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The pharmacokinetics of a single oral dose of 1.75 mg glibenclamide were studied in 15 healthy Caucasians including five poor metabolisers of debrisoquine and five poor metabolisers of S-mephenytoin. Plasma glibenclamide concentrations and the urinary concentrations of trans-4- and cis-3-hydroxyglibenclamide were analyzed by h.p.l.c. Thirty-six +/- 6% (mean +/- s.d., n = 15) of the given dose of glibenclamide was excreted in 48 h urine as hydroxylated metabolites, 27 +/- 4% as trans-4-hydroxyglibenclamide and 8 +/- 2% as cis-3-hydroxyglibenclamide. There were no differences in the plasma pharmacokinetics of glibenclamide or in the urinary excretion of the metabolites between poor and extensive metabolisers of debrisoquine, neither between the two mephenytoin hydroxylator phenotypes. The study thus indicates that the disposition of glibenclamide is not influenced by these two independent polymorphisms of drug oxidation.

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Eight patients aged 57-86 years with non-insulin-dependent diabetes mellitus (NIDDM) taking long-term glibenclamide treatment (5-15 mg/day) were given oral trimethoprim-sulphamethoxazole due to an acute bacterial infection. After 4-6 days of combined treatment, the total plasma glibenclamide concentrations were determined every second hour for 12 h, and the area under the curve (AUC) was computed. A second plasma glibenclamide profile was obtained 2-4 weeks after withdrawal of trimethoprim-sulphamethoxazole. The levels of plasma glibenclamide did not differ between the two occasions, nor did the simultaneously determined levels of blood glucose and plasma insulin. It is concluded that there is no consistent pharmacokinetic interaction between glibenclamide and trimethoprim-sulphamethoxazole in NIDDM patients.

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A selective and sensitive high-performance liquid chromatographic method for determination of intact glibenclamide in human plasma or urine has been developed. With glibornuride as internal standard, acid-buffered plasma or urine was extracted with benzene. The organic layer was evaporated and the residue was dissolved in equilibrated mobile phase (acetonitrile-phosphate buffer 0.01 M pH 3.5, 50:50). An aliquot of 20 microliters was chromatographed on a Spherisorb ODS reversed-phase column, and quantitation was achieved by monitoring the ultraviolet absorbance at 225 nm. The response was linear (0-1000 ng/ml) and the detection limit was 5-10 ng/ml in plasma or urine. The within-assay variation was less than or equal to 10%. No interferences from metabolites or endogenous constituents could be noted. The utility of the method was demonstrated by analysing glibenclamide in samples from diabetic subjects on therapeutic doses of the drug.

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The risks of drug contamination after transfer manipulations between vials used in admixture preparations were estimated. The transfers were performed inside a safety cabinet using sodium pertechnetate 99Tcm in saline as a 'model' admixture. An air contamination monitor was attached to the safety cabinet above the transfer manipulation area. The monitor filter and all utensils used were collected for measurement of contamination levels in each sample trial. Three types of transfer were performed; one 'open' procedure and two 'closed' procedures, one including an air vent needle in the receiving vial and the other without air vent needle in the receiving vial. The closed procedure including an air vent needle appears to combine good personnel- and product protection.

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A comparison was made of the effects of two intravenous regimens for postoperative total parenteral nutrition, namely, a conventional (control) regimen (group I) and a single-solution regimen of the same composition (group II). The effects examined were: hemoglobin concentration, prothrombin time, serum protein and electrolyte concentrations, and nitrogen and electrolyte balances. The 18 patients undergoing abdominal surgery were allocated at random to the two groups and the experiment was run for 3 days. During the day of the operation and the next 3 days both groups showed a decrease in the hemoglobin concentration and in the serum levels of iron, albumin, transferrin and cholesterol, while the asparagine aminotransferase increased. During total parenteral nutrition the prothrombin time and erythrocyte sedimentation rate increased in both groups. The nitrogen balance improved gradually in both groups and on the 3rd day was positive in group II. The calcium and magnesium balances indicated a higher retention and the phosphate balance a lower retention of these ions in group II than in group I. The urinary phosphate excretion rate during total parenteral nutrition decreased in both groups. This study indicates that the single-solution regimens used in intravenous nutrition caused no adverse metabolic effects and was used as efficiently as a conventional regimen in the early postoperative period.

