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Biomedical subjects

A Pani

Publications and source records attributed to A Pani.

At least 37 records · Page 2Linked to original sources
PubMed1998

Potent and selective inhibitors of human immunodeficiency virus protease structurally related to L-694,746.

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2(R)-hydroxy-1(S)- indanyl]-5(S)-[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R) - [[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1' phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20,000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.

Amides↗
PubMed1997

Role of cholesterol synthesis and esterification in the growth of CEM and MOLT4 lymphoblastic cells.

CEM and MOLT4 are human T-cell lines isolated from patients with acute cell leukaemia. In culture they show important differences in cholesterol metabolism, CEM being less efficient at synthesizing cholesterol and having a lower activity of 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase. To investigate further the relationship between regulation of intracellular cholesterol metabolism at various steps and rate of cell growth, cholesterol synthesis, esterification and efflux were evaluated in CEM and MOLT4 cells at different times during exponential and stationary growth in vitro. It was shown that, although CEM cells have a lower rate of cholesterol synthesis, they grow at a faster rate than MOLT4 cells. However, CEM cells exhibit an increased capacity to esterify cholesterol associated with a decreased efflux of newly synthesized cholesterol into the medium. These results provide evidence for an association between the capability to synthesize and retain cell cholesterol esters and the growth rate potential.

Acetates↗
PubMed1996

Pyrazole-related nucleosides. 4. Synthesis and antitumor activity of some 1-tetrahydropyranyl-4-substituted pyrazoles.

Continuing our studies on the structure-activity relationships of some pyrazole nucleosides (1a-h) structurally related to ribavirin, tiazofurin and selenazofurin, we describe here the synthesis and antitumor/antiviral/antimicrobial activity of a new series of 1-tetrahydropyranyl-4-substituted pyrazoles. In this study, the tetrahydropyranyl moiety (THP), designed as a mimic of the glycosidic portion of the parent compounds 1a-h, has led to a few derivatives with moderate cytotoxic activity against leukemia/lymphoma and solid tumor-derived cell lines (IC50 14-100 microM). The compounds obtained through substitution of the ribofuranosyl moiety by the THP moiety were still active, the free heterocyclic bases were devoid of any activity.

Animals↗
PubMed1996

Synthesis, antiviral and antiproliferative activity of a new class of 5-(alkyl or arylthio)-6-vinyl uracils.

Uracil derivatives bearing substituted or unsubstituted vinyl groups at position C6 and alkyl- or arylthio groups at position C5 were synthesized and tested in vitro for antiviral and antiproliferative activity. None of the compounds were active against HIV-1. However, some of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations. The maximum potency of antiproliferative activity correlates with the presence of unsubstituted vinyl groups and alkyl- or arylthio substituents.

Anti-HIV Agents↗
PubMed1995

[A measure of productivity in cardiology based on medical acts].

BACKGROUND: The decreased availability of economic resources, opposed to the increased demand for medical assistance, requires the use of methods to assess hospital efficiency. Purpose of our study was to evaluate and quantify the "products" of a cardiology department, as well as the changes in time of their production, by means of a catalogue of medical acts, set up for the French health system (CdAM). METHODS: The study includes the 224 admissions occurring in October 1987 and the 209 admissions of October 1992. Medical acts were recorded for all admissions, by number of acts as well as by weight of acts; this weight (expressed as complexity/cost index or ICR) takes into account the use of resources in terms of medical staff and nursing staff, together with technical resources, for each act. In 1987 and 1992, 1736 and 1603 acts were performed respectively, corresponding to a total weight of 24308 and 32194 ICR. RESULTS: The increased ICR appears to be related to an increase of invasive procedures, particularly of interventional electrophysiology and haemodynamics. By considering case mix, we observed an increment of ICR for the diagnosis of angina (from 194.3 to 227.4 ICR per patient), of arrhythmias (from 178.0 to 273.1) and of cardiomyopathy (from 95.6 to 179.7). CONCLUSIONS: In conclusion, CdAM allows to evaluate the cardiologic activity also in the Italian situation; the ICR of each act permits to estimate the human and technical burden, with subsequent easy internal and external comparisons.

Cardiology Service, Hospital↗
PubMed1995

Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives.

2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are potent and selective inhibitors of the replication of the human immunodeficiency virus type 1 (HIV1) in several cell culture systems. Equipotent in terms of antiviral activity, both compounds selectively inhibit the reverse transcription of HIV-1 by virtue of their conversion into ddATP. In human lymphoid cells ddAdo is converted to the active metabolite, ddATP, but it also undergoes rapid deamination, via adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and ddATP), as well as to IMP and to adenylate ribonucleotides. With the main object of blocking the deamination of ddAdo, we studied its anti-HIV-1 activity in the presence of different adenosine deaminase inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl) adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase inhibitors tested by us showed a significant increase in the antiviral activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA and CF concentrations up to 250 and > 12,500 times lower than their respective maximum non toxic doses. In combination with EHNA or CF, ddAdo could be used at concentrations up to ten times lower than those required to obtain the same degree of inhibition when ddAdo (or ddIno) was used alone. The use of EHNA or CF in combination with ddAdo at concentrations that inhibit the multiplication of HIV-1, allowed uninfected cells to maintain their normal multiplication rates. In fact, in combination experiments, cytotoxic effects were evident only with doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those required to inhibit HIV-1 significantly. The in vivo implications of these results for anti-HIV chemotherapy are discussed.

Adenine↗
PubMed1994

The antimitotic drug 4,6-dimethyl-2-amino-3,4,5- trimethoxyphenyl-pyrimidine inhibits the nucleoside transport system of cells from various animal species.

