Pharmacokinetics of graded oral doses of sulindac in man.

Pharmacokinetics of graded doses of sulindac were studied on 9 healthy volunteers. Serum concentrations of sulindac (inactive prodrug), sulindac sulfide (active metabolite) and sulindac sulfone (inactive metabolite) were measured both after a single dose of 150 mg, 175 mg or 200 mg and on the 6th and 7th days after b.i.d. administration of the same doses. The peak and minimum concentrations of sulindac were practically not dependent on the dose. The concentration-time curves remained similar after a single dose and after the repetitive dosing. On the contrary, both sulindac sulfide and sulfone gave about twice as high serum levels at steady-state as after a single dose. As judged from several pharmacokinetic parameters, a dose of 150 mg gave significantly smaller values than the higher doses but there was no significant difference between 175 mg and 200 mg in sulindac sulfide and sulfone concentrations. The average half-lives of sulindac, sulindac sulfide and sulfone were 1.7 -4.2 h, 15.3-16.1 h and 16.6-19.6 h, respectively. Both sulindac sulfide and sulfone tended to accumulate at a repetitive dose of 200 mg. The appropriate dose of sulindac appears to be 175 mg twice daily.

Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route.

Serum kinetics of metronidazole and tinidazole were compared in four separate randomized crossover studies. Single doses of each drug were given to healthy volunteers through intravenous infusion (500 mg over 20 min, six persons), by mouth (500 mg, nine persons), by rectum (1,000 mg, six persons), or intravaginally (500 mg, six persons). Concentrations of the unchanged drugs in serum, measured by high-pressure liquid chromatography, were similar after oral and intravenous administration, with mean peaks of 9.0 and 9.4 micrograms/ml for metronidazole and 7.5 and 10.1 micrograms/ml for tinidazole. Concentrations of tinidazole were significantly higher than those of metronidazole from 4 h onwards after intravenous infusion, and from 3 h onwards after administration by mouth. After rectal administrations, a significant difference was seen only at 48 h. After vaginal dosing, however, concentrations of metronidazole were significantly higher than those of tinidazole between 1.5 and 12 h. Bioavailability of either drug, calculated according to the formula (area under the curve for oral administration)/(area under the curve for infusion), was practically complete after oral administration and was poorer after rectal and especially vaginal administration. Whenever the parameters were calculable, the elimination half-life of tinidazole (range of means, 14.0 to 14.7 h) was significantly longer and total clearance (40.3 to 47.6 ml/min) was lower than the corresponding values of metronidazole (7.9 to 8.8 h and 71.8 to 80.1 ml/min, respectively).

Uninterrupted prolonged ethanol oxidation as a main pathogenetic factor of alcoholic liver damage: evidence from a new liquid diet animal model.

Marked fatty infiltration and degenerative or mild inflammatory changes including eosinophilic cytoplasmic degeneration in centrilobular cells and focal inflammatory changes with cell necrosis were observed in livers of rats maintained for 12 weeks on a nutritionally adequate and balanced liquid ethanol diet. The animals continuously oxidized ethanol due to the supplementation of the diet with a low dose of 4-methylpyrazole (4-MP, an alcohol dehydrogenase inhibitor), that decreased ethanol elimination by about 20%. In other, equicalorically pair-fed groups of rats receiving (a) a similar ethanol-containing liquid diet without 4-MP or (b) a diet with 4-MP and 20% less ethanol, only a few minor changes were seen. The liver histology of rats pair-fed a control diet with a 4 times higher doses of 4-MP was completely normal. The results indicate that the prolonged imbalance of hepatic metabolism due to the uninterrupted oxidation of ethanol is a crucial factor in the development of alcoholic liver injury.

Pharmacokinetic interactions of timolol with vasodilating drugs, food and phenobarbitone in healthy human volunteers.

Pharmacokinetic interactions of oral timolol maleate 10 mg, with food (3566 kJ), single oral doses of prazosin 1 mg and dihydralazine 25 mg, and with a 1 week pretreatment with phenobarbitone 100 mg daily were examined in a randomized crossover study in 12 healthy volunteers. After fasting, the peak level (Cmax = 29.1 +/- 3.2 ng/ml; mean +/- SEM) was reached at 1.3 +/- 0.1 h (Tmax). The total area under the serum concentration-time curve (AUC0-infinity) was 154.4 +/- 33.8 ng x h/ml, total clearance (Cltot) 751.5 +/- 90.6 ml/min, renal clearance (Clren) 97.2 +/- 10.1 ml/min, elimination half-life (t1/2) 2.9 +/- 0.3 h and 24-h recovery in urine (X0u-24) 11.1 +/- 1.4% of the dose. Food and prazosin did not significantly affect the fate of timolol maleate. Dihydralazine enhanced Cmax (38.2 +/- 4.6 ng/ml) only when compared to phenobarbitone treatment, and did not affect any other parameters. Phenobarbitone pretreatment somewhat lowered Cmax (25.5 +/- 3.9 ng/ml), AUC0-infinity (117.5 +/- 22.1; p less than 0.05 vs food) and X0u-24 (8.7 +/- 1.2%), evidently by increasing Cltot (957.5 +/- 116.9 ml/min; p less than 0.05 vs food), but it did not affect Clren. It is concluded that the pharmacokinetics of timolol maleate can be altered to a limited extent in opposite directions by dihydralazine and phenobarbitone.

