Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride (Amaryl) after intravenous administration.

Glimepiride is a new sulphonylurea which is eliminated by the formation of a hydroxy-metabolite (hydroxy-gli) and a carboxymetabolite (carboxy-gli). Animal studies have shown hydroxy-gli to exhibit some hypoglycaemic effects while carboxy-gli does not appear to have any pharmacological activity. Pharmacokinetic and pharmacodynamic effects of hydroxy-gli were assessed in humans. 12 healthy male volunteers received an intravenous injection of hydroxy-gli (1.5 mg) or placebo in a single blind, randomised, cross-over study. Samples were collected for up to 24 hours (blood) or 48 hours (urine) following administration of hydroxy-gli or placebo. Hydroxy-gli significantly decreased the minimum serum concentration (Cmin) of glucose by 12% and the average serum glucose concentration over the first four hours of treatment (Cavg0-4) by 9% compared with placebo (P < or = 0.05). In addition, maximum serum C-peptide concentration (Cmax) and Cavg0-4 were both increased by 7% after hydroxy-gli (p < or = 0.05). Serum insulin concentrations (Cmax and Cavg0-4) increased by 4% but the differences from placebo were not statistically significant. No adverse events were reported during the study. In conclusion, the hydroxymetabolite of glimepiride shows pharmacological activity in human subjects.

Absolute bioavailability of glimepiride (Amaryl) after oral administration.

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.

Dose linearity assessment of glimepiride (Amaryl) tablets in healthy volunteers.

Twelve healthy fasting male volunteers received glimepiride in 1, 2, 4 or 8 mg single oral doses. On the days when glimepiride was taken, the subjects were given a standardised carbohydrate diet (18 bread exchange units) and drank 125 ml of water hourly. Blood and urine samples were taken before drug administration and afterwards for up to 36 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). The areas under the curve for glimepiride after oral doses of 1 to 8 mg and the urinary recovery of its metabolites M1 and M2 were dose linear. All confidence intervals were well contained within the bioequivalence range of 80-125%. There was a statistically significant difference for Cmax values of glimepiride between doses after dose normalisation. A dose-dependent increase for Cmax was nevertheless clearly observed with a correlation coefficient of r=0.90. The pharmacokinetics of glimepiride are dose linear in the dose range 1 to 8 mg, and glimepiride was safe and well tolerated in healthy volunteers.

Dose relationship of stimulated insulin production following intravenous application of glimepiride in healthy man.

This study evaluates stimulated insulin production rate (incremental AUC x MCR (metabolic clearance rate) of C-peptide) and blood glucose (BG) response after i.v. administration of glimepiride (Hoe 490, GLI, CAS 93479-97-1) (0.25, 0.50, 0.75, 1.00, 1.25, 1.50 mg) in healthy man (27 +/- 4 yrs). It was shown that i.v. bolus administration of GLI (0.25, 0.50, 1.25 and 1.50 mg) caused a dose-related rise in insulin production from 18 +/- 17 to 25 +/- 13, 36 +/- 14 and 54 +/- 34 pmol/kg body weight, respectively. This effect did not yet plateau at 1.5 mg GLI and was paralleled by a fall in BG (decremental area below BG baseline) by 40 +/- 36, 69 +/- 20, 161 +/- 47 and 113 +/- 62 mmol.min/l. It is concluded that insulin release is increased by i.v. GLI in a dose related manner, while a parallel decline in BG was induced only up to 1.25 mg GLI. The less marked fall of BG after injection of 1.50 mg GLI may reflect interference by insulin-counterregulatory hormones secondary to induced hypoglycaemia.

Safety, tolerance and pharmacokinetics of cefpirome administered intramuscularly to healthy subjects.

The pharmacokinetics of cefpirome were studied in healthy male subjects following single (0.5, 1.0 and 2.0 g) and multiple (1.0 g every 12 h for 3.5 days) intramuscular injections. High pressure liquid chromatography was used to determine cefpirome concentrations in plasma and urine. Cefpirome was absorbed rapidly, mean peak times were 1.6-2.3 h. Pharmacokinetics were linear over the 0.5 to 2.0 g range with mean total body clearance ranging from 148 to 154 mL/min. The peak plasma concentration and area under the curve increased in a dose proportional manner. The terminal half-life (2 h) was not influenced by dose or duration of dosing. There was no drug accumulation after multiple in administrations. About 70-80% of an administered dose was excreted in the urine as unchanged cefpirome. Cefpirome was well tolerated, slight to moderate pain being reported in less than 30% of the injections.

