In order to test the efficacy of a combination of natural D-camphor and an extract of fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen) on orthostatic hypotension, two similar, controlled, randomized studies were carried out in a balanced crossover design in 24 patients each with orthostatic dysregulation. The camphor-crataegus berry combination (CCC) was orally administered as a single regimen in 3 different dosages of 5 drops, 20 drops and 80 drops; a placebo with 20 drops of a 60% alcoholic solution served as control. Orthostatic hypotension was assessed with the tilt table test before and after medication. Source data of both studies were pooled and meta-analytically evaluated for all 48 patients. CCC drops decreased the orthostatic fall in blood pressure versus placebo, as almost uniformly established at all times by mean arterial pressure and diastolic blood pressure. Mean arterial pressure demonstrated the very fast onset of action by a clearly dose-dependent statistically significant effect even after 1-minute orthostasis. Increase of mean arterial pressure as compared to the orthostasis test before medication was on average 4.5 mmHg. CCC affected diastolic blood pressure after 1 minute of orthostasis in all dosages as compared to placebo. A statistically significant effect of the highest dose of 80 drops on diastolic blood pressure could be demonstrated after 1-, 3-, and 5-minute orthostasis. The hemodynamic findings of a stabilizing effect on arterial pressure in orthostasis corroborate the long-term medical experience with CCC and justify the indication orthostatic hypotension.

BACKGROUND: Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. AIMS: We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. METHODS: The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. RESULTS: The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. CONCLUSION: The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

AIM: Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. METHODS: Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). RESULTS: After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. CONCLUSION: Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

The efficacy of classic homeopathic therapy is scientifically not well proven. Few of the studies available are acceptable from a scientific point of view. In this paper we will describe a study protocol for a trial of classic homeopathy in chronic headache, which not only is in accordance with currently accepted scientific research standards but also accounts for the special needs of homeopathic therapy. The prescribing practioners are allowed to use any homeopathic drug at any potency or dosage, this enables them to ful fill the homeopathic principle of individuality. At the same time, the study is strictly controlled, randomized and double blind. The prescribing physician sends the homeopathic medication selected for a patient to a notary public, who either forwards it to the patient or substitute placebo, according to the randomization plan. Hence, the trial is not testing a specific drug, but the rationale of individual homeopathic drug selection and the efficacy of the selected drugs in headache patients in general. Patients suffering from chronic headaches for at least 1 year and with headaches at least once a week on average are eligible for the study. Exclusion criteria follow the generally accepted standards and account for the special needs of homeopathic therapy. Data are to be recorded in a patient's diary containing the outcome variables occurrence, duration, intensity of headaches and use of analgesic drugs. After a baseline period of at least 6 weeks the first consultation will take place, with the proper remedy selected and sent to the patient via the notary. After 6 weeks a first follow-up will allow the physician to modify the treatment if necessary. After another 6 weeks the final examination will take place. The duration of the homeopathic treatment, then, is 12 weeks. A total of 100 patients in two groups of 50 are to be treated in the study. The study started in the later part of 1991, and is scheduled to last for 2 1/2 years. We expect a critical discussion of the results from conventional medicine or from homeopathy, depending on the outcome of the study. The study protocol is being published in advance to enable the reviewers of the study to check the original study design and the a priori hypotheses adopted.

