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Biomedical subjects

E Nüesch

Publications and source records attributed to E Nüesch.

At least 19 recordsLinked to original sources
PubMed1992

[Mucus models for investigation of intestinal absorption mechanisms. 3. A mathematical simulation model of drug diffusion through enteral mucus].

The diffusion of drug substance in a closed three-compartment model through a mucus layer to equilibrium is simulated by available pharmacokinetic programs. The obtained curves conform very well to the values experimentally found. If mucus is replaced by buffer solution an explicit equation from the literature, the method used and the experimental findings give the same results. Examination of the rate constants k1 for the diffusion in, kD through and k2 from the mucus shows the significance of the relation k1/k2 > 1, = 1, < 1 as a measure for the affinity of the active agent to the mucus. The discussion of the kinetic parameters shows, as in previous results, no criterion for assuming specific mucus binding. Because of its unspecifity the usual term "mucus binding" should be replaced by "mucus retention".

Diffusion↗
PubMed1991

Pharmacokinetic investigation of oral and i.v. dihydroergotamine in healthy subjects.

A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized cross-over trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz = 33 l/kg) and a high plasma clearance (CLP = 2 l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8'-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.

Administration, Oral↗
PubMed1991

Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine.

Drug level monitoring during routine clinical visits in the course of phase III trials provides a means to document pharmacokinetic variability in a patient population. Such a pharmacokinetic screen was performed for the new calcium antagonist isradipine. A total of 697 blood samples were collected at any time after the morning dose from 252 patients who had received oral doses of isradipine. Three approaches of data analysis based on exploratory (graphical and statistical) techniques were used to relate plasma level to patient demographic data and laboratory parameters. The pharamacokinetics of isradipine seemed to be influenced by the demographic variables of age (already detected in conventional studies) and weight, as well as by the blood serum levels of inorganic phosphorous, uric acid, alkaline phosphatase, and bilirubin, but only to a small, clinically irrelevant extent. The findings from the three approaches were complementary. They suggest that a pharmacokinetic screening in clinical trials is feasible at reasonable experimental cost and effort and provides useful data on interindividual and intraindividual pharmacokinetic variability in patients.

Adult↗
PubMed1990

Pharmacokinetics of isradipine in patients with chronic liver disease.

The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (12C 5 mg) and i.v. (13C 1 mg). Systemic availability was significantly increased from 17% to 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.6 l.min-1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capacity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration. The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.

Administration, Oral↗
PubMed1987

The effect of a new inotropic agent, DPI 201-106, on systolic time intervals and the electrocardiogram in healthy subjects.

1. DPI 201-106 (DPI) is a novel inotropic agent, with Na+ channel agonistic action combined with a sensitization of contractile proteins to Ca++. In a double-blind trial in healthy volunteers (n = 20) cardiovascular effects (blood pressure, heart rate, ECG) of single oral doses were studied. In addition systolic time intervals (STIs) were assessed in 10 of these subjects. DPI plasma concentrations were measured by h.p.l.c. 2. Preejection period was shortened by 14 ms (P less than 0.01) and 30 ms (P less than 0.01) 1 h after 30 and 60 mg, respectively, suggesting a dose-dependent inotropic effect. Heart rate was slightly reduced after both doses. Mean blood pressure remained unchanged. 3. Corrected QT interval duration (QTc) was prolonged by a mean of 7 ms (NS) and 22 ms (P less than 0.001) 1 h after 30 and 60 mg, respectively. PQ and QRS intervals remained unaffected. 4. Peak plasma levels were attained at 1-2 h and the terminal elimination half-life was approximately 15 h. 5. It is concluded that DPI has positive inotropic and negative chronotropic properties which make it potentially useful for the treatment of heart failure.

Adult↗
PubMed1986

Analgesic activity of propyphenazone in patients with pain following oral surgery.

The acute analgesic effect of single oral doses of 150 and 300 mg propyphenazone, 1000 mg acetylsalicylic acid (ASA) and placebo was investigated in 210 patients with pain following dental surgery. At most time points over the 3-hour observation period all the active medications had a significantly greater analgesic effect than placebo according to all the methods of pain assessment used. Both doses of propyphenazone reached their peak activity sooner than ASA, and their duration of action tended to be shorter. On a per milligram basis, the relative analgesic potency of propyphenazone was about twice that of ASA. All test substances were well tolerated. Side effects, such as tiredness, nausea, headache, dizziness etc., were reported by less than 20% of the patients. The nature of the adverse reactions was similar for all medications, and as they were recorded most frequently after placebo, they cannot therefore be definitely ascribed to one or the other of the active test substances.

Adolescent↗
PubMed1986

Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subjects.

Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life = 12.1 +/- 5.0 h, apparent volume of distribution at steady-state = 5.6 +/- 2.11 X kg-1, apparent clearance = 0.51 +/- 0.11 l X h-1 X kg-1. The time lag between drug ingestion and first blood level was short, 0.38 +/- 0.11 h. Drug absorption lasted for 2.8 +/- 1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.

Adult↗
PubMed1986

Pharmacokinetics of a long-acting bromocriptine preparation (Parlodel LA) and its effect on release of prolactin and growth hormone.

The pharmacokinetics and endocrine actions of a long-acting form of bromocriptine (Parlodel) were examined in a controlled study in 10 healthy volunteers receiving a single i.m. injection of 50 mg. Six further subjects took bromocriptine 1.25 mg t.i.d. for 3 days p.o. In the subjects given the slow release preparation, the plasma bromocriptine concentrations increased sharply to a maximum of 1.65 mg/l 2 h after injection. This fast release process was followed by slow clearance with a half-life of 16 days. The substance was still detectable in plasma 35 days postinjection. Plasma prolactin (PRL) fell rapidly from a mean of 5.6 ng/ml to reach significantly lower levels at 60 and 120 min. Inhibition was maintained for up to 35 days, when plasma PRL was still significantly below the values recorded at baseline and in the control group. Plasma GH peaked at 3.6 ng/ml at 120 min and subsequently declined slowly to stabilize between 1.4 and 2.2 ng/ml for about 12 h, falling to below the 1 ng/ml limit for the remainder of the study period. In contrast, individuals receiving oral bromocriptine exhibited a significant elevation following the first dose and an equivalent increment after the morning dose on Day 3. Thus, the results show a prolonged inhibitory effect on PRL of this long-acting bromocriptine preparation in parallel with its slow plasma clearance. The stimulant effect on GH secretion is short lived, presumably due to desensitisation of specific receptors.

Adult↗
PubMed1986

Relationship between plasma concentrations and cardiac beta-adrenoceptor blockade--a study with oral and intravenous bopindolol.

Bopindolol, an esterified beta-adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio-receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. After intravenous administration the half-life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one-compartment model occurred with a half-life of about 4 h. There were indications for a longer beta phase of elimination with a half-life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%. Cardiac beta-adrenoceptor blockade was determined as the reduction in exercise-induced tachycardia. With oral doses the maximum effect was reached after 3 h (-29 beats min-1 after 1 mg, -40 beats min-1 after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (-33 beats min-1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Endocrine profile of a long-acting somatostatin derivative SMS 201-995. Study in normal volunteers following subcutaneous administration.

The pharmacokinetics and the endocrine profile of a new low molecular somatostatin derivative, SMS 201-995, were investigated in a group of 35 normal subjects. Clearance studies (n = 6) for this peptide showed a prolonged half-life in plasma, 113 min, following single sc injections of 50 or 100 micrograms. Arginine stimulation tests (n = 6) were conducted immediately and 180 min after sc injection of 50 micrograms of SMS 201-995. The stimulatory effect of arginine on GH and insulin was counteracted by the peptide at the P less than 0.001 and P less than 0.02 significance level, respectively. Delayed arginine stimulation revealed a persistent blockade of the GH release (P less than 0.02), whereas a recovery of the insulin response was observed. Plasma glucagon increments following a standard protein meal (n = 10) were significantly (P less than 0.001) inhibited by previous sc injection of 50 micrograms of SMS 202-995. Pretreatment with 50 and 100 micrograms of SMS 202-995 sc (n = 9) inhibited (P less than 0.001) the stimulatory effect of TRH (200 micrograms iv) on TSH without modifying basal levels. The injection of 100 micrograms/h during sleep completely abolished the nocturnal GH peak in 4 volunteers. No rebound rise after decline of the suppressive action on GH was recorded in any of the trials. Safety chemistries and blood coagulation studies remained normal and no side-effects or untoward reactions were recorded throughout the investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Pharmacokinetics of SMS 201-995 in healthy subjects.

The pharmacokinetics of a new somatostatin derivative, SMS 201-995, was investigated in a group of eight healthy subjects. SMS 201-995 was given intravenously in doses of 25 micrograms, 50 micrograms, 100 micrograms, and 200 micrograms and also subcutaneously in doses of 50 micrograms, 100 micrograms, 200 micrograms, and 400 micrograms in accordance with a randomized Latin-square design. Blood samples were taken up to 8 h. The tolerability of SMS 201-995 was very good. Routine blood chemistry variables remained normal. After intravenous administration of SMS 201-995 initial half-lives ranging from 9 +/- 2 min to 14 +/- 4 min and second half-lives of from 72 +/- 22 min to 98 +/- 37 min were calculated for the different doses. SMS 201-995 was rapidly absorbed after subcutaneous injection with a half-life ranging from 5.3 +/- 2.2 min to 11.7 +/- 7.6 min. The disposition half-life was from 88 +/- 20 min to 102 +/- 16 min for the different doses. Cp(tmax) and AUC (0 - infinity) increased dose-dependently after both routes of administration, pointing to linear pharmacokinetics for SMS 201-995. On the basis of its good tolerability, slow plasma clearance, and long action, SMS 201-995 represents a valuable tool for further clinical studies.

