Biomedical subjects

G Houin

Publications and source records attributed to G Houin.

At least 55 records · Page 3Linked to original sources

PubMed1998

In vitro study of the percutaneous absorption of four aromatic amines using hairless rat skin.

Using hairless rat skin maintained in a Franz diffusion cell, the percutaneous penetration of four aromatic amines: para-chloroaniline (PCPA), meta-trifluoromethylaniline (mTFMA), dichloro-3,4-aniline (3,4-DCA) and dichloro-3,5-aniline (3,5-DCA) were studied. The purpose of the studies was to determine the permeation parameters (rate of permeation, permeability rat constant) in order to compare the rate of absorption of the four amines. The results show that the four amines penetrate significantly across the skin, but with different rates. 10 h after in vitro application (2 mg/cm2), the extent of permeation was PCPA >> mTFMA > 3,4-DCA > 3,5-DCA.

Aniline Compounds↗

PubMed1997

Simple high-performance liquid chromatographic method to analyse megazol in human and rat plasma.

A simple and sensitive high-performance liquid chromatographic method has been developed to measure megazol in human plasma. The method was optimized and validated according to the Washington Concensus Conference on the Validation of Analytical Methods (V.P. Shah et al., Eur. J. Drug Metab. Pharmacokinet., 15 (1991) 249). The criteria of complete validation were specificity, linearity, precision, analytical recovery, dilution and stability. It involved extraction of the plasma with dichloromethane, followed by reversed-phase high-performance liquid chromatography using a Kromasil C8 column and UV detection at 360 nm. The retention times of the internal standard (tinidazol) and megazol were 6.10 and 9.60 min, respectively. The standard curve was linear from 2 ng ml-1 (limit of quantification) to 2000 ng ml-1. The coefficients of variation for all the criteria of validation were less than 6%; 85 to 92% extraction efficiencies were obtained. Megazol was stable during the storage period (one month at -20 degrees C) in plasma and for two months at 25 degrees C in standard solution. The method was tested by measuring the plasma concentration following oral administration to rat and was shown to be suitable for pharmacokinetic studies.

Animals↗

PubMed1997

Pharmacology in space: pharmacotherapy.

This chapter summarized the information available on the pharmacological kits onboard spacecraft and on the use of drugs in space, while the next chapter is dedicated to the impacts of weightlessness on drug pharmacokinetics. The need of a selected group of drugs for the use of astronauts during short-term and long-term spaceflights has been discussed. Recommendations are made for a Space Pharmacopoeia as well as for the areas of research needed to adapt medication to the weightlessness of the space environment. Although the usefulness of these drugs has been clearly demonstrated, their use also raises several problems. Physiological changes due to weightlessness may induce changes in pharmacokinetic behavior of drugs and influence their dosage regimen. Inflight data obtained by salivary drug monitoring have shown changes in the distribution of scopolamine and a significant change in the disposition of the common pain-relief agent acetaminophen taken inflight, in both drug concentration and time course. The authors of this study emphasize, however, that their data are preliminary and as yet incomplete. Further simulation studies and, if possible, inflight experiments are required. In vitro studies of the antibacterial activity of antibiotics under space conditions have shown an increased resistance of Escherichia Coli to colistin and kanamycin, and a lowered resistance of Staphylococcus Aureus to oxacillin, chloramphenicol, and erythromycin. The possible consequences of these findings for the treatment of infections contracted by astronauts are yet to be elucidated. There is still a lack of pharmacological countermeasures, particularly for preventing the progressive bone demineralization occurring in weightlessness. The treatment of space motion sickness with drugs carries with it the problem of undesirable side-effects on psychomotor performance. In order to arrive at the most appropriate medical kit for a particular mission, the best trade-off of risk versus benefit for the individual and the mission must always be attempted for any pharmacological agent.

Aerospace Medicine↗

PubMed1997

Pharmacology in space: pharmacokinetics.

