Biomedical subjects

B Diquet

Publications and source records attributed to B Diquet.

At least 19 recordsLinked to original sources

PubMed2005

Hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil.

Here we report on a case of hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil. Alternative causes of liver injury were excluded. The pathophysiological mechanism remains unclear, with a possibility of allergic reaction. In view of the widespread use of both drugs, clinicians should be aware of this drug-induced liver injury.

Adverse Drug Reaction Reporting Systems↗

PubMed2005

Population pharmacokinetic analysis for nelfinavir and its metabolite M8 in virologically controlled HIV-infected patients on HAART.

AIMS: To describe the pharmacokinetics of nelfinavir and its main metabolite M8 in HIV-infected patients with a sustained virological response, to characterize the effect of covariates and to estimate inter- and intra-individual variability in the pharmacokinetics. METHODS: Three hundred and twenty concentrations of both nelfinavir and M8 were measured in 46 patients enrolled in the COPHAR 1-ANRS 102 study. Blood samples were taken at a first visit (one sample before drug administration and four samples at fixed times after) and at a second visit 1 to 3 months later (one before and one 3 h after drug administration). The data from both visits on nelfinavir and M8 were modelled jointly in all patients using a population approach. RESULTS: A one-compartment model with first-order absorption and elimination best described nelfinavir data, with an additional compartment incorporating a first order rate-constant describing the metabolism of the drug to M8. For nelfinavir, the apparent volume of distribution (V/F ) (95% confidence interval for the mean), was 309 l (185, 516), the absorption rate constant (k(a)) was 0.4 h(-1) (0.2, 0.8), and the apparent clearance (CL/F ) was 37.3 l h(-1) (32, 44). For M8, V(m) /(Fk(m)) and CL(m)/(Fk(m)) were 866 l h(-1) (351, 2161) and 1670 l (965, 2894), respectively. The interindividual variabilities were 34.9%, 34.3% and 62.2% for V/F, CL/F and CL(m)/(Fk(m)), respectively. The interoccasion variability was 27.8% for CL/F. The mean half-lives were 05.38 h and 00.44 h for nelfinavir and M8, respectively. Significant but opposite effects of comedication with zidovudine were found on nelfinavir CL/F and M8 CL(m)/(Fk(m)), but they were not considered to be clinically relevant. CONCLUSIONS: A joint model was found to describe adequately nelfinavir and M8 concentrations and was used to estimate pharmacokinetic parameters for M8. The model can be used to build reference pharmacokinetic profiles for therapeutic drug monitoring of the drug.

Adult↗

PubMed2004

Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans.

Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (> or =3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2-3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1-1.2 L/kg), larger for fexofenadine (5.4-5.8 L/kg) and particularly large for desloratadine (approximately 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (approximately 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84-95% (faeces) and 8-15% (urine) for 14C-mizolastine. The absolute bioavailability is 50-65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions.

Absorption↗

PubMed2003

P-glycoprotein in blood CD4 cells of HIV-1-infected patients treated with protease inhibitors.

OBJECTIVE: Many factors are involved in the virological failure of antiretroviral treatments such as low pharmacological plasma levels of drugs, poor adherence to therapy and emergence of viral resistance. P-glycoprotein (P-gp) has been demonstrated to play a role in multidrug resistance in the therapy of solid tumours, haematological malignancies and Plasmodium falciparum infection. HIV-1 protease inhibitors (PIs) have been described to be substrates of P-gp. In vitro and in vivo studies performed in mice have demonstrated that P-gp may affect the oral bioavailability and intracellular accumulation of PIs. P-gps have been detected on peripheral CD4 blood cells in HIV-1-infected, but antiretroviral-naive patients. METHOD: We quantified P-gp expression and performed functional tests of P-gp activity in the CD4 cells in HIV-1-infected patients, with and without virological failure, treated with PIs, and in healthy patients (control group). RESULT: Out of the 18 HIV-infected patients studied, P-gp expression and function were found in the CD4 cells of six patients (four of 10 without, and two of eight with virological failure). Out of the 43 healthy patients studied, P-gp expression and function were found in the CD4 cells of 11 patients (26%). We found P-gp in peripheral CD4 cells of patients treated with PIs, with and without virological failure, within the same frequency than in antiretroviral naive patients or than in non HIV-infected patients. CONCLUSIONS: P-gp expression in peripheral CD4 blood cells does not seem to be enhanced by PI treatment and does not seem to be linked particularly to virological failures. These facts do not preclude of the role of P-gp on PI absorption or efficacy in other compartments of the body such as gut, lymph nodes or brain in HIV-1 PI-treated patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Medication misuse in hospitalized patients with renal impairment.

