Use of artesunate in the treatment of severe imported malaria in France: review of the effectiveness and real-life safety in two French university hospitals.

BACKGROUND: Intravenous artesunate (AS) is the first-line treatment for patients with severe imported malaria (SIM) worldwide. However, after 10 years of use in France, AS hasn't yet received marketing authorization.The purpose of this study was to assess the real-life effectiveness and safety of AS in the treatment of SIM in two Hospitals in France. METHODS: We performed a bicenter retrospective and observational study. All patients treated with AS for SIM between 2014 and 2018 and 2016-2020 were included. The effectiveness of AS was evaluated by parasite clearance, number of deaths, and the length of hospital stay. The real-life safety was assessed by related adverse events (AE) and monitoring of biological blood parameters during the hospital stay and follow-up period. RESULTS: 110 patients were included during the six-year study period. 71.8% of patients were parasite-negative of their day 3 thick and thin blood smears after AS treatment. No patients discontinued AS due to an AE and no serious AE were declared. Two cases of delayed post-artesunate hemolysis occurred and required blood transfusions. CONCLUSION: This study highlights effectiveness and safety of AS in non-endemic areas. Administrative procedures must be accelerated in order to obtain full registration and facilitate access to AS in France.

Stability studies of five anti-infectious eye drops under exhaustive storage conditions.

Several ocular infections require anti-infectious eye drops prepared by hospital pharmacy. Stability of these preparations is described in the literature, but studies do not always adequately consider physico-chemical parameters or storage conditions. We describe herein a complete study conducted on five anti-infectious eye drops containing vancomycin, gentamicin, ceftazidime, amphotericin B and voriconazole. We looked for significant changes in active pharmaceutical ingredient content, pH, osmolality and subvisible particles. Our study was designed to monitor stability at ambient temperature, at 2-8 °C, and also at 2-8 °C after various freezing periods. Under ambient storage conditions, eye drops were stable for 15 days, except for ceftazidime, which was stable for less than 1 day only. Under refrigeration conditions (2-8 °C), amphotericin B and voriconazole were stable for 60 days, vancomycin and gentamicin were stable for 30 days while ceftazidime was only stable for 15 days. After 90 days freezing and thawing, voriconazole remained stable at 2-8 °C for 60 days, vancomycin and amphotericin B for 30 days and gentamicin only for 21 days. Ceftazidime eye drops were stable for only 7 days at 2-8 °C after 60 days freezing. Our results are compared to the most relevant publications. Results of this study allow the compounding of large batches of harmonized anti-infectious eye drops.

Comparative study on two kidney graft rinsing and preservation solutions in terms of the post-transplantation risk of delayed graft function and cost.

OBJECTIVE: To determine whether Belzer solution (Viaspan, Bristol-Myers Squibb, Brussels, Belgium), which is more expensive than Eurocollins solution, was better at preventing delayed graft function (DGF) and whether it was cost-effective as it could potentially reduce post-transplantation complications. METHOD: The risk of occurrence of complications associated with the use of these two rinsing and preserving solutions was estimated from a survey of 106 patients undergoing renal transplantation between 1 January 1993 and 31 March 1998. Both efficacy and adverse outcomes were recorded along with the costs directly associated with the transplantation procedure in the hospital setting: hospitalization, rinsing and preserving solutions, medical and technical interventions and diagnostic tests. RESULTS: For the 45 kidney grafts rinsed and preserved with Eurocollins (strategy S1: n1 = 45) the cost/graft was estimated at 40 euros. With Viaspan (strategy S2: n2 = 61) the corresponding cost/graft was 424 euros. Logistic regression analysis showed that Viaspan was better than Eurocollins solution (ebeta = 0.437; P = 0.05) in preventing DGF. Overall, S2 was less expensive than S1, from the hospital's perspective. The mean difference per patient was 278 euros, which amounts to a saving of 2% of the total cost per renal transplantation. For rinsing and preserving kidney grafts Belzer solution is therefore preferable to Eurocollins solution.

[Prescriptions and consumption of hypnotic and anxiolytic drugs in the South University Hospital of Marseille]. / Prescription et consommation des médicaments hypnotiques et anxiolytiques dans les services de médecine des hôpitaux sud du CHU de Marseille.

An investigation of prescription and consumption of hypnotic and anxiolytic drugs in hospital was carried out and has associated a transverse prescription study and a prospective consumption study. The prescription study was undertaken on one day in several medical departments of Sainte-Marguerite Hospital in Marseille in February 1999. Of the 91 hospitalized patients included, 42 (46 per cent) had been prescribed a hypnotic or anxiolytic. Furthermore, the quantities of drugs taken out of the pharmacy during the month of February were 1.54 time more than those prescribed. This discrepancy was even more obvious in the case of certain benzodiazepines such as bromazepam (ratio from 1 to 4) and lorazepam (ratio from 1 to 8). Self-prescription and patients being supplied without a prescription are the hypotheses advanced to explain this phenomenon.

