Monique Dumas

Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADM

Reversal of multidrug drug resistance (MDR) has been achieved in vitro by a variety of agents including verapamil, quinidine, cyclosporine A, and amiodarone. The toxicity of these agents precludes the achievement of sufficient levels in the serum to circumvent efficiently the MDR in vivo. The authors previously demonstrated that quinine, the widely used antimalarial agent, is able to reverse primary resistance of rat colon cancer cells to anthracyclines. In this report, the efficiency of quinine formiate in reversing the doxorubicin (ADM) (Adriamycin, Adria Laboratories, Columbus, OH) resistance of the well‐defined MDR human leukemic cell line K562/ADM was demonstrated. In culture medium, quinine is slightly less effective than verapamil in increasing the cytotoxicity and uptake of ADM when both drugs are used at the same concentration. A nontoxic dose of 5 μg/ml is necessary to reverse the MDR in K562/ADM cells. In patients receiving quinine formiate in a continuous intravenous infusion, a significant correlation (r = 0.84) was found between the serum levels of quinine and the ability of sera to increase ADM uptake in K562/ADM cells. When quinine is administered at a conventional dose (25 to 30 mg/kg/d), serum levels consistently reach more than 8 μg/ml without severe side effects; ear noises and vertigo are the dose‐limiting side effects. At these concentrations, quinine induces a more than double increase in ADM uptake in K562/ADM cells. Pharmacokinetic data indicate that quinine should be administered 24 to 36 hours before anti‐cancer drugs in clinical trials that test its efficiency as a modifier of MDR in human hematologic malignant neoplasms.

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II)

SummaryIt has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group andP-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum.

SummaryIt has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m2 by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m2 furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.

Effects of Leptin on Lipopolysaccharide-Induced Remodeling in an In Vitro Model of Human Myometrial Inflammation

ABSTRACT Reorganization of myometrial extracellular matrix (ECM) is essential for the uterus to achieve powerful synchronous contractions during labor. Remodeling of the ECM has been implicated in membrane rupture and cervical ripening. Because maternal obesity is associated with both delivery disorders and elevated circulating leptin levels, this study aimed to assess the ability of leptin to interfere with lipopolysaccharide (LPS)-induced myometrial ECM remodeling. Myometrial biopsy samples were obtained from women undergoing cesarean delivery before labor onset. Myometrial explants were incubated for 48 h with LPS and leptin. LPS challenge was associated with a marked decrease in collagen content and in heat shock protein (HSP) 47 expression, reflecting a disruption in collagen synthesis and an increase in matrix metalloproteinase (MMP) 2 and MMP9 activity and in MMP2, MMP9, and MMP13 expression. Leptin prevented an LPS-induced decrease in myometrial collagen content in a concentration-dependent manner. This effect was associated with an increase in HSP47 expression and a decrease in MMP2 and MMP9 activity and expression. These results show that leptin prevents LPS-induced myometrial remodeling through collagen synthesis stimulation and inhibition of MMP2 and MMP9. Our study strengthens the hypothesis that leptin plays a role in the development of obesity-related delivery disorders.

Urinary β2-microglobulin early indicator of high dose cisdiamminedichloroplatinum nephrotoxicity? Influence of furosemide

SummaryTo evaluate the efficacy of β2-microglobulin as an indicator of cisplatinum nephrotoxicity, creatinine clearance and urinary β2-microglobulin were measured in 19 patients during 5 h after administration of a single dose of 80 mg/m2 cisplatinum. Eleven patients received furosemide as a concomitant therapy. Serum creatinine and β2-microglobulin remained unchanged. A decrease of creatinine clearance was observed. Urinary β2-microglobulin increased between 1 and 3 h after administration. This suggests transient tubular damage immediately after the treatment course. The concomitant administration of furosemide does not modify these results. However, patients who developped long-term nephrotoxicity had no early rise of urinary β2-microglobulin excretion; thus, it is not possible to predict cumulative nephrotoxicity by measuring β2-microglobulin immediately after the first course of high-dose cisplatinum.

