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G Houin

Publications and source records attributed to G Houin.

At least 73 records · Page 4Linked to original sources
PubMed1995

[Prediction of carboplatin clearance from morphological and biological patient characteristics].

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

Adult↗
PubMed1995

Sublingual apomorphine: a new pharmacological approach in Parkinson's disease?

Apomorphine, a potent dopamine agonist with mixed D1 and D2 properties, has long been recognized to have antiparkinsonian effect. Its oral administration is limited by both its hepatic first pass metabolism and adverse side effects (nausea, vomiting, azotemia). It is now widely used by subcutaneous route for the treatment of severe "off" periods seen with levodopa treatment. However, the use of penjects can be difficult in some patients with severe tremor or akineto-rigid symptoms during "off" periods. Our group has recently investigated the effect of sublingual administration of apomorphine in patients suffering from Parkinson's disease. Sublingual apomorphine was shown to reduce extrapyramidal symptoms. The main characteristics of the pharmacodynamic effects of sublingual apomorphine in parkinsonians and the relationship between pharmacodynamic and pharmacokinetic effects are discussed. Sublingual apomorphine has the advantage of being easier to administer than subcutaneous injection. For the moment, the long-term use of sublingual apomorphine is limited by two major problems: first, time for dissolution and switch "on" (which is longer than after subcutaneous route) and secondly, the occurrence of local side effects (stomatitis). Further clinical studies using either more efficient (tablets with faster dissolution) and better tolerated sublingual formulations or other dopamine agonists should be carried on before recommending this approach in the treatment of Parkinson's disease.

Administration, Sublingual↗
PubMed1994

Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY216.

This study compares the pharmacokinetic and the antithrombotic properties of two pentasaccharides with high affinity to antithrombin III with those of a conventional low molecular weight heparin, CY216, in the rabbit. On a weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR 80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7 and 26 times more potent antifactor Xa inhibitory agents than CY216. They were devoid of antithrombin activity, whereas the antifactor Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27 for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then remained constant up to the highest dose tested (500 U/kg). The clearance of NPS was unrelated to the dose and comparable to that of CY216 over 50 U/kg, whereas that of SPS was 10 times lower. Consistent results were observed after continuous intravenous infusions for 9 hours and subcutaneous administration. The duration of the antithrombotic effect was compared after a single subcutaneous injection of 250 U/kg of either compound in the stasis-Wessler model using human serum as thrombogenic stimulus. Two hours after the injection, the three compounds provided a thrombus prevention of greater than 95% and mean plasma activities of 0.8, 0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after injection, the antithrombotic effects of CY216 and NPS had totally vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for SPS. For the latter compound, significant antithrombotic effects and detectable anti-Xa activities were still recorded 48 hours after the injection. The antithrombotic potency of the three compounds was also compared as their ability to inhibit the growth of a standardized venous thrombosis during 4 hours. The lowest total doses providing the maximum inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS, and SPS, respectively. These doses generated mean steady state antifactor Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These observations indicate that the amplification mechanisms triggered by thrombin bound to fibrin and leading to the generation of new thrombin are essential to ensure venous thrombosis growth and that these mechanisms may be efficiently inhibited by pure antifactor Xa targeting agents.

Animals↗
PubMed1994

Assessment of hepatic insufficiency model in the rabbit using carbon tetrachloride intoxication.

The objective of the present study was to compare two doses (0.035 and 0.1 mL/kg) of carbon tetrachloride given intragastrically or intraperitoneally to rabbits during 8 weeks to induce a model of liver insufficiency. All animals developed pericentrolobular fibrosis. The intensity of the fibrosis was proportional to the dose. An increase in the plasma enzymatic activities (ALAT, ASAT, gamma GT) was related to the dose. Plasma proteins and creatinine levels remained unaltered during the experiment. Hepatic microsomal cytochrome P450 was reduced in treated animals in relation to the dose, as was glutathione-S-transferase enzymatic activity, whereas no change was observed in UDP glucuronyltransferase activity. When antipyrine was administered to the intragastric group, a reduction of total body clearances and an increase in half-lives and areas under the curve were observed in relation to a reduction of oxidation capacities. After intraperitoneal intoxication, only the total body clearance with a 0.1 mL/kg dose increased significantly. With the exception of the intragastric dose of 0.035 mL/kg, the pharmacokinetics of indocyanine green showed a decrease in total body clearances and an increase in areas under the curve. Distribution volumes decreased in treated animals whereas half-lives remained constant. After an intragastric dose of 0.035 mL/kg, only an increase in half-life and a decrease in total body clearance were observed. All these results indicate that rabbits chronically intoxicated with CCl4 may be an adequate model for studying the influence of hepatic insufficiency on pharmacokinetic disposition.

