Biomedical subjects

M O Richard

Publications and source records attributed to M O Richard.

At least 19 recordsLinked to original sources

PubMed1994

Plasma 5-fluorouracil and alpha-fluoro-beta-alanin accumulation in lung cancer patients treated with continuous infusion of cisplatin and 5-fluorouracil.

This study was undertaken to investigate the day-to-day pharmacokinetic variability of 5-fluorouracil (5FU) given as a continuous i.v. infusion concomitantly with cisplatin. Ten lung cancer patients were investigated during the first course of chemotherapy. All patients had advanced, previously untreated, inoperable non-small-cell lung cancer. They received continuous infusions of cisplatin given at 100 mg/m2 over 5 days and of 5FU given at 1 g/m2 daily from day 2 to day 5. Both drugs were infused i.v. for 24 h/day at a constant rate with a volumetric pump. Blood samples were drawn from day 2 to day 5, every 4 h from 8 a.m. to 8 p.m. and every 2 h during the night (8 p.m. to 8 a.m.). Plasma 5FU and FBAL concentrations were determined simultaneously by gas chromatography-mass spectrometry. Plasma 5FU concentrations varied widely over the 4-day treatment course for each patient. Despite continuous constant-rate 5FU administration, plasma 5FU concentrations were significantly lower between 8 a.m. and 8 p.m. than during the night. Mean plasma concentrations of 5FU and FBAL increased significantly from the 1st day (0.42 and 1.19 micrograms/ml for 5FU and FBAL, respectively) to the 4th day of 5FU infusion (0.67 and 1.78 micrograms/ml for 5FU and FBAL, respectively). Further study is warranted to elucidate the mechanisms of the observed increase in plasma 5FU concentrations as well as its relationship with cisplatin coadministration and to assess the clinical relevance of this plasma 5FU accumulation.

Aged↗

PubMed1993

Lack of effect of magnesium-aluminium hydroxide on the absorption of theophylline given as a pH-dependent sustained release preparation.

Antacids can modify the pharmacokinetic parameters of sustained-release preparations of theophylline by changing the gastric pH. Though this has been studied with various theophylline/antacid combinations, the specific preparations investigated here have not previously been tested. The objective of the study was to assess any change in the availability of theophylline from a sustained-release preparation (SR), induced by the coadministration with an antacid. The study was designed as a double-blind randomized crossover trial in the Pneumology Departments of three general hospitals. Fifteen patients were studied. They all had stable asthma treated with theophylline and no major organ failure or gastro-intestinal lesions requiring the use of antacids. The antacid (aluminium hydroxide 800 mg and magnesium hydroxide 800 mg), or placebo, tid, was added to a stable regimen of theophylline SR bid, for 4 days, in crossover fashion. Plasma theophylline concentrations were measured before and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after the morning dose of Armophylline on the fourth day of each treatment period; the maximum plasma concentration (Cmax), and time to Cmax (tmax) were noted, and the area under the 24-h time-concentration curve (AUC0-24) and mean plasma concentration (Cmean) were computed. Peak expiratory flows on the same day, before and 3, 6 and 12 h after the morning dose of Armophylline were also measured. There was no change in any of the parameters studied. The addition of the antacid to theophylline, each given according to standard clinical practice, did not modify the pharmacokinetics of the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Dose-response study of metoclopramide in gastroesophageal reflux in infancy.

Twenty-four infants, 1 to 18 months-old, who were referred to four centers for suspected gastroesophageal reflux and whose esophageal pH after a standard formula meal given at 9 to 10 am (Ho-day 1) fulfilled the criterion of being < 4 for more than 5% of the time between H1 and H6, entered a double-blind placebo-controlled dose-response trial of metoclopramide (M). Twenty-four hours later (day 2), patients were randomly assigned to receive either placebo or a single 0.1, 0.2, or 0.4 mg/kg dose of metoclopramide, 30 min before the formula meal (n = 6/group) and the procedure was repeated. Metoclopramide plasma concentration was measured 1 h after dosing (C1h). On day 1, the time during which the esophageal pH was < 4 (time pH < 4), and five other parameters, were not significantly different in the treatment groups. On day 2, time pH < 4 (m(SD)) decreased from 33(13) to 30(33), 39(27), to 36(47), 42(15) to 18(13) and 48(25) to 31(46) min in the placebo, 0.1, 0.2, and 0.4 mg/kg metoclopramide groups, respectively. Possibly due to the large interindividual variability, no significant differences in parameters were observed between the different groups. None of the parameters correlated with the metoclopramide dose. Time pH < 4 expressed as the difference between day 1 and day 2, relative to day 1, decreased significantly as a function of C1h. No side effects were observed. A similar study should be performed after repeated dosing regimen.

