Naturopathic Medicine in Pain Management 4/11/2008

4/11/2008
Naturopathic Medicine in
Pain Management
Rick Marinelli, N.D., M.Ac.O.M.
Clinical Professor NCNM
1600 SW Cedar Hills Blvd.
Portland, Oregon, 97225
www.natural-healthmedicine.com
Naturopathic Principles
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First do no harm
Find the cause
Treat the whole person
Prevention is the best cure
Let nature do the healing
Physician as teacher
Naturopathic Physicians in
Oregon
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Are primary care yet focus on chronic conditions
Order and utilize all types of diagnostic tests
Have a Formulary
Tend to emphasize healthy lifestyle changes,
especially
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Diet
Exercise
Relaxation and stress reduction
The use of herbal, homeopathic, and nutritional
supplements
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4/11/2008
First Intervention is Dietary and
Individualized
• Emphasis is initially on reducing refined
carbohydrates, optimizing protein, fatty acid and
micronutrient intake
• Excess CHO intake has negative effect on insulin
metabolism, weight gain, inflammation (perhaps
60%)
• Insufficient protein limits repair and regeneration
(~30% < RDA)
• Excess (n-6 PUFAs) promote inflammation,
cancer, poor circulation and contribute to decline
Excess CHOs
• Decreased tolerance to carbohydrates with aging
• Epidemic of obesity, DM continuum,
cardiovascular disease, hypertension
• Need
N d lless caloric
l i intake
i k with
i h aging
i andd less
l
calories decreases aging rate
• Generally better to markedly increase vegetables
(increased flavonoid and micronutrient intake) and
fruit intake than to rely on grains for
carbohydrates
Protein Optimization
• Protein synthesis is decreased with aging
and therefore increased intake is usually
necessary
• Protein-energy malnutrition is associated
with impaired muscle function, decreased
bone mass, immune dysfunction, anemia,
reduced cognitive function, poor wound
healing, delayed recovery from surgery,
and ultimately increased morbidity and
mortality
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4/11/2008
Protein Optimization
• Common medical conditions such as
gastrointestinal disease, malabsorption
syndromes, acute and chronic infections, and
hypermetabolism often cause anorexia,
anorexia
micronutrient deficiencies, and increased
energy and protein requirements
• Chronic pain patients are major users of
prescription medications, which can cause
malabsorption of nutrients, gastrointestinal
symptoms, and loss of appetite
Micronutrients for OA
• A daily 12oz nutritional beverage containing milkbased micronutrients, vitamins, and minerals was
beneficial in alleviating pain symptoms and
dysfunction in subjects with osteoarthritis (n=31)
Nutrition 2002 May;18(5):388-92
• Low intake of micronutrients (vitamins C, E, and
D, and beta-carotene) may adversely influence the
progression of knee OA and the incidence of hip
OA Curr Rheumatol Rep. 1999 Oct;1(1):48-53
Fatty Acid Immune Modulation
• Reduction in the amount of fat intake enhances
several indices of immune response, including
lymphocyte proliferation, natural-killer-cell
activity cytokine production,
activity,
production and delayed
delayed-type
type
hypersensitivity
• Intake of omega-3 fatty acids reduced production
of inflammatory eicosanoid mediators
(prostaglandin E2 and leukotriene B4) by
neutrophils, monocytes, and lymphocytes
• Nutrition 2001 Jul-Aug;17(7-8):669-73
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4/11/2008
Omega 6s as Agents of
Inflammation and Decline
• Omega-6 PUFAs , abundant in the Western
diet, are precursors for a number of key
mediators of inflammation including the 2series of prostaglandins and IL-6
IL 6
• PGE2 , a cyclooxygenase (COX) metabolite of
arachidonic acid, an omega-6 PUFA, is a potent
mediator of inflammation and cell proliferation
• Omega 6s examples include safflower, corn,
soybean, and cottonseed oils
• Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1751-6
Omega-6s More Toxic Than You
Think
• Known to increase not only risk of cancer
but metastatic invasion Br J Cancer 2006 Mar 7
• Soybean oil emulsion (TPN) decreased
lymphocyte proliferation and provoked neutrophil
and lymphocyte apoptosis and necrosis JPEN 2006
Mar-Apr;30(2):115-23.
• Compared to omega-3s, impaired immune
function and symptoms in Crohn’s and Sjogren’s
Aliment Pharmacol Ther 2005 Dec;22(11-12):1121-8,
Invest Opthalm Vis Sci 2005 Dec;46(12):4474-9.
Fatty Acid Modulation
Omega 3s (N-3)
• N-3 Fatty acids favorably affect
atherosclerosis, coronary heart disease,
inflammatory disease, behavioral
disorders
• Docosahexaenoic acid, DHA (22:6n3), which is a vital component of the
phospholipids of cellular membranes,
especially in the brain and retina, is
necessary for their proper functioning
• Importance of n-3 fatty acids in health and disease, Connor
WE Am J Clin Nutr 2000 Jan;71(1 Suppl):171S-5S
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Fish Oil as Solution
• Increasing the omega-3 content of
membrane phospholipid results in a
decrease in mitogen-induced PGE(2)
synthesis
h i
• Data suggest that replacement of omega6 PUFA with omega-3 PUFA in cell
membranes can result in a decreased
cellular response to mitogenic and
inflammatory stimuli
• Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1751-6
Fish Oil as Healer
• Reduction in strokes
• Decrease in arthritis pain
• Decrease in collagen and bone degrading
enzymes
• Modulate inflammation in IBD,
autoimmune disorders, RA, dermatitis,
asthma, sickle cell pain episodes
• Preliminary evidence of cancer prevention,
(lung, breast, colon), treatment of cachexia
N-3 FA in Arthritis
• N-3 fatty acids specifically modulate catabolic
factors involved in articular cartilage
degradation
• Dose related reduction in the expression and
activity of proteoglycan degrading enzymes
(aggrecanases)
• Reduced expression of inflammation-inducible
cytokines (interleukin (IL)-1alpha and tumor
necrosis factor (TNF)-alpha) and cyclooxygenase
(COX-2)
– but not the constitutively expressed cyclooxygenase
COX-1
• J Biol Chem 2000 Jan 14;275(2):721-4
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Fish Oil in Arthritis
• Omega 3s reduced, in a dose-dependent
manner, the endogenous and IL-1-induced
release of proteoglycan metabolites from
articular cartilage explants and specifically
abolished endogenous aggrecanase and
collagenase proteolytic activity
• Omega 3s abolished the expression of mRNA
for mediators of inflammation (cyclooxygenase
2, 5-lipoxygenase, 5-lipoxygenase-activating
protein, TNF- alpha, IL-1alpha, and IL-1beta)
without affecting the expression for other
proteins involved in normal tissue homeostasis
Arthritis Rheum. 2002 Jun;46(6):1544-53.
Omega-3 in Cancer
• Modulation of omega-3/omega-6 polyunsaturated
ratios with dietary fish oils in men with prostate
cancer.
Urology. 2001 Aug;58(2):283-8.
• M
Modulation
d l i off experimental
i
l colon
l tumorigenesis
i
i
by types and amounts of dietary fatty acids.
Cancer Res. 2001 Mar 1;61(5):1927-33.
• Three percent dietary fish oil concentrate
increased efficacy of doxorubicin against mda-mb
231 breast cancer xenografts.
Clin Cancer Res. 2001 Jul;7(7):2041-9.
