Jugos de fruta y productos herbáceos como perpetradores de interacciones farmacocinéticas mediadas por enzimas metabolizadoras y transportadores de membrana. Relevancia en clínica / Pharmacokinetic interactions of fruit juices and herbal preparations

Drug disposition in the human body is strongly influenced by transporters and metabolizing enzymes expressed in key organs including intestine, liver and kidney. Since drugs and chemicals present in foods such as fruit juices and herb-based products are substrates of the above-mentioned proteins, there is a high probability of pharmacokinetic interactions. Findings from preclinical and clinical studies helped to characterize the mechanisms by which the components of fruit juices and herbs act as perpetrators of pharmacokinetic interactions. The aim of this review is to provide an overview of pharmacokinetic fruit juice- and herb-drug interactions that could be relevant in the clinical setting.

Syndrome of inappropriate antidiuretic hormone secretion induced by the phytotherapy Harpagophytum procumbers: case report / Síndrome da secreção inapropriada do hormônio antidiurético induzida pelo fitoterápico Harpagophytum procumbers: relato de caso

Abstract Introduction: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the inability of antidiuretic hormone (ADH) suppression, compromising the mechanisms of water excretion and urinary concentration. It manifests as hyponatremia and its symptoms, especially neurological. There are many causes that trigger such disease, notably: central nervous system disorders, malignant neoplasm, drugs and others. Case Report: A 65 years female hypertensive patient presented clinical and laboratory manifestations of hyponatremia due to SIADH. It happened twice under use of herbal medication for osteoarthritis treatment. Discussion: The drug-related hyponatremia can be triggered by direct effect of the drug or by association with SIADH. The clinical manifestations presented could have been related to psychiatric condition and may have severe outcome if not properly diagnosed. The association of an herbal medicine to SIADH could be confirmed after a new episode of hyponatremia related to Harpagophytum procumbers reintroduction. Our literature review did not find this herbal medicine associated with SIADH, so far. Conclusion: SIADH may be caused by herbal medicine described from now on their association in the literature.

Resumo Introdução: A síndrome da secreção inapropriada do hormônio antidiurético (SIADH) consiste na incapacidade de supressão do hormônio antidiurético (ADH), comprometendo os mecanismos de excreção da água e concentração urinária. Possui como manifestações a hiponatremia e seus sintomas, sobretudo neurológicos. Há variadas causas que desencadeiam tal distúrbio, a se destacarem: distúrbios do sistema nervoso central, neoplasias malignas e drogas, dentre outros. Relato de Caso: Paciente feminina, 65 anos, hipertensa, apresentando manifestações clínicas e laboratoriais correspondentes à hiponatremia. O fato ocorreu em duas ocasiões em vigência de medicação fitoterápica para tratamento de osteoartrite. Discussão: A hiponatremia relacionada às drogas pode ser provocada pelo efeito direto do medicamento ou por desencadear SIADH. As manifestações clínicas apresentadas poderiam ter sido atribuídas a um quadro psiquiátrico, o que poderia ter desfecho grave, caso não diagnosticada corretamente. A associação de um fitoterápico à SIADH pôde ser confirmada após novo episódio de hiponatremia relacionado à reintrodução do Harpagophytum procumbers. Nossa revisão da literatura não encontrou este fitoterápico associado à SIADH, até o momento. Conclusão: SIADH pode ser ocasionada por medicamento fitoterápico doravante descrita sua associação na literatura.

Hepatotoxicity by herbs: a practical review of a neglected disease / Hepatotoxicidad por hierbas: una revisión práctica de una enfermedad subestimada

Herbs are commonly used worldwide for the treatment of various diseases, constituting a multi-billion dollar market. Unfortunately, hepatotoxicity induced by herbs is also common. The true incidence and prevalence are not known. There is need for more strict regulations andexperimental and pre-clinical studies regarding its efficacy and safety. There is no gold standard for the diagnosis of herbs-induced liver injury (HILI) and it constitutes a diagnostic challenge for the clinician, whereestablishing causality could be cumbersome. Clinical presentation varies from asymptomatic cases with mildly abnormal liver tests to fulminant liver failure requiring liver transplantation. In this review, we will discuss the epidemiology, clinical manifestations, challenges and diagnostic approach of HILI and will also present some exemplary cases from the University of Miami, Division of Hepatology.

