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Biomedical subjects

B Hallén

Publications and source records attributed to B Hallén.

At least 19 recordsLinked to original sources
PubMed1997

Tolterodine--a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data.

Tolterodine is a new, potent and competitive muscarinic receptor antagonist in clinical development for the treatment of urge incontinence and other symptoms of unstable bladder. Tolterodine has a high affinity and specificity for muscarinic receptors in vitro and it exhibits a selectivity for the urinary bladder over salivary glands in vivo. A major active metabolite, (PNU-200577) the 5-hydroxymethyl derivative of tolterodine, has a similar pharmacological profile. Based on pharmacological and pharmacokinetic data, it has been concluded that this metabolite contributes significantly to the therapeutic effect of tolterodine. The bladder selectivity demonstrated by tolterodine and PNU-200577 in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. Moreover, this favourable tissue-selectivity seems to occur also in humans. Tolterodine is well tolerated and it exerts a marked effect on bladder function in healthy volunteers. Phase II data indicate that tolterodine is an efficacious and safe treatment for patients with idiopathic detrusor instability or detrusor hyperreflexia. An optimal efficacy/side-effect profile is obtained with tolterodine, at a dosage of 1 or 2 mg twice daily, which seems to have less propensity to cause dry mouth than the currently available antimuscarinic drugs.

Animals↗
PubMed1995

Concomitant single-dose and multiple-dose pharmacokinetics of terodiline in man, with a note on its enantiomers and major metabolites.

Single-dose and multiple-dose pharmacokinetics of terodiline were studied in 20 healthy volunteers by giving an initial oral dose of deuterium-labelled terodiline (12.5 mg or 25 mg) followed by multiple doses of Mictrol tablets (12.5 mg b.i.d. for 14 days and 25 mg b.i.d. for 14 days or vice versa). The enantiomer serum concentration ratio of S(-)/R(+) terodiline was close to unity at steady-state as well as during the disposition phase. The average single-dose kinetic parameters for the racemate after the 12.5 mg dose were: maximum serum concentration 41 micrograms/l, the corresponding time 3.4 hr, terminal half-life 61 hr, oral clearance 77 ml/min., renal clearance 12 ml/min. and apparent volume of distribution 382 1. The single-dose kinetics for the 25 mg dose and the multiple-dose kinetic parameters showed that linear kinetics prevailed. The average steady-state serum concentration was 275 micrograms/l at the lower dose and 509 micrograms/l at the higher dose. The degree of fluctuation during a dosage interval was 19% and the time to steady-state was about 9 days. The fraction unbound was about 8%. Unconjugated p-hydroxylated terodiline, p-hydroxy-m-methoxyterodiline and hydroxy-tert-butyl-terodiline constituted 15%, < 1% and 5%, respectively, of the terodiline steady-state levels.

Adult↗
PubMed1995

[Patient insurance in preventive activities. Wealth of injury material demonstrates risks of complications].

The patient insurance system in Sweden has manifest advantages where the mapping out of complications to medical treatment is concerned. The insurance data base contains a wealth of information which can be used for preventive purposes--not only overall statistics, but also patients' records and expert opinions in damage cases. During the 20 years since patient insurance was introduced, cases of special fundamental interest have been published, injury statistics have reported to clinics and departments, and certain issues have undergone special scrutiny--e.g. neural damage during surgery, infections arising from cataract surgery, bile duct injuries, injuries at delivery and damage resulting from physiotherapy.

Adult↗
PubMed1994

A comparison of propofol and methohexital as anesthetic agents for ECT: effects on seizure duration, therapeutic outcome, and memory.

