Herb-Drug Interactions

Transcription

1 Topics Herb-Drug Interactions Herb-Drug Interaction Herbs with higher risk of adverse reactions Management techniques Current regulation John K. Chen, Ph.D., Pharm.D., O.M.D., L.Ac. Art of Medicine Press Evergreen Herbs and Medical Supplies Lotus Institute of Integrative Medicine Herb-Drug Interactions Basic Concept and Understanding of Interaction Pharmacokinetic Interaction Pharmacodynamic Interaction Examples of Herb-Drug Interactions Examples of Herb-Herb Interactions Pharmacokinetic Interactions Absorption Distribution Metabolism Elimination Absorption Binding in the Gastrointestinal Tract Change in ph in the Stomach Change in Intestinal Motility Binding in the GI Tract Questran (cholestyramine) Colestid (colestipol) Xenical (orlistat) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 1

2 Wu Bei Zi (Galla Chinensis) Chi Shi Zhi (Halloysitum Rubrum) Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 997 Yu Yu Liang (Limonitum) Absorption All three herbs have a strong binding affinity, and when they physically bind to another substance, the result is a large, insoluble complex that cannot be absorbed through the intestines. Therefore, it is recommended that the ingestion of drugs and these herbs be separated by at least 2 hours to avoid interference with proper absorption. 2 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 998 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 998 Xiao Hui Xiang (Fructus Foeniculi) Xiao Hui Xiang (Fructus Foeniculi) Ciprofloxacin: It was found that there was a decrease of maximum plasma concentration by 83%, of area under the curve by 48%, and of urinary recovery by 43%, when the herb and drug were taken together. The mechanism of the herb-drug interaction was attributed to the high content of metal cations present in the herb. The researchers concluded that if the two agents are to be used concurrently, an adequate dosing interval is required to ensure efficacy of ciprofloxacin. 7 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 466 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 2

3 Di Yu (Radix Sanguisorbae) Di Yu (Radix Sanguisorbae) Ciprofloxacin: It was found that there is a decrease of maximum plasma concentration by 94%, area under the curve by 78%, and urinary recovery by 79%, when the drug and herb are taken together. The mechanism of the interaction was attributed to the high content of minerals present in the herb. To avoid drug-herb interaction and interference with the bioavailability of ciprofloxacin, the researchers concluded that an adequate time should be allowed between the two agents. 16 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 567 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 567 ph in the stomach Hai Piao Xiao (Endoconcha Sepiae) Antacid Maalox Mylanta Tums Others ph in the stomach Histamine-2 Receptor Antagonist Tagamet (cimetidine) Pepcid (famotidine) Axid (nizatidine) Zantac (ranitidine) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 3

4 Huang Lian (Rhizoma Coptidis) Wu Zhu Yu (Fructus Evodiae) Zuo Jin Wan (Left Metal Pill) Others Aspirin: Administration of Zuo Jin Wan was found to have marked protective effect against aspirin-induced damages to the stomach mucus membrane. Zhong Yao Yao Li Yu Lin Chuang (Pharmacology and Clinical Applications of Chinese Herbs) 1993;9(4):9. ph in the stomach Proton Pump Inhibitor Prilosec (omeprazole) Nexium (esomeprazole) Pravacid (lansoprazole) Protonix (pantoprazole) Intestinal Motility Drugs that increase intestinal motility may decrease absorption Reglan (metoclopramide) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 4

5 Intestinal Motility Da Huang (Radix et Rhizoma Rhei) Drugs that decrease intestinal motility may increase absorption Antipsychotics: Haldol (haloperidol), Thorazine (chlorpromazine ), etc. Drugs that dry up the digestive tract Opioids: morphine, Vicodin, Tylenol/codeine, Darvocet, Lorcet, etc. Mang Xiao (Natrii Sulfas) Others Absorption Solution: Take herbs and drugs separately by 3-4 hours Distribution Two factors that contribute to Distribution Interactions: Narrow range of safety index High protein bounding ratio Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 5

