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Biomedical subjects

G Gosselin

Publications and source records attributed to G Gosselin.

At least 73 records · Page 4Linked to original sources
PubMed1997

Effect of stereoisomerism on the cellular pharmacology of beta-enantiomers of cytidine analogs in Hep-G2 cells.

The beta-L enantiomers of 2',3'-dideoxycytidine (beta-L-ddC) and its 5-fuoro derivative, 2',3'-dideoxy-5-fluorocytidine (beta-L-FddC), were demonstrated to be active against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication in vitro. In the present study, we investigated the cellular pharmacology of beta-L-ddC and beta-L-FddC and compared it with that of beta-D-2',3'-dideoxy-5-fluorocytidine (beta-D-FddC). Beta-L-FddC (10 microM) was found to be phosphorylated rapidly in Hep-G2 cells to its 5'-mono-, di-, and triphosphate derivatives with intracellular triphosphate levels achieving 26.6 +/- 10.9 pmol/10(6) cells after 72 hr. In contrast, the active 5'-phosphorylated derivative of beta-D-FddC achieved lower levels with triphosphate levels of only 2.3 +/- 0.5 pmol/ (10(6) cells under the same conditions. Beta-L-ddC was also phosphorylated rapidly. A 5'-diphosphocholine (18 +/- 5.8 pmol/10(6) cells) and a 5'-diphosphoethanolamine (13.6 +/- 0.9 pmol/10(6) cells) derivative were detected in beta-D-FddC-treated cells after 72 hr, whereas in beta-L-FddC- and beta-L-ddC-treated cells, only the 5'-diphosphocholine derivative (10.9 +/- 2.8 and 60.4 +/- 5.7 pmol/10(6) cells, respectively) was detected. Beta-L-FddC-5'-triphosphate (beta-L-FddCTP), beta-D-FddC-5'-triphosphate (beta-D-FddCTP), and beta-L-ddC-5'-triphosphate (beta-L-ddCTP) followed a single phase elimination process with an intracellular half-life (T1/2) of 10.5, 5.7, and 12.3 hr, respectively. Furth ermore, beta-L-FddCTP, beta-D-FddCTP, and beta-L-ddCTP levels of 6.7 +/- 2.3, 0.3 +/- 0.1, and 12.0 pmol/10(6) cells, respectively, were still detectable 24 hr following drug removal. The higher intracellular 5'-triphosphate levels of beta-L-FddC and the extended T1/2 of its 5'-triphosphate are consistent with the more potent in vitro antiviral activity of beta-L-FddC in Hep-G2 cells when compared with its beta-D enantiomer, beta-D-FddC.

Antiviral Agents↗
PubMed1997

Lack of enantiospecificity of human 2'-deoxycytidine kinase: relevance for the activation of beta-L-deoxycytidine analogs as antineoplastic and antiviral agents.

We demonstrate that human 2'-deoxycytidine kinase (dCK) is a nonenantioselective enzyme because it phosphorylates beta-D-2'-deoxycytidine (D-dCyd), the natural substrate, and beta-L-2'-deoxycytidine (L-dCyd), its enantiomer, with the same efficiency. Kinetic studies showed that L-dCyd is a competitive inhibitor of the phosphorylation of D-dCyd with a Kl value of 0.12 microM, which is lower than the K(m) value for D-dCyd (1,2 microM). Chemical modifications of either the base or the pentose ring strongly decrease the inhibitory potency of L-dCyd, L-dCyd is resistant to cytidine deaminase and competes in cell cultures with the natural D-dCyd as substrate for dCK, thus reducing the incorporation of exogenous [3H]dCyd into DNA. L-dCyd had no effect on the pool of dTTP deriving from the salvage or from the de novo synthesis, does not inhibit short term RNA and protein syntheses, and shows little or no cytotoxicity. Our results indicate a catalytic similarity between human dCK and herpetic thymidine kinases, enzymes that also lack stereospecificity. This functional analogy underlines the potential role of dCK as activator of L-deoxycytidine analogs as antiviral and antineoplastic agents and lends support to the hypothesis that herpesvirus thymidine kinase might have evolved from a captured cellular dCK gene, developing the ability to phosphorylate thymidine and retaining that to phosphorylate deoxycytidine.