Las hierbas y productos derivados son comúnmente usados alrededor del mundo para el tratamiento de varias enfermedades, constituyendo un mercado multibillonario. Desafortunadamente, hepatotoxidad inducida por estos productos también es común. Existe la necesidad de regulaciones más estrictas, y de estudios experimentales y pre-clínicos acerca de su eficacia y seguridad. No existe un gold-standard para el diagnóstico de injuria hepática inducida por hierbas (HILI), constituyendo un reto diagnóstico para el clínico, donde el establecer una relación de causalidad puede resultar muy difícil. La presentación clínica puede variar desde casos asintomáticos con enzimas hepáticas levemente elevadas hasta casos de falla hepática fulminante requiriendo transplante hepático. En esta revisión, discutiremos brevemente la epidemiologia, manifestaciones clínicas, retos y aproximación diagnostica de la injuria hepática inducida por hierbas y finalmente mostraremos algunos casos ejemplares extraídos de nuestro archivo en la División de Hepatología de la Universidad de Miami.

Hepatotoxicidad asociada a hierbas y productos nutricionales de origen botánico / Herbals and herbal nutritional products hepatotoxicity

Las hierbas y otros productos de origen botánico, han sido utilizados por siglos en diversas culturas con fines medicinales y dietéticos. Contrario a la creencia de ser productos naturales y seguros, su potencial hepatotóxico es reconocido en diversos estudios a nivel mundial, lo que constituye un problema de salud que amerita mayor atención. La prevalencia reportada de hepatotoxicidad asociada a productos botánicos es variable y depende de diversos factores como población estudiada, período y diseño del estudio. Se han reportado un total de 60 productos a base de hierbas con fines medicinales y dietéticos, que pueden causar lesión hepática; sin embargo, el mecanismo fisiopatológico no está completamente dilucidado. Su cuadro clínico y características histológicas, no difieren de la lesión hepática asociada a medicamentos y la mayoría de los pacientes tienen un patrón de lesión hepatocelular. El diagnóstico se hace por exclusión, representando un desafío clínico importante, por lo que resulta fundamental la sospecha clínica y el diagnóstico diferencial de otras patologías agudas y crónicas. De allí que las investigaciones futuras están orientadas a mejorar los métodos diagnóstico existentes e introducir nuevas tecnologías toxicológicas, genéticas e inmunológicas. El manejo es complejo y representa un reto para el especialista puesto que no existe antídoto; el manejo se basa en suspender el uso del producto y en el tratamiento sintomático que disminuya la progresión a la falla hepática aguda fulminante.

Herbs and other botanicals have been used in different cultures with medicinal and dietary purposes for centuries. Contrary to the belief of being natural and safe products, their hepatotoxic potential is recognized in several studies worldwide, and represent a health problem that deserves greater attention. The reported prevalence of hepatotoxicity associated with botanicals is variable and depends on various factors such as population, period and design of the study. There have been reports of a total of 60 products with herbal medicinal and dietary purposes, which may cause liver damage; however, the pathophysiological mechanisms involved are not fully elucidated. Their clinical and histological features, not unlike liver injury associated with drugs in most patients, have a pattern of hepatocellular injury. Diagnosis is by exclusion, and represents a clinical challenge. It is essential the clinical suspicion and the differential diagnosis with other acute and chronic conditions. Hence, future researches are aimed at improving existing diagnostic methods and introducing new toxicological, genetic and immunological technologies. Treatment is complex and presents a challenge for the specialist, as there are no antidotes. Management based on the discontinued use of the product and in the symptomatic treatment, decreases the progression to an acute fulminant hepatic failure.