6 Normal Range of Safety Narrow Range of Safety OD Conc. Max Conc. OD Max Min Min No Effect No Effect Time Time Protein Binding Protein Binding Protein Drug 1% Free Molecule: Effective 99% Protein Bound: Ineffective Protein Binding Drug Protein Binding 2% Free Molecule: Effective Competition 98% Protein Bound: Ineffective Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 6

7 Distribution Interaction Narrow Range of Safety Normal situation: 99% protein bound: 1% free With displacement 98% protein bound: 2% free Conc. OD Max Min 100% increase in effect! No Effect Time Narrow Range + Protein Displacement Distribution Conc. OD Max Min Narrow range of safety index Highly protein bound Coumadin (warfarin) Dilantin (phenytoin) No Effect Time Others Distribution Dilemma: Difficulty/Impossible to predict interactions Solution: Initiate the herbs at a lower dose; Gadually increase the dose of the herbs; Monitor the patient closely Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 7

8 Metabolism Liver Enzyme Inducer: Increased metabolism of herbs/drugs Decreased therapeutic effect Liver Enzyme Inhibitor: Decreased metabolism of herbs/drugs Increased therapeutic effect Metabolism Liver Enzyme Inducer: Dilantin (phenytoin) Tegretol (carbamazepine) phenobarbitals pentobarbital secobarbital rifampin Metabolism Liver Enzyme Inducer: Increased metabolism of herbs/drugs Decreased therapeutic effect Gradual onset of enzyme induction (takes about 1-2 month before effect is observed) Liver Enzyme Induction Increased Metabolism Decreased Concentration. Over 1 to 2 Months Metabolism Liver Enzyme Inhibitor: Tagamet (cimetidine) E.E.S. (erythromycin) Alcohol (ethanol) Diflucan (fluconazole) Sporonox (itraconazole) Nizoral (ketoconazole) Metabolism Liver Enzyme Inhibitor: decreased metabolism of herbs/drugs increased therapeutic effect Rapid onset of enzyme inhibition (takes about 2 weeks before effect is observed) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 8

9 Metabolism Liver Enzyme Inhibition Liver Enzyme Inducer: increased metabolism decreased effect increase the dosage Liver Enzyme Inhibitor: decreased metabolism increase effect Inhibited Metabolism. Within 2 Weeks. Increased Concentration decrease dosage Metabolism Huang Yao Zi (Herba Dioscoreae Bulbiferae) Guan Ye Lian Qiao (Herba Hypericum) [AKA: St. John s Wort] Huang Yao Zi (Herba Dioscoreae Bulbiferae) Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 718; 173 Guan Ye Lian Qiao (Herba Hypericum) Guan Ye Lian Qiao (Herba Hypericum) Metabolic effect: St. John s Wort may induce the cytochrome P-450 system of the liver, leading to increased metabolism and reduced plasma concentration of certain drugs. St. John s Wort may lower the plasma levels of many drugs, such as cyclosporine (Sandimmune/Neoral), ethinyloestradiol and desogestrel (combined oral contraceptive), theophylline (Theo-Dur), digoxin (Lanoxin), and indinavir (Crixivan). 11 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 176 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 176 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 9

10 Dang Gui (Radix Angelicae Sinensis) Dang Gui (Radix Angelicae Sinensis) Acetaminophen: It has been shown that Dang Gui treats acetaminophen-induced liver damage, presumably because Dang Gui promotes the generation of hepatocytes. 45,46 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 918 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 918 Niu Bang Zi (Fructus Arctii) Niu Bang Zi (Fructus Arctii) Acetaminophen: Niu Bang Gen (Radix Arctii) has marked hepatoprotective effects. Niu Bang Gen suppressed the elevated SGOT and SGPT levels induced by carbon tetrachloride or acetaminophen in a dose-dependent manner. It also alleviated the severity of liver damage based on histopathological observations. Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 70 Niu Bang Zi (Fructus Arctii) Others Acetaminophen: The mechanism of this hepatoprotective action is based on the antioxidative effect of Niu Bang Gen on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from carbon tetrachloride or acetaminophen. 9 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 70 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 10

