéuticas fundamentales para el
tratamiento de los pacientes. Seguidamente, el Farm. Fernando Estévez
Castillo, desarrolló su exposición, brindando elementos fundamentales para el
conocimiento del profesional prescriptor, intercambiando experiencias y
opiniones con los alumnos, quienes participaron activamente durante toda la
clase.
El Farm. Fernando Estevez Castillo durante su exposición.
Esta actividad se viene repitiendo todos los años ininterrumpidamente, y ha
despertado gran interés entre los asistentes, ya que también se presentan
trabajos de investigaciones recientes, publicados en las más importantes
Revistas Científicas.
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JORNADA DE ACTUALIZACION EN FITOTERAPIA
Colegio de Farmacéuticos de la Provincia de Santa Fe 1° Circ.
Ciudad de Santa Fe
El 7 de Setiembre, se desarrolló en el Auditorio del Colegio de Farmacéuticos
de la Provincia de Santa Fe 1°Circ., de la Ciudad de Santa Fe, la Jornada de
Actualización en Fitoterapia, organizada por el Instituto de Preparados
Magistrales de dicho Colegio.
El evento contó con la participación de dos disertantes; el Dr. Jorge Alonso
(médico) y el Farm. Fernando Estévez Castillo, quienes abordaron la
temática propuesta, durante la extensa jornada, que comenzó a las 9.00 hs y
culminó a las 19.00 hs., y fueron acompañados por una nutrida asistencia de
Farmacéuticos y Médicos de distintas ciudades de la Provincia de Santa Fe y
también de Entre Ríos, que colmaron las instalaciones del Auditorio.
Izq.: Dr. Jorge Alonso, Der.: Farm. Fernando Estevez Castillo
La apertura de la Jornada estuvo a cargo del Farm. Hector Mainero,
Presidente del Instituto de Preparados Magistrales, quién destacó la
importancia de la actividad a desarrollar, y el interés despertado entre los
colegas farmacéuticos y médicos de la Provincia. Luego siguieron las
disertaciones, cuyo temario transcribimos a continuación:
Fitomedicina en Latinoamérica y el Mundo. Aspectos docentes. Su incorporación en la APS.
Drogas Vegetales Antiinflamatorias. Mecanismos de acción. Recomendaciones posológicas.
Drogas vegetales utilizadas para el Aparato respiratorio: Antitusivos, mucolíticos-expectorantes
y antiasmáticos. Fitodermatología: Productos naturales en Acné, Psoriasis, Vitiligo, Eczema
atópico. (Dr. Jorge Alonso)
Legislación Nacional y provincial: Medicamentos fitoterápicos, Suplementos dietarios y recetas
magistrales en base a drogas vegetales o preparados de origen vegetal. Interpretación y
aplicación de las diferentes normativas. Procesos extractivos: expresión, maceración,
lixiviación, etc. Productos extractivos: clasificación, definición y características generales de
cada uno (extractos secos, fluidos, blandos, secos, tinturas, etc.). Diferencias entre las Tinturas
Madre preparadas por las Farmacopeas Homeopáticas y las tinturas de Farmacopea Nacional
Argentina. Principales formas farmacéuticas de uso fitoterápico: tisanas, jarabes, gotas, óvulos,
cremas, geles, pomadas, aceites, comprimidos. Excipientes utilizados, manuales operatorios y
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formulaciones sugeridas para las patologías abordadas por el Dr. Jorge Alonso. (Farm.
Fernando O. Estevez Castillo)
La Jornada tuvo como característica fundamental, el intenso intercambio de
preguntas, ideas y propuestas, entre los disertantes y asistentes, abordando la
problemática nacional y provincial (en números anteriores de Homeonews, se
planteó la problemática de una Colega de Rosario), para un mejor desarrollo de
la actividad profesional en beneficio de la salud de la población.
Colegas que asistieron a la Jornada
Por último quiero agradecer al C
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participar en calidad de disertante, y en especial a la FFaarrm
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Vignolo y a la Farm. Ana María González, por ser además excelentes
anfitriones y estar pendientes de todos los detalles para alcanzar el éxito
de la actividad.
I JORNADAS NACIONALES DE FITOMEDICINA Y PROMOCION
DE LA FITOMEDICINA VETERINARIA
San Miguel de Tucumán - Tucumán
Los días 1 y 2 de Noviembre, tuvieron lugar en el Auditorio del Hotel Sheraton
de la Ciudad de San Miguel de Tucumán, las I Jornadas Nacionales de
Fitomedicina y Promoción de la Fitomedicina Veterinaria, organizadas por
el Laboratorio Calcagno y la Cátedra de Farmacognosia de la Facultad de
Bioquímica, Química y Farmacia de la Universidad Nacional de Tucumán.
