Search PubMed⌕ Search

Biomedical subjects

M Alam

Publications and source records attributed to M Alam.

At least 127 records · Page 7Linked to original sources
PubMed1996

Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

Cell Line↗
PubMed1996

Expression of virulence-related properties by, and intestinal adhesiveness of, Vibrio mimicus strains isolated from aquatic environments.

A study of the major pathogenic characteristics of Vibrio mimicus was carried out with 77 strains isolated from aquatic environments in Okayama, Japan. Of the strains tested, 96% demonstrated in vitro adherence to the rabbit intestinal mucosa, of which 36, 20, and 43% belonged to the strongly, moderately, and weakly adhesive groups, respectively. Of the 27 strains which appeared to be enterotoxigenic in the experiments using rabbit ileal loops, 74% belonged to the strongly adhesive group. All strains of V. mimicus at early log phase showed cell-mediated hemagglutination, and 70% of strongly hemagglutinative strains belonged to the strongly adhesive group, implying a possible correlation between cell-mediated hemagglutination and bacterial adherence. However, no significant correlation could be detected in the production of putative exocellular pathogenic factors and bacterial adherence or enterotoxigenicity.

Animals↗
PubMed1996

Purification and characterization of novel hemagglutinins from Vibrio mimicus: a 39-kilodalton major outer membrane protein and lipopolysaccharide.

Two hemagglutinins (HAs) mediating the agglutinability to rabbit erythrocytes were isolated from 32-h culture supernatant of enterotoxigenic strain E-33 of Vibrio mimicus by ultrafiltration followed by gel filtration and anion-exchange column chromatography. The HAs were designated R-HA and C-HA on the basis of specific hemagglutinating activity towards rabbit erythrocytes only (R-HA) and towards chicken and rabbit erythrocytes (C-HA). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subsequent staining with Coomassie brilliant blue revealed no detectable protein band and a single band of Mr 39,000 in the case of R-HA and C-HA, respectively. However, silver staining of the gel containing R-HA revealed the appearance of low-molecular-weight material. These two HAs differed from each other and from previously reported HA/protease in receptor specificity, molecular composition, and biochemical and immunochemical properties. No simple sugar other than glycoproteins, including mucin, inhibited hemagglutinating activities of both C-HA and R-HA. Rabbit antibody against R-HA or C-HA could agglutinate E-33 whole cells, implying a possible cell surface origin of the two HAs. The isolated E-33 lipopolysaccharide (LPS) or its polysaccharide moiety conferred biochemical and immunochemical properties identical to those of R-HA, confirming that the R-HA represents polysaccharide of LPS. The LPS preparations from heterologous strains of Vibrio mimicus and Vibrio cholerae non-O1 confirmed that the hemagglutinating ability is a common function of LPS. On the other hand, the antibody against C-HA specifically recognized a major outer membrane protein (OMP) with an Mr of around 39,000 in both homologous and heterologous strains of V. mimicus, suggesting an OMP origin of C-HA. Furthermore, the antibody recognized a major OMP with an Mr of around 37,000 in V. cholerae. Although the immunogenicity of LPS and OMP is well documented for important intestinal pathogens, the hemagglutinating properties of such attractive cell surface components are hitherto unrecognized and will definitely contribute towards understanding their role in bacterial adherence.

Amino Acids↗
PubMed1996

Harziphilone and fleephilone, two new HIV REV/RRE binding inhibitors produced by Trichoderma harzianum.

During the screening of the natural products for their ability to inhibit the binding of REV (regulation of virion expression) protein to [33P] labeled RRE (REV responsive element) RNA, two novel fungal metabolites, harziphilone and fleephilone, were isolated from the butanol-methanol (1:1) extract of the fermentation broth of Trichoderma harzianum by bioassay guided fractionation. The structures of these two new compounds were established by spectroscopic methods. Harziphilone and fleephilone showed inhibitory activity against the binding of REV-protein to RRE RNA with IC50 values of 2.0 microM and 7.6 microM, respectively. However both compounds did not protect CEM-SS cells from acute HIV infection at concentration levels up to 200 micrograms/ml using an XTT dye reduction assay. In addition, harziphilone demonstrated cytotoxicity at 38 microM against the murine tumor cell line M-109.

Anti-HIV Agents↗
PubMed1996

Structure-activity relationship of quaternary ammonium ions at the external tetraethylammonium binding site of cloned potassium channels.

