Switch from a ZDV/3TC-based regimen to a completely once daily (QD) regimen of emtricitabine/tenofovir DF fixed dose combination plus a third QD agent (SONETT)

Abstract Objectives To assess the efficacy and safety of a treatment switch from a twice-daily (BID) regimen containing zidovudine (ZDV) and lamivudine (3TC) plus a third agent to a once daily (QD) regimen containing the fixed-dose combination of tenofovir DF/emtricitabine (TDF/FTC, Truvada®) plus a divergent third QD agent in HIV-1 infected patients. Methods Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA 50 cells/μl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. Results During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs). At week 48, plasma HIV-1 RNA was p Conclusions Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.</p

Differential Coordination Demands in Fe versus Mn Water-Soluble Cationic Metalloporphyrins Translate into Remarkably Different Aqueous Redox Chemistry and Biology

The different biological behavior of cationic Fe and Mn pyridylporphyrins in Escherichia coli and mouse studies prompted us to revisit and compare their chemistry. For that purpose the series of ortho and meta isomers of Fe(III) meso-tetrakis-N-alkylpyridylporphyrins, alkyl being methyl to n-octyl, were synthesized and characterized by elemental analysis, UV/vis spectroscopy, mass spectrometry, lipophilicity, protonation equilibria of axial waters, metal-centered reduction potential, E(1/2) for M(III)P/M(II)P redox couple (M = Fe, Mn, P=porphyrin), k(cat) for the catalysis of O(2)(•−) dismutation, stability towards peroxide-driven porphyrin oxidative degradation (produced in the catalysis of ascorbate oxidation by MP), ability to affect growth of SOD-deficient E. coli and toxicity to mice. Electron-deficiency of the metal site is modulated by the porphyrin ligand, which renders Fe(III) porphyrins ≥ 5 orders of magnitude more acidic than the analogous Mn(III) porphyrins, as revealed by the pK(a1) of axially coordinated waters. The 5 log units difference in the acidity between the Mn and Fe sites in porphyrin translates into the predominance of tetracationic (OH)(H(2)O)FeP complexes relative to pentacationic (H(2)O)(2)MnP species at pH ~7.8. This is evidenced in large differences in the thermodynamic parameters - pK(a) of axial waters and E(1/2) of M(III)/M(II) redox couple. The presence of hydroxo ligand labilizes trans-axial water which results in higher reactivity of Fe- relative to Mn center. The differences in the catalysis of O(2)(•−) dismutation (log k(cat)) between Fe and Mn porphyrins is modest, 2.5-5-fold, due to predominantly outer-sphere, with partial inner-sphere character of two reaction steps. However, the rate constant for the inner-sphere H(2)O(2)-based porphyrin oxidative degradation is 18-fold larger for (OH)(H(2)O)FeP than for (H(2)O)(2)MnP. The in vivo consequences of the differences between the Fe- and Mn porphyrins were best demonstrated in SOD-deficient E. coli growth. Based on fairly similar log k(cat)(O(2)(.(−)) values, very similar effect on the growth of SOD-deficient E. coli was anticipated by both metalloporphyrins. Yet, while MnTE-2-PyP(5+) was fully efficacious at ≥20 μM, the Fe analog, FeTE-2-PyP(5+) supported SOD-deficient E. coli growth at 200-fold lower doses in the range of 0.1 to 1 μM. Moreover the pattern of SOD-deficient E. coli growth was different with Mn- and Fe porphyrins. Such results suggested different mode of action of these metalloporphyrins. Further exploration demonstrated that: (1) 0.1 μM FeTE-2-PyP(5+) provided similar growth stimulation as 0.1 μM Fe salt, while 20 μM Mn salt provides no protection to E. coli; and (2) 1 μM Fe porphyrin is fully degraded by 12 hours in E. coli cytosol and growth medium; while Mn porphyrin is not. Stimulation of the aerobic growth of SOD-deficient E. coli by the Fe porphyrin is therefore due to iron acquisition. Our data suggest that in vivo, redox-driven degradation of Fe porphyrins resulting in Fe release plays a major role in their biological action. Possibly, iron reconstitutes enzymes bearing [4Fe-4S] clusters as active sites. Under same experimental conditions, (OH)(H(2)O)FePs do not cause mouse arterial hypotension, whereas (H(2)O)(2)MnPs do, which greatly limits the application of Mn porphyrins in vivo