Antineoplastic Agents↗
PubMed1996

Synthesis, in vitro antiviral evaluation, and stability studies of bis(S-acyl-2-thioethyl) ester derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability.

A new series of hitherto unknown 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) phosphonodiester derivatives incorporating carboxyesterase-labile S-acyl-2-thioethyl (SATE) moieties as transient phosphonate-protecting groups was prepared in an attempt to increase the oral bioavailability of the antiviral agent PMEA. We report here a direct comparison of the in vitro anti-HIV and anti-HSV activities as well as the in vitro stability between the bis(SATE) derivatives and the already known PMEA prodrugs, namely, bis[(pivaloyloxy)methyl (POM)]- and bis[dithiodiethyl (DTE)]PMEA. All of the compounds tested showed an enhanced in vitro antiviral activity compared to the parent PMEA. The bis(POM)- and bis(tBu-SATE)PMEA derivatives were the most effective. However, striking differences between these two compounds were found during the stability studies. In particular the bis(tBu-SATE)PMEA was found to be more stable than bis(POM)PMEA in human gastric juice and human serum, suggesting it could be considered as a promising candidate for further in vivo development.

Adenine↗
PubMed1996

Effect of beta-enantiomeric and racemic nucleoside analogues on mitochondrial functions in HepG2 cells. Implications for predicting drug hepatotoxicity.

A group of enantiomeric nucleoside analogues with beta-D or beta-L configuration, which represent potential candidates for the treatment of hepatitis B virus (HBV) infection, were incubated in human hepatoblastoma HepG2 cells at concentrations between 0.1 and 10 microM for 4-14 days. Then the effect on mitochondrial DNA (mtDNA) content, lactic acid production, lipid droplet formation, and mitochondrial morphology were evaluated. No effect on lactic acid production was detected in cells treated with beta-L-2',3'-dideoxy-3'-thiacytidine (3TC), beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (beta-L-FTC), beta-D-2',3'-dideoxy-5-fluoro-3'-thiacytidine (beta-D-FTC), racemic cis 2',3'-dideoxy-5-fluoro-3'thiacytidine [(+/-)-FTC], and 2,4-diamino-7-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl) pyrrolo[2',3'-d]pyrimidine (T70178), whereas a slight increase was associated with beta-D-2-hydroxymethyl-5-(2,6-diaminopurin-9-yl)-1,3-dixolane++ + (beta-D-DAPD) and 4-amino-7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimi dine -5-thiocarboxamide (T70182) at 10 microM. A concentration-dependent increase in lactic acid production was observed in cells exposed to beta-D-2',3'-dideoxy-3'-thiacytidine [(+)-BCH-189], racemic cis 2',3'-dideoxy-3'-thiacytidine [(+/-)-BCH-189], beta-D-2',3'-dideoxy-5-fluorocytidine (beta-D-FddC), beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FddC), beta-D-2-hydroxymethyl-5-(5-fluorocytosin-I-yl)-1,3,-dioxolane (beta-D-FDOC), 2,4-diamino-7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) pyrrolo[2,3-d]pyrimidine (T70080), and 4-amino-7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo [2,3-d]pyrimidine (T70179). Inhibition on mtDNA content was demonstrated to be concentration-dependent with (+)-BCH-189, beta-D-FddC, and T70080, whereas 3TC, (+/-)-BCH-189, beta-L-FTC, beta-D-FTC, (+/-)-FTC, beta-L-FddC, beta-D-DAPD, T70178, T70179, and T70182 had no effect. beta-D-FDOC resulted in a marked inhibition of mtDNA synthesis at 10 microM but not at lower concentrations. Cells treated with 3TC, (+/-)-BCH-189, beta-L-FTC, beta-D-FTC, (+/-)-FTC, beta-L-FddC, beta-D-DAPD, T70178, T70179, and T70182 did not show morphological changes compared with the control. In contrast, increased cytoplasmic lipid droplets associated with a loss of cristae in mitochondria were detected in cells treated with either beta-D-FDOC, beta-D-FddC, or T70080, (+)-BCH-189 treatment resulted in loss of cristae in mitochondria. In summary, 3TC, beta-L-FTC, beta-D-FTC, (+/-)-FTC, beta-D-DAPD, T70178, and T70182 exhibited a relatively safe profile, supporting their further development.

Antiviral Agents↗
PubMed1996

Human pulmonary circulation is an important site for both clearance and production of endothelin-1.

