Published on January 3, 2008
Garlic: Garlic History Chemistry organosulfur compounds alliin allicin Ajoene S-allylcysteine interconversions and odor Slide3: Alliin is a major component found in fresh and dried (carefully) garlic. Allicin is odiferous and pharmacologically active Slide4: Ajoene and like allylsulfides are major components of garlic oil Slide5: S-allylcysteine and like compounds are major components of aged garlic Pharmacology: Pharmacology cholesterol lowering decease atherosclerosis triglyceride lowering antihypertensive antimicrobial insecticide increased fibrinolysis decreased plaque size decreased platelet aggregation increased catalase and glutathione peroxidase decreased cancer induction (animal studies) In vivo evidence – cholesterol lowering: In vivo evidence – cholesterol lowering most early studies (>40) show lowering effects but studies are often not of high quality Meta-analyses have shown a cholesterol lowering effect of 5-12% (Ann Int Med 119:599-605,1993;J R Coll Physicians-London 28:39-45,1994, Ann Int Med 133:420-429, 2000) Slide8: Adapted from Silagy and Nei, JRCollege of Physicians London 28:39-45,1994 Slide9: Stevinson et al. Ann Int Med 133:420-429, 2000 Evidence – cholesterol lowering: Evidence – cholesterol lowering Some recent well designed studies show no effect on cholesterol lowering (see next slide) Kwai story Kanner et al (J Am Coll Nutr 2001;20:225-231) used a high potency, enteric coated garlic powder prep for 12 weeks to lower total and LDL cholesterol (n=46, 9.6mg/d allicin) Slide11: Copyright restrictions may apply. Gardner, C. D. et al. Arch Intern Med 2007;167:346-353. Six-month percent change (mean and SE) relative to the end of the run-in phase in participants with available data Slide12: Kanner et al. J Am College Nutr 2001;20:225-231. N=42 EC garlic powder tab standardized to 2.4mg allicin/tab Dose:2 BID or 9.6mg allicin/d for 12 weeks Diet modification run-in period of 1-2 weeks prior to study What is the benefit of Garlic in general cardiovasuler disease?: What is the benefit of Garlic in general cardiovasuler disease? One study showed decrease in plaque size (n=152, 48mos) compared to placebo (Koscielny et al. Atheroscerosis 144:237-249,1999) Another study indicated that chronic garlic intake increased the elasticity of the aorta (Circulation 1997;96:2649-2655 Some evidence (Arch Intern Med. 2001 26;161:813-24) for small reduction in sytolic and diastolic but more study is needed before recommendations can be made Garlic has modest platelet adhesion inhibition effects Other garlic benefits?: Other garlic benefits? Evidence - cancer A meta-analysis showed modest protective effects for diet intake for colorectal RR=0.69 and stomach cancers (RR=0.53) Fleischauer et al. Am J Clin Nutr 2000 Oct;72(4):1047-52. However, supplements did not reduce precancerous lesions. Yu, YC et al. J Natl Cancer Inst. 2006 Jul 19;98(14):945-6. Evidence - infections A 12 weeks use of a potent garlic supplement reduced the incidence of the common cold compared to placebo (n=146); Rx 24 colds vs placebo 65 colds. Recovery was faster in the Rx. Josling P. Advances in Therapy 2001;18:189-193. 0.6% cream of ajoene may help with tinea infections. Insect Repellent Lab studies no (Rajan et al. Med Vet Entomol 2005;19:84-89.) ; field studies maybe (RR=0.7, 1.2g/d in crossover study in Swedish military) Stjernberg et al. JAMA 2000;248:831. Garlic: Garlic Adverse effects Nothing special Drug interactions: platelet anti-adhesion effects; careful with aspirin and warfarin Reduced AUC of saquinavir in volunteers. May induce p-glycoprotein (more later) but effect may be product dependant. Avoid garlic use with anti HIV therapies Garlic: Garlic Summary Efficacy: the literature is conflicting for use in hyperlipidemia and hypertension maybe mild benefit if excellent product is used; other cardiovascular benefits are possible. Safety: good Drug interactions: warfarin; possibly aspirin and other antiplatelet adhesion drugs; not with HIV drugs Product selection: avoid