Fish Oil as Stroke Prevention in
Women
• A significantly reduced risk of thrombotic infarction
was found among women who ate fish 2 or more times
per week (multivariate RR, 0.49; 95% CI, 0.26-0.93)
• Women in the highest quintile of intake of long-chain
omega-3 polyunsaturated fatty acids had reduced risk of
total stroke and thrombotic infarction, with multivariate
RRs of 0.72 (95% CI, 0.53-0.99) and 0.67 (95% CI,
0.42-1.07), respectively
JAMA 2001 Jan 17;285(3):304-12
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Omega-3 In Other Disorders
• The emerging role of omega-3 polyunsaturated fatty acids
in the management of patients with IgA nephropathy
• J Ren Nutr. 2001 Jul;11(3):122-8.
• Prevention of sudden death in CAD
• Am J Clin Nutr. 2003 Jul;78(1):65-71
• Lower risk of death (especially arrhythmic IHD
death) in ischemic heart disease
• Circulation 2003 Mar 18;107(10):1372-7
• Decreases perimenopausal bone loss
• Prostaglandins Leukot Essent Fatty Acids. 2003
Jun;68(6):361-72
Exercise Improves Health,
Vitality, Bodily Pain
• General practitioners were prompted by the patient to
give oral and written advice on physical activity during
usual consultations
• For every 10 green prescriptions written, one person
achieved
hi d andd sustained
i d 150 minutes
i
off moderate
d
or
vigorous leisure activity per week, at 12 months
• Measures of self rated "general health," "role
physical," "vitality," and "bodily pain" improved
significantly
• Trend (but not significant) in lowering BP
• BMJ 2003 Apr 12;326(7393):793.
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EXERCISE
Stretching and Strength Training
• Increases muscle mass and vascularity thereby increasing
oxygenation
• Increases hGH, testosterone, and decreases insulin
resistance
• Increases ligamentous strength and mass
• Increases TIMPs
• Inhibits Myosin Heavy Chain degradation
• A great anti-depressant as well
Strength training in the elderly: effects
on risk factors for age-related diseases
• In addition to improved strength, function,
endurance, muscle mass and power
• Reduces insulin resistance
• Decreases
D
bboth
h totall andd intra-abdominal
i
bd i l fat
f
• Increases resting metabolic rate in older men
• Prevents the loss of BMD with age
• Reduces risk factors for falls
• May reduce pain and improve function
• Sports Med. 2000 Oct;30(4):249-68
Water, Nature Cure and
Naturopathy
• Central thesis: Fresh air, sunshine, a proper diet
without overeating, exercise, scientific relaxation,
constructive thinking and the right mental attitude,
along with prayer and meditation create a sound
mind in a sound body
• Most people must be concomitantly treated with
herbs, supplements or drugs till a healthier state is
reached
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Herbal and Supplemental
Approaches to Pain Management
• Nutraceuticals
– Common examples are the GAGs ( GS, CS, HA) MSM,
DLPA, Amino acids, fish oils, antioxidants, vitamins,
minerals,, and enzymes,
y
, pprobiotics
• Herbal extracts
– Vast pharmacopoeia from Western and Eastern
traditions
– Common examples include Hypericum, Gingko,
Corydalis, Ginger, Capsicum, Willow, Feverfew,
Bromelain, Kava, Turmeric, Valerian, Licorice,
Boswellia, Hawthorne, Scutellaria, Noni, Mangosteen
Glucosamine as a Collagen Type II
Enhancing, Pain Relieving
Supplement
• Glucosamine sulfate is a Biological Response
Modifier of chondrocytes under conditions of joint
stress Osteoarthritis
Ot
th iti Cartilage.
C til
2003 May;11(5):335-42
M 11(5) 335 42
• Reduces knee OA symptoms and progression
– Lancet. 2001 Jan 27;357(9252):251-6.
• Decreases MMP-3 and aggrecanase expression
– Osteoarthritis Cartilage. 2003 Jun;11(6):424-32.
Chondroitin Sulfate
• While GS is extracted from crab, shrimp, or
lobster shell and is a smaller molecule and easily
absorbed, CS is extracted from trachea cartilage,
is a larger proteoglycan and is not a easily
absorbed orally
• CS is probably more chondroprotective than
chondroregenerative, inhibits bradykinin
formation
• Topical applications may be better than oral CS
GAIT trial showed combination with Glucosamine
helped those most severely affected New Engl J Med
2006 Feb 23;354(8):795-808
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Proteolytic Enzymes in
Inflammation
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Bromelain
B
l i
Plant Proteases
Trypsin/Chymotrypsin
Pancreatic enzymes
Proteolytic Enzymes in
Inflammation: Historical
• Clinical application of plant protease (Kimotab) in the
surgical field.
Nippon Geka Hokan. 1966 Mar 1;35(2):395-40
• Clinical note on fluidifying activity on bronchial
secretions by a plant proteolytic enzyme].
Gaza Int Med Chir. 1965 Sep 15;70(17):1455-67
• Enzyme therapy of pulpo-apical affections. The
lysozyme].
Rev Fr Odontostomatol. 1968 Aug-Sep;15(7):947-50
Bromelain : Ananas comusus
• Introduced in the U.S. 1957 ; was marketed as
Ananase in the ’60s
• Therapeutic applications
– Aids digestion
– Anti-inflammatory
Anti inflammator
– Prevents edema
– Inhibition of platelet aggregation
– Enhanced wound healing
– Enhanced antibiotic absorption/antibiotic
activity
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Bromelain : Ananas spp
Anti-inflammatory and Wound Healing
Activity
• Several mechanisms of action
– Activation of proteolysis at site of inflammation
– Fibrinolysis
Fib i l i via
i plasminogen-plasmin
l
i
l
i system
t
– Depletion of kininogen
– Inhibition of inflammatory prostaglandins and
induction of PGE1
– Induction of the wound healing cytokine IL-6
Clin Exp Immunol 2006 Jan;143(1):85-92
Bromelain : Ananas spp
• Studies in RA/OA with/without curcumin
there was reduced need for corticosteroids
• Significant reduction in swelling, bruising,
pain, healing time post-surgery
• Athletic injuries reduction of bruising ,
edema, healing time
Bromelain : Ananas spp
Clinical Applications
• Thrombophlebitis - numerous studies
• DBPC of 73 patients with acute thrombophlebitis
reduced all symptoms of inflammation including
pain edema,
pain,
edema redness,
redness elevated skin temperature at
dose of 400-800 mg (high-strength, >1800 mcu)
• Seligman B: oral Bromelains as adjuncts in the
treatment of acute thrombophlebitis. Angiology
20, 22-26, 1969
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Bromelain : Ananas spp
Clinical Applications
• Musculoskeletal injuries(contusions, muscle
strains/sprains, ligament tears)
– By decreasing fibrin, bromelain helps promote
circulation and post-traumatic resorption of
inflammatory by-products
• Masson M. Bromelain in the treatment of blunt
injuries to the musculoskeletal system. A case
observation study by an orthopedic surgeon in
private practice. Fortschr Med 113(19):303-306.
1995
Bromelain : Ananas spp
Clinical Applications
• May help post-operative ileus
Life Sci 2006 Jan
25;78(9):995-1002
• May benefit chronic inflammatory,
inflammatory malignant and
autoimmune diseases via the innate as well as the
adaptive immune system Eur J Med Res 2005 Aug
17;10(8):325-31
• Acute sinusitis in children In Vivo 2005 MarApr;19(2):417-21.
