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Biomedical subjects

J F Thiercelin

Publications and source records attributed to J F Thiercelin.

At least 19 recordsLinked to original sources
PubMed1999

Disposition of tiludronate (Skelid) in animals.

The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been studied after oral and intravenous doses. Like other bisphosphonates, tiludronate was characterized by poor absorption from the gastrointestinal tract. Peak plasma concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon (4.5 h). Food intake highly impaired intestinal absorption The affinity of tiludronate for bone and the slow release from this deep compartment could account for the large volume of distribution and the low plasma clearance found in all species. Tiludronate has low affinity for red blood cells and binds moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared to be the main target for deposition. Distribution into bone was not homogenous, with higher levels in the trabecular bone than in the corticol part of the long bones. The uptake of tiludronate into bone was unequivocally less in the older animal. No metabolism occurred in the tested animal species. The major route of elimination of the absorbed drug is urine. Preclinical observations made with tiludronate, like with other bisphosphonates, were predictive of results obtained in clinical investigation.

Aging↗
PubMed1996

Multiple dose pharmacokinetics of tiludronate in healthy volunteers.

OBJECTIVES: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. METHODS: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. RESULTS AND CONCLUSIONS: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg.1(-1), and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg.1(-1) for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1-84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way.

Adolescent↗
PubMed1995

Human pharmacokinetics of tiludronate.

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

Administration, Oral↗
PubMed1992

Effects of zolpidem versus diazepam and placebo on breathing control parameters in healthy human subjects.

The following study explores the possibility that zolpidem, a new hypnotic agent derived from imidopyridine, may induce changes in ventilatory function in normal subjects. The study, conducted double-blind on 16 subjects (eight men and eight women, aged 21 to 33 years) was undertaken in two successive phases: phase A with a cross-over, intended to compare the ventilatory effects of 10 mg oral dose of diazepam with a placebo, and then phase B, with a Latin square design, intended to compare the effects of 10 and 20 mg oral doses of zolpidem with 10 mg oral doses of diazepam and a placebo. Central inspiratory drive was assessed by occlusion pressure (P0.1) and breathing pattern in air and during carbon dioxide rebreathing. Measurements were performed one and three hours after each drug or placebo administration. Zolpidem did not affect tidal volume (Vt), slopes S1, S2 or P0.1, but decreased the duration of the phases of the respiratory cycle ti by 14% (p less than 0.01) and ttot by 15% (p = 0.03) after three hours post dosing without any change in ventilation, Vt/ti or ti/ttot. Nevertheless, these timing changes, although statistically significant, seem to have no clinical relevance to overall ventilation regulation in normal subjects. On the other hand, diazepam slightly changed S2 at three hours post dosing (0.14 +/- 0.07 versus 0.17 +/- 0.10 after the placebo; p = 0.06) without modifying the other parameters.

Administration, Oral↗
PubMed1991

Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses.

In a double-blind, placebo-controlled, cross-over experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0-54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1-4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng.ml-1, respectively. In 50% of the subjects Cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng.ml-1.h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18.1, and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

1. The effects of zolpidem 20 mg, flunitrazepam 2 mg and placebo, administered at bed time, were studied in 12 healthy young male volunteers. 2. The assessments included, at awakening, subjective ratings of overnight sleep, cognitive function, psychomotor performance (digit symbol substitution, choice reaction time, flicker fusion threshold), subjective ratings of alertness, and plasma assay of residual drug concentration. Daytime sleep propensity during the day after dosing was evaluated with the multiple sleep latency test. 3. Compared with placebo, both active drugs improved subjective assessment of the ease of getting to sleep. At awakening, under flunitrazepam treatment, the reduction of performance, on memory and psychomotor tests, paralleled an increased subjective rating of sleepiness, but zolpidem treatment left subjects unimpaired compared with placebo. Similarly, daytime sleep propensity was enhanced throughout the following day under flunitrazepam treatment, but not under zolpidem treatment. Plasma assay for residual drug concentration at awakening found significant amounts of flunitrazepam and marginal amounts of zolpidem. 4. Results indicate that zolpidem 20 mg is devoid of residual effects in a range of tasks that were sensitive enough to demonstrate a prolonged wakefulness impairment following flunitrzepam 2 mg in healthy volunteers.