Effect of acetylsalicylic acid on plasma thromboxane B2 and platelet aggregation in man.

The effect of acetylsalicylic acid (ASA) on plasma thromboxane A2 (TXA2) and platelet aggregation was studied in 12 healthy, non-smoking, male students, in a double-blind, cross-over study, after single doses and 14-days on ASA 50, 100, 250 and 1000 mg/day. Platelet production of TXA2 was assessed by measuring the thromboxane B2 (TXB2) content of clotted venous blood by RIA. Platelet aggregation induced by ADP and adrenaline was studied by the method of Born. All doses of ASA completely suppressed the production of TXB2 within 3 h, with the exception of the 50 mg dose, which effected only 61% suppression (p less than 0.001). After administration for 14 days the suppression was complete, even including the lowest dose. At that time ASA had blocked the secondary phase of adrenaline- and ADP-induced platelet aggregation. It is concluded that the maximal antithromboxane and antiaggregatory effects, which last for at least 24 h, can be achieved by continuous daily administration of ASA 50 mg.

Penetration of metronidazole and tinidazole into the aqueous humor in man.

500 mg of metronidazole or tinidazole were given as a 20-min infusion each to 10 patients who were hospitalized for elective cataract extraction. Metronidazole and tinidazole concentrations in aqueous humor were 5.2 +/- (SE) 0.5 and 5.3 +/- 0.7 micrograms/ml, respectively, 20-70 min after the end of the infusion. Aqueous humor/serum concentration ratios were 0.38 and 0.47 on the average for metronidazole and tinidazole, respectively.

The pharmacokinetics of metformin: a comparison of the properties of a rapid-release and a sustained-release preparation.

The pharmacokinetic differences between a rapid-release metformin preparation of 500 mg (RRM) and a sustained-release metformin preparation of 500 mg (SRM), whose gastrointestinal side effects may be less, were compared after a single dose and after continuous 5-day use during a steady-state phase. In the single-dose trial the mean peak serum level of 1.00 micrograms/ml from RRM and 0.61 micrograms/ml from SRM were reached at 3 h, and at 3 and 4 h, respectively, after ingestion of the drugs. Serum metformin levels from RRM were consistently higher up to 8 h, and the AUC0-8h value for RRM was from 4.25 and 2.49 for SRM (p less than 0.001). Over a 24-h period 40% of the given dose was recovered in urine from RRM. The value for SRM was 25%. The elimination half-life was 2.0 h for RRM and 2.6 h for SRM. During the steady-state trial the mean basal serum metformin concentration was higher after SRM (0.33 micrograms/ml) than after RRM (0.20 micrograms/ml), although the mean peak serum metformin level remained lower after SRM. On the 5th day the AUC0-8h values obtained after RRM and SRM were comparable (6.88 vs 6.59; N.S.).

Pharmacokinetics and tolerance of slow-release indomethacin tablets in rheumatoid arthritis.

The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (tmax 3.7 h and less than 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.

Impairing effect of food on ketoconazole absorption.