Oral Enzyme Equivalence With
NSAIDs in Arthritis
• In patients suffering from painful osteoarthritis of the
knee, periarthritis of shoulder, and painful vertebral
syndromes there was a statistical equivalence of the
pain-scores, comparing diclofenac and enzymes. The
study demonstrated equivalence of the treatment with
NSAIDs compared to therapy with enzymes.
• Wien Med Wochenschr 1999;149(21-22):577-80
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NSAIDs vs. Oral Enzymes in
Rheumatic Disease
• Data of 3326 patients treated for rheumatic
diseases between 1/93 and 3/95 were registered by
380 physicians
• Joint diseases, spinal diseases, rheumatic soft
tissue diseases
• Treatment success (freedom from symptoms) with
OE can be expected with a higher probability than
with NSAID. OE were well tolerated showing
much less adverse events when compared with
conventional doses of NSAID.
• Arzneimittelforschung 2000 Aug;50(8):728-38
Oral Enzymes vs. Diclofenac in
Knee OA
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Double blind prospective RCT
N=103
Enzymes (ERC) = rutosid, trypsin, bromelain
Tx for 6 wks
Outcome = Lequesne’s Algofunctional Index, and
a “complaint index”, physician assessment
• Conclusion: Enzymes as safe and effective as
NSAIDs in painful OA episodes
Clin Rheum 2004 Oct;23(5):410-5
Oral Enzymes in Alzheimer’s
Disease
• Complexes with trypsin, alphachymotrypsin, and bromelain strongly
degrade (1,25) I-Amyloid beta 1--42
• These results suggest that up-regulation
of Amyloid beta catabolism could
probably reduce the risk of developing
AD by preventing Amyloid beta
accumulation in brain and vasculature Exp
Neurol 2001 Feb;167(2):385-92
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Oral Enzymes in Myocardial
Infarction
• Facilitates normalization of the
atherogenic potential and has a positive
action on the mediators of the
i fl
inflammatory
process.
The effect of Wobenzym on the
atherogenic potential and inflammatory
factors at the rehabilitation stage for
patients who have had a myocardial
infarct Lik Sprava 2000 Jul-Aug;(5):111-4
Oral Enzymes in Chronic
Prostatitis
• Urethrogenic prostatitis:
1) association with pancreatic pathology, 2) the
presence of noninfectious agent, 3) autoimmune
character
h
t
• Treatment includes Wobenzyme as part of a
pathogenetic therapy with positive results
• Lik Sprava 1998 Aug;(6):118-20
Flavonoids
• Are pigments in food and herbs
• Tea, apples, wine, berries, fruits,vegetables and
nuts are primary dietary sources
• Inverse relationshipp of dietaryy flavonoids and
cardiovascular disease, stroke, and cancer in
multiple analyses from Zutphen Elderly Study
• Common flavonoids are polyphenols such as
resveratrol, catechins, quercitin, naringen,
pro/anthocyanidins
• Generally have antioxidant, circulation enhancing,
collagen stabilizing effect. New evidence suggests
may control aging through sirtuin activation.
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Flavonoids
• Middleton et al. The effects of plant flavonoids on
mammalian cells: implications for inflammation,
heart disease,
disease and cancer.
cancer
Pharmacol Rev 2000 Dec;52(4):673-751
• Reduces ROS that are pivotal in hypertension,
atherosclerosis, Type II DM, cancer, Alzheimer’s,
shortened lifespan, pain and disease. Activate
sirtuins like caloric restriction J Hypertens 2005
Jul;23(7):1285-309
Grape Seed Extract
Oligoproanthocyanidins(OPCs)
Pharmacology
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•
•
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Increase intracellular Vit. C
Decrease capillary permeability
Scavenge free radicals and oxidants
Inhibit destruction of collagen by crosslinking collagen fibers
• Inhibits the release and synthesis of
histamine, PGs, leukotrienes, serine
proteases
Schwitters, Masquelier.OPC in Practice: Bioflavanols and their
Application.Alfa Omega, Rome1993
Green Tea and Osteoarthritis
• ECGC selectively inhibits IL-1β induced
catabolism of chondrocytes
• ECGC selectively inhibits IL-1β induced activity
and expression of COX
COX-22 and NO synthase
synthase-22 in
human chondrocytes
• J Orthop Res. 2003 Jan;21(1):102-9
• Free Radic Biol Med. 2002 Oct 15;33(8):1097-105
• Arthritis Rheum. 2002 Aug;46(8):2079-86.
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Inhibiting Soft-tissue Inflammation
and Collagen Degradation(GTP)
• Green tea polyphenols(GTP) inhibit MMP-2,
MMP-9 and MMP-12 in vitro (elastin,gelatin) and
in vivo1 (human glioblastoma,pituitary tumors)
• Most potent of these were the catechins ECG and
EGCG but included resveratrol, genistein, and
organosulfur compounds from garlic
• 1Biochim Biophys Acta 2000 Mar 16;1478(1):51-60
Flavonoid Antioxidants and Sterols
in Vegan Diet and Rheumatic
disease
• Uncooked vegan diet and consisting of berries,
fruits, vegetables and roots, nuts, germinated seeds
and sprouts resulted in a decrease of their joint
stiffness and pain as well as an improvement of
their self-experienced health in RA and FM pts.
Toxicology 2000 Nov 30;155(1-3):45-53
• Ajoene, a natural product with non-steroidal antiinflammatory drug (NSAID)-like properties?
Biochem Pharmacol 2001 Mar 1;61(5):587-93
Addressing Soft-tissue Inflammation
and Collagen Degradation
Serine Protease and MMP Inhibitors
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OPCs/ Bioflavonoids/Antioxidants in general
Catechins (green tea polyphenols)
Boswellia
Scutellaria, Triptyrigium, Angelica spp,Evodia
GS,CS (Glycosaminoglycans,GAGs)
Omega 3 oils
NAC/MSM/Allicins (organosulfur compounds)
Tetracyclines (Streptomyces spp)
Statins (Aspergillis spp, Monascus purpureus)
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Antioxidants as Adjuvants in
Rheumatic disease
• Group I: Intramuscular methotrexate (CAS 59-05-2; 12.5
mg/week), oral sulphasalazine (CAS 599-79-1; 0.5 g b.i.d.) and
indometacin (CAS 53-86-1; 100 mg suppository at bed-time).
Groupp II: the patients received the standard treatment plus a
combination of antioxidants. Group III:received a high dose of
vitamin E (400 mg t.i.d.) in addition to the standard treatment.