Effects of tauroursodeoxycholate solutions on cyclosporin A bioavailability in rats.

Cyclosporin A (CsA) exhibits poor bioavailability after oral administration of Sandimmune, with wide intra- and interindividual variations. Our study sought to determine the effect of the coadministration of CsA standard oily formulation and tauroursodeoxycholate (TUDC) and that of an aqueous micellar solution containing TUDC, monoolein, and CsA in promoting and regulating CsA bioavailability in the rat Pharmacokinetic parameters of CsA were determined in fasted rats after either an intravenous administration (5 mg/kg) or a single oral CsA dose of 10 mg/kg. Compared with oral Sandimmune, the CsA micellar solution significantly improved the CsA bioavailability by 160% and decreased the interindividual variability in bioavailability expressed as percent coefficient of variation from 32% to 15%. The concentration-time profile was modified with a 3.5-fold increase in C(max), a reduction of t(max), and an increased trough concentration. Bioavailability slightly improved in rats receiving standard oily solution plus concomitant TUDC, although not significantly. Data indicate that the structure of the CsA carriers greatly affect drug bioavailability and that aqueous micellar solutions of CsA-TUDC-monoolein constitute efficient vehicles, thus providing for CsA high absorption with low variability.

Improvement of cyclosporin A-induced cholestasis by tauroursodeoxycholate in a long-term study in the rat.

Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat. After randomization into three groups (N = 8), rats received daily for 17 days: cyclosporin A intraperitoneally alone (30 mg/kg) or cyclosporin A intraperitoneally and tauroursodeoxycholate (60 mg/kg) by gavage; control received the cyclosporin A excipient. Under tauroursodeoxycholate, cholestatic parameters (bile flow, bile salt secretion, serum bile salts, serum bilirubin) improved significantly without affecting cyclosporin A blood levels, and excretion of the drug and its metabolites in bile increased by 47%. Serum creatinine levels were better preserved, although not significantly. These results show that tauroursodeoxycholate prevents cyclosporin A-induced cholestasis in long-term treatment in rats, possibly by facilitating the drug elimination in bile.

[The kinetics of IL-2 after pleural administration in the treatment of neoplastic pleurisy]. / Cinétique de l'IL-2 après administration pleurale dans le traitement des pleurésies néoplasiques.

The half-life of interleukin-2 (IL-2) is short after intravenous bolus injections (6 to 10 minutes) and elevated doses are necessary for its anti tumour action on account of severe side-effects which limit its use. Studies have shown good tolerance and efficacy of elevated doses of recombinant IL-2 after intrapleural administration in the treatment of neoplastic pleurisy. After a phase one study to determine the maximum tolerated dose (24 x 10(6) IU/m2 per day), we have studied the pharmacokinetics of 21 x 10(6) IU/m2 per day of recombinant IL-2 administered as a continuous intrapleural infusion over 5 days in 6 patients who presented with a neoplastic pleurisy (3 had malignant mesotheliomas and 3 had adeno-carcinomas of unknown primary site). Three patients presented with a partial objective response and no toxic effects beyond grade 2 were noted. Specimens were taken from the pleura and blood following the infusion and were taken at 2, 6, 8, 32, 44, 56, 80 and 120 hours after the end of the infusion. After calibration with IL-2 (Roussel Uclaf) the concentrations were assessed using radio-immuno-assay (Amersham). Very elevated pleural levels were obtained for 5 patients with very significant areas under the curve (SSC). All the patients presented with diffuse lesions of the parietal pleura whose initial evaluation included thoracoscopy. The inverse was a patient who was suffering from pleural nodular lesions who had very low pleural levels at the lower limit of detectability. The blood concentrations were low in all patients and the area under the curve was 1000 times less elevated than for the pleura.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of intrapleural recombinant interleukin-2 in immunotherapy for malignant pleural effusion.

BACKGROUND: The authors measured pharmacokinetic parameters before, during, and after immunotherapy by continuous intrapleural infusion of recombinant interleukin-2 (rIL-2) and correlated the resulting data with clinical effects in nine patients with malignant pleural effusion. METHODS: The underlying disease was malignant mesothelioma in five patients and adenocarcinoma in four patients. Continuous intrapleural infusion of rIL-2 was performed for 5 days at 21 x 10(6) IU/m2/day. Maximum tolerated dose previously was determined to be 24 x 10(6) IU/m2/day in a Phase I study. Peak levels, the areas under the concentration curve (AUC), and drug half-lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 12, 24, 48, 72, 96, and 120 hours during infusion and at 2, 6, 8, 32, 44, 56, 80, and 120 hours after the end of infusion. RESULTS: High and prolonged intracavitary drug levels were achieved in all but two patients, with a statistically significant correlation between peak values and AUC. Four patients achieved objective responses according to World Health Organization criteria. Neither of the patients with undetectable rIL-2 levels had response to therapy. Serum rIL-2 levels were low regardless intrapleural levels. Mean AUC was lower in the plasma than in the pleural fluid. CONCLUSIONS: This study demonstrates that continuous intrapleural infusion of rIL-2 is an active method of treatment for malignant pleural effusion. The low serum levels associated with this method greatly improve tolerance. The results also indicate that the concentration and duration of intrapleural rIL-2 levels may depend on the extent of pleural invasion. Additional study is needed to confirm this finding.