Administration, Oral↗
PubMed1990

Can therapeutic efficacy be predicted from phase I data?

The aim of phase I studies per se is to explore the tolerance of new compounds which have demonstrated a certain level of activity in animals at sufficiently low non-toxic doses. In most cases, these studies are conducted in 2 steps in a limited number of healthy male volunteers: a single rising dose study followed by a repeated dose study in which the pharmacokinetic features of the drug are explored. In such a context, it would be quite presumptuous to ascertain the therapeutic efficacy of a drug from those initial human studies. At best, these trials can provide pharmacological and/or biological indications which are related to some degree to the expected efficacy of the drug: hypnotics, anticancer drugs, antibiotics, platelet antiaggregants, beta-blockers, etc. In these examples it is recommended to design controlled study protocols so as to better investigate these potentially interesting signs of activity. In the majority of cases, however (psychoactive drugs, analgesic, anti-inflammatory drugs, gastro-intestinal compounds), phase I studies will unfortunately not provide much information regarding the expected therapeutic activity.

Drug Evaluation↗
PubMed1990

Development and pharmacokinetics of a new sustained-release formulation of diltiazem.

Among the antihypertensive agents, calcium antagonists and in particular diltiazem play a leading role. To improve the conditions of diltiazem administration in the treatment of hypertensive patients a galenic formulation allowing administration of a single daily dose has been developed. The studies discussed in the following are concerned with the pharmacotechnical and pharmacokinetic development of sustained-release microgranules (sustained-release diltiazem). Bioavailability studies were performed after single-dose administration and after repeated-dose administration which were compared to the conventional formulation of diltiazem, Tildiem. After single-dose administration the following results were achieved: a relative bioavailability of 1.06 +/- 0.35; a prolongation of tmax of 7.16 +/- 2.66 vs. 2.46 +/- 0.80 h; and a longer final half-life of 11.8 +/- 5.3 vs. 5.6 +/- 1.1. After repeated administration of sustained-release diltiazem at a single daily dose of 240 mg compared to repeated administration of the conventional formulation of diltiazem at doses of 120 mg every 12 h over a period of 6 days, the following results were obtained: a relative bioavailability of 0.90 +/- 0.17; a lowering effect on Cmax of 191 +/- 65 vs. 230 +/- 95 ng/ml; statistically equivalent minimum concentrations of 62 +/- 21 ng/ml vs. 74 +/- 33 ng/ml. In an additional study, the effect of concurrent food intake on the bioavailability of diltiazem was confirmed. An increase in bioavailability of 28% in combination with an increase in interindividual variability was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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↗
PubMed1989

Route of administration and sex differences in the pharmacokinetics of aspirin, administered as its lysine salt.

One thousand milligrams of aspirin, as its lysine salt was administered intravenously, orally, and intramuscularly to nine male and nine female young healthy adult volunteers. After intravenous injection mean (+/- SD) values of clearance, steady-state volume of distribution, and terminal half-life were 12.2 +/- 2.2 ml/min/kg, 0.219 +/- 0.042 liter/kg, and 15.4 +/- 2.5 min, respectively, with no differences between males and females. Following administration aspirin was absorbed more quickly in females than in males (mean absorption times of 16.4 and 21.3 min, respectively although the bioavailability, 54%, was the same in both groups. In contrast, following intramuscular administration, aspirin was absorbed more slowly in females than males (mean absorption time of 97 and 53 min, respectively) but again the bioavailability, 89%, was the same in both groups. The data suggest that in the female the intramuscular injection is going into fat. Salicylic acid concentration-time profiles showed a less pronounced sex difference and were comparable among the routes of administration.

Absorption↗
PubMed1988

Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic.