• With adjuvant therapy of either the antioxidant
combination or a high dose of vitamin E the
symptoms of arthritis were better controlled from
the first month (n=30)
• Arzneimittelforschung 2001;51(4):293-8
Antioxidants As Adjuvants in
Alzheimer’s Disease
• The products of inflammatory reactions such as
prostaglandins (PGs; PGE1 and PGA1), free radicals,
cytokines, and complement proteins are neurotoxic and
inhibited by antioxidants
• NSAIDs inhibit the synthesis of PGs, reduce the rate of
deterioration of cognitive functions in patients with
advanced AD
• Cholinergic drugs are routinely used in the treatment of
AD to improve cognitive functions
• Therefore a combination of all are more likely to be
effective
• Clin Neuropharmacol 2000 Jan-Feb;23(1):2-13
Antioxidants in Pancreatitis
• Treatment with a complex containing Lmethionine, beta-carotene, vitamin C,
vitamin E and organic selenium
• Of 10 patients with chronic pancreatitis
who completed treatment, the intensity of
pain was reduced considerably in 9 (61.5
+/- 21.5 mm vs. 19.6 +/- 26.1 mm, p =
0.03), and pain was completely absent in
3 of these patients
Rev Esp Enferm Dig 2000 Jun;92(6):375-85
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Antioxidants: Chronic Hepatitis C
• Phase I Clinical Trial, n=50
• Treated with Glycyrrhizin, Schisandra, Silymarin,
ascorbic acid, lipoic acid, L-glutathione, and alphatocopherol), along with four different intravenous
tocopherol)
preparations (Glycyrrhizin, ascorbic acid, L-glutathione,
B-complex)
• Results: A combination of antioxidants induced a
favorable response in 48% of the patients, was
well tolerated and “may have a beneficial effect on
necro-inflammatory variables.“
J Clin Gastroenterolgy 2005 Sep;39(8):737-42.
Inflammation in Type II Diabetes,
PCOS
• Elevated levels of CRP and IL-6 predict the
development of type 2 DM. These data support a
possible role for inflammation in diabetogenesis.
JAMA 2001 Jul 18;286(3):327
18;286(3):327-34
34
• “Women with PCOS have significantly increased
CRP concentrations relative to women with
normal menstrual rhythm and normal androgen
levels. We propose low grade chronic
inflammation as a novel mechanism contributing
to increased risk of CHD and type 2 diabetes in
these women J Clin Endocrinol Metab 2001 Jun;86(6):2453-5
Inflammation in Diabetes
• Flavonoids diosmin (90%) and hesperidin (10%), in a
group of 28 Type 1 diabetic patients in a double blind
placebo-controlled study. Parameters of glycation and
oxidative stress were measured before and after the
i t
intervention
ti
• Decrease in glycation and HgbA1c unrelated to
glycemic control was noted, with increased
glutathione peroxidase activity
• Diabetes Nutr Metab 1999 Aug;12(4):256-63
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Vit C in Inflammatory
Atherosclerosis
• Peripheral arterial disease (PAD) is a severe
atherosclerotic condition frequently accompanied
by inflammation and oxidative stress
• Subclinical vitamin C deficiency (<11.4
micromol/L) confirmed by low serum alkaline
micromol/L),
phosphatase activity, was found in 14% of the
PAD patients
• Vitamin C concentrations are lower in intermittent
claudication patients, is associated with higher
CRP levels and severity of PAD
• Circulation 2001 Apr 10;103(14):1863-8
Low DHEAS in Inflammatory
Disorders
• Mean DHEAS level was markedly lower in
pemphigus (as with systemic lupus erythematosus,
rheumatoid arthritis, polymyalgia rheumatica,
giant cell arteritis) (n
(n=46)
46)
• DHEAS levels were independent of steroid
treatment
• “DHEAS deficiency is a permanent feature in
these autoimmune diseases, and may contribute to
their etiology and/or pathophysiology”
• Clin Exp Rheumatol 1995 May-Jun;13(3):345-8
Low DHEAS in Inflammatory
Arthritis/Synovitis
• Serum DHEAS and its relation to clinical
variables in RA, spondyloarthropathy, and
inflammatory arthritis in 87 pts was performed
• “Low
Low DHEAS concentrations are commonly
encountered in inflammatory arthritis, especially
in women”
• “DHEA replacement may be indicated in many
patients with IA”
• Arthritis Res 2001;3(3):183-8
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Physical Medicine Modalities in
Naturopathic Medicine
•
•
•
•
•
Traditional hydrotherapy
Manual therapy/Manipulation
Electrotherapy
Ultra/Infra-Sound
Needling therapies
–
–
–
–
Acupuncture/Dry-needling
Myofascial trigger point injections
Neural therapy/Mesotherapy
Prolotherapy (aka Regenerative Injection Therapy, RIT))
Ligaments and Tendons at the
Fibro-Osseous Junction
• Hackett postulated in 1939 that the major cause of
back pain was tendon and ligament relaxation
• In his initial animal experiments he demonstrated
a 30-40%
30 40% increase in tendon size after injection
with Sylnasol, later with zinc sulfate, and silica
oxide
• Introduced the term prolotherapy in 1956,
emphasized the postulates of Steindler, developed
maps of pain referral patterns
Newer Studies In Prolotherapy
• Randomized prospective double-blind placebocontrolled study of dextrose prolotherapy for knee
osteoarthritis with or without ACL laxity
• CONCLUSION: Prolotherapy injection with 10%
dextrose resulted in clinically and statistically
significant
f
improvements in knee osteoarthritis.
Preliminary blinded radiographic readings (1-year
films, with 3-year total follow-up period planned)
demonstrated improvement in several measures
of osteoarthritis severity. ACL laxity, when present
in these osteoarthritic patients, improved.
N=110
Altern Ther Health Med 2000 Mar;6(2):68-74,
77-80
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Newer Studies In Prolotherapy
• “Long-term effects of dextrose prolotherapy
for anterior cruciate ligament laxity”
– At the 3 year follow-up, pain at rest, pain with walking,
and pain with stair use had improved by 45%, 43%, and
35% respectively
• CONCLUSION: In patients with symptomatic
anterior cruciate ligament laxity, intermittent
dextrose injection resulted in clinically and
statistically significant improvement in ACL
laxity, pain, swelling, and knee range of motion
• Altern Ther Health Med. 2003 May-Jun;9(3):58-62
Newer Studies In Prolotherapy
• Randomized, prospective, placebo-controlled doubleblind study of dextrose prolotherapy for joints:
evidence of clinical efficacy
• CONCLUSION
CONCLUSION: Dextrose
D t
prolotherapy
l th
was
clinically effective and safe in the treatment of
pain with joint movement and range limitation in
osteoarthritic finger joints.
N=150 joints in 27 patients
J Altern Complement Med 2000 Aug;6(4):311-20
Newer Studies in Prolotherapy
Prolotherapy can be an effective therapeutic
modality that reduces TMJ pain and noise in a
majority of patients Cranio 2005 Oct;23(4):283-8
Chronic groin pain that
h preventedd full
f ll sports
participation in elite kicking athletes treated with
dextrose prolotherapy. 22/24 had no pain and had
returned to full competition after a mean of 2.8
treatments. Conclusions: “Dextrose prolotherapy
showed marked efficacy for chronic groin pain in
this group of elite rugby and soccer athletes.” Arch
Phys Med Rehab 2005 Apr;86(4):697-702
21
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Categories of Herbs for Pain
Control
• Analgesics
• Anti
Anti-convulsants
convulsants
• Anti-depressants
• Antiinflammatories
• Anxiolytics
i
• Narcotics
• Sedatives
• Alteratives/Adapto
gen
Materia Medica
•
•
•
•
•
•
•
•
Bromelain
Cayenne
Feverfew
Ginger
Gingko
Boswellia
Corydalis
Guggulipid
•
•
•
•
•
•
•
•
Kava
St. John’s wort
Turmeric
Valerian
Griffonia (5-HTP)
Hawthorne
Licorice
Grape Seed Extract
Ginger : Zingiber officianalis
Therapeutic Applications
•
•
•
•
•
•
N/V
Motion sickness
Arthritis
Analgesic
Migraine HA
Cardiotonic
22
4/11/2008
Ginger : Zingiber officianalis
Pharmacology
• Analgesic, antioxidant
• Inhibition of inflammatory prostaglandins,
thromboxane and leukotriene synthesis
• Inhibition of platelet aggregation
• Cholesterol-lowering, choleretic effect
• Cardiotonic, GI protective actions, thermogenic
properties, antibiotic activity
• Vanilloid (VRI) receptor agonist
Kiuchi F et al.: Inhibition of prostaglandin and leukotriene biosynthesis by
gingerols and diarylhepatanoid. Chem Pharm bull 40, 387-391, 1992
Neuropharmacology 31, 1165-1169, 1992
Br J Pharmacol 2002 Nov;137(6):793-8.