Diminution of an acute cyclosporin-induced cholestasis by tauroursodeoxycholate in the rat.

CsA is a commonly used immunosuppressive drug known to possibly induce cholestatic side effects. Ursodeoxycholic acid (UDC), a nonhepatotoxic bile acid, has proved to be efficient for several types of cholestasis. The aim of this experiment was to evaluate the ability of tauroursodeoxycholate (TUDC) in preventing CsA-induced cholestasis on bile duct-cannulated rats. After bile flow stabilization, a bolus of 30 mg/kg CsA was given i.v. to one group (n = 7) and was associated with a 2 mumol/kg/min TUDC infusion in another group (n = 7). The control group was injected with CsA-solvent. CsA, as used here, had a rapid and marked cholestatic effect. However, both bile flow and bile salt secretion were significantly enhanced in the TUDC group when compared to the CsA alone-treated group and showed no difference with the solvent control group. In addition, TUDC significantly increased elimination of CsA and its metabolites in bile. In contrast to what was found for endogenous bile salts, TUDC uptake was not affected by CsA. The anticholestatic effect of TUDC probably resulted from preventing CsA-induced hepatocyte membrane damage and from easing biliary excretion of CsA. Such properties could be helpful for CsA-treated liver recipients who are especially exposed to cholestatic problems, and thus, to toxic CsA accumulation in the liver. Moreover, regulation of CsA elimination might prevent, in part, its general toxicity.

Lack of effect of spiramycin on cyclosporin pharmacokinetics.

1. The influence of spiramycin coadministration on cyclosporin pharmacokinetics was studied in five renal transplant patients. The plasma concentrations of cyclosporin were measured both by non-specific radioimmunoassay (RIA) and high-performance liquid chromatography (h.p.l.c.). 2. The kinetics of cyclosporin were followed before treatment, and after 1 day and then 2 weeks of oral treatment with spiramycin (3 X 10(6) iu, twice daily). The main pharmacokinetic parameters (the area under the plasma drug concentration-time curve, the maximum plasma drug concentration and the time to reach it) obtained both by RIA and h.p.l.c. were not modified by spiramycin cotreatment after 1 day, nor after 2 weeks of spiramycin administration. Therefore, the pharmacokinetics of cyclosporin (parent drug and parent drug plus metabolites) are not influenced by the coadministration of spiramycin macrolide at therapeutic dosage. 3. Spiramycin may be preferable to other macrolide antibiotics known to interact with cyclosporin such as erythromycin or josamycin.

Metabolism of cyclosporin A. III. Interaction of the macrolide antibiotic, erythromycin, using rabbit hepatocytes and microsomal fractions.

The interaction between cyclosporin A (CsA) and the macrolide antibiotic, erythromycin, has been studied in freshly isolated rabbit hepatocytes and in rabbit liver microsomal fractions. In hepatocytes, CsA was rapidly accumulated inside the cells and metabolized to its different groups of derivatives (mono- and/or dihydroxylated and/or N-demethylated metabolites) [Fabre, Bertault-Peres, Fabre, Maurel, Just, and Cano: Drug Metab. Dispos. 15, 384 (1987)]. In the presence of erythromycin in the extracellular compartment, CsA metabolism was inhibited in a concentration-dependent manner. However, erythromycin did not affect intracellular CsA accumulation and binding of CsA to its intracellular protein binding site(s). Since CsA was specifically metabolized by the cytochrome P-450 LM3c isozyme [Bertault-Peres, Bonfils, Fabre, Just, Cano, and Maurel: Drug Metab. Dispos. 15, 391 (1987)], we further studied the effect of erythromycin on CsA metabolism by liver microsomal fractions. In the presence of erythromycin, CsA metabolism was also decreased. Lineweaver-Burk analysis of erythromycin-CsA interaction demonstrated that erythromycin was a competitive inhibitor (Ki = 156 microM) of CsA metabolism (Km = 0.43 microM; Vmax = 4.8 nmol/min). In agreement with these data, CsA inhibited (i) erythromycin N-demethylation to a large extent and (ii) the appearance of the erythromycin-cytochrome P-450 LM3c complex. We could conclude that the interaction between CsA and erythromycin most likely results from the fact that both drugs are extensively metabolized by the same cytochrome P-450 form: P-450 LM3c or P-450 III A4 according to the new nomenclature.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of cyclosporin A. I. Study in freshly isolated rabbit hepatocytes.

