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Biomedical subjects

J A Coates

Publications and source records attributed to J A Coates.

14 recordsLinked to original sources
PubMed1994

Susceptibility in cell culture of feline immunodeficiency virus to eighteen antiviral agents.

The in-vitro susceptibilities of two strains of feline immunodeficiency virus to 18 antiviral agents were determined in two cell lines. In terms of inhibiting p24 antigen production, the nucleoside-analogue reverse transcriptase inhibitors were the most effective compounds. Inhibition was also observed with aurintricarboxylic acid, phosphonoformate and butyldeoxynorjirimycin, but not with the other agents tested.

Animals↗
PubMed1994

Accuracy of end-tidal and transcutaneous PCO2 monitoring during sleep.

STUDY OBJECTIVE: Although it is intuitively desirable, the measurement of arterial carbon dioxide tension (PaCO2) during diagnostic polysomnography and nocturnal trials of positive pressure therapy is invasive and potentially expensive. The accuracy of end-tidal carbon dioxide tension (PETCO2) and transcutaneous carbon dioxide (tcPCO2) monitoring in these contexts has not been systematically evaluated. This investigation was undertaken to evaluate the accuracy of PETCO2 and tcPCO2 in patients undergoing polysomnography. METHODS AND PROCEDURES: Values of PETCO2 were compared with PaCO2 in 19 patients spontaneously breathing room air (condition 1), in 13 patients receiving supplemental oxygen via nasal cannula (condition 2), and in 22 patients receiving nocturnal positive pressure ventilatory assistance (all but one with continuous positive airway pressure or bilevel positive airway pressure) (condition 3). The accuracy of tcPCO2 monitoring during sleep was also examined by comparing tcPCO2 values with simultaneously recorded PaCO2 values obtained during sleep in patients undergoing nocturnal polysomnography. Data were collected using three commercially available brands of tcPCO2 monitors (capnograph R, n = 17 patients; capnograph S, n = 17; and capnograph N, n = 15). RESULTS: Accuracy of PETCO2--There was significant scatter in the PaCO2 vs PETCO2 relationship such that only 23 percent of the variability in PaCO2 was explained by variation of PETCO2 during condition 1 and only 15 percent and 20 percent of the variability in PaCO2 was explained by variation of PETCO2 during conditions 2 and 3, respectively. 21.3 percent of patients had average PETCO2 values in error by > 10 mm Hg during condition 1, while during conditions 2 and 3, 46.2 and 63.7 percent of patients had average values in error by > 10 mm Hg, respectively. Accuracy of tcPCO2--While capnographs S and N generally overestimated PaCO2 with a wide scatter, capnograph R tended to have offsetting overestimations and underestimations of PaCO2 with a wide scatter. With each capnograph, a relatively small portion of the variability of the PaCO2 was explained by variability of the tcPCO2 (r2 = 0.2, 0.45 and 0.64 for capnographs S, N, and R, respectively). Across the three capnographs, 43.1 to 66.7 percent of measurements were in error by > 10 mm Hg, and 5 to 20 percent of measurements reflected errors > 20 mm Hg. There was no consistent relationship between the tcPCO2 error and the level of PaCO2, nor was the tcPCO2 error consistent in individual patients. There was no relationship between tcPCO2 accuracy and body mass index. CONCLUSION: Neither PETCO2, measured within a face mask, nor tcPCO2 is a consistently accurate reflection of PaCO2. This limits the utility of these variables in monitoring patients during diagnostic and therapeutic sleep studies, and in particular, during trials of nocturnal ventilatory assistance where adequate levels of support are to be established and unacceptable hyperventilation and respiratory alkalosis must be recognized.

Adult↗
PubMed1993

4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro.

The sialidase (neuraminidase) inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en) has been examined for the ability to inhibit the growth of a wide range of influenza A and B viruses in vitro in comparison with amantadine, rimantadine, and ribavirin. 4-Guanidino-Neu5Ac2en inhibited plaque formation by laboratory-passaged strains of influenza A and B viruses, with 50% inhibitory concentrations ranging from 0.005 to 0.014 microM. A wider range of values (0.02 to 16 microM) was obtained with more recent clinical isolates, but in all cases 4-guanidino-Neu5Ac2en inhibited influenza A and B virus replication at lower concentrations than amantadine, rimantadine, or ribavirin. Inhibition by 4-guanidino-Neu5Ac2en was not obviously affected by the passage history of the viruses or by resistance to amantadine or rimantadine. 4-Guanidino-Neu5Ac2en was a very potent inhibitor of the sialidases of all the influenza viruses examined, with 50% inhibitory concentrations ranging from 0.00064 to 0.0079 microM. No cytotoxicity was observed with 4-guanidino-Neu5Ac2en at up to 10 mM. 4-Guanidino-Neu5Ac2en therefore represents a new potent and selective inhibitor of influenza A and B virus sialidase activity and replication in vitro.

