LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

III. LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

Poor quality of herbs that require proper curing and of proprietary medicines is also found to be a major cause of herbal poisoning. The relative proportions of therapeutic and toxic components of plants vary depending on the part of the plant used, stage of ripeness, geographic area where the plant is grown, and storage conditions. Therefore, batch-to-batch reproducibility of active chemical ingredients should ideally be assessed in the production of marketed products, but in practice the active ingredients are often not known and most herbal suppliers and practitioners do not have the facilities or training to undertake chemical standardization, so product variation in herbal medicines can be significant.

Adverse Effects of CHM 889

A. Aconites One of the major causes of serious and sometimes fatal toxicity in Hong Kong

has been the use of aconites from the dried rootstocks of Aconitum carmichaeli and A. kusnezoffii (5–7). These preparations are commonly used in TCM for

their anti-inflammatory analgesic effects. They contain C 19 -diterpenoid esters, aconitine, mesaconitine, hypaconitine, and other derivatives, which activate sodium channels resulting in neurological and cardiac toxicity. Aconitine was previously popular in Western medicine but fell into disrepute toward the end of the nineteenth century when cases of toxicity were recognized, and its only role in Western medicine now is in experimental pharmacology to induce arrhythmias in animal preparations.

The initial symptoms of toxicity include paresthesias in the mouth and tongue with progression to involve the extremeties. Nausea and vomiting are common and there may be muscle weakness, hypotension, and dizziness (42– 44). The most serious effects are arrhythmias, which include both bradycardia and tachyarrhythmias such as ventricular flutter or fibrillation (45–48). A number of deaths have occurred from these ventricular arrhythmias (49).

Toxicity was often related to the use of excessive doses of these herbs or to inadequate processing. Like most herbs in CHM the aconites are subjected to a process of ‘‘curing,’’ which in this case involves steaming or boiling in water to reduce the toxicity by converting aconitine alkaloids to aconines and benzoylaconitines. The processed herb is supplied to the patient with a combination of other herbs and the patient is instructed to prepare a decoction by boiling the herbs for a certain period of time. This will further reduce the toxicity of the aconites. Thus there are a number of stages in this process where variations in technique may lead to excessive amounts of the toxic ingredients remaining in the preparation that the patient ingests. In some cases the dosage prescribed was too high. The recommended dosage in the Pharmacopoeia of the People’s Republic of China is 1.5–3 g for both caowu (main root of A. kusnezoffii) and for chuanwu (main root of A. carmichaeli) and 3–5 g for fuzi (lateral root of A. carmichaeli). Some prescriptions have included 6 g or more of each of the first two aconite preparations. Other factors that may contribute to toxicity include differences in the amount of alkaloids present in the plant roots at the time of harvest and the use of inappropriate combinations with other herbs.

IV. HEAVY METAL CONTAMINATION Heavy metals have been used over the centuries for their medicinal effects

although they have largely been replaced in allopathic medicine by less toxic pharmaceuticals. In the theory of TCM heavy metals may be used as active

890 Tomlinson et al.

ingredients of some herbal prescriptions and Chinese proprietary medicines often contain cinnabar (mercuric sulfide), realgar (arsenic sulfide), or litharge (lead oxide) as part of the traditional formula. Furthermore, during growth and storage, crude plant material can become contaminated by pesticide residues, microorganisms, aflatoxins, radioactive substances, and heavy metals; lead, cadmium, mercury, arsenic, and thallium have been reported as contaminants of some herbal preparations (50). In a case series of five patients in England with lead poisoning from Asian traditional remedies, the preparations implicated contained 6–60% by weight of lead (51).

A proprietary medicine, ‘‘Niuhuang Jiedu Pian,’’ was incriminated in a fatal case in Macau (52). The patient, a 13-year-old girl had taken a high

dosage of this proprietary medicine and developed an illness involving multiorgan failure, which was considered to be compatible with arsenic toxicity. When the tablets were analyzed they were found to contain excessive amounts of arsenic and this product and other similar ones were withdrawn from the market in Macau until they were proven to free of arsenic contamination. A number of cases of acute or chronic arsenic poisoning were reported from Singapore in children and adults taking ‘‘Sin Lak Pill’’, ‘‘Lu Shen Wan,’’ and other ‘‘antiasthma’’ preparations (53). These proprietary medicines, which were manufactured in China, Hong Kong, and other Asian countries, were found to contain levels of inorganic arsenic ranging from 25 to 107,000 ppm. In Taiwan, heavy-metal poisoning of newborn infants fed ‘‘Ba Pao Neu Hwang San’’ is reported annually (54). In 1983, the death of a 5- month-old female infant resulted from consumption of the drug, which was found to have contained lead at 44,000 ppm. Despite such cases this TCM is still widely used. In 1992, a survey revealed mercury contamination of this product ranging from 34,500 to 65,700 ppm (54).

V. ADULTERATION WITH WESTERN DRUGS Data from Taiwan have highlighted the widespread use of adulterants in

TCM preparations. Examination of 2,609 products found 23.7% were adulterated and of these 52.8% contained two or more adulterants (55). Of the adulterants 34.5% contained caffeine, 27.0% paracetamol, 24.6% indo- methacin, 20.6% hydrochlorothiazide, and 14.8% prednisolone (55). TCM hospitals had the lowest rates of adulteration (9.0%) with herbalists providing the least authentic preparations, with 34.6% containing adulterants (55). Ginseng preparations in the United States were found to be adulterated with a number of different components including Mandragora officinarum (scopol- amine), Rauwolfia serpentia (reserpine), and Cola species.