Estas Jornadas fueron gratuitas (previa inscripción) y contaron con la asistencia
de una gran cantidad de estudiantes y profesionales de la salud (farmacéuticos,
médicos y veterinarios).
Se desarrolló, el día viernes 1°, de 9 a 19 hs, y el sábado 2, de 9 a 13:30 hs,
con la disertación de especialistas locales y nacionales, así como también con
la presentación de un importante número de Posters.
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El Dr. Jorge Alonso (izq.) y el Farm. Hugo Calcagno (der.) durante sus disertaciones.
Todas las disertaciones fueron de un gran nivel, destacando entre otros, las del
Dr. Jorge Alonso (Síndrome metabólico; Obesidad: nuevos avances y
desarrollo de fitofármacos; Fibromialgia: beneficios de la medicina
ortomolecular y la nutrigenómica y Antitumorales de origen vegetal), y las del
Veterinario Jorge Omar Rodríguez (Bases de la Fitomedicina Veterinaria y
Fitomedicación en Medicina Veterinaria), por la claridad en sus exposiciones y
los innumerables ejemplos de aplicaciones de los Fitomedicamentos en la
clínica diaria.
Izq.: Farm. Fernando Estévez Castillo; Der.: Dr. Jorge Omar Rodríguez (Veterinario).
Por otro lado, el Farm. Hugo Calcagno disertó sobre: “Formulación magistral
en la Fitomedicina. Incumbencia de todos los profesionales de la salud y
veterinarios” y el Farm. Fernando Estévez Castillo presentó “Arnica: el
antiinflamatorio natural”.
También hubo otras presentaciones, a través de videos, de productos
característicos de Tucumán, tales como: “Tucumán, capital mundial del limón”;
“Desde la Tierra: caña de azúcar” y “Exportación de arándanos de el
Aeropuerto Benjamín Matienzo de Tucumán”, que mostraron la gran capacidad
de dicha provincia para la producción de insumos de origen vegetal con fines
alimenticios y su potencial para la producción de medicamentos fitoterápicos.
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Auditorio del Sheraton colmado por los asistentes a la Jornada.
Todas las actividades tuvieron la presencia de gran cantidad de asistentes,
quienes además pudieron participar a través de preguntas a los
Conferencistas, luego de sus exposiciones o durante los Coffee-Breaks
ofrecidos.
Por último quisiera felicitar a los organizadores, en especial al Farm.
Hugo Calcagno Guerineau, por la excelente organización de las I
Jornadas Nacionales de Fitomedicina.
RECURSOS HUMANOS
Toxicidad en las Empresas
¿Podemos permitirnos jefes tóxicos que trabajen para nosotros? (de Juan
Carlos Cubeiro)1
Se habla mucho de la gente tóxica, de las personas problemáticas que elevan
la presión arterial de los demás por ser agresivas, autoritarias, chismosas,
envidiosas, neuróticas, manipuladoras, quéjicas… hasta el punto de reducirles
la esperanza de vida diez años. Cuando pensamos en ellas, solemos adoptar
la perspectiva del colaborador, del colega, del que las sufre, pero rara vez la
del CEO, la del primer ejecutivo/a de la organización. ¿Cuál es el impacto en
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los negocios y en la estrategia de contar con jefes tóxicos entre los mandos
intermedios o en la alta dirección?
Desde un enfoque estratégico, los jefes tóxicos son un depreciador del
talento de los profesionales de la empresa. En primer lugar, porque el
talento es la capacidad por compromiso en el contexto adecuado, y esa
toxicidad se contagia como un virus para reducir el compromiso, para que
decaiga la energía que se pone en el proyecto. El malestar reduce
drásticamente la implicación. Y en segundo lugar, la toxicidad va en contra de
las 4 C del contexto empresarial: de la cultura corporativa, entendida como
«la forma de hacer las cosas», que se enturbia; del clima laboral, que en más
de un 70% es resultado de los comportamientos de quien dirige el equipo; de
la compensación, que va más allá de la retribución fija y variable, y del grado
de cooperación, porque las personas tóxicas minan la confianza, que es el
gran activo social de una comunidad humana.