11 Elimination Nephrotoxic drugs: amphotericin B methotrexate tobramycin gentimicin Elimination Prevent ototoxicity and nephrotoxicity due to aminoglycosides Compound injection with Huang Qi (Radix Astragali) and Lu Han Cao (Herba Pyrolae) May prevent ototoxicity and nephrotoxicity due to aminoglycosides in guinea pigs Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 847 Elimination Nephrotoxic herbs: Guang Fang Ji (Radix Aristolochiae Fangchi) Guan Mu Tong (Caulis Aristolochiae Manshuriensis) Ma Dou Ling (Fructus Aristolochiae) Qing Mu Xiang (Radix Aristolochiae) Xi Xin (Herba Asari) Aristolochic acid Slimming regimen in Belgium 5 drugs and 2 herbs fenfluramine, diethylpropion, cascara powder, belladonna extract, acetazolamide, Fen Fang Ji (Radix Stephaniae Tetandrae) Hou Po (Cortex Magnoliae Officinalis) Aristolochic acid Aristolochic acid Fang Ji: Fen Fang Ji (Radix Stephaniae Tetandrae) Guang Fang Ji (Radix Aristolochiae Fangchi) Mu Tong: San Ye Mu Tong (Caulis Akebiae) Chuan Mu Tong (Caulis Clematidis Armandii) Guan Mu Tong (Caulis Aristolochiae Manshuriensis) Ma Dou Ling (Fructus Aristolochiae) Qing Mu Xiang (Radix Aristolochiae) Xi Xin (Herba Asari) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 11

12 Others Pharmacokinetic Interactions Absorption Distribution Metabolism Elimination Pharmacodynamic Interactions Synergistic Effect 1+1=3 Antagonist Effect 1+1=1 Herb-Herb Interactions Synergistic Effect with Herbs Shi Gao (Gypsum Fibrosum) and Zhi Mu (Radix Anemarrhenae) Ru Xiang (Gummi Olibanum) and Mo Yao (Myrrha) Tao Ren (Semen Persicae) and Hong Hua (Flos Carthami) Herb-Herb Interactions Shi Ba Fan (Eighteen Incompatibles) Antagonist Effect with herbs Ren Shen (Radix Ginseng) and Wu Ling Zhi (Excrementum Trogopteri seu Pteromi) Ren Shen (Radix Ginseng) and Lai Fu Zi (Semen Raphani) Gan Cao (Radix et Rhizoma Glycyrrhizae) is incompatible with: Gan Sui (Radix Kansui) Jing Da Ji (Radix Euphorbiae Pekinensis) Hong Da Ji (Radix Knoxiae) Yuan Hua (Flos Genkwa) Hai Zao (Sargassum) Fu Zi (Radix Aconiti Lateralis Praeparata), Zhi Chuan Wu (Radix Aconiti Praeparata) and Zhi Cao Wu (Radix Aconiti Kusnezoffii Praeparata) are incompatible with: Ban Xia (Rhizoma Pinelliae) Chuan Bei Mu (Bulbus Fritillariae Cirrhosae) Zhe Bei Mu (Bulbus Fritillariae Thunbergii) Gua Lou (Fructus Trichosanthis) Gua Lou Zi (Semen Trichosanthis) Gua Lou Pi (Pericarpium Trichosanthis) Tian Hua Fen (Radix Trichosanthis) Bai Ji (Rhizoma Bletillae) Bai Lian (Radix Ampelopsis) Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: Li Lu (Radix et Rhizoma Veratri) is incompatible with: Ren Shen (Radix et Rhizoma Ginseng) Dang Shen (Radix Codonopsis) Nan Sha Shen (Radix Adenophorae) Bei Sha Shen (Radix Glehniae) Dan Shen (Radix et Rhizoma Salviae Miltiorrhizae) Xuan Shen (Radix Scrophulariae) Ku Shen (Radix Sophorae Flavescentis) Chi Shao (Radix Paeoniae Rubra) Bai Shao (Radix Paeoniae Alba) Xi Xin (Radix et Rhizoma Asari) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 12