OBJECTIVES: The potential consequences of medication misuse in renal impairment have not been assessed in a population of in-patients. The purpose of this study was to determine the frequency and potential consequences of a lack of dosage adjustment in hospitalized patients with renal impairment. DESIGN: Order sheets for in-patients having a creatinine above 0.7 mg/dl were analysed. We considered the appropriateness of prescriptions for medications having potential nephrotoxicity and/or eliminated through renal excretion or metabolism (TEM medications) and having manufacturer's guidelines for dosage adjustment in renal impairment. MAIN MEASURES: On the basis of these guidelines, each line of prescription was rated as 'appropriate order', 'inappropriate dosage', or 'contra-indicated order'. Experts also rated prescriptions as potentially fatal or severe, serious, significant, or without potential for increased adverse effects. RESULTS: Two hundred and two order sheets were completed for 164 patients. They totalled 1469 lines of prescription, 85% of which were TEM medications, with guidelines for dosage adjustment for 71% of them (n = 886). Of these 886 prescriptions, 34% were inappropriate, 14% being contra-indicated and 20% with inappropriate dosage given the patient's renal function. Among the 202 order sheets, 75% included at least one inappropriate prescription. Sixty-three per cent included at least one prescription with potentially adverse consequences, 3% of these having potentially fatal or severe consequences. CONCLUSION: This study confirms that physicians do not take into account sufficiently patient renal function when prescribing. In light of these results, improving the quality of drug prescription in patients with renal impairment could be of importance for improving the quality of care.

Aged↗

PubMed2002

Sensitive determination of nefopam and its metabolite desmethyl-nefopam in human biological fluids by HPLC.

Nefopam (NEF) and desmethyl-nefopam (DMN) were assayed simultaneously in plasma, globule and urine samples using imipramine as internal standard. A liquid-liquid extraction procedure was coupled with a reverse phase high-performance liquid chromatography system. This system requires a mobile phase containing buffer (15 mM KH(2)PO(4) with 5 mM octane sulfonic acid: pH 3.7) and acetonitrile (77:33, v/v) through (flow rate=1.5 ml/min) a C(18) Symmetry column (150x4.6 I.D., 5 micrometer particle size: Waters) and a UV detector set at 210 nm. Internal standard was added to 1 ml of plasma or globule sample or 0.5 ml of urine sample, prior to the extraction under alkaline ambiance with n-hexane. The limits of quantification were 1 and 2 ng/ml for both molecules in plasma and globule, respectively; 5 and 10 ng/ml for NEF and DMN in urine, respectively. The method proved to be accurate and precise: the relative error at three concentrations ranged from -13.0 to +12.3% of the nominal concentration for all molecule and biological fluid; the within-day and between-day precision (relative standard deviation %) ranged from 1.0 to 10.1% for all the molecules and biological fluids. The method was linear between 1 and 60 ng/ml for both molecules in the plasma; 2 and 25 ng/ml for both molecules in the globule; 25 and 250 ng/ml for NEF and 50 and 500 ng/ml for DMN in the urine: correlation coefficients of calibration curves (determined by least-squares regression) of each molecule were higher than 0.992 whatever the biological fluid and during the pre-study and in-study validations. This method was successfully applied to a bio-availability study of NEF in healthy subjects.

