Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers.

AIMS: To assess the tolerability and pharmacokinetic profile of single and repeat doses of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. METHODS: A total of 31 subjects participated in two placebo-controlled, rising-dose studies. The first study assessed the pharmacokinetics and tolerability of single doses of marimastat of 25, 50, 100, 200, 400 and 800 mg. In the second study, continuous dosing over 6.5 days with three incremental dose levels of 50, 100 and 200 mg twice daily was assessed. Full pharmacokinetic profiles were obtained on days 0 and 6, and trough concentrations were measured on all days. For each pharmacokinetic profile in the studies, summary measures including Cmax, tmax, elimination half-life and AUC were calculated. Urinary drug weights were also measured. All adverse events were documented, and haematological and biochemical variables, vital signs and ECGs were monitored throughout the study. RESULTS: Peak plasma concentrations were observed at 1.5-3 h for all subjects at all doses. Peak levels were approximately proportional to dose, as was drug exposure as calculated by AUC. Data from both studies indicate that the terminal elimination half-life is of the order of 8-10 h, and that there is no unexpected drug accumulation. Marimastat was well-tolerated, with adverse effects being mild and occurring with similar frequency to placebo. Small but reversible elevations in liver transaminases were noted with repeat dosing of marimastat, the most significant of these occurring at a dose of 200 mg twice daily. CONCLUSION: Single and repeat oral doses of marimastat in healthy male subjects appear to be well-tolerated. The drug is rapidly absorbed with high peak levels achieved. It has a terminal elimination half-life of 8-10 h which would support twice daily dosing in further clinical trials.

Interaction of antimicrobial agents with human peripheral blood leucocytes: uptake and intracellular localization of certain sulphonamides and trimethoprims.

The uptake of sulphamethoxazole, sulphadiazine, sulphamerazine, sulphanilamide, trimethoprim and brodimoprim by human peripheral blood leucocytes, has been investigated. High performance liquid chromatography (HPLC) was used to assay drug concentrations before and after incubation with leucocyte suspensions. Using radiolabelled material the intracellular localization of two of these compounds was also determined. The results indicated that all the investigated drugs were taken up by leucocytes. Differential studies demonstrated that mononuclear cells accumulated higher drug concentrations (0.13-0.55 microgram/10(7) cells), than resting neutrophils (0.02-0.26 microgram/10(7) cells) with the exception of sulphanilamide, which was taken up to a greater extent by neutrophils (0.75 microgram/10(7) cells). During neutrophil phagocytosis intracellular levels of all the drugs except brodimoprim increased from 3 to 130-fold as compared to resting neutrophils. The uptake of 14C-sulphanilamide and 14C-trimethoprim, in neutrophils and mononuclear blood cells, as assessed by measurement of the cell-associated radioactivity, correlated well with that determined by the HPLC procedure. In the intracellular localization studies 14C-sulphanilamide and 14C-trimethoprim exhibited similar distribution profiles. In neutrophils, 35-40% of radiolabelled drug was located in both the microsome and cytosol fractions whereas in peripheral blood mononuclear cells 40-60% was found in the cytosol and 10-20% in the microsome fraction. The results of this study suggest that, following activation, leucocytes may actively transport these drugs and release them locally at sites of infection. The ability of neutrophils to further concentrate the drugs during phagocytosis may result in reduced survival time of some ingested bacteria. These concepts may be important in designing treatment stratagems for intracellular pathogens.

The effect of PK5078, a new serotonin uptake inhibitor, on serotonin levels and uptake in human platelets, following administration to healthy volunteers.

PK 5078 is a recently developed compound which inhibits specifically the neuronal reuptake of serotonin and enhance its release. PK 5078 was administered to healthy male volunteers in single and multiple oral doses and the effects on platelet serotonin uptake and content were examined. A significant dose-related inhibition of 3H-serotonin uptake by platelets was observed following single oral doses of PK 5078 (25-150 mg), with maximal inhibition at 75 mg. This was evident 2 h after dosing and was still marked after 10 h. Plasma collected from the subjects after dosing also had a considerable dose-related effect on the uptake of 3H-serotonin by untreated platelets. No significant alteration in platelet serotonin content was observed after single doses of PK 5078. When PK 5078 (50 mg) was administered twice daily for 9 days there was a rapid and sustained reduction in 3H-serotonin uptake by platelets, which returned to pretreatment levels 2 days after discontinuation of the drug. A similar response was observed when plasma from these subjects was incubated with untreated platelets. The rate of depletion of endogenous platelet serotonin was much slower with minimum levels being attained on the morning after the final dose. The recovery following withdrawal was also slow with serotonin levels approaching pre-dose values 14 days after the final dose of PK 5078.

Platelet uptake of serotonin following repeated administration of 3-cyano-imipramine to healthy volunteers.

In a double blind, placebo-controlled study the effects of daily oral administration of 3-cyano-imipramine on the 3H-serotonin uptake capacity of platelets were investigated in healthy volunteers. The initial dose was 1 mg, rising to 3 mg daily for 7 days. A rapid and profound inhibition of 3H-serotonin uptake was observed in platelets isolated from the treated subjects. During repeated administration, uptake was reduced to less than 10% of pre-drug values. Five days after the final dose uptake had only partially recovered, to 53% of pre-drug values. A similar inhibition profile was observed when serum from the treated subjects was incubated with normal platelets and 3H-serotonin. The results establish 3-cyano-imipramine as a potent inhibitor of platelet serotonin uptake in humans.

Effects of a single oral dose of 3-cyano-imipramine on serotonin uptake and content of platelets in healthy volunteers.

Changes in platelet serotonin uptake and content were investigated following administration of a single oral dose of 3-cyano-imipramine to healthy volunteers. The uptake of 3H-serotonin by platelets harvested from these subjects was almost completely inhibited 4 h after dose administration. This inhibition continued for at least 24 h. Plasma taken from the subjects inhibited the uptake of 3H-serotonin by platelets isolated from non-treated subjects. A small but significant reduction in platelet serotonin content was observed 3.75 h after dosing and was still evident after 24 h.