The effects of the anesthetic agents propofol and methohexital on seizure duration, clinical outcome, recovery, and memory in electroconvulsive therapy (ECT) were studied in a double-blind trial. The study comprised 53 patients, 47 patients with major depression and six patients with other diagnoses according to DSM-III. Several recent clinical studies with a crossover design have shown a reduced seizure duration for anesthesia with propofol in comparison with both methohexital and thiopental. Propofol significantly reduced the seizure duration in this study without reducing the therapeutic outcome as measured by the Montgomery-Asberg Depression Rating Scale. Propofol did not significantly alter the length of the course of ECT; however, a slightly prolonged course for women cannot be completely ruled out. There were no significant differences between the two agents in effects on recovery times after anesthesia and on anterograde memory. In general, it seems that propofol is as effective as methohexital as an induction agent for ECT.

Adult↗
PubMed1994

Bioavailability and disposition of terodiline in man.

Terodiline was concomitantly administered intravenously (12.5 mg) and orally ([2H]terodiline, 12.5 mg) to 10 healthy volunteers. In four of the subjects, a tracer dose of the intravenously given terodiline was 3H-labeled. In a separate study, six subjects were given [3H]terodiline orally. Estimated pharmacokinetic parameters were as follows: systemic clearance, 93 mL/min; renal clearance, 14 mL/min; volume of distribution at steady-state, 407 L; terminal half-life, 54 h; and mean residence time, 77 h. After intravenous infusion, a rapid distribution phase (half-life, 4.5 min) could be observed. The maximum serum concentration after the oral dose was 29 micrograms/L and the time to maximum concentration was 5 h (estimated by noncompartmental analysis). Absorption commenced within the first hour and by deconvolution the maximum rate of absorption was determined to occur between 1 and 3 h, and by 3.4 h 90% of the available dose had been absorbed. Calculation of bioavailability by noncompartmental AUC, two-compartmental analysis, urinary excretion, and 24-h oral/intravenous concentration ratio gave similar results (ANOVA test, not significant). About 75% and 25% of administered radioactivity could be recovered in urine and feces, respectively. Intact terodiline in feces accounted for about 1% of the dose. p-Hydroxyterodiline was quantitated in feces and accounted for about 5% of the dose. Another metabolite, 3,4-dihydroxyterodiline, which has not previously been detected in urine or serum, was also identified.

Administration, Oral↗
PubMed1993

Pharmacokinetics of R(+)-terodiline given intravenously and orally to healthy volunteers.

(+)-Terodiline was given orally (25 mg) and intravenously (12.5 mg) to eight healthy volunteers. The pharmacokinetics of (+)-terodiline could be described by a one compartment model. The lag time of absorption was 0.6 +/- 0.5 hr (mean +/- S.D.), the absorption half-life 0.9 +/- 0.5 hr, the time to maximum serum concentration 5.6 +/- 2.2 hr and the corresponding maximum serum concentration 62 +/- 22 micrograms/l. The volume of distribution was found to be 372 +/- 84 1, the systemic clearance 86 +/- 29 ml/min., the mean residence time 81 +/- 38 hr and the observed terminal half-life of elimination 56 +/- 26 hr. The urinary excretion of the intravenous dose was 12 +/- 6% and the renal clearance 10 +/- 5 ml/min. The bioavailability of (+)-terodiline was 93 +/- 19%. The present results indicate that (+)-terodiline as well as the racemate can be characterized as low clearance long half-life drugs. One subject was a poor hydroxylator of debrisoquine and exhibited a 3-fold decrease in clearance and increase in half-life of (+)-terodiline relative to extensive metabolizers. Observed pharmacological effects were mild accomodation disturbances and dry mouth, i.e. the same effects as those that may be seen at a corresponding dose of terodiline given as a racemic mixture.

Absorption↗
PubMed1990

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect.

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.

Administration, Oral↗
PubMed1989

Tolerability and steady-state pharmacokinetics of terodiline and its main metabolites in elderly patients with urinary incontinence.