Adverse Effects of CHM 891

VI. HERB-DRUG INTERACTIONS Interactions between herbs and drugs have been the subject of a number of

reviews (21,22,26,56–60). However, data regarding interactions with CHM are relatively few and the subject has not been studied systematically although attempts are being made to remedy this (40). The study of some of these interactions has provided insights into the mechanisms involved and helps to predict what other problems may occur. Problems are most likely to be encountered with drugs that have a narrow therapeutic window such as warfarin, digoxin, or cyclosporin. Much of the evidence of interactions of CHM with such drugs comes from anecdotal reports and the true risk is difficult to assess (61).

A. Grapefruit Juice Drug interactions with grapefruit juice serve as a good example of how an

apparently innocuous dietary constituent can interact with potent drugs, which could result in serious toxicity. A number of Chinese herbal medicines are derived from citrus fruits such as chen pi (rind of Citrus reticulata) or zhi shi (unripe fruits of Citrus aurantium) and these could have similar effects although it has been suggested that the interaction is specific for grapefruit products and in vitro findings suggested the flavonoid, naringenin, or the furanocoumarin, 6V,7V-dihydroxybergamottin, were the active components causing drug interactions (62).

The serendipitous finding that grapefruit juice increased the oral bioavailability of felodipine and to a lesser extent nifedipine provided the instigation for a series of investigations to explore the mechanism of this effect (63). Lown and colleagues reported that grapefruit juice decreased small- bowel epithelial cell CYP3A4 concentration by 62%, but did not alter CYP3A4 mRNA levels or the concentrations of small-bowel CYP1A1, CYP2D6, or P-glycoprotein, or colonic CYP3A5, or the activity of hepatic CYP3A4 (64). They concluded that grapefruit juice caused selective post- translational downregulation of CYP3A4 expression in the intestinal wall. This interaction is likely to have the greatest effect in individuals with the highest inherent baseline enteric CYP3A4 and with drugs with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 (62). Clinically relevant interactions are likely with cyclosporin, terfenadine, saquinavir, some HMG CoA reductase inhibitors, and a number of other drugs. Understanding this mechanism should help to limit possible adverse drug interactions and might also be useful to develop possible beneficial drug combinations that could lower treatment costs or increase efficacy.

892 Tomlinson et al.

B. St. John’s Wort St. John’s wort, derived from the flowering tips of Hypericum perforatum,

provides another example where a herbal drug that has gained considerable popularity in Western countries proved to be capable of causing important herb-drug interactions. It appeared to be a safe alternative antidepressant with an efficacy similar to low-dose tricyclic antidepressants or selective serotonin reuptake inhibitors (65–69) apart from the risk that it might interact with the serotonin reuptake inhibitors to produce a mild serotonin syndrome (26,56,70,71). However, in 1999 reports started to appear of interactions between St. John’s wort and a variety of drugs and it was shown to reduce the plasma concentrations of digoxin (72) and theophylline (73) and to result in breakthrough bleeding during oral contraceptive use (74). Case reports then emerged suggesting interactions with cyclosporin could reduce the immuno- suppressive effect resulting in rejection of transplanted organs including heart (75,76), liver (77), and renal (78–80) transplants. It was also shown to decrease plasma levels of the HIV protease inhibitors indinavir (81) and nevirapine (82), as well as amitriptyline (83) and some HMG CoA reductase inhibitors (84).

Studies examining the mechanism of these interactions showed that administration of St. John’s wort extract to rats for 14 days resulted in a 3.8- fold increase in expression of the intestinal drug efflux transporter P-glycoprotein, the product of the multidrug resistance (MDR) gene 1, and in a 2.5- fold increase in hepatic CYP3A2expression (85). In healthy volunteers administration of St. John’s wort extract for 14 days resulted in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 assessed by 14C-erythromycin breath test (85). Likewise, St. John’s wort given for 16 days produced a 4.2-fold increase in expression of P -glycoprotein and enhanced the P-glycoprotein-mediated drug efflux func- tion in peripheral blood lymphocytes of healthy volunteers (86).

Another study using an in vivo probe drug cocktail approach showed that short-term administration of St. John’s wort had no effect on CYP activities whereas long-term (2weeks) administration decreased the bioavailability of oral midazolam by >50% but when midazolam was given intra- venously there was only a 20% decrease, indicating relatively selective induction of CYP3A activity in the intestinal wall (87). There was no change in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St. John’s wort administration (87). However, in the LS180 intestinal cell model St. John’s wort increased the expression of CYP1A2in a concentration- and time- dependent manner (88). Conversely, incubation of St. John’s wort in vitro with a panel of recombinant human CYP isoforms showed inhibition of the 1A2, the 2C6, and especially the 2C19 isoforms (89).

Adverse Effects of CHM 893

A molecular mechanism for the interaction was demonstrated as hyperforin, a constituent of St. John’s wort with antidepressant activity, was found to be a potent ligand for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 (90). Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Activation of this nuclear receptor would lead to upregulation of the expression of P-glycoprotein/ MDRI and CYP3A4 expression in the intestinal wall and to a lesser extent CYP3A4 in the liver.