Kwai? Suggest enteric coated garlic powder tablets standardized to about 2mg allicin/tab. Dose: equivalent of about 4g (2-4 cloves) of fresh garlic per day (~8-12mg allicin). Want >4mg allicin delivered past the stomach Questions remaining include Who can benefit from use; Other uses? Echinacea: Echinacea Botany Echinacea purpurea, E. augustifolia, E. pallida History Echinacea: Echinacea Chemistry high molecular weight polysaccharides heteroxylan arabinogalactan phenylpropanoid - chicoric acid alkylamides flavonoids Pharmacology phagocyte activation release of TNF, interleukin-1 and B2 increase immune response local anaesthesia antimicrobial antioxidant Prevention of colds/flu: Prevention of colds/flu Melchart et al., Archives of Family Medicine 7:541-545,1998 n=302, double blind, placebo controlled, randomized prevention trial in Germany no difference in time to first cold (t=66 vs t-65 in the placebo (patients believed they had more benefit from echinacea, however)(p<.04) Grimm and Muller, Am J Med 106:138-143, 1999 similar prevention trial and results as above Turner et al., Antimicrob Agents Chemother 44:1708-1709, 2000 experimental cold prevention - no effect Bastyr study in Seattle Slide27: Shah et al. Lancet Infect Dis 2007;7:473-80. Note: Cohen study used a mix of ginkgo, vitamin C and propolis (500mg of each/day) Echinacea: Echinacea Evidence for Efficacy for treatment of cold/flu In a recent review, Linde et al. concluded that there is some evidence that preparations based on the aerial parts of Echinacea purpurea might be effective for the early treatment of colds in adults but results are not fully consistent. Linde K, Barrett B, Wolkart K, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2006;(1):CD000530. . A study evaluated the pressed juice (5ml BID) of E. purpurea in 80 subjects. Days of illness in treated = 6 vs 9 in placebo (p=0.01). Cold symptoms were less severe in Rx group. (Schulten et al, Arzneim.-Forsch./Drug Research 2001;51:563-568 Brinkeborn et al (Phytomedicine 1999;6:1-5) reported a reduction in symptoms in treated compared to placebo in a large (n=246) study. Used E. purpurea extract (95% herb, 5% root) or a concentrate of same or E. purpurea root extract. The arial parts-based products showed benefit. The root extract did not. Slide29: Schulten et al. Arzneim-Forsch/Drug Research 2001;51:563 n=80 p<0.05 Slide31: More recent studies Taylor et al. JAMA 2003;290:2824-2830. UW study in treating URI in children n= 407 no benefit (used pressed juice product) Yale and Liu Arch Intern Med 2004;164:1237-1241. Rx for colds in adults N=128 no benefit (used pressed juice) Goel et al. J Clin Pharm Ther 2004;29:75-83 N=282 adults. Used potent product (Echinilin) and high loading dose. Echinilin, a water/ethanol extract of E. purpurea plants contained alkamides/chicoric acid/polysaccharides in a concentration of 0.25/2.5/25 5 mg/ml in 40% ethanol. Got benefit from treatment. Turner et al. N Engl J Med 2005;353:341-8. Used 3 different E. augustifolia root extracts. N=399 BUT only ~50/group. Low dose used. All given rhinovirus 39. Slide33: Goel et al. J Clin Pharm Ther 2004;29:75-83 N=282 echinilin standardized; 10 stat then 1 qid Slide34: Goel et al. J Clin Pharm Ther 2004;29:75-83 N=282 echinilin standardized; 10 stat then 1 qid Slide35: Other immune stimulant uses? Cancer AIDS bacterial and fungal infections Products (which is best??) tablets 250mg tincture root extract or extract of tops or pressed juice Echinacea: Echinacea Summary Efficacy: evidence for treatment not prevention; take at first sign of cold/flu; reduce severity and duration about 25% Safety: good; rare allergy; not where immunostimulation would be undesirable (e.g. lupus, rheumatoid arthritis); outcomes in 206 pregnant women taking echinacea were OK but----- Drug interactions: not documented but don’t give to patients taking immunosuppressive drugs Product selection: standardized extracts usually contain about 4% phenolics Dose: use loading dose (2x) then 1 QID Questions remaining include Which