Clinical Features of Drug-induced Liver Injury According to Etiology

Drug-induced liver injury (DILI) is an increasingly common cause of acute hepatitis. We examined clinical features and types of liver injury of 65 affected patients who underwent liver biopsy according DILI etiology. The major causes of DILI were the use of herbal medications (43.2%), prescribed medications (21.6%), and traditional therapeutic preparations and dietary supplements (35%). DILI from herbal medications, traditional therapeutic preparations, and dietary supplements was associated with higher elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels than was DILI from prescription medications. The types of liver injury based on the R ratio were hepatocellular (67.7%), mixed (10.8%), and cholestatic (21.5%). Herbal medications and traditional therapeutic preparations were more commonly associated with hepatocellular liver injury than were prescription medications (P = 0.002). Herbal medications and traditional therapeutic preparations induce more hepatocellular DILI and increased elevations in AST and ALT than prescribed medications.

Ginkgo biloba effects on mice fetal liver / Efectos de la ginkgo biloba en el hígado fetal de ratón

Ginkgo biloba is considered to be an alternative drug for various indications; unfortunately very few studies are available on its side effects. This present study describes the harmful effects of Ginkgo biloba on developing fetal liver. Two experimental groups of six pregnant female mice each were given Ginkgo biloba at human therapeutic dose (A) and a higher dose (B) throughout the gestation period. A third group (C) was taken as a control and given distilled water only. Fetal livers were examined and the effects of the drug observed. There were signs of congestion and fatty change along with dilatation of sinusoids in a dose dependent manner concluding that Ginkgo biloba affects fetal liver.

La Ginkgo biloba es considerada, en varias indicaciones, como un medicamento alternativo; sin embargo, existen pocos reportes disponibles sobre sus efectos secundarios. Este estudio describe los efectos nocivos de Ginkgo biloba en el desarrollo del hígado fetal. Dos grupos experimentales de 6 ratones hembras preñadas recibieron Ginkgo biloba en la dosis terapéutica humana (A) y una dosis más alta (B) por el período de gestación. Un tercer grupo control (C) recibió agua destilada. Los hígados fetales fueron examinados y observados los efectos de la droga. Hubo signos de congestión y degeneración grasa, junto con la dilatación de sinusoides en función de la dosis. Como conclusión la Ginkgo biloba afecta el hígado fetal.

Pharmacokinetic-interaction of Vitex negundo Linn. & paracetamol.

Background & objectives: Currently, herbal preparations are clinically used as functional food, food supplements or as add on therapy, which affects the bioavailability and also the net therapeutic potential of co-administered allopathic drugs. Therefore, it is important to assess the interaction among these two classes of drugs. Here we studied the interaction between orally-administered ethanolic extract of leaves of Vitex negundo Linn. (Verbenaceae) (VN extract) and paracetamol in albino rats. Method: Solvent free dried extract of VN leaves was orally given to experimental rats in different doses (62.5-1000 mg/kg/b.wt.), daily for six consecutive days. On days 3 and 6, paracetamol (100 mg/kg/b.wt.) was orally administered to these extract treated rats and control rats (drug vector). At various time intervals (5 min - 120 min), blood was collected from each animal and paracetamol concentration was determined in plasma by using HPLC with UV detector at 249 nm. Various pharmacokinetic parameters were calculated by non compartmental model. Results: A significant decline in plasma concentration of paracetamol with time-gap was recorded with the increasing dose of VN extract, without affecting its Tmax (maximum time to achieve peak plasma concentration). There was a significant decrease in the extent of absorption and decline in intensity of therapeutic response (as evidenced by reduced AUC value and decline in Cmax). Further, compared to control, the relative bioavailability of paracetamol, in presence of VN extract, decreased significantly. Interpretation & conclusions: VN extract or its ayurvedic formulation if co-administered with allopathic drug like paracetamol, the dose of allopathic drug needs to be adjusted in order to achieve desired therapeutic response of paracetamol.

