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Biomedical subjects

C Graffner

Publications and source records attributed to C Graffner.

At least 37 records · Page 2Linked to original sources
PubMed1985

Preformulation studies in a drug development program for tablet formulations.

Recently developed techniques were applied in a preformulation program to select a compound and a suitable salt for use in a one-month toxicological test. The program showed that valuable information can be obtained prior to the choice of a compound as a candidate for a solid-dosage form. Information about the physical and mechanical properties of the chosen compound can be obtained with a limited amount of substance, i.e., surface color and hygroscopicity (1-2 g), dissolution rate and solubility (1-2 g), powder properties (1-2 g), and compaction properties (5-7 g).

Chemical Phenomena↗
PubMed1984

Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets.

In two different absorption studies, quantitative correlations between the in vitro dissolution rate and the bioavailability have been shown after single administration of various tablet compositions of alaproclate hydrochloride to healthy subjects. Both statistical moment analysis and the use of empirical single value parameters were tested. For conventional tablets a linear relationship was obtained between mean dissolution time in vitro and in vivo. A similar relationship was obtained between the mean dissolution time in vitro and the mean residence time for controlled release tablets of the matrix type. It was also possible to establish an in vitro--in vivo correlation for these latter tablets by using the single point estimate of maximum plasma concentration as in vivo parameter. When comparing the mean dissolution time in vitro to the total area under the plasma drug concentration-time curve attained after different types of tablets, it is obvious that the extent of bioavailability of alaproclate will not fall below 80% of the value found for an aqueous solution until the mean dissolution time in vitro exceeds approximately 3 hr. Statistical moment analysis seems to have a broader applicability than the use of empirical point estimates, and it seems to be useful both for conventionally dissolving tablets and controlled release tablets.

Absorption↗
PubMed1984

Relationship of N-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism.

The metabolism of the new reversible A-selective monoamine oxidase inhibitor amiflamine was studied in relation to polymorphic hydroxylation of debrisoquine in 24 healthy subjects. Amiflamine is metabolized by two consecutive N-demethylations. By construction of urinary recovery ratios analogous to that of debrisoquine/4-hydroxydebrisoquine, correlations between debrisoquine metabolic ratio and amiflamine/demethylated metabolites were significant and consistent within slow and rapid hydroxylators of debrisoquine. It is concluded that debrisoquine hydroxylation and amiflamine N-demethylation might be under common genetic regulation.

Administration, Oral↗
PubMed1983

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis.

The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3 +/- 4.8 h (+/- SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5 +/- 4.6 h, which was calculated to correspond to removal of 25 +/- 14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10-55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2 +/- 4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.

Aged↗
PubMed1983

Plasma concentration of disopyramide given as capsules and controlled release tablets.

Steady state plasma levels and clinical effects of disopyramide have been compared following administration of standard capsules and controlled release (CR) tablets. Nineteen patients (29-70 years) with atrial or ventricular arrhythmias were treated for two weeks with disopyramide capsules 200 mg t.i.d. and then with CR tablets 300 mg b.i.d. for 14 weeks. After treatment either with capsules or CR tablets, plasma concentrations of disopyramide and its metabolite N-deisopropyldisopyramide were similar within 1 dosage interval. Maximum and minimum concentrations of the parent drug were 10.1 +/- 0.9 mumol/l (mean +/- SEM) and 5.7 +/- 0.5 mumol/l with CR tablets, and 10.2 +/- 0.5 mumol/l and 5.6 +/- 0.5 mumol/l with standard capsules. The bioavailability of disopyramide was the same after capsules and CR tablets. Disopyramide, independent of the formulation, produced good antiarrhythmic effects. The side-effects reported on questioning were mainly of the anti-cholinergic type and there was no significant difference between the formulations with respect to their incidence, type or severity. Of 16 patients who stated a preference for one of the dosage forms, 11 prefered the CR tablets. The study confirms the good antiarrhythmic effect of disopyramide and shows that the CR preparation permits twice daily administration of disopyramide.

Adult↗
PubMed1982

Compartment model of prenalterol.

In previous pharmacokinetic studies in healthy subjects the time course of plasma concentration of prenalterol was described by a short distribution phase (alpha-phase) with a mean half-life of about 8 minutes and an elimination phase (beta-phase) with an average half- life of about two hours [1, 2]. The aim of this joint study was to check the pharmacokinetic data obtained after intravenous single dose administration with the computer program TOPFIT [3] using different compartment models and to test the predictive power of the chosen kinetic model for plasma concentration data after repetitive intravenous prenalterol dosing.

