Developmental toxicity, antioxidant, and marker enzyme assessment of swertiamarin in zebrafish (Danio rerio).

A secoiridoid glycoside called swertiamarin has been widely used as a herbal medicine for many decades. In particular, swertiamarin from the Enicostema axillare herb has been used as a multipurpose drug to treat innumerable health problems. As this medicine is consumed orally, its toxicity level should be determined. To examine the safety of this compound, toxicology work was done in zebrafish, and this is the first report to describe swertiamarin toxicity in zebrafish. Zebrafish embryos were used in this swertiamarin toxicity study, and morphological changes were observed. Further, the compound was also studied in adult zebrafish to determine the impact of the compound on the fish liver. Enzyme profiling with superoxide dismutase, glutathione peroxidase, catalase, reduced glutathione levels, glutathione S-transferase, lactate dehydrogenase, glutamic oxaloacetic transaminases, lipid peroxidation, Na+ /K+ -ATPase, and glutamic pyruvic transaminases) was evaluated (p ≤ 0.05). Results suggest that swertiamarin is a safe drug only at a low concentration (40 µM). This study also shows that even herbal medicinal compounds may be toxic to humans at higher dosages. Hence, irrespective of whether a drug is synthetic or natural, it needs to be tested for its toxicity before use in humans.

Final report on the safety assessment of Piper methysticum leaf/root/stem extract and Piper methysticum root extract.

Piper methysticum leaf/root/stem extract is the cosmetic ingredient name for a material derived from the leaves, roots, and stems of the Piper methysticum G. Forster plant, commonly known as kava kava. This and other kava-derived ingredients are used as skin-conditioning agents at concentrations from 0.0001% to 0.1%. The Food and Drug Administration issued a consumer advisory in 2002 expressing concern about liver damage in individuals who have ingested kava products. The available oral toxicity data support the concern about liver damage on ingestion but do not resolve the question, for example, whether these ingredients would be substantially absorbed through the skin. Other data needs are described, including toxicology data for yangonin, methysticin, and kavain, which may be present in kava-derived ingredients. Accordingly, the available data are insufficient to support the safety of these ingredients in cosmetics.

Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage?

The US Food and Drug Administration has issued a warning that tipranavir may be associated with increased risk of intracranial hemorrhage. We studied 2 large cohorts to estimate the background rate of intracranial hemorrhage and compared it with rates reported among persons who had been exposed to tipranavir.

Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance.

BACKGROUND: Despite the availability of a growing number of potent antiretroviral agents, efforts to completely suppress viral replication in patients with HIV-1 infection are limited because of the increasing risk of resistance. Tipranavir (TPV) is the first in a class of antiretroviral agents known as nonpeptidic protease inhibitors (PIs). TPV exhibits a resistance profile distinct from that of other currently available PIs, making it a potential option for treatment experienced patients with resistance to multiple Pls. OBJECTIVE: This article discusses the clinical pharmacology and efficacy of TPV in the treatment of HIV-1 infection in patients who are highly treatment experienced or harbor PI-resistant virus. METHODS: A search was conducted of English language, peer-reviewed articles and abstracts indexed on the MEDLINE and Current Contents databases (1966-May 2007) using the terms tipranavir, Aptivus, nonpeptidic protease inhibitor, human immunodeficiency virus, and protease resistance. Product information and abstracts from national and international AIDS and retrovirus meetings (2005-2006) were also reviewed. RESULTS: Use of TPV in combination with ritonavir (TPV/r) was approved by the US Food and Drug Administration based on 2 Phase III studies. In these studies, HIV-infected patients with extensive treatment experience with antiretroviral agents, including PIs, nucleoside analogues, and nonnucleoside reverse transcriptase inhibitors, were randomized to receive TPV/r or a ritonavir-boosted comparator PI. All patients had evidence of resistance to multiple PIs. The specific comparator (amprenavir, indinavir, lopinavir, or saquinavir) was selected for each patient with the aid of resistance testing. Each patient also received an optimized background regimen of antiretroviral agents, which could include enfuvirtide. At 24, 48, and 96 weeks, the TPV/r group had higher rates of virologic response (defined as > or =1 log10 decrease in HIV RNA) and viral suppression (to <400 and <50 copies/mL) than did the comparator group. CONCLUSIONS: Although TPV has a mechanism of action similar to that of earlier-generation PIs, it has activity against HIV-1 strains with resistance to multiple PIs. Currently, TPV/r is indicated for use in highly treatment experienced patients with multiple PI resistance.

Tipranavir: new drug. HIV protease inhibitor. A last resort.

(1) Despite the availability of multidrug antiretroviral therapies, about 3% to 4% of HIV-infected patients exhaust nearly all available treatment options. (2) Tipranavir, an HIV protease inhibitor, is marketed in France for patients with multidrug resistance. (3) Two randomised unblinded trials are currently comparing the tipranavir + ritonavir combination with other protease inhibitors as adjuncts to optimised antiretroviral treatment in 1159 patients selected on the basis of laboratory criteria. Interim results at 48 weeks show that significantly more patients have an undetectable viral load with tipranavir + ritonavir than with other protease inhibitors (22.8% versus 10.2%). Enfuvirtide co-administration seems to reinforce the effect of tipranavir + ritonavir. In contrast, tipranavir does not seem to be more effective than other HIV protease inhibitors to which a given patient's viral population remains sensitive. (4) Tipranavir seems to be associated with higher risks of hepatic disorders, hypertriglyceridaemia, hypercholesterolaemia, and potentially severe bleeding than other protease inhibitors. (5) Tipranavir inhibits the activity of most cytochrome P450 isoenzymes. This creates a strong potential for drug interactions, but clinical experience is limited. (6) Patients on tipranavir must take 2 capsules twice a day. (7) In practice, tipranavir should be saved as a last-resort HIV protease inhibitor.

Tipranavir: a protease inhibitor for HIV salvage therapy.

OBJECTIVE: To review the efficacy, safety, pharmacology, virology, pharmacokinetics, and resistance of the nonpeptidic protease inhibitor (PI) tipranavir. DATA SOURCES AND STUDY SELECTION: A PubMed search (1966-February 2006) was conducted using the key words tipranavir or PNU-140690, with the limitation of English-language reports. Pharmacokinetic and randomized clinical trials originating from major HIV conferences, such as the Conference on Retroviruses and Opportunistic Infections, International AIDS Society, European AIDS Conference, and Interscience Conference on Antimicrobial Agents and Chemotherapy, published only in abstract form, from 2000 to February 2006, were reviewed for relevance and included in this review. DATA SYNTHESIS: Phase III studies have shown that tipranavir is effective in the treatment of PI-resistant HIV compared with other PI-containing regimens. Adverse effects associated with tipranavir/ritonavir therapy include gastrointestinal reactions, hepatotoxicity, and elevations in cholesterol and triglyceride levels. Resistance data suggest that tipranavir/ritonavir should be reserved for salvage therapy in antiretroviral-experienced patients who have previously failed standard PI therapies. The potential for hepatotoxicity and drug interactions and the expense of tipranavir due to required ritonavir boosting may limit its widespread use. CONCLUSIONS: Tipranavir/ritonavir is an essential addition to the antiretroviral armamentarium for HIV-infected patients with limited treatment options.