ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man.

ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose-related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose-dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half-life of 2.34 (s.e. mean 0.16) h and mean disposition half-life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti-Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.

Effects of single and multiple doses of ketoconazole on adrenal function in normal subjects.

The plasma cortisol response to 0.25 mg tetracosactrin given by intramuscular injection was suppressed by nine oral doses of 200 mg ketoconazole given 12 hourly to nine normal female subjects. No effect was noted following a single 200 mg oral dose of ketoconazole. This suppressive effect was reversible within at least 5 days of discontinuation of ketoconazole.

Pharmacokinetic investigation of the absorption of oxprenolol from Oros delivery systems in healthy volunteers: comparison of in vivo and in vitro drug release.

The absorption kinetics of oxprenolol have been investigated in eight healthy volunteers after single dosing with 16/260 Oros drug delivery systems. Oxprenolol disposition kinetics in individual subjects were estimated from intravenous dose data. Loo-Riegelman analysis of the plasma concentration data indicated an extended duration of drug absorption for the Oros system. Initially, the in vivo absorption rate was similar to the in vitro release rate but after 5-6 h it slowed perceptibly. However, at later times similar in vivo and in vitro rates were again observed. The absolute bioavailabilities for prototype and clinical trial systems were shown to be similar, at approximately 42%, and no significant differences in plasma profiles or pharmacokinetic constants were detected between the two Oros forms. A comparison of plasma concentration data in seven subjects who received the prototype system on two occasions in separate studies indicated a consistent level of drug absorption from this preparation. Approximately 10-15% of the administered dose was found in Oros systems recovered from faeces. The quantity of drug remaining was poorly correlated with the observed areas under the plasma concentration-time curve.

Pharmacokinetics and bioavailability of sultamicillin estimated by high performance liquid chromatography.

Sultamicillin is an orally absorbed double ester of sulbactam (penicillanic acid sulphone, a semisynthetic inhibitor of the beta-lactamases of many Gram-positive and Gram-negative species) and ampicillin. First-pass hydrolysis of this prodrug liberates equimolar proportions of sulbactam in plasma, saliva and urine is described and was used to determine the absolute bioavailability of sulbactam and ampicillin from sultamicillin in six normal male volunteers who each received a single 750 mg oral dose of sultamicillin or an iv dose of the equivalent amounts of ampicillin (441 mg) and sulbactam (294 mg). Treatments were given in random order with not less than four days intervening. The mean peak plasma concentrations and time to peak of sulbactam and ampicillin following the 750 mg oral half lives, systemic and renal clearances for sulbactam and ampicillin were similar. The bioavailability for both drugs from sultamicillin as estimated from both plasma and urine pharmacokinetics was better than 80%. We conclude that sultamicillin is an extremely efficient prodrug for ampicillin and sulbactam and that the HPLC assay method is accurate, rapid and easier to perform than the differential microbiological assay.

Effect of pirprofen on glibenclamide kinetics and response.

Pirprofen (a new non-steroidal anti-inflammatory agent), 200 mg 8 hourly, or placebo was administered orally to eight normal volunteers to investigate its effect on the pharmacokinetics and glucose and insulin responses after 1 mg i.v. glibenclamide. No significant changes were produced in these measures and in vitro studies showed no displacement of glibenclamide by pirprofen from plasma protein binding.

Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay.

A simple high performance liquid chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10-500 microgram/l and the minimum level of detection was 2 microgram/l. Within-assay coefficients of variation were 11.6% (20 microgram/l); 5.3% (50 microgram/l); 6.8% (100 microgram/l); between-assay coefficients of variation were 8.4% (20 microgram/l); 4.7% (50 microgram/l) and 7.4% (100 microgram/l). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47 +/- 0.42 h (SD) and no evidence for a non-linear beta-phase or slowly equilibrating 'deep' compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78 +/- 29 ml X h-1 X kg-1 and the apparent volume of distribution in the beta-phase was 155 +/- 44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.

Pharmacokinetics of single doses of sulphinpyrazone and its major metabolites in plasma and urine.