The elderly form an important target group for the treatment of urinary urge incontinence with drugs such as terodiline (Mictrol, Terolin). In order to evaluate its steady-state pharmacokinetics and tolerability in geriatric patients terodiline 12.5 mg b.d. was given to 28 hospitalized patients with urinary incontinence (mean age 85 years) for six weeks. The patients were monitored during the study and for 6 weeks afterwards, blood samples being taken at regular intervals. In addition to these multi-diseased and polymedicated patients, a small, homogenous group of healthy volunteers (mean age 40 years) was studied as a reference group, being given terodiline 12.5 mg b.d. for 2 weeks. Terodiline was generally well tolerated by the patients and no significant change in blood pressure or heart rate were found. One patient was withdrawn due to adverse effects. The mean terminal half-life of terodiline was 131 h and the clearance after oral administration (clearance/systemic availability) was 39 ml.min-1. The corresponding figures for the healthy volunteers were 57 h and 75 ml.min-1. The average steady-state serum concentration was 518 micrograms.l-1 in the geriatric patients and 238 micrograms.l-1 in the healthy volunteers. Steady-state was reached within 3 weeks in 20 of the 28 patients and within 5 weeks in 7 patients. In the geriatric patients the steady-state serum concentration of the main metabolite p-hydroxyterodiline, during the last three weeks on terodiline was 45 micrograms.l-1, 57 micrograms.l-1, and 45 micrograms.l-1, respectively, and a similar value was found in the healthy volunteers, 47 micrograms.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Single- and multiple-dose pharmacokinetics of terodiline in geriatric patients.

As a target group, geriataric patients were selected for pharmacokinetic studies with terodiline (Mictrol), an anticholinergic and calcium antagonist drug effective in the treatment of urinary incontinence. The single-dose kinetics in the geriatric patients (mean age 82 years) differed significantly from that previously found (Hallén et al. 1987) in healthy volunteers (mean age 35 years). There were higher peak serum concentrations (110 vs 79 micrograms.l-1), increased half-life (189 vs 60 h), lower renal clearance (4.0 vs 10.9 ml.min-1) and lower total clearance (29 vs 75 ml.min-1). Multiple-doses of 12.5 mg b.d. for 6-8 weeks resulted in a mean steady-state concentration of 642 micrograms.l-1, which was in agreement with the single dose parameters. The studied geriatric patients can be characterized not only as old, but also as frail, bedridden, having several diseases and polymedicated. The differences in pharmacokinetics between younger and elderly subjects can be attributed to a variety of complex factors, which may alter the clearance and/or the volume of distribution.

Aged↗
PubMed1988

Cardiac arrest during anaesthesia. A computer-aided study in 250,543 anaesthetics.

With the aid of a computer-based anaesthetic record-keeping system, all cardiac arrests during anaesthesia at the Karolinska Hospital between July 1967 and December 1984 were retrieved. There were a total of 170 cardiac arrests and 250,543 anaesthetics in the data file, which gives an incidence of 6.8 cardiac arrests per 10,000 anaesthetics. Sixty patients died, constituting a mortality of 2.4 per 10,000 anaesthetics: 42 were considered as inevitable deaths (rupture of aortic or cerebral aneurysm, multitrauma, etc.); 13 cases of cardiac arrest were considered as non-anaesthetic, i.e. complications due to surgery and other procedures. Nine of these patients died. 115 cases of cardiac arrest were considered as caused by the anaesthetic and nine of these patients died. Thus mortality caused by anaesthesia was 0.3 per 10,000 anaesthetics. The most common cause of cardiac arrest due to anaesthesia was hypoxia because of ventilatory problems (27 patients), postsuccinylcholine asystole (23 patients) and post-induction hypotension (14 patients). The highest mortality was seen when spinal or epidural anaesthetics were given to patients with impaired physical status including hypovolaemia. The incidence of cardiac arrest has declined considerably during the period studied, and this coincides with an increasing number of qualified anaesthetists employed in the department during the same period.

Aged↗
PubMed1988

Relationship between gastric emptying and serum concentrations of emepronium in dogs and human volunteers.