BACKGROUND: Animal studies suggest a major role of the pulmonary circulation in the clearance of circulating endothelin-1 (ET-1). The contribution of the human pulmonary circulation to plasma ET-1 clearance, however, has never been quantified. The absence of an AV gradient in plasma ET-1 has previously been interpreted as evidence that the lungs do not have a role in modulating circulating ET-1 levels. This study was designed to quantify and discern between pulmonary ET-1 clearance and production in humans. METHODS AND RESULTS: We studied 13 subjects by combining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventricular ejection fractions (61 +/- 7%, mean +/- SD) and baseline hemodynamics. Mean pulmonary ET-1 extraction was 47 +/- 7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestration rate constant: Kseq = 0.048 +/- 0.019 s-1. There was no significant difference between irET-1 levels from the pulmonary artery and aorta (0.61 +/- 0.29 and 0.68 +/- 0.33 pg/mL, respectively; P = .22); the normal lung consequently produces an amount of ET-1 that is quantitatively similar to the amount that has been extracted. CONCLUSIONS: The human lung is an important site for both clearance and production of ET-1. There is a normal physiological balance of ET-1 across the pulmonary circulation, which explains the absence of difference in AV ET-1 levels despite a 47 +/- 7% clearance. Reduced pulmonary clearance or increased production of this peptide may contribute to the increase in circulating levels found in various cardiovascular conditions.

Aged↗
PubMed1996

Effects of modifications in the pentose moiety and conformational changes on the binding of nucleoside ligands to uridine phosphorylase from Toxoplasma gondii.

One hundred and fifty analogues of uridine, with various modifications to the uracil and pentose moieties, have been tested and compared with uridine with respect to their potency to bind to uridine phosphorylase (UrdPase, EC 2.4.2.3) from Toxoplasma gondii. The effects of the alpha- and beta-anomers, the L- and D-enantiomers, as well as restricted syn and anti rotamers, on binding were examined. Pseudo-, lyxo-, 2,3'-anhydro-2'-deoxy-, 6,5'-cyclo-, 6,3'-methano-, O5',6-methano- and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding xylosides, which were better than the deoxyribosides. The binding of deoxyribosides was in the following manner: 2',3'-dideoxynucleosides > 2',5'-dideoxynucleosides > 2'-deoxyribosides > 3'- and 5'-deoxyribosides. alpha-2'-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding beta-anomers. The acyclo- and 2,2'-anhydrouridines bound strongly, with the 2,2'-anhydro-derivatives being the better ligands. 2,5'-Anhydrouridine bound to UrdPase less effectively than 2,2'-anhydrouridine and acyclouridine. Arabinosyluracil was at best a very poor ligand, but bound better if a benzyl group was present at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding by increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, alpha- and beta-anomers of the 2'-deoxyribosides, acyclonucleosides, and 2,2'-anhydronucleosides. Among all the compounds tested, 5-(benzyloxybenzyl)-2,2'-anhydrouridine was identified as the best ligand of T. gondii UrdPase with an apparent Ki value of 60 +/- 3 nM. It is concluded that the presence of an N-glycosyl bond is a prerequisite for a nucleoside ligand to bind to T. gondii UrdPase. On the other hand, the presence of a 2'-, 3'-, or 5'-hydroxyl group, or an N-glycosyl bond in the beta-configuration, enhanced but was not essential for binding. Furthermore, the potency of the binding of 2,2'-anhydrouridines (fixed high syn isomers) in contrast to the weaker binding of the 6,1'-anhydro- or 2,5'-anhydrouridines (fixed syn isomers), and the complete lack of binding of the 6,5'-cyclo, O5',6-methano- and 6,3'-methanouridines (fixed anti isomers) to T. gondii UrdPase indicate that the binding of ligands to this enzyme is in the syn/high syn conformation around the N-glycosyl bond. The results also indicate that the parasite but not the mammalian host UrdPase can participate in hydrogen bonding with N3 of the pyrimidine ring of nucleoside ligands. T. gondii UrdPase also has a larger hydrophobic pocket adjacent to the C5 of the pyrimidine moiety than the host enzyme, and can accommodate modifications in the pentose moiety which cannot be tolerated by the host enzyme. Most prominent among these modifications is the absence and/or lack of the ribo orientation of the 3'-hydroxyl group, which is a requirement for a ligand to bind to mammalian UrdPase. These differences between the parasite and host, enzymes can be useful in designing specific inhibitors or "subversive" substrates for T. gondii UrdPase.

