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Biomedical subjects

G Pons

Publications and source records attributed to G Pons.

At least 73 records · Page 4Linked to original sources
PubMed1992

Vigabatrin. Clinical pharmacokinetics.

Vigabatrin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is supplied as a racemic mixture, with the S(+) enantiomer possessing pharmacological activity. [R,S]-Vigabatrin plasma concentrations can be estimated using high-performance liquid chromatographic methods. Only gas chromatography-mass spectrometry methods allow quantification of the S(+) and R(-) enantiomers. Vigabatrin was rapidly absorbed reaching peak concentrations within 1 to 2h. Area under plasma concentration-time curves indicated dose-linear pharmacokinetics. There was no effect of food on the absorption of vigabatrin. The absorption characteristics of the enantiomers were similar to those of the [R,S]-vigabatrin. No chiral inversion was detected after administration of the pure S(+) enantiomer. Vigabatrin is not protein bound. The apparent volume of distribution of [R,S]-vigabatrin was approximately 0.8 L/kg. Despite the lack of protein binding, cerebrospinal concentrations of the [R,S]-vigabatrin were only 10% of the plasma concentration 6h after a single oral dose. The half-life of [R,S]-vigabatrin was between 5.3 and 7.4h, the half-life of the enantiomers were 7.5 and 8.1h for the S(+) and the R(-) forms, respectively. The major route of elimination was renal excretion; urinary recovery of the [R,S]-vigabatrin was close to 70%. Pharmacokinetic studies in epileptic children did not show any significant effect of maturation on the disposition of the S(+) enantiomer: the half-life and the renal clearance were similar to adult values. Data suggest a lower bioavailability in children. In adults with epilepsy, the half-life of the [R,S]-vigabatrin ranged from 4.2 and 5.6h, similar to that measured in healthy adults. In elderly nonepileptic volunteers the pharmacokinetics of the enantiomers of vigabatrin showed delayed absorption, a major increase in peak concentration and a prolonged half-life. These changes were attributed to decreased renal clearance of vigabatrin. A nonlinear relationship between renal clearance and creatinine clearance was suggested. Vigabatrin caused a 20% fall in plasma phenytoin concentrations, the mechanism of which has not been elucidated. There were no other interactions with most concurrently administered anticonvulsants. The usual dosage of vigabatrin as add-on treatment in adults is 2 to 4g daily. Higher dosages up to 80 mg/kg daily were required in children. A dosage adjustment was recommended in any patient with decreased renal clearance. Although anticonvulsant effects were clearly related to dosage, monitoring of plasma concentrations of vigabatrin as a guide to dosage is unlikely to be of as much value as with other antiepileptic drugs. The action of the drug long outlasts its presence in plasma.

Administration, Oral↗
PubMed1991

Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration.

Twelve children 1-5 y old were randomly assigned to receive midazolam 0.2 mg.kg-1 either by the intravenous (IV) or intranasal (IN) routes. After IN administration the rapid onset of absorption was observed (tmax 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration. The results are consistent with an estimated mean bioavailability of 55%.

Administration, Intranasal↗
PubMed1991

Pharmacokinetics of tiaprofenic acid in children after a single oral dose.

Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg.kg-1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC. No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age: tmax = 2.12 h, Cmax = 8.78 mg.l-1, AUC(0----8 h) 33.9 mg.h.l-1, AUC = 39.3 mg.h.l-1, t1/2 = 2.35 h, Vt = 0.319 l.kg-1, CL = 0.094 l.h-1.kg-1. Renal clearance was 14 ml.h-1.kg-1.33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates. The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg.kg-1 TA. Volume of distribution and t1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3-11 year-old children from that in adults.

Administration, Oral↗
PubMed1991

Caffeine acetylator phenotyping during maturation in infants.

Caffeine acetylator phenotype was studied during maturation in 54 8- to 447-d-old children hospitalized for minor disease (group A) and in five 3- to 630-d-old children with Pierre Robin syndrome (group B). In group A, the children received 2.5 mg/kg caffeine orally once between birth and 15 mo. Group B patients were chronically treated with caffeine (2.3 to 15.8 mg/kg/d) for prevention of apneas, and the acetylator phenotype was serially determined. Phenotyping was performed on a spot urine sample collected 2-6 h after drug administration. Caffeine metabolites [5-acetylamino-6-formylamino-3-methyl uracil (AFMU), 1-methylxanthine, 1-methyluric acid, 1,7-methyluric acid, and 1,7-methylxanthine] were measured using HPLC. Acetylator phenotype was determined on the basis of AFMU/1-methylxanthine (ratio 1) and AFMU/AFMU + 1,7-methyluric acid + 1-methylxanthine + 1,7- methylxanthine + 1,7-methyluric acid (ratio 2) molar ratios. In group A, all children were slow acetylators before 83 d of age (ratio 1 less than 0.4; ratio 2 less than 0.08), whereas older children included slow and fast acetylators. The acetylation molar ratios differed significantly between age groups and increased with age. The cumulative percentage of fast acetylators increased with age but the plateau was not yet reached at 15 mo. In three children, the phenotyping was repeated after 15 mo: the second determination was consistent with the first one. In group B, all children appeared as slow acetylators on the first phenotyping. Four of them appeared subsequently as fast acetylators; one remained a slow acetylator until 11 mo.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1991