Alanine Transaminase↗
PubMed1994

Microdialysis: an alternative for in vitro and in vivo protein binding studies.

The aim of the present study was to compare the performance of conventional equilibrium dialysis method with a microdialysis method in studying drug protein binding. The two methods were assessed by comparing the measured mean unbound drug fraction in different plasma species in vitro in plasma of four different species and at two concentrations of the non-indolic melatonin analog S 20098. For the microdialysis study, the unbound drug fraction was calculated after correction for membrane recovery. Plasma protein binding of S 20098 ranged from 75 to 95%. In humans, rabbits and rats (10 ng/ml), equal unbound percentages were found between equilibrium dialysis and microdialysis. Microdialysis gave slightly but significantly higher values in rat (2000 ng/ml), and in monkey plasma independent of the drug concentration. Microdialysis was also performed in vivo in freely moving rats under steady-state conditions, yielding similar unbound fraction values (26.0 +/- 0.9%) to those obtained using microdialysis probes in rat plasma in vitro (24.4 +/- 1.6%). These results support the use of in vivo microdialysis in pharmacokinetic studies in freely moving animals.

Acetamides↗
PubMed1994

Pharmacokinetic study of yohimbine and its pharmacodynamic effects on salivary secretion in patients treated with tricyclic antidepressants.

The pharmacokinetic parameters and the time course of the effect after acute oral administration of yohimbine on salivary secretion in patients treated with tricyclic antidepressants were investigated. Yohimbine (10 mg) increased both salivary outflow and plasma noradrenaline levels for 4 h. Pharmacokinetic parameters (t1/2, tmax, Cmax and AUCexp) and plasma concentrations of noradrenaline were higher in patients treated with tricyclic antidepressants than in controls. At this dose, yohimbine induced a relatively large number of side effects. A lower dose (4 mg) increased salivary secretion for 3 h without any side effects in patients treated with tricyclic antidepressants but not in healthy volunteers. These data describe an interaction between yohimbine and tricyclic antidepressants and thus show that a relatively low dose (4 mg) of yohimbine could be useful in the treatment of dry mouth due to tricyclic antidepressants.

Administration, Oral↗
PubMed1994

Comparison of the "zero crossing" method in derivative spectroscopy and ultrafiltration for the determination of free and bound fractions of mitoxantrone.

In vitro mitoxantrone binding to human serum, human serum albumin (HSA, 600 microM) and alpha-1-acid glycoprotein (AAG, 15 microM) was investigated by ultrafiltration and the first-derivative spectrophotometry based on the "zero crossing" method. The binding of mitoxantrone to isolated proteins was studied at eight concentrations whose range depended on the protein used. The results showed that mitoxantrone binding to human plasma and HSA involved a saturable binding. The AAG binding involved a saturable binding followed by a non saturable process. Within the concentration range studied, the percent and binding parameters which characterize the drug-protein interaction were comparable in both methods.

Humans↗
PubMed1994

Pharmacokinetics of carboplatin in a patient suffering from advanced ovarian carcinoma with hemodialysis-dependent renal insufficiency.

Pharmacokinetics of carboplatin were determined in a patient suffering from advanced ovarian cancer with total hemodialysis-dependent chronic renal failure undergoing 3 consecutive cycles of chemotherapy. Dosage was adjusted to reach active AUC (area under the plasma concentration versus time curve) of ultrafilterable carboplatin. A hemodialysis, performed 24 h after administration results in a decrease of 20% of ultrafilterable carboplatin AUC. The relative dialysis efficacy of ultrafilterable carboplatin was great: 84 +/- 3%. The chemotherapy regimen consisted of carboplatin-cyclophosphamide combination for 6 cycles every 4 weeks. After treatment completion, the patient showed a complete response and remains disease free 16 months after the end of the treatment. Carboplatin-based chemotherapy can be given to patients undergoing chronic hemodialysis without life-threatening toxicity with a dialysis performed 24 h after the administration and with a dose adjustment of carboplatin to reach a AUC of 6 mg/ml.min for untreated patients. In these conditions, response in platinum-sensitive tumors can be obtained.