C. Danshen Danshen, the root of Salvia miltiorrhiza, is a herb commonly used in TCM

for the treatment of atherosclerotic cardio- and cerebrovascular diseases. It has been reported to have a number of anticoagulatory effects, including inhibition of platelet aggregation, antithrombin III–like activity, antagonism of extrinsic blood coagulation, and profibrinolytic properties (91). One study showed some components may have scavenging effects on free radicals (92). When taken in combination with the anticoagulant warfarin, excessive anticoagulation has been reported in a number of cases (93–96). This could represent a pharmacodynamic interaction on different coagulation mechanisms, but as danshen does not usually affect the PT directly the increases seen in prothrombin time suggests a pharmacokinetic effect and danshen has also been reported to increase plasma concentrations of both R- and S -warfarin and decrease clearance in a rat model (97). Much of the activity of danshen has been attributed to the tanshionone components that can

be identified following hydrophobic extraction, and include tanshionone IIA and sodium tanshionone sulfonate. Recently, the sulfonate has been reported to be a noncompetitive inhibitor of CYP2C9 in human hepatic microsomes (98).

D. Dong Quai Dong quai, or danggui, is the Chinese herb prepared from the dried root of

Angelica sinensis . It is used as an antispasmodic, a ‘‘blood purifier,’’ and a tonic and as a treatment for various gynecological disorders including menstrual cramping, irregular menses, and menopausal symptoms. Phyto- chemical analyses showed it contains coumarin derivatives and other constituents possessing antithrombotic and antiarrhythmic effects (99) and it is recommended to avoid using it in patients with coagulation disorders (100). Some of the pharmacological effects may be related to the phytoestrogen content and gynecomastia has been reported in a man taking a dong quai

894 Tomlinson et al.

preparation (101) although no evidence of an estrogen effect was seen in a study in postmenopausal women (102), and in an in vitro study it did not have an estrogen effect but it did increase the growth of a human breast cancer cell line (103). A case was described of a patient stabilized on warfarin who showed an increase in prothrombin time and INR after taking dong quai (104). The exact mechanism of the interaction is not known although one study showed that dong quai affected the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits (105).

E. Ginkgo (Ginkgo biloba) The fruits and seeds of ginkgo have been used in TCM for thousands of years

and leaf extracts are one of the most commonly used European herbal extracts (22,106). The active components have been attributed with a number of activities that promote small-vessel blood flow, including that in the cerebral arteries, as well as antiplatelet and other hemorrheological actions, antihy- poxic, neuroprotective, membrane-stabilizing, and capillary-fragility-decreasing effects (21,22,106). Ginkgo has been reported to provide moderate improvements in symptoms of intermittent claudication (107) and a stan- dardized form of the leaf extract (EGb761) has been approved in Germany for the treatment of dementia (21,22).

Ginkgo appears to be relatively safe with side effects that are usually mild and limited to gastrointestinal complaints, headache, nausea, and vomiting (22,106). However, a small number of serious bleeding problems have been reported for subjects taking ginkgo preparations, who in most cases were receiving concurrent anticoagulant drugs. These have included two subdural hematomas (108,109), one in a patient who was taking paracetamol and an ergotamine-caffeine preparation (109), one intracerebral hemorrhage when ginkgo was taken with warfarin (110), one subarachnoid hemorrhage (111), and a case of hyphema resulting from combination with aspirin (112). The significance of these reports is uncertain but it seems advisable for patients taking anticoagulants or antiplatelet drugs not to take ginkgo (22).

A study using probe drugs for CYP1A2, CYP2D6, CYP2E1, and CYP3A4 activity showed no significant effect on CYP activity with 28-day supplementation with a G. biloba preparation (40).

F. Other Herbs Garlic or dasuan, the tuber of Allium sativum L., is used in TCM both orally

and topically for various effects including as an anthelmintic, antiseptic, antidote, and tonic. Various preparations of garlic exhibited an inhibitory effect on human CYP-mediated metabolism of marker substrates for 2C9*1,

Adverse Effects of CHM 895

2C19, 3A4, 3A5, and 3A7 but not 2D6, whereas extracts of fresh garlic stimulated CYP2C9*2 metabolism of the marker substrate in an in vitro system (113). Using the probe drug approach, in vivo garlic oil reduced CYP2E1 activity after 28 days but had no effect on CYP1A2, CYP2D6, or CYP3A4 activity (40).

Piperine, a major component of black pepper, inhibited P-glycoprotein- mediated digoxin and cyclosporin A transport in Caco-2cells and CYP3A4- mediated verapamil metabolism in human liver microsomes, so it could affect plasma concentrations of drugs subject to first-pass elimination by these mechanisms (114).

VII. CONCLUSIONS When used as monotherapy or in appropriate combinations recommended by

an experienced TCM practitioner, most of the herbal preparations used in CHM obtained from reliable sources are relatively safe with minor adverse effects. However, when obtained from unscrupulous sources there is an increased chance of misidentification, adulteration, or contamination that may be associated with serious adverse events. Additionally, concomitant use of pharmaceutical drugs may lead to herb-drug interactions that may be potentially fatal. Studies with grapefruit juice and St. John’s wort have demonstrated some mechanisms by which pharmacokinetic interactions may occur. However, despite clear evidence that herbal preparations may lead to severe interactions, information regarding possible and proven interactions is very limited. Care should be taken when herbal preparations are given with pharmaceutical drugs and physicians must identify the use of such herbal preparations to reduce the chances of these interactions occurring.

REFERENCES 1. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL.