Adult↗

PubMed2002

Simultaneous determination of quinapril and its active metabolite quinaprilat in human plasma using high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatography (HPLC) procedure for the simultaneous determination of quinapril and its active metabolite quinaprilat in human plasma samples is described. A one-step solid-phase extraction (SPE) with C18 cartridges was coupled with a reversed-phase HPLC system. The system requires two mobile phases composed of tetrabutyl ammonium hydrogensulfate (10 mM adjusted to pH 7)-acetonitrile (62:38, v/v) for quinapril, and (25:75, v/v) for quinaprilat elution through a C18 Symmetry column and detection at a wavelength of 215 nm. Calibration curves were linear over the ranges 20 to 1,000 ng/ml for quinaprilat and 10 to 500 for quinapril. The limits of quantification were 20 and 10 ng/ml for quinaprilat and quinapril, respectively. Extraction recoveries were higher than 90% for quinapril and 80% for quinaprilat. This method has been successfully applied to a bioequivalence study of quinapril in healthy subjects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects.

OBJECTIVE: To determine the cardiovascular, subjective effects and potential of abuse liability of single dose (-) ephedrine (E) administered orally (50 mg) or intranasally (10 mg and 5 mg). METHODS: Sixteen healthy Caucasian men with no history of drug/alcohol/nicotine abuse or dependence received intranasal single doses of E 5 mg, 10 mg and oral doses of 50 mg and placebo in a double-blind, double-dummy, crossover study. Dependent measures included assessment of subjective feelings by Addiction Research Centre Inventory (ARCI). Profile of Mood States (POMS). visual analogue scales (VAS); "drug liking", "any drug effect", subjective quality of sleep and blood pressure and heart rate. Plasma E concentrations were also determined. RESULTS: (-) E increased supine systolic, diastolic blood pressure (P < 0.01). Changes in supine systolic blood pressure (areas under the 8 h of the experimental sessions) were -59 +/- 47 mmHgh with placebo, -59 +/- 57 mmHg-h with E5 mg by the nasal route, -18 +/- 48 mmHg x h with E 10 mg by the nasal route and 13 +/- 58 mmHgh with E 50 mg by the oral route (P<0.001). (-) E-induced orthostatic hypotension (P < 0.01) (maximal systolic blood pressure drop: E 50 mg 14 +/- 10 mmHg, P < 0.03; E 10 mg 11 +/- 6 mmHg, P = 0.08 compared with placebo) and resulted in decreased tiredness (placebo -2 +/- 39 mm x h, E 5 mg -17 +/- 39 mm x h, E 10 mg -30 +/- 42 mm x h, E 50 mg -24 +/- 35 mm x h; P < 0.03). E did not modify ARCI subscales--in particular the "amphetamine" subscale--but showed a tendency for drug liking (P= 0.09). On the "any drug effect" questionnaire, subjects could identify drug effect (P=0.007). Maximal plasma E concentration (Cmax) and areas under the curves for up to 8 h were proportional to the doses. Elimination half-life was approximately 6 h. A clockwise hysteresis was observed for systolic blood pressure in all but one subject with E 50 mg by the oral route. CONCLUSION: E even at low doses and by the nasal route can decrease tiredness in healthy persons; this is accompanied by a substantial increase in blood pressure and orthostatic hypotension exposing individuals in case of intensive physical exercise to cardiovascular risks. No clear evidence of abuse liability in healthy drug naive subjects was observed.

Administration, Intranasal↗

PubMed2001

Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects.

AIMS: Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. METHODS: The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day-1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. RESULTS: Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml-1 h to 7011 ng ml-1 h (P < 0.001) and the elimination half-life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml-1 vs 109 ng ml-1, P < 0.001). CONCLUSIONS: Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.

Adult↗

PubMed2001

Clinical pharmacokinetics of mizolastine.