Aged↗
PubMed1994

The use of medicaments in space--therapeutic measures and potential impact of pharmacokinetics due to weightlessness.

In support of the preparatory programme for the European manned space infrastructure, the Long-Term Programme Office (LTPO) within ESA's Space Station and Microgravity Directorate initiated a series of studies aimed at a better understanding of the physiological and psychological aspects of living in space. In this context, in 1991 MEDES (Institut de medecine et physiologie spatiale) was contracted by the Agency to investigate the type and efficacy of drugs available for use by astronauts during space missions to counteract the effects of weightlessness or for medical treatments. This paper summarises the main outcome of this research, in the context of the so-called 'Pharmemsi Study'. The first part is dedicated to the content of the medical kits used by astronauts in flight, while the second describes how weightlessness can modify the action of drugs (i.e. pharmacodynamics and pharmacokinetics parameters) on the human body. Recommendations are given on 'Space Pharmacopoeia' as well as the areas of research needed to adapt medication to the weightless environment.

Aerospace Medicine↗
PubMed1994

Pharmacological properties of CY 216 and of its ACLM and BCLM components in the rabbit.

This study compares some in vivo pharmacological properties of CY 216 and of its ACLM and BCLM components having a molecular weight above and below 5.4 kDa respectively. The anti-factor Xa/antithrombin ratio of these compounds determined in a rabbit plasma system were 2.5 and 1.2 for CY 216 and ACLM respectively while BCLM was devoid of anti-thrombin effect. After bolus intravenous injection, continous infusion and subcutaneous administration, the clearances of anti-factor Xa activity generated by ACLM were, on the average, 2 and 1.5 times higher than those generated by BCLM and CY 216 respectively. The clearances of the anti-thrombin activity were comparable for CY216 and ACLM, and higher than those of the antifactor Xa activity. The duration of the antithrombotic effect was investigated in the Wessler model after a single subcutaneous injection of 1000 anti-factor Xa units of one of the compounds. Using thromboplastin as thrombogenic stimulus, the most efficient agent was ACLM and the antithrombotic activity was essentially correlated to the circulating anti-thrombin activity. Using human serum as thrombogenic stimulus, ACLM and BCLM were more efficient than CY 216 and the antithrombotic activity was mainly correlated to the anti-factor Xa activity. The ability of the 3 compounds to inhibit venous thrombosis growth was compared: they were found equipotent and the antithrombotic effect was independent of the anti-thrombin activity. The prohaemorrhagic properties were compared in the rabbit ear model. The activity of the 3 compounds were comparable and significantly less prohaemorrhagic than unfractionated heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Evidence for a second site of absorption of veralipride in the human small intestine. Use of a new drug delivery telemetric shuttle.

A new telemetric shuttle was used to coadminister veralipride (CAS 66644-81-3) and veralipride-D3 in order to test the assumption that veralipride is absorbed at two sites of the small intestine. Two different pharmacokinetic approaches were used to interpret the obtained data. According to the results, the second site of absorption of veralipride is located at a distance corresponding to 2/3 of the total length of the small intestine.

Animals↗
PubMed1994

Pharmacokinetic compartmental model with n sites of absorption along the gastrointestinal tract.

A double site of absorption model was previously proposed to depict the "double peak phenomenon" in plasma concentration observed after oral administration of veralipride. We intend to generalize this model to the case where the drug reaches not two but n (n > or = 2) successive absorption sites along the gastrointestinal tract. Fractions of dose absorbed in each site are given as well as the area under concentration curves related to the central compartment. The effect of the number of absorption sites on absorbed amounts, on area under the curves and bioavailability is taken into account. Furthermore, as an example, we give simulated plasma concentration curves for a three-absorption site model.

Biological Availability↗
PubMed1994

Intramuscular dermatan sulfate MF701 in patients with hip fracture: relationship between pharmacokinetics and antithrombotic efficacy.

