Renal function and aspirin resistance in patients with coronary artery disease.

Aspirin resistance and chronic renal failure are both potentially important clinical issues in coronary artery disease. To test the hypothesis of a relationship between the two, we recruited 169 stable outpatients with proven coronary artery disease (myocardial infarction, coronary artery bypass grafting, intra-coronary stents) taking 75 mg aspirin daily. Blood was taken for light transmission aggregometry to agonists arachidonic acid (0.5mg/mL) and adenosine diphosphate (10 µmol/L), for platelet marker soluble P selectin (enzyme linked immunosorbent assay), resting and stimulated expression of CD62P (flow cytometry) and for renal function (estimated glomerular filtration rate). The estimated glomerular filtration rate was lower when aspirin resistance was defined by response to arachidonic acid after 3, 5 and 7 minutes (approximately 30% of patients) (p<0.021), and when defined by response to adenosine diphosphate after 3 minutes (approximately 17% of patients)(p=0.015) compared to those who were sensitive to aspirin. Mean [standard deviation] soluble P selectin levels were 57 [23] ng/mL in 49 patients with aspirin resistance, and 50 [15] ng/mL in the 119 aspirin sensitive patients (p=0.02). Estimated glomerular filtration rate correlated inversely with platelet CD62P expression at rest (r=-0.22, p=0.004), and when stimulated by arachidonic acid (r=-0.21, p=0.007) and by adenosine diphosphate (r=-0.17, p=0.023). Aspirin resistance was more than twice as prevalent in those with the greatest renal disease (50% of patients) compared to those with the best renal function (21.4%). Our data point to a weak relationship between worsening glomerular filtration rate and aspirin resistance. Nevertheless, we suspect that failure of patients to be fully responsive to aspirin may be important in the pathophysiology of thrombosis in renal dysfunction.

Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship.

Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4'-trimethoxystilbene was the most potent and selective antiproliferative agent (IC50 89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4' position namely (E)-3-methoxy-4'-hydroxystilbene, (E)-3,5-dimethoxy-4'-hydroxystilbene (pterostilbene), (E)-4-methoxy-4'-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent.

Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function.

We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.

Renal humoral modulation of skeletal muscle tone in mice: implications for 'the pulmonary-renal cascade'.

The pulmonary-renal cascade may regulate the respiration and skeletal muscle contractility. To evaluate this working hypothetical model, we conducted experiments to ascertain the skeletal muscle tone of the Swiss mice (20-35 g). The animals were evaluated for their skeletal muscle tone via several techniques i.e. inclined plane test, grip strength test and swim test. Groups of mice (n=6) were pre-treated with mefenamic acid (60 mg/kg, i.p), carbenoxolone (100 mg/kg i.p) or vehicle only 15 minutes before the treatment with heparin (500 U/kg, i.v), urokinase (5500 U/kg, i.v) and erythropoietin (150 U/kg, i.v). Heparin potentiated the loss of skeletal muscle tone induced by mefenamic acid and carbenoxolone while urokinase & erythropoietin significantly enhanced the skeletal muscle tone as evaluated by all or one of the tests. Other groups of mice (n=6) were pretreated with mefenamic acid (1 mg i.c.v), carbenoxolone (160 microg i.c.v) or minoxidil (30 microg i.c.v) and the effects of heparin & urokinase and erythropoietin on skeletal muscle tone were evaluated. To study the effects of heparin and urokinase on nerve regeneration, two groups of mice underwent a sham and sciatic nerve crush procedure. The mice treated with urokinase recovered much faster as compared to those treated with heparin or saline. These experimental results suggest that gap junction blockers and potassium channel openers interact with heparin, urokinase and erythropoietin to control the skeletal muscle tone.

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides.

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.

Ellis-van Creveld Syndrome.

A 21 years old male with typical features of Ellis-Van Creveld Syndrome is presented for its rarity. This is the second living case being reported from India.