Ginger : Zingiber officianalis
Anti-inflammatory
• Several studies have shown efficacy in RA
and OA, muscle discomfort
• Recommended dosage 500-1,000mg
500 1 000mg a day.
day
Many patients took 3-4x this dose with
quicker and better relief
• Srivastava et al.: Ginger in rheumatic disorders. Med
Hypothesis 29, 25-28, 1989
• Srivastava et al.: Ginger in rheumatism and
musculoskeletal disorders. Med Hypothesis 39,342-348,
1992
Ginger : Zingiber officianalis
Knee Osteoarthritis
• Statistically significant effect on reducing symptoms of
OA of the knee
• RCT (n=247), multicenter trial, parallel, 6 wk trial
• Less
L knee
k
pain
i with
ith standing,
t di
after
ft walking
lki
• Reduction in the Western Ontario and McMaster
Universities osteoarthritis composite index
• Good safety profile, with mostly mild GI
adverse events in the ginger extract group.
• Arthritis Rheum. 2001 Nov;44(11):2531-8
23
4/11/2008
Ginger: Zingiber officianalis
Historically used to treat cardiovascular
problems now shown to be effective in
problems,
hypertension, arrhythmia and increasing
cardiac output Vascul Phamacol 2005 Oct;43(4):234-41
Ginger : Zingiber officianalis
Analgesic
• Analgesic effects in animals is thought to be the
result of shagaol inhibiting the release of
Substance P
• Onogi T, et al.: Capsaicin-like effect of (6)
shogoal on substance P-containing primary
afferents rats; A possible mechanism of its
analgesic action. Neuropharmacology 31, 11651169, 1992
Ginger : Zingiber officianalis
Antioxidant
• Potent inhibitor of oxidation of LDL, lowers
cholesterol, attenuates atherosclerotic change1
• Potent antioxidant in lipid peroxidation generally,
including linoleic acid2
1Furhman et al. Ginger extract consumption reduces plasma
cholesterol, inhibits LDL oxidation and attenuates development
of atherosclerosis in atherosclerotic, apolipoprotein E-deficient
mice.
J Nutr 2000 May;130(5):1124-31
• 2Shobana S, Naidu KA, Antioxidant activity of selected Indian
spices. Prostaglandins Leukot Essent Fatty Acids 2000
Feb;62(2):107-10
•
24
4/11/2008
Ginger : Zingiber officianalis
Cardiotonic
• Gingerol has shown potent cardiotonic
activity in animal models (positive inotropic
and chronotropic action)
• Shoji N, et al.: Cardiotonic principles of ginger (Z.
officianalis). J Pharm Sci 10, 1174-1175, 1982
• Kobayashi M, et al.: Cardiotonic action of (8) gingerol, an
activator of the Ca++-pumping ATPase of sarcoplasmic
reticulum of guinea pig arterial muscle. J Pharmacol Exp
Ther 246, 667-673, 1988
Gingko biloba (yin kuo)
Traditional/Modern Use
• Chinese used fruits/seeds since 2800 B.C. to
“benefit the brain”, relieve symptoms of cough
and asthma, to eliminate filaria
• Last survivor of the 150M yr old order of
Gingkoacea
• Now used primarily as GBE in Europe for
circulatory system disorders, cerebrovascular
insufficiency,as an anti-asthmatic, and as a
nootropic (mild-moderate dementia)
• 1988 in Germany there were more Rxs for GBE
than any other drug(5.4M)
“Active Constituents” of
Gingko
• Active constituents: used as a standardized extract
of 24% flavonoid glycosides (gingkoheterosides),
6% terpenes (gingkolide
(gingkolide, bilobalide).
bilobalide) Also
contains proanthocyanidin flavonoids
• Impressive literature for improving
cerebral/peripheral blood flow, free-radical
scavenging, reduction of clotting , as nootropic,
anti-asthmatic, nerve regeneration
25
4/11/2008
Gingko: Gingko biloba
Pharmacology
• Membrane-stabilizing effect by activating
Na+ pump
• Effects on vascular endothelium by
stimulating EDRF and prostacyclin
• Effects are greatest in areas of poor
perfusion
• Fungfeld EW (ed.):Rokan (Gingko biloba). Recent Results in
Pharmacology and Clinic. Springer-Verlag, NY, 1988
• DeFeudis FV(ed.): Gingko biloba Extract (Egb 761);
Pharmacological Activities and Clinical Applications. Elsevier, Paris,
1991
Gingko: Gingko biloba
Pharmacology
•
•
•
•
Inhibits platelet activating factor (PAF)
Increases synthesis of prostacyclin
Competes with binding sites for PAF
PAF induces inflammatory and allergic processes,
including neutrophil activation, increases in
vascular permeability, smooth muscle contraction
(bronchconstriction, coronary artery spasm)
• Koltai M et al. PAF. Drugs 42(1),9-29,1991
• Koltai M et al. PAF. Drugs 42(2),174-204, 1991
Gingko ~ CNS activity
• Neuroprotective effect in ischemia and
traumatic brain injury1
• Enhanced neurotrophic
p and neuritogenic
g
effect post-injury2
• 1Advances in Gingko biloba Extract Research on
the CNS, Elsevier, 1992
• 2Advances in Gingko biloba Extract Research on
Neuronal Plasticity, Elsevier, 1996
26
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Gingko biloba
Clinical Applications
• Chronic cerebrovascular insufficiency
• Peripheral vascular insufficiency
• Age-related
g
memory/cognitive
y g
impairment.
