Biomedical subjects
Publications and source records attributed to M Furlanut.
The pharmacokinetics of chlorpromazine after intravenous infusion were studied in 25 children. The pharmacokinetic parameters studied are markedly different from those reported for adults. A clear relationship was demonstrated between age, serum terminal half-life (r = 0.75) and systemic clearance (r = -0.43). It appears that the pharmacokinetics of chlorpromazine are more rapid in children than in adults.
Pharmacokinetics of single dose (25 mg i.m.) of imipramine was studied in geriatric and young adult patients with mood disorders requiring antidepressant treatment. Imipramine and its principal metabolites were determined by means of a high performance liquid chromatography method with electrochemical detection. Serum concentrations analysis was performed according to a bicompartmental open model. A relationship between age and kinetic parameters such as area under the curve, elimination phase constant, half-life and total body clearance was observed. Significant differences were demonstrated between elderly and young adult patients when comparing these parameters. It is concluded that geriatric patients treated with imipramine should receive doses of about 60% of those of young adults.
The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection. The mean peak serum concentration of 212.63 micrograms/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h-1. Mean values for half-life, apparent volume of distribution (Vz), total body clearance (CL), and renal clearance (CLR) were 3.24 h, 0.21 l.kg-1, 16.67 ml.min-1 and 13.60 ml.min-1 respectively. There was an inverse relationship between age and Vz, whereas CL and CLR were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria. The study demonstrated that i.m. cefonicid 50 mg.kg-1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.
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Chlordesmethyldiazepam a long-acting benzodiazepine was compared with lorazepam a short-acting one in a double-blind placebo cross-over study against generalized anxiety disorders. Chlordesmethyldiazepam therapy was more effective than lorazepam. Clinical efficacy, drowsiness and insomnia seem well correlated with pharmacokinetic properties of these two benzodiazepines. These results further support the use of a long-acting benzodiazepine rather than a short-acting one as an anti-anxiety agent.
Benperidol in a 4 mg single dose was administered orally to five healthy male volunteers. The drug was rapidly absorbed (tmax = 2.27 +/- 0.57 h) and largely distributed, the volume of distribution being 5.19 +/- 1.99 l.kg-1. Elimination half-life was 7.65 +/- 2.14 h. Urinary excretion represented only a minimal fraction of ingested dose (0.1 +/- 0.007%). Variability of the area under the curve makes a first-pass metabolism a reasonable possibility. Acute dystonias appeared in two subjects.
The absorption and disposition kinetics of the enantiomers of the nonsteroidal antiinflammatory drug flunoxaprofen were studied in six healthy volunteers after oral administration of either R,S(+/-)-flunoxaprofen or R(-)-flunoxaprofen. The apparent values of the volume of distribution and systemic clearance of the S(+)-enantiomer were significantly lower than those of the R(-)-enantiomer. There was no significant difference in the absorption and elimination half-lives between the two isomers. The S(+)- to R(-)-isomer plasma concentration ratio increased with time with an apparent inversion half-time of about 50 h. This observation suggests metabolic inversion of R(-)- to S(+)-enantiomer, although the possibilities of stereoselective bioavailability or interaction between the two isomers can not be excluded.
A high-pressure liquid chromatographic (HPLC) method for the serum assay of benperidol is described. One ml of serum is required for a single estimation. The method involves a simple and rapid extraction step (BondElut columns), HPLC separation (C8 10-mu column), and electrochemical detection (+0.65 V). Haloperidol is used as internal standard. On the basis of this procedure, recovery (93-97%) and reproducibility (intra-assay and inter-assay coefficients of variation less than 9%) are satisfactory. The detection limit is 0.2 ng/ml of serum. After therapeutic doses, trough serum levels ranged from 3.8 to 12 ng/ml in five patients.
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A 15-year old boy, suffering from partial complex seizures, was treated with primidone (PR) and carbamazepine (CBZ). In spite of daily doses in the usual range (PR = 12 mg/kg, CBZ = 30 mg/kg), he was not free from seizures and serum levels of CBZ were remarkably low (4.8 micrograms/ml). A good control of seizures was obtained after gradually stopping treatment with PR. This lead to a substantial increase of CBZ serum levels to a decrease of carbamazepine-10, 11-epoxide levels and a 60% reduction in total CBZ clearance.