Animals↗
PubMed1992

Cellular metabolism of (-) enantiomeric 2'-deoxy-3'-thiacytidine.

The metabolism of (-) enantiomeric 2'-deoxy-3'-thiacytidine (3TC) was examined in human immunodeficiency virus type 1 (HIV-1)-infected and mock-infected human cells. 3TC 5'-triphosphate levels accumulated comparably in HIV-1-infected and mock-infected phytohaemagglutinin-stimulated peripheral blood lymphocytes (PBL) and reached 40% or more of total intracellular 3TC metabolites after 4 hr. The rate of decay of 3TC triphosphate in HIV-1-infected and mock-infected PBL measured as a half-life (T1/2) ranged from 10.5 to 15.5 hr. 3TC did not significantly affect metabolism of deoxynucleotides in the U937 cell line, and was shown to be resistant to the action of human platelet pyrimidine nucleoside phosphorylase.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Characterisation and correction of a mammalian cell mutant defective in late step of base excision repair.

An Indian muntjac cell line, SVM, is unusually sensitive to cell killing induced by a range of alkylating agents. Cells transfected with the Escherichia coli ada gene or human genomic DNA have allowed the response of SVM to alkylating agents to be dissociated into two distinct components. Thus, in SVM, which expresses very low levels of alkyltransferase (AT), O6-alkylguanine appears to be the major cytotoxic, clastogenic, and recombinogenic lesion following exposure to agents such as methylnitrosourea (MNU). However, SVM is also very sensitive to agents such as dimethylsulfate (DMS), which produce only very low levels of O6-methylguanine damage. Sensitivity to DMS resides in an inability to complete base excision repair, with the appearance of persistent single-strand DNA breaks (SSBs), and does not appear to involve defects in glycosylase, apurinic/apyrimidinic endonuclease, or DNA ligase activities. Another, possibly related, phenotypic trait in SVM is its limited ability to ligate transfected linear plasmid DNA. Transfectants of SVM, harboring human DNA sequences, show a significant correction of DMS-induced cytotoxicity and clastogenicity and a reduction in the levels of DMS-induced DNA SSBs. The DMS-resistant transfectants have an increased ability to ligate linear plasmid DNA, and also express AT, making these lines resistant to alkylating agents such as MNU. These results suggest that cells possess a mechanism that regulates AT expression, plasmid break-joining ability, and certain aspects of base excision repair. Transfectants of SVM containing human DNA provide a means to isolate genes involved in a coordinate response to alkylation damage.

Alkylating Agents↗
PubMed1992

The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro.

Racemic 2'-deoxy-3'-thiacytidine (BCH 189) is a dideoxycytidine analog having a sulfur atom in place of the 3' carbon. The enantiomers of BCH 189 have been resolved and found to be equipotent in antiviral activity against human immunodeficiency virus types 1 and 2. However, the (-)-enantiomer (3TC) is considerably less cytotoxic than the (+)-enantiomer.

Antiviral Agents↗
PubMed1992

(-)-2'-deoxy-3'-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro.

The (-)-enantiomer of 2'-deoxy-3'-thiacytidine (3TC) was found to be a potent and selective inhibitor of human immunodeficiency virus types 1 (HIV-1) and 2 (HIV-2) in vitro. We determined its antiviral activity against a number of laboratory strains of HIV-1 and HIV-2 in a range of CD4-bearing lymphocyte cell lines (mean 50% inhibitory concentration [IC50] range, 4 nM to 0.67 microM). 3TC was also active against a range of HIV-1 strains in peripheral blood lymphocytes (mean IC50 range, 2.5 to 90 nM). The IC50 for cytotoxicity in seven lymphocyte cell cultures, including human peripheral blood lymphocytes, ranged from 0.5 to 6 mM. 3TC had no detectable antiviral activity against a range of other viruses or in cells chronically infected with HIV-1 or HIV-2. The effects of time of addition of the compound and varying the multiplicity of infection on the antiviral activity of 3TC were determined. The results showed that 3TC is a potent and selective inhibitor of HIV-1 and HIV-2 replication in vitro.

Cell Death↗
PubMed1991

Carbovir: the (-) enantiomer is a potent and selective antiviral agent against human immunodeficiency virus in vitro.