Changes in the chemical structure of the tetraethylammonium (TEA) ion reduce binding affinity at the external TEA receptor of outwardly rectifying potassium channels. To study the mechanism of selective binding, we applied a variety of hydrophilic quaternary ammonium (QA) ions to the noninactivating mutant of Shaker B T449Y, to Kv3.1, and to Kv3.1 mutants, expressed in Xenopus oocytes. In outside-out patches, QA ions in which ethyl groups of TEA were replaced by methyl groups had a lower affinity than TEA, whereas changes in binding affinity were minor when propyl groups were substituted for ethyl groups. All channels tested showed this pattern. Changes in free energy of binding correlated well with changes in the computed free energy of hydration of the TEA derivatives that we used. The affinity for TEA derivatives was reduced in Kv3.1Y407T, which is in support of the hypothesis that cation pi-electron interaction is involved. Binding affinities of QA ions were higher in Kv3.1 Y407F than in the wild-type, suggesting that the hydroxyl groups of the tyrosines reduce QA binding. The rank order of potency of the QA ions toward the different channels studied was the same. These results indicate that external QA ions bind strongly to hydrophobic pi-electron-rich functions. The selectivity, however, is determined by the physical properties of the QA ion.

Animals↗
PubMed1995

Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors.

BACKGROUND: Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied. METHODS AND RESULTS: We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20 +/- 0.07 to 0.39 +/- 0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67 +/- 0.22 to 1.22 +/- 0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7 +/- 9.6% to 27.1 +/- 11.8% (P = .007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4 +/- 10.4% to 23.7 +/- 8.9%) in the placebo group but not in patients who continued to receive digoxin (P = .002). CONCLUSIONS: The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Aldosterone↗
PubMed1995

Conformationally defined 6-s-trans-retinoic acid analogs. 2. Selective agonists for nuclear receptor binding and transcriptional activity.

We recently demonstrated in animal models that a new conformationally defined RA isomer (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) was as effective as RA in the prevention of skin papillomas but was less toxic. In order to provide more details concerning this improved action, we report here the preparation of a homologous conformationally defined 6-s-trans-retinoid (1) and investigate its ability to interact with proteins and to activate gene expression. Four configurational isomers of 1 were evaluated in binding assays for cellular retinoic acid binding protein, CRABP (isolated from chick skin); CRABP-I and CRABP-II (cloned from mouse); nuclear retinoic acid receptors (RARs); and nuclear retinoid X receptors (RXRs). In each assay the all-E-isomer of this retinoid had an activity that was comparable to that of (all-E)-RA. However, the 9Z-isomer was at least 200-fold less active than (all-E)-RA in binding to different RARs, while it was only 6-20 times less active than (9Z)-RA in binding to different RXRs. In an in vivo transient transfection assay, the all-E-isomer activated a reporter gene containing a retinoic acid response element (RARE) with efficiency similar to (all-E)-RA when expression vectors for either RAR alpha, RAR beta, RAR gamma alone or RAR alpha together with RXR alpha were cotransfected. In contrast, the 9Z-isomer was much less active than (9Z)-RA in the same assay systems. However, (9Z)-1 efficiently enhanced the DNA binding and transactivational activity of RXR alpha homodimers. Taken together, these studies demonstrate that the all-E- and 9Z-isomers of this retinoid are selective and potent agonists of RAR and RXR binding and activation.

Animals↗
PubMed1995

Effects of long-term therapy with enalapril on severity of functional mitral regurgitation in dogs with moderate heart failure.

OBJECTIVES: This study examined the effects of early long-term monotherapy with enalapril on the severity of functional mitral regurgitation in dogs with moderate heart failure. BACKGROUND: Functional mitral regurgitation often develops in patients with heart failure and, depending on its severity, can have a marked adverse impact on the stroke output of the failing left ventricle and contribute to progressive deterioration of the heart failure state. METHODS: Left ventricular dysfunction (ejection fraction 30% to 40%) was produced in 14 dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 months of therapy with enalapril (10 mg twice daily, n = 7) or no therapy at all (control, n = 7). The severity of functional mitral regurgitation was quantified by Doppler color flow mapping in seven control and six enalapril-treated dogs. Mitral annular diameter was assessed by echocardiography and left ventricular volumes and shape by ventriculography. Measurements were made before initiation and after completion of therapy. RESULTS: In control dogs, the severity of mitral regurgitation increased during the follow-up period ([mean +/- SEM] 14 +/- 4 vs. 23 +/- 4%, p < 0.001) and was associated with increased left ventricular end-systolic and end-diastolic volumes. In contrast, the severity of regurgitation was not significantly changed in dogs treated with enalapril (18 +/- 3 vs. 16 +/- 6%, p < 0.59) and was associated with preservation of left ventricular volumes. CONCLUSIONS: In dogs with moderate heart failure, early long-term therapy with enalapril prevents progressive worsening of functional mitral regurgitation. This beneficial effect is most likely achieved by prevention of progressive left ventricular dilation.

Animals↗
PubMed1995

The selectivity of different external binding sites for quaternary ammonium ions in cloned potassium channels.

