Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man

Summary The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p<0.05) than after recovery (9.3±1.0 versus 10.6±0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7±2.6 versus 10.3±2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7±0.3 to 2.4±0.3 l/h, and it was increased in hypothyroid patients from 2.1±0.4 to 2.5±0.5 l/h (p<0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxy-methylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10–30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.     

Cimetidine-phenytoin interaction: Effect on serum phenytoin concentration and antipyrine test

Summary In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7±1.3 mg/l to 9.1±1.4mg/l after three weeks on cimetidine (p<0.01), and fell to 5.8±1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2–4 months, antipyrine clearance increased from 0.67±0.06ml/min/kg to 1.61±0.22 ml/ min/kg, and antipyrine half-live fell from 10.9±1.3h to 4.5±0.6h as compared to the values before phenytoin treatment (p<0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01±0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1±0.5h, (p<0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8±0.3h in the patients on longterm phenytoin treatment. There was a significant positive correlation (p<0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.Part of this work was presented at the Joint Meeting of the Scandinavian and German Pharmacological Societies, September 1980 [14]     

Effect of rifampicin treatment on the kinetics of mexiletine

Summary To study the effects of enzyme induction on its pharmacokinetics, a single oral dose of the new antiarrhythmic agent mexiletine hydrochloride 400 mg was administered to 8 healthy volunteers before and after treatment with rifampicin 300 mg b.i.d. for ten days. The absorption and distribution of mexiletine were not changed after rifampicin, but its elimination half-life fell from 8.5±0.8 h (mean±SE) to 5.0±0.4 h (p<0.01), and its nonrenal clearance increased from 435±68 ml/min to 711±101 ml/min (p<0.01). The mean renal clearance of mexiletine did not change, but it showed an exponential correlation with urinary pH. The amount of unchanged mexiletine excreted in urine over two days decreased from 32±7 to 18±3 mg (p<0.01). The half-life of antipyrine fell from 11.8±0.4 to 5.5±0.3 h and its clearance increased from 40±3 ml to 74±3 ml/min (p<0.01). There was a significant (p<0.05) positive linear correlation between both the half-lives and the clearances of antipyrine and mexiletine. The clearances were positively correlated with serum -glutamyl transpeptidase. The results suggest that the dosage of mexiletine should be adjusted when enzyme inducing drugs are started or stopped during therapy with it.     

Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine

Summary The effect of short-term hepatic enzyme induction with carbamazepine (CBZ) on circulating thyroid hormone concentrations was studied in 10 healthy male subjects. CBZ 400 mg per day was given for 21 days in 6 subjects and for 14 days in a further 4. In the former group the effect of therapy on the pituitary/thyroid axis was also assessed by measuring thyroid stimulating hormone (TSH) response to thyrotrophin-releasing hormone. CBZ therapy resulted in induction of hepatic monooxygenase activity, evidenced by a fall in antipyrine half-life (11.1±0.7 to 7.6±0.7 h; p<0.001), and a rise in antipyrine clearance (0.72±0.06 to 0.98±0.1 ml min^–1 kg^–1; p<0.001). A significant fall in total serum thyroxine (T4) (81.9±2.9 to 75.1±2.9 nmol l^–1), and triiodothyronine (T3); (1.59±0.07 to 1.37±0.05 nmol l^–1) and free T4 (16.03±0.82 to 14.2±0.8 pmol l^–1) was seen after CBZ therapy. (all p<0.05). No significant change in reverse T3 or thyroid binding globulin occurred. In the 6 subjects studied for 21 days, maximal changes were found following 14 days' treatment. Basal and stimulated TSH remained unaltered. These effects on circulating thyroid hormone concentrations are likely to be secondary to hepatic enzyme induction leading to accelerated nondeiodinative hepatic hormone disposal. The reason for the failure of pituitary TSH secretion to rise in response to the fall in circulating T4 and T3 is unclear but may have implications for chronic treatment with CBZ in epileptic patients.     

Studies of the different metabolic pathways of antipyrine in man

Summary 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 48h, 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 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.     

The effect of liver cirrhosis on the pharmacokinetics of phenprocoumon

Summary Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12–0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6–7 days after drug administration. The binding of [³H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64±0.16 ml/h/kg mean ± SEM) than in the healthy volunteers (0.90±0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144±14 ml/h/kg) compared with normal (113±11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5±2.9 ml/h/kg) compared with normal (35.6±3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.     

Serum and saliva levels of a trimethoprim-sulfamethopyrazine combination in man

Summary The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml^–1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml^–1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying –15/+1 mm Hg. standing –25/–8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.     