The time-courses of flecainide plasma and tissue levels were studied in Wistar male rats after i.v. administration (4 mg/Kg). Drug assay in plasma and tissue was performed with a specific and accurate HPLC technique. The final half lives in plasma and tissues were about 4 hours, except in the brain where the half life value was 9.8 hours. The mean tissue/plasma (T/P) ratios in myocardial, kidney, liver, skeletal and muscle tissues were 9.11, 13.8, 14.37, 6.31 respectively, while in the brain the T/P ratio rose progressively over the sampling time to 10.0. These data suggest that flecainide may accumulate in the central nervous system during prolonged treatment. Flecainide levels in adipose tissue were very low. Finally, there was an early "bulge" in the concentration curve, possibly reflecting enterohepatic circulation or non-linear elimination kinetics.
Carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-epox) steady-state serum concentrations were measured in 82 children who had generalized tonic-clonic, or partial seizures. There was no correlation between a given dose and serum concentrations, whether other anticonvulsant drugs were used or not. Epileptic children receiving polytherapy (CBZ associated with one or more of the following drugs: phenobarbital, primidone, phenytoin, ethosuximide) had significantly different CBZ clearance values and percent CBZ-epox than did patients given CBZ alone. Even though given lower doses, girls had higher CBZ concentrations and lower CBZ clearance values than did boys. Older girls had lower serum concentrations of CBZ-epox than did younger girls. Seizure-free children had higher CBZ serum levels and lower CBZ clearance values than did those with uncontrolled seizures. The percentage of CBZ-epox in children with uncontrolled seizures was significantly higher than in children without seizures. These data indicate that serum levels of CBZ and CBZ-epox correlate more with factors such as associated drugs, age, and sex than with administered dose. Therefore, CBZ serum level monitoring represents an essential means of individualization of anticonvulsant drug therapy.
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A patient ingested about 5 g of orphenadrine hydrochloride. He had gastric lavage and oral administration of activated charcoal. The main symptoms were neuropsychiatric in nature. Possible relation between serum levels of the drug and time course of the toxic effects are described.
Flunoxaprofen is a new nonsteroidal antiinflammatory agent that, like benoxaprofen, inhibits leukotriene rather than prostaglandin synthesis. The absorption and disposition kinetics of flunoxaprofen and benoxaprofen have been compared in six healthy volunteers after oral administration of 100 mg of each drug. The two drugs showed similar absorption characteristics, whereas the distribution and elimination processes were much faster for flunoxaprofen. The renal route of elimination appeared to contribute significantly less to the disposition of flunoxaprofen. These kinetic characteristics render less likely the risk of excessive drug accumulation with flunoxaprofen, especially in the presence of reduced renal function.
Cyanotic crises occurred in a breast-fed infant whose mother was under treatment with dipyrone for a sore throat. No abnormalities were found at physical and routine laboratory examinations. Dipyrone concentrations in mother's serum and milk and in infant's serum and urine were 3.3, 4.3 and 3.2, 3.74 micrograms/ml respectively. It is concluded that the adverse effect could be due to dipyrone ingested with mother's milk.
Tolerability, serum levels and urinary excretion of benoxaprofen (B) in therapeutic doses of 400 or 600 mg as a capsule were studied in 22 healthy volunteers after single or multiple doses. B was determined by a HPLC procedure. Apart from a skin reaction in one patient, no major problems were encountered by patients. Mean serum peak values after 400 and 600 mg were 49.84 and 94.54 micrograms/ml respectively. Mean time to peak was 5.6 hours and mean half-life ranged between 45.38 (400 mg regimen) and 63.48 hours (600 mg regimen). Urinary excretion was only a fraction of the doses ingested: 14.39% after a single dose; 35.5% after multiple doses. This may depend on other pathways of elimination of the drug because steady state is reached according to half-life.
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