p
Mildmoderate dementia of Alzheimer’s type
• Vertigo /tinnitus, cochlear deafness
• Retinopathy/macular degeneration
• Neuralgia/neuropathy
• Depression
• Sexual dysfunction due to SSRIs
Gingko biloba
Retinal Effects
• Improvement in long-distance visual acuity
in macular degeneration and DM
retinopathy
• Protective effects against free-radical
damage to retina
• Shown to prevent DM retinopathy in
diabetic rats
• DeFeudis FV(ed.): Gingko biloba Extract (Egb 761);
Pharmacological Activities and Clinical Applications. Elsevier, Paris,
1991
• Lanthony et al, Gingko biloba. J Fr Ophtalmol 11, 671-674, 1988
Gingko in Ischemic Heart Disease,
Cerebral Infarction, Chronic Inflammation,
and Aging
• GBLE has an antioxidant action as a free radical
scavenger
• GBLE exerts an anti-inflammatory
anti inflammatory effect on
inflammatory cells by suppressing the production
of active oxygen and nitrogen species
• Beneficial effects on neuronal degenerative
diseases by preventing chronic oxidative damage
• Antioxid Redox Signal 1999 winter;1(4):469-80
27
4/11/2008
Gingko biloba
Effects on Peripheral Vasculature
• Marked improvement in intermittent claudication DM
PVD, Raynaud’s, acrocyanosis, postphlebitis syndrome
• Shown to be superior
p
to exercise,, pentoxifylline
p
y
(Trental)
(
)
in pain-free walking distance, plethysmographic/doppler
US findings, blood lactate levels Angiology 45, 339-345, 1994
• RCT (n=111) of EGb 761 (40mg tid) in peripheral
occlusive arterial disease patients with Fontaine stage
II b is very safe and causes a significant and
therapeutically relevant prolongation of the patients'
walking distance Vasa 1998 May;27(2):106-10
Gingko biloba
Nerve cell effects
• Membrane-stabilizing and free-radical scavenging
are most evident in brain and nerve cells
• GBE promotes ↑ in nerve transmission rate,
synthesis
h i andd turn-over off bbrain
i NTs,
NT normalizes
li
ACh receptors in the hippocampus
• Normalizes circulation in areas most affected by
microembolization (hippocampus and striatum)
• Fungfeld EW (ed.):Rokan (Gingko biloba). Recent Results in
Pharmacology and Clinic. Springer-Verlag, NY, 1988
Gingko biloba
Nerve cell effects
• Exerts protective effect on neurodegenerative, sensory,
and vascular diseases
• EGb 761-induced inhibition of glucocorticoid
production is due to specific transcriptional suppression
of the adrenal PBR (peripheral-type benzodiazepine
receptor) gene
• Seven genes were identified whose expression was
strongly modified by the EGb 761 treatment and likely
linked to neuroprotective action including genes
involved in antioxidant defenses and in stress response
• Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):641-6
• Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):633-9.
• Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):601-11.
28
4/11/2008
Gingko biloba
Memory Effects
• In DBPC study of post menopausal women taking
120mg of gingko qd:
• Significantly better than the placebo group in a
matching-to-sample
hi
l test off nonverbal
b l memory
• Test of frontal lobe function (rule shifting) and in the
Paced Auditory Serial Addition Test (PASAT) (which
measures sustained attention but also involves frontal
lobe function), the group treated with Ginkgo
performed significantly better than the placebo group
• Pharmacol Biochem Behav. 2003 Jun;75(3):711-20
Gingko biloba
Memory Effects
• AGAINST: Trial results do not support the view that
Ginkgo is beneficial for patients with dementia or ageassociated memory impairment J Clin Epidemiol. 2003
Apr;56(4):367-76
• FOR:These results suggest that C4A(Egb761)
treatment may reduce the risk of developing
Alzheimer's dementia in elderly women (n=1462
women, age > 75) J Gerontol A Biol Sci Med
Sci. 2003 Apr;58(4):372-7
• Overall, the results from both objective, standardized,
neuropsychological tests and a subjective, follow-up self-report
questionnaire provided complementary evidence of the potential
efficacy of Ginkgo biloba EGb 761 in enhancing certain
neuropsychological/memory processes of cognitively intact older
adults, 60 years of age and over Hum Psychopharmacol. 2002
Aug;17(6):267-77
Gingko biloba
Memory Effects:AGAINST
• 6-week study, RCT
• N=203, age >60, normal cognitive function
(mini mental state exam, score >26), dose 40mg
tid
• Indicate that ginkgo did not facilitate
performance on standard neuropsychological
tests of learning, memory, attention, and
concentration or naming and verbal fluency in
elderly adults without cognitive impairment
when taken as manufacturers suggest
• JAMA 2002 Aug 21;288(7):835-40
29
4/11/2008
Gingko biloba
Dosage/side-effects
• 80 mg capsules of SE, dose from 80mg to 240mg
in divided doses
• In 9,772 taking GBE (leaf-extract) side-effects
uncommon ; 21 cases of GI discomfort,, 7 cases of
HA, 6 cases of dizziness
• Contact with fruit-pulp can cause Rhus-like
reaction
• Exercise caution if patient is on anti-coagulant or
ASA therapy
• EGb 761 is a standardized extract(SE) of dried leaves of Ginkgo
biloba containing 24% ginkgo-flavonol glycosides, 6% terpene
lactones such as ginkgolides A, B, C, J and bilobalide
St. John’s Wort : Hypericum
perforatum
Therapeutic Actions
•
•
•
•
•
Anti-depressant/SAD
A ti i l
Anti-viral
Antioxidant
Sleep disorders
Topical as wound-healing agent
St. John’s Wort : Hypericum
perforatum
Pharmacology
• Hypericin and psuedohypericin exhibit strong
anti-viral activity against HSV1,2, influenza A/B,
EBV vesicular stomatitis virus
EBV,
• Meruelo et al. Therapeutic agents with dramatic
antiretroviral activity and little toxicity at effective
doses: Aromatic polycyclic diones hypericin and
psuedohypericin.Proc Natl Acad Sci USA 1988;
85:5230-5234
30
4/11/2008
St. John’s Wort : Hypericum
perforatum
Pharmacology
• Constituent hyperforin has significant serotonergic
activity and inhibits synaptosomal uptake of
dopamine norepinephrine
dopamine,
norepinephrine, GABA and L
Lglutamate
• Chatterjee et al. Hyperforin as a possible
antidepressant component of hypericum extracts.