13 Shi Jiu Wei (Nineteen Counteractions) Liu Huang (Sulfur) and Po Xiao (Sal Glauberis) Shui Yin (Hydrargyrum) and Pi Shuang (Arsenolite) Lang Du (Radix Euphorbiae Fischerianae) and Mi Tuo Seng (Lithargyrum) Ba Dou (Semen Crotonis) and Qian Niu Zi (Semen Pharbitidis) Ding Xiang (Flos Caryophylli) and Yu Jin (Radix Curcumae) Ya Xiao (Nitrum) and San Leng (Rhizoma Sparganii) Xi Jiao (Cornu Rhinoceri) and Zhi Cao Wu (Radix Aconiti Kusnezoffii Praeparata) Xi Jiao (Cornu Rhinoceri) and Zhi Chuan Wu (Radix Aconiti Praeparata) Ren Shen (Radix et Rhizoma Ginseng) and Wu Ling Zhi (Faeces Trogopteri) Rou Gui (Cortex Cinnamomi) and Chi Shi Zhi (Halloysitum Rubrum) Drug-Drug Interactions Synergistic Effect with Drugs Bactrim (sulfamethoxazole and trimethoprim) Augmentin (amoxilicillin & clauvulanate p.) Vicodin (hydrocodon & acetaminophen) Tylenol #3 (codeine & acetaminophen) cocktail approach to treating HIV & cancer. Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: Drug-Drug Interactions Antagonist effect with drugs Tetracycline / ciprofloxacin with iron activated charcoal with poisons Herb-Drug Interactions General Interactions Anticoagulants / Antiplatelets Diuretics Antidiabetics Sedatives / Hypnotics Specific Interactions Chinese Herbal Toxicology Serious poisonings due to Chinese herbal medicine 61% by aconite roots 15% by herbs with anticholinergic properties (datura and areca) 24% others.. Toxicology... aconite roots Tetraplegia caused by... Chuan Wu (Radix Aconiti Preparata) Cao Wu (Radix Aconiti Kusnezoffii) Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 438 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 13

14 Toxicology... aconite roots Aconitine Cardiac arrest cause by... Aconitine containing herbs severe overdose ventricular tachycardia, fibrillation, cardiac arrest, and death. Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: General Antidotes Rou Gui (Cortex Cinnamomi), 3-5 grams in tea. Decoction of Sheng Jiang (Rhizoma Zingiberis Recens), Gan Cao (Radix Glycyrrhizae), Gan Jiang (Rhizoma Zingiberis), Lu Dou (Semen Phaseoli Radiati), Hei Dou (Semen Glycine Max), Huang Lian (Rhizoma Coptidis), Ren Shen (Radix Ginseng) and Huang Qi (Radix Astragali). Specific Antidotes Irregular heartbeat: decoction of Ku Shen Gen (Radix Sophorae Flavescentis), 20 grams Gan Cao (Radix Glycyrrhizae), 10 grams Coldness of the extremities, extremely weak pulse, and shortness of breath: decoction of Ren Shen (Radix Ginseng), Gan Cao (Radix Glycyrrhizae), and Gan Jiang (Rhizoma Zingiberis). Toxicology... A/C herbs Herbs with anti-cholinergic properties Man Tuo Luo (Datura metel, D. innoxia, D. stramonium, D. tabula, D. fastusa) Bing Lang (Semen Arecae) Da Fu Pi (Pericarpium Arecae) Other Issues Pregnancy Nursing Geriatrics Pediatrics Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 14