Analysis of Variance↗

PubMed1992

Could saliva stand for plasma in theophylline monitoring in asthmatic children? Still a controversial problem.

Theophylline determination in saliva was proposed several years ago as a convenient and non-invasive alternative to monitoring plasma in children and adults. Published data demonstrated that theophylline saliva concentration linearly correlates plasma concentration. However, the variability found in interindividual serum/saliva ratios and the wide scattering among the data points precluded the clinical use of saliva for theophylline monitoring. The purpose of this study was to compare different standardized methods for obtaining stimulated saliva intending to reduce the variability in plasma/saliva ratios and to determine the most reliable one. A group of 150 ambulatory chronic asthmatic 4.5 to 20.83 (10 +/- 3.7; M +/- SD) year-old patients receiving theophylline 6.85 +/- 1.88 mg/kg every 12 h as slow release preparations for 4 to 100 days was studied. One ml venous blood and salivary specimens were simultaneously collected 5.15 +/- 0.36 h after the morning maintenance dose. In a subgroup of 75 patients, saliva was collected using first a new device called salivette, immediately followed by the collection of an expectorated sample 30 s after citric acid crystals stimulation. In the other patients saliva was collected using citric acid containing salivette. Theophylline concentration was determined using HPLC. For all types of saliva collection, salivary and plasma theophylline concentrations correlated significantly. However whichever method was used, based on the -2 to +2 SD interval, a large range of plasma theophylline was predicted from a single salivary theophylline concentration. Despite a further standardization of the sampling of saliva, saliva theophylline could not accurately predict plasma concentration.

Adult↗

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

[Maximal ventilatory pressure through the mouth in adults: normal values and explanatory variables].

Mouth pressure measured during maximal inspiratory or expiratory efforts depends on the force exerted by ventilatory muscles. Normal values and anthropometric factors accounting for maximal inspiratory and expiratory pressures (MIP, MEP) are not fully agreed upon to date. We measured MIP and MEP in 253 normal subjects (135 females and 118 males, age 15-59 years) using a digital transducer (163 Sibelmed). All subjects had normal forced vital capacity (FVC) and one second forced expiratory volume (FEV1). Sex, age, height and weight were recorded for all subjects and were entered as independent variables in computation of linear multiple regressions with MEP or MIP the dependent variables. MEP and MIP were greater in males than in females (p less than 0.01) with MIP lower than MEP in both sexes (p less than 0.01). In both males and females, FVC and FEV1 depend on age and height (p less than 0.01). In the entire group, we found a correlation of MIP in females and MEP in males with age (p less than 0.01) and of both MIP and MEP in females with weight (p less than 0.01). However, in subjects aged 20-59 years, there was no significant dependence of MIP and MEP on age, and when the weight of subjects was normal (n = 170), MIP and MEP were independent of weight. We conclude that in adults aged 20-59 years and with normal weight, maximal ventilatory pressures depend solely on sex. In this subgroup mean (+/- SD) values of MEP and MIP were 111 +/- 25 cmH2O and 79 +/- 19 cmH2O respectively in females and 192 +/- 42 cmH2O and 117 +/- 25 cmH2O in males.

Adolescent↗

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

Evolution of atenolol kinetics when hypothyroidism is corrected.

A single oral dose of atenolol 100 mg was given to 7 hypothyroid patients (4 F, 3 M), before and after correction of hypothyroidism, mean delay 3.5 months (2 to 6.5 months). There was no change in the elimination parameters of atenolol, but the maximal plasma atenolol concentration was increased (1.66 to 7.37 mg.l-1) as was the AUC (14.9 to 52.1 mg.l-1.h) when the hypothyroidism had been treated. Only one patient differed: he had had a supra-selective vagotomy, and had similar curves before and after treatment of the hypothyroidism, both being similar to the plasma concentration curves found in the other patients after correction of the hypothyroidism. The results suggest an increase in the bioavailability of atenolol when hypothyroidism is corrected. The findings in the patient with vagotomy suggest that the decreased bioavailability during hypothyroidism might be related to changes in intestinal pH. Further studies are needed of the impact of hypothyroidism on gastric and pancreatic or biliary function and its consequences for drug absorption, and drug pharmacokinetics.

Adult↗

PubMed1990

Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels.

