stilbenes and Nausea

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Nausea; Neoplasms; Stilbenes; Structure-Activity Relationship

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.

Topics: Abdominal Pain; Adult; Antineoplastic Agents, Phytogenic; Area Under Curve; Chromatography, High Pressure Liquid; Diarrhea; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glucuronides; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Metabolic Clearance Rate; Middle Aged; Nausea; Resveratrol; Stilbenes; Young Adult

Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin.. Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion.. Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles.. This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Stilbenes; Thrombocytopenia; Treatment Outcome; Vomiting

Thirty-nine patients with tapeworm infection were treated with five grams of crude aqueous extract of Artocarpus lakoocha wood, "Puag-Haad". Seven of them vomited the drug immediately. Of the 32 patients, segments with scolices of Taenia saginata and of Taenia solium were recovered from 24 and 2 patients respectively. The side effects were vomiting and nausea.

Topics: Adolescent; Adult; Anticestodal Agents; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Nausea; Plant Extracts; Plants, Medicinal; Stilbenes; Taeniasis; Thailand

Topics: Aged; Breast Neoplasms; Bromocriptine; Carbidopa; Drug Therapy, Combination; Estrogen Antagonists; Female; Humans; Levodopa; Middle Aged; Nausea; Prolactin; Remission, Spontaneous; Stilbenes; Tamoxifen; Time Factors; Vomiting

Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer. Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m

Topics: Animals; Blood Pressure; Diarrhea; Dogs; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography; Female; Heart; Male; Nausea; Stilbenes