Unconventional medicine in the United States: Prevalence, costs, and patterns of use. N Engl J Med 1993; 328:246–252. 2. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998; 280:1569–1575. 3. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998; 104:170–178. 4. Tai YT, But PH, Tomlinson B. Adverse effects from traditional Chinese medicine: a critical reappraisal. J Hong Kong Med Assoc 1993; 45:197–201. 5. Chan TY, Chan JC, Tomlinson B, Critchley JA. Chinese herbal medicines revisited: a Hong Kong perspective. Lancet 1993; 342:1532–1534.

896 Tomlinson et al. 6. Chan TY, Chan JC, Tomlinson B, Critchley JA. Poisoning by Chinese herbal

medicines in Hong Kong: a hospital-based study. Vet Hum Toxlcol 1994; 36:546–547. 7. Tomlinson B, Chan TY, Chan JC, Critchley JA, But PP. Toxicity of complementary therapies: an Eastern perspective. J Clin Pharmacol 2000; 40:451–456. 8. O’Hara M, Kiefer D, Farrell K, Kemper K. A review of 12commonly used medicinal herbs. Arch Fam Med 1998; 7:523–536. 9. But PPH. Attitudes and approaches of traditional chinese medicine to herbal toxicity. J Nat Toxins 1995; 4:207–217. 10. Chan TY, Chan AY, Critchley JA. Hospital admissions due to adverse reactions to Chinese herbal medicines. J Trop Med Hyg 1992; 95:296–298. 11. Ng TH, Chan YW, Yu YL, Chang CM, Ho HC, Leung SY, But PP. Encephalopathy and neuropathy following ingestion of a Chinese herbal broth containing podophyllin. J Neurol Sci 1991; 101:107–113. 12. But PP, Tomlinson B, Cheung KO, Yong SP, Szeto ML, Lee CK. Adulterants of herbal products can cause poisoning [letter]. Br Med J 1996; 313:117. 13. Yang CM, Deng JF, Chen CF, Chang LW. Experimental podophyllotoxin (bajiaolian) poisoning. III. Biochemical bases for toxic effects. Biomed Environ Sci 1994; 7:259–265. 14. Kao WF, Hung DZ, Tsai WJ, Lin KP, Deng JF. Podophyllotoxin intoxication: toxic effect of bajiaolian in herbal therapeutics. Hum Exp Toxicol 1992; 11:480– 487. 15. Chan JC, Chan TY, Chan KL, Leung NW, Tomlinson B, Critchley JA. Anticholinergic poisoning from Chinese herbal medicines. Aust NZ J Med 1994; 24:317–318. 16. Chan JC, Tomlinson B, Kay R, Chan TY, Critchley JA. Acute confusion, Chinese herbal medicines and tuberculous meningitis [letter]. Aust NZ J Med 1994; 24:590–591. 17. Lin TJ, Deng JF, Tsai MS. Chinese traditional medicine poisonings in Taiwan. Int J Intens Care 2002; 9:118–127. 18. But PP. Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 1994; 97:371–374. 19. Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341:387–391. 20. Vanherweghem JL, Tielemans C, Simon J, Depierreux M. Chinese herbs nephropathy and renal pelvic carcinoma. Nephrol Dial Transplant 1995; 10:270–273. 21. Cupp MJ. Herbal remedies: adverse effects and drug interactions. Am Fam Physician 1999; 59:1239–1245. 22. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998; 158:2200– 2211.

Adverse Effects of CHM 897 23. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of

randomised clinical trials. Eur J Clin Pharmacol 1999; 55:567–575. 24. Awang DV. Maternal use of ginseng and neonatal androgenization [letter]. JAMA 1991; 266:363. 25. Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988; 159:1121–1122. 26. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs:

a systematic review. Drugs 2001; 61:2163–2175. 27. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr 2001; 73:1101–1106. 28. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999; 58:1685–1693. 29. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. Can Med Assoc J 1996; 155:293–295. 30. Awang DV. Siberian ginseng toxicity may be case of mistaken identity. Can Med Assoc J 1996; 155:1237. 31. Koren G, Randor S, Martin S, Danneman D. Maternal ginseng use associated with neonatal androgenization. JAMA 1990; 264:2866. 32. Waller DP, Martin AM, Farnsworth NR, Awang DV. Lack of androgenicity of Siberian ginseng [letter]. JAMA 1992; 267:2329. 33. Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983; 249:2018. 34. Palmer BV, Montgomery AC, Monteiro JC. Gin seng and mastalgia. Br Med J 1978; 1:1284. 35. Siegel RK. Ginseng abuse syndrome: problems with the panacea. JAMA 1979; 241:1614–1615. 36. Jones BD, Runikis AM. Interaction of ginseng with phenelzine [letter]. J Clin Psychopharmacol 1987; 7:201–202. 37. Shader RI, Greenblatt DJ. Phenelzine and the dream machine—ramblings and reflections [editorial]. J Clin Psychopharmacol 1985; 5:65. 38. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997; 54:692–693. 39. Zhu M, Chan KW, Ng LS, Chang Q, Chang S, Li RC. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999; 51:175–180. 40. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002; 72:276–287. 41. Kuo SC, Teng CM, Lee JC, Ko FN, Chen SC, Wu TS. Antiplatelet components in Panax ginseng. Planta Med 1990; 56:164–167. 42. Chan TY, Tomlinson B, Critchley JA. Aconitine poisoning following the ingestion of Chinese herbal medicines: a report of eight cases. Aust NZ J Med 1993; 23:268–271. 43. Chan TY, Tomlinson B, Chan WW, Yeung VT, Tse LK. A case of acute aconitine poisoning caused by chuanwu and caowu. J Trop Med Hyg 1993; 96:62–63.