15 Herbs & Pregnancy Prohibited herbs: Ba Dou (Fructus Crotonis) Qian Niu Zi (Semen Pharbitidis) Ban Mao (Mylabris) Shang Lu (Radix Phytolaccae) She Xiang (Moschus) San Leng (Rhizoma Sparganii) E Zhu (Rhizoma Curcumae) Shui Zhi (Hirudo) Meng Chong (Tabanus) Herbs & Pregnancy Use with caution: Tao Ren (Semen Persicae) Hong Hua (Flos Carthami) Da Huang (Radix et Rhizoma Rhei) Zhi Shi (Fructus Aurantii Immaturus) Fu Zi (Radix Aconiti Lateralis Praeparata) Gan Jiang (Rhizoma Zingiberis) Rou Gui (Cortex Cinnamomi) Others: Herbs that induce contraction of uterus Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 1145 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 1145 Nursing Presence of herbs in the breast milk Lipophilic vs. hydrophilic substances Dosing Geriatric patients Pediatric patients Body weight Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 1144 Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 1148 Common Adverse Reactions Nausea and vomiting Constipation or diarrhea Headache Allergic reaction Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 15

16 Regulatory Issues Drug vs. Supplement vs. Food Aristolochic acid Pyrrolizidine alkaloids Ephedrine alkaloids Citrus herbs Manufacturing issues Aristolochic acid Slimming regimen in Belgium 5 drugs and 2 herbs fenfluramine, diethylpropion, cascara powder, belladonna extract, acetazolamide, Fen Fang Ji (Radix Stephaniae Tetandrae) Hou Po (Cortex Magnoliae Officinalis) Aristolochic acid Fang Ji: Fen Fang Ji (Radix Stephaniae Tetandrae) Guang Fang Ji (Radix Aristolochiae Fangchi) Mu Tong: San Ye Mu Tong (Caulis Akebiae) Chuan Mu Tong (Caulis Clematidis Armandii) Guan Mu Tong (Caulis Aristolochiae Manshuriensis) Ma Dou Ling (Fructus Aristolochiae) Qing Mu Xiang (Radix Aristolochiae) Xi Xin (Herba Asari) Pyrrolizidine alkaloids Comfrey Kuan Dong Hua (Flos Farfarae) Ephedrine Alkaloids Ma Huang (Herba Ephedrae) Ban Xia (Rhizoma Pinelliae) Citrus Herbs Zhi Shi (Fructus Immaturus Citri Aurantii) Zhi Ke (Fructus Citri Aurantii) Chen Pi (Pericarpium Citri Reticulatae) Qing Pi (Pericarpium Citri Reticulatae Viride) Chemical Composition:synephrine; N-methyltyramine; hesperidin; neohesperidin; nobiletin; desmethyl nobiletin; quinoline; narcotine; noradrenaline; quinoline; tryptamine; tyramine; n-methyltyramine; naringin; rhoifolin; tengeretin; and lonicerin. Modern Pharmacology of Chinese Herbs, 1997; 636 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 16

17 Others Manufacturing Issues Heavy metals Drugs Undeclared ingredients Toxicology... others CPM may contain western drugs, including paracetamol, aspirin and antihistamines, which may or may not be listed in the leaflet Po Yin Tan contained lead and mercury a 2-month-old boy was using a herbal powder with high lead content (23.3% of lead by weight) Tse Koo Choy contained calomel (mercurous chloride) Toxicology... others Warning Issued on Herbal Remedy The California Department of Health Services (DHS) recently issued a warning to the public not to use a CPM product call Zhong Gan Ling because it contained ingredients that can cause serious illness and death. Harmful ingredient is dipyrone, which causes agranulocytosis Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 17