The possible pharmacokinetic mechanisms affected by microgravity are listed in Table 5. In studies of pharmacokinetics in humans, one has generally only access to drug concentrations in plasma and urine which are the results of several concurrent mechanisms. During weightlessness, different changes may occur in each step of the drug disposition process. The most important changes need to be identified and then predicted for the main drugs used in space. The use of a drug as a probe (Table 6) will permit to estimate the changes in specific pharmacokinetic parameters during spaceflight. However, this type of studies is technically difficult to carry out in space, but simulation studies on the ground are easier to perform. Two studies of hepatic blood flow showed no changes in this parameter during bedrest, but a more recent study showed changes in lidocaine disposition during a four-day head-down-tilt. Due to the large differences between individuals, pharmacokinetic changes must be fairly large (> 10-20%) to be observed in studies with probes. To detect a small change in weightlessness will require a number of subjects far higher than can be achieved in spaceflight. In summary, spaceflight is known to change many physiological parameters. The pharmacokinetics of drug disposition is determined by the combination of several complex phenomena. Each step of this process may be influenced by physiopathological changes occurring in spaceflight. This review shows how from a theoretical point of view absorption, distribution and elimination of drugs may be affected by weightlessness. The physiological changes most frequently involved in these modifications are the changes in blood flow due to the fluid shift.

Biological Availability↗

PubMed1997

Influence of maternal blood flow on the placental transfer of three opioids--fentanyl, alfentanil, sufentanil.

The placental transfer of three opioids used in peridural analgesia, fentanyl, alfentanil and sufentanil, and two reference substances, antipyrine and *H2O, was determined ex vivo in the human placental cotyledon system. (1) In the first set of experiments, the infusion rates were constant and fixed at physiological flow rates. Under these conditions, the magnitude of the materno-fetal transfer was in the following order: *H2O = antipyrine = fentanyl > alfentanil > sufentanil. No particular influence of molecular weight, lipophilia, pKa or the degree of ionization could be discerned. (2) In the second set of experiments, the influence of different flow rates, reflecting various pathophysiological conditions, was examined. There was a linear relationship between the maternal flow and the materno-fetal transfer of the three opioids. On the other hand, for antipyrine and tritiated water, the relationship was logarithmic, a difference attributed to the marked lipophilia of the opioids. (3) At high maternal flow rates, saturation was observed for all five substances due to the short duration of contact with the membrane. There were logarithmic relationships between the maternal flow and the materno-fetal transfer. (4) These findings emphasize the importance of the lipophilic and hydrophilic characteristics of drugs on placental transfer, especially in the event of fluctuations in maternal flow.

Alfentanil↗

PubMed1997

The dosing-time dependent influence of chronic cyclosporin A treatment on daily profiles of plasma glucose and insulin in the Wistar rat.

The dosing-time dependent effects of cyclosporin A (CsA) on glucose and insulin plasma levels were evaluated in the light of possible alterations of their biological rhythms. Male Wistar rats weighing 200-250 g were habituated to a 12:12 h light-dark cycle. At the beginning of the experiments, on day D0 (before any treatment), significant rhythms were obtained for plasma glucose and immunoreactive insulin (IRI). The plasma glucose showed a 12 h periodicity and the plasma IRI a more pronounced rhythm, with both 12 h and 24 h significant components. Plasma glucose and IRI were then determined in drug-treated (20 mg CsA/kg b.wt/day; dosing time point: T01, T07, T13, or T20) and control rats during and after a 21-day treatment period. The CsA-treated rats developed hyperglycemia and a marked enhancement of the amplitude of the daily glucose rhythm. The magnitude of these effects differed among the groups (p < 0.001). Most pronounced alterations were observed on day 21 (D21) in group T07: M = 22.5 +/- 4.0 mmol/l; A = 9.2 +/- 6.0 mmol/l. The mean plasma insulin showed little though significant (p < 0.01) decreases. For instance, on D21 in group T01, M = 28.5 +/- 3.6 microU/ml, and in group T07, M = 28.7 +/- 2.5 microU/ml. In parallel, plasma CsA levels increased during the 21-day period and differed among groups (p < 0.01). The highest levels (4-5 mg/l) were obtained in T07 and T19 on D21. After drug cessation, the levels of plasma glucose were reduced, but stayed higher than control values. Body weights were monitored; the rate of growth was lower (p < 0.01) in CsA-treated rats than in controls (2.93 +/- 0.11 versus 5.1 +/- 0.11 g/day, respectively).