Un menor talento colectivo en la práctica influye negativamente sobre los
procesos, que se vuelven menos eficientes (el orgullo de pertenencia es el
mayor predictor de la eficiencia empresarial) e innovadores (la innovación
depende inicialmente de la creatividad y las personas felices son el triple de
creativas). Como consecuencia, los clientes están menos fidelizados ya que los
jefes tóxicos contagian de insatisfacción a los empleados, que lo transmiten a
los clientes finales. ¿El resultado? Menor cuota de mercado y menor
satisfacción del cliente, con resultados evidentes en la rentabilidad de la
compañía.
En términos de intangibles, la toxicidad de jefas y jefes impacta
desfavorablemente en el capital humano, en el capital clientes, en la
marca como tal y en las expectativas de futuro.
¿Qué podemos hacer como CEOs para atajar este problema?
En primer lugar, darle al asunto la consideración que merece, porque es
estratégico. En segundo, darnos cuenta de que las personas se vuelven tóxicas
(no nacen tóxicas) por estrés, por estrategia y por su naturaleza, lo que en la
práctica implica que la cultura empresarial debe evitar el estrés en lo posible (la
tensión constructiva es muy diferente a la ansiedad), debe dejar de
promocionar a quienes dan una imagen de ganadores pero en realidad son
tóxicos y debe seleccionar a personas cooperadoras y generosas, no a
individualistas carentes de empatía.
Finalmente, los CEOs debemos dar ejemplo en nuestro comportamiento
cotidiano en contra de la toxicidad. Si la admitimos continuadamente, nos
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convertimos en involuntarios cómplices con las consecuencias que hemos
apuntado.
¿Cuáles son las principales características de estos jefes tóxicos? (de
Hugo Urdaneta Fonseca)2
-Su cerebro emocional, no se activa al procesar información.
-Son inmunes ante el dolor de terceros.
-Por sus características normalmente son brillantes y ocupan importantes
posiciones en empresas y en la política.
-Son sumamente inteligentes.
-Son manipuladores.
-Quieren controlarlo todo.
-Tienen una extraordinaria capacidad para la oratoria.
-Les encanta el poder y lo buscan a cualquier precio.
-Al no sentir emociones no les importa quién se interponga en su camino.
-Utilizan el miedo para alcanzar sus objetivos.
-Muy frecuentemente en el fondo suelen tener complejo de inferioridad y falta
de autoestima, por lo que persiguen a los mejores de sus subordinados, al
sentirse amenazados por ellos.
Serpientes vestidas de traje.
Los psicólogos Paul Babiak y Robert Hare (3), este último uno de los mayores
expertos en psicopatía del mundo, en un libro con un título muy sugestivo
“Serpientes vestidas de traje” mencionan: las características de personalidad
destructivas que presentan los psicópatas son invisibles a muchos con quien
ellos actúan. Son expertos manipulando, especialmente en las entrevistas, se
muestran seguros de sí mismo y encantadores y por ende a menudo prosperan
a un ritmo rápido, en momentos de cambio organizacional e incertidumbre,
pueden infligir daño considerable. Son especialistas en explotar debilidades en
las comunicaciones y promover conflictos interpersonales.
¿Qué consecuencias generan estos jefes tóxicos en las organizaciones?
1.- Incremento en la rotación de trabajadores, sobre todo los de más talento y
potencial que no están dispuestos a calarse las manipulaciones de sus jefes.
2.- Trabajadores sumisos, con miedo a tomar decisiones que impliquen riesgos
o que contradigan a sus jefes.
3.- Ausencia total de creatividad e innovación como consecuencia del miedo y
del temor a ser castigado por los posibles errores cometidos al intentar algo
nuevo.
4.- Deterioro de la salud física y psíquica de los empleados.
5.- Agrupamiento en asociaciones sindicales de manera de protegerse contra
las tiranías de los jefes.
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6.- Saboteos, paralizaciones y huelgas en el peor de los casos por parte de
trabajadores.
7.- Demandas laborales.
8.- Deterioro paulatino del clima laboral, ya que el mecanismo de la
manipulación conlleva a una falta de comunicación efectiva y feedback
constructivo.
¿Cuál es el costo de mantener estos jefes tóxicos, para una
organización?
La rotación, los permisos por enfermedad, los gastos médicos, las demandas
laborales, el saboteo, los paros y la baja motivación entre otras consecuencias
disparan los costos, destruyen la moral de los trabajadores y reducen la
productividad de las empresas a medio plazo.