A simple non-invasive procedure for the investigation of cytochrome P-450 IIIA dependent enzymes in humans.

Urinary 6 beta-hydroxycortisol (6 beta OHF) is a specific marker of the induction of the cytochrome P-450 IIIA. Often, the production of 6 beta OHF is expressed from 24-h urine collection as the ratio 6 beta OHF/17-hydroxycorticosteroids or even better 6 beta OHF/free cortisol in order to adjust for minor day to day variation in adrenal cortisol production. A 24-h urine collection is a non-invasive method applicable to clinical studies in adult man, but more difficult to realize in newborn and infants. Therefore, we have tested the validity of a single urine sampling for the determination of the 6 beta OHF/free cortisol ratio as a clinical test to estimate cytochrome P-450 IIIA enzyme activity. Urinary 6 beta OHF and free cortisol have been measured in 19 healthy volunteers by high performance liquid chromatography methods using the same extraction procedure. A good correlation was found between 6 beta OHF/free cortisol ratio in morning urine samples and in 24h-collections (r = 0.899). Thus, a morning spot urine sampling is a simple procedure that may be helpful for investigations on cytochrome P-450 IIIA enzyme activity in humans, particularly in newborn and in children.

Adult↗
PubMed1991

Side effects of antiepileptic drugs in children.

Side effects of antiepileptic drugs in children have to be considered at all stages of maturation: during pregnancy, at birth, during breast feeding and in older children treated for epilepsy. The offspring of drug treated epileptic mothers have a higher incidence of congenital malformations than do those of normal controls or of non treated epileptic mothers. According to recent prospective studies teratogenicity appears to be attributable to antiepileptic drugs rather than to epilepsy since more congenital anomalies have been found among infants of treated epileptic mothers than among untreated epileptic mothers. Monotherapy might be associated with a less pronounced risk for facial defects than is polytherapy. Some studies suggest that the actual drug used is significant for the teratogenic effect: a significant association was seen between maternal use of valproic acid and spina bifida; facial clefts were associated with both phenytoin and phenobarbitone use and also with polytherapy. These side effects do not however justify discouraging a woman on antiepileptic medications from having a child, nor do they perhaps justify changing a satisfactory drug regimen during pregnancy when the epilepsy is well controlled. The use of combinations of anticonvulsants should be avoided as well as anticonvulsants considered as not being safe (valproic acid, diones). However the danger of precipitating severe seizures or status epilepticus by overcautious treatment should be avoided because it poses a greater hazard to the fetus as compared to the low risk of teratogenicity due to anticonvulsants. Infants born to mothers taking either phenytoin or barbiturate derivatives or both may show clinical signs of bleeding and diminished level of coagulation factors, usually during the first 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1990

Pharmacokinetics of oral cyclosporin A in diabetic children and adolescents.

Cyclosporin A (CsA) pharmacokinetics was studied in 19 diabetic children (mean age: 10.6 y). They were divided into prepubertal (I) and pubertal (II) groups according to plasma oestradiol or testosterone concentrations. The kinetic study was performed after a 72 h wash out period and a single oral dose of 7.5 mg/kg CsA. CsA in blood was measured by HPLC. The kinetic parameters: Cmax, tmax, t 1/2, AUC, CL/f, Vz/f and tss were calculated. No significant difference was found between the two groups. A significant negative correlation was found between Vz and both total cholesterol (r = -0.46), VLDL + LDL - cholesterol (r = -0.49) and VLDL + LDL - phospholipids (r = -0.58). CsA kinetics at steady-state were simulated by superimposition of single dose kinetics derived from each single dose. Measured steady-state blood concentrations were correlated (r = 0.80) with the values predicted by the simulation. The results suggest that CsA adjustment dosage of the CsA may be performed after a single oral dose using blood levels measured by HPLC. This procedure requires validation in further studies.

Administration, Oral↗
PubMed1990

Moclobemide excretion in human breast milk.

