Kinetic analysis and subambient temperature on-line on-column derivatization of an active aldehyde.

The chromatographic analysis of aldehydes under typical reversed-phase conditions may be a challenging task due to an equilibrium process leading to the formation of a gem diol species regardless of acidic or basic conditions. Initially, a reversed-phase HPLC gradient elution was developed to determine the amount of a n acetylenic aldehyde in a reaction mixture. Significant fronting was observed under acidic and basic conditions even at -5 degrees C. In order to circumvent this problem, a reversed-phase HPLC gradient method on a C18 column at subambient temperature was developed using diethylamine as a mobile phase additive for on-line on-column derivatization of the aldehyde moiety. The on-line on-column reaction rate for the derivatization of the aldehyde with diethylamine was determined as a function of column temperature. An Arrhenius plot was constructed and the activation energy was calculated. The chromatographic behavior of the derivatized acetylenic aldehyde and products formed in-situ in the chromatographic system were studied at various temperatures ranging from -10 to 60 degrees C. It was found that the reaction products could be controlled by adjusting the column temperature. Different reaction pathways were identified as a function of temperature. The products and the reaction pathways were characterized by NMR, LC-MS and UV spectra.

Mechanistic aspects of chiral discrimination on an amylose tris(3,5-dimethylphenyl)carbamate.

The separation of [2R-[2alpha(R*),3alpha]]-5-[[2-[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]-3(S)-4-fluorophenyl)4-morpholinyl]-methyl]-N,N-dimethyl-1H-1,2,3-triazole-4-methanamine hydrochloride from its enantiomer was achieved on an amylose tris-3,5-dimethylphenyl carbamate stationary phase. The retention of the enantiomers is dominated by weak hydrogen bonds while the enantioselectivity is governed by other kinds of interactions, e.g., inclusion in the amylose carbamate chains. Van't Hoffplots of 1nalpha vs. reciprocal temperature were non-linear and could be divided into two linear regions. One region at low temperature (5 degrees C- approximately 20 degrees C) and another one between 25 degrees C-70 degrees C with the change in slope occurring between 16 degrees C and 20 degrees C. DSC experiments suggested that the behavior can be attributed to breakage of H-bonds triggering a conformational change. Molecular simulation indicated a correlation between the interaction energies and the elution order obtained experimentally. The most retained enantiomer (R,R,S-enantiomer) interacts with the stationary phase through a hydrogen bond between the triazole proton and the C=O groups of the stationary phase, as well as through an inclusion in the cleft of the stationary phase. The other enantiomer exhibits a bifurcated H-bond between the triazolic proton and the C=O groups of the stationary phase leading to a less stable complex.

A practical synthesis of a COX-2-specific inhibitor.

A number of synthetic strategies to the Cox-2 specific inhibitor 1 have been described. These studies have led to the identification of a novel pyridine construction using annulation of ketone 2 using a vinamidinium species 29 and ammonia in 97% assay yield. Three approaches to the synthesis of ketone 2 are described that allow for its preparation in large quantities in >65% overall yield from methyl 6-methylnicotinate.

Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial.

BACKGROUND: Onychomycosis is an increasing problem with limited therapeutic options. OBJECTIVE: We evaluated the safety and efficacy, of oral terbinafine, a new fungicidal antimycotic, in patients with toenail onychomycosis. METHODS: A North American multicenter, double-blind, placebo-controlled study evaluated the mycologic and clinical efficacy of oral terbinafine 250 mg/day for 12 or 24 weeks in 358 patients with toenail onychomycosis. RESULTS: A total of 74% of patients treated with 12 or 24 weeks of terbinafine achieved a successful clinical outcome. Approximately 11% of terbinafine responders showed evidence of relapse 18 of 21 months after cessation of treatment. Terbinafine was well tolerated; most adverse events were transient and mild to moderate in severity. CONCLUSION: The results of this study confirm that oral terbinafine is a safe and effective therapy for the treatment of onychomycosis.

[3H]benzylpempidine, a new radioligand for probing a putative channel site on nicotinic cholinergic receptors.