product? Tincture? Tablets? Root extract? Flowering tops? Pressed juice? E. purpurea? E. augusifolia? E. pallida? (GWE recommends Echinamide in 2007) Saw palmetto: Saw palmetto Botany Serenoa repens, Sabal, American dwarf palm tree, cabbage palm History Chemistry fatty acids sitosterols flavones, isoflavones, coumestrans# Pharmacology lipid extracts of berry inhibit testosterone 5-reductase and therefore conversion of testosterone to dihydrotestosterone Saw palmetto: Saw palmetto Pharmacology (continued) block binding of DHT to receptors block nuclear not cytosolic estrogenic, progestogenic and androgenic receptors in prostate inhibit cyclooxygenase (one report of a bleed) and 5-lipooxygenase thereby decreasing inflammation inhibit prolactin at receptor level inhibit testosterone metabolism in prostate tissues in vitro observations: no big plasma changes in hormones. No PSA changes. Favorable cytological changes occur in the prostate. Saw palmetto: Saw palmetto Evidence for efficacy in BPH Carraro et al (Prostate 1996;29:231-240) multicentered European randomized trial of 1098 patients compared Permixon ( hexane extract of saw palmetto) vs. finasteride (Proscar) 6 months Rx of Permixon 160mg BID or finasteride 5mg am (placebo pm)#2 Most studies but not all (see recent Bent study) have showed benefit vs placebo, e.g. study by Gerber et al. (Urology 2001;58:960-5) Slide43: Carraro et al., Prostrate 29:231-240, 1996 Slide44: From Wilt et al. JAMA 280:1604-1609, 1998 Slide45: From Wilt et al. JAMA 280:1604-1609, 1998 Slide46: Gerber et al. Urology 2001;58:960-965 Slide47: Bent et al. NEJM 2006;354:557-566 n=255 Rx for 12 mos. Used Indena carbon dioxide extract product yielding 160mg/capsule (91% fatty acids). One BID. Slide48: Chronic noninfective protatitis-no benefit Adverse effects: one report of hemorrhage during surgery due to prolactin inhibition and some isoflavone content, avoid in pregnancy and lactation Dose: 160mg twice a day or 320mg q d of a 85-95% lipid extract Saw Palmetto: Saw Palmetto Summary Efficacy: overall evidence in reducing symptoms of BPH Safety: good; one report of hemorrhage during surgery; avoid in pregnancy Drug interactions: none noted so far Product selection: want standardized extract containing 85-95% fatty acids and sterols Dose: about 160mg of extract BID for treatment; some use 320mg q d Questions remaining include Will saw palmetto prevent BPH and even prostate cancer? Maybe avoid CO2 extract? Slide50: Pygeum and BPH not as well studied as saw palmetto extract of the bark of an evergreen tree (Prunus africana) found in Africa tree nearly endangered so use is not to be encouraged saw palmetto is cultivated studies support its use for BPH (e.g. Wilt et al. Cochrane Database Syst Rev. 2002;(1):CD001044); takes a few months to work products should be standardized to contain 14% triterpenes and 0.5% docosanol dose: 100mg qd is therapeutically equivalent to 50mg BID no special safety problems; better than Saw palmetto?? Combination products with Saw palmetto better?? Ginkgo biloba: Ginkgo biloba Botanical Aspects History Chemistry bioflavonoid glycosides quercetin, kaempherol, isorhamnetin terpenoids Ginkgolides A,B,C,J bilobalide Ginkgo biloba: Ginkgo biloba Pharmacology Antioxidant/antiinflammatory Free radical scavenger Anti PAF (ginkgolide B)- but may not occur in vivo in humans Decreased platelet activation by collagen (ex-vivo human study) Complex effects on insulin responses to glucose load (increased in normals but decreased in diabetics) Vasodilation Lower blood pressure Increased capillary blood flow Stimulation of endothelium-derived relaxing factor Inhibition of endothelial nitric oxide synthesis Neuroprotective effects and neurotransmitter modulations (animal and in vitro studies) Common Uses: Common Uses Claudication (peripheral vascular disease) Dementia treatment (multi-infarct and Alzheimer's) Cerebral insufficiency Age-associated memory impairment Memory enhancement (in healthy patients) Tinnitus Altitude (mountain) sickness Vertigo Macular