898 Tomlinson et al. 44. Chan TY, Tomlinson B, Critchley JA, Cockram CS. Herb-induced aconitine

poisoning presenting as tetraplegia. Vet Hum Toxicol 1994; 36:133–134. 45. Tai YT, But PP, Young K, Lau CP. Cardiotoxicity after accidental herb- induced aconite poisoning [see comments]. Lancet 1992; 340:1254–1256. 46. Tai YT, Lau CP, But PP, Fong PC, Li JP. Bidirectional tachycardia induced by herbal aconite poisoning. Pacing Clin Electrophysiol 1992; 15:831–839. 47. Tomlinson B, Chan TY, Chan JC, Critchley JA. Herb-induced aconitine poisoning [letter]. Lancet 1993; 341:370–371. 48. Chan TY, Tomlinson B, Tse LK, Chan JC, Chan WW, Critchley JA. Aconitine poisoning due to Chinese herbal medicines: a review. Vet Hum Toxicol 1994; 36:452–455. 49. Dickens P, Tai YT, But PP, Tomlinson B, Ng HK, Yan KW. Fatal accidental aconitine poisoning following ingestion of Chinese herbal medicine: a report of two cases. Forens Sci Int 1994; 67:55–58. 50. Ernst E, Thompson CJ. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther 2001; 70:497–504. 51. Bayly GR, Braithwaite RA, Sheehan TMT. Lead poisoning from Asian traditional remedies in the West Midlands—report of a series of five cases. Hum Exp Toxicol 1995; 14:24–28. 52. Cunha J, Pereira L, Pun MI, Lopes V, Vong SK. Arsenic and acute lethal intoxication. Hong Kong Pharm J 1998; 7:50–53. 53. Kang-Yum E, Oransky SH. Chinese patent medicine as a potential source of mercury poisoning. Vet Hum Toxicol 1992; 34:235–238. 54. Chi YW, Chen SL, Yang MH, Hwang RC, Chu ML. [Heavy metals in traditional Chinese medicine: ba-pao-neu-hwang-san]. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1993; 34:181–190. 55. Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol 1997; 37:344–350. 56. Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355:134–138. 57. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000; 57:1221–1227. 58. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol 2001; 52:587–595. 59. Ioannides C. Pharmacokinetic interactions between herbal remedies and medicinal drugs. Xenobiotica 2002; 32:451–478. 60. Scott GN, Elmer GW. Update on natural product-drug interactions. Am J Health Syst Pharm 2002; 59:339–347. 61. Vaes LP, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother 2000; 34:1478–1482. 62. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice–drug interactions. Br J Clin Pharmacol 1998; 46:101–110. 63. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337:268–269. 64. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA,

Adverse Effects of CHM 899 Brown MB, Guo W, Watkins PB. Grapefruit juice increases felodipine oral

availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99:2545–2553. 65. Firenzuoli F, Luigi G. Safety of Hypericum perforatum. J Altern Comp Med 1999; 5:397–398. 66. Kim HL, Streltzer J, Goebert D. St. John’s wort for depression: a meta-analysis of well-defined clinical trials. J Nerv Ment Dis 1999; 187:532–538. 67. Whiskey E, Werneke U, Taylor D. A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review. Int Clin Psychopharmacol 2001; 16:239–252. 68. Kasper S. Hypericum perforatum—a review of clinical studies. Pharmacop- sychiatry 2001; 34:S51–S55. 69. Di Carlo G, Borrelli F, Izzo AA, Ernst E. St. John’s wort: prozac from the plant kingdom. Trends Pharmacol Sci 2001; 22:292–297. 70. Beckman SE, Sommi RW, Switzer J. Consumer use of St. John’s wort: a survey on effectiveness, safety, and tolerability. Pharmacotherapy 2000; 20:568–574. 71. Barbenel DM, Yusufi B, O’Shea D, Bench CJ. Mania in a patient receiving testosterone replacement postorchidectomy taking St. John’s wort and sertra- line. J Psychopharmacol 2000; 14:84–86. 72. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66:338–345. 73. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother 1999; 33:502. 74. Ernst E. Second thoughts about safety of St. John’s wort. Lancet 1999; 354:2014–2016. 75. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000; 355:548–549. 76. Ahmed SM, Banner NR, Dubrey SW. Low cyclosporin-A level due to Saint- John’s-wort in heart transplant patients. J Heart Lung Transplant 2001; 20:795. 77. Karliova M, Treichel U, Malago M, Frilling A, Gerken G, Broelsch CE. Interaction of Hypericum perforatum (St. John’s wort) with cyclosporin A metabolism in a patient after liver transplantation. J Hepatol 2000; 33:853–855. 78. Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J. Profound drop of cyclosporin A whole blood trough levels caused by St. John’s wort (Hypericum perforatum). Transplantation 2000; 69:2229–2230. 79. Mandelbaum A, Pertzborn F, Martin-Facklam M, Wiesel M. Unexplained decrease of cyclosporin trough levels in a compliant renal transplant patient. Nephrol Dial Transplant 2000; 15:1473–1474. 80. Barone GW, Gurley BJ, Ketel BL, Abul-Ezz SR. Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation 2001; 71:239–241. 81. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John’s wort. Lancet 2000; 355:547–548.