18 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 18

19 Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 19

20 Chinese Herbal Toxicology Aconitine Serious poisonings due to Chinese herbal medicine 61% caused by aconite roots Fu Zi (Radix Aconiti Lateralis) Chuan Wu (Radix Aconiti) Cao Wu (Radix Aconiti Kusnezoffii) Vet Human Toxicol, 1995 April 37(2) Copyright Chen and Chen. Chinese Medical Herbology and Pharmacology. Page: 438 GMP and Quality Control Visit the Farmers Purchase the Samples from Seed to Shelf Pao Zhi Preparation Extraction of Herbs Certificate of Analysis QC Test Import the Herbs QC Test of Herb Residues Record Keeping QC Test QC Test of Finished Products QC Test for Shelf-life John K. Chen, O.M.D., Pharm.D., Ph.D. Storage Packaging Customer Service Four Governing Principles GAP (Good Agricultural Practice) for Raw Materials GMP (Good Manufacturing Practice) for Extraction of Herbs GLP (Good Laboratory Practice) for Quality Control PMS (Post-Marketing Surveillance) GAP (Good Agricultural Practice) Evergreen purchases only geo-authentic herbs. Evergreen avoids use of endangered animals and plants. Evergreen always prefers wild-crafted herbs whenever possible. Evergreen uses only pharmaceutical-grade raw material. Evergreen always imports herbs in bulk. Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 20

21 We purchase Chuan Bei Mu (Bulbus Fritillariae Cirrhosae) grown in Sichuan province, the region with ideal climate and soil to produce the most effective herb. We buy from farmers that follow the Good Agricultural Practice (GAP), to ensure sustainable farming of quality and a wide range of affordable Chinese herbs. Evergreen Herbs protects the integrity of TCM by not using endangered animal and protected plant species. We use only pharmaceutical-grade herbs, and purchase them directly from the farmers. Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 21

22 We purchase all the herbs in bulk form not sliced or powdered to facilitate macroscopic examination. All in-coming herbs are stored in a controlled environment. Quarantine: All in-coming herbs are quarantined for inspection and testing by quality control personnel. Pass Raw materials are not used until they pass all safety and efficacy tests. Herbs that pass quality control tests are stored in drums to prevent mix-ups. We store many herbs in industrial-size refrigerators to avoid spoilage. Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 22

23 GMP (Good Manufacturing Practice) GLP (Good Laboratory Practice) Identity Purity Safety Efficacy Identity 1. Macroscopic exam: to determine the look, taste, and smell 2. Microscopic exam: to differentiae the cellular structure 3. Chemical exam: to identify the marker compound and chemical composition Macroscopic examination of bulk herbs Macroscopic exam of bulk herbs in slices Macroscopic examination of bulk herbs Macroscopic exam of bulk herbs in slices Han Fang Ji - Stephania Guang Fang Ji - Aristolochia Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 23

24 Microscopic exam of cellular structures: This step is essential in determining the authenticity. Some herbs are hard to distinguish visually. So we screened these herbs under the microscope to exam their cellular structures. TLC (Thin Layer Chromatography) assures the identity of raw material and finished products. Huang Qi (Radix Astragali) Huang Qi (Radix Astragali) Presence of precise marker compound astragaloside IV Accurate identification vs. standardized solution. Purity Total Ash and Acid-Insoluble exams assure minimal presence of dirt and soil. Dirt Soil Heavy metals Lead Cadmium Mercury Arsenic Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 24

25 ICP-OES tests to guarantee that herbs are not contaminated with heavy metals, such as lead, arsenic, mercury, cadmium, etc. Safety Micro-organisms Herbicides Pesticides Aflatoxins Ochratoxins Microbial tests ensure the absence of E. coli, Salmonella, Staphylococcus, yeast, mold, and other micro-organisms. GC/MS tests assure the safety from herbicides and pesticides. HPLC-DL exams assure safety from aflatoxins and ochratoxins, by-products from mold linked to hepatitis and nephritis. Efficacy TLC (Thin Layer Chromatography): for qualitative analysis HPLC (High Performance Liquid Chromatography): for qualitative and quantitative analysis Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 25