Life Sci 1998 63:6 499-510
CNS Sensitization With Wind-up
Phenomena And….. Depression, Sleep
Disturbance, Fatigue
• “PGE2, acting via an EP2-like receptor, directly
depolarizes spinal neurons. Moreover, these findings
imply an involvement of spinal cord-generated
prostanoids in modulating sensory processing through
an alteration
lt ti in
i dorsal
d
l horn
h
neuronall excitability”
it bilit ”
• J Neurosci 2001 Mar 1;21(5):1750-6
CNS Sensitization With Wind-up
Phenomena And….. Depression, Sleep
Disturbance, Fatigue
• Hypericum has demonstrated action as an
p
p restoringg agent
g 2,
anti-depressant
1, sleep
anti-nociceptive3 independent of
endogenous opioid enhancement
• Clin Ther 2000;22:411-419
• German Comm E Monographs
• J Ethnopharmacol 1999; 67:307-312
31
4/11/2008
St. John’s Wort : Hypericum
perforatum
Antidepressant
• Official German Comm E Monograph lists
psychovegetative
h
i disturbances,
di b
depressive
d
i states,
fear, nervous disturbance as indications for use
• Many studies have shown as effective as standard
anti-depressants but better tolerated with fewer
side-effects
St. John’s Wort : Hypericum
perforatum
Antidepressant
• In multiple studies hypericum has been
shown to be equipotent to SSRIs in
relieving depression with greater safety
profile and better tolerance
• European Neuropsychopharmacology 1999, 9: 461-468
• Clinical therapy 2000, 22: 411-419
• International clinical psychopharmacology 2000, 15: 6168
• Compr psychiatry 2000, 41: 133-137
St. John’s Wort : Hypericum
perforatum
Antidepressant
• In severe depression Hypericum(LI 160) @600mg
tid vs. imipramine 50mg tid
• Both
B h drugs
d
gave similar
i il reductions
d i
in
i HAMD,
HAMD
CGI and D-S and considered effective while
Hypericum had less side-effects
• Vorbach EU, et al. Pharmacopsychiatry
1997;30(Suppl):81-5
32
4/11/2008
St. John’s Wort : Hypericum
perforatum
Antidepressant
• Recent study compared once a day Hypericum
dosing (900mg) to Citalopram (20mg) in a
randomized placebo controlled multi-center trial
(n=388) in moderate depression
• Findings: Citalopram and Hypericum were
superior to placebo but Hypericum was better
tolerated than citalopram or placebo
Pharmacopsychiatry 2006 Mar;39(2):66-75
St. John’s Wort : Hypericum
perforatum
Dosage
• Anti-depressant dosage of standardized extract
(0.3% hypericin) is 300mg tid cc for mildmoderate depression
• Better effects will be obtained by higher doses
• Anti-viral optimal dosage unknown but studies in
HIV have shown encouraging results with 1mg
hypericin qd
• As topical usually in combination with Arnica,
Bellis, Eupatorium, Belladonna (Traumeel)
St. John’s Wort : Hypericum
perforatum
Potential Adverse Effects
Induction of Cytochrome P450 (CYP 3A4)
resulting in serum reduction of theophylline,
digoxin cyclosporine,
digoxin,
cyclosporine coumarin,
coumarin OCPs,
OCPs indinavir
and xenobiotics
National Academy of Science USA 2000, 97,7500-7502
Lancet 2000, 355, 134-138
Also amitriptyline, irinotecan, alprazolam,
simvastatin, dextromethorphan Eur J Clin
Pharmacol 2006 Mar;62(3):225-33
33
4/11/2008
St. John’s Wort : Hypericum
perforatum
Adverse Effects
• Can cause severe photosensitivity in animals
(h
(hypericism)
i i )
• Reports of photosensitivity in humans is rare up to
11.25mg of total hypericin (tanning improved)
• The usual cautions with MAO inhibitors may
apply (avoid tyramine foods, l-dopa, 5-HTP, Tyr)
• May cause mild gastric upset in sensitive
individuals
Valerian: Valeriana
officianalis
• Dioscorides et al described as Phu
• Traditionally used for muscle spasms,
emotional tension, insomnia, hysteria,
fatigue, menstrual cramps, climacteric
complaints
• >120 chemical components from
root/essential oil
Valerian : Valeriana officianalis
Therapeutic uses
• Sedative
• Anxiolytic
• Spasmolytic
• Anti-stress
34
4/11/2008
Valerian : Valeriana
officianalis
Pharmacology
• Active constituents valeric a. isovaleric a.
(sesquiterpenes), valepotriates, iridoids,
hydroxypinoresinol which vary according to
source
• Normalizes CNS (sedative in agitation, stimulant
in extreme fatigue)
• Binds BZ receptors and enhances GABA
• Smooth muscle relaxant, choleretic, anti-tumor
and antibiotic activity
J Pharm Pharmacol 1999 May;51(5):505-12
Valerian : Valeriana officianalis
Clinical applications
• Primarily as sedative in the treatment of
insomnia
p
sleep
p qquality,
y deeper
p stage
g 3 and 4
• Improves
with less morning sleepiness
• Mild muscle relaxant activity due to CNS
depression
• Aid in benzodiazepine, barbituate
withdrawal
Valerian : Valeriana officianalis
Clinical applications
• Several RCT have demonstrated improvement in
slow wave sleepp latency
y1,2, increased REM vs.
NREM1,2, equivalency with oxazepam 2 in sleep
induction with markedly fewer adverse effects
•
•
1Pharmacopsychiatry
2000 Mar;33(2):47-53
Komplementarmed Klass Naturheilkd 2000
Apr;7(2):79-84
2Forsch
35
4/11/2008
Valerian : Valeriana officianalis
Dosage
•
•
•
•
Dried root (or as tea): 1-2g
Tincture (10-20%) : 1-1.5 tsp (4-6ml)
Fluid extract (1:1) : 0.5-1 tsp (1-2ml)
Valerian extract (0.8% valeric acid) :150300mg
• The above 30-45’ h.s. or up to qid
Valerian : Valeriana officianalis
Toxicity
• GRAS approved for food use by FDA
– Safety of valepotriates questioned, best to use watersoluble extracts standardized for valeric acid content
• Recently shown to have neuroprotective effects by
decreasing neuronal hyperexcitability, decreasing
membrane peroxidation in hippocampal
synaptosomes exposed to amyloid beta peptide
Neurotox Res 2004;6(2):131-40
Griffonia simplicifolia ~
5-HTP
• 5-HTP readily crosses blood-brain barrier
• Approximately 70% absorption
• Increases serotonin in the CNS
• Also increases melatonin, dopamine,
norepinephrine, and beta endorphin in the CNS
• Van Praag et al. Nutrition and the Brain. NewYork.
Raven press;1986:89-139
36
4/11/2008
Serotonin Pharmacology
Serotonin Deficiency
has been implicated in
• Mood disorders
• Premenstrual
syndrome
• Autism
• Eating disorders
• Fibromyalgia
•
•
•
•
•
•
Migraine
Pain in general,
Insomnia
Sleep disorders
Appetite control
Alcohol abuse
Clinical Studies ~ Depression
• 5-HTP vs. Conventional Anti-Depressants
• Compared
p
with fluvoxamine 150mgg tid and
5-HTP 100mg tid had similar effects (5-HTP
considered superior but not statistically)
• 5- HTP was better tolerated
• Poldinger et al. Psychopathology 1991;24:53-81
Clinical Studies ~ Depression
• 5-HTP vs. Conventional Anti-Depressants
– In severe depression vs.
chlorimipramine/imipramine,
p
p
, 5-HTP shown to
be as effective with doses up to 1200mg qd
– fewer side effects were noted
• Angst J et al. Arch Psychiatr Nervenkr
1977;224:175-186
37
4/11/2008
Migraine Headaches ~ 5-HTP
• 124 subjects with 5-HTP 600mg qd vs.
methysergide for 6 mos
– 75% had prevented or substantially decreased #
of migraines
– not considered statistically significant
– Titus et al. Eur Neurol 1986;25:327-329
Fibromyalgia
• Three trials report improvement with 5-HTP
• DBPC with 5-HTP 100mg tid for 30d in 50 pts.
