Toxicological evaluation of Oviductus ranae: Acute, sub-acute and genotoxicity studies in mice and rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Oviductus ranae (OR) is a traditional animal-based Chinese medicine, which has been listed in the Chinese Pharmacopoeia since 1985 edition. Although its medicinal application has been widely acknowledged, there is little available information on its potential toxicity. AIM OF THE STUDY: The aim of this study was to investigate the acute, sub-acute, and genetic toxicities of OR. MATERIALS AND METHODS: In acute toxicity evaluation, OR was administered orally to mice at doses of 2.5, 5.0, 10.0, and 20.0g/kg BW for one time. Mortality, clinical signs, and body weight were observed for 14 days after treatment. In sub-acute toxicity evaluation, OR was administered orally to rats once a day for 28 consecutive days at doses of 1.75, 3.50, and 7.00g/kg BW. Animals were observed for general behaviors, mortality, food intake, and body weight changes. At the end of treatment, relative organ weight, pathology, hematological and biochemical parameters were monitored. In genotoxicity evaluation, bacterial reverse mutation assay (Ames test) was performed by treating OR with four different Salmonella typhimurium strains at doses of 8, 40, 200, 1000, and 5000µg/plate without or with S-9 mix, respectively. The genotoxicity of OR was also evaluated by micronucleus and sperm malformation assays in mice at doses of 2.5, 5.0, and 10.0g/kg BW, respectively. RESULTS: The results of acute toxicity study showed that the LD50 value of OR is higher than 20.0g/kg BW in mice. Death and abnormal clinical symptoms were not found during the period of experiment. In sub-acute toxicity, we found that the no-observed-adverse-effect levels (NOAEL) of OR in rats is up to 7.00g/kg BW. No statistically significant or toxicologically relevant defferences in body weight, food intake, relative organ weight, pathology, hematological and biochemical parameters were observed, when compared with control group. Results of Ames test, micronucleus and sperm malformation assays indicated that OR has no mutagenicity in vitro at a limited dose of 5000µg/plate, and dose not induce micronuclei and sperm malformation in mice at the dose of up to 10.0g/kg BW in mice. CONCLUSIONS: In conclusion, OR is a tranditional Chinese medicine with high safety.

Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences.

This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.

Preclinical toxicological evaluations of the sclerotium of Lignosus rhinocerus (Cooke), the Tiger Milk mushroom.

ETHNOPHARMACOLOGICAL RELEVANCE: Lignosus rhinocerus (Tiger Milk mushroom) is distributed in South China, Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea. In Malaysia, it is the most popular medicinal mushroom used by the indigenous communities to relieve fever, cough, asthma, cancer, food poisoning and as a general tonic. In China, this mushroom is an expensive traditional medicine used to treat liver cancer, chronic hepatitis and gastric ulcers. The sclerotium of the mushroom is the part with medicinal value. This rare mushroom has recently been successfully cultivated making it possible to be fully exploited for its medicinal and functional benefits. The present study was carried out to evaluate the chronic toxicity of the sclerotial powder of Lignosus rhinocerus cultivar (termed TM02), its anti-fertility and teratogenic effects as well as genotoxicity. MATERIALS AND METHODS: Sprague Dawley rats (10 rats/group/sex) were fed orally with 250, 500 and 1000 mg/kg of sclerotial powder of TM02. The sclerotial powder was orally administered once daily and consecutively for 180 days. At the completion of the oral feeding period, analysis of hematological and clinical biochemical parameters, urine profiles, organ weight as well as histopathological analysis were carried out. The effect of the sclerotial powder on fertility and its possible teratogenicity were examined by feeding rats orally with 100 mg/kg sclerotial powder consecutively for 7-8 weeks. Genotoxicity was evaluated by Ames test using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and Escherichia coli WP2 uvrA. RESULTS: The results showed that oral administration of the sclerotial powder of the Lignosus rhinocerus cultivar at daily dose of up to 1000 mg/kg for 180 days had no adverse effect on the general clinical observations, body weight, hematology, clinical biochemistry, urinalysis, absolute organ weight as well as relative organ weight, nor induced histological changes in the organs. Oral administration of 100 mg/kg sclerotial powder of the Lignosus rhinocerus for 7-8 weeks did not affect the fertility of the rats nor induce teratogenic effect on their offspring. Lignosus rhinocerus sclerotial powder up to 5000 µg/plate in the presence and absence of metabolic activation did not cause gene mutations by base pair changes or frameshifts in the genome of the tester strains used. CONCLUSION: Our results showed that the no-observed-adverse-effect level (NOAEL) dose of the sclerotial powder of Lignosus rhinocerus in 180-day chronic toxicity study is more than 1000 mg/kg. Oral feeding of the sclerotial powder at 100mg/kg did not induce adverse effect on rats' fertility nor causing teratogenic effect on their offspring. In the reverse mutation Ames test, the sclerotial powder at all tested concentration did not show any genotoxicity.

The marginalization of hormesis.

Despite the substantial development and publication of highly reproducible toxicological data, the concept of hormetic dose-response relationships was never integrated into the mainstream of toxicological thought. Review of the historical foundations of the interpretation of the bioassay and assessment of competitive theories of dose-response relationships lead to the conclusion that multiple factors contributed to the marginalization of hormesis during the middle and subsequent decades of the 20th Century. These factors include the following: (a) the close association of hormesis with homeopathy, which led to the hostility of modern medicine toward homeopathy, thereby creating a guilt-by-association framework, and the carryover influence of that hostility toward hormesis in the judgements of medically based pharmacologists/toxicologists; (b) the emphasis of high-dose effects linked with a lack of appreciation of the significance of the implications of low-dose stimulatory effects; (c) the lack of an evolution-based mechanism(s) to account for hormetic effects; and (d) lack of appropriate scientific advocates to counter aggressive and intellectually powerful critics of the hormetic perspective.