Animals↗
PubMed1996

Decomposition pathways and in vitro HIV inhibitory effects of isoddA pronucleotides: toward a rational approach for intracellular delivery of nucleoside 5'-monophosphates.

The decomposition pathways and kinetics in various biological media and the in vitro anti-HIV-1 and anti-HIV-2 activities of four derivatives of the 5'-mononucleotide of isoddA incorporating carboxylate esterase-labile transient phosphate protecting groups are reported and compared: namely, two mononucleoside aryl phosphoramidate derivatives 1a,b and two mononucleoside phosphotriester derivatives incorporating two S-acyl-2-thioethyl groups 2a,b. All four compounds show better antiviral activity, compared to the parent nucleoside analog isoddA. The results highlight that both types of compounds act as pronucleotides, i.e. they exert their antiviral effect via intracellular delivery of the 5'-mononucleotide of isoddA. The results may give insights for the design of new more efficient pronucleotides.

Cell Line↗
PubMed1996

Selective protection of toxicity of 2',3'-dideoxypyrimidine nucleoside analogs by beta-D-uridine in human granulocyte-macrophage progenitor cells.

beta-D-Uridine protected human granulocyte-macrophage lineage cells in both semi-solid (granulocyte-macrophage colony-forming units, CFU-GM) and liquid cultures against the toxic effects of 3'-azido-3'-deoxythymidine (AZT), 3'-fluoro-3'-deoxythymidine (FLT) and a combination of AZT and FLT, without impairment of the activities of these respective drugs against human immunodeficiency virus (HIV) replication. In addition, beta-D-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3'-amino-3'-deoxythymidine (AMT). Beta-L-uridine and alpha-D-uridine, two stereoisomers of the natural form, and the base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas beta-D-uridine-5'-bis(SATE)phosphotriester, a prodrug of beta-D-uridine-5'-monophosphate, successfully protected cells against AZT toxic effects, suggesting that beta-D-uridine needs to be metabolized to its nucleotides to exert a pharmacological effect. These data suggest in addition that AZT, FLT and AMT share a common target site(s) of toxicity involved in myelosuppression.

Antiviral Agents↗
PubMed1996

Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators.

In the Studies of Left Ventricular Dysfunction (LVD), enalapril or placebo was administered in a double-blind fashion to 6797 participants with ejection fraction < or = 0.35. During 40 months' average follow-up, 28.1% of participants randomized to enalapril reported side effects compared with 16.0% in the placebo group (p < 0.0001). Enalapril use was associated with a higher rate of symptoms related to hypotension (14.8% vs 7.1%, p < 0.0001), azotemia (3.8% vs 1.6%, p < 0.0001), cough (5.0% vs 2.0%, p < 0.0001), fatigue (5.8% vs 3.5%, p < 0.0001), hyperkalemia (1.2% vs 0.4%, p = 0.0002), and angioedema (0.4% vs 0.1%, p < 0.05). Side effects resulted in discontinuation of blinded therapy in 15.2% of the enalapril group compared with 8.6% in the placebo group (p < 0.0001). Thus enalapril is well tolerated by patients with LVD; however, hypotension, azotemia, cough, fatigue, and other side effects result in discontinuation of therapy in a significant minority of patients.

Aged↗
PubMed1996

Coronary Angioplasty in the Treatment of Post-Cardiac Transplant Coronary Artery Disease.

Accelerated coronary disease following cardiac transplantation is an important obstacle to long-term survival and its management is not well defined. Coronary angioplasty has been proposed as a palliative treatment in some patients with discrete proximal lesions. Of 172 patients who underwent cardiac transplantation between April 1983 and November 1995, 8 underwent subsequent coronary angioplasty of 11 lesions. The majority was performed in asymptomatic patients, 5 for angiographic abnormalities alone, and 3 for documented painless ischemia. Primary angiographic success was obtained in 91% (10/11) of lesions dilated. Complications included 1 acute occlusion and 1 arteriovenous fistula. Three patients died, 1, 8 and 10 months after angioplasty. After an average of 36-month follow-up, 4 (out of 8) patients had no cardiac event (myocardial infarction, second angioplasty, retransplantation or death). Thus, coronary angioplasty can be performed with acceptable risk in selected patients with cardiac transplantation.