¿Qué pueden y deben hacer las organizaciones?
Lo único que no deben hacer las organizaciones es no hacer nada, no
querer ver la realidad. En este caso la alta gerencia y la organización de
Recursos Humanos o Gestión Humana, deben jugar un rol proactivo en la
identificación de estos jefes que más que crear, destruyen valor, para
tomar las decisiones que sean necesarias.
Jefes y empleados tóxicos ¿quiénes son los más peligrosos en las
empresas? (de Iprofesional – Cecilia Novoa)3
Con su pesimismo, quejas y mal humor, estos “personajes” son quienes,
generalmente, siembran la semilla de la discordia puertas adentro de las
organizaciones y contribuyen a generar un mal clima laboral. Claro que,
muchas veces, son las propias empresas las que permiten e incluso, con el fin
de tener un “informante”, fomentan, la aparición de dichos perfiles.
Los más peligrosos
Aunque estos empleados tóxicos pululan a diario por los pasillos y plantas de
las compañías, todos los expertos sondeados por este medio coincidieron en
que la situación es aún más complicada cuando la toxicidad proviene de
los jefes o de aquellas personas con equipos a cargo.
Según Eduardo Press, director de la Escuela Argentina de Psicología
Organizacional, cuanto más abajo de la pirámide está la persona tóxica y, por
lo tanto, menor nivel de compromiso tiene, más fácil resulta para la empresa
resolver el caso y, si no revierte su conducta, “deshacerse de ella”.
Por el contrario, “cuando el tóxico es un jefe, gerente o director, más altas son
las posiciones de quienes decidieron incorporar o promover a esa persona en
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la compañía y más difícil es que alguien reconozca y acepte que la elección fue
errónea”, agrega.
Gloria Cassano, directora de la consultora de Recursos Humano Homónima,
también asegura que el problema más serio es cuando el tóxico es alguien que
tiene gente a cargo, porque genera un clima desagradable que impide a sus
colaboradores ser eficientes. De acuerdo con la especialista, este tipo de jefes
suele escatimar información y provocar roces con el criterio de "divide y
reinarás". Además, no sólo tienen un sector que trabaja desorganizadamente
sino que también muestran problemas para relacionarse con sus pares.
Cassano destaca que esta actitud genera "quintismo" y la empresa tiene
problemas que recaen sobre los propios empleados, que deben trabajar más
tiempo y con resultados pobres.
Asimismo, al estilo de liderazgo de aquel que cree que todo lo sabe, que es
poco humilde para reconocer sus errores y que tiende a opinar de todo (de
economía, de finanzas, marketing, recursos humanos, producción, ventas),
también le calzaría bien la definición de tóxico ya que suelen ser difíciles de
soportar.
Empresas esquizofrénicas
Desde el IAE Business School, Hatum (profesor Asociado de Comportamiento
Humano) comenta: “Un jefe tóxico, además de ser un mal jefe, forma parte de
una organización tan esquizofrénica que lleva a que la gente se convierta
también en tóxica”.
Además -advierte el profesor de la escuela de negocios-, es una persona que
no debería crecer en la compañía porque no cuenta con todas las
competencias necesarias en la carrera directiva, que tienen que ver con
poder dirigir, delegar y desarrollar personas.
Pero, ¿por qué estos perfiles llegan a posiciones de responsabilidad?
Hatum cree que pueden ser necesarios o funcionales para las organizaciones
cuando, por ejemplo, se deben tomar decisiones con un alto impacto negativo.
Y perduran porque muestran una buena performance ya que consiguen
los resultados que los accionistas esperan. Esto suele ocurrir, sobre todo,
cuando la organización no tiene del todo consolidados los valores que espera
de un directivo.
Claro que, más allá de lograr los objetivos, estos ejecutivos intoxican. Y
aunque la corrosión que generan no se ve de inmediato, en el mediano y largo
plazo tiene un fuerte impacto nocivo en la reputación de la compañía en el
mercado. Así, ésta termina por no ser atractiva como lugar para trabajar.
En opinión de Hatum, el mayor ruido se genera cuando el ejecutivo tóxico
es promovido a un lugar que debe ser ejemplificador. En estos casos -
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remarca- la dirección debería hacer una evaluación seria acerca de los pro y
contras de ascenderlo porque, “por más que tenga una performance
inobjetable, termina generando un clima de trabajo que es un horror”.