Mizolastine is a new histamine H1 receptor antagonist. Mizolastine 10 mg/day is effective in allergic rhinitis and chronic idiopathic urticaria. In young healthy volunteers, absorption of mizolastine is rapid with time (tmax) to peak concentration (Cmax) of about 1 hour. The absolute bioavailability of mizolastine 10mg tablets is about 65%. Distribution is rapid with a mean distribution half-life of 1.5 to 1.9 hours. Mizolastine is >98% bound to serum albumin and the apparent volume of distribution is between I and 1.4 L/kg. Mizolastine is extensively metabolised by hepatic glucuronidation and sulphation, with no major active metabolite, and excreted in faeces. The terminal elimination half-life (t1/2beta) is 7.3 to 17.1 hours. The apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, with steady state reached from day 3 and no accumulation between days 1 and 7. Cmax and area under the concentration-time curve (AUC) are linearly related to dose. Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4. In vivo, no interactions were observed between mizolastine and lorazepam or ethanol. A significant increase in Cmax and trough plasma concentration (Cmin) of digoxin occurred after coadministration with mizolastine, without change in AUC, tmax or clinical parameters. Significant increases in theophylline Cmin and AUC were observed after coadministration with mizolastine. Mizolastine Cmax and AUC were increased when coadministered with erythromycin, with no change in t1/2beta. Concomitant administration of mizolastine and ketoconazole increased mizolastine AUC values with no change in t1/2beta. In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers, except for duration of absorption, which was almost doubled in the patients. Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on clearance and distribution. Pharmacokinetic parameters of mizolastine in elderly individuals were similar to those observed in healthy young volunteers. In patients with chronic renal insufficiency, t1/2beta was prolonged by 47% compared with young healthy volunteers. In patients with cirrhosis, tmax was longer, Cmax was lower, distribution half-life was prolonged and AUC was 50% higher than in healthy volunteers. In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flare inhibition was found to correlate with mizolastine Cmin values. No direct relationship was found between drug concentrations in skin blister fluid and antihistamine activity.

Adult↗

PubMed2000

Oral ganciclovir systemic exposure is enhanced in HIV-infected patients with diarrhea and weight loss.

OBJECTIVE: To determine whether diarrhea and intestinal malabsorption during HIV infection alter oral ganciclovir systemic exposure. METHODS: We studied the oral disposition of ganciclovir in 42 HIV-infected patients stratified into three groups: A (n = 15), HIV (stage A and B); B (n = 13), AIDS (stage C); and C (n = 14), AIDS with chronic diarrhea and wasting syndrome (10% or more weight loss). Each patient was evaluated for nutritional (body mass index, serum albumin and transferrin), immunologic (CD4 count, plasma viral load) and intestinal status (D-xylose test, fecal fat and nitrogen excretion, and intestinal permeability). Following an overnight fast, 1 g oral ganciclovir was given to patients. Six blood samples were collected over 24 hours. Serum was analyzed for ganciclovir by high performance liquid chromatography. Drug disposition was characterized using a population pharmacokinetic approach. RESULTS: Mean intestinal permeability increased as HIV disease progressed (0. 05, 0.1, and 0.2 for groups A, B, and C, respectively). Average weight-adjusted maximum concentration (Cmax) in group C was twofold more than that in group A and B patients (12.5 versus 6 and 6.4 ng/ml/kg), and average area under the curve (AUC0-infinity) was threefold greater in group C patients (193 versus 59 and 65 ng. hour/ml/kg in groups A and B, respectively). Mean oral clearance was threefold lower in group C (96 versus 258 and 212 L/hour in groups A and B, respectively). CONCLUSION: Because systemic exposure of oral ganciclovir is enhanced in AIDS patients with diarrhea and wasting syndrome, oral ganciclovir therapy may benefit these patients.

Administration, Oral↗

PubMed2000

Determination of twelve antiretroviral agents in human plasma sample using reversed-phase high-performance liquid chromatography.