A study was undertaken to assess the receptor binding characteristics of [3H]4-benzylpempidine to an allosteric site on calf brain membranes associated with nicotinic cholinergic receptors and to compare the binding affinity of novel arylpempidine analogs with their ability to antagonize the behavioral effects of nicotine in mice. Scatchard analysis of the binding yielded a K(d) of 20 nM and a B(max) of 330 fmols/mg membrane protein. [3H]4-benzylpempidine appears to be a more satisfactory ligand than [3H]mecamylamine, since it possessed a 50-fold greater affinity and its binding was far less sensitive to inorganic ions and Tris. Among the arylpempidine analogs 4-m-chlorobenzylidenepempidine and 4-benzylidenepempidine had the lowest K(i) values (1.4 nM and 5.0 nM, respectively) and were the most potent in antagonizing nicotine-induced seizures in mice. Although the K(i) values for pempidine and mecamylamine were 1-2 orders of magnitude greater than any of the arylpempidines, the dose required to antagonize nicotine-induced seizures in mice was comparable to the arylpempidines. One explanation for this apparent discrepancy in the correlation of binding affinity and nicotine antagonism is the lower brain penetration of arylpempidines compared to mecamylamine, following their systemic administration to mice.

Functional analysis of the Pseudomonas aeruginosa autoinducer PAI.

A series of structural analogs of the Pseudomonas aeruginosa autoinducer [PAI, N-3-oxo-dodecanoyl homoserine lactone] were obtained and tested for their ability to act as autoinducers in stimulating the expression of the gene for elastase (lasB) by measuring beta-galactosidase production from a lasB-lacZ gene fusion in the presence of the transcriptional activator LasR. The data suggest that the length of the acyl side chain of the autoinducer molecule is the most critical factor for activity. Replacement of the ring O by S in the homoserine lactone moiety can be tolerated. Tritium-labelled PAI ([3H]PAI) was synthesized and used to demonstrate the association of [3H]PAI with cells overexpressing LasR. The PAI analogs were also tested for their ability to compete with [3H]PAI for binding of LasR. Results from the competition assays suggest that once again the length of the acyl side chain appears to be crucial for antagonist activity. The presence of the 3-oxo moiety also plays a significant role in binding since analogs which lacked this moiety were much less effective in blocking binding of [3H]PAI. All analogs demonstrating competition with PAI in binding to LasR also exhibited the ability to activate lasB expression, suggesting that they are functional analogs of PAI.

[Development of feeding activities in dairy cows at the start of lactation and relation to the quantities of feed ingested]. / Evolution des activités alimentaires des vaches laitières en début de lactation et liaison avec les quantités d'aliments ingérés.

Feeding behaviour was measured in 12 multiparous dairy cows all day long during the first 5 weeks of lactation. These cows received corn silage ad libitum and concentrates representing 21 to 27% of total dry matter intake, depending on the week. During the first week of lactation, total eating and ruminating times were 364 and 426 min; eating and ruminating rates were 39.0 and 32.5 g DM/min. The feed intake increase during the first 5 weeks of lactation was accompanied by an increase in ruminating time (+ 22%) and eating rate (+ 26%). These two parameters were very sensitive to short-time decreases in DM intake. Animal variations of eating and ruminating rates, but not variations of total eating and ruminating times, were related to those of dry matter intake. Thus, animals which had the highest dry matter intake were those which had the highest eating and ruminating rates.

[Various blood parameters of energy metabolism in dairy cows at the start of lactation]. / Evolution de différents paramètres sanguins du métabolisme énergétique chez la vache laitière en début de lactation.

Thirty eight lactating dairy cows were given ad libitum a diet of maize silage supplemented with concentrate (3 to 5.5 kg/day). Five blood samples were taken from 25 cows from the last week of pregnancy to the 8th week of lactation. The other thirteen cows were subjected to a more frequent sampling (three times a week during the first five weeks of lactation). Each plasma sample was analyzed in order to assess its glucose, acetone, beta-hydroxybutyrate and non-esterified fatty acids contents. The glucose content of the plasma was minimum and the acetone content was maximum at the end of the second week of lactation when the cumulated energy balance was at its most negative level. It appeared that the individual glucose and acetone contents were closely related to the cumulated energy balance, while the non esterified fatty acids content was closely related to the energy balance at the time of sampling. From all the data obtained, a good negative curvilinear relation between the glucose content and the ketone bodies content was observed. These results are discussed with the mobilization of body reserves during the early lactation and its consequences.

[Syncope with a rare etiology, cardiac hydatidosis]. / Syncopes d'étiologie rare, hydatidose cardiaque.

A case of left ventricular hydatid disease causing mitral insufficiency and revealed by accelerated idioventricular rhythm (AIVR) is reported. The traditional and more recent diagnostic procedures including echocardiography and immunology are reviewed. The persistence of AIVR and mitral insufficiency after excision of the cyst are discussed with respect to the surgical treatment.