degeneration Premenstrual syndrome (PMS) Decreased libido and erectile dysfunction Depression and seasonal affective disorder (SAD) Chemotherapy adjunct (reduce adverse vascular effects) Multiple sclerosis Glaucoma Acute ischemic stroke Ginkgo and Dementia, Alzheimer’s Disease: Ginkgo and Dementia, Alzheimer’s Disease >30 double blind, placebo controlled trials evaluating ginkgo have been published. Most show ginkgo to be better than placebo. The benefits have been modest, however. Slide57: Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of cognitive impairment and dementia: a meta-analysis of randomized trials. Am J Med 2000;108(4):276-281. Ginkgo - JAMA article: Ginkgo - JAMA article LaBars et al., JAMA 278:1327-1332, 1997 (Oct 22) USA study 6 research centers N=309 1 year 202 evaluable at 52 weeks In ginkgo group 24% had 4 point improvement on ADAS-Cog vs 14% in placebo group adverse effects: same as placebo conclusions: modest improvement, improvement recognized by caregivers Slide61: Mini-mental state exam scores EGb761 160mg/d n=76 Mazza, M., Capuano, A., Bria, P. & Mazza, S. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. European Journal of Neurology 2006;13 (9): 981-985. Ginkgo and Memory Enhancement in Healthy Adults: Ginkgo and Memory Enhancement in Healthy Adults Crews et al. HerbalGram 2005;67:43-62 6/7 acute studies show improvement in memory tests 7/9 long term studies show improvement in memory tests Slide63: N=203 >60 years old, 40mg Ginkoba TID x 6 weeks Slide64: N=262 Ginkgold 60mg BID x 6 weeks Ginkgo biloba – peripheral circulation: Ginkgo biloba – peripheral circulation Slide67: Adapted from Vasa 27:106-110,1998 Slide68: Pittler and Ernst. Am J Med 108:276-281, 2000 Ginkgo biloba: Ginkgo biloba Other Uses (much less well studied) Impotence (associated with SSRI antidepressants) – several small studies show some improvement but others do not Tinnitus- (recent studies indicated no help, e.g. n=1121, BMJ 2001;322:73) Vertigo- several small studies showed improvement PMS- a study in France (n=165) indicated improvement prevent altitude sickness- (studies show promise; start 1-5d before trip but recent large (n=487) study showed effect of acetazolamide but not ginkgo) Macular degeneration-one study showed improvement A fixed combination of ginkgo and ginseng shows promise for beneficial effects on memory and (one study) attention deficit hyperactivity disorder Ginkgo biloba: Ginkgo biloba Other Uses (much less well studied) Raynaud’s Syndrome – one study showed decreased attacks Diabetic Retinopathy – one study showed improved color vision Glaucoma – one study showed improvement SAD – no benefit Activities of Daily Living in Older Adults – one study showed improvement Anxiety- one study showed improvement in youg adults with anxiety MS- one study showed improvement in functionality in adults with MS Slide71: Safety Rare bleeds Ginkgo seeds contain 4-methoxypyridoxine and can cause siezures. Two cases of seizure episodes associated with ginkgo extracts (contamination?)- maybe avoid ginkgo in the seizure prone Ginkolic acids are toxic but removed during extract prep Drug interactions Seems not to have effects on CYP in vivo (more later) Additive effects with antiplatelet adhesion drugs Effects on insulin are complex-careful in diabetes Ginkgo Bleeds associated with ginkgo use: Bleeds associated with ginkgo use Ginkgo biloba: Ginkgo biloba Summary Efficacy: evidence for benefit in dementia, poor memory and poor peripheral circulation Safety: good but watch for rare bleeding episodes, seizures? Drug interactions: warfarin; possibly aspirin and other antiplatelet adhesion drugs (ticlopidine) Product selection: look for EGb761 or LI 1370 extracts; these are the best studied; 24% flavone glycosides and 6% terpene lactones Dose: 1-2 60mg tabs, BID Questions remaining include Extent of memory improvement in younger patients? Delay Alzheimer’s and dementia? Help in other circulatory disorders? Synergistic with other drugs and treatments? Optimum dose and treatment time?