A new high-performance liquid chromatography (HPLC) with UV detection assay was developed for the simultaneous determination of protease inhibitors (PIs), nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs, NNRTIs) using a single 1-ml plasma samples. A solid-liquid extraction procedure without internal standard was coupled with two separate reversed-phase HPLC systems; one for the determination of amprenavir, efavirenz, indinavir, nelfinavir, ritonavir, saquinavir (run time=32 min) and one for the determination of abacavir, didanosine, lamivudine, stavudine, nevirapine, zidovudine (run time=40 min). The first requires a mobile phase containing sodium phosphate buffer+ion pair-acetonitrile (50:50, v/v) through a C18 Symmetry column (250x4.6 mm I.D., 5 microm particle size), using variable wavelengths (241, 254 and 261 nm). The second system requires three mobile phases (potassium phosphate buffer+ion pair-acetonitrile) for different elution through a C18 Symmetry Shield column (250x4.6 mm I.D., 5 microm), using a single wavelength (260 nm). Peak-areas are linear; correlation coefficients are better than 0.998 for all compounds, with both inter- and intra-day relative standard deviations lower than 12%. Extraction recoveries are higher than 93% for PIs and NNRTIs and higher than 70% for NRTIs. The method is specific and sensitive and was used to determine trough and peak levels of antiretroviral drugs in HIV infected patients under various combinations of RTIs and PIs.

Anti-HIV Agents↗

PubMed2000

Sensitive determination of ephedrine and norephedrine in human plasma samples using derivatization with 9-fluorenylmethyl chloroformate and liquid chromatography.

A high-performance liquid chromatography procedure for the determination of ephedrine and norephedrine using fluorimetric detection in plasma samples is described. A double liquid-liquid extraction was performed, followed by derivatization with 9-fluorenylmethyl chloroformate. The extracts were chromatographed with a 5-microm C18 (150x4.6 mm I.D.) column using a mobile phase composed of acetonitrile and water (52:48; v/v). The excitation and emission wavelengths were respectively 264 nm and 313 nm. Calibration curves were linear over the range 0 to 300 ng/ml for each analyte. The specificity of the method was demonstrated with several FMOC-reacting drugs. The limits of quantification are similar to those obtained with the reference method: 2 ng/ml for ephedrine and 5 ng/ml for norephedrine. This method has been successfully applied to the determination of ephedrine and norephedrine plasma levels after administration of low doses of ephedrine to healthy subjects.

Chromatography, High Pressure Liquid↗

PubMed2000

Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy.

We investigated human immunodeficiency virus (HIV) type 1 RNA, proviral DNA, and antiretroviral drug-resistant variants in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. The prevalence of detectable HIV-1 RNA in genital secretions was inversely related to the number of antiretroviral drugs taken by the patients. Proviral DNA was detected in approximately half of all samples of cervicovaginal secretions from HIV-1-infected women, regardless of the presence or absence of HIV-1 RNA in cervicovaginal secretions and of the antiretroviral regimen. In cervicovaginal secretions of most women with persisting genital viral replication, HIV variants exhibiting mutations associated with drug resistance against protease and reverse-transcriptase pol genes were found. Our observations indicate that antiretroviral therapy is not effective in purging the female genital tract of cell-associated provirus and that antiretroviral drugs that penetrate the female genital tract at suboptimal concentrations exert a potent selective pressure on genital HIV variants when local replication of free HIV-1 RNA persists.

Adult↗

PubMed2000

Potentiation of vitamin K antagonists by high-dose intravenous methylprednisolone.