Nutritional changes in powdered red pepper upon in vitro infection of Aspergillus flavus / Alterações nutricionais em pimenta vermelha em pó após infecção in vitro com Aspergillus flavus

Quantitative losses in various biochemical constituents like capsaicin, carotenes, ascorbic acid, polyphenols,mineral matter, sugars (soluble and insoluble), protein and fat were estimated after the successful growth ofAspergillus flavus for 30 days on powdered red pepper. The fungal biomass was measured by ergosterolcontent and Aflatoxin B1 by HPLC. Amongst the various nutritional constituents evaluated for nutritionallosses and changes the highest nutritional loss was reported in total carotenoids (88.55%) followed by totalsugars (85.5%). The protein content of the infected sample increased from 18.01% to 23%. The nutritional profile of chilli powder (Capsicum annum var. sannam L.) shows highest share of total soluble sugars (32.89%) and fiber content (21.05%), followed by protein (18.01%) and fat (13.32%) making it an ideal solid - substrate for mould growth. At the end of incubation the fungal biomass was 192. 25 mg / 100 gram powder, total plate count 17.5 X 10 4 CFU/g and Aflatoxin B1 content was 30.06 μg / kg.

Foram avaliadas as perdas de vários constituintes bioquímicos como capsaicina, carotenos, acido ascórbico,polifenóis, matéria orgânica, açucares (solúveis e insolúveis), proteína e gordura em pimenta vermelha em pó após a multiplicação de Aspergillus flavus por 30 dias. A biomassa fúngica foi mensurada pelo conteúdo de ergosterol e aflatoxina por HPLC. Entre os vários constituintes avaliados, a maiorperda foi a de carotenóides totais (88,55%), seguido de açucares totais (85,5%). O conteúdo protéico da amostra infectada aumentou de 18,01% para 23%. O perfil nutricional da pimenta em pó (Capsicum annum var. sannam L.) indica alto teor de açucares totais (32,89%) e fibras (21,05%), seguido de proteína (18,01%) e gordura (13,32%), tornando-a umsubstrato ideal para crescimento de fungos. Ao final dos 30 dias, a biomassa fúngica foi 192,25 mg/100g, a contagem total em placas foi 17,5 x 104 CFU/g e o conteúdo de aflatoxina B1foi 30,06 μg/kg.

[Evaluation of fetal toxicity of HESA-A, a natural anticancer agent, in mice]

HESA-A is an active natural compound with herbal and marine origin. It contains inorganic, organic and aqueous fractions, and has shown antioxidant, cytotoxic and anticancer effects. In this study, the teratogenic effects of HESA-A in mice have been evaluated. Several doses of HESA-A were administered orally to pregnant mice on days 6 to 14 of gestation. Various parameters in pregnant mice and embryos during and after pregnancy were evaluated and recorded. At the end of pregnancy, embryos were sectioned out and studied for external morphological abnormalities and by specific skeletal staining for skeletal malformations. Weight gain of pregnant mice showed that only the highest dose [800 mg/kg] caused gain retardation. Also, only the highest dose led to reduction of uterus weight, number of viable embryos, and weight and crown-lump length of embryos. Increase in fetal resorption by the highest dose of HESA-A was another important observation. Low and medium doses of HESA-A did not cause any significant external or skeletal abnormalities. However, higher doses caused embryo malformations such as short limbs, spinal abnormalities, dermal cysts, microphtalmia, and cleft palate. According to this study, only high doses of HESA-A, which are many times higher than the usual therapeutic doses, may cause embryonic toxicity. Mechanisms of these abnormalities are not clear and need to be determined

Efficacy and safety of zidovudine and zalcitabine combined with a combination of herbs in the treatment of HIV-infected Thai patients.

