FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double-blind, placebo-controlled, timelagged study of six different single ascending oral doses of FTY720 ranging from 0.25 to 3.5 mg was conducted in stable renal transplant patients receiving a cyclosporine-based regimen. Absolute and subset lymphocyte counts, as well as absolute differential leukocyte counts, were determined by differential blood counts and flow cytometry at screening and multiple intervals thereafter. A pharmacodynamic model was established. Twenty-four single doses of FTY720 that were administered caused a transient, reversible pan-lymphopenia within 4 h. Lymphocyte subgroup analysis revealed that almost all subsets declined, with CD4-and CD45RA-positive cells being affected the most. Natural killer cells, granulocytes and monocytes were not influenced by FTY720. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Pharmacokinetik/ pharmacodynamic modelling revealed a nonlinear dose effect and resulted in a good fit with observed values. These data show that FTY720 is highly effective in humans, with single oral doses of FTY720 ranging from 0.25 to 3.5 mg causing a reversible selective panlymphopenia.

The α-glucosidase inhibitor voglibose (AO-128) was designed to prevent rapid postprandial blood glucose rises in non-insulin-dependent diabetics. We analyzed its effect on the entero-insular axis in 72 healthy volunteers in a double-blind study design before, after the 1st dose, and on the 7th day of a 7-day treatment protocol (3 daily loads). Six parallel groups of 12 volunteers received voglibose (0.5, 1.0, 2.0, or 5.0 mg) or placebo (two groups). Blood was drawn at regular intervals up to 180 min after a standardized breakfast to analyze the levels of glucose, insulin, C peptide, gastric inhibitory polypeptide, and glucagon-like peptide 1 (GLP-1). As expected, after ingestion of voglibose, slight to moderate gastro-intestinal discomfort but no severe side-effects were reported. In a dose-dependent manner, voglibose significantly reduced postprandial increases of blood glucose, insulin, and C peptide. At the lower loads (0.5 and 1 mg voglibose three times daily), these effects were more pronounced after 7 days. The postprandial increase of gastric inhibitory polypeptide was already reduced after the first load of 2 and 5 mg voglibose. In comparison to the placebo group, this inhibition became also significant for the lower loads after 7 days. Interestingly, GLP-1, originating from the lower intestines, was increasingly released under voglibose treatment. The first administration of 1 mg voglibose enhanced GLP-1 secretion > 80% above controls. Treatment with 1 mg voglibose three times daily over 7 days revealed a maximal mobilizing effect on endogenous GLP-1 ( > 90% above controls) which was not further increased by 2- or 5-mg loads. We conclude that voglibose treatment effectively inhibits intestinal disaccharidases and thereby mobilizes the endogenous pool of insulinotropic GLP-1.

Fleroxacin (Ro 23-6240; AM-833) is a new trifluorinated quinolone exhibiting high activity against a broad spectrum of gram-negative and gram-positive bacteria. Healthy male volunteers received, according to a randomized scheme, oral doses of 200, 400, or 800 mg of fleroxacin in tablet form, an intravenous infusion of 100 mg, or 400 mg of fleroxacin orally together with 1,000 mg of probenecid. Fleroxacin is characterized pharmacokinetically by a long elimination half-life (9 to 10 h) and high concentrations in plasma (e.g., maximum concentration of 2.3 ,ig/ml after an oral dose of 200 mg). The volume of distribution clearly exceeds 1 liter/kg and suggests a good tissue penetration. Within 60 h, the cumulative urinary recovery of unchanged drug amounted to 50 to 60% of the dose. The renal clearance of unbound drug was 137 ml/min, and probenecid had no significant effect on renal elimination. A good linear correlation (r = 0.999) was found between doses from 100 to 800 mg and the resulting values of area under the concentration-time curve. The absolute bioavailability of the administered tablet was practically 100%. During oral multiple dosing of 800 or 1,200 mg of fleroxacin once a day over 10 consecutive days, the accumulation of the drug in plasma was close to the theoretically predicted value of 1.3 and reflected the persistence of linear pharmacokinetics. Early pharmacokinetic and tissue distribution studies in different animal species revealed that this new quinolone was rapidly and completely absorbed following oral administration and that drug levels in lungs, spleen, liver, and kidneys exceeded the corresponding levels in serum (9).Elimination half-lives (t4/2) were species dependent and reached more than 9 h in dogs.In this study the pharmacokinetics of fleroxacin in healthy volunteers were investigated after single and multiple dosing; factors studied included dose proportionality, absolute bioavailability of the used tablet, and the influence of probenecid on renal excretion.