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In 13 patients with maturity-onset diabetes mellitus which did not respond to diet therapy alone, serum concentration of glipizide, blood glucose (B-G) concentration, serum immunoreactive insulin (S-IRI) and plasma glycerol (P-G) were monitored hourly over 12 hours after placebo, an initial dose of glipizide (5 mg p.o.) and long-term treatment with glipizide (range 7.5--20 mg, mean 10.4), which produced fasting B-G of less than 8 mmol/l. During the long-term treatment, glipizide was given in a random, cross-over pattern, either as a single dose in the morning or as a three-part divided dose regime, in the same total daily amount. The duration of the immediate effects of glipizide on B-G, S-IRI and S-IRI/B-G was 9, 4.5 and 6.5 hours, respectively. The mean apparent half-life of glipizide was 4.1 hours, the mean distribution volume 0.13 l/kg and the mean plasma clearance 0.023 l/kg x h. The area under the concentration curve from 7.30 a.m. to 7.30 p.m. was 15% higher after the single dose regime. The serum levels of glipizide at 10 hours were only 30% lower than after the three-part divided dose regime. There were no significant differences between the single and divided dose regimes as regards B-G, S-IRI and S-IRI/B-G, although the mean B-G for the 12-hour period was somewhat lower after the former than after the latter (7.0 against 8.7 mmol/l).

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Sixty consecutive patients, 15-60 years old, with ANLL were divided randomly into three groups for induction treatment with one of the following regimens: R1, daunorubicin (DNR) 1.5 mg/kg on day 1 + ARA-C 2 mg/kg body weight on days 1-5; R2, DNR 1.5 mg/kg on days 1 and 2 + ARA-C 2 mg/kg on days 4-8; R3, DNR-DNA complex 1.5 mg/kg on days 1 and 2 + ARA-C 2 mg/kg on days 4-8. Maintenance treatment consisted of monthly courses of DNR 1.5 mg/kg (R1, R2) or DNR-DNA 1.5 mg/kg (R3) combined with ARA-C 1 mg/kg on days 1-5, alternating with thioguanine 2 mg/kg PO on days 1-5 combined with ARA-C 1 mg/kg IV on days 1-5. Fourteen patients of 20 went into complete remission with R1, 13 or 18 with R2, and 15 of 22 with R3. The overall remission frequency was 70% and there was no significant difference between the different groups. The median time in first remission and the median survival time were 300 and 510 days, respectively, with R1; 335 and 495 days with R2; and 295 and 677 days with R3. There was no statistically significant difference between the groups treated according to the different regimens concerning the time in first remission. Survival was slightly better with R3 than with R1. Treatment with the DNR-DNA complex caused less pronounced thrombocytopenia and fewer 'minor' cardiac abnormalities than treatment with free DNR in the same dosage schedule.

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Serum chlorpropamide concentrations (s-CPA) were determined and related to clinical findings in 83 outpatients with maturity onset diabetes. The daily doses of CPA (mg/kg) varied six-fold, but s-CPA ranged 18-fold between the patients. There was a significant correlation between dose and s-CPA (r = 0.61), which rose to 0.75 in the 30 patients who had prescribed no other drugs. Patients given other drugs concomitantly were over-represented amongst subjects with extreme values of apparent plasma clearance of CPA. There was no correlation either between serum creatinine or age and s-CPA. Of the 83 patients 40 (48%) had acceptable blood and urinary glucose values according to our criteria; but as 17 were overweight, only 23 patients (28%) had acceptable clinical control. Of the remaining 60 patients, too low a dose was being given to only 12, and dietary failure was the most probable explanation in the others. Thirteen patients (16%) probably did not need CPA. It is likely that this is a partial explanation for the high utilisation of oral antidiabetic drugs in Sweden. There was no general correlation between dose or s-CPA and blood glucose values, but analysis of s-CPA may still be of value in explaining unexpected changes in clinical control.

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The utilisation of hypnotics, sedatives, and minor tranquillisers (HSmT) was studied by means of drug-delivery and hospital occupancy statistics for 1975-1977 in a Swedish university hospital. A total of 0.53 so-called defined daily doses (DDD)/bed-day were delivered in 1975, implying that every second patient might have regularly been prescribed HSmT. The benzodiazepines were predominant with 71% of the deliveries. Five major drugs accounted for 88%. The drug pattern and the range of DDD/day-bed (0.09-1.18) differed considerably between the departments. Drugs not recommended by the hospital's Pharmacy and Therapeutics Committe accounted only for 3% of deliveries. In a drug surveillance study performed in two medical wards, HSmT were prescribed for 43% of 274 patients. Drug delivery and prescription data were in broad agreement. Drug information activities in the hospital had a clearly discernable influence on the delivered DDD/bed-day. This measure is an inexpensive indicator of drug utilisation in a hospital and a suitable basis for therapeutic audit.

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Forty-four adult patients under 60 years of age with acute nonlymphoblastic leukemia were randomized for induction treatment with one of the following three regimens: R 1 = courses of daunorubicin on day 1 + ARA-C on days 1--5; R 2 = courses of daunorubicin on days 1 and 2 + ARA-C on days 4--8; R 3 = courses of daunorubicin-DNA complex on days 1--2 + ARA-C on days 4--8. Out of 14 patients, 9 went into remission on R 1, 6 out of 14 on R 2, and 8 out of 16 on R 3. The preliminary results suggest that daunorubicin-DNA complex has the same efficacy for inducing remission as daunorubicin alone, if the same time intervals and dosages are used.

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