Animals↗

PubMed1996

Multicenter studies on the pharmacokinetic profile of sustained-release oral diltiazem (300 mg) after once a day repeated administration: influence of age.

The influence of age on the pharmacokinetics of the oral sustained release diltiazem Mono-Tildiem LP 300 mg was investigated in 12 middle-aged (40-64 years), 12 elderly (65-80 years) patients and compared to a control group of 54 young healthy volunteers (18-36 years). Each subject received daily a single dose of diltiazem slow release (300 mg) in the morning for 5 consecutive days. On the fifth day of treatment, the pharmacokinetic parameters of diltiazem and of 2 of its circulating metabolites (N-monodemethyldiltiazem and deacetyldiltiazem) were evaluated. The mean diltiazem Cmax was 199.3 +/- 117.8 ng/ml, 254.8 +/- 85.2 ng/ml and 154.5 +/- 63.2 ng/ml in middle-aged, elderly, and young healthy subjects, respectively. Mean plasma Cmin concentration was also higher in elderly subjects than in middle-aged and young subjects: 129.7 +/- 77.9 ng/ml versus 66.8 +/- 56.8 and 66.3 +/- 32.3 ng/ml, respectively. The AUC0-24 showed the same trend: 4,042 +/- 1,136 ng/ml.h in elderly, 2,995 +/- 1,905 ng/ml.h in middle-aged, and 2,564 +/- 1,205 ng/ml.h in young subjects. These parameters were statistically higher (p < 0.01) in the elderly subjects than those obtained in younger people. No statistical difference was observed between young volunteers and middle-aged patients. The Tmax did not differ significantly with age (5.1 +/- 4.4, 6.8 +/- 2.8, 6.1 +/- 3.5 hours, respectively). The ratios between the AUC of each metabolite and that of the parent compound did not vary with the age. These results suggest that in elderly people (> 65 y) the bioavailability of diltiazem is increased, probably due to a reduction of the first-pass effect. Based on the pharmacokinetic results, although safety data did not show any specific trend with age, a precautionary reduction of the dose at the start of the treatment seems advisable.

Adolescent↗

PubMed1996

In vitro and in vivo protein binding of methotrexate assessed by microdialysis.

The purpose of the study was firstly to estimate methotrexate protein binding using microdialysis, and secondly to determine the influence of the protein content in the dialyzed medium on the dialysis membrane recovery. In vitro recovery was estimated by both water recovery method and concentration difference method. The relative recovery was independent of methotrexate concentration: 39.3% +/- 2.86% and 39.2 +/- 1.27% for 50 microM and 300 microM, respectively. A significant influence of the presence of proteins on the dialysis membrane recovery was observed: 55.9% +/- 2.7%, 42.3% +/- 7.5% and 45.5% +/- 0.1% for buffer, human serum albumin (HSA) (600 microM) and human plasma, respectively. Methotrexate binding to human and rat plasma proteins showed a nonsaturable phenomenon. The bound percentages and corresponding total binding capacities were 58.7% +/- 3.13% and 1.44 +/- 0.033 mM-1 and 71.7% +/- 4.38% and 2.18 +/- 0.09 mM-1 for the human and rat plasma, respectively. For HSA this binding was saturable with an affinity constant of 4.75 +/- 0.66 mM-1. After intravenous administration (250 mg/kg) the in vivo rat plasma binding of methotrexate was roughly 20% higher (93.6%) than the in vitro methotrexate plasma binding. The in vivo relative recovery of methotrexate was found to be 12.6% +/- 1.8% versus 25.4% +/- 3.3% in vitro. This study showed that the protein content can directly affect microdialysis probe recovery. However, by taking into account this recovery, microdialysis allows to measure the protein binding of methotrexate.