Influence of cefpirome on pharyngeal and faecal flora after single and multiple intravenous administrations of cefpirome to healthy volunteers.

The effect of single and multiple 2 g doses of i.v. cefpirome on pharyngeal and faecal flora was studied in ten male volunteers. There was no effect on pharyngeal flora. After a single dose, cefpirome had no effect on faecal flora but numbers of Escherichia coli were reduced below the detection limit during multiple dose treatment. No strains of Clostridium difficile were selected in this study and only a slight increase in the numbers of Candida spp. were found. Cefpirome, therefore, has little, if any, effect on faecal or pharyngeal flora.

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.

Effects of HOE 760 (histamine H2-receptor antagonist) on diazepam pharmacokinetics.

A double-blind cross-over study of the effects of HOE 760 (histamine H2-receptor blocker) on diazepam pharmacokinetics was conducted in 12 healthy men. HOE 760 or placebo was given daily for 12 days and, after a wash-out period of 9 days, the alternate medication was given for 12 days. Diazepam 10 mg was given intravenously on day 6 of each of the 12-day periods. Blood was taken up to 1 week after the diazepam injections for assay of diazepam and desmethyldiazepam. The co-administration of HOE 760 did not affect the pharmacokinetics of diazepam and desmethyldiazepam.

Dose linearity testing of intravenous ofloxacin, a novel gyrase inhibitor.

After intravenous bolus injection of single doses of 25, 50, 75 and 100 mg of ofloxacin (HOE 280) to 34 healthy male volunteers, concentrations of unchanged drug were estimated at various times in serum and urine over 32 and 48 h. Ofloxacin concentrations were determined using high-pressure liquid chromatography (HPLC). A linear relationship between dose and Cmax (r = 0.91), AUC0-32 (r = 0.95), AUC infinity (r = 0.96) and urinary recovery (r = 0.98) was demonstrated for the doses tested (25-100 mg). The biological half-life (t1/2,beta was determined by fitting a two-compartment open model to the data: t1/2,beta was about 4.5-5.1 h (HPLC, mean values) and was not dose-dependent. Clinically relevant high concentrations of unchanged ofloxacin were detected in urine after the lowest dose (25 mg) for about 24 h, and after the highest dose (100 g) for at least 36 h. General tolerance was good. A slight transient drop in blood pressure was seen after 25 mg in one case; in another, local venous irritation and later restlessness were observed after 75 mg. No specific countermeasures, except for a saline injection into the vein, were needed. All volunteers completed the study as planned.

Safety, tolerance and pharmacokinetics of 2.0 g cefpirome (HR 810) after single and multiple dosing.

After intravenous injection of a single dose of 2.0 g cefpirome (HR 810) and multiple doses of 2.0 g b.i.d. (11 doses) to 10 healthy male volunteers in an open design, concentrations of unchanged drug were measured at various times in serum and urine over 24 and 96 h, respectively. Cefpirome concentrations were determined using high-pressure liquid chromatography (HPLC). The biological half-life (t1/2, beta) found by fitting a two-compartment open model to the data was 2 h. No accumulation of the serum levels could be detected during the multiple-dose phase. Urinary concentrations of unchanged cefpirome effective against most clinically relevant bacteria were detected for at least 36 h. The drug was safe and well tolerated. No drug-related changes were observed for blood pressure, heart rate, ECG, haematology, clinical chemistry or urinalysis, including beta 2-microglobulin in serum and creatinine clearance.

The effects of forskolin eye drops on intra-ocular pressure.

