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N Mousseau

Publications and source records attributed to N Mousseau.

29 records · Page 2Linked to original sources
PubMed1991

Chromatographic and spectroscopic characterization of sulphur-bound dimetridazole and ranidazole derivatives.

The 5-nitroimidazoles, dimetridazole and ronidazole, two important veterinary drugs, were reacted under reductive conditions with the sulfhydryl-containing substrates cysteine and glutathione to yield 5-amino-4-S-substituted imidazoles. After purification by reversed-phase liquid chromatography (RP-LC), the four adducts were characterized by RP-LC with photodiode array detection using conditions where their parent drugs were not eluted from the column. Structural identification was conducted by spectroscopic techniques, mainly 1-dimensional and 2-dimensional NMR. While the dimetridazole adducts were found to be monosubstituted at the C-4 position, the two ronidazole products contained two units of the sulfhydryl substrate, located at the C-4 and C-6 positions.

Chromatography, Liquid↗
PubMed1988

High-performance liquid chromatographic determination of diltiazem and four of its metabolites in plasma: evaluation of their stability.

A rapid, specific and reproducible high-performance liquid chromatographic method was developed for the simultaneous determination of diltiazem and four of its metabolites in plasma. The method involves extraction with methyl tert.-butyl ether, back-extraction into 0.017 M phosphoric acid followed by reversed-phase chromatography on a 3-micron particle, 15-cm ODS column with UV detection at 237 nm. Overall the recovery of each compound was reproducible and greater than 85%. Calibration curves were linear over the concentration range 10-250 ng/ml, with within-day or between-day coefficients of variation not exceeding 12%. A stability study indicates that while diltiazem is stable for at least six weeks in frozen plasma, more than 30% degradation of the major metabolite, N-monodesmethyldiltiazem, was observed after four weeks at -20 degrees C. The assay procedure has been applied to monitoring of plasma levels in patients receiving chronic oral therapy.

Biotransformation↗
PubMed1988

Perioperative variability of binding of lidocaine, quinidine, and propranolol after cardiac operations.

This study examined the effect of changes in plasma concentrations of total protein, albumin, alpha 1-acid glycoprotein, and free fatty acids occurring after heart operations on the protein binding of chemically basic drugs. Plasma protein and free fatty acid concentrations were measured simultaneously with in vitro determinations of the protein binding of lidocaine, quinidine, and propranolol: immediately before operation, immediately on weaning from cardiopulmonary bypass, on arrival in the recovery room, and 12, 24, 72, and 120 hours postoperatively. Initial decreases in the concentrations of all proteins were followed by a rise in alpha 1-acid glycoprotein to 254% of baseline at 72 to 120 hours. The free fractions of drug were initially increased to 168% of baseline for lidocaine, 206% for quinidine, and 200% for propranolol and fell progressively with time, reaching sustained troughs of 65% for lidocaine, 50% for quinidine, and 57% for propranolol at 72 to 120 hours. Regression analysis indicated a major influence of changing alpha 1-acid glycoprotein concentrations on free fractions of all three drugs, with a smaller effect of albumin that reached statistical significance only for lidocaine. There were no significant perioperative changes in plasma concentrations of free fatty acids when the in vitro effects of heparin were controlled. In conclusion, sequential changes in plasma protein concentrations after cardiac operations predictably alter the protein binding of lidocaine, quinidine, and propranolol and should be considered when interpreting total plasma drug concentrations.

Blood Proteins↗
PubMed1983

Influence of protamine on heparin-induced increases of lidocaine free fraction.

It has been suggested that heparin-induced increases in drug free fraction are largely artifactual as a result of continued in vitro activity of lipoprotein lipases after blood samples collection. The influence of different concentrations of protamine (1.0, 2.5, 5.0 and 10.0 mg/ml), an inhibitor of lipoprotein lipases, on lidocaine free fraction was studied before (control) and 10 min after heparinization (3000 IU) in 7 cardiac catheterized patients. Heparin increased the mean free fraction of lidocaine by 85% (p less than 0.001) and was associated with more than 2-fold increases in free fatty acids (FFAs). The presence of protamine at 2.5, 5.0 and 10.0 mg/ml diminished both the heparin-induced elevation of lidocaine free fraction (p less than 0.001) and FFAs (p less than 0.001). At a protamine concentration of 10.0 mg/ml, the FFAs remained higher than control value (p less than 0.05) while the free fraction was not different from control preheparin value. There were significant relationships (p less than 0.01) between log protamine concentration and the changes in both free fraction (r2 = 0.906) and FFAs (r2 = 0.931). The inhibitor also reduced (p less than 0.01) the lidocaine free fraction in control samples but these changes were not correlated with changes of FFAs. These results indicate that it is impossible, at this point, to abolish the artifactual effect of heparin without altering protein binding of lidocaine.

Adult↗
PubMed1980

Quantitation of acetazolamide in plasma by high-performance liquid chromatography.