The combined use of a hypnotic and a neuroleptic is a rather frequent situation, encountered especially in the psychiatric sphere. We therefore tested zolpidem and chlorpromazine in six healthy subjects by using a double-blind latin square design. All of them received single doses of 20 mg zolpidem (ZOL), 50 mg chlorpromazine (CPZ) and the combination of ZOL + CPZ. The medication was given as a single dose in the morning and each treatment being separated by a 1-week interval. Zolpidem produced moderate to severe sedation varying according to the subjects. Psychometric performances (manual dexterity, Stroop test), alertness and psychomotricity (visual analogue scales) were reduced up to 3 h after drug intake. Chlorpromazine alone did not have much effect. Combined administration of ZOL and CPZ was rather more effective than ZOL alone. The pharmacokinetics of ZOL or CPZ remained unchanged except for the elimination half-life of CPZ, which increased significantly when administered along with ZOL. No other pharmacodynamic or pharmacokinetic interaction between ZOL and CPZ was evident. The fact that the ZOL and CPZ combination accentuated the pharmacodynamical effects can be explained to result from the summation of each of their own pharmacological effect.

Adult↗
PubMed1988

Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine.

Zolpidem is a new imidazopyridine derivative acting as a hypnotic which may be prescribed with H2 receptor antagonists in patients with peptic ulcer. A cross-over study (cimetidine, 1 g daily for 19 days; ranitidine, 300 mg daily for 19 days; wash-out period: 20 days) was carried out in six healthy volunteers. Zolpidem, 20 mg was administered orally at 09h00 prior to any treatment and on days 2 and 17 of each treatment period. Antipyrine clearance was also determined before and on day 18 of each treatment period. Under these experimental conditions, the inhibitory effect of cimetidine on the Cyt P-450 mono-oxygenase system has been demonstrated (reduced clearance of antipyrine, p less than 0.01) but the pharmacokinetics of zolpidem did not appear to be modified. Zolpidem induced hypnotic effects for the first 3 h which tend to be prolonged by the combination with cimetidine. Psychometric and pharmacokinetic evaluations did not show significant interactions with either anti-H2 receptor agent following zolpidem administration.

Adult↗
PubMed1986

Pharmacokinetics of betaxolol in middle aged patients.

The pharmacokinetics of betaxolol was studied in 8 middle-aged (40-60 years) subjects after oral (20 mg) and intravenous (10 mg) administration. The principal parameters were almost identical to those observed in young healthy volunteers. The recommended therapeutic regimen, a single daily dose of 20 mg, appears well suited for middle aged, hypertensive patients.

Administration, Oral↗
PubMed1985

Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine.

Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti-epileptic drug. The increase in total clearance resulted largely from increased formation clearances of the 4-hydroxy and 3-hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme-inducing drugs. It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.

Adult↗
PubMed1984

Effects in man of progabide on prolactin release induced by haloperidol or domperidone.

The effects of progabide, a GABA receptor agonist, on haloperidol-induced and domperidone-induced hyperprolactinaemia have been studied in man. There was a moderate inhibition by progabide of the rise in prolactin after domperidone. No such effect was found after haloperidol. The results support the view that in man, as in animals, GABA agonists have an inhibitory effect on prolactin release, probably at the level of the hypothalamus and anterior pituitary.

Adult↗
PubMed1984

Metronidazole kinetics and bioavailability in patients undergoing gastrointestinal surgery.

Kinetics and bioavailability of metronidazole were studied in 17 patients admitted in our emergency care unit for gastrointestinal surgery. All were treated with intravenous metronidazole (500 mg three times a day) before, during, and for 4 days after surgery. Seven of the patients continued the intravenous regimen and seven were switched to oral therapy with the same dose and dosing interval for 4 additional days. Kinetic evaluations were performed at steady state on days 4 and 8. The main unexpected result was a consistent 51% increase in AUC with no increase in elimination t 1/2 when intravenous was changed to oral therapy. This change was accompanied by an upward 75% shift in the trough metronidazole plasma concentrations. There was no change when patients remained on intravenous metronidazole. Reduction of clearance on oral treatment appears to be the most likely explanation.

Administration, Oral↗