4,6-dimethyl-2-amino-3,4,5-trimethoxyphenyl-pyrimidine (B-31) is a pyrimidine derivative previously reported to arrest the mitotic cycle of mammalian cells in metaphase. In the present study it is shown that B-31 also acts as a specific inhibitor of the cellular uptake of nucleosides. The uptake of purinic and pyrimidinic nucleosides is inhibited by 80-90% at concentrations in the range 5-20 micrograms/ml, whereas those of nucleobases, leucine, choline and glucose are unaltered at the maximum nontoxic dose of B-31 (25 micrograms/ml). Various mammalian (human, monkey and murine) and avian cell are equally sensitive to the inhibition of nucleoside transport. The antimitotic effect of B-31, by contrast, is species-specific: human cells are the most sensitive whereas monkey and chicken fibroblasts appear resistant to this effect. Both effects can be reversed by removal of B-31 from the medium; inhibition of nucleoside transport can also be reversed by high doses of the nucleosides themselves.

Animals↗
PubMed1993

Modulatory effect of N-acetyl-L-cysteine on the HIV-1 multiplication in chronically and acutely infected cell lines.

N-acetyl-L-cysteine (NAC) is known to antagonize the PMA- or cytokine-stimulated HIV-1 replication in latently and acutely infected monocytic and lymphocytic cell lines, and to reduce the virus multiplication in acutely infected, PHA-stimulated PBMC. We here report on the modulatory effects of NAC on the HIV-1 multiplication in both chronically and acutely infected lymphocytes that produce high virus levels independently from cytokine activation. In both cases, NAC doses of 0.12 and 0.25 mM decreased, whereas doses of 0.5-2 mM increased the infectious HIV-1 yield. At these concentrations, the modulatory effect of NAC on the HIV-1 multiplication paralleled that on cell proliferation, suggesting a close correlation between the two phenomena; in fact, under conditions where NAC could not modulate the cell growth, the drug also failed to modulate the HIV-1 multiplication. High NAC concentrations (4-16 mM), which were able to increase the proliferative rate of both chronically infected H9/IIIB and normal T lymphocytes, increased up to 6-fold the virus multiplication in H9/IIIB cells but were inhibitory to HIV-1 in acutely infected cells. This inhibition was due to the fact that, like dextran sulfate, NAC interfered with an early event in the virus growth cycle. The finding that high NAC doses were also capable of preventing syncytium formation in H9/IIIB and C8166 (or MT-4) cocultures further indicated an interference of the drug with receptor-binding-related events.

Acetylcysteine↗
PubMed1993

Complement C3 gene expression and regulation in human glomerular epithelial cells.

Extra-hepatic synthesis of complement is thought to mediate local tissue inflammatory injury. To investigate this phenomenon in the glomerular epithelial cell (GEC), we examined the biosynthesis and regulation of gene expression of the third component of complement in isolated human GEC derived from normal tissue. Metabolic labelling and immunoprecipitation studies demonstrated that C3 protein was synthesized, processed and secreted by GEC under basal conditions. The secreted C3 alpha and beta polypeptide chains had identical electrophoretic mobilities with those of hepatic C3. Examination of cellular RNA using semi-quantitative polymerase chain reaction (PCR) showed that C3 gene expression was present in unstimulated GEC and was increased by stimulation with interferon-gamma (IFN-gamma) in a time- and dose-dependent manner. Tumour necrosis factor-alpha (TNF-alpha), while mediating an increase in monocyte U937 C3 expression, revealed no evidence of regulation of GEC C3 gene expression. These results indicate that human GEC spontaneously express the C3 gene and that increased gene expression is regulated by IFN-gamma. These observations may reflect part of a wider mechanism of protection against or mediation of local, immune-mediated tissue injury.

Cells, Cultured↗
PubMed1992

Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides.

Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.

Animals↗
PubMed1991

4-Diazo-5-alkylsulphonamidopyrazoles: synthesis and evaluation of biological activity.

A series of 4-diazo-5-alkylsulphonamidopyrazoles (5) was prepared and tested for antitumor, antiviral and antimicrobial activity. Compounds (5a) and (5b) showed a selective, although not very potent cytostatic activity against L1210 and a human T lymphoblastoid cell line (C8166). Compounds (5a) and (5d-h) showed a selective anti-coxsackie B1 virus activity, whereas 5b was also endowed with some activity against Bacillus subtilis.

Anti-Bacterial Agents↗
PubMed1990

Synthesis and antimicrobial and cytotoxic activities of pyrrole-containing analogues of trichostatin A.

A number of aroylpyrroleacrylic acid derivatives were synthesized by standard procedures and evaluated for cytotoxicity in Vero cells and for capacity to inhibit the multiplication of viruses, bacteria, and fungi. While none of the test compounds showed any activity against bacteria and fungi, most of them inhibited the replication of some DNA viruses at concentrations allowing the exponential growth of uninfected cells. In particular three compounds (8, 9c, and 10h) showed an antiviral activity at doses that were from 4- to greater than 8-fold lower than the maximum nontoxic doses.

Animals↗
PubMed1989

5-(2-bromoethyl)-2'-deoxyuridine: a selective inhibitor of herpes simplex viruses in vitro.

A new pyrimidine analog, 5-(2-bromoethyl)-2'-deoxyuridine (BEUdR), was tested in vitro for antiviral activity on Herpes simplex virus types 1 and 2. As reference compounds, ACG, BVUdR and PAA were used. Compared to ACG and BVUdR, BEUdR resulted less potent on both HSV-1 and HSV-2. However, a 50% inhibition of the multiplication of uninfected cells could be obtained only at very high BEUdR concentration (ID50 = 8500 microM). This makes BEUdR the least toxic analog known and gives it a selective index comparable to, if not better, than of ACG and BVUdR.

Antiviral Agents↗