Single oral doses of ketoconazole (200 mg) or miconazole (250 mg) were given in a randomized cross-over study to 10 healthy volunteers. Ketoconazole with administered (i) after fasting (both brand 1 [Orion Pharmaceutical Co.] and brand 2 [Janssen Pharmaceutica] were tested), (ii) after a standardized meal (660 kilocalories; 2,772 kJ) (brand 1), and (iii) with 300 ml of orange juice (pH 3.8) (brand 1). Miconazole was administered after fasting. Venous blood samples for high-performance liquid chromatography determinations of ketoconazole and gas chromatographic analyses of miconazole were drawn periodically up to 24 h. The concentrations of ketoconazole in sera attained with the two brands were not statistically different. The peak concentrations of ketoconazole attained with brand 1 were 4.1 +/- 0.3 micrograms/ml (mean +/- standard error of the mean) after fasting, 2.3 +/- 0.3 micrograms/ml after the standardized meal (P less than 0.01), and 3.6 +/- 0.2 micrograms/ml with orange juice. The peak concentrations were reached in 1.4, 2.3 (P less than 0.05), and 1.8 h, respectively, whereas the areas under the serum concentration-time curves were 14.4 +/- 2.21, 8.6 +/- 1.33 (P less than 0.05), and 13.4 +/- 1.30 micrograms.h/ml, respectively. The half-lives (1.7 to 2 h) did not vary significantly among the different regimens. Compared with ketoconazole, oral absorption of miconazole was poor (peak concentration, 0.47 +/- 0.7 micrograms/ml; time to reach the peak concentration, 2.6 h; area under the serum concentration-time curve, 1.10 +/- 0.20 micrograms.h/ml).

Tolerance and serum levels of haloperidol during parenteral and oral haloperidol treatment in geriatric patients.

Eleven geriatric chronic psychotic hospital patients were treated with monthly intramuscular haloperidol decanoate injections for 5 months. The first and second haloperidol decanoate dose was 20 times and thereafter 15 times the "optimal" oral haloperidol dose. The serum haloperidol concentrations were fairly stable during the whole month following parenteral administration. After the second and third injection the concentration was about twice as high as during oral treatment. No clinically significant changes were established in routine haematological or biochemical laboratory tests studied during the trial. No significant changes in serum prolactin levels were observed after parenteral haloperidol compared to the levels during oral treatment. No local or systemic side effects were observed during the trial. The psychiatric status of the patients was fairly constant during the whole study. Haloperidol decanoate was thus shown to be therapeutically effective and it can be administered safely to geriatric patients.

Pharmacokinetics of diazepam administered rectally in geriatric patients: comparison of suppositories with rectal tubes in a cross-over study.

The pharmacokinetics of diazepam administered as suppositories or as a solution in rectal tubes were compared in six geriatric hospital patients. A single dose of 10 mg was administered in a cross-over study with a one week interval. There was no statistically significant difference in the bioavailability, the mean maximum serum concentration or the time of achievement of the maximum with these preparations. However, the peak serum concentration was somewhat higher with suppositories but the absorption was somewhat faster via rectal tubes. The serum N-desmethyldiazepam concentration increased during the whole 24 hour observation period, there was no difference between the preparations. Our results are in good agreement with most studies of the pharmacokinetics of diazepam. The basal substance of the suppository is of the utmost importance to the absorption of diazepam. The rectal tube for administration of diazepam did not have any advantage over the optimally formulated (a mixture of macrogols) suppository in geriatric patients. In fact, the use of rectal tubes is more expensive, the tube may not be completely emptied, and the solution may not be completely retained in the rectum.

Efficacy and side effects of lorazepam, oxazepam, and temazepam as sleeping aids in psychogeriatric inpatients.

The efficacy and side effects of 2 mg of lorazepam, 30 mg of oxazepam, and 20 mg of temazepam as sleeping aids were investigated in 20 psychogeriatric inpatients. The drugs were administered in a random order, double-blind, for 7 night each. All of these short half-life benzodiazepines proved efficacious in maintaining sleep. None of them reduced initial sleep latency. Oxazepam and to a lesser degree temazepam induced withdrawal insomnia during the first night after the treatments. The withdrawal of lorazepam induced a delayed but prolonged insomnia in 3 patients. Both lorazepam and oxazepam had muscle relaxant side effects after awakening.

The effect of protein-binding on the excretion of three sulphonamide preparations in the milk of dairy cows, examined by chemical and microbiological methods.

The relationship between the protein-binding of sulphonamides and their excretion in the milk of dairy cows was studied using three preparations commercially available in Finland. After a preparations containing sulfadiazine and sulfadimidine was given intravenously to dairy cows the drugs were excreted into milk to a greater extent than in the case of sulfamethoxypyridazine and especially of sulfaphenazole given similarly. An inverse relationship was found between the degree of protein-binding in the serum and the excretion into milk. The antimicrobially active concentrations of sulphonamides in serum and milk persisted for less than 24 hours when the doses recommended by the manufacturers were used. From a pharmacological point of view the sulfadiazine-sulfadimidine combination seems to be the drug of choice. Although no traces of sulphonamides were detected 48 hours after the dosing, the question of milk residues could not be answered because the minimum detection level of the methods used in the study was approximately 1 microgram/ml. The IDF standard method for the detection of penicillin in milk is not suitable for the detection of sulphonamide residues in milk.