Two studies were performed to investigate the effects of forskolin (Hoechst Research) on intra-ocular pressure (IOP). In the first study two 1.0% formulations of forskolin eye drops were compared with placebo in 10 healthy volunteers. Oxybuprocaine eye drops were used for local anaesthesia before measurement of IOP by applanation tonometry. This was followed by instillation of either medication or placebo on a randomised cross-over basis and hourly measurement of IOP. No significant differences were present between the forskolin treatments and placebo. For 6 hours after drug application a definite decrease in IOP relative to base-line values was observed after each of the forskolin treatments as well as after placebo. In a subsequent study only one formulation of 1% forskolin was compared with placebo. Proxymetacaine eye drops were used for local anaesthesia. Forskolin resulted in a significant reduction in IOP relative to placebo. It is concluded that forskolin reduces IOP in healthy volunteers, and that oxybuprocaine reduces IOP in its own right.

Pharmacokinetics of ramipril in the elderly.

Ramipril (HOE 498) is a pro-drug of which the main metabolite (HOE 498 diacid or ramiprilat) is a potent angiotensin converting enzyme inhibitor. Thirteen healthy white volunteers (5 females and 8 males, ages 65 to 76 years) participated in a study to investigate the pharmacokinetics of HOE 498 in the elderly. After administration of 10 mg of HOE 498, sequential urine and serum specimens were obtained for assay of HOE 498 and metabolites (HOE 498-glucuronide, diacid, diacid-glucuronide, diketopiperazine and diketopiperazine acid). Side effects, clinical chemistry and hematology were monitored. HOE 498 reached peak concentrations of 62.4 +/- 23.3 ng/ml in serum after 0.7 +/- 0.3 hours. Serum levels decreased with an apparent half-life of 0.9 +/- 0.4 hours. The diacid was rapidly formed in serum, reaching peak concentrations of 40.6 +/- 14.0 ng/ml after 2.0 +/- 0.6 hours and declining with a half-life of 2.2 +/- 0.5 hours. A prolonged terminal phase of serum concentration versus time curve was observed at concentrations less than 1 ng/ml. The mean recovery of HOE 498 and metabolites in urine, up to 26 hours after administration, was 35 +/- 14% of the dose. The apparent half-lives, calculated from urine parameters, for HOE 498 and the diacid were 2.6 +/- 0.9 and 4.0 +/- 1.1 hours, respectively. The mean peak concentration and half-life of HOE 498 in serum are slightly higher in the elderly than in younger volunteers. Complete urinary collection was not possible, but urinary recovery did not seem different from younger volunteers.

The effects of metamizol on prostaglandin synthesis in man.

Clinical pharmacological investigations on the inhibition of prostaglandin synthesis are presented, comparing metamizol and indomethacin with respect to platelet aggregation, platelet thromboxane synthesis, total body PGE2-synthesis and side effects. Prostaglandin synthesis is clearly and persistently inhibited by metamizol in man.

[Effect of forskolin eyedrops on intraocular pressure in healthy males]. / Uber die Wirkung von Forskolin-Augentropfen auf den Augeninnendruck gesunder männlicher Personen.

Suspensions of Forskolin in concentrations of 0.3; 0.6; and 1.0% decreased effectively the intraocular pressure of healthy subjects when instillated in the conjunctival sac. The suspensions were compared with placebo in double blind studies. The maximum effect was reached 3 hours after application of the 0.3% (22.8%) and 0.6% (27.8%) suspensions and 4 hours after the 1.0% (26.5%) suspension. The higher concentrations decreased the intraocular pressure to the same extent as the lowest concentration but the effect lasted longer: 4 hours after instillation of the 0.3% suspension, 5 hours after instillation of the 0.6% suspension and 7 hours after the 1.0% suspension. The suspensions were well tolerated. Subjective sensations like burning, itching and augmentated lacrimation were observed only in a minor amount and for a short period of time.

Pharmacokinetics and biotransformation of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498) in rat, dog and man.