Journal Article↗
PubMed1996

Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase.

We extended our previous study with 3'-azido-3'-deoxythymidine nucleotides [Proc. Natl. Acad. Sci. USA 91:5771-5775 (1994)] and examined the effects on human immunodeficiency virus type 1 (HIV-1) integrase of the nucleotides of three nucleoside analogues currently under evaluation in clinical trials: beta-D-2',3'-didehydro-3'-deoxythymidine, beta-D-2'-ara-fluoro-2', 3'-dideoxyadenosine, and beta-L-2',3'-dideoxy-3'-thiacytidine. Beta-D-2',3'-Didehydro-3'-deoxythymidine and beta-D-2'-ara-fluoro-2',3'-dideoxyadenosine nucleotides had IC50 values for strand transfer of 100 and 200 microM, respectively, whereas the corresponding 2',3'-dideoxynucleoside triphosphates, ddT triphosphate and ddA triphosphate, did not inhibit the integrase at 800 and 200 microM, respectively. Beta-L-2',3'-Dideoxy-3'-thiacytidine triphosphate had no effect up to 500 microM. The L-enantiomers of 5-fluoro-2',3'-dideoxycytidine monophosphate and triphosphate had IC50 values of approximately 40 microM, whereas their D-enantiomer isomers showed no inhibition at 200 microM. NAD, pyridoxal phosphate, and coumermycin A1, which exhibit no antiviral activity but are typically used to probe nucleotide binding sites, were also tested. NAD was inactive, and its etheno derivative exhibited activity at 1 mM. In contrast, pyridoxal phosphate (IC50 = 18 microM and coumermycin A1 (IC50 = 5 microM were potent inhibitors. None of the coumermycin monomeric derivatives were active integrase inhibitors. The physiological ribonucleotides ATP and GTP inhibited HIV-1 integrase at or near cellular concentrations, suggesting that they may regulate HIV-1 integrase activity in cells. In general, the active nucleotides tested inhibited binding of HIV-1 integrase to its substrate DNA an inhibited an integrase deletion mutant containing only amino acids 50-212, indicating that nucleotides bind to the enzyme catalytic core. Consisently, the choice of nucleophile in the 3'-processing reaction was blocked to the same extent regardless of the nucleotide used (water, glycerol, or the viral DNA hydroxyl) by the enzyme. These observations suggest new strategies for antiviral drug development that could be based on nucleotide analogues as inhibitors of HIV-1 integrase.

Antiviral Agents↗
PubMed1996

[Does gender affect long-term results of coronary angioplasty in patients with multivessel disease?].

Multivessel coronary angioplasty, defined as angioplasty of 2 or 3 main coronary vessels performed during the same procedure, was performed in 203 selected patients between 1981 and 1986. The results in men (n = 159, group I) were compared with those in women (n = 44, group II). The angiographic appearances were comparable in the two groups, but the women were older, more often hypertensive and diabetic, and more symptomatic than the men (82% vs 57% in grades 3 or 4 of the Canadian Cardiovascular Society (CCS) Classification; p < 0.009). Complete revascularisation with angioplasty of all stenoses > 50% was attempted during the same session. The primary success rate per lesion was comparable in the two groups (90% in men, 93% in women; NS), as was the number of segments successfully dilated per patient (2.2 +/- 0.7 in group I and 2.2 +/- 0.8 group II; NS). Angioplasty was complicated by myocardial infarction and/or emergency coronary bypass surgery in 11 men and 2 women (NS). Clinical follow-up was obtained for an average of 71 +/- 22 months in the men and 70 +/- 22 months in the women in 96% of cases. The global seven year survival rate without recurrent infarction or cardiovascular death was 81% in men and 83% in women (NS). The number of repeat revascularisation procedures was comparable in the two groups (46% in women and 43% in men; NS) as was the number and duration of hospital admissions during follow-up (8.4 +/- 12.3 days in the women and 6.7 +/- 8.4 days in the men; NS). The functional status at the end of follow-up was the same in the two groups with 84% of men and 81% of women being asymptomatic or grade 1 of the CCS classification. The authors conclude that the long-term results of multivessel angioplasty are good and comparable in men and women. This revascularisation procedure should be considered as an alternative to surgery in women and men.