Toxic liver diseases caused by drugs, herbs and dietary supplements are often recognized late because their hepatotoxic potency is considered to be minimal or non-existent and specific laboratory parameters to definitively establish the diagnosis are lacking. As gold standard for the diagnosis, a positive (unintentional) re-exposure test is considered which is seldom available. A system for evaluation is therefore necessary which takes into account various parameters and defines the grades of causality. By means of a qualitative pre-test with a few questions a screening may be possible as to whether the causality is not probable or not evaluable. Subsequently, a quantitative assessment of the degree of the causality with a main test should be done; this corresponds to the slightly modified and well validated score of the CIOMS (Council for International Organizations of Medical Sciences). The evaluation is achieved using various criteria such as latency period, time between the end of the therapy and begin of the reaction, course of values for the enzyme activities of the liver after cessation of the therapy, risk factors such as age, alcohol consumption and comedication, exclusion of diseases of other organs including chronic liver disease, previous information about hepatotoxicity of the alleged substance and possible results of an unwanted re-exposure. The various answers to these questions are quantitatively assessed, the resulting scores added, and finally an assignment to one of the grades of causality is made. If, on the basis of the main test, there are still doubts about the correct diagnosis, a further test is required to consider the differential diagnosis of additional diseases and chronic liver diseases of other causes. This stepwise approach is essential since ad-hoc decisions regarding causality are not without problems, and other diseases as causes for increased liver values are easily overlooked and not treated adequately in time. By means of this procedure an improvement in the drug safety can be expected, which is fruitful for the patient and helpful to the physician in charge, the health institutions and the drug companies.

Objective: Information about adverse drug reactions plays an important role when assessing the benefit/risk profile of a drug. Identifying rare adverse drug reactions, however, is a difficult task. This paper illustrates the advantages of using a prescription database for this purpose. Methods: The mediplus((R)) database used in our analysis covered data from 320,644 outpatients observed between July 1999 and June 2002. The example of bleeding complications during intake of antidementia drugs is used to illustrate this approach. The comparison of cohorts and subgroups is nearly always a problem in surveys. For our analyses we considered a set of patients who had taken a selected medication for a certain period of time and compared the frequency of adverse events with those occurring when the same patients did not take this medication. Hence, the comparison with versus without a certain medication is based on the same set of patients as in a cross-over study. Results: Our evaluations indicate that the rate of bleeding complications is low when taking any of the widely used antidementia drugs, glutamate modulators, cholinesterase inhibitors, calcium antagonists or the phytomedicine Ginkgo biloba. Conclusion: Basing the comparison of the rates of complications during periods with and without intake of a certain drug on the same set of patients may be a useful tool for assessing adverse drug reactions from data reported in prescription databases.

In a randomized, double-blind, placebo-controlled, parallel group, phase III clinical trial efficacy and safety of Korodin, a combination of natural D-camphor and an extract from fresh crataegus berries, was investigated in patients 50 years and older with orthostatic hypotension. At visit 1 eligibility of patients was checked and a placebo medication was given to all patients. At visit 2 orthostatic hypotension had to be reconfirmed, then the patient was randomized either to Korodin or placebo, study medication (25 drops) was applied once and then outcome was measured. After 7 days of home treatment with daily 3 x 25 drops outcome was measured at visit 3. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were documented 10, 5, 2 and 0 min before as well as 1, 3, 5, 8, and 10 min after getting in the upright position at visit 1, at visit 2 before and after application of study medication and at visit 3. Primary outcome was the change of mean arterial blood pressure (MAP) from just before standing up to the nadir within the first 3 min after standing up. Secondary outcome variables were SBP, DBP, HR, quality of life (SF-12) and seven typical signs and symptoms of orthostatic hypotension. The study was performed in a rehabilitation clinic and in two doctor's practices in Germany from November 2002 to May 2003. During this time, 57 patients were admitted to the study, 39 patients were eligible and randomized, 38 patients were treated according to protocol and evaluated, 21 patients with Korodin and 17 patients with placebo. After a single application the median decrease of MAP was 11.4 mmHg for Korodin and 14.0 mmHg for placebo. Compared to baseline, the median MAP improved 4.3 mmHg for Korodin and 0.3 mmHg for placebo. After 1 week of treatment the decrease of median MAP after standing up was 9.3 mmHg for Korodin and 13.3 mmHg for placebo. Compared to baseline, the improvement was 5.9 mmHg for Korodin and 1.6 mmHg for placebo. Efficacy of 1 week treatment was significant. For the single application a superiority of Korodin over placebo was seen; however, it was not significant. All secondary outcome variables confirmed these findings, except for the physical summary score in the quality of life evaluation (SF-12 questionnaire). Only one adverse event occurred, but this was not serious and without relationship to the study medication. The other safety variables (SBP, DBP, HR, ECG, physical examination) did not show any problems. This study demonstrates that Korodin is efficacious for orthostatic hypotension in patients over 50 years.