900 Tomlinson et al. 82. de Maat MM, Hoetelmans RM, Math t RA, van Gorp EC, Meenhorst PL,

Mulder JW, Beijnen JH. Drug interaction between St. John’s wort and nevirapine. AIDS 2001; 15:420–421. 83. Johne A, Schmider J, Brockmoller J, Stadelmann AM, Stormer E, Bauer S, Scholler G, Langheinrich M, Roots I. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J Clin Psychopharmacol 2002; 22:46–54. 84. Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A. Different effects of St. John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 2001; 70:518–524. 85. Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K. St. John’s wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68:598–604. 86. Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely J. St. John’s wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol 2002; 53:75–82. 87. Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St. John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70:317–326. 88. Karyekar CS, Eddington ND, Dowling TC. Effect of St. John’s wort extract on intestinal expression of cytochrome P4501A2: studies in LS180 cells. J Postgrad Med 2002; 48:97–100. 89. Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA- expressed cytochrome P450 enzyme catalytic activity. Life Sci 2002; 71:1579– 1589. 90. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000; 97:7500–7502. 91. Chan TY. Interaction between warfarin and danshen (Salvia miltiorrhiza). Ann Pharmacother 2001; 35:501–504. 92. Zhao BL, Jiang W, Zhao Y, Hou JW, Xin WJ. Scavenging effects of Salvia miltiorrhiza on free radicals and its protection for myocardial mitochondrial membranes from ischemia-reperfusion injury. Biochem Mol Biol Int 1996; 38:1171–1182. 93. Tam LS, Chan TY, Leung WK, Critchley JA. Warfarin interactions with Chinese traditional medicines: danshen and methyl salicylate medicated oil. Aust NZ J Med 1995; 25:258. 94. Yu CM, Chan JC, Sanderson JE. Chinese herbs and warfarin potentiation by ‘‘danshen.’’ J Intern Med 1997; 241:337–339. 95. Izzat MB, Yim AP, El-Zufari MH. A taste of Chinese medicine! Ann Thorac Surg 1998; 66:941–942. 96. Cheng TO. Warfarin danshen interaction. Ann Thorac Surg 1999; 67:894. 97. Chan K, Lo AC, Yeung JH, Woo KS. The effects of danshen (Salvia

Adverse Effects of CHM 901 miltiorrhiza ) on warfarin pharmacodynamics and pharmacokinetics of warfarin

enantiomers in rats. J Pharm Pharmacol 1995; 47:402–406. 98. Takahashi K, Ran LH, Watanabe M, Hanatani T, Takahashi K, Komatsu K, Azuma J. Prediction of herb drug interaction through cytochrome P450 (CYP) by Chinese traditional medicine (danshen). 9th International Symposium of the Pacific Rim Association for Clinical Pharmacogenetics, Hong Kong, Oct. 19–20, 2001. 99. Zhu DP. Dong quai. Am J Chin Med 1987; 15:117–125.

100. Roemheld-Hamm B, Dahl NV. Herbs, menopause, and dialysis. Semin Dial 2002; 15:53–59. 101. Goh SY, Loh KC. Gynaecomastia and the herbal tonic ‘‘dong quai.’’ Singapore Med J 2001; 42:115–116. 102. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-con- trolled trial. Fertil Steril 1997; 68:981–986.

103. Amato P, Christophe S, Mellon PL. Estrogenic activity of herbs commonly used

as remedies for menopausal symptoms. Menopause 2002; 9:145–150. 104. Page RL, 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999; 19:870–876. 105. Lo AC, Chan K, Yeung JH, Woo KS. Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. Eur J Drug Metab Pharmacokin 1995; 20:55–60.

106. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John’s wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med 2002; 136:42–53.

107. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2000; 108:276– 281.

108. Gilbert GJ. Ginkgo biloba. Neurology 1997; 48:1137. 109. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with

chronic Ginkgo biloba ingestion. Neurology 1996; 46:1775–1776. 110. Matthews MK, Jr. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998; 50:1933–1934. 111. Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet, 1998; 352:36. 112. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract [letter]. N Engl J Med 1997; 336:1108. 113. Foster BC, Foster MS, Vandenhoek S, Krantis A, Budzinski JW, Arnason JT, Gallicano KD, Choudri S. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharmaceut Sci 2001; 4:176–184.

114. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002; 302:645–650.

Index

Acacetin, 102 [Adverse effects] Access-related issues, 3

anticholinergic toxicity and, 886 ACE (angiotensin-converting enzyme)

aristolochic acid and, 886 activities, 444–446

chansu and, 887 Aconites, 889

ginseng and, 887–888 Aconitum carmichaeli and Acontium

guiji and, 885–886 kusnezoffii ,889

heavy metal contamination and, Acute liver injuries, 267

889–890 Adrenomimetic, 47t

overviews of, 885 Adriamycin-induced nephrotoxicity

future perspectives of, 895 prevention, 801–802

interactions, 882–901. See also Adulteration, 79–80, 878–890. See also

Interactions (herb-drug, Adverse effects; Toxicity

herb-herb) overviews of, 878–890

overviews of, 883–884, 895 use criteria and, 79–80

processing-related issues of, Adverse effects, 857–901. See also

888–889 under individual topics

reference resources about, 895–901 Adulteration and, 79–80, 878–890

Si (silicon)-based oligonucleotide coexistance-related issues of, 43–44

chip authentication and, contamination, misidentification,

857–871 and substitution and, 885–890

of specific HMPs (herbal medicinal aconites and, 889

products) ginseng, 887–888 horny goat weed (Epimedium

Page references followed by

species), 242 and page references followed by t denote

f denote figures

rosemary (Rosmarinus tables .