Eficácia e tolerabilidade da homeopatia e da fluoxetina no tratamento da depressão / Efficacy and tolerability of homeopathy and fluoxetine in the treatment of depression

A busca por tratamentos "naturais" ou em conformidade com crenças e valores próprios, bem como experiências nas quais o tratamento com antidepressivos causou efeitos adversos desagradáveis ou pareceu ineficaz são razões apontadas por pacientes com depressão para o uso de alternativas ao tratamento convencional. O tratamento homeopático é uma dessas alternativas, apesar da falta de estudos clínicos que indiquem a eficácia de qualquer método de homeopatia no tratamento da depressão. Apesar de ter sido reconhecida como especialidade médica desde 1980, o ensino da homeopatia no Brasil era realizado à parte das escolas de medicina até 2003, quando a Faculdade de Medicina de Jundiaí (FMJ ­ Jundiaí, São Paulo) iniciou uma especialização em homeopatia segundo o método mais aperfeiçoado de Hahnemann. Os alunos são treinados em ambulatórios integrados ao sistema único de saúde de Jundiaí. Um desses ambulatórios é voltado ao tratamento homeopático da depressão, objeto dos dois artigos do presente estudo. O primeiro artigo relata o tratamento de uma série de 15 casos de depressão tratados durante 7 a 14 semanas com o método mais aperfeiçoado de Hahnemann. O escore de depressão, avaliado pela escala de depressão de Montgomery e Åsberg (MADRS) diminuiu da média basal de 24,87 (± 5,81) para 9,73 (± 8,16; p< 0,0001) na segunda avaliação e apenas um paciente não apresentou resposta e remissão do episódio depressivo. Estes resultados ressaltaram a necessidade de um estudo randomizado e controlado para avaliação do tratamento homeopático da depressão. O segundo artigo teve como objetivo investigar a não-inferioridade e tolerabilidade dos medicamentos homeopáticos na dinamização cinqüenta-milesimal (LM) em relação à fluoxetina, em um estudo prospectivo, randomizado, duplo-cego e double-dummy, uma vez que um estudo controlado com placebo não foi autorizado pela Comissão Nacional de Ética em Pesquisa. Noventa e um pacientes com depressão moderada a grave foram aleatoriamente alocados para receber, durante oito semanas, uma potência LM de um medicamento individualizado em solução alcoólica (1 gota três vezes por semana) e cápsulas de placebo, ou 20 mg de fluoxetina por dia e gotas de álcool a 30 por cento. Aqueles que não responderam após 4 semanas de tratamento receberam, de maneira cega, 40 mg de fluoxetina/dia ou uma medicação homeopática diferente e respectivos placebos. As medidas de eficácia foram a evolução do escore médio MADRS e as taxas de resposta e remissão na 4ª e 8ª semanas de tratamento. Uma margem de 1,45 foi especificada para a análise de não-inferioridade com base em dados da literatura. A tolerabilidade foi avaliada por meio da escala de avaliação de efeitos adversos da Sociedade Escandinávia de Psicofarmacologia. Os resultados mostraram que não houve diferença significativa entre os dois grupos em relação à evolução dos escores médios de depressão na 4ª (p=0.654) e 8ª (p=0.965) semanas de tratamento. Também não houve uma diferença significativa nas taxas de resposta ou remissão nos dois grupos. A análise de não-inferioridade mostrou que as potências LM não foram inferiores à fluoxetina, uma vez que os limites superiores dos intervalos de confiança foram inferiores à margem de não-inferioridade: as diferenças médias (homeopatia ­ fluoxetina) foram -3,04 (95 por cento IC = -6,95; 0,86) e -2,4 (95 por cento IC = -6,05; 0,77) na 4a e 8a semanas, respectivamente. Tolerabilidade: não houve diferenças significativas entre as taxas de efeitos colaterais entre os dois grupos, apesar dos pacientes tratados com fluoxetina terem apresentado uma maior porcentagem de efeitos adversos perturbadores e uma maior tendência a serem excluídos por efeitos adversos. Conclusões: este estudo exemplifica a possibilidade de se realizarem estudos randomizados e controlados no tratamento homeopático da depressão e indica a não-inferioridade em relação à fluoxetina no tratamento da fase aguda da depressão moderada a grave.(AU)

Background: Homeopathy is a Complementary and Integrative Medicine used in depression. Aims: this study investigated the non-inferiority and tolerability of individualized homeopathic medicines (Q-potencies) in acute depression, using fluoxetine as active control. Methods: Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg/day (up to 40 mg/day) in a prospective, randomized, double-blind double-dummy 8 week, single-center trial. Primary efficacy measure was the analysis of the mean change in the MADRS depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Results: Mean MADRS scores differences were not significant at the 4th (p=0.654) and 8th weeks (p=0.965) of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy ­ fluoxetine) were -3.04 (95% CI = -6.95; 0.86) and -2.4 (95% CI = -6.05; 0.77) at weeks 4th and 8th, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported adverse side effects and a there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. Conclusions: This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of outpatients with moderate to severe depression.(AU)