Adult↗
PubMed1982

Pharmacokinetic comparison of pindolol 30 mg retard and 15 mg normal tablets.

In a cross-over pharmacokinetic study in 8 healthy volunteers a retard formulation containing pindolol 30 mg was compared with the normal 15 mg. pindolol tablet. The pindolol 30 mg retard tablet led to the same maximum plasma level as a single dose of the normal pindolol tablet. A plasma concentration higher than half of the maximum was maintained twice as long after the retard than after the normal 15 mg pindolol tablet. The bioavailability of the two forms was practically identical.

Adult↗
PubMed1982

Effects of age and smoking on the pharmacokinetics of pindolol and propranolol.

1 Pharmacokinetic investigations were carried out in a group of 32 ambulant normal male volunteers in order to determine the effect of age and smoking on steady-state plasma levels of pindolol and propranolol. There were four groups of 8: young non-smokers (YNS), young smokers (YS), old non-smokers (ONS) and old smokers (OS). Each subject received, in a randomized cross-over sequence, 5 mg pindolol and 80 mg propranolol three times daily for 2 days with an interval of at least 14 days between the two treatment periods. 2 Neither age nor smoking was shown to have any influence on the time to reach a peak plasma level after pindolol or propranolol. Age, on the other hand, significantly increased the peak plasma levels and the areas under the plasma concentration time curves, and decreased the elimination rate constants, the differences between the age groups being more pronounced for propranolol than for pindolol. No effect of smoking on these parameters was observed. 3 Differences were found between pindolol and propranolol in respect of time to reach a peak plasma level, peak plasma levels and area under the plasma concentration time curves in the groups ONS and YS when related to the YNS control group. Changes observed (with the exception of the time to reach a peak level) tended to be less for pindolol and were considered to be of little clinical relevance.

Adult↗
PubMed1982

Influence of smoking and age on pharmacokinetics of beta-receptor blockers.

The influence of age and smoking on pharmacokinetics of pindolol and propranolol was investigated. Although there was a statistically significant difference in certain pharmacokinetic parameters (maximum plasma concentration, area under the curve, elimination constant and elimination half-life) between elderly patients (more that 60 years) and young persons (20-30 years) no significant differences were found as far as smoking and nonsmoking is concerned. This is in contrast with some reports in the literature. The higher plasma concentrations of both investigated drugs may be the result of a decreased metabolism of propranolol in older persons, in a decreased hepatic blood flow and a decreased renal elimination. Because of the lower sensitivity of beta-receptors in old persons, the higher plasma concentrations of beta-receptor blockers in this group of patients should not result in a diminished dose of the investigated beta-receptor blockers in the elderly.

Adrenergic beta-Antagonists↗
PubMed1981

A pharmacodynamic and pharmacokinetic comparison of pindolol 20 mg retard and a conventional tablet.

In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken) t. d. s., and one tablet of pindolol 20 mg retard (Visken retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.

Administration, Oral↗
PubMed1980

Assessment of analgesics in dental surgery outpatients.

The usefulness of the dental outpatient model for evaluating the efficacy of mild analgesics, first described by Cooper and Beaver, is demonstrated in five separate, double-blind, randomised, single-dose, parallel-group studies. Pain intensity and pain relief were recorded at hourly intervals for 3 h following the administration of aspirin 1000 mg and placebo. In all five studies aspirin was significantly more effective than placebo, with relatively small variability of the response between the studies. The method is simple, reliable and sensitive and complements the inpatient studies of postoperative pain hitherto more frequently used.

Aspirin↗
PubMed1980

Analgesic effect of fluproquazone in postoperative patients.

In 4 double-blind, randomized, stratified, parallel group studies, single oral doses of fluproquazone (75 to 200 mg), a new nonsteroidal anti-inflammatory analgesic, were compared with aspirin (1,000 mg) and placebo in a total of 672 hospitalized patients with moderate or severe pain following episiotomy or other surgical interventions. A dose-dependent effect of fluproquazone which was highly significantly superior to placebo and which resembled the effect of aspirin with respect to onset, degree, and duration was noted in all studies. Fluproquazone, 100 to 150 mg, was found to be approximately equiactive to 1,000 mg of aspirin and better tolerated.

Adult↗