Two controlled studies of the efficacy of isoniazid alone in preventing relapse in patients with bacteriologically quiescent pulmonary tuberculosis at the end of one year of chemotherapy.

An earlier report showed that, in patients with bacteriologically quiescent pulmonary tuberculosis at the end of 1 year of chemotherapy, isoniazid alone in a single daily dose of 150-200 mg, given as maintenance therapy in the second year, did not markedly prevent relapse over a 4-year period of follow-up in patients who had had residual cavitation (the "open-negative" syndrome) at 1 year, but was highly effective in patients who had not. As a result of these findings, two controlled studies, reported here, were undertaken.The first study was undertaken in patients with bacteriologically quiescent disease and residual cavitation at 1 year, and investigated the value of isoniazid in a higher daily dose (400 mg) throughout the second year; this is known to be the optimum therapeutic dose when isoniazid is prescribed alone for 1 year in the initial treatment of the disease. The second study was carried out in patients with bacteriologically quiescent disease and no residual cavitation at 1 year, and sought to determine the value of a shorter duration (6 months) of chemotherapy in the second year with a daily dose of 300 mg of isoniazid. Neither of the two isoniazid regimens was highly satisfactory, although both appeared to have had some effect in preventing relapse during the 4-year period of follow-up.

Attack rate of tuberculosis in a 5-year period among close family contacts of tuberculous patients under domiciliary treatment with isoniazid plus PAS or isoniazid alone.

This report from the Tuberculosis Chemotherapy Centre, Madras, considers the risk, over a 5-year period, to close family contacts of sputum-positive patients treated at home for 1 year with a standard regimen of isoniazid plus PAS or one of 3 regimens of isoniazid alone. The attack rate of tuberculosis in the contacts did not appear to be influenced by the treatment received by the patients in the first year or by the duration in the 5-year period for which the patients had (1) positive sputum smears, (2) positive cultures, or (3) isoniazid-resistant cultures. Further, over half the cases of tuberculosis developed in the first year, many of these being in the first 3 months. These findings confirm the conclusions reached from an earlier study, namely, that the major risk to the contacts is from exposure to the infectious patient before diagnosis, and that the risks from the other possible sources of infection (the patient during treatment and the urban environment of Madras) are, in comparison, small.

A 5-year study of patients with pulmonary tuberculosis treated at home in a controlled comparison of isoniazid plus PAS with 3 regimens of isoniazid alone.

This report from the Tuberculosis Chemotherapy Centre, Madras, describes the progress, over a 5-year period, of 341 patients with newly diagnosed, sputum-positive tuberculosis. All the patients were treated on a domiciliary basis. In the first year, the patients received, on the basis of random allocation, a standard regimen of isoniazid plus PAS or 1 of 3 regimens of isoniazid alone. Previous reports have shown that the response in the first year was substantially superior with the standard regimen, and that the bacteriological relapse rates in the second year were fairly similar for the 4 regimens. The findings in the present report extend the latter conclusion to the end of 5 years. Further, when considered together with the findings in an earlier study, they have shown that isoniazid, given as maintenance chemotherapy in the second year, was highly effective in preventing bacteriological relapse in patients who, at 1 year, had bacteriologically quiescent disease and no residual cavitation; the effect was, however, less marked in patients with residual cavitation at 1 year.Patients who were clear-cut failures of the allocated chemotherapy and those who had a bacteriological relapse in the second or subsequent years were usually re-treated with streptomycin plus PAS or streptomycin plus pyrazinamide, and if this was ineffective, with cycloserine plus thioacetazone or cycloserine plus ethionamide.Considering the findings over the 5-year period for all patients, 16 died from non-tuberculous causes and 1 took his discharge prematurely. Of the remainder, 86% had bacteriologically quiescent disease at 5 years, 6% had bacteriologically active disease and 8% had died of tuberculosis. These findings confirm the value of well-organized domiciliary chemotherapy, which was established by an earlier report from the Centre, and are particularly encouraging for developing countries such as India, where tuberculosis is a major problem and resources are limited.