Clinical trials with increased dosages, relative to the standard regimen, of the anticholinergic drug emepronium (Cetiprin Novum) resulted in a clear improvement in micturition- and urodynamic parameters in urinary incontinent patients. In the present study possible effects on the gastric emptying were tested in dogs and in human volunteers. In dogs a wide dose range of emepronium (5-100 mg/kg p.o.) was used to establish a relationship between serum concentration and effect on the gastric emptying. Gastric emptying was slightly decreased after 25 mg/kg (peak conc. of emepronium about 100 micrograms/l) and markedly decreased after 50 mg/kg (500 micrograms/l) and 100 mg/kg (5000 micrograms/l). In the volunteers no effect of emepronium on gastric emptying was observed, either after 200 mg q.i.d. or after 400 mg q.i.d. (about 3 and 6 mg/kg q.i.d.), which resulted in peak serum concentrations of 100-300 micrograms/l).

Adult↗
PubMed1987

Propofol vs thiopentone as anaesthetic agents for short operative procedures.

In a randomized open study, 120 healthy female patients were included. For short gynaecological procedures they were anaesthetized with either propofol 2.5 mg X kg-1 (n = 60) or thiopentone 5 mg X kg-1 (n = 60) in combination with nitrous oxide/oxygen (67%/33%). Supplementary doses of propofol (10-20 mg) or thiopentone (25-50 mg) were given when necessary during the procedure. Induction characteristics for propofol and thiopentone 1 min after start of induction were similar. Propofol seemed to have a more depressant effect than thiopentone on the circulatory response to anaesthesia. Recovery times from the end of the operative procedure until the patients opened their eyes on command and were orientated were shorter in the propofol patients compared to the thiopentone patients. In the propofol group, patients recalled discomfort on injection more often than patients anaesthetized with thiopentone. Otherwise, the side-effects were similar in both groups. We conclude that propofol is similar to thiopentone in its anaesthetic qualities during induction and maintenance of short anaesthetic procedures. Propofol was associated with a more rapid emergence from anaesthesia than thiopentone.

Anesthesia, Intravenous↗
PubMed1987

Gastrointestinal transit rate-related absorption of emepronium: a study in mice.

The gastrointestinal (GI) absorption in mice of the anticholinergic quaternary ammonium compound emepronium, assessed by the urinary excretion of radioactivity and unchanged drug, increased from 1% to 7% and from 0.5% to 5%, respectively, in the dose range 0.1 to 40 mg/kg, whereafter a plateau was reached. Changes in the metabolism were evident at doses exceeding 80 mg/kg when 80% of the radioactivity was excreted as unchanged emepronium, as compared to 50% at lower doses. No dose-dependent urinary excretion of radioactivity was detected following intravenous injection. The increase in the fraction of the dose excreted in the urine after oral administration therefore cannot be easily explained by a dose-dependent metabolism or renal excretion. However, a relationship was seen between the reduced gastrointestinal motility, produced by increasing doses of the drug, and the increased bioavailability. Atropine sulphate given subcutaneously (1-50 mg/kg) more than doubled the urinary recovery of a small pharmacologically inactive oral dose of emepronium (5 mg/kg) and thus confirmed the transit rate-dependent absorption of emepronium. The superimposed effect of the pharmacological action on the GI transit rate, derived from the inherent property of an anticholinergic drug, may be of special significance for a drug with a low degree of absorption and a high variability, such as has been observed in clinical trials with the quaternary drug emepronium (Cetiprin).

Animals↗
PubMed1987

Species differences in the intestinal excretion of emepronium.

A substantial proportion of a parenteral dose of emepronium given to dogs is excreted via the gastrointestinal tract by biliary excretion and by excretion through the intestinal mucosa (Hallén et al. 1979). In the present paper the different routes of elimination were further investigated in mouse and man and compared to the dog. The disposition of emepronium-derived radioactivity (14C) in the three species showed that about 45% was excreted via urine and 55% via faeces. The proportion of the faecal excretion of 14C that could be referred to the intestinal route differed between the species and was about 20% in man, 60% in the mouse and most pronounced, 80%, in the dog.

Aged↗