The work reported in the preceding sections justifies, we think, a number of definite conclusions. In addition to this, some of the experiments indicate a line of thought which may lead to considerable alteration in our conceptions, both of phenomena of bacterial hypersensitiveness and of infection. 1. In guinea pigs two fundamentally different types of intradermal reactions may be observed. One of these is the immediate, transitory reaction which develops in animals sensitized against proteins (horse serum, etc.) and may be regarded as one of the manifestations of general protein hypersensitiveness, or anaphylaxis; the other is the tuberculin type of skin reaction which develops more slowly, leads to a more profound injury of the tissues and is independent of anaphylaxis as ordinarily conceived. 2. The tuberculin type of hypersensitiveness (as well as probably the typhoidin, mallein, abortin reactions, etc.) does not develop at all in guinea pigs sensitized with proteins, like horse serum, etc. While this form of hypersensitiveness may eventually be induced with materials not bacterial in origin, it has been observed up to date only as a reaction of bacterial infection. 3. Methods of treatment with protein material from bacterial cultures which sensitize guinea pigs to anaphylactic reactions with the bacterial extracts, do not sensitize them to the tuberculin type of reaction. Such sensitization is easily accomplished only by infecting the animals with living organisms. No reliable method of sensitizing guinea pigs to such reactions with dead bacterial material has as yet been worked out, though a few hopeful experiments have been obtained with massive injections of large amounts of the acid-precipitable substances (nucleoproteins?) from bacterial extracts. 4. In animals made hypersensitive to the tuberculin type of reaction by infection with living bacteria, the reaction may be elicited by intradermal injections of bacterial extracts from which all coagulable proteins, nucleoproteins, and Bence-Jones proteins have been removed, as well as this can be done by boiling with acid, etc. This proteose residue alone suffices to elicit such reactions. The exact chemical nature of the so called proteose residue must be further studied and analyzed when we have had opportunity to produce bacterial extracts in large quantity. These points seem incontrovertible on the basis of our own experiments, as well as those of other workers. There thus seem to develop two definite forms of hypersensitiveness in guinea pigs infected with bacteria, typical anaphylaxis in which the protein material of the bacterial cells is concerned, which develops late and which can be induced by repeated injections of dead bacterial material, and a hypersensitiveness to non-protein constituents which differs from the former, both in the laws that govern sensitization and in the manifestations which follow injections into the sensitized animals. While there is virtual agreement among immunologists concerning the essential mechanism of protein anaphylaxis, its dependence upon an antigen-antibody reaction, and the dominating rôle played by the sessile antibodies, the mechanism of hypersensitiveness to tuberculin and similar bacterial substances is still a problem of much uncertainty. The most striking difference between the two phenomena lies, as we have seen, in the criteria of sensitization, in that hypersensitiveness to the tuberculin type of reaction can hardly ever be induced by any of the ordinary methods of preparation with the constituents of dead bacteria, but develops promptly (7 to 10 days) in the course of actual infection with living organisms. The considerable specificity of such reactions forces the conclusion that the sensitizing substance must, in some way, be derived from the infecting microorganisms. The idea that the failure of sensitization with dead culture materials is perhaps due to the elaboration in the body of infected animals of bacterial products not represented in extracts of test-tube cultures is rendered unlikely by the fact that in the tuberculin-sensitive, infected animals, we can produce the reactions by the application of such dead extracts. It is neither logical nor in keeping with biological experience to assume that one substance will sensitize to reaction with another. This mistake was made early in the study of anaphylaxis in another connection and caused considerable delay of progress. Krause has shown that tuberculin sensitiveness may be blunted in infected animals by massive, but sublethal injections of tuberculin, and we have obtained some indications of the same thing. Moreover, others as well as ourselves have seen tuberculin reactivity decline in guinea pigs and in man in the stages of very severe infection. These facts would eliminate any assumption of mere cumulative injury as explaining this type of reaction, and stamp it as a mechanism at least analogous to ordinary anaphylaxis. The only remaining possibility to explain the difference between infected animals and those treated with dead bacterial constituents would be to assume that the difference must lie in the manner in which the sensitizing substance is administered to the animals, and that sensitization with the proteose residue materials depends upon criteria of sensitization differing in regard to the time and quantity factors from those governing protein sensitization. If one considers the relatively simpler chemical structure and perhaps physically greater diffusibility of the materials concerned in this reaction, one might readily expect such differences in the methods needed for sensitization. In keeping with such a line of reasoning our experiments have shown that the tuberculin active materials are constantly and rapidly being diffused out into the culture fluid from growing organisms, in quantities greater than can be extracted from similar amounts of the dead bacteria. It seems reasonable to assume from this that the same thing may happen in the animal body harboring a growing focus. And it would seem quite likely that the association of the tuberculin type of reaction with actual infection may depend upon the fact that sensitization to these non-protein substances depends upon a constant steady absorption of large amounts of the material. Moreover, the only hopeful experiments on the artificial production of tuberculin sensitiveness in guinea pigs obtained by us were those in which massive doses of the nucleoprotein material injected into guinea pigs gave rise to a moderate skin sensitiveness. Does the so called proteose residue form antibodies, and, if so, are substances analogous to antibodies involved in the tuberculin type of hypersensitiveness? The failure to transfer passively this form of hypersensitiveness to normal animals with the blood and tissues of tuberculin-sensitive ones would suggest that no antibodies are involved. But this is not conclusive on the basis of available experimental facts. We are inclined to believe that antibodies of a sort are involved, for the following reasons:(a) In our experiments with the uteri of highly sensitive extract-treated guinea pigs and of tuberculous guinea pigs, we have occasionally had positive reactions when the proteose residue alone was used.(b) We believe that these proteose substances are entirely analogous to the substances studied by Avery and Dochez (22) in the urine and blood of typhoid and pneumonia patients. They obtained precipitin reactions against homologous immune sera with the urine of infected cases concentrated by evaporation after boiling with acetic acid to remove coagulable proteins.(c) Petroff, with whom we discussed this proteose residue early in our work, has produced it, and tells us that he has obtained precipitin reactions with it by titrating it against the serum of a sheep treated for a long time with tubercle bacillus products. In suggesting an antibody response to a non-protein antigen we are aware that we are opposing what has been regarded as a well established doctrine in immunity; this is justified, or at least mitigated, we believe, by the consideration that reactions of the antigen-antibody type are the only explanation of specificity; and tuberculin, mallein, and typhoidin reactions are to a considerable degree specific. If such reaction bodies cannot be produced by precisely the same methods of administration as to time and quantity which are successful in calling forth protein antibodies, this should not astonish us, since, after all, the substances that we are dealing with are simpler in chemical structure than are the proteins, and physically are probably of relatively greater diffusibility. It may be that the greater diffusibility of the proteose-like substances transfers much of the actual reaction phenomena to an intracellular location, and that this to some extent influences the presence of circulating antibodies. It may also be that these more diffusible non-protein antigens are more rapidly eliminated from the animal body than are the proteins. Indeed, the above mentioned observations of Avery and Dochez, and the recent work of Wildbolz (23), Lanz (24), Imhof (25), and Gibson and Carroll (26), who demonstrated tuberculin active antigens in the urine of active cases, would corroborate such a view. The evidence available at the present time, however, concerning antibody formation to these non-protein substances is, we recognize, largely indirect, at least as far as our own work is concerned, and we present it in the present connection purely as a working hypothesis. Finally, perhaps the most important theoretical consideration indicated by our experiments is the following. We have in the tuberculin reaction a form of hypersensitiveness which seems to be (in guinea pigs, at least) analogous entirely to the typhoidin reaction, the mallein reaction, and the abortin reaction. Whenever reactions of this type have been carefully studied, whatever the bacteria involved, they have been associated with infection as in tuberculosis, and have been followed by analogous clinical manifestations. It would seem perhaps that we are dealing with a law applicable to bacterial infection in general. It would appear that certain non-coagulable substances of uncertain chemical constitution are being constantly elaborated in the course of bacterial growth, and passed into the circulation of infected animals. As a result of this, infected animals become sensitized to these heat-and acid-resistant materials, in tuberculosis in the course of I to 2 weeks, in the case of more rapidly growing bacteria perhaps sooner. Early in the course of infection, the animal becomes sensitized and subsequently the further elaboration and distribution of these materials from the bacterial focus plays a fundamental part in the injury of the animal. These proteose-like substances, like tuberculin, possessing but slight toxicity for the normal animal, become highly toxic to the sensitized one. Thus, these substances, while not being true exotoxins in the ordinary sense, would still represent a highly toxic bacterial product comparable in its injurious effect to toxins when produced in the body of an animal thus sensitized. If there is any value in these deductions the attention of bacteriologists should be turned to the non-protein constituents of bacterial cells in their further immunological studies, as well as to the protein materials. It is obvious that the next step in our investigations must consist in producing the non-coagulable material from bacterial extracts in considerable quantity, to determine their antibody-forming properties in detail, and elucidate, if possible, the laws which govern sensitization with them. This work has been begun, but it has seemed advisable to publish this as far as we have gone because it will take a long time before it can be completed.

