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Biomedical subjects

P Samuel

Publications and source records attributed to P Samuel.

At least 19 recordsLinked to original sources
PubMed2006

Effects of consuming foods containing oat beta-glucan on blood pressure, carbohydrate metabolism and biomarkers of oxidative stress in men and women with elevated blood pressure.

OBJECTIVE: To assess the effects of consuming foods containing oat beta-glucan on blood pressure, carbohydrate homeostasis and biomarkers of oxidative stress. DESIGN: A randomized, double-blind, controlled clinical trial. SETTING: The trial was conducted at two clinics. SUBJECTS AND INTERVENTIONS: Ninety-seven men and women with resting systolic blood pressure 130-179 mm Hg and/or diastolic blood pressure 85-109 mm Hg were randomly assigned to consume foods containing oat beta-glucan or control foods for 12 weeks. Resting blood pressures, insulin and glucose values before and after standard breakfast meals, and four biomarkers of oxidative stress were measured before and at the end of the treatment period. RESULTS: Changes from baseline to week 12 in mean peak insulin and incremental area under the insulin curve differed significantly between groups (P=0.037 and 0.034, respectively), with the beta-glucan group showing declines and the control group remaining essentially unchanged. Blood pressure responses were not significantly different between groups overall. However, in subjects with body mass index above the median (31.5 kg/m(2)), both systolic (8.3 mm Hg, P=0.008) and diastolic (3.9 mm Hg, P=0.018) blood pressures were lowered in the beta-glucan group compared to controls. No significant differences in biomarkers of oxidative stress were observed between treatments. CONCLUSIONS: The results of the present trial suggest beneficial effects of foods containing beta-glucan from oats on carbohydrate metabolism, and on blood pressure in obese subjects.

Area Under Curve↗
PubMed2005

Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives.

Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds.

Amides↗
PubMed2005

Enzymatic hydrolysis of stampidine and other stavudine phosphoramidates in the presence of mammalian proteases.

Mammalian proteases have not been implicated in the metabolism of any nucleoside phosphoramidate prodrug. The results presented herein provide unprecedented and conclusive experimental evidence that mammalian proteases are capable of hydrolyzing stavudine phosphoramidates. Specifically, cathepsin B and Proteinase K are able to metabolize stampidine and other phosphoramidate derivatives of stavudine. Additionally, cathepsin B exhibits chiral selectivity at the phosphorus center. The elucidation of the metabolic pathways leading to activation of stampidine may provide the basis for pharmacologic interventions aimed at modulating the metabolism and thereby improving the therapeutic window of stampidine as an anti-HIV agent.

Amides↗
PubMed2005

Protease-mediated enzymatic hydrolysis and activation of aryl phosphoramidate derivatives of stavudine.

Several proteases are capable of hydrolyzing the aryl substituted phosphoramidate derivatives of stavudine resulting in the formation of the active metabolite, alaninyl d4T monophosphate. Subtilisin Protease A, Subtilisin Griseus, Subtilisin Carlsberg, Papaya, Bacillus were amongst the most effective proteases in hydrolyzing stavudine derivatives and specificity of their activity was confirmed using several protease inhibitors to block the hydrolysis of these phosphoramidate derivatives. We found that these proteases exhibit chiral selectivity at the phosphorus center of stavudine derivatives. Our results indicate that cellular proteases may be responsible for the activation of these phosphoramidate derivatives. In addition, we show that the enzymatic hydrolysis takes place at the carboxymethyl ester side chain of these pro-drugs and the direct attack on the phosphorus center by these enzymes does not occur. Finally, we describe a novel activation pathway hitherto unknown for the activation and viral inhibitory characteristic shown by these phosphoramidate derivatives of stavudine.

Amides↗
PubMed2005

Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates.

Stampidine and other halogen substituted stavudine phosphoramidates can be activated by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D-amino acid substituted isomers {Rp or Sp}are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that the L-amino acid configured isomers {Rp or Sp} are preferred in the lipase binding pocket.

Amides↗
PubMed2005

Do injections of 5-fluorouracil after trabeculectomy have toxic effects on the anterior segment?

