A simple and sensitive bioassay method for measuring (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) concentrations in human serum and urine has been established. This method is based on the inhibitory effect of BVDU on varicella-zoster virus (VZV) focus formation in vitro. The minimal concentration of BVDU that could be detected in serum by this method was 0.2 microgram/ml. Following a single oral administration of 250 mg BVDU, serum BVDU concentrations of 1.2-2.2 micrograms/ml were attained 1 hr later; at 5 and 7 hr, serum BVDU levels were below 0.2 microgram/ml. Upon repeated administration of 125 mg BVDU at 8 hr intervals, the serum BVDU concentrations reached 0.7-1.1 microgram/ml at 2 hr after the fourth administration. These concentrations are approximately 300-450-fold higher than the 50% inhibitory dose of BVDU for VZV in vitro. Urinary BVDU concentrations were on average 10 to 20 times higher than the serum BVDU concentrations.
A variety of semisynthetic derivatives of natural antibacterial glycopeptide antibiotics such as vancomycin, eremomycin, ristocetin A, teicoplanin A(2)-2, DA-40926, their aglycons, and also the products of their partial degradation with a destroyed or modified peptide core show marked anti-retroviral activity in cell culture. In particular, aglycon antibiotic derivatives containing various substituents of a preferably hydrophobic nature displayed activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and Moloney murine sarcoma virus at a 50% inhibitory concentration in the lower micromolar (1-5 microM) concentration range while not being cytostatic against human lymphocytic cells at 250 microM or higher. The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process.
At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as (<i>S</i>)-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John's first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (<i>i</i>), TDF and TAF for the treatment of hepatitis B (HBV) infections (<i>ii</i>), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections (<i>iii</i>).
Various polynucleotides were examined for antiviral activity and toxicity in mice. Although the antiviral potency of the various interferon inducers varied, there was a concomitant variation in toxicity. This was reflected by a fivefold range in therapeutic ratio for the various compounds. In addition, no polynucleotide proved to be a more potent interferon inducer than polyinosinic.polycytidylic acid [(poly rI).(poly rC)]. Our results suggest that there may be intrinsic limitations to the development of polynucleotide interferon inducers having improved therapeutic ratios.
We report the synthesis of novel 1-(2'-deoxy-4'-thio-beta-D-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides and the subsequent preparation of a series of N3-substituted analogues. All the novel compounds were evaluated against a range of viruses, however they lacked any measurable activity. The lack of anti-herpetic activity may be a result of the parent nucleoside having poor affinity for herpes simplex virus type 1 thymidine kinase. Conformational analysis of the parent nucleoside showed a twist (3T2) sugar conformation commonly displayed by 2'-deoxy-4'-thionucleosides and the anti-human immunodeficiency virus type 1 agents zidovudine and 3'-fluoro-ddT.
A powder metallurgy (PM) process to fabricate alumina parts through indirect selective laser sintering (SLS ® ) of alumina-polystyrene composite powder particles is presented.The PM process includes powder production through dispersion polymerisation, SLS ® , debinding and solidstate sintering.Dimensional changes, which occur during the debinding and solid-state sintering, are assessed.Warm isostatic pressing (WIP) and both pressureless and pressure infiltration are introduced as extra steps of the PM process chain.The influence of WIP and the infiltration steps on the changes in density, geometry and microstructure during the PM process are investigated.
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