Synthesis and acid ionization constants of cyclic cystine peptides

Cyclic peptide disulfides of the general formula were synthesized from the corresponding peptide derivatives [Boc-Cys(Trt)(Gly)-_n-Cys(Trt)-OBu^t] by oxidation with iodine in methanol and by subsequent removal of the terminal groups with trifluoroacetic acid. Acid ionization constants of the obtained peptides were determined by potentiometric titration in aqueous KCl (0.1 mol/L) medium. All compounds have two dissociable hydrogens, corresponding to carboxyl (pK¹= 2.35–2.84) and to terminal amino group (pK₂= 5.61–6.93); pK₁, values show first an upward and then a downward trend with the increase in ring size; the opposite is true for pK₂, values. These trends could be tentatively attributed to the intramolecular salt bridge (-COO——-NH⁺₃-) formation.     

Counseling Fathers (2010) by C.Z. Oren and D.C. Oren

No abstract available for this article.     

Drug-drug interactions and the pharmacotherapy of HIV infection

Knowledge of drug-drug interactions is crucial to HIV therapeutics. Recent reports in this area include reduced atazanavir exposure with coadministration of omeprazole or rifampin; increased hepatic toxicity with coadministration of saquinavir and rifampin; reduced buprenorphine exposure with concurrent efavirenz administration; absence of clinically significant interactions of depomedroxyprogesterone with nevirapine, efavirenz, or nelfinavir; increased atazanavir and saquinavir exposure with the double-boosted regimen of atazanavir/saquinavir/ritonavir; reduced amprenavir, lopinavir, and saquinavir exposure with the addition of tipranavir/ritonavir therapy; and reduced lopinavir and amprenavir exposure with the addition of fosamprenavir or fosamprenavir/ritonavir to lopinavir/ritonavir. This article summarizes a presentation on drug-drug interactions in HIV therapeutics by Angela D. M. Kashuba, PharmD, at the International AIDS Society-USA course in Los Angeles in April 2005.     

Measuring Adherence by Visual Inspection of Returned Empty Gel Applicators in the CAPRISA 004 Microbicide Trial

In the CAPRISA 004 trial, adherence was estimated as the proportion of reported sex acts covered by two gel doses, which was assessed by counting returned empty gel applicators. The returned empty applicators were inspected visually in a standardized manner for residue on the outside of the applicator, as an indicator of vaginal insertion. Over 15 months, spanning 11,839 study visits by 838 women, a total of 59,800 returned empty applicators were inspected. By visual assessment, 77.5 % of these applicators appeared to have been inserted. To test the accuracy of the assessment we fitted a Cox model and found that the risk for HIV infection was doubled when less than half of the returned empty applicators had been assessed as not inserted in the vagina. Visual inspection enhanced both the accuracy of the adherence measurement and aided identification of mechanical problems with applicator use experienced by women in the trial.     

Antiviral agents and HIV prevention: controversies, conflicts, and consensus

Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.     

A GCH1 haplotype confers sex‐specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21–5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry. Am. J. Hematol. 89:187–193, 2014. © 2013 Wiley Periodicals, Inc.