Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers.

AIMS: The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied. METHODS: In a randomized, crossover study with four periods, twenty-four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1-4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively. RESULTS: The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15-mg rizatriptan were 16, 33, 72, and 127 ng ml-1 h, respectively, in males; and 19, 42, 97, and 161 ng ml-1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was approximately 40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min-1, respectively, in males; and 821 and 174 ml min-1, respectively, in females. CONCLUSIONS: The disposition kinetics of oral rizatriptan were linear for doses of 2. 5-10 mg in males, and for doses of 2.5-5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.

Evolution of NADH dehydrogenase subunit 2 in east African cichlid fish.

The complete sequence (1047 bp) of the mitochondrially encoded ND2 gene was obtained from 31 species of cichlid fishes to investigate the evolutionary history of the species flocks of the East African lakes. The observed pattern of nucleotide substitution in this sequence is typical of mitochondrial genes, showing a high transition bias and rapid mutational saturation, especially at codon positions where base frequencies are unequal. The base composition of the third position of codons is heterogeneous among species, suggesting frequent shifts in the pattern of substitution. Phylogenetic analysis of the sequences shows that the mtDNA variation in Lake Malawi cichlids is nested monophyletically within the range of variation shown by Tanganyikan cichlids. The closest Tanganyikan relatives of the Malawi flock are members of the tribe Tropheini. Classifications based on morphology are generally supported by the mtDNA data, with some significant exceptions in the Tropheini and Lamprologini. Because of an apparently rapid radiation of the Tanganyikan lineages, it is difficult to assess the basal topology of the Tanganyikan radiation at this time. Divergences among tribes are consistent with an intralacustrine radiation within the past 10 million years.

Lovastatin does not affect oral glucose tolerance in hypercholesterolemic patients.

In 15 non-diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double-blind, two-panel, parallel design, patients on a low cholesterol diet received lovastatin (n = 7) or placebo (n = 8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL-cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug-related adverse effect during the study. This study demonstrated that short-term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.

Similar morphologies of cichlid fish in Lakes Tanganyika and Malawi are due to convergence.

The species flocks of cichlid fishes in the lakes of East Africa are the most spectacular example of adaptive radiation among living vertebrates. Similar highly derived morphologies are found among species in different lakes. These similarities have been variously interpreted either as evidence for migration of ancestral species between the lakes, or of striking convergence of morphology. To distinguish among these competing hypotheses we sequenced a portion of the mitochondrial DNA control region from six pairs of morphologically similar taxa from Lakes Malawi and Tanganyika. Our results clearly indicate a separate origin of these morphologies in the two lakes. They also suggest that the Tanganyikan radiation is relatively old, and that the species flocks in lakes Malawi and Victoria are derived from one of the ancient lineages found in Lake Tanganyika. These findings have important implications for understanding the pattern of morphological and behavioral evolution in these fish.

Vindesine for metastatic malignant melanoma. A phase II trial.

Sixteen patients, 13 of whom had received prior chemotherapy, were treated with vindesine for advanced malignant melanoma. Previous treatment included vinca alkaloids in six. Thirteen patients received vindesine, 4 mg/m2 and three received vindesine, 3 mg/m2 by weekly I.V. injection. There were two partial (12%) and no complete responses among all of the patients. Both responses occurred in subcutaneous lesions and lasted for 4 and 6 weeks, respectively. Fifteen patients could be evaluated for treatment-related toxicity. The most common side effect was modest leukopenia (less than 3000/microliter) in 10 patients (67%). The lowest leukocyte count recorded was 1100/microliter. Thrombocytopenia was not encountered. Neurotoxicity, manifest most commonly as mild or moderate peripheral paresthesiae, was seen in eight patients (53%).

Vindesine in bronchogenic carcinoma: a phase II trial.

Twenty-seven patients with advanced bronchogenic carcinoma were treated with vindesine, 3 mg/m2/week. Twenty-three patients were evaluable for response. Two of six patients with small-cell carcinoma and one of 17 patients with non-small-cell carcinoma had partial responses. Two other patients with non-small-cell carcinoma had minor responses. The duration of the responses was 2-4 months. Neurologic toxicity occurred in 14 patients and was mild except in two patients. There was a median hemoglobin fall of 2.2 g/dl and a median leukocyte nadir of 2800/microliter during vindesine therapy. Thrombocytopenia occurred in 2 patients and mild thrombocytosis occurred in 10 patients. Seven patients experienced phlebitis or cellulitis at the site of drug administration which could be prevented with small doses of intravenous methylprednisolone. These results suggest that vindesine is well tolerated and possesses some activity in patients with previously treated bronchogenic carcinoma.

Treatment of psoroptic mange with avermectins.

Good control of Psoroptes cuniculi was achieved in rabbits treated with various avermectin analogues by topical application or by subcutaneous injection of the 22,23-dihydroavermectin B1.