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1.
Antivir Ther ; 15(2): 185-92, 2010.
Article in English | MEDLINE | ID: mdl-20386073

ABSTRACT

BACKGROUND: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. METHODS: The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. RESULTS: Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. CONCLUSION: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.


Subject(s)
Anti-HIV Agents/therapeutic use , Dioxolanes/therapeutic use , HIV Infections/drug therapy , HIV-1/drug effects , Purine Nucleosides/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Zidovudine/therapeutic use , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacology , Dioxolanes/administration & dosage , Dioxolanes/adverse effects , Dioxolanes/pharmacology , Double-Blind Method , Drug Therapy, Combination , Female , HIV Infections/virology , Humans , Male , Middle Aged , Purine Nucleosides/administration & dosage , Purine Nucleosides/adverse effects , Purine Nucleosides/pharmacology , RNA, Viral/blood , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/pharmacology , Treatment Outcome , Viral Load , Young Adult , Zidovudine/administration & dosage , Zidovudine/adverse effects , Zidovudine/pharmacology
2.
Antimicrob Agents Chemother ; 52(12): 4241-50, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18838591

ABSTRACT

In vitro selection studies and data from large genotype databases from clinical studies have demonstrated that tenofovir disoproxil fumarate and abacavir sulfate select for the K65R mutation in the human immunodeficiency virus type 1 polymerase region. Furthermore, other novel non-thymine nucleoside reverse transcriptase (RT) inhibitors also select for this mutation in vitro. Studies performed in vitro and in humans suggest that viruses containing the K65R mutation remained susceptible to zidovudine (ZDV) and other thymine nucleoside antiretroviral agents. Therefore, ZDV could be coformulated with these agents as a "resistance repellent" agent for the K65R mutation. The approved ZDV oral dose is 300 mg twice a day (b.i.d.) and is commonly associated with bone marrow toxicity thought to be secondary to ZDV-5'-monophosphate (ZDV-MP) accumulation. A simulation study was performed in silico to optimize the ZDV dose for b.i.d. administration with K65R-selecting antiretroviral agents in virtual subjects using the population pharmacokinetic and cellular enzyme kinetic parameters of ZDV. These simulations predicted that a reduction in the ZDV dose from 300 to 200 mg b.i.d. should produce similar amounts of ZDV-5'-triphosphate (ZDV-TP) associated with antiviral efficacy (>97% overlap) and reduced plasma ZDV and cellular amounts of ZDV-MP associated with toxicity. The simulations also predicted reduced peak and trough amounts of cellular ZDV-TP after treatment with 600 mg ZDV once a day (q.d.) rather than 300 or 200 mg ZDV b.i.d., indicating that q.d. dosing with ZDV should be avoided. These in silico predictions suggest that 200 mg ZDV b.i.d. is an efficacious and safe dose that could delay the emergence of the K65R mutation.


Subject(s)
Anti-HIV Agents/administration & dosage , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , Models, Biological , Mutation , Reverse Transcriptase Inhibitors/administration & dosage , Zidovudine/administration & dosage , Adult , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacokinetics , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Chemistry, Pharmaceutical , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HIV-1/genetics , Humans , Kinetics , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacokinetics , Zidovudine/metabolism , Zidovudine/pharmacokinetics
3.
Sex Transm Dis ; 34(8): 545-52, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17297383

ABSTRACT

OBJECTIVES: To determine the safety and effectiveness of single-dose rifalazil, a new rifamycin, for the treatment of nongonococcal urethritis (NGU). STUDY DESIGN: Randomized, double-blind trial comparing rifalazil, 2.5, 12.5 or 25 mg, with 1.0 g azithromycin for the treatment of NGU. One hundred and seventy men were evaluated for Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma genitalium infection before therapy and 2- and 5-weeks posttreatment. RESULTS: C. trachomatis, M. genitalium, and U. urealyticum were present in 42%, 24%, and 28% of subjects, respectively. Microbiologic eradication of C. trachomatis with rifalazil 25 mg at 2- and 5- weeks was 85% and 83%, respectively. Rifalazil was ineffective in eradicating M. genitalium and U. urealyticum. Overall clinical cure rates at 2- and 5-weeks were 86% (95% CI 67-96) and 59% (39-78) in the rifalazil-treated 25 mg group, and 77% (56-91) and 63% (41-81) in the azithromycin-treated group. CONCLUSIONS: Rifalazil was well tolerated and eradicates C. trachomatis but not M. genitalium and U. ureaplasma in men with NGU.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Rifamycins/therapeutic use , Sexually Transmitted Diseases, Bacterial/drug therapy , Urethritis/drug therapy , Adult , Anti-Bacterial Agents/administration & dosage , Azithromycin/administration & dosage , Chlamydia Infections/drug therapy , Chlamydia Infections/pathology , Chlamydia trachomatis , Double-Blind Method , Drug Administration Schedule , Humans , Male , Mycoplasma Infections/drug therapy , Mycoplasma Infections/pathology , Mycoplasma genitalium , Rifamycins/administration & dosage , Sexually Transmitted Diseases, Bacterial/microbiology , Sexually Transmitted Diseases, Bacterial/pathology , Treatment Outcome , Ureaplasma Infections/drug therapy , Ureaplasma Infections/pathology , Ureaplasma urealyticum , Urethritis/pathology
4.
J Reprod Med ; 49(1): 23-7, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14976791

ABSTRACT

OBJECTIVE: To assess the role of smoking on low birth weight (LBW). STUDY DESIGN: From Massachusetts for 1998, 79,904 birth certificates were reviewed. Birth weight, gestational age, plurality and maternal race were analyzed in relation to the mother's smoking status during the pregnancy. The etiologic fraction (EF) was calculated for smoking and LBW for the group as a whole as well as for various subgroups. RESULTS: A total of 11.7% of women acknowledged smoking during pregnancy. The overall LBW rate was 6.83%. The relative risk (RR) of LBW among smokers was 1.58. For all births the EF for smoking was 6.4% (95% CI: 5.4-7.3). For singleton pregnancies it was 10.9% (95% CI: 9.6-12.1) (14% for singleton whites and 7.2 for singleton blacks). At term, the EF of smoking on LBW was 13.4% (95% CI: 11.5-15.3), with an EF of 16.7% (95% CI: 14.5-18.7) for term singletons (21.4% among whites and 14.6% among blacks). Among very LBW infants, smoking accounted for 1.7% (95% CI:--0.5-3.8) of the outcome (5.8% among singletons). When stratifying for the effect of smoking, the rate of LBW was 6.38% among nonsmokers, 9.5% (RR 1.48, 1.38-1.61) among light smokers, 11.67% (RR 1.82, 1.63-2.05) among moderate smokers and 11.72% (RR 1.84, 1.33-2.54) among heavy smokers. Sixty percent of the overall population effect of smoking on LBW was in the category of light smokers. CONCLUSION: The amount of LBW attributable to smoking was 6.4% in this sample. Among those who smoked, LBW was 58% more likely than among nonsmokers, and 60% of the overall population effect of smoking on LBW was noted among light smokers.


Subject(s)
Fetal Growth Retardation/etiology , Infant, Low Birth Weight/growth & development , Prenatal Exposure Delayed Effects , Smoking/adverse effects , Female , Fetal Growth Retardation/epidemiology , Humans , Infant, Newborn , Massachusetts/epidemiology , Pregnancy , Pregnancy Outcome , Retrospective Studies , Risk , Smoking/epidemiology
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