OBJECTIVE: To discourage fibrosis of the filtering bleb, 5 fluorouracil (5-FU) may be injected after trabeculectomy. 5-FU is an antimetabolite that also can damage extraocular tissues at concentrations as low as 0.5%. This study ascertained whether repeated injection of 5-FU has toxic effects on intraocular structures. METHODS: After unilateral trabeculectomy in anesthetized New Zealand rabbits, 5-FU (5.0 mg/0.1 mL) was injected at the trabeculectomy site every 5 days for 15 days. Evaluation included slit-lamp examination, confocal microscopy, and intraocular pressure (IOP). After sacrifice, aqueous humor (AH) was drawn and eyes excised for scanning electron microscopy (SEM) and light microscopy. RESULTS: The 5-FU injection not decrease IOP beyond trabeculectomy alone. Bleb height remained constant, thickness increased, and vascularity decreased. No changes in cornea or anterior segment were observed. No inflammation was observed in the bleb or surrounding tissues by slit-lamp or histologic examination. Protein in AH increased from 0.6 +/- 0.5 microg/mL at baseline to 19.8 +/- 4.4 microg/mL after trabeculectomy but only to 0.9 +/- 0.6 microg/mL after trabeculectomy plus 5-FU. Both in vivo confocal microscopy and SEM revealed deleterious effects on corneal epithelial and endothelial cells with a minor shift toward smaller cells. CONCLUSIONS: In this study 5-FU did not provoke an intraocular inflammatory response and had minimal effect on extraocular structures. Changes in corneal epithelium and endothelium detectable by confocal microscopy suggest a small toxic effect. These in vivo measurements by confocal microscopy were confirmed by SEM. Repeated administration did not cause additional cumulative toxic effects in the anterior segment. Therefore, multiple injections of 5- FU into the filtering bleb pose minimal risk to intraocular structures.

Animals↗
PubMed2004

Lipase-mediated stereoselective hydrolysis of stampidine and other phosphoramidate derivatives of stavudine.

Enzymatic hydrolysis of stampidine and other aryl phosphate derivatives of stavudine were investigated using the Candida Antarctica Type B lipase. Modeling studies and comparison of the hydrolysis rate constants revealed a chiral preference of the lipase active site for the putative S-stereoisomer. The in vitro anti-HIV activity of these compounds correlated with their susceptibility to lipase- (but not esterase-) mediated hydrolysis. We propose that stampidine undergoes rapid enzymatic hydrolysis in the presence of lipase according to the following biochemical pathway: During the first step, hydrolysis of the ester group results in the formation of carboxylic acid. Subsequent step involves an intramolecular cyclization at the phosphorous center with simultaneous elimination of the phenoxy group to form a cyclic intermediate. In the presence of water, this intermediate is converted into the active metabolite Ala-d4T-MP. We postulate that the lipase hydrolyzes the methyl ester group of the l-alanine side chain to form the cyclic intermediate in a stereoselective fashion. This hypothesis was supported by experimental data showing that chloroethyl substituted derivatives of stampidine, which possess a chloroethyl linker unit instead of a methyl ester side chain, were resistant to lipase-mediated hydrolysis, which excludes the possibility of a direct hydrolysis of stampidine at the phosphorous center. Thus, our model implies that the lipase-mediated formation of the cyclic intermediate is a key step in metabolism of stampidine and relies on the initial configuration of the stereoisomers.

Amides↗
PubMed2004

Phenyl phosphoramidate derivatives of stavudine as anti-HIV agents with potent and selective in-vitro antiviral activity against adenovirus.

Adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, nephritis, and gastroenteritis in immunocompromised patients, including HIV-infected individuals. Here we report the identification of halo-substituted stavudine phenyl phosphoramidate derivatives as a new class of dual-function anti-HIV agents with potent and selective anti-adenovirus (ADV) activity. We examined the investigational stavudine phenyl phosphoramidate derivative stampidine and 12 structurally similar stavudine derivatives for anti-ADV activity. All 13 derivatives of stavudine, including stampidine, were substantially more potent than stavudine and inhibited ADV-induced plaque formation at nanomolar IC(50) values. Compounds with halo substitutions in the phenyl ring as well as the unsubstituted compound 607 were more potent than compounds with methoxy, methyl, or cyano substitutions. Compound 113 (stampidine) with a 4-Br substitution and compound 609 with a 4-Cl substitution were identified as the most potent lead anti-ADV agents. Compound 113/Stampidine inhibited ADV-induced plaque formation in skin fibroblasts in a concentration-dependent fashion with a mean (+/-S.E.M.) IC(50) value of 17 +/- 2 nM without any evidence of cytotoxicity even at 100 microM. Similarly, compound 609 inhibited ADV-induced plaque formation with an IC(50) value of 27 +/- 3 nM. We next sought to determine if the lead compounds 113 and 609 can also inhibit other viruses. Both compounds exhibited potent anti-HIV activity at nanomolar concentrations. However, neither compound exhibited any antiviral activity against non-HIV viruses, including Cytomegalovirus (CMV), Type I or Type II herpes simplex viruses (HSV-1, HSV-2), enterovirus ECHO 30, or respiratory syncytial virus (RSV) (IC(50) > 100 microM). The remarkable anti-ADV potency of the lead compounds stampidine and compound 609 warrants the further development of these promising new antiviral agents for possible clinical use in ADV infected patients.

Adenoviridae↗
PubMed2004

A comparative study of the hydrolysis pathways of substituted aryl phosphoramidate versus aryl thiophosphoramidate derivatives of stavudine.