“El tóxico puede llegar a tener también una personalidad abrasiva, ya que
tiende a pasar por encima de gente y generar cadáveres en su ámbito
laboral, más allá de que alcance los objetivos económicos y financieros que se
le piden”, enfatiza el experto en comportamiento humano. En estos casos,
sugiere Hatum, las empresas deberían poner en la balanza la eficacia, por un
lado, y, por el otro, el respeto por los procesos, los valores y la gente y analizar
cuál de los dos aspectos es más importante.
Fuga de talentos
Para los empleados, en tanto, es muy difícil trabajar con un jefe tóxico.
Por este motivo, los que se terminan quedando a su lado son los perfiles más
sumisos y los que no poseen otras oportunidades.
Logicamente, los talentosos o de alto potencial, ni bien se les presenta la
posibilidad, se van de la compañía. ”Es difícil que trabajen con grandes
talentos porque, inexorablemente, éstos se terminan cambiando de empresa”,
subraya Hatum.
De acuerdo con lo expresado por Meleg, (Piroska Meleg, directora de la
consultora que lleva su nombre) siempre los que ocupan un lugar diferenciado
y de mayor poder, como son los jefes, tienen mayor efecto sobre su entorno.
En cambio, continúa, si es el jefe el que está planteando relaciones
inadecuadas, contraproducentes o hasta destructivas, esto se convierte en una
exigencia muy grande para que el grupo pueda neutralizarla, dado el lugar de
poder que ocupa. Por ello, conocer y caracterizar las actitudes y conductas
interpersonales, la sensibilidad y la inteligencia relacional de los que están en la
conducción, se hace especialmente crítico.
En su opinión, una organización con un management sano, alineado y
comprometido con valores humanos de excelencia y que los vive en el día el
día, no sólo estará entre los 'mejores lugares para trabajar', sino que puede
estar tranquila de que los resultados de su negocio serán siempre los mejores
posibles. Porque las energías de su gente estarán volcadas, como
corresponde, en producir, en realizar, en construir y lograr”.
1
Juan Carlos Cubeiro. Socio Director de Ideo Business, actividad que compagina con la docencia como profesor
de Liderazgo y Dinamización de Equipos en la universidad de Deusto y de Estrategia y Gestión por Competencias en
San Pablo-CEU y en ESADE. Se le considera uno de los mayores expertos españoles en Talento, Liderazgo
y Coaching. Desde 1987, ha trabajado como consultor en Arthur Andersen, Coopers & Lybrand, Areté y HayGroup,
donde fue Director Europeo de Gestión y Desarrollo del Talento. En estos años ha dirigido proyectos de consultoría
estratégica para más de trescientas compañías, entre ellas el ochenta por ciento de las grandes empresas españolas.
Colabora habitualmente con los diarios económicos españoles El Economista, Infoempleo, Expansión y Cinco Días, así
como con revistas de gran prestigio, como Emprendedores o Executive Excellence, entre otras. Licenciado en Ciencias
Económicas y Empresariales por la Universidad Nacional de Educación a Distancia (UNED), diplomado en Marketing
Internacional por la Saint Louis University y doctorado en Organización de Empresas.
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2
Hugo Urdaneta Fonseca. Consultor, Coach y Facilitador. Durante 26 años ocupó posiciones de dirección en
Planificación y Recursos Humanos en distintas empresas multinacionales y nacionales como Lagoven, Petróleos de
Venezuela, Baker Hughes (sector petrolero), Compañía Anónima Nacional de Telecomunicaciones de Venezuela
CANTV, Movilnet, Verizon (sector telecomunicaciones), Seguros Catatumbo (sector banca y seguros), y Minera Loma
de Níquel, Anglo American PLC, (sector minero). Sociólogo, graduado en la Universidad del Zulia, Venezuela, Master
en Gerencia de Recursos Humanos, en la Universidad St Edwards en Austin, Texas, Master Practitioner en
Programación Neuro Lingüística, NLP Coach e Hipnosis, ambos certifi cados internacionalmente por Richard Bandler y
The Society of Neuro Linguistic Programming (USA) y el Consorcio Internacional de PNL, Santiago de Chile. Fue
presidente de la Asociación Venezolana de Gestión Humana (ANRI – AVGH). Miembro del Comité de Recursos
Humanos de la Cámara de Comercio Venezolana Americana – Venamcham-, y vinculado a otras importantes cámaras
e instituciones. Ha diseñado e implantado unidades de RRHH en diversas empresas, así como sus distintos procesos y
sistemas, destacándose los de gestión del cambio y la cultura organizacional, desarrollo y formación gerencial, y
gestión estratégica de las relaciones laborales. Desde el año 2009 está dedicado a la consultoría, para ayudar a las
organizaciones a adaptarse a la creciente, cambiante y compleja situación socio – política y laboral del país, ofreciendo
su vasta experiencia y conocimientos diseñando nuevos modelos y enfoques de dirección, liderazgo, cambio y
relaciones laborales, que permitan incrementar el desempeño y la confianza organizacional, y la competitividad y
rentabilidad de las organizaciones.