In this paper we describe the in vitro antiviral activity of the (-) enantiomer of carbocyclic 2',3'-deoxydidehydroguanosine, (-) carbovir, a nucleoside analogue that has selective and potent anti-HIV activity in a series of lymphocyte culture systems. The cellular cytotoxicity of this compound has also been evaluated in a number of systems and compared to the saturated dideoxynucleoside analogues AZT and ddC.

CD4-Positive T-Lymphocytes↗
PubMed1991

Fluorocarbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluorocarbocyclic 2'-deoxy guanosines.

A series of four isomeric 2'- and 6'-fluorocarbocyclic guanosine analogues have been prepared and evaluated as potential anti-herpes agents. The racemic 2' beta-fluoro isomer 2-amino-1,9-dihydro- 9-[(1 alpha, 2 alpha, 3 beta, 4 alpha)-2-fluoro-3-hydroxy-4- (hydroxymethyl)cyclopentyl]-6H-purin-6-one (11a, C-AFG) and its 2' alpha-fluoro epimer 11b plus the chiral 6' beta-fluoro isomer 2-amino-1,9-dihydro-9-[[1S-(1 alpha, 2 alpha, 3 alpha, 4 beta)]- 2-fluoro-4-hydroxy-3-(hydroxymethyl)cyclopentyl]-6H-purine-6-one (11c) and its 6' alpha-fluoro epimer 11d were prepared from their respective fluoro amino diol hydrochlorides (6a,d). For comparison, the furanosyl compound 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)guanine (17, AFG) was prepared by coupling 2-amino-6-chloropurine with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha- D-arabinofuranosyl bromide followed by base hydrolysis. The 6' alpha-fluoro derivative 11d exhibited comparable activity to that of acyclovir (ACV) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro but was greater than 30-fold more active than ACV against HSV-1 and HSV-2 in vivo in the mouse systemic model. The 2' beta-fluoro derivative (11a, C-AFG) was extremely potent in vitro against HSV-1 and HSV-2 (ID50 0.006 and 0.05 micrograms/mL) and in vivo it was greater than 2 orders of magnitude more potent than ACV against HSV-1 and 70-fold more potent against HSV-2. The 2' alpha-fluoro 11b and 6' beta-fluoro 11c isomers were much less active.

Antiviral Agents↗
PubMed1990

Fluoro carbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluoro carbocyclic pyrimidine nucleosides including carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil and carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil.

The racemic carbocyclic 2'-fluoroarabinosyl pyrimidine nucleosides 8, 9 (C-FIAU), 12, and 13 (C-FMAU) and the 2'-fluororibosyl pyrimidine nucleosides 17, 20, and 21 were prepared from their respective protected 2'-fluoro amino diols 5 and 14. The carbocyclic 2'-2'-difluorothymidine analogue 27 was obtained from the protected difluoro amino diol 24 which was prepared from the ketone 23 and (diethylamino)sulfur trifluoride (DAST). The chiral carbocyclic 2'-deoxy-6'-fluorouridines 33, 34, 38, and 39 were synthesized from the protected 6'-fluoro amino diols 30 and 36, which were prepared by reduction of the azides 28 and 35. C-FMAU (13) and C-FIAU (9) were active in vitro against HSV-1 with ID50 values of 4.4 and 11 micrograms/mL, respectively, but they were inactive against HSV-2. The cytidine analogues 12 and 20 displayed modest activity in vitro against HSV-1 and HSV-2 but were inactive against human influenza A virus.

Animals↗
PubMed1983

Identification and characterization of a herpes simplex virus gene product required for encapsidation of virus DNA.

A mutant of herpes simplex virus type 1, 17tsVP1201, has a temperature-sensitive processing defect in a late virus polypeptide. Immunoprecipitation studies with monoclonal antibodies showed that the aberrant polypeptide in mutant virus-infected cells was the nucleocapsid polypeptide known as p40. Since a revertant, TS(+) for growth, processed the polypeptide normally under conditions restrictive for the mutant, the processing event must be essential for virus replication. Electron microscopic analysis of mutant virus-infected cells grown at the nonpermissive temperature revealed that the nuclei contained large aggregations of empty nucleocapsids possessing some internal structure. Therefore, although the mutant synthesized virus DNA at the nonpermissive temperature, the DNA was not packaged into nucleocapsids. When mutant virus-infected cells were shifted from 39 to 31 degrees C in the presence of cycloheximide, the polypeptide p40 was processed to lower-molecular-weight forms, and full nucleocapsids were detected in the cell nuclei. The aberrant polypeptide of the mutant, however, was not processed in cells mixedly infected with 17tsVP1201 and a revertant at the nonpermissive temperature, suggesting that the defect of the mutant was in the gene encoding p40 rather than in a gene of a processing enzyme.

Capsid↗