Hepatotoxicity by drugs and dietary supplements (DDS) is a rare and unpredictable event but with the risk of a life-threatening clinical course when it occurs. It may emerge despite intensive chemical, toxicological and observational studies that indicate no hepatotoxic signals. This suggests major clinical and regulatory issues that must be addressed in the area of accurate testing, reporting, and accessibility of reliable n data. Consequently, in a clinical setting, safety concerns are key elements in the treatment of patients, and require that the diagnosis of DDS hepatotoxicity clearly be established. Causality of DDS hepatotoxicity may be pursued using a diagnostic algorithm consisting of a pre-test, a main-test as the scale of the updated CIOMS (Council for International Organizations of Medical Sciences), and a post-test. The results of these tests are then sent item by item to the National Health Agency, where the case will undergo further evaluation for pharmacovigilance, strategic aspects and safety issues. After this analysis, all items of the tests are included in the regulatory database freely accessible to the health and scientific community. With this diagnostic and regulatory algorithm the risk of misdiagnoses and inappropriate regulatory measures may be minimized and the safety improved. In conclusion,DDS hepatotoxicity is a rare but is a potentially life-threatening entity requiring a reliable diagnosis with the aid of a diagnostic algorithm, and a thorough pharmacovigilance evaluation by national and international health agencies. Safety aspects in DDS hepatotoxicity represent a major clinical and regulatory issue and should consequently be addressed.<br />