After oral administration, 2 mg/kg in rat and dog, 10 mg in man, of the carbon-14-labeled angiotensin I converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498), absorption (rat 56%, dog 43%, man 56%) occurred rapidly and induced maximum blood levels between 0.25 and 1 h. The radioactivity disappeared from the blood in one or two phases with half-lives of 0.6 h in the rat, 1/3.8 h in dog and 0.5/2.9 h in man. Studies in rats have shown that the radioactivity is distributed rapidly to all tissues. Markedly higher concentrations than in the blood were found in the liver, kidneys, and particularly in the lungs. The elimination from the lungs, which showed the highest concentrations until 5 d after administration, occurred with a half-life of 63 h. In rats, 26% of the dose was excreted with the urine and 71% with the feces. About one third of the dose was eliminated with the bile and about 13% was reabsorbed from the bile. The excretion in the breast milk of rats was low. Placental transfer in pregnant rats was low and transient. The radioactivity recovered from the urine of dogs amounted to 15%, that recovered from the feces amounted to 79%. In man, 56% of the radioactivity was excreted with the urine and less than 40% with the feces. Whereas in rat urine one metabolite dominates, the metabolite patterns in urine and serum/plasma of man and dog - which are very much alike - reveal a different biotransformation with three main metabolites. Unchanged Hoe 498, as well as its dicarboxylic acid and other metabolites appear only in low concentrations in this pattern.

A radioimmunoassay for determination of glibenclamide and other sulfonylureas.

An antiserum was prepared for the determination of glibenclamide and for the estimation of other commercially available sulfonylureas. Rabbits were immunized with a glibenclamide-BSA conjugate. Tritiated glibenclamide was used as the tracer. The assay was performed in the presence of 8-anilinonaphthalenesulfonic acid to displace glibenclamide bound to serum protein, and free and antibody bound tracer were separated by dextran-coated charcoal. For glibenclamide determination in serum and plasma the limit of detection was 3 ng/ml. Sensitivity calculated for the whole determination range was 102 cpm for a 10 % concentration difference. Specificity studies showed a cross-reaction of less than 0.1 % for glibenclamide metabolite M1 and 9 % for metabolite M2. Other sulfonylurea drugs display cross-reactivities from 0.1% (chlorpropamide) to 190% (gliquidone). Both intra-assay and inter-assay imprecision were below 10 %. Accuracy was established by comparison of the present method with HPLC. The assay was applied to the specific determination of glibenclamide in clinical trials and for diagnosing factitious hypoglycemia caused by sulfonylureas.

Bioavailability and pharmacodynamics of a sustained-release glibenclamide product (Deroctyl) in comparison to a standard tablet formulation (Euglucon, Daonil).

Pharmacodynamics and tolerance, as well as the bioavailability of two oral dosage forms of 5 mg glibenclamide were determined in eight healthy male volunteers in a double-blind crossover study. These preparations were Euglucon (regular tablets) and Deroctyl (sustained-release capsules). Blood glucose levels were determined by the hexokinase method and serum glibenclamide, insulin, and C-peptide levels by radioimmunoassay. Following Deroctyl both the rate and extent of absorption of glibenclamide and therefore its serum levels were much lower than that observed after the same dose of Euglucon. The differences between Cmax, AUC0-4, AUC0-8, and AUC0-24 were statistically significant. For glucose, only Cmin values were found to be significantly lower following Euglucon. For insulin AUC0-8 and AUC4-8 values and for C-peptide AUC0-4 and AUC0-8 values were found to be significantly greater following Euglucon. A single oral dose of either preparation was well tolerated and no side effects occurred. It is concluded that Derocytl is not bioequivalent to Euglucon: its relative bioavailability is only 62.5% (AUC0-24).

Kinetics of UV-erythema in normal subjects.

In the expanding field of clinical dermatopharmacology we standardized an erythema model for testing drugs with effects on UV-induced inflammation in normal male Caucasian subjects. Using a light source with fibre-optic transmission and precise radiation characteristics, some of the shortcomings of conventional UV-application could be overcome. The radiation geometry during the various experiments was kept constant by a tube, permitting a defined area of exposure. Up to eight skin areas of the backs of normal volunteers were radiated with 86.2% UV-A and 13.8% UV-B. After exclusion of hyporeactive and hyperreactive subjects a good intrasubject reproducibility was obtained repeatedly over at least 3 months. According to the definition of bioavailability, our method allows the measurement of the rate and extent of UV-induced erythema. This model has been used for testing topical steroids, non-steroidal antiphlogistics in a variety of pharmaceutical formulations.