1. Six lactating white women, aged 24-36 years, received a single oral dose of 300 mg moclobemide, between 09.00 h and 11.00 h, 3 to 5 days after the delivery of a full term neonate. 2. Complete milk collections were obtained before, 3, 6, 9, 12 and 24 h after drug administration by means of a breast pump. Venous blood samples were drawn before, and 0.5, 1, 3, 4.5, 6, 9, 12, 24 h post-dosing. 3. Moclobemide, and its major metabolite (Ro 12-8095) were measured in milk and plasma samples using h.p.l.c. The active metabolite (Ro 12-5637) could only be detected in plasma. 4. Moclobemide and its metabolites were not detectable in 24 h plasma samples. Cmax, tmax and t1/2 for moclobemide were (mean +/- s.d.) 2.70 +/- 1.24 mg l-1, 2.03 +/- 1.19 h and 2.26 +/- 0.26 h, respectively. 5. The concentrations of moclobemide and Ro 12-8095 in milk were highest at 3 h after drug administration and the drug and metabolite were not detectable after 12 h. Ro 12-5637 was not detected in any milk sample. The percentages of the dose excreted as moclobemide and Ro 12-8095 were (mean +/- s.d.) 0.057 +/- 0.020% and 0.031 +/- 0.011%, respectively. An average 3.5 kg breast-fed neonate would therefore be exposed to only a 0.05 mg kg-1 moclobemide dose (approximately 1% of the maternal dose on the mg kg-1 basis). The low amount of moclobemide excreted into breast milk is unlikely to be hazardous to suckling infants.

Adult↗
PubMed1990

Pharmacokinetics of the individual enantiomers of vigabatrin (gamma-vinyl GABA) in epileptic children.

1. The pharmacokinetics of the enantiomers of vigabatrin were investigated after oral administration of a single 50 mg kg-1 dose of the racemate to two groups of six epileptic children (I: 5 months-2 years, II: 4-14 years). 2. The mean (+/- s.d.) values of maximum plasma concentration and area under the plasma concentration-time curve of the R(-) enantiomer were significantly higher than those of S(+) vigabatrin in both groups: R(-) Cmax: 21 +/- 6.6 (I)-41.3 +/- 13.9 (II) vs S(+) Cmax: 13.9 +/- 4.5 (I)-23.8 +/- 12.2 (II) mg l-1; R(-) AUC: 106 +/- 28.5 (I)-147 +/- 34 (II) vs S(+) AUC: 90.9 +/- 27.9 (I)-117 +/- 26 (II) mg l-1 h. In group I, the half-life of the R(-) isomer was significantly shorter than that of the S(+) isomer; in group II, the half-lives were comparable. 3. For the R(-) enantiomer the area under the curve, and the elimination half-life increased linearly with age. 4. During chronic administration (50 mg kg-1 vigabatrin racemate twice a day for 4 days), the morning trough plasma drug concentrations did not increase.

Adolescent↗
PubMed1990

Effect of hypophysectomy on caffeine elimination in rats.

Two groups of 8-week-old Sprague-Dawley male rats were used: 8 hypophysectomized (H[-]), operated on day 0, treated by daily sc tetracosactid (ACTHs: 10 micrograms), and thyroxine (T4:5 micrograms/100 g); 7 sham-operated, treated by sc saline solution. ACTHs, T4, saline solution were administered on days 7-16. The animals received po caffeine (CAF) 4 mg/kg as citrate salt on day 15. Ten blood samples were drawn from the tail. Plasma CAF concentrations were determined by HPLC. CAF apparent clearance and apparent volume of distribution were lower in H(-) rats than in controls: 0.281 +/- 0.072 vs 0.455 +/- 0.165 l/kg/h (-38%; P less than 0.05) and 0.520 +/- 0.239 vs 1.28 +/- 0.266 l/kg (-59%; P less than 0.01) respectively. CAF half-life was lower in H(-) rats than in controls: 1.33 +/- 0.621 vs 2.12 +/- 0.676 h (-37%; P less than 0.01). CAF is a drug with a low hepatic extraction ratio and low plasma protein binding. CAF clearance is therefore primarily dependent on intrinsic clearance, which depends on the activity of the enzymes involved in CAF metabolism. These data suggest that hepatic CAF metabolism is reduced in H(-) rats treated by SC ACTHs and T4. The decrease in CAF apparent volume of distribution is probably related to dehydration, as suggested by increase in urine flow and hematocrit. The CAF half-life was probably low because the volume of distribution was proportionally more decreased than the clearance. Our results suggest that the pituitary gland plays a role in the regulation of hepatic CAF metabolizing enzymes.

Adrenocorticotropic Hormone↗
PubMed1990

Nitrofurantoin excretion in human milk.