Animals↗

PubMed1996

Minimal experimental requirements for structural identifiability in linear compartmental models. The software 'IDEXMIN'.

Identifiability is a structural property of compartmental systems and is of a great interest in the pharmacokinetic field. Preliminary testing for identifiability, independent of the detailed experimental data but based on the model used and the experimental schedule, enables the researcher to design precise and straightforward experiments which will lead to the structural identifiability of the system. A computer program for PC (denoted IDEXMIN) has been designed in order to test for identifiability in any n compartment system and, in the case of non-identifiability, to define the minimal experimental data required to enable the model to be identifiable. All identifiability calculations are based on the K matrix of Delforge. Commandability and controllability of a system are verified before testing for identifiability.

Computer Simulation↗

PubMed1995

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Adult↗

PubMed1995

Impact of a four-day head-down tilt (-6 degrees) on lidocaine pharmacokinetics used as probe to evaluate hepatic blood flow.

The impact of a microgravity simulation using a head-down tilt (-6 degrees) on lidocaine pharmacokinetics used as a probe to evaluate hepatic blood flow is discussed. Eight healthy male subjects were selected for a 7-day study, including a 4-day head-down tilt from day 2 to day 5. Subjects were given 1 mg/kg of lidocaine on days 1 through 5 and 7. Blood sampling, cardiac output, and hepatic artery blood flow velocity measurements were done within 6 hours after administration. Cardiac output increased significantly during head-down tilt, and returned to basal values during the recovery period. Blood flow velocity in the hepatic artery increased during the first day of the down tilt. Slight side effects (buzzing noise in the ears and sleepy feeling) were reported within minutes after the injection of lidocaine. Lidocaine disposition was modified during head-down tilt: a significant decrease in maximal concentration (1.47 +/- 0.26 mg/L on day 1 and 0.96 +/- 0.30 mg/L on day 2); an increase in elimination clearance from 8.24 +/- 3.22 mL/kg.minutes-1 to 11.63 +/- 3.00 mL/kg.minutes-1; an increase in volume of distribution on day 2 and a decrease to lower than basal value on the other days (2.77 +/- 1.73 L/kg on day 1 and 2.33 +/- 0.48 L/kg on day 7). Half-life regularly decreased from 264 +/- 210 minutes to 160 +/- 60 minutes between day 1 and day 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 MG) after repeated administration in healthy volunteers.

The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3-4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the "once a day" formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.

Administration, Oral↗

PubMed1995

A pharmacologically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer.

Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml-1 min.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Effect of adrenaline on plasma concentrations of fentanyl during epidural anaesthesia for caesarean section.

The present study was designed to assess the effect of adrenaline on the plasma concentrations of fentanyl in mothers and umbilical vessels after epidural administration for caesarean section. Thirty patients undergoing elective caesarean section were allocated randomly into two groups. Group 1 (n = 16) received 100 microg fentanyl, 10 ml of 0.5% bupivacaine and 10 ml 2% lidocaine, while group II (n = 14) received 100 microg fentanyl, 10 ml of 0.5% bupivacaine with adrenaline 1:200 000, and 10 ml of 2% lidocaine with adrenaline 1:80 000. Blood samples were obtained from the maternal antecubital vein (MV) at various times up to 6 hours after epidural injection, and from umbilical vein (UV) and arteries (UA) at birth for determination of plasma fentanyl by radioimmunoassay. Fentanyl Cmax and Tmax in MV did not differ significantly between the two groups. In umbilical vessels, plasma fentanyl concentrations were comparable in the two groups: (0.12 +/- 0.08 ng ml(-1) and 0.13 +/- 0.08 ng ml(-1) in UV and 0.08 +/- 0.07 ng ml(-1) and 0.06 +/- 0.05 ng ml(1) in UA of groups I and II respectively). The maximum plasma concentration in UV was 0.24 ng ml(-1) in group I and 0.25 ng ml(-1) in group II. There was no significant correlation between umbilical vessel (vein or artery):MV ratio and dose to delivery interval and no difference between the two groups in Apgar score or umbilical cord pH.