Two groups of 23 and 84 patients with hip fracture received intramuscularly 100 and 300 mg dermatan sulfate (MF701) b.i.d., respectively, for the prophylaxis of deep vein thrombosis. Median duration of treatment was 17 and 16 days, respectively. Four blood samples were collected from each patient while under treatment. Plasma levels of dermatan sulfate were determined by a chromogenic substrate assay. A one-compartment model for multiple doses was employed to estimate the pharmacokinetic parameters. Fitting was applied to mean plasma concentrations calculated for each sampling time and weighted according to the number of samples available at each time. Thrombin clotting time was measured on the same plasma samples. Antithrombotic efficacy was assessed by bilateral venography. Plasma levels of dermatan sulfate increased gradually throughout the treatment, indicating a marked accumulation process. Time to reach steady-state was 14 or 9 days with 100 or 300 mg b.i.d., respectively. This was due to an apparent prolonged terminal half-life (68 or 43 h), which actually reflected slow absorption from the injection sites. The clinical efficacy of MF701 in preventing DVT was found to be dependent on the plasma concentration of the drug and also, but less significantly, on the prolongation of thrombin clotting time. Dermatan sulfate plasma levels greater than 9 micrograms/ml are advisable to optimize efficacy in hip fracture patients.

Aged↗
PubMed1994

Indocyanine green pharmacokinetics in rats with progressive carbon tetrachloride-induced hepatocellular insufficiency.

Indocyanine green (ICG, CAS 3599-32-4) kinetics were used to assess hepatic function in rats with progressive hepatic disease induced by carbon tetrachloride administered by two different routes (intragastric and intraperitoneal). Four groups of animals with hepatic insufficiency (4, 6, 8, 10 weeks of intoxication) and two control groups (with or without phenobarbital/oil) were studied. After an i.v. bolus (1 mg/kg) of ICG, blood samples were collected for 120 min at definite time. For the intragastric route, ICG clearance and volume of distribution at steady-state were significantly decreased (p < 0.05), area under the curve and terminal half-life were significantly increased (p < 0.05). By contrast, no significant difference was observed after intraperitoneal administration, although the same pathological pattern was observed between the two routes of administration. This study proved the clinical importance of drug pharmacokinetics knowledge in liver disease and confirmed that ICG disposition is an adequate method for assessing hepatic function and dysfunction in animals with progressive liver disease.

Animals↗
PubMed1993

Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas.

We have studied the plasma and peripheral leukocyte pharmacokinetics of mitoxantrone associated, in a high-dose regimen, with cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation. Nineteen patients with refractory lymphoma were involved in a clinical trial with escalated doses (15-90 mg/m2) of mitoxantrone administered by 30-min i.v. infusion 8 days before an autologous bone marrow transfusion. Mitoxantrone was measured by high-performance liquid chromatography in plasma and peripheral lymphocytes. The plasma pharmacokinetics of mitoxantrone was linear between 15 and 90 mg/m2: total body clearance (19.3 +/- 6.2 liter/h/m2) and volume of distribution at steady state (486 +/- 254 liter/m2) were not altered by increasing the dose. The exposure of bone marrow transplant to the plasma residual concentration of mitoxantrone was correlated with the limiting hematological toxicity of the regimen (P < 0.001). At all times, the mitoxantrone concentration in peripheral cells was much higher than in plasma and was retained at a constantly high concentration level. Whereas cellular versus plasma maximum concentration ratio was near 1, the area under the concentration +/- time curve ratio reached 100, suggesting a long elimination half-life from cells. Plasma and cellular pharmacokinetics data of mitoxantrone reinforce the idea that this drug is a good candidate for high-dose chemotherapy regimen.

Adult↗
PubMed1993

Mean residence time in multicompartmental models with time delays.

Calculation of the mean residence time (MRT) of a drug in a stationary compartmental model is classically carried out from several expressions. Nevertheless, one or more time delays between compartments modify the mean residence times. It is the aim of this paper to propose a general method for MRT calculations, in any n-compartmental models which may include time delays. As examples, catenary and mammillary models are considered.

Administration, Oral↗
PubMed1993

Effect of drug transit time between exchange locus with plasma and sampling site.

In pharmacokinetic models used to describe the behavior of drugs in living organisms, generally neither the amount of drug flowing in pipes between compartments nor the transfer delay between the plasma-lymph exchange areas and a site of measurement are taken into account. Several former publications dealt with exchanges between two or more different organs assuming that the blood flow was constant or that the variation of the lymphatic flow was negligible or noting that the amount of drug present in pipes was not easily taken into account. In this article, we deal with concentration in a site of interstitial exchanges with regard to concentration in a sampling site with a varying blood flow, assuming that the transit time depends both on the fluid flow and the path length through pipes. In all considered cases, the plasma concentration profile may be highly altered by a change in the flow rate.

Humans↗