Thirteen newborn infants (five premature, eight full term) with severe seizures and not responding to phenobarbital and diazepam received a lidocaine (LD) infusion. The schedule was 4 mg/kg/h on the 1st day, 3 mg/kg/h on the 2nd day, 2 mg/kg/h on the 3rd day, and 1 mg/kg/h on the 4th day. The LD plasma levels were measured every 24 h just before decreasing the dose. The control of seizures was achieved in 11 of 13 patients, with plasma LD concentration ranging from 2.8 to 10.5 mg/L. The LD concentration was linearly correlated with the dose in each group. In the premature group, LD clearance was always smaller than in the full-term group. Although no side effects were observed on heart rate and blood pressure, it is suggested that the dose of LD be adjusted to maintain the LD concentrations between 3-6 mg/L.

Diazepam↗

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

Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function.

To elucidate the pathogenesis of bronchospasm in congestive heart failure, we studied 23 patients with chronic impairment of left ventricular function due to coronary artery disease or dilated cardiomyopathy. In 21 of them we found marked bronchial hyperresponsiveness to methacholine. The mean dose (+/- SD) of methacholine that elicited a 20 percent decrease in the forced expiratory volume in one second (FEV1) was 421 +/- 298 micrograms, nearly the same as in patients with symptomatic asthma. In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function. Administration of the bronchodilator albuterol led to a partial (43 percent) reversal of the methacholine-induced bronchial obstruction. In 12 patients, pretreatment with the alpha-adrenergic agonist methoxamine (10 mg by inhalation), a potent vasoconstrictor, fully prevented the methacholine-induced decrease in FEV1. The protective effect of methoxamine was blocked by the alpha-adrenergic antagonist phentolamine in all six patients who received this agent. We conclude that bronchial hyperresponsiveness to cholinergic agonists is frequent in patients with impaired left ventricular function and may contribute to the wheezy dyspnea commonly observed in such patients. The bronchoconstriction may be mediated at least in part by dilatation of the bronchial vessels.

Adult↗

PubMed1989

Pharmacokinetics of intravenous salbutamol in renal insufficiency and its biological effects.

Salbutamol was administered intravenously to 5 patients with renal function impairment for estimation its pharmacokinetic parameters. The mean terminal half-life was 256 min, similar to previously reported values in healthy adults. The mean clearance (167 ml/min) and the mean volume of distribution (551) were decreased. These parameters were not correlated with the creatinine clearance. A slight but significant decrease was observed in the plasma potassium level up to 125 min after the salbutamol infusion. The heart rate was significantly increased, and the increase in 3 patients was correlated with the salbutamol concentration. The biological effects of the drug were less marked than expected.

Acute Kidney Injury↗

PubMed1989

Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients.

Nalbuphine is a new agonist and antagonist opioid analgesic agent that undergoes an important hepatic metabolism. In this study, we compared the pharmacokinetics of intravenous and oral nalbuphine in three groups of subjects: group I consisted of 14 children from 1 1/2 to 5 years of age (group IA) and from 5 through 8 1/2 years of age (group IB), group II consisted of 9 healthy male volunteers from 23 to 32 years of age, and group III consisted of 9 elderly patients from 65 to 90 years of age. All subjects and patients had normal hepatic and renal functions. The children received an intravenous injection of nalbuphine (0.2 mg/kg), and the subjects and patients in groups II and III received, at random, 10 mg intravenous injections and 30 mg oral doses of nalbuphine on two separate occasions. The distribution of nalbuphine was not modified with age. Elimination half-life (t1/2) was significantly shorter in group I (0.9 hour) than it was in group II (1.9 hours) and in group III (2.3 hours). Systemic clearance of nalbuphine decreased significantly with age. Absolute bioavailability of nalbuphine increased from F = 12% in group II to 46.3% in group III (p less than 0.01). These findings suggest that doses and rates of administration of nalbuphine should be adapted in younger patients and in elderly patients.

Administration, Oral↗

PubMed1989

Pharmacokinetics of propofol in young children after a single dose.

The pharmacokinetics of propofol were studied following a single bolus injection (2.5 mg kg-1) in 10 healthy children (4-7 yr). Propofol was distributed rapidly and extensively (Vss 10.9 (1.2) litre kg-1) and cleared rapidly from the body (Cl 30.6 (2.9) ml min-1 kg-1). With the exception of a larger central compartment volume (V alpha 722 (113) ml kg-1), these data are similar to those reported for young adults who received an identical dose and who underwent sampling over the same period. The larger value of V alpha is consistent with the higher induction dose requirement reported for children.

Child↗