Lack of interaction between tramadol and coumarins.

The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple-dose administration. Nineteen patients receiving long-term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double-blind, placebo-controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89-1.10), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.

Gastrointestinal blood loss after non-steroidal anti-inflammatory drugs. Measurement by selective determination of faecal porphyrins.

1. A method for the detection of gastrointestinal blood loss based upon the selective measurement of faecal porphyrins was tested in two studies in healthy volunteers. 2. In the first study subjects (n = 6) received intragastric autologous blood (saline, 2 and 6 ml as a single dose) resulting in a dose dependent increase in faecal porphyrins. 3. In a subsequent placebo controlled cross over study in 12 subjects acetylsalicylic acid (ASA), nabumetone (a new NSAID) or placebo were administered for 5 days with a washout period of 9 days. They were no dietary restrictions. 4. All faeces were collected during the treatment period and both the full faecal homogenate and a random faecal sample were analyzed for deutero- and pemptoporphyrin content by h.p.l.c. Additionally a benzidine reaction was performed. 5. There was a highly significant correlation (r = 0.95) between the values obtained from random samples and the full homogenate. ASA increased the faecal porphyrin excretion (P less than 0.001) compared with placebo in contrast to nabumetone. Complaints of dyspepsia were most common after ASA. 6. Measurement of faecal porphyrins is useful for monitoring NSAID induced upper gastrointestinal blood loss and lacks some of the practical constraints of other methods.

Studies of interaction of a low-molecular-weight heparinoid (Org 10172) with cloxacillin and ticarcillin in healthy male volunteers.

Pharmacokinetic and pharmacodynamic interactions between Org 10172 (intravenous bolus injection of 3,250 anti-Xa units), which is a low-molecular-weight heparinoid, cloxacillin (500 mg orally four times daily for 3 days), and ticarcillin (4,000 mg intravenously four times daily for 2 days) were evaluated in two separate studies with healthy male volunteers (n = 18). Both cloxacillin and ticarcillin caused a significant increase in elimination half-life of anti-Xa activity, i.e., from 31 +/- 10 to 54 +/- 23 h and from 27 +/- 6 to 42 +/- 13 h, respectively (P less than 0.05). Ticarcillin decreased clearance (11%) and increased apparent volume of distribution (35%) (P less than 0.05), while for cloxacillin, these differences did not reach statistical significance. These changes in disposition of Org 10172 by the penicillins were not accompanied by important pharmacodynamic changes as evaluated by coagulation tests, platelet aggregation, and bleeding time. Cloxacillin appeared to influence blood coagulation (prolongation of the activated partial thromboplastin time and shortening of thrombin time; P less than 0.05) and facilitated thrombin-induced platelet aggregation, which coincided with a shorter bleeding time during the combined treatment in comparison with the time during treatment with Org 10172 alone (P less than 0.05). In conclusion, the disposition of Org 10172 was slightly changed by cloxacillin and ticarcillin, and, unexpectedly, cloxacillin appeared to have mild procoagulant effects.

Comparative trial of lisinopril and nifedipine in mild to severe essential hypertension.

A total of 136 patients with mild to severe uncomplicated essential hypertension were evaluated in a multicenter, randomized, double-blind, double-placebo, parallel study to compare the effect of lisinopril, a new angiotensin-converting enzyme inhibitor, with that of nifedipine. Following a 2-week placebo control period the patients were treated with either 20-80 mg/day of lisinopril (n = 89) or with 40-80 mg/day of nifedipine (n = 47). Blood pressure was significantly reduced in both groups after 4, 8, and 12 weeks of treatment. There was no difference in the effect of lisinopril compared to nifedipine. No serious clinical or laboratory adverse experiences were observed during the study. The incidence of clinical side effects was significantly lower in the lisinopril group than in the nifedipine group (21.3 vs. 48.9%, p less than or equal to 0.01). There were no significant changes in laboratory data in either group. The results indicate that lisinopril is as effective as nifedipine in the treatment of uncomplicated essential hypertension and that lisinopril is well tolerated and has an acceptable safety profile.

Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects.

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only.

Correlation between antipyrine metabolite formation and theophylline metabolism in humans after simultaneous single-dose administration and at steady state.

To nine healthy male volunteers two model substrates for oxidative drug-metabolizing enzyme activity, viz, antipyrine (A) and theophylline (T) were administered simultaneously by the p.o. route. To six of them, the same two drugs were also administered simultaneously at zero-order rate with an osmotic rectal drug delivery system in order to obtain steady-state plasma concentrations. Plasma A and T concentrations were measured simultaneously by a high-performance liquid chromatographic method and urinary excretions of the major metabolites arising from A (4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine) and from T (3-methylxanthine, 1-methyluric acid and 1,3-methyluric acid) were also measured by high-performance liquid chromatography. Correlations between total plasma clearance and metabolic clearances of A and T and clearances for production of the various metabolites were investigated in order to determine whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system. Total plasma clearances of the two drugs were found to correlate reasonably well (r = 0.72) but not well enough to be of useful predictive value. The strongest correlations (r = 0.91) were found between the clearance for production of 4-hydroxyantipyrine and both total and metabolic clearances of T. The clearances for production of all metabolites of T also correlated better with the clearance for production of 4-hydroxyantipyrine (r ranging from 0.79-0.86) than with the clearance of norantipyrine and 3-hydroxymethylantipyrine (r ranging from 0.42-0.58).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half-life was 27.3 +/- 1.3 h in males, 27.7 +/- 1.5 h in females in the follicular phase and 29.6 +/- 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/- 2.7 ml/min, 58.2 +/- 3.3 and 55.8 +/- 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 +/- 2.3 and 31.2 +/- 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/- 4.6 and 45.6 +/- 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/- 0.1%) to females in the luteal phase of the cycle (12.4 +/- 0.5%) to females using OC-steroids (13.5 +/- 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (Cli = 323 +/- 30 ml/min in females using OC-steroids, 530 +/- 37 ml/min in males and 459 +/- 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.

Differential effects of enzyme induction on antipyrine metabolite formation.

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

Studies of the different metabolic pathways of antipyrine in man. Oral versus i.v. administration and the influence of urinary collection time.

The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8 +/- 1.9% of the dose was excreted in urine as unchanged antipyrine in 48 h, 24.9 +/- 6.3% as 4-hydroxyantipyrine, 16.5 +/- 3.2% as norantipyrine, 13.0 +/- 2.2% as 3-hydroxymethyl-antipyrine and 5.8 +/- 1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36 h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.

Double blind study of the effect of glafenine (Glifanan) on oral anticoagulant therapy with phenprocoumon (Marcumar).

The interaction between phenprocoumon (Marcumar) and glafenine (Glifanan) was investigated in a double blind study of twenty patients receiving long term treatment with phenprocoumon. Thrombotesttime (TT) values had been stable for more than three months before the study. Patients taking glafenine showed a significant increase in TT during the second and third week of the trial (P less than 0.05) compared with the placebo group. tthe increase in TT was not significant in the fourth week. The average concentrations of phenprocoumon were similar in both groups, which suggests that displacement of the drug from binding was not important. Concentrations of clotting factors II, VII and X showed a decrease in all patients at the time of the maximum TT values. A possible explanation for this interaction is discussed, but the mechanism remains uncertain.