26 Bai Shao (Radix Paeoniae Alba) Bai Shao (Radix Paeoniae Alba) Presence of precise marker compound paeoniflorin Accurate identification vs. standardized solution. HPLC (High Performance Liquid Chromatography) tests to assure identity, purity and potency of herbs. ~ Processing ~ 炮制 pao zhi the art and the science of preparing herbs. Pao Zhi (Processing) eliminates toxicity To guarantee that aconitine [the toxic compound] has been properly eliminated, we perform TLC test to make sure it is < 0.01%. Toxic: [Fresh] Sheng Fu Zi (Radix Aconiti Lateralis) Safe: [Prepared] Fu Zi (Radix Aconiti Lateralis Praeparata) Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 26

27 To guarantee that aconitine [the toxic compound] has been properly eliminated, we perform TLC test to make sure it is < 0.01%. Pao Zhi (Processing) changes the therapeutic effect [Fresh] He Shou Wu (Radix Polygoni Multiflori) contains emodin and sennoside and causes diarrhea. Pao Zhi (Processing) changes the therapeutic effect HPLC peaks indicate the presence of emodin and sennoside in [fresh] He Shou Wu (Radix Polygoni Multiflori). [Prepared] He Shou Wu (Radix Polygoni Multiflori) with black beans and heat tonifies Kidney yin and jing (essence). HPLC chart of [prepared] He Shou Wu (Radix Polygoni Multiflori) proving the absence of emodin and sennoside. Certificate of Analysis This report details all the specifications, test results, and test methods. Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 27

28 Product ID This includes Chinese name, pinyin name, latin name, and Item number. Dates Manufacturing date, Expiration date, Date of analysis. Heavy Metal Test (As, Cd, Pb, Hg) Physical Analysis This determines The purity of herbs with minimal amount of water, fiber, and other inactive components. The specifications meets or exceeds standards established by US Pharmacopoeia, EU Pharmacopoeia, ad WHO (World Health Organization. Microbial Tests This assures safety from bacteria, yeast, mold, and other micro-organisms. Pesticides/ Herbicide GC/MS tests are performed to make sure pesticides/ herbicides are not detected (ND). Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 28

29 Aflatoxins HPLC/DL tests are performed to guarantee safety from aflatoxin B 1, B 2, G 1, G 2. Certificate of analysis is performed for each batch of herbs, and is always available upon request. Additional tests for pesticides and herbicides performed in the US by independent third-party laboratories. Additional exam to ensure aflatoxins levels are below US FDA and EU standards. Additional tests for heavy metals (As, Cd, Pb, Hg) are performed in the US by third-party laboratories. Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 29

30 Third party laboratories using LC/MS/MS tests to confirm the absence of aristolochic acid, a compound potentially damaging to the kidney below 0.25 ppm. Department of Health Services Approval Confirmation of test results by California Department of Health Services. FDA Approval Confirmation of test results by US FDA. PMS (Post-Marketing Surveillance) After the products are finished We keep samples of raw herbs used. We keep samples of finished products produced. We test for stability of the finished product every six months. until one year past expiration date Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 30

31 Every single batch of herbs is stored for at least one year past expiration date. What You See. What You Don t See Macroscopic /organoleptic exams (taste, smell, color, shape) Microscopic exams (cell wall identity) TLC for qualitative analysis HPLC for qualitative and quantitative analysis Total ash and acid insoluble ash contents Loss on drying C/S tests for micro-organisms (Salmonella, E. coli, S. aureus, fungus, mold) ICP-OES tests for heavy metals (arsenic, cadmium, lead, mercury) GC/MS for oragnocholorine and organophosphorus (testing over 100 pesticides, herbicides & fungicides) HPLC-DL for aflatoxins and ochratoxins LC/MS/MS for aristolochic acid = SAFETY GMP and Quality Control Evergreen Herbs East Gale Ave. City of Industry, CA Tel: ; Fax: Copyright Written by John K. Chen, Pharm.D., Ph.D., O.M.D., L.Ac. Herb-Drug Interactions 31