A randomized double blind placebo controlled trial to determine the efficacy and safety of combined-herbs (SH) given with zidovudine (ZDV) and zalcitabine (ddC) for the treatment of HIV infection in Thai adults was conducted in 3 hospitals in northern Thailand during 2002 to 2003. The eligible subjects were HIV-infected Thai adults who had never received anti-retrovirals, had a Karnofski Performance Score (KPS) of > or = 70, and had no opportunistic infections. The subjects were randomized to receive either a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and SH 2.5 g three times per day or a combination of ZDV 200 mg three times per day, ddC 0.75 mg three times per day, and placebo 2.5 g three times per day for 24 weeks. The main outcome measures were HIV-RNA, CD4 cells, and blood chemistry profiles prior to the treatment and then every 4 weeks for 24 weeks. The baseline characteristics of 60 evaluable subjects, 40 in the SH group and 20 in the placebo group, were not significantly different. HIV RNA at week 4 and thereafter was significantly decreased from the baseline value in both groups (p<0.001). However, the decline in HIV RNA in the SH group was significantly more than that in the placebo group. The CD4 cells in the SH group at week 12 and thereafter were significantly increased from the baseline value. Serious adverse events in the two groups were not observed. It is concluded that an addition of SH herbs to two nucleoside reverse transcriptase inhibitors has greater antiviral activity than antiretrovirals only. The SH herbs may be an alternative for the third anti-retroviral agent in the triple drug regimen for the treatment of HIV infected patients in countries with limited resources.

Herbal Preparation-induced Liver Injury / 대한소화기학회지

Recently the use of herbal preparations as remedies for various medical conditions, has been rapidly increasing in Korea. In our previous study, 38.9% of patients with chronic liver disease were found to use some sorts of herbal preparations. They believe herbal preparations are safe although the ingredients has never been rigorously substantiated. Toxicities of certain herbal preparations are caused by their contaminants and adulterated ingredients or concurrently used conventional drugs rather than specific components of the herbal preparations. Furthermore, in most instances, multiple herbal ingredients are used by the prescribers of oriental medicine. All of these conditions frequently impose diagnostic difficulties. There are myriads of plant-derived hepatotoxic substances which may or may not cause liver injury in individuals. The severity of liver injury depends largely on the toxicity of the substance, the amount of exposure and the individual's susceptibility. These toxic substances cause liver injury not only through the mechanism of intrinsic hepatotoxicity but also through the idiosyncrasy as in conventional drug-induced injury. Therefore, theoretically, it is possible to apply pre-existing CAMs (Causality Assessment Methods) to the assessment of causality in cases with diagnostic difficulties.

Efectos adversos e interacciones de productos botánicos medicinales / Adverse effects and interactions of medicinal herbal products

The use of medicinal products derived from plants (phytomedicinals) has been increasing dramatically in the past years this has forced the health professional to increase their knowledge in the risks and benefits in the use of such products. This article reviews the most important adverse effects and interactions from the phytomedicinals and presents this information in the perspective of a responsible Integrative Medicine practice focused in achieving optimal therapeutic goals

Herbal medicine: current status and the future.

The number of patients seeking alternate and herbal therapy is growing exponentially. Herbal medicines are the synthesis of therapeutic experiences of generations of practicing physicians of indigenous systems of medicine for over hundreds of years. Herbal medicines are now in great demand in the developing world for primary health care not because they are inexpensive but also for better cultural acceptability, better compatibility with the human body and minimal side effects. However, recent findings indicate that all herbal medicines may not be safe as severe consequences are reported for some herbal drugs. Most herbal products on the market today have not been subjected to drug approval process to demonstrate their safety and effectiveness. Thousand years of traditional use can provide us with valuable guidelines to the selection, preparation and application of herbal formulation. To be accepted as viable alternative to modern medicine, the same vigorous method of scientific and clinical validation must be applied to prove the safety and effectiveness of a therapeutical product. In the present review we attempted to describe the present scenario and project the future of herbal medicine.