officinalis L.), 463–464

904 Index [Adverse effects]

[Andrographis paniculata (Burm. f.) schisandrin B and

Nees (Acanthaceae)] dibenzocyclooctadiene

overviews of, 441–442, 453 lignans, 302–303

RCTs (randomized clinical trials) St. John’s wort (Hypericum

and research studies of, perforatum ), 771–774

447–453 standardization and, 888–889

reference resources about, 453–455 toxicity. See Toxicity

therapeutic uses of, 444–453 Aesculus hippocastanum , 8 51

ACE (angiotensin-converting Agastache rugosa , 93

enzyme) activities, 444–446, Agastinol/agastenol, 102

446f

Agent combinations, 525–526 overviews of, 444 Age-related macular degeneration, 151t

systolic blood pressure effects, Aggarwal, Bharat A., 781–812

444–446 Aging and Apoptosis Research Center

TLC (thin-layer chromatographic) Program, 530

analyses of, 453 Alcohol interactions, 46t

Ang, Hooi Hoon, 643–656 Ali’s walking stick, 643–656. See also

Ang, Wang, 657–658 Tongkat Ali (Eurycoma

Angelica sinesis , 893–894 longifolia Jack)

Angelicae, 46t Allium cepa , 648

Angiotensin-converting enzyme Allocation-related issues, 10–14

activities, 444–446 Almond (Prunus amygdalus), 94

Anoxia, KCN-induced, 696–697 Aloe vera , 93

Antiaging effects, 130, 463 Alpha-National Association, 874

of rosemary (Rosmarinus officinalis Alpinia galanga , 648

L.), 463 ALS (amyotrophic lateral sclerosis), 150t

of tea (Camellia sinensis), 130 Alternative medicine. See TCM

Antiatherosclerosis effects, 529–530 (traditional Chinese medicine)

Antibacterial effects, 240, 350, Altitude sickness, 152t

567–568, 768–770 Alzheimer’s disease effects, 150t, 798

of Cassia tora L., 567–568 of curcumin (Curcuma longa), 798

of horny goat weed (Epimedium of ginkgo (Ginkgo biloba), 150t

species), 240 AMA (American Medical Association),

of Ligusticum chuanxiong Hort., 254 36–37

of shiitake mushrooms (Lentinus Amomun xanthioides , 93–94

edodes ), 350 Amyotrophic lateral sclerosis, 150t

of St. John’s wort (Hypericum Andrographis paniculata (Burm. f.)

perforatum ), 768–770 Nees (Acanthaceae), 441–455

Anticancer effects, 240, 338–342, chemical components and structures

690–692, 721–746, 770–771, of, 443–444, 443f

782–785 future perspectives of, 453

of curcumin (Curcuma longa), 782–785 illustrations of, 442

of echinacea (Echinacea augustifolia, National University of Singapore

Echinacea purpurea , Echinacea and, 453

pallida ), 721–746

Index 905 [Anticancer effects]