Exposure to high altitude results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2,500 m to severe symptoms above 4,000 m. In a previous study, changes in the pharmacokinetics of meperidine were observed after exposure to high altitude. This study was conducted to investigate whether similar changes occur for acetazolamide, which is prescribed for prophylaxis of acute mountain sickness. Acetazolamide 250 mg was administered orally to young, healthy male volunteers in groups of 12 each: those residing at sea level (group L), these same volunteers on the day after arrival at high altitude (4,360 m, group HA), and volunteers living at high altitude for 10 months or longer (group HC). Serial blood samples were collected for 24 hours and acetazolamide concentrations were measured in whole blood, plasma, and plasma water. The elimination rate constant (lambda z) was significantly increased in group HA compared with group L. Clearance uncorrected for bioavailability (Cl/F) increased significantly in group HA compared with group L, and further increased in group HC. Apparent volume of distribution (Vz/F) was decreased by 17% in group HA compared with group L, and increased by 37% in group HC compared with group HA. Mean residence time (MRT) was significantly decreased in group HA compared with groups L and HC. Erythrocyte (RBC) uptake increased significantly after a significant increase in RBC count in group HC compared with group L. The extent of protein binding (EPB), however, was significantly decreased in group HA compared with groups L and HC. Free acetazolamide concentrations were significantly lower in group HC than in group L 12 hours after administration. Based on these observations, it is suggested that patients travelling to high altitude, especially altitudes above 4,000 m, should be closely monitored and acetazolamide dosage adjusted as necessary.

Four studies of identical design, each on 18 young healthy subjects, were undertaken to study the pharmacokinetics and beta 1-receptor blockade at steady state after a once daily dose (od) of 100, 200, 300 and 400 mg of metoprolol CR/ZOK (a new controlled release preparation) in comparison with 100 mg dosages (od, bid, tid and qid, respectively) of conventional metoprolol tablets (CT). All studies were of randomized three-way crossover design with 7-day double-blind treatment periods separated by 7-day single-blind washout periods. A number of predose plasma concentrations and assessments of beta 1-blockade were made during the study and a full pharmacokinetic and pharmacodynamic study was performed on day 7. The maximal plasma concentration, Cmax, was significantly lower after metoprolol CR/ZOK compared to CT after all doses--the most pronounced difference being observed after the 100 mg dose when both preparations were given once daily (145 nmol/L vs 606 nmol/L) and the least difference after the 400 mg dose when metoprolol CT was given every 6 hours (837 nmol/L vs 1111 nmol/L). The maximal plasma concentration occurred later after metoprolol CR/ZOK than CT in all studies (median 2.5-4.1 hours vs 1.0-1.2 hours). The trough plasma concentration, Cmin, was significantly higher after 100 mg metoprolol CR/ZOK compared to CT dosed once daily; CminS were comparable between the two preparations in the 200 mg and 300 mg studies and lower after metoprolol CR/ZOK in the 400 mg study (278 nmol/L vs 469 nmol/L). In all four studies the AUCs were significantly lower after metoprolol CR/ZOK compared to CT with the mean relative bioavailability being approximately similar (73-84%). All metoprolol treatments produced a statistically significant beta 1-blockade (measured as percent reduction of exercise induced tachycardia) throughout the whole day compared to placebo except in the 100 mg study where the effect of once daily CT did not differ from placebo during the last 6 hours. Consequently, a significantly higher beta 1-blockade was observed after metoprolol CR/ZOK compared to CT in this latter period. The maximum beta 1-blockade (Emax) after CR/ZOK 100 mg was significantly lower than after CT 100 mg once daily (12.6% vs 23.3%) but when CT was given in divided doses from 200 to 400 mg daily, Emax did not differ between the two formulations. Once daily administration of 100 mg of both products resulted in a significantly higher beta 1-blockade 24 hours after dosing with CR/ZOK compared to CT, but when CT was taken in divided doses this difference between the treatments was less pronounced.(ABSTRACT TRUNCATED AT 400 WORDS)