Referencias
1-http://www.canalceo.com/juan-carlos-cubeiro-jefes-toxicos/
2-http://huconsulting.net/Blog/?p=59
3- Nota publicada en iprofesional.com, por Cecilia Novoa http://www.iprofesional.com/notas/95640-Jefesy-empleados-tóxicos-quines-son-los-ms-peligrosos-en-las-empresas
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Para más información:
Av. Luis María Campos 585 – Buenos Aires – Argentina (C1426BOD)
Tel.: (54) (11) 4771-1734 / 4772-2428
Fax: (54) (11) 4775-4380
e.mail: info@drmadaus.com.ar
CURSOS
Sociedad Latinoamericana de Fitomedicina
Cursos a distancia para profesionales de la Salud
Curso de Fitomedicina:
Son 40 módulos en formato PDF totalmente ilustrados. Se entregan de a 4
módulos por semana. Se abordan las principales patologías humanas de
acuerdo a los diferentes sistemas o aparatos. Se incluyen formulaciones para
todos los casos con aval de las principales farmacopeas de todo el mundo. El
examen consiste en un múltiple choice de 30 preguntas, o sino, el cursista
puede optar por la redacción de una monografía con tema a determinar
oportunamente.
Curso de Fitodermatología y Fitoestética:
Se trata de 16 módulos en formato PDF totalmente ilustrados. Se abordan las
principales patologías dermatológicas (acné, psoriasis, vitiligo, alopecía,
celulitis, rosácea, legislación, etc). Se incluyen formulaciones para todos los
casos con aval de las principales farmacopeas de todo el mundo. El examen
consiste en un múltiple choice de 30 preguntas o sino, el cursista puede optar
por la redacción de una monografía con tema a determinar oportunamente.
Homeonews
62
Curso de Alimentos Funcionales y Nutracéuticos:
Este curso consta de 30 módulos en formato PDF totalmente ilustrados, donde
el alumno podrá tener acceso a toda una gama de información moderna
relacionada con la actividad científicamente demostrada por aquellos principios
activos comprendidos en nuestros alimentos y en productos nutracéuticos. El
rol preventivo que cumplen en muchas enfermedades, así como el
mejoramiento de procesos crónicos tras su consumo, hace de esta temática
una materia obligada para todo profesional de la salud. El examen consiste en
un múltiple choice de 30 preguntas o la redacción de una monografía.
Curso de Medicina Indígena Americana:
El curso consta de 20 módulos totalmente ilustrados, acompañados de papers
y trabajos científicos de gran valor documental. Se hará un análisis de cada
una de las etnias y civilizaciones más importantes que ocuparon los territorios
desde Alaska hasta Tierra del Fuego. Se verán su organización social,
aspectos religiosos, ceremoniales y alimenticios, más el abordaje medicinal de
las diferentes patologías acordes a su cosmovisión sobre el concepto saludenfermedad. El examen consiste en un múltiple choice o en la redacción de
una monografía acerca de alguna etnia en particular.
Nota: Los cursistas en todo momento podrán hacer sus preguntas para resolver dudas, así
como solicitar material adicional (trabajos científicos) relacionados a áreas de su particular
interés. El material total de los cursos será recibido hasta el mes de ABRIL. Los exámenes
de los cursos serán en el mes de Julio o Diciembre (en fecha a determinar). De aprobarse el
examen, el alumno recibirá su correspondiente certificado avalado por la Sociedad
Latinoamericana de Fitomedicina, con 240 horas cátedra en el caso del curso de Fitomedicina,
ó 200 horas cátedra para los cursos de Fitodermatología, Medicina Indígena y Alimentos
Funcionales.
Inscripción, programa e informes:
Solicitar enviando mail a: fitomedic@gmail.com y a
fitomedicina@sinectis.com.ar
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SUSCRIPCION GRATUITA A HOMEONEWS
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Domicilio particular:
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Domicilio laboral:
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Homeonews N 17 2013

Transcription

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