Journal Article↗

PubMed1995

Microdialysis probes calibration: gradient and tissue dependent changes in no net flux and reverse dialysis methods.

Probe calibrations are required for accurate estimations of extracellular concentrations in microdialysis experiments. Several methods have been developed and validated for in vivo determination of dialysis membrane recovery such as the perfusion rate method and the No Net Flux method. In this study, the No Net Flux and the reverse dialysis methods were investigated. Both measure the net transport of drug across the dialysis membrane. The recovery was defined as R = (Cin - Cout)/Cin, where Cin and Cout were the concentrations of a compound in the perfusate and in the dialysate, respectively. First, the accuracy of the No Net Flux method to estimate in vivo recovery was compared in two situations: diffusion from the probe into the dialysis medium and diffusion from the outer medium into the probe. The point of no net transport was used to estimate the concentration surrounding the probe. Neither difference between extracellular concentrations (intercept values) nor difference between recoveries were observed. Then the reverse dialysis method was tested to estimate the relative loss of drug from the perfusate when the probe was placed in a drug-free medium. Finally comparisons of the behavior of the drug diffusion across the membrane under increasing gradient conditions have shown an asymptotic profile, specific of the tissue; blood, muscle, and adipose tissue. The faster a drug was removed by microvascular transport (blood > muscle > adipocytes), the higher was the recovery, until the perfusate concentration reached a threshold value where the transport process became gradient limited and no more tissue limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Estimation of the effective amount entering the body for drugs subject to enterohepatic recirculations.

A pharmacokinetic model is used to take into account multiple recirculations of drug occurring at various times after gall bladder emptying. If a dose D is initially administed, due to recirculation, an effective amount A* reaches the body. This value A* is expressed as a function of D and the model parameters, after oral administration or intravenous injection. Using areas under curves in two different situations, the reabsorption rate may be identified.

Administration, Oral↗

PubMed1995

Pharmacokinetic and bioavailability of diltiazem sustained-release: influence of food and time of administration.

Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained-release formulation (Mono-Tildiem LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained-release formulation. The influence of these factors was investigated over two different open, randomized, cross-over studies in 12 healthy volunteers. Although a significant decrease in Tmax and an increase in Cmax occurred when diltiazem sustained-release was administered with food intake, AUC0-48, and therefore the fraction absorbed, were not modified either by concurrent food intake or by different times of administration. The minor modifications of pharmacokinetic parameters of diltiazem sustained release observed were unlikely to induce any clinical consequence.

Administration, Oral↗

PubMed1995

[Relations between hematological toxicity and total and free plasma levels of etoposide in daily oral administration].

This study was undertaken in order to evaluate the inter- and intra-individual pharmacokinetic variabilities and their impact on the toxicity of oral Vépéside Sandoz administered daily for 21 days. The pharmacokinetic results confirmed the low bioavailability of this formulation (14% +/- 10%) and its large interindividual variability. Moreover, a great intraindividual variability was shown between day 1 and day 21. This fact can explain that the relationship between the relative decrease in neutrophil count and the pharmacokinetic parameters was observed only with either the mean area under the curve of concentrations versus time (AUC) or the mean residual concentrations (Cr). The determination of the fraction of plasma etoposide unbound, which ranged from 4.6 to 24.8%, improved the pharmacokinetic-pharmacodynamy relationship for AUC but not for Cr. This study showed the potential interest of etoposide drug monitoring. However, no dosage adjustment could be performed with this oral etoposide formulation because of its large intraindividual bioavailability. Since this study was performed, the Sandoz company withdrew this formulation, and replaced it by one identical with that available in other countries.

Administration, Oral↗