藏、汉族健康人对安替比林及醋氨酚代谢的种族差异

用随机交叉设计,研究了藏、汉族健康人安替比林和醋氨酚的代谢差异。16例汉族人安替比林T_1/2为18.8±4.89h,17例藏族人为15.0±3.02h(P<0.05),汉族人安替比林清除率是1.35±0.37L·h^-1,藏族人是1.71±0.44Lt·h^-1(P<0.05)。汉族人醋氨酚T_1/2是3.1±0.86h,藏族人是3.2±1.12h(P>0.05)。实验结果表明,藏、汉族健康人安替比林的代谢有显著差异,藏族人安替比林清除率比汉族人增加了20%。藏、汉族醋氨酚的代谢无明显差异。     

Induction of the metabolism of etizolam by carbamazepine in humans

Objective To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam.Methods Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography.Results Carbamazepine treatment significantly decreased the peak plasma concentration (17.5±4.1 ng/ml versus 13.9±4.1 ng/ml; P<0.05), total area under the plasma concentration–time curve (194.8±88.9 ng h/ml versus 105.9±33.0 ng h/ml; P<0.001), and elimination half-life (11.1±4.6 h versus 6.8±2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters.Conclusions The present study suggests that carbamazepine induces the metabolism of etizolam.     

The effect of rifampicin on norethisterone pharmacokinetics

Summary The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450–600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of 1 mg norethisterone from 37.8±13.1 to 21.9±5.9 ng/ml X h (p<0.01). The plasma norethisterone half life (-phase) was also reduced from 6.2±1.7 to 3.2±1.0 h (p<0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A. U. C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.     

Elimination of hexamethylene diisocyanate cross-linked polypeptides in patients with normal or impaired renal function

Summary Infusions of 3.5% isocyanate cross-linked polypeptide solution 500 ml were given to 52 patients with normal or impaired renal function: glomerular filtration rate (GFR)=0–133 ml/min. The serum concentration and urinary excretion of hydroxyproline were measured and the equivalent polypeptide concentrations were calculated from the results. In patients with normal renal function (GFR>90 ml/min) the proportion of polypeptide excreted in the urine up to 12 h was 45.4±2.6% ( ±SEM), up to 24 h 47.7±2.9% and up to 48 h 49.3±3.4%. In patients with moderate renal insufficiency (GFR=30–90 ml/min) there was no decrease in polypeptide excretion and even in patients with more serious impairment of GFR (11–30 ml/min) 48-h urinary polypeptide excretion was still 40.6±5.9%. In patients with GFR of 2–10 ml/min polypeptide excretion fell to 10.7±3.2% during the first 12 h, although there was an increase in later collection periods as compared to patients with normal renal function –19.9±3.9% in 24 h and 27.0±3.5% in 48 h. The elimination half-life (t_1/2) calculated from serum concentrations was 505±30 min ( ±SEM) in patients with normal renal function (GFR>90 ml/min). Only when the GFR fell below 30 ml/min did it slowly begin to increase. In patients with minimal residual renal function (GFR=0–0.5 ml/min), who were on haemodialysis, the elimination half-life was 985±49 min, i.e. approximately twice the normal. Twice weekly infusion of 3.5% polypeptide solution 500 ml over a period of 6 weeks did not produce any significant cumulation in haemodialysis patients (GFR=0–0.5 ml/min). A weekly dose of polypeptide 35 g appeared to be quite safe when given for several weeks, even to anuric patients. As no significant amount of polypeptide was lost during haemodialysis, the dose can be chosen without taking into account any effect of intermittent haemodialysis.     

Papaverine disposition in cardiac surgery patients and the effect of cardiopulmonary bypass

Summary Cardiac surgery involving cardiopulmonary bypass (CPB) causes substantial physiologic changes which may potentially alter the pharmacokinetic properties of drugs used during and after the procedure. Studies with fentanyl have implied a relationship between prolonged elimination half-lives following CPB and decreased liver perfusion during and after the procedure. To further test this hypothesis, the effects of CPB on the pharmacokinetics of papaverine, a coronary vasodilator currently being added to the cardioplegic solution to prevent vasospasm, were studied. The drug was given to two groups of patients, one (n=6) undergoing surgery with and one (n=5) without CPB, the latter serving as controls. Plasma papaverine concentrations declined biexponentially in the control patients with a mean elimination half-life of 1.30±0.25 h, total plasma clearance of 13.8±3.75 ml/min/kg, volume of distribution of 1.52±0.45 l/kg and volume of distribution, steady-state, of 0.992±0.530 l/kg. For the CPB group, only half-life was estimated, and averaged 2.77±0.28 h, significantly greater (p<0.01) than that in the controls. These results further confirm the increased half-lives seen with other hepatically cleared drugs following CPB and have implications in the clinical management of patients given drugs eliminated in this manner.     