Tetraethylammonium (TEA) is thought to be the most effective quaternary ammonium (QA) ion blocker at the external site of K+ channels, and small changes to the TEA ion reduce its potency. To examine the properties of the external QA receptor, we applied a variety of QA ions to excised patches from human embryonic kidney cells or Xenopus oocytes transfected with the delayed rectifying K+ channels Kv 2.1 and Kv 3.1. In outside-out patches of Kv 3.1, the relative potencies were TEA > tetrapropylammonium (TPA) > tetrabutylammonium (TBA). In contrast to Kv 3.1, the relative potencies in Kv 2.1 were TBA > TEA > TPA. In Kv 3.1 and Kv 2.1, external tetrapentylammonium (TPeA) blocked K+ currents in a fast, reversible and, in contrast to TEA, time-dependent manner. The external binding of TPeA appeared to be voltage independent, unlike the effects of TPeA applied to inside-out patches. External n-alkyl-triethylammonium compounds (C8, C10 chain length) had a lower affinity than TEA in Kv 3.1, but a higher affinity than TEA in Kv 2.1. In Kv 3.1, the decrease in QA affinity was large when one or two methyl groups were substituted for ethyl groups in TEA, but minor when propyl groups replaced ethyl groups. Changes in the free energy of binding could be correlated to changes in the free energy of hydration of TEA derivatives calculated by continuum methodology. These results reveal a substantial hydrophobic component of external QA ion binding to Kv 2.1, and to a lesser degree to Kv 3.1, in addition to the generally accepted electrostatic interactions. The chain length of hydrophobic TEA derivatives affects the affinity for the hydrophobic binding site, whereas the hydropathy of QA ions determines the electrostatic interaction energy.

Animals↗
PubMed1995

Indomethacin inhibits cell proliferation and increases cell losses in rat gastrointestinal epithelium.

Gastrointestinal cell proliferation was estimated in histological sections of rats treated with low and high doses of parenteral indomethacin for 3 to 60 days. Mitoses were arrested with vincristine and cells in S phase were labeled with tritiated thymidine. Short-term, low-dose treatments reduced the mitotic activity in the oxyntic and small intestinal epithelium, whereas moderate doses restored the mitotic index and high doses increased the proliferative activity and produced epithelial hyperplasia. Long-term, low-dose treatments increased cell proliferation in the small intestine and reduced the number of villous cells. Indomethacin did not affect the proliferative response elicited by refeeding in the oxyntic mucosa, but the simultaneous administration of prostaglandin E2 analog increased the number of arrested mitoses. The turnover of labeled cells was accelerated by indomethacin, particularly in the small intestine. These findings indicate that prostaglandins are regulators of the cell kinetics of the gastrointestinal epithelium but, at the same time, they disclose the presence of trophic mechanisms that are independent of the synthesis of endogenous prostaglandins.

Animals↗
PubMed1995

Effect of the somatostatin analogue, octreotide, on exercise-induced hypotension in human subjects with chronic sympathetic failure.

1. In autonomic failure, supine exercise lowers blood pressure and worsens postural hypotension. The somatostatin analogue, octreotide, reduces post-prandial and postural hypotension, but its effects on exercise-induced hypotension and on postural hypotension post-exercise are unknown. 2. Eighteen subjects with chronic sympathetic denervation were studied; 12 had pure autonomic failure and six had additional neurological features of the Shy-Drager syndrome. Haemodynamic, hormonal and biochemical changes were measured before, during and after incremental supine leg exercise on two occasions: on no treatment and after subcutaneous octreotide. Exercise was performed 120 min after octreotide in eight subjects and 60 min after octreotide in ten subjects. 3. Octreotide did not improve exercise-induced hypotension; the blood pressure fall was greater during exercise, but the blood pressure level was no different than without treatment. Heart rate, stroke distance, cardiac index and systemic vascular resistance were similar at rest and changed to the same degree with exercise on and off octreotide. After octreotide, resting levels of serum growth hormone, plasma noradrenaline, adrenaline and renin were unchanged, but glucose was higher and insulin was lower. There was no change in biochemical and hormone levels during exercise either off or on octreotide. 4. After octreotide, although the rate of blood pressure recovery was similar post-exercise, the levels of blood pressure were higher than in the non-treatment phase and postural hypotension was improved before and after exercise. 5. In conclusion, in primary autonomic failure, octreotide did not improve exercise-induced hypotension in the supine position, suggesting that octreotide-sensitive vasodilatory peptides do not contribute to the blood pressure fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Production of antigenically related exocellular elastolytic proteases mediating hemagglutination by vibrios.