Adrenergic beta-Agonists↗
PubMed1981

Pharmacokinetic studies in man of the selective beta 1-adrenoceptor agonist, prenalterol.

The pharmacokinetics of prenalterol, a selective beta 1-adrenoceptor agonist, has been studied in healthy subjects, by following the plasma concentration and urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. Each of six healthy subjects received a single i.v. dose (2.5 mg) and three oral doses (2.5, 5.0 and 10 mg) of prenalterol. The oral dose was administered as a solution. Three of the subjects received the intravenous and oral doses of 2.5 mg as tritiated drug. Prenalterol was rapidly and completely absorbed after oral administration. The peak plasma concentration was attained after about 0.5 h. About 25% of prenalterol reached the systemic circulation. Prenalterol was extensively distributed to extravascular tissues with a half-life of the distribution phase close to 7 min. About 90% of the dose was excreted in urine within 24 h irrespective of the route of administration, indicating complete absorption of the drug. On average 60% of the i.v. and 13% of the oral doses were excreted as unchanged drug. The elimination half-life of the compound was 1.8 h, and the decline in the plasma concentration of the metabolites indicated a slower elimination rate than for the unchanged drug. Dose-dependent kinetics were not observed after the oral doses examined.

Administration, Oral↗
PubMed1981

Relative absorption of disopyramide as determined by liquid chromatography following acute administration of standard capsules and controlled-release tablets.

The absorption of disopyramide has been studied in healthy volunteers following an acute dose of 300 mg in standard capsules (C) and three controlled-release (CR) tablets with different in vitro release rates. Plasma concentrations and the urinary excretion of unchanged compound and its main metabolite, N-deisopropyldisopyramide, were determined simultaneously by using a rapid and sensitive method based on liquid-solid chromatography. The rate of absorption was rapid following C, and maximal concentrations were reached within 1.5-2 h. A CR formulation produced a slower rate of absorption and the rate correlated with the drug in vitro release rate. The maximal concentration of disopyramide was reduced following CR tablets. The extent of absorption was the same following C and two of the CR formulations, whereas the CR composition with the slowest in vitro release rate presented a somewhat reduced extent of absorption. About 70% of the given dose was recovered in urine as disopyramide (50%) and metabolite (20%). The elimination half-life of disopyramide and N-deisopropyldisopyramide was close to 4 and 7 h, respectively.

Absorption↗
PubMed1980

Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets.

Plasma concentrations and bioavailability of disopyramide following repeated administration of standard capsules and controlled-release tablets have been compared. Ten patients were randomized into two groups; Group I received disopyramide capsules 150 mg every 6 h for five days. Group II received the same preparations in the reverse order. There was a more rapid rise in disopyramide concentration after the capsules: the maximum of 10.7 +/- 0.6 mumol/l (mean +/- SEM) was reached within 1.8 +/- 0.4 h as compared to 10.6 +/- 0.4 mumol/l within 4.0 +/- 0.3 h after the controlled-release tablets. No significant difference in the fluctuations in individual plasma concentrations during each dose interval at steady state were observed after ordinary capsules compared to controlled-release tablets. The extent of bioavailability was the same. Eight patients reported some side-effects during the capsule period and nine during the controlled-release tablet period.

Aged↗
PubMed1980

Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta 1-adrenoceptor agonist, prenalterol, in man.

The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective beta 1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables--triglycerides, glucose, lactate pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.

Adrenergic beta-Agonists↗
PubMed1980

Tocainide kinetics after intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction.

Tocainide is structurally related to lidocaine but may be used orally as well as intravenously. A therapeutic plasma concentration range of 25 to 45 mumole/l has been suggested. Tocainide kinetics were studied in 6 healthy subjects and 16 patients with acute myocardial infarction. There was good accordance in kinetics of healthy subjects and patients. After intravenous administration the mean t1/2 was about 14 hr, volume of distribution about 3.0 l/kg, and corrected renal clearance about 140 ml/min. An average of 35% of the dose was recovered unchanged in urine. After oral administration the absorption rate was rapid relative to the elimination rate, extent of bioavailability was complete, and the apparent volume of distribution was the same as that after intravenous injection. A dose regimen of 750 mg intravenously directly followed by 800 mg orally and subsequently 400 mg 3 times daily resulted in therapeutic plasma levels within 15 min. The plasma levels remained within the therapeutic range throughout a period of observation from 48 to 168 hr.

Administration, Oral↗
PubMed1980

Prevalence and treatment of hypomagnesemia in the elderly studies in a representative in 70-year-old population and in geriatric patients.