1 High pressure liquid chromatographic assays for the estimation of sulphinpyrazone and its sulphide, sulphone and p-hydroxy metabolites in plasma and urine are described. 2 Five normal volunteers received 200 mg and 400 mg sulphinpyrazone orally. Sulphinpyrazone was rapidly absorbed and eliminated with a half-life of approximately 4 h irrespective of dose. Peak plasma concentrations and area under the plasma concentration-time curves (AUC) were consistent with linear pharmacokinetic behaviour. 3 Plasma concentrations of the sulphone were low and peaked before those of the sulphide; its mean half-life was 3.1 h. The sulphide, which may be the sulphinpyrazone metabolite with activity on platelets, was eliminated with a mean half-life of 13.4 h. The AUC increases with dose of both metabolites suggested non-linearity. 4 Approximately 45-50% of the administered dose was eliminated in the urine as unchanged drug or as sulphone or p-hydroxy-sulphinpyrazone. The sulphide metabolite was not detected in the urine. The renal clearance of sulphinpyrazone was approximately 18 ml min-1 and that for the sulphone was similar. Sigma minus plots of the urinary excretion yielded half-lives of 3.5 h for the sulphone and 1 h for p-hydroxy-sulphinpyrazone.

A study of repeated administration of fenbufen in patients with chronic rheumatic disorders and renal impairment.

Male and female patients suffering from rheumatoid arthritis with normal renal function or with renal impairment were treated in hospital with 300 mg of fenbufen 8 hourly for fourteen days. Concentrations of fenbufen and its principal metabolites were measured by high pressure liquid chromatography on days 0, 7, 10 and 14 and also four days after discontinuation of the drug. Renal impairment does not produce cumulation of either fenbufen or its major metabolites in the plasma. The metabolite profile of the drug was similar to that observed in patients with normal renal function.

Bioavailability of phenylbutazone from a new enteric-coated formulation with superior dissolution characteristics.

The bioavailability of an improved formulation of enteric-coated phenylbutazone with faster dissolution, more consistent in vitro rate of drug release and improved stability was compared in 8 normal subjects at doses of 100 and 200 mg with commercially available Butacote. Phenylbutazone was more rapidly absorbed from the new formulation and higher plasma concentrations were achieved at shorter intervals after dosing. Drug elimination rate was unaffected by reformulation and despite faster absorption the total amounts of drug reaching the circulation from the new and commercial products were similar. It was concluded that replacing Butacote by the new formulation would provide the same therapeutic benefit.

Plasma mexiletine concentrations following combined oral and intramuscular administration.

Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil--for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75-2 microgram/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.

Kinetics of single doses of fenbufen in patients with renal insufficiency.

Fenbufen (gamma-oxo[1,1'-biphenyl]-4-butanoic acid) is a nonsteroidal anti-inflammatory analgesic that is metabolized to four major metabolites: gamma-hydroxy [1,1'-biphenyl]-4-butanoic acid (II), [1,1'-biphenyl]-4-acetic acid (III), 4'hydroxy [1,1'-biphenyl]-4-acetic acid (IV), and gamma, 4'-dihydroxy [1, 1'-biphenyl]-4-butanoic acid (V). Fenbufen and metabolites II and III circulate to plasma and are pharmacologically active; metabolites IV and V are normally excreted in urine. Single 800-mg doses of fenbufen were safely administered to 10 healthy subjects and to 16 patients with varying degrees of renal insufficiency. Drug and metabolite concentrations in serum and urine were determined at intervals for 3 days. It was found that renal impairment altered the metabolic pattern of fenbufen. Although t1/2 beta was the same for fenbufen and II, their plasma levels fell. No change was found in the plasma levels of III. There was evidence of moderate cumulation in plasma of the two more polar urinary metabolites (IV, V) corresponding to the degree of renal insufficiency. The total of all five compounds excreted into the urine was diminished. To account for this, either biliary and gastrointestinal excretion increased or there may have been further hepatic biotransformation of the metabolites.

Bencyclan: a new drug with unusual membrane stabilising properties in erythrocytes.

Bencyclan, a drug recently introduced to treat peripheral circulatory disease, has been shown to stabilise human erythrocytes in hypotonic saline. Two peaks of maximum stabilisation are present: at 10(-5)--10(-4) M and at 10(-3) M drug concentration.

The influence of aromatic amines and folate on acid production by Escherichia coli.

Folinic acid, adrenaline and noradrenaline, substances known to stimulate oxygen consumption by E. coli, are shown in this experiment to do so by different mechanisms. This work demonstrates stimulation of acid production by folinic acid and inhibition by adrenaline and noradrenaline.