A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of these two types of d4T derivatives indicated that replacement of oxygen with sulfur decreases the rate of hydrolysis by twofold. Additionally, the activation energy (E(a)) for the sulfur analogs is comparatively higher than that of the oxygen analogs. Notably, an intermediate was formed in the hydrolysis reaction of the sulfur analogs of d4T that was absent in the case of the oxygen analog, and the tentative structure of the intermediate was proposed based on LC/mass spectroscopy data. Using both HPLC and (31)P-NMR techniques, we identified the hydrolysis product of the phosphoramidate derivatives and were able to show in in vitro studies that porcine liver esterase can hydrolyze the methyl ester portion of the phosphoramidate derivatives. Aryl phosphoramidate derivatives of d4T were 1000-fold more active than the corresponding aryl thiophosphoramidate derivatives, indicating that the energy of activation of hydrolysis of these phosphoramidate derivatives plays a significant role in their biological potency.

Amides↗
PubMed2004

Leprosy case detection using schoolchildren.

An innovative method that combined awareness creation with screening of high school students by their peers was undertaken in 26 randomly selected schools in the project area of the Schieffelin Leprosy Research and Training Center, Karigiri, Vellore, India. This method entailed educating teachers and student leaders in grades 8-12 about leprosy and how to suspect leprosy among their peers. The student leaders in turn conducted a similar awareness programme for their peers and encouraged them to report if they suffered from any skin problem or skin lesion. Based on the reporting by their peers, the class leaders prepared a 'suspect list'. Within a fortnight of the awareness program, a trained leprosy worker visited the school and examined all the students on the 'suspect list'. Those diagnosed to have leprosy were referred to a medical officer, who then confirmed the diagnosis and initiated treatment. Among the 23,125 students enrolled in the 26 randomly selected schools, 234 student leaders were educated about leprosy and trained to detect suspect lesions among their peers. A total of 2200 (9.5%) children reported with skin lesions to their leaders and after screening by a leprosy supervisor and confirmation by a medical officer, 14 new cases (NCDR 6.05/10,000) were detected. This rate was found to be comparable with case detection rates of annual school surveys done during the National Leprosy Eradication Programme (NLEP), when all schoolchildren were examined. The paper suggests that schoolchildren can be used effectively in leprosy case detection and this method has the additional advantage of creating awareness among them, their teachers and communities.

Adolescent↗
PubMed2003

Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/Fc epsilon RI receptor mediated mast cell leukotriene release.

Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/Fc epsilon RI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (compound 5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea (24) and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea (25) were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (37; IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (50; IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (35; IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. These results establish the substituted halopyridyl, indolyl and naphthyl thiourea compounds as a new chemical class of anti-allergic agents inhibiting IgE receptor/Fc epsilon RI-mediated mast cell LTC(4) release. Further lead optimization efforts may provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.

Animals↗
PubMed2002

Effects of aryl substituents on the anti-HIV activity of the arylphosphoramidate derivatives of stavudine.

We compared the anti-HIV activity of 13 phenyl phosphate derivatives of stavudine (2',3'-didehydro-2',3'-dideoxythymidine/d4T) by examining their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells. Our results show that the introduction of electron-withdrawing substituents enhances the activity of these phosphoramidate derivatives. The rate of chemical hydrolysis under alkaline conditions (but not the lipophilicity) predicted the potency of the compounds.

Anti-HIV Agents↗
PubMed2002

Synthesis and anti-HIV activity of carbamates of antiviral agent stavudine.

An efficient synthesis of carbamate analogues of the NRTI compound stavudine, has been achieved in five steps starting from commercially available thymidine. The synthesis involves conversion of thymidine into stavudine followed by condensation with carbaimidazole derivative obtained from various aromatic and heterocyclic amines in dimethylformamide solvent. The analogues thus obtained were further purified by crystallization to furnish analytically pure products. Examination of biological activity of these carbamate derivatives of stavudine showed that they inhibited HIV replication only at micro-molar concentrations.

Anti-HIV Agents↗
PubMed2000

Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.

This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.

Adult↗
PubMed2000

Ultrasound investigation of the rotator cuff after computed arthrotomography coupled to bursography.

OBJECTIVES: To evaluate the diagnostic performance of ultrasound rotator cuff imaging after injection of contrast medium into the glenohumeral joint and subacromial bursa. PATIENTS AND METHODS: Twenty-eight patients underwent ultrasonography before and after injection into the glenohumeral joint and subacromial bursa of a mixture of iodinated contrast medium and lidocaine solution. Findings were compared with those from computed tomography of the joint and bursa. RESULTS: Sixteen 16 (16/28, 57%) post-contrast ultrasound scans revealed or confirmed rotator cuff lesions. For supraspinatus and infraspinatus lesions, there were three false-negatives and no false-positives. Three false-negatives were recorded for subscapularis lesions. All false-negatives occurred both before and after the contrast medium injections. CONCLUSION: Injecting contrast medium into the glenohumeral joint and subacromial bursa improves the diagnostic yield of rotator cuff ultrasonography. We suggest that ultrasonography be performed after injections of drugs into the shoulder structures, particularly the subacromial bursa.

Acromioclavicular Joint↗