Within in the framework of the longitudinal gerontological and geriatric population study in Göteborg, Sweden, S-Magnesium (S-Mg) was examined in 55 70-year-old males and 55 70-year-old females with a as many probands without diuretic treatment. Probands with diuretic treatment had lower S-Mg than others (p smaller than 0.001). Females had higher S-Mg values than males both in those with (p smaller than 0.05) and without (p smaller than 0.01) diuretic treatment. Sixteen per cent of the males and 7 per cent of the females with diuretics had S-Mg below 0.7 mmol/l compared to none in those without. Out of 161 geriatric inpatients those 50 (17 males and 33 females) with the lowest S-Mg values took part in a double blind comparison between supplementation with a magnesium chloride and a placebo solution during three weeks. The daily dose was 12.5 mmol MgCl2. The tolerance of the solution was tested in 30 young healthy individuals and was found to be good. During treatment with magnesium chloride, S-Mg increased 0.09 plus or minus 0.08 mmol/l (p smaller than 0.001) and during treatment with placebo 0.08 plus or minus 0.09 mmol/l (p smaller than 0.01). The difference between the two groups was not significant. S-potassium, however, increased significantly more in the patients treated with magnesium chloride (p smaller than 0.01). The increase in the treatment group was 0.31 plus or minus 0.32 mmol/l compared to a decrease of 0.02 plus or minus 0.42 mmol/l in the placebo group.

Adult↗
PubMed1979

Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man.

The haemodynamic effects of the selective beta1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selective beta1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/l) prenalterol had to be administered in doses that were twelve times higher than before the beta-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.

Adrenergic beta-Agonists↗
PubMed1979

Pharmacokinetics of metoclopramide intravenously and orally determined by liquid chromatography.

1 A rapid and sensitive method, based on liquid chromatography, has been developed for determination of metoclopramide concentrations in plasma and urine samples. Concentrations down to 15 nmol/1 (5 ng/ml) of plasma and 100 nmol/1 (30 ng/ml) of urine could be determined with a relative standard deviation of less than or equal to 10%. The method was used to study disposition of metoclopramide in healthy volunteers following single doses intravenously and orally as aqueous solution and a slow release tablet. 2 The initial distribution after intravenous administration was very rapid. The elimination half-life postdistribution was 4.9 h. The apparent volume of distribution, Vd, was 3.0 1/kg body weight. On average 19% was excreted unchanged after intravenous administration of 5 and 10 mg (15 and 30 mumol) of drug. The rate of absorption of metoclopramide was delayed after administration of a slow release tablet and the maximum plasma concentration was about 50% lower than after a solution. The extent of bioavailability was the same following the two different formulations suggesting a first-pass elimination of 25-40%.

Administration, Oral↗
PubMed1975

Pharmacokinetics of procainamide intravenously and orally as conventional and slow-release tablets.

Pharmacokinetics of procainamide were studied in healthy volunteers after single doses intravenously and orally as conventional and slow-release tablets and after repeated oral doses to steady state. The initial distribution after intravenous administration was rapid and the overall elimination in the beta-phase corresponded to t1/2 of 2.7 hr. The mean volume of the central compartment was small and only 4 percent of V-d (beta), which was 2.3 l/kg body weight. About 65 percent was excreted unchanged after intravenous administration and about 55 percent after a single oral dose of 500 mg. The recovery of the metabolite N-acetylprocainamide was 12 percent after both routes of administration. Procainamide was completely absorbed from the gastrointestinal tract and the first-pass elimination was very limited. The rates of absorption from the tablet compositions were well correlated to the in vitro dissolution properties. Administration of slow-release tablets every 8 hr gave about the same mean plasma level at steady state as ordinary tablets given every 4 hr, and the availability was the same from both preparations. The occasional high plasma concentration peaks after ordinary tablets were not observed after the slow-release tablets. Renal clearance was about 500 ml/min, indicating an active secretion in the tubules.

Acetylation↗
PubMed1975

Elimination rate of N-acetylprocainamide after a single intravenous dose of procainamide hydrochloride in man.

Equations were derived which made it possible to determine the elimination rate of N-acetylprocainamide from urinary data after intravenous administration of procainamide hydrochloride. A single dose of 500 mg of the drug was infused intravenously in four healthy subjects. On the basis of theose equations, the formation rate of the metabolite could be calculated presuming that all rate processes were occurring by first-order processes. However, close examination of the excretion rate data appears to support the contention that the formation or excretion of N-acetylprocainamide may be occurring by a saturable process

Acetylation↗