– Significant improvement in #s of TPs,
TPs
subjective pain severity, AM stiffness, anxiety,
fatigue
– low incidence of side-effects
– Caruso, et al. J Int Med Res. 1990;18:201-209
Cautions with 5-HTP
• Serotonin syndrome possible if taken with SSRI or
MAOI such as Nardil or Parnate
• Reported
R
d with
i h L-Tryptophan@1200mg
LT
h @1200
qd
d plus
l
MAOI
• Not reported with 5-HTP@200mg qd plus MAOI
• Beginning dose 5-HTP@50mg tid suggested
• Can increase 5-HTP to 100mg tid if response after
two weeks is inadequate
38
4/11/2008
Cautions with 5-HTP
• Serotonin syndrome has agitation, confusion,
delirium, tachycardia, diaphoresis, BP fluctuation
• If suspect, di
discontinue
i
5-HTP,
5 HTP SSRI
SSRI, MAOI
• 5-HTP should not be used or used cautiously with
SSRI or MAOI
• When changing over consider washout period (314d) or possibility of serotonin syndrome
symptoms exist
Boswellia serrata ~ Salai guggul
Frankincense/Indian Olibanum
• Traditional gum resin exudate uses have been for
arthritis,
h i i abdominal
bd i l pain,
i diarrhea,
di h hepatic
h
i
disorders,neurologic disorders,and as a topical for
sores
• Used in Ayurvedic, Unani and Chinese herbal
medicine, commonly used with Ginger, Turmeric,
Commiphora, Corydalis in formulae
Boswellia serrata ~ Salai
guggul
Pharmacology
• Studies show that β-boswellic acids are
p
inhibitors of leukotriene
specific,non-redox
synthesis either interacting directly with 5lipoxygenase or blocking its translocation
(but did not affect the 12-lipoxygenase and the
cyclooxygenase activities)
• Ammon HP, Safayhi H, Mack T, Sabieraj J
Ethnopharmacol 1993 Mar 38:2-3 113-9
• Ammon HP Eur J Med Res 1996 May 24 1:8
369-70
39
4/11/2008
Boswellia serrata ~ Salai
guggul
Pharmacology
• Inhibits Human Leukocyte Elastase (HLE) a
serine protease which initiates injury that
triggers
i
the
h inflammatory
i fl
process
• Safayhi H, et al. Inhibition by boswellic
acids of human leukocyte elastase. J
Pharmacol Exp Ther 281;460-463
Boswellia serrata ~ Salai
guggul
Pharmacology
• Boswellic acids and triterpene constituents
have been shown to inhibit leukemia cells in
vitro and induce apoptosis
p p
and
differentiation
• Jing Y, et al Chin Med Sci J 1992 Mar 7:1 12-5
• Shao Y,et al. Planta Med 1998 May 64:4 328-31
• Jing Y, et al. Leuk Res 1999 Jan 23:1 43-50
Boswellia serrata ~ Salai
guggul
Clinical Applications
• Recent studies have demonstrated efficacy
in models of inflammation and as an
analgesic
• Reddy GK et al. Studies on the metabolism of
glcosaminoglycans under the influence of new
herbal antiinflammatory agents. Biochemical
Pharmacology, Vol 38(20), 3527-3534, 1989
• Ammon et al. Mechanism of antiinflammatory
actions or curcumin and boswellic acids.J
Ethnopharmacol 1991 May-Jun 33:1-2 91-5
40
4/11/2008
Boswellia serrata ~ Salai guggul
Clinical Applications
• Ulcerative colitis(Grade II,III)
•
(350 mg tid for 6 weeks) on stool properties, histolopathology and
scan microscopy of rectal biopsies, blood parameters including Hb,
serum iron, calcium, phosphorus, proteins, total leukocytes and
eosinophils was studied. Patients receiving sulfasalazine (1 g thrice
daily) served as controls. All parameters tested improved after
treatment with Boswellia serrata gum resin, the results being similar
compared to controls: 82% out of treated patients went into remission;
in case of sulfasalazine remission rate was 75%.
• Eur J Med Res 1997 Jan 2:1 37-43
Boswellia serrata ~ Salai guggul
Clinical Applications
• Knee Osteoarthritis, DBPC trial, n=30
• Given BSE or placebo for 8 wks, after the first
intervention, then washed out and crossed over
• ALL patients
i
receiving
i i BSE reportedd decreased
d
d
knee pain, increased knee flexion, and increased
walking distance
• BSE was generally well-tolerated except for minor
GI ADRs
Phytomedicine 2003 Jan;10(1):3-7.
Boswellia serrata ~ Salai
guggul
Dosage and Side-Effects
• Anti-inflammatory:
– 200mg TID
• as Boswellia serrata extract containingg 60-70%
organic acids or
• 50mg TID if standardized to boswellic acids(
100%)
• Free of typical NSAID toxicity, welltolerated, no GI or kidney complaints
41
4/11/2008
Boswellia serrata ~ Salai
guggul
Clinical Applications
• In veterinary medicine has been used for
disabling OA ,chronic post-operative knee
arthritis general stifle problems
arthritis,
problems, sore backs,
backs
bowed tendons and bone spurs
• McCrea B. Ancient Indian Herb proving
itself a winner for modern day equine
athletes. J Am Hol Vet Med Assoc 12(1),19
Boswellia serrata ~ Salai
guggul
Clinical Applications
• Bronchial asthma
– In a double-blind, placebo-controlled study forty patients, 23 males and 17
females in the age range of 18 - 75 years having mean duration of illness,
bronchial asthma, of 9.58 +/- 6.07 years were treated with a preparation
of gum resin of 300 mg thrice daily for a period of 6 weeks
weeks. 70% of
patients showed improvement of disease as evident by disappearance of
physical symptoms and signs such as dyspnoea, rhonchi, number of
attacks, increase in FEV subset1, FVC and PEFR as well as decrease in
eosinophilic count and ESR. In the control group of 40 patients 16 males
and 24 females in the age range of 14-58 years with mean of 32.95 +/12.68 were treated with lactose 300 mg thrice daily for 6 weeks. Only
27% of patients in the control group showed improvement. The data show
a definite role of gum resin of Boswellia serrata in the treatment of
bronchial asthma.
• Eur J Med Res 1998 Nov 17 3:11 511-4
Herbal Medicines for
Fibromyalgia
• Hypericum : standardized to hypericin and
hyperforin content; 600mg BID PC
• Magnesium: 200-300mg BID to tolerance
• Malic
M li acid:
id 200-300mg
200 300
BID
• If insufficient response add 5-HTP 100mg QDTID
• If sleep problems are still present after 2 weeks
consider sleep aids such as melatonin, kava,
zizyphus, valerian
42
4/11/2008
Migraine Strategies
• Address the musculoskeletal dysfunction in the
neck and jaw (if applicable)
• Normalize hormonal triggers
• Find and avoid dietary and environmental triggers
• Mg taurate, B vitamins, antioxidants in
individually optimized doses
• 5-HTP 50-150mg h.s., or during the day not to
exceed 300mg.
Neuralgia Approaches
• If impingement or local hypoxia is present it must
be addressed first
• Magnesium, Gingko, Hypericum, Kava, Valerian
may be particularly helpful
• B vitamin deficiencies often contribute
• GABA or gabapentin is often specific
• Needling therapies (acupuncture , neural therapy,
mesotherapy) is generally most helpful
• Undiagnosed DM or continuum should be strongly
suspected
Magnesium
New mechanisms to consider
•
•
•
•
Essential for production of ATP and Glutathione
Lowers Il-6 which leads to lower MMP-1
Inhibits MMP-1----Angiology 1999 Jul;50
Inhibits MMP-2 in cardiac fibroblasts in a dose
dependant fashion--- Basic Res. Cardiology 2004
July ‘99
• Magnesium is a N-methyl-D-asparate (NMDA)
receptor antagonist---Masui. 1998
Sep;47(9):1109-13.
43
4/11/2008
Magnesium and
MMPs cont.
• A magnesium deficient diet feed to mice for 42
days lead to aortic wall thinning and severely
damaged collagen and elastin via increased
expression of MMP-2
MMP 2 and MMP
MMP-9---9
Magnes
Magnes.
Res. 2003 Mar;16
• In a dose dependant manner, rat VSMC’s
produced more MMP-2 with and without PDGF
and were not influenced by verapamil and
nifedipine in the context of a magnesium deficient
diet.---Atherosclerosis 2003 Feb;166
Thank You!
Rick Marinelli, ND, MAcOM
44