A 12-week,randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT

Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP).

Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10?mg increments every 12?h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12?h for 12 weeks. Oxymorphone immediate release was available every 4–6?h, as needed, for the first 4 days and twice daily thereafter.

Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4?mm at screening to 22.7?mm (?p < 0.0001). After random­ization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (?p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group.

Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12?week double-blind treatment period in opioid-naive patients with CLBP.     

Pharmacokinetic studies on flupenthixol and flupenthixol decanoate in man using tritium labelled compounds

Two groups of 5 patients were given tritium labelled flupenthixol orally or tritium labelled flupenthixol decanoate in oil intramuscularly. The patients were schizophrenics, who had been treated with one of the two drugs for at least 6 months prior to the study. Blood samples were drawn from the patients at different times after administration. From the flupenthixol decanoate group was also drawn a sample of cerebrospinal fluid 11 days after administration. Total radioactivity was measured in serum and cerebrospinal fluid. After oral administration of flupenthixol peak concentrations were seen at 3–8 h after administration. After injection of flupenthixol decanoate the maximum values were found at 11 to 17 days after injection. A plateau with a duration of 2–3 weeks surrounded the maximum. The concentrations in the samples of cerebrospinal fluid were estimated to 29–55% of the corresponding serum values. The study indicates that the depot preparation given with intervals of 2–3 weeks can replace the normal oral flupenthixol treatment. In addition the study support the clinical impression of drug sparing effect seen when changing from oral tablet treatment to injection of the depot preparation. The discrepancies between the present study and the clinical impression of flupenthixol decanoate are discussed.     

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers

Rationale and objective Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P ₄₅₀ (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam.Methods Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration.Results Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (±SD) values of area under the plasma concentration–time curve and elimination half-life for placebo versus itraconazole were 1328±330 ng h/ml versus 1445±419 ng h/ml and 32.1±9.3 h versus 31.1±8.4 h, respectively.Conclusion The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors.     

Antipyrine clearance,aminopyrine N-demethylase,and bilirubin udp-glucuronyl transferase activity in patients with amoebic liver abscess

Three indices of drug metabolism, antipyrine clearance in vivo, and aminopyrine N-demethylase and bilirubin UDP-glucuronyl transferase activity in liver biopsies, were studied in fifteen patients with amoebic liver abscess (with and without jaundice). The mean (± S.E.) antipyrine half-life in patients with jaundice was 21.64 (±1.52)h and in patients without jaundice was 19.36 ( ± 0.93)h. It was significantly prolonged in both groups of patients as compared to controls (11.63 ± 0.86 h). It showed a good correlation with serum albumin (p<0.01), prothrombin time index (p<0.01), and aminopyrine N-demethylase (p<0.05). Aminopyrine N-demethylase was found to be decreased in patients without jaundice but no significant change could be observed in patients with jaundice. Bilrubin UDP-glucuronyl transferase showed no significant change in either of the groups.     

Decreased plasma half-life of phenylbutazone in workers exposed to chlorinated pesticides

Summary The plasma half-life of a single oral dose of phenylbutazone was investigated in 14 men occupationally exposed to a mixture of insecticides, mainly lindane, and in 12 matched controls with significantly lower plasma levels of lindane. — The mean plasma half-life of phenylbutazone was significantly shorter (p<0.05) in the subjects exposed to lindane than in the non-exposed controls, but there was no relationship between the half-life of phenylbutazone and the plasma level of lindane. No correlation was found between the plasma half-life of phenylbutazone and that of antipyrine determined in the same subjects two years previously. If the plasma half-life of phenylbutazone is accepted as an index of the metabolism of this drug, then the shorter half-lives found in the exposed subjects suggest that the metabolism of this compound can be enhanced by such environmental factors as exposure to chlorinated insecticides.     

Studies on the different metabolic pathways of antipyrine in man: I. Oral administration of 250, 500 and 1000 mg to healthy volunteers

1 The plasma elimination rate of antipyrine, as measured by the salivary concentration decay, and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxy-antipyrine was studied in five healthy volunteers, who received 250, 500 and 1000 mg antipyrine orally in a cross-over design.