A method for estimating acetazolamide concentrations in human plasma is described. Buffered plasma (pH 4.8) containing chlorothiazide as an internal standard is extracted twice with ethyl acetate. The extract is evaporated, redissolved, and chromatographed on silica gel with hexane-chloroform-methanol-acetic acid (65:25:10:0.25) as the mobile phase. The extraction efficiencies were greater than 90%, the coefficients of variation at 1 and 30 micrograms/ml of plasma were 3.5 and 2.0%, respectively, and the calibration curves were linear and had an intercept of essentially zero. The suitability of the method for pharmacokinetic studies was verified in a normal volunteer dosed with 250-mg (solution) and 500-mg (sustained-release tablet) acetazolamide formulations.

Acetazolamide↗
PubMedDate not supplied

Use of capillary electrophoresis for the characterization of human serum albumin heterogeneity.

Human serum albumin (HSA) is used in large amounts as an excipient in many biopharmaceutical formulation to prevent loss of the active ingredient through adsorption and/or degradation. Traditionally, iso-electric focusing has been used to demonstrate charge heterogeneity in HSA preparations. In an effort to develop new methods for the analysis of formulation components, a capillary zone electrophoresis method was developed for the analysis of HSA. Under initial separation conditions using untreated silica capillaries and 20 mM sodium phosphate, pH 6.0 as electrophoretic buffer, HSA migrated as a single peak. Addition of 1,4-diaminobutane allowed separation of several components which could be further resolved by varying the buffer pH. Optimal separation conditions were attained at 5 mM 1,4-diaminobutane and pH 8.5. The reproducibility of the separation conditions was verified by using capillaries from a different manufacturer. A comparative analysis of HSA preparations from different manufacturers provided evidence that the method may be used to qualitatively differentiate individual preparations. The analysis of rhEPO formulations, composed largely of HSA, showed levels of heterogeneity comparable to that of HSA preparations. Electrospray ionisation mass spectrometry (ESA-MS) was used as an independent method to confirm the heterogeneous nature of HSA.

Electrophoresis, Capillary↗
PubMedDate not supplied

Dissociation of authentic and artifactual effect of circulating heparin on drug protein binding.

The purpose of this study was to dissociate the authentic and artifactual effect of in vivo heparin on drug protein binding using protamine as an inhibitor of ex vivo lipolysis. A mixture of ethylenediamine tetra-acetic acid (EDTA, 5 mg ml-1) and protamine in the concentration range of 0 to 7.5 mg ml-1 was added to blood samples from 23 cardiac catheterized patients before (control) and 10 min after 3000 IU of intravenous heparin. In control samples, protamine does not interfere with the protein binding of lidocaine (L), quinidine (Q) or propranolol (P) when plasma pH is readjusted to 7.4. In the absence of protamine, heparin induced a significant increase in the free fraction by 40, 130, and 30 per cent for L, Q, and P, respectively (p less than 0.001), while free fatty acid (FFA) levels increased 2 to 6 fold. When protamine was present, the heparin-induced elevation in free fraction was significantly lower for L (16 per cent) and Q (77 per cent) but not for P; FFA levels were decreased at all protamine concentrations. Residual increases in free fraction and FFA levels compared to control values may represent the true in vivo effect of heparin at the peak activity of lipoprotein lipases. For L and Q, variations in free fraction were strongly associated with variations in FFA, but for P, no significant correlation was observed (r = 0.492). These results indicate that variations in free fraction of L and Q caused by heparin are, to a large extent, artifactual but may be prevented by use of protamine in collection tubes (5 to 7.5 mg ml-1). For P, the increase in free fraction was not mediated by variations of FFA indicating that another mechanism must be involved.

Adult↗
PubMedDate not supplied

Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound.

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in tissue remodeling under normal physiological and pathological conditions and are thus attractive targets for both diagnostic and therapeutic purposes. Here, we examined the effect of AE-941, an orally bioavailable standardized extract made of cartilage that shows significant antiangiogenic and antimetastatic properties in vivo, on the activity of various members of the MMP family. MATERIALS AND METHODS: The effect of AE-941 on the activity of MMPs was assessed by fluorimetric assays and by substrate gel zymography. RESULTS: AE-941 markedly inhibits the gelatinolytic activity of MMP-2 and to a lesser extent those of MMP-1, MMP-7, MMP-9 and MMP-13. AE-941 also inhibited the elastinolytic activities of MMP-2 and MMP-9 as well as MMP-12 (metalloelastase), porcine pancreatic elastase (PPE), and human leukocyte elastase (HLE). Western blot analysis revealed the presence within AE-941 of immunoreactive TIMP-like proteins, suggesting that these proteins may be at least partly responsible for the observed MMP inhibition. CONCLUSIONS: Taken together, these results demonstrate that AE-941 contains TIMP-like proteins that could be responsible for the specific inhibition of MMPs. Given the recent studies suggesting the presence within this compound of specific inhibitor(s) of endothelial cell proliferation, AE-941 appears as a pleotropic agent able to interfere with several biochemical steps leading to angiogenesis and to other physiopathological conditions. Since AE-941 is currently under Phase III clinical investigations, these findings are also of considerable importance for our understanding of its anticancer properties.

Angiogenesis Inhibitors↗