BACKGROUND: Oral anticoagulants and pulse high-dose intravenous methylprednisolone are often administered concomitantly, but no data on potential interactions are available. OBJECTIVE: To assess possible potentiation of oral anticoagulation by high-dose intravenous methylprednisolone. DESIGN: Prospective cohort study. SETTING: University hospital in Paris, France. PATIENTS: 10 consecutive patients concomitantly receiving methylprednisolone and oral anticoagulants (fluindione and acenocoumarol) and 5 consecutive controls receiving methylprednisolone alone. MEASUREMENTS: Serial determinations of the international normalized ratio (INR) and clotting factors during administration of pulse methylprednisolone. The total plasma fluindione concentration was determined in 3 patients. RESULTS: The mean INR was 2.75 (range, 2.02 to 3.81) at baseline and increased to 8.04 (range, 5.32 to 20.0) after methylprednisolone administration. Plasma fluindione concentrations and the INR increased after methylprednisolone administration. Methylprednisolone alone did not increase prothrombin time. CONCLUSIONS: The action of oral anticoagulants is potentiated by intravenous high-dose methylprednisolone. The INR should be monitored daily during concomitant administration of these medications.

Acenocoumarol↗

PubMed2000

Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection: pharmacokinetics, tolerability, and efficacy.

Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (approximately 3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.

Adult↗

PubMed2000

Prediction of fluindione maintenance dosage hampered by large intraindividual variability.

In a previous study, the authors proposed a method to individualize fluindione dosage regimen, based on a pharmacokinetic/pharmacodynamic model describing the evolution of the International Normalized Ratio (INR). In this method, daily maintenance dosage for a target INR depends on the product of individual Cl and C50. The present work shows the results of a follow-up study in 50 patients for whom target INR was 2.5. INR measurements and dosage regimens were recorded both during hospital stay and during the 1st month of treatment. Patients were defined as equilibrated after 1 month if the last two INRs were in the range 1.5-3.5 under a stable dosage regimen. Actual maintenance dose was compared with the dose predicted using the three first INRs measured in the hospital. Intraindividual variability of Cl*C50 between hospital stay and after 1 month was evaluated. After 1 month, only 27 patients (54%) were equilibrated. Actual maintenance dose varied from 5 to 30 mg daily. There was no bias between predicted and actual maintenance dose (1.4 mg), but a large root mean squared error (8 mg) was found. The intraindividual variability in Cl*C50 between hospital and maintenance regimen was high (93%), which may explain the dispersion in the predicted maintenance dose.

Anticoagulants↗

PubMed2000

Early virological failure in naive human immunodeficiency virus patients receiving saquinavir (soft gel capsule)-stavudine-zalcitabine (MIKADO trial) is not associated with mutations conferring viral resistance.

The MIKADO trial was designed to evaluate the efficacy of stavudine-zalcitabine-saquinavir (soft gel capsule) [d4T-ddC-SQV(SGC)] in 36 naive patients (-3.3 log(10) units at week 24 [W24]). Among the 29 patients remaining on d4T-ddC-SQV(SGC) until W24, 10 harbored a virological failure (viral load of >200 copies/ml at W24) (group 1). To determine the reasons for therapeutic failure, genotypic and phenotypic resistance test results and SQV concentrations in plasma were analyzed and compared to those in successfully treated patients (viral load of <200 copies/ml at W24) (group 2). Reverse transcriptase and protease genotypic analyses in group 1 revealed the acquisition of only one SQV-associated mutation (L90M) in only two patients. There was no significant increase in the 50 or 90% inhibitory concentration of SQV in patients with or without the L90M mutation. However, the fact that two patients developed an L90M mutation only 4 weeks after relapse points to the need for genotypic resistance testing in the context of an initial failure of the antiretroviral regimen. At W24, the median SQV concentration in group 1 (71 ng/ml) was significantly lower than in group 2 (475 ng/ml), and the plasma SQV concentration was correlated with the viral load at W24 (r = -0.5; P<0.05) and with the drop in viral load between day 0 and W24 (r = -0.5; P<0.01). These results and the fact that the plasma SQV concentrations in the two groups prior to relapse (W12) were not significantly different strongly suggest that the early failure of this combination is not due to viral resistance but to a lack of compliance, pharmacological variability, and drug interactions or a combination of these factors.

Anti-HIV Agents↗