Antiplatelet and antithrombotic effect of F 16618, a new thrombin proteinase-activated receptor-1 (PAR1) antagonist

BACKGROUND AND PURPOSE New antithrombotic agents with the potential to prevent atherothrombotic complications are being developed to target receptors on platelets and other cells involved in plaque growth. The aim of this study was to investigate the antiplatelet effects of Fu200316618, a new non‐peptidic PAR1 (thrombin receptor) antagonist.

Differential retention of doxorubicin in the organs of two strains of rats.

Abstract— Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg−1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.

Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

Leptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence.

966 Feasibility of 5-FU therapeutic monitoring

5-FV therapeutic monitoring was performed, in 26 patients with localized or disseminated epidermoid tumour of various origin, during 64 chemotherapy cycles containing 5-FV 1000xa0mg/m 2 in continuous infusion (J1–J5) and CDDP (100xa0mg/m 2 J1 or 20xa0mg/m 2 /j J1–J5). Blood samples were collected daily (8 a.m., 4 p.m.). 5-FV HPLC analysis used the method of Christophidis. Dose reduction of 5-FV was programmed according to the method of R. Fety using the J1–J2 and the J1–J5 5-FV area under the curve (AUC). An average of 2 cycles was administered. During the 1st cycle: J1–J2 5-FV AUC averaged 15751 μg 1 −1 h −1 ± 12309 (3902–56620) confirming the great interpatient variability. In 4 patients J1–J2 5-FV AUC > 20000 μg 1 −1 h −1 obliged to cancel chemotherapy at β. J1–J5 5-FV AUC averaged 46161 μg 1 −1 h −1 xa0±xa020020 (18380–90200). We observed a 5-FV accumulation process, characterised by an increase of daily 5-FV AUC in 18 patients. 5-FV dose reduction was scheduled in 27 cases and necessitated a further decrease during the chemotherapy cycle in 9 cases. 5-FV monitoring allowed a reduction in the toxicity which were less frequent for the cycles with J1–J2 5-FV AUCxa0 −1 h −1 or J1–J5 5-FV AUC −1 h −1 . Fourteen objective responses were obtained with 2 complete responses. J1–J5 5-FV AUC did not differ between responders and non responders. These time consuming techniques must find their role during more prolonged chemotherapy.

Comparative pharmacokinetics of tetrahydropyranyl‐doxorubicin and doxorubicin in rat isolated lung

Abstract— Rat isolated perfused lungs (Sprague‐Dawley rats, n = 20) were studied to compare the pulmonary uptake of a new anthracycline, tetrahydropyranyl‐doxorubicin (THP‐DXR) with that of doxorubicin (DXR). Lung perfusions were initiated with a constituted medium containing either drug at concentrations of 1, 10 or 100 μm. Lungs were perfused by recirculation for 60 min. Thirteen perfusate samples were collected over 60 min and subjected to HPLC for assay. The perfusate concentration of THP‐DXR decreased to 24 ± 5% of the initial concentration and to 8 ± 2%, 20 and 60 min after the beginning of the infusion, respectively. Corresponding values for DXR were 77 ± 16 and 52 ± 15%, respectively (P < 0·05). During the THP‐DXR perfusion, the area under the perfusate concentration vs time curve (AUC) was decreased to one‐third and the clearance was increased 3‐fold (P < 0·05). The pulmonary concentration of THP‐DXR reached 0·032 ± 0·01 μmol g−1 60 min after the beginning of a perfusion of 1 μm of the drug. This concentration increased to 0·379 ± 0·11 μmol g−1 when the initial dose concentration was 10 μm. Corresponding lung concentrations for DXR were 0·013 ± 0·001 and 0·150 ± 0·04 μmol g−1, respectively (P < 0·05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10 μm initial concentration of either drug was used. An initial concentration of 100 μm of THP‐DXR, unlike DXR, consistently induced oedema in the perfused lung. No metabolite of either drug was revealed during the course of our study. These findings suggest: (1) a higher lung affinity for THP‐DXR; (2) a correlation between lung uptake and dose consistent with a passive diffusion transport mechanism for both drugs; (3) a higher acute toxicity induced by THP‐DXR; (4) the absence of metabolic activity in the lung with regards to both anthracyclines.