The metabolism of cyclosporin A (CsA), a widely used immunosuppressive agent, was evaluated in freshly isolated rabbit hepatocytes by HPLC which separated CsA from its major group of derivatives, e.g. "first generation" metabolites (monohydroxylated and N-demethylated) and "second generation" derivatives (dihydroxylated and dihydroxy-N-demethylated). After exposure of hepatocytes to radiolabeled CsA (0.5 mg/liter), CsA was rapidly accumulated inside the cells and metabolized. The dihydroxylated metabolites represent the major intracellular forms after 1 hr. CsA metabolites synthesized inside the cells are then rapidly detected in the extracellular compartment. Unchanged drug and the various metabolites are concentrated inside the cells with transmembrane chemical gradients ranging between 20:1 and 40:1. Transport and metabolic processes for CsA have been evaluated over the following CsA extracellular concentration range, 0.1-10 mg/liter. Metabolism appears to be the rate-limiting step. The apparent affinity constant of CsA for the enzyme system involved in its metabolism is approximately 15 microM. Besides the lipophilicity of the molecule, which is responsible for the retention of CsA and its metabolites in the intracellular compartment, the presence of a binding component(s) in the hepatocytes was also demonstrated. CsA and its metabolites seem to have similar affinities for this binding site. These studies demonstrate that CsA is rapidly transformed inside the hepatocytes to various metabolites which may play an important role in the pharmacological activity of the drug and/or in its clinical toxicity.

Metabolism of cyclosporin A. II. Implication of the macrolide antibiotic inducible cytochrome P-450 3c from rabbit liver microsomes.

The in vitro metabolism of cyclosporin A (CsA) was investigated by rabbit liver microsomes in order to identify the form(s) of cytochrome P-450 responsible for its biotransformation. Metabolites including monohydroxy-, N-demethylated, dihydroxy- and dihydroxy-N-demethylated derivatives were detected and quantified by HPLC from incubates of liver microsomes, CsA, and NADPH. Kinetic data indicated that monohydroxy- and N-demethylated derivatives were first generated and then served as substrates for production of dihydroxylated derivatives. Liver microsomes from phenobarbital-, beta-naphthoflavone-, triacetyloleandomycin-, erythromycin-, or rifampicin-treated and untreated rabbits were investigated, but only microsomes from animals treated with macrolide antibiotics (specific inducers of form P-450 3c) exhibited a type I binding spectrum upon CsA addition (Ks = 1.5 +/- 0.5 microM) and extensively metabolized the drug to all groups of derivatives (Km = 5.0 +/- 0.5 microM, Vmax = 1.0 +/- 0.2 nmol/mg/min). A linear correlation existed between CsA oxidase activity and P-450 3c specific content. Antibodies to P-450 3c strongly inhibited CsA oxidase activity of microsomes from macrolide antibiotic-induced animals, whereas antibodies to other forms, including P-450 2, 3b, 4, and 6, did not. When highly purified forms of P-450, including P-450 2, 3b, 3c, and 4, were assayed in a reconstituted system, only P-450 3c exhibited type I binding spectrum upon CsA addition (Ks = 1.4 +/- 0.5 microM) and extensively metabolized the drug to all derivatives. We conclude that the macrolide antibiotic-inducible form P-450 3c (or P-450 3c related from(s)) is responsible for the major part of CsA metabolism by rabbit liver microsomes.

Clinical pharmacokinetics of ciclosporin A in bone marrow transplantation patients.

Ciclosporin A (CsA) plasma concentrations were monitored by radioimmunoassay after administration IV and PO to 15 patients before allogeneic bone marrow transplantation. The clearance (10.4 +/- 5.41 1/h), half-life (26.4 +/- 14.6 h), and bioavailability (16% +/- 10%) calculated directly from experimental data showed wide interindividual variations. The kinetics after IV infusion, monitored over 2-5 days, appeared to be triphasic. A three-compartment open mamillary model was thus used to simulate the distribution and elimination kinetics of CsA. The distributive delay between administration PO and absorption in the plasma was approximated using a series of six additional compartments connected with a single transfer rate constant. Then, for each patient, the experimental data corresponding to both IV and PO administration were fitted using a single set of rate constants. Clearance and bioavailability calculated from model parameters correlated well with direct estimations obtained from the areas under the concentration time curves. Drug monitoring and linear modeling will be used in an attempt to achieve stable predetermined plasma concentrations of CsA in bone marrow transplantation patients receiving the drug either IV or PO.