2 The mean antipyrine half-life and metabolic clearance were 11.5 ± 2.5 h (range 10.2-16.9 h) and 3.4 ± 0.9 l/h (range 1.7-4.2 l/h) respectively after 500 mg. These values were not significantly different after 250 or 1000 mg (P > 0.1; paired t-test).

3 In 52 h urine 3.3 ± 1.2% of the dose of 500 mg antipyrine was excreted unchanged as antipyrine, 28.5 ± 2.2% as 4-hydroxy-antipyrine, 16.5 ± 6.0% as norantipyrine, 35.1 ± 7.2% as 3-hydroxymethyl-antipyrine and 3.3 ± 0.8% as 3-carboxy-antipyrine. The values obtained at the other dose levels were not significantly different (P > 0.1; paired t-test).

4 At all dose levels 4-hydroxy-antipyrine and norantipyrine were excreted in urine entirely as glucuronides. After 500 mg antipyrine, 3-hydroxymethyl-antipyrine was excreted as glucuronide to the extent of 58 ± 9% of the total excreted amount. This percentage was not significantly different at the other dose levels. 3-Carboxy-antipyrine was excreted in the free form at all three dose levels.

5 From 12 h of drug intake onwards, the urinary excretion rate curves of antipyrine and all its metabolites declined mono-exponentially with about the same half-life as the parent compound in saliva. The half-lives calculated from the excretion rate curves of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine correlated significantly with the half-life of antipyrine in plasma. At all dose levels a relative delay in urinary excretion of 3-hydroxymethyl-antipyrine was observed compared to the urinary excretion of antipyrine and the other metabolites.

6 The ratios of the cumulative amounts of metabolites excreted in 24 h, were essentially the same as those measured in the 52 h samples.

     

Effectiveness and pharmacokinetics of indomethacin in premature newborns with patent ductus arteriosus

Summary A review of the published data on pharmacological closure of PDA in premature newborns shows that doses of 0.2 mg/kg indomethacin are less successful when given enterally (18 to 85% closure) than when given intravenously (88 to 90% closure). The elimination half-life is markedly prolonged in premature newborns compared to adults but there are wide differences between the patients and some discrepancies between mean values reported by various authors. The present study compares clinical and pharmacological results obtained in two groups of low birth weight infants with symptomatic PDA and treated with 0.2 mg/kg indomethacin: 7 patients treated enterally (group A) and 11 patients treated intravenously (group B). Permanent closure of the ductus was observed in 4 cases in group A and in 9 cases in group B. Transient closure was observed twice in each group. Of a total of 18 infants, 15 were saved (83%). One baby treated with indomethacin in spite of preexisting oliguria died from persistent anuria. Indomethacin plasma levels were measured by gas chromatography. The mean elimination half-life of the drug in group A (40.3±12.2 h) did not differ from that in group B (33.9±11.7 h). The apparent plasma half-life appears to be inversely correlated with gestational age (r=0.66,p<0.05). No relationship between peak plasma levels and ductal closure was established, but a significant difference was found for area under the curve (0 to 24 h) between patients in whom a permanent closure was obtained and those in whom the closure was either transient or absent.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

Haemodynamic effects of intravenous cibenzoline in patients with coronary heart disease

Summary The pharmacokinetic parameters of antipyrine (AP) were examined in 45 normal healthy subjects (18 heavy smokers, 5 mild smokers, and 22 nonsmokers) and in 12 patients with Gilbert's syndrome (GS), amongst whom 2 mild and 1 heavy smokers were included. Heavy smokers were defined as persons smoking more than 20 cigarettes/day and mild smokers as those smoking less than 10 cigarettes/day. Significant differences (unpaired Student's t-test) in the elimination t_1/2 of AP among the study groups and in its total plasma clearance (CL) were observed without any change in the apparent volume of distribution. The individual CL values varied within the same study groups, but the mean±SD (0.026±0.004 l/h/kg) in the GS patients did not significantly differ from that in normal nonsmokers (0.025±0.006 l/h/kg) or in normal mild smokers (0.028±0.001 l/h/kg). When the 3 patients with GS who smoked were excluded, the mean CL of the group (0.025 l/h/kg) was again comparable to that of the normal nonsmokers and mild smokers. The mean (±SD) CL in normal heavy smokers (0.040±0.012 l/h/kg) was significantly greater than in normal mild smokers (p<0.05), in normal nonsmokers (p<0.001) and in patients with GS (p<0.001). The results suggest that drug oxidation capacity estimated from the total plasma CL of AP appears unimpaired in GS.