Six lactating white healthy women (26-36 years old, weighing 45-58 kg) were treated with 50 mg nitrofurantoin tablets, a urinary antiseptic. They received either 50 mg (group I; n = 3) or 100 mg (group II; n = 3) 3 times a day (09.00, 16.00, 19.00 h) for 24 h, 2-5 days after the delivery of a full-term neonate. The study was performed on the 4th dose at 09.00 h just before breakfast. Milk samples were collected before, 3 and 6 h after the nitrofurantoin administration with an Egnell SMB breast pump. The complete milk samples were collected from each breast, and pooled. 5 ml venous blood samples were drawn before, 1, 2, 3 and 6 h after nitrofurantoin administration. Plasma and milk nitrofurantoin concentrations were measured by HPLC. Apparent elimination half-life and apparent plasma clearance were the same in both groups, 0.8 +/- 0.09 h and 27.6 +/- 5.57 l/h, respectively. Nitrofurantoin was not detectable in the milk just before the 4th administration. The amount excreted in the milk within 6 h after nitrofurantoin administration was 22-57 micrograms (I) and 61-284 micrograms (II) which represents 0.05-0.11% (I) and 0.06-0.28 (II) of the nitrofurantoin dose. The nitrofurantoin concentration ratio of the breast milk to the plasma collected at 3 h was 2.2 +/- 1.2 (I) and 2.3 +/- 1.6 (II). These results show that nitrofurantoin excretion in human milk is low: below 0.12 (I) and 0.29% (II). It suggested that breast-fed newborn infants from mothers treated with nitrofurantoin would be exposed to small amounts of drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Sequence of rat skeletal muscle phosphoglycerate mutase cDNA.

A cDNA clone coding rat skeletal muscle phosphoglycerate mutase was isolated from a rat muscle lambda gt10 cDNA library and its sequence was determined. The deduced protein possesses 252 amino acids and is 94% homologous with respect to human muscle phosphoglycerate mutase. No amino acids changes occur at the active site and structural predictions suggest strong conformational homologies with other enzymes of the mutase family.

Amino Acid Sequence↗
PubMed1989

Dihydrolipoamide dehydrogenase: functional similarities and divergent evolution of the pyridine nucleotide-disulfide oxidoreductases.

Dihydrolipoamide dehydrogenase (E3) is the common component of the three alpha-ketoacid dehydrogenase complexes oxidizing pyruvate, alpha-ketoglutarate, and the branched-chain alpha-ketoacids. E3 also participates in the glycine cleavage system. E3 belongs to the enzyme family called pyridine nucleotide-disulfide oxidoreductases, catalyzing the electron transfer between pyridine nucleotides and disulfide compounds. This review summarizes the information available for E3 from a variety of species, from a halophilic archaebacterium which has E3 but no alpha-ketoacid dehydrogenase complexes, to mammalian species. Evidence is reviewed for the existence of two E3 isozymes (one for pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex and the other for branched-chain alpha-ketoacid dehydrogenase complex) in Pseudomonas species and for possible mammalian isozymes of E3, one associated with the three alpha-ketoacid dehydrogenase complexes and one for the glycine cleavage system. The comparison of the complete amino acid sequences of E3 from Escherichia coli, yeast, pig, and human shows considerable homologies of certain amino acid residues or short stretches of sequences, especially in the specific catalytic and structural domains. Similar homology is found with the limited available amino acid sequence information on E3 from several other species. Sequence comparison is also presented for other member flavoproteins [e.g., glutathione reductase and mercury(II) reductase] of the pyridine nucleotide-disulfide oxidoreductase family. Based on the known tertiary structure of human glutathione reductase it may be possible to predict the domain structures of E3. Additionally, the sequence information may help to better understand a divergent evolutionary relationship among these flavoproteins in different species.

Amino Acid Sequence↗
PubMed1989

Zolpidem excretion in breast milk.

Five, lactating, healthy white women were treated with a single 20 mg tablet of zolpidem 3-4 days after the delivery of a full term baby. The drug was administered at 20.00 h, 30 min after dinner, and milk samples were collected before and 3, 13 and 16 h. Venous blood 5 ml was taken before and 1.5, 3, 13, 16 h after zolpidem administration. The apparent elimination half life, estimated from plasma zolpidem concentrations was 2.6 h. The amount of zolpidem excreted in the milk at 3 h ranged between 0.76 and 3.88 micrograms, which represented 0.004 to 0.019% of the administered dose; no detectable (below 0.5 ng/ml) zolpidem was found in the milk at subsequent sampling times. The ratio of the zolpidem concentrations in breast milk and plasma at 3 h was 0.13. The apparent breast milk clearance of zolpidem, calculated from the ratio of the total amount of zolpidem excreted in milk to its AUC in plasma was 1.48 ml/h. The results show that the excretion of zolpidem in human milk is very low (below 0.02%) and that most of it takes place during the first 3 h following drug intake.

Adult↗