OBJECTIVES: Black cohosh (BC) is a herbal drug or herbal dietary supplement used for treatment of menopausal symptoms. Recently, however, reports have appeared about the occurrence of rare toxic liver disease in an assumed relationship with the use of BC. METHODS: We have analyzed and reviewed the data of all 69 reported cases with suspected BC hepatotoxicity. Causality for BC was assessed utilizing the scale of the original structured quantitative Council for International Organizations of Medical Sciences (CIOMS), or the main-test as its updated form. RESULTS: With the hepatotoxicity specific causality assessment methods, there was an excluded, unlikely, unrelated or unassessable causality for BC in 68 of 69 cases with liver disease. One patient had a possible causality for BC and a symptomatic cholelithiasis with confounding variables of fatty liver of unknown etiology; unknown BC brand including possible herbal mixture; unknown daily BC dosage; and an unassessable duration of BC usage. In general, the cases of the 69 patients were poorly documented. Confounding variables were: failure to identify the BC product; use of herbal mixtures with multiple ingredients in addition to BC; co-medication with synthetic drugs and dietary supplements including herbal ones; missing temporal association between BC use and development of liver disease; not specified modalities of BC treatment; failure of dechallenge after BC discontinuation; pre-existing liver diseases; insufficiently excluded other liver diseases; presence of alternative liver diseases. CONCLUSIONS: The analysis of 69 cases shows little, if any, supportive evidence for a significant hepatotoxic risk of BC.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava-herbs mixtures. AIM OF THE STUDY: To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands. MATERIALS AND METHODS: Causality of hepatotoxicity by aqueous kava extracts and kava-herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences). RESULTS: Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava-herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava-herbs mixtures were used. CONCLUSIONS: Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.