Anti-inflammatory effects, 169–170, of horny goat weed (Epimedium

253, 415, 689–690 species), 240

of chrysanthemum (Chrysanthemum of scrophulariaceae (Brand hancei

morifolium Ramat), 415 Hook. f.), 690–692

of ginger (Zingiber officinale Roscoe, of shiitake mushrooms (Lentinus

Zingiberacae), 169–170 edodes ), 338–342, 340t,

of Ligusticum chuanxiong Hort., 253 341f–342f

of scrophulariaceae (Brand hancei of St. John’s wort (Hypericum

Hook. f.), 689–690 perforatum ), 770–771

Antilipoxygenase activities, 496–498 Anticarcinogenic effects, 168–294–295,

Antimetastatic effects, 522–525 522–527

Antimutagenic activities, 840–841 of ginger (Zingiber officinale Roscoe,

Antinausea effects, 170–171 Zingiberacae), 168–169

Antioxidant effects. See also under of schisandrin B and

individual topics dibenzocyclooctadiene

of Cassia tora L., 559–561 lignans, 294–295

of Chromolaena odorata (L.) R. King Anticholinergic toxicity, 886

and H. Robinson, 814–833 Anticlooxygenase activities,

of chrysanthemum (Chrysanthemum 496–498

morifolium Ramat), 409–410, Anticoagulation effects, 255

428–430 Anticomplementary activities, 843

of Cordyceps sinensis (Berk.) Sacc., Anticonvulsive effects, 254

670–671, 671t Antidepressants, tricyclic, 47t

of eucommia (Eucommia ulmoides Antidiabetic properties, 329–333

Oliver), 841–842 Antiephritic activities, 693–695

of ginger (Zingiber officinale Roscoe, Antiestrogenic vs. estrogenic activities,

Zingiberacae), 167–168 415–417

of hawthorn (Crataegus), 476–480, Antifungal effects, 245, 567, 842–843

477f–480f of Cassia tora L., 567

of licorice (Glycyrrhiza glabra, of eucommia (Eucommia ulmoides

Glycyrrhiza inflata ), 600–605, Oliver), 842–843

601f–604f of Ligusticum chuanxiong Hort.,

of prickly pear (Opuntia ficus indica), 254

543–551, 543t, 545t, 546f–547f, Antigenotoxic activities, 561–563,

548t

565–566 of rosemary (Rosmarinus officinalis Antihepatotoxic effects, 240

L.), 459–460 Antihypertensive effects, 409, 527–530,

of RSV (reseratol), 493–496 842

of schisandrin B and dibenzocy- of chrysanthemum (Chrysanthemum

clooctadiene lignans, 296–300 morifolium Ramat), 409

of scrophulariaceae (Brand hancei of eucommia (Eucommia ulmoides

Hook. f.), 687–689 Oliver), 842

of SMS (Shengmai San), 635–641 of ginseng, 527–530

of spirulina, 318–321 Antihypotensive effects, 566

Antiparasitic activities, 350

906 Index Antiplatlet effects, 253, 529–530

Arthritis symptom suppression, of ginseng, 529–530

794–795 of Ligusticum chuanxiong Hort., 253

Arthrospira plantensis , 315–326. See Antiproliferation activities, 418–420,

also Spirulina 419f

Ashar, Bimal H., 53–72 Antispasmodial effects, 567

Aspirin, 46t

Antitumor effects, 338–342, 526–527, Asteracaea family, 813–836. See also 667–668

Chromolaena odorata (L.) of Cordyceps sinensis (Berk.) Sacc.,

R. King and H. Robinson 667–668

Atherogenic LDL (low-density of ginseng, 526–527

lipoprotein) modifications, of shiitake mushrooms (Lentinus

595–597 edodes ), 338–342, 340t,

Atherosclerosis effects, 273–274, 341f–342f

595–597, 599–600, 786–791 Antiviral effects, 240, 296, 768–770, 842

of curcumin (Curcuma longa), of eucommia (Eucommia ulmoides

786–791 Oliver), 842

of Dan Shen (Saliva miltiorrhiza of horny goat weed (Epimedium

Bunge), 273–274 species), 240

of licorice (Glycyrrhiza glabra, of schisandrin B and

Glycyrrhiza inflata ), 595–597, dibenzocyclooctadiene

599–600 lignans, 296

Averrhoa bilimbi Linn, 327–334 of St. John’s wort (Hypericum

chemical components and structures perforatum ), 768–770

of, 328–329, 329f Aphrodisiac properties, 647–651

illustrations of, 328f Apoptosis, 127–129, 388–391, 423–425,

overviews of, 327–328, 333 503–506, 527, 690–692

RCTs (randomized clinical trials) chrysanthemum (Chrysanthemum

and research studies of, morifolium Ramat) and,

reference resources about, 333–334 cruciferous vegetables (Brassicaceae)

therapeutic uses of, 328–333 and, 388–391

antidiabetic properties, 329–333 ginseng and, 527

ethnopharmacological uses, RSV (reseratol) and, 503–506

328–329 scrophulariaceae (Brand hancei

hypoglycemic activities, 329–333 Hook. f.) and, 690–692

Aviram, Michael, 595–614 tea (Camellia sinensis) and, 127–129, 128t

Ba Pao Neu Hwang San, 890 Appel, Elizabeth, 134

Bacterial infections, 745–746 Apricot seed (Prunus armeniaca), 94

Bamboo leaf (Lophatherum gracile), 94 Aristolochia fanchi ,886

Banlangen, 47t Aristolochia indica , 648

Bao, Yongping, 87–115 Aristolochic acid, 886

Basidiomycoto mushrooms, 355–363. Aromatic amines, heterocyclic, 118

See also Shiitake mushrooms Arsenic sulfide, 890

(Lentinus edodes)

Index 907 Bastard cardamom (Amomun

Broccoli and brussel sprouts, 365–405. xanthioides ), 93–94

LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

III. LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

Parts

Dokumen yang terkait

The Effect of Vessel Seaworthiness and Crew’s Competence on Marine Safety

The Study of Eficiency and Discipline on Shipment From Warehouse to Tanjung Priok Port

The Effect of Recruitment and Employee Selection on Employee Placement and Its Impacts Towards Employee Performance at PT Sriwijaya Air

The Linkage of the Board of Directors and the Status of Aviation Industry Licensing Law

Theory and Problems of

Problem and solution IPhO 3

Problem and Solution IPhO 1

THEORETICAL COMPETITION Questions and Solutions

Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia

KARAKTERISTIK FISIK, KIMIA, DAN ORGANOLEPTIK IKAN CAKALANG ( Katsuwonus pelamis) ASAP DI KENDARI Physical, Chemical, and Organoleptic Characteristics of Smoked Skipjack Tuna (Katsuwonus pelamis) in Kendari City

Dukungan

Links

LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

III. LACK OF STANDARDIZATION OR INADEQUATE PROCESSING

Parts

Dokumen yang terkait

The Effect of Vessel Seaworthiness and Crew’s Competence on Marine Safety

The Study of Eficiency and Discipline on Shipment From Warehouse to Tanjung Priok Port

The Effect of Recruitment and Employee Selection on Employee Placement and Its Impacts Towards Employee Performance at PT Sriwijaya Air

The Linkage of the Board of Directors and the Status of Aviation Industry Licensing Law

Theory and Problems of

Problem and solution IPhO 3

Problem and Solution IPhO 1

THEORETICAL COMPETITION Questions and Solutions

Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia

KARAKTERISTIK FISIK, KIMIA, DAN ORGANOLEPTIK IKAN CAKALANG ( Katsuwonus pelamis) ASAP DI KENDARI Physical, Chemical, and Organoleptic Characteristics of Smoked Skipjack Tuna (Katsuwonus pelamis) in Kendari City

Dokumen yang Anda mencari sudah siap untuk unduhkan