Exocellular proteases produced by Vibrio fluvialis, V. furnissii, V. metschnikovii and V. campbellii were characterized and compared to those of V. mimicus protease (VMP) and V. vulnificus protease (VVP). These proteases possessed both elastolytic and hemagglutinating abilities and were identified, except that of V. metschnikovii, as metalloprotease. Conversely, V. metschnikovii protease failed to exhibit some of the salient features for metalloproteases suggesting the existence of protease(s) other than metalloprotease. However, antibodies against VVP cross-reacted to these proteases and to VMP indicating antigenic relatedness amongst vibrio proteases. This study, thus, demonstrated the prevalent distributions of antigenically related proteases both in pathogenic and non-pathogenic vibrios, bringing their status as a virulence determinant into question.

Antigens, Bacterial↗
PubMed1995

Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease.

A series of aminodiol inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were identified by using an in vitro peptide cleavage assay. BMS 182,193, BMS 186,318, and BMS 187,071 protected cells against HIV-1, HIV-2, and simian immunodeficiency virus infections, with 50% effective doses ranging from 0.05 to 0.33 microM, while having no inhibitory effect on cells infected with unrelated viruses. These compounds were also effective in inhibiting p24 production in peripheral blood mononuclear cells infected with HIV-1 IIIB and against the zidovudine-resistant HIV-1 strain A018C. Time-of-addition studies indicated that BMS 182,193 could be added as late as 27 h after infection and still retain its antiviral activity. To directly show that the activity of these compounds in culture was due to inhibition of proteolytic cleavage, the levels of HIV-1 gag processing in chronically infected cells were monitored by Western blot (immunoblot) analysis. All compounds blocked the processing of p55 in a dose-dependent manner, with 50% effective doses of 0.4 to 2.4 microM. To examine the reversibility of BMS 186,318, chronically infected CEM-SS cells were treated with drug and virions purified from the culture medium. Incubation of HIV-1 particles in drug-free medium indicated that inhibition of p55 proteolysis was slowly reversible. The potent inhibition of HIV-1 during both acute and chronic infections indicates that these aminodiol compounds are effective anti-HIV-1 compounds.

Antiviral Agents↗
PubMed1995

Transesophageal echocardiography in evaluation of atrial masses.

Clinical and transthoracic echocardiographic findings in 92 patients who had atrial mass lesions identified by transesophageal echocardiography were retrospectively analyzed. Transthoracic echocardiography failed to diagnose or misdiagnosed 16 patients with small (< 3 cm) atrial thrombi, patients with thrombi localized to the appendage, or patients with technically difficult studies. The 3 patients with atrial myxoma who were not detected or were misdiagnosed by transthoracic echocardiography had small tumors (< 3 cm) or origin from the free wall of the atrium away from the atrial septum. Transthoracic study also failed to diagnose or misdiagnosed normal anatomic variants in 17 of 32 patients. In conclusion, transesophageal echocardiography is superior to the transthoracic study in evaluating the etiology and significance of atrial mass lesions.

Diagnosis, Differential↗
PubMed1995

Transesophageal echocardiographic evaluation of left main coronary artery.

Transesophageal echocardiography (TEE) demonstrated the left main coronary trunk in 30 of 32 patients. Of these 30 patients, 10 had angiographically normal and 20 stenotic left main coronary arteries. The TEE study revealed no stenosis in 9 of 10 patients with normal left main trunks and atherosclerotic lesions in all 20 patients with stenotic left main trunks. TEE demonstrated additional areas of stenosis in the left main coronary artery in 3 patients, which included ostial lesions in 2 patients. These features were not observed by angiography. Furthermore, when compared with angiography, TEE overestimated severity of stenosis in 4 patients. In conclusion, TEE is a useful test in demonstrating normal as well as stenotic left main coronary trunks.

Coronary Angiography↗
PubMed1995

Conductometric study of interaction between dyes and surface active agents.

The interaction of anionic surface active agents e.g. sodium decyl sulphate (SDS), sodium dodecyl sulphate (SDDS), sodium tetradecyl sulphate (STDS), sodium hexadecyl sulphate (DHDS) and sodium octadecyl sulphate (DODS) with cationic dyes, methylene blue (MB), crystal violet (CV) acridine orange (AO), rhodamine 6G (Rh 6G) and quinacrine dihydrochloride (QD) has been studied in three regions by conductometric titration. In the first region ion pair association occurs and the species (cationic and anionic) exist in equilibrium with homogeneous solution. In the second region complexation occurs by 1:1 with MB, CV and AO and by 2:1 with QD and Rh 6G forming a heterogeneousphase, separation and equilibration containing free ions and ion-pair. In the third region the micelle formation occurs by the excess of anions in the presence of cations as well as ion-pair formation and separated complex ions that give solubilization of the complex to a homogeneous clear solution.

Journal Article↗