Actuarial Analysis↗
PubMed1996

New insights regarding the potential of the pronucleotide approach in antiviral chemotherapy.

The rationale for a pronucleotide approach based on the use of phosphotriesters which incorporate enzyme-mediated bio-labile protection is discussed in detail. Among the studied bio-labile phosphate protecting groups, the S-acyl-2-thioethyl (SATE) groups appeared the most promising as exemplified in cell culture systems in the case of the pronucleotides of 3'-azido-3'-deoxythymidine, 2',3'-didehydro-3'-deoxythymidine, 2',3'-dideoxyadenosine and acyclovir In vivo implementations of such bis(SATE) pronucleotides have been planned for future animal studies.

Acyclovir↗
PubMed1995

Mononucleoside phosphotriester derivatives with S-acyl-2-thioethyl bioreversible phosphate-protecting groups: intracellular delivery of 3'-azido-2',3'-dideoxythymidine 5'-monophosphate.

The synthesis, in vitro anti-HIV-1 activity, and decomposition pathways of several mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) incorporating a new kind of carboxylate esterase-labile transient phosphate-protecting group, namely, S-acyl-2-thioethyl, are reported. All the described compounds showed marked antiviral activity in thymidine kinase-deficient CEM cells in which AZT was virtually inactive. The results strongly support the hypothesis that such pronucleotides exert their biological effects via intracellular delivery of the 5'-mononucleotide of AZT. This point was corroborated by decomposition studies in cell extracts and culture medium.

Antiviral Agents↗
PubMed1995

Lack of long-term ventricular arrhythmia reduction by enalapril in heart failure. SOLVD Investigators.

Previous studies have indicated that angiotensin-converting enzyme inhibitors may reduce the frequency of ventricular arrhythmias in patients with heart failure. These reports were mostly small and of short duration. We prospectively studied 734 patients recruited in 11 universities for 1 year who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine the long-term effects of enalapril and placebo on the frequency and complexity of ventricular arrhythmias in patients with symptomatic (treatment trial) or asymptomatic (prevention trial) heart failure and depressed left ventricular function (ejection fraction < or = 35%). Five hundred fifty-three patients from the prevention trial and 181 from the treatment trial of SOLVD underwent ambulatory electrocardiographic monitoring at baseline, and then at 4 and 12 months of double-blind therapy with either placebo or enalapril (2.5 to 10 mg twice daily). The prospectively defined primary analysis was by intent-to-treat and revealed no significant differences in ventricular premature complexes between the placebo and enalapril groups at baseline (87 +/- 13 vs 84 +/- 13/hour), 4 months (100 +/- 15 vs 85 +/- 12/hour), or 12 months (80 +/- 12 vs 90 +/- 14/hour). Likewise, there was no difference between the placebo and enalapril groups in runs of nonsustained ventricular tachycardia: baseline (8.3 +/- 4.1 vs 1.9 +/- 0.4 runs/day), 4 months (16 +/- 12 vs 7.2 +/- 4.1 runs/day), or after 12 months of blinded therapy (11 +/- 7.0 vs 6.1 +/- 4.4 runs/day).(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1995

Comparative analysis of anti-human immunodeficiency virus type 1 activities of dideoxynucleoside analogs in resting and activated peripheral blood mononuclear cells.

We determined the anti-human immunodeficiency virus type 1 (anti-HIV-1) activities of various dideoxy-nucleoside analogs by using phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBMs) and resting PBMs (R-PBMs) as target cells. The comparative order of anti-HIV-1 activity in PHA-PBMs was azidothymidine (AZT) > dideoxycytidine (ddC) > dideoxythymidinene (d4T) > dideoxyinosine (ddI) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) > 2'-beta-fluoro-dideoxyadenosine (F-ara-ddA), while that in R-PBMs was ddC > ddI, PMEA, and F-ara-ddA, >> AZT and d4T. A pronucleotide, bis-(S-acetylthioethanol)phosphotriester-ddAMP, which bypasses the anabolic monophosphorylation step for the intracellular delivery of ddAMP, was highly active both in PHA-PBMs and R-PBMs. These data may have basic and clinical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy with dideoxynucleosides, and in the development of active pronucleotides.

Antiviral Agents↗