BACKGROUND: Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. AIMS: We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. METHODS: The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. RESULTS: The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. CONCLUSION: The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

OBJECTIVE:: Black cohosh (BC), synonym for Actaea racemosa and Cimicifuga racemosa, is a herbal remedy for the treatment of menopausal symptoms. Recently, worldwide discussions have emerged as to whether its use may be associated with the risk of rare hepatotoxicity in a few susceptible women. METHODS:: We have evaluated the causal relationship in nine cases with suspected hepatotoxicity by the use of BC. The updated Council for International Organizations of Medical Sciences scale was used to quantitatively assess the causality for BC. RESULTS:: In eight of nine patients with liver disease, causality for BC +/- comedication was excluded (n = 4) or unlikely (n = 4). The failure to ascribe causality in these cases was mainly due to alternative diagnosis, missing temporal association and dechallenge, and presentation of low quality data. In only one case, causality was possible for a BC preparation of an unknown brand taken for 2 months with an unknown daily dose. Confounding factors in this case include symptomatic cholelithiasis and fatty liver. Comedication with synthetic drugs and herbal or other dietary supplements was reported in five of nine patients. CONCLUSIONS:: In nine cases of patients with liver disease, causality for BC +/- comedication was possible (n = 1), unlikely (n = 4), or excluded (n = 4). Due to this lack of significant circumstantial evidence, the present study shows little, if any, hepatotoxic risks by the use of BC in the analyzed cases.

Kava extracts are used widely for different purposes and were thought to be safe. Recently, several cases of hepatotoxicity have been published. To explore possible mechanisms of kava hepatotoxicity, we prepared and analyzed three different kava extracts (a methanolic and an acetonic root and a methanolic leaf extract), and investigated their toxicity on HepG2 cells and isolated rat liver mitochondria. All three extracts showed cytotoxicity starting at a concentration of 50mug/ml (lactate dehydrogenase leakage) or 1mug/ml (MTT test). The mitochondrial membrane potential was decreased (root extracts starting at 50mug/ml) and the respiratory chain inhibited and uncoupled (root extracts) or only uncoupled (leaf extract) at 150mug/ml, and mitochondrial beta-oxidation was inhibited by all extracts starting at 100mug/ml. The ratio oxidized to reduced glutathione was increased in HepG2 cells, whereas the cellular ATP content was maintained. Induction of apoptosis was demonstrated by all extracts at a concentration of 150mug/ml. These results indicate that the kava extracts are toxic to mitochondria, leading to inhibition of the respiratory chain, increased ROS production, a decrease in the mitochondrial membrane potential and eventually to apoptosis of exposed cells. In predisposed patients, mitochondrial toxicity of kava extract may explain hepatic adverse reactions of this drug.

Kava (Piper methysticum) extract products have been implicated in a number of severe hepatotoxicity cases. However, systematic toxicological studies regarding kava consumption have not been reported. In this study, 6 major kavalactones and different solvent fractions of kava roots, leaves, and stem peelings were evaluated for their mutagenic potential. None of the kavalactones was found to be positive in the experimental concentration ranges tested by the umu test (a sensitive test for point mutations). However, among the different solvent fractions, the n-butanol fraction of kava leaves was positive. Further investigations using bioassay-directed isolation and analysis indicated that 2 C-glycoside flavonoid compounds accounted for the positive mutagenic results. Two isolated compounds were identified as 2''-O-rhamnosylvitexin and schaftoside by NMR and MS techniques.

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.