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Biomedical subjects

G Alvan

Publications and source records attributed to G Alvan.

At least 19 recordsLinked to original sources
PubMed1996

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans.

1. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3. After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4. The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l-1 and AUC (0, th) 144 nmol l-1h, mean MDL Cmax 183 nmol l-1 and AUC 2627 nmol l-1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l-1 and AUC 10512 nmol l-1h, MDL concentrations below limit of quantitation). 5. We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.

Adult↗
PubMed1996

Formation of meprobamate from carisoprodol is catalysed by CYP2C19.

Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.

Administration, Oral↗
PubMed1994

Carisoprodol elimination in humans.

The elimination of the muscle relaxant drug, carisoprodol, was examined in 10 healthy volunteers after an oral dose of 700 mg. In nine subjects, carisoprodol was rapidly eliminated, with a mean half-life of 99 +/- 46 min, and extensively converted to meprobamate. Within 2.5 h after carisoprodol intake, meprobamate serum concentrations exceeded those of carisoprodol. Serum levels of meprobamate recorded (15-25 mumol/L) indicate that meprobamate might contribute to the effect(s) of carisoprodol. One subject eliminated carisoprodol with an overall half-life of 376 min, and only small amounts of meprobamate were recorded. This subject was found to be a poor metabolizer of mephenytoin. In spiked human sera, protein binding of carisoprodol was in the range of 41-67%, whereas meprobamate was bound to a lesser extent, 14-24%.

Adult↗
PubMed1988

Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis.

The renal handling of ceftazidime was studied in 8 patients with cystic fibrosis and 10 healthy controls. The renal clearance of ceftazidime (CLRcz) was measured after an intravenous single dose and during low and high plasma concentration steady-state infusions. The glomerular filtration rate (GFR) was simultaneously estimated by inulin clearance (CL inul). The average CLRcz (mean +/- SD) was higher in cystic fibrosis patients (125 +/- 20 ml/min/1.73 m2) than in healthy controls (100 +/- 9 ml/min/1.73 m2) [p less than 0.005]. Also CL inul (mean +/- SD) was increased in cystic fibrosis patients (132 +/- 30 ml/min/1.73 m2) compared with healthy controls (103 +/- 8 ml/min/1.73 m2) [p less than 0.02]. The mean renal clearance ratios of ceftazidime to inulin were close to unity after both the single dose and low and high dose steady-state infusions both in cystic fibrosis patients and in controls. These findings suggest that the glomerular filtration rate is the principal determinant of the elimination rate of ceftazidime. However, in all cystic fibrosis patients with a CL inul exceeding 125 ml/min/1.73 m2 the clearance ratio was below unity, indicating tubular reabsorption of ceftazidime occurs in these individuals. The results demonstrate a higher but also more variable GFR in cystic fibrosis patients (74 to 174 ml/min/1.73 m2), resulting in increased and accordingly variable ability to eliminate ceftazidime in cystic fibrosis. However, these pharmacokinetic changes are not large enough to call for special dosage considerations for ceftazidime in cystic fibrosis.

Adolescent↗
PubMed1984

Imbalance between alpha- and beta-adrenoceptor binding sites in marker cells in cystic fibrosis.

We investigated the characteristics of adrenergic receptor binding in peripheral blood cells from 6 patients with cystic fibrosis(CF) and 20 age-matched control subjects. There was a tendency (p = 0.08) towards a difference in dissociation constant of specific (125I)-hydroxybenzylpindolol (IHYP) binding in polymorphonuclear leukocytes (beta 2-adrenoceptor) from CF patients (113.0 pM +/- 32.8, SD) and controls (84.3 pM +/- 30.4, SD). We found no consistent differences in maximum binding capacity (Bmax) for either (3H)-yohimbine(YOH) binding in platelets (alpha 2-adrenoceptor) or IHYP bindings between the two groups. The ratio of YOH versus IHYP binding sites was significantly greater in CF patients (1.51 +/- 0.48) than in controls (1.07 +/- 0.34) (P less than 0.05). This might provide a possible explanation for the increased vasoconstriction and decreased heart rate response to adrenergic agonists in CF patients.

Blood Platelets↗
PubMed1983

Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria.

Twelve children with acute falciparum malaria were treated with 25 mg/kg chloroquine orally in three divided doses at 24 h intervals. Concentrations of chloroquine and its metabolite, desethylchloroquine, were measured in plasma from the beginning of treatment for up to 7 days using a high pressure liquid chromatography (h.p.l.c.) technique. Chloroquine was detectable in plasma within 30 min of giving the drug. Peak level was reached in 1-8 h after the first dose of 10 mg/kg and the peak concentrations ranged between 65 and 263 ng/ml. Chloroquine concentration declined slowly in plasma after stopping drug administration so that the concentration at the seventh day was 37.5% of the concentration on the third day. The apparent half-life was 3-4 days. Desethylchloroquine was detectable in plasma within 30 min of giving chloroquine and peak levels were reached in 2-12 h. Peak concentration after the first dose of chloroquine ranged between 9 and 62 ng/ml. Desethylchloroquine was also slowly cleared from plasma and mean concentration at the end of 7 days was 49% of the mean concentration at the end of 3 days.

Child↗
PubMed1982

Additive intraocular pressure reducing effect of topical timolol during systemic beta-blockade.

The effect on intraocular pressure (IOP) of topical timolol was studied in 30 patients with arterial hypertension treated with oral alprenolol, metoprolol or timolol. No patient had any known eye disorder. Topical administration of timolol induced a significant reduction of IOP regardless if the patients had systemic beta-blockade or not. Treatment with topical timolol alone was equally effective in reducing IOP as combined topical and oral therapy. Patient compliance was checked with plasma concentrations of the different beta-blockers.

Administration, Oral↗
PubMedDate not supplied

Failure of vitamin C to affect the pharmacokinetic profile of antipyrine in man.

A possible interaction of vitamin C with the metabolism of drugs which are oxidized (e.g., antipyrine and diphenylhydantion) is indicated from data in animals. The effect of megadoses of vitamin C (300 mg/day to 4800 mg/day) was therefore tested in human volunteers receiving antiprine (single oral dose) or diphenlhydantoin (chronic therapy). The half-life, volume of distribution, and plasma clearance of antipyrine were not affected by vitamin C treatment. Steady-state plasma levels of diphenylhydantoin in two epileptic patients were similar before and during vitamin C (1.2 Gm/day for 18 days) treatment. It is concluded that vitamin C, in commonly used megadoses, has no effect on the metabolism of antipyrine or diphenylhydantoin in men.

Antipyrine↗
PubMedDate not supplied

Concentration dependent plasma protein binding of salicylate in rheumatoid patients.

Acetylsalicylic acid in daily doses from 3 to 6g was prescribed to 8 patients with rheumatoid arthritis. Various assessments of clinical effect, as well as steady-state plasma concentrations and degree of plasma protein binding, were determined at each dose. The unbound fraction of salicylate increased with the dose, resulting in very high free concentrations of drug in some patients. No statistically significant relationship between total or unbound plasma concentration and the measurements of clinical efficacy were obtained. The marked increase with the dose in unbound salicylate concentration is interpreted as the result of the saturable elimination known to occur for this drug.

Adult↗