Infections Subject

The initial search for an inhibitor of the SARS 3CL protease focused on preexisting drugs and compounds, some tested empirically and others selected based on modeling. The HlV-1 PI nelfinavir and lopinavir/ritonavir have been considered, with the latter actually used clinically in SARS CoV-infected subjects. The rhi-novirus inhibitor ruprintrivir and related compounds have also been tested (reviewed in Fear et al. 2007). However, in the absence of any elements of specificity, these preexisting compounds would be expected to have low potency. 

Gruzdev B, Rakhmanova A, Doubovskaya E, Yakovlev A, Peelers M, Rinehart A, de Dier K, Baede-van Dijk B, Parys W, van t Klooster G (2003) A randomized, double-bhnd, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral n Ve, HIV-1 infected subjects. AIDS 17 2487-2494... 

Hanna G, Lalezari J, HelUnger J, Wohl D, Masterson T, Fiske W, Kadow J, Lin P, Giordano M, Colonno R, Grasela D (2004) Antiviral activity, safety, and tolerability of a novel, oral smaU-molecule HlV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects a novel, oral small-molecule HlV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. In 11th conference on retroviruses and opportunistic infections, San Francisco, CA... 

Melmed, R. N., et al. (1989). Serum neopterin changes in HIV-infected subjects Indicator of significant pathology, CD4 T cell changes, and the development of AIDS. J. Acquir. Immune Defic. Syndr. 2,70-76. 

Little, S.J., Holte, S., Routy, J.P., Antiretroviral resistance and response to initial therapy among recently HIV-infected subjects in North America, Antivir. Ther., 6(Suppl. 1), 21,2001. 

Exhibit 6.6 Phase III Study A Study of Lopinavir/Ritonavir Tablets Comparing Once-Daily Versus Twice-Daily Dosing in Antiretroviral-Experienced, HIV-1 Infected Subjects... 

Study Design Treatment, randomized, open label, active control, parallel assignment, safety/efficacy study Official Title A Phase III, Randomized, Open-Label Study of Lopina-vir/Ritonavir Tablets 800/200mg Once-Daily Versus 400/100mg Twice-Daily When Co-administered With Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects Primary Outcome Measures ... 

Famularo G., Moretti S., Alesse E., Trinchieri V., Angelucci A., Santini G., Cifone G., and De Simone C. (1999). Reduction of glutamate levels in HIV-infected subjects treated with acetylcarnitine. J. NeuroAIDS 2 65-73. 

Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997 41(5) 898-905. 

Nl, Nyberg, W., Absorption and excretion of vitamin B12 in subjects infected with Di-phyllobothrium latum and in non-infected subjects following oral administration of radioactive B12. Acta Haematol. 19, 90-92 (1958). 

Dejesus E,Wald A, Warren T, et al.Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects.J Infect Dis 2003 188(7) 1009-1016. 

The Phase Ha study demonstrated the antiviral potency of M3, following once-daUy oral dosing for 10 days in HIV-infected subjects not on other antiretroviral therapy. Viral load was reduced significantly compared with placebo. On day 11, following complete dosing, the median reduction at the 200-mg dose was a 91% decrease. In the Phase Ha trial, M3 was well tolerated, aU adverse experiences were mild or moderate, and no dose-Umiting toxicity was identified (122, 123). 

Andrade AS, McGruder HF, Wu AW, Celano SA, Skolasky RL, Seines OA, Huang IC, McArthur JC (2005) A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment. Clin Infect Dis 41 875-882. 

Villani P, Viale P, Signorini L, Cadeo B, Marchetti F, Villani A, Fiocchi C, Regazzi MB, Carosi G. Pharmacokinetic evaluation of oral levofloxacin in human immunodeficiency virus-infected subjects receiving concomitant antiretroviral therapy. Antimicrob Agents Chemother 2001 45(7) 2160-2. 

HIV-infected subjects (111). The reduction in prophylactic efficiency was more pronounced in subjects who took a single double-strength tablet. 

In one pharmacokinetic study in eight HIV-infected subjects, the renal clearance of zidovudine was significantly reduced by trimethoprim (201). The authors concluded that zidovudine dosages may need to be reduced if trimethoprim is given to patients with impairment of liver function or glucuronidation. Zidovudine, on the other hand, did not alter the pharmacokinetics of trimethoprim. 

Spain BA, Soliman DM, Sidner RA, Twigg HL. Enhanced proliferation and IL-2 secretion by lung lymphocytes from HIV-infected subjects. Am J Physiol 1995 269(4 Pt 1) L498-L506. 

Evaluation of APV pharmacokinetics following GW433908 administration to healthy subjects compared to HIV-infected subjects, both with and without ritonavir, was required. In the Phase 3 study (the last one in Table 16.1), only 3 samples... 

The clinical implication of this analysis is that the A UC and C ax in healthy and HIV-infected subjects were considered similar. This interpretation is less interesting from the methodological standpoint and is presented only for completeness. 

S. Weller, K. M. Radomski, U. Lou, and D. S. Stein, Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 44(8) 2052-2060 (2000). 

K. Ruxrungtham, M. Boyd, S. E. BelUbas, X. Zhang, A. Dorr, S. Kolis, T. Kinchelow, N. Buss, and I. H. Patel, Lack of interaction between enfnvirtide and ritonavir or ritonavir-boosted saquinavir in FllV-l-infected subjects. Clin Pharmacol Ther... 

Differences in opsonic activity occur between normal serum and serum from infected patients (Table 3). The infected serum produces the same diminished latency period on normal cells as on cells from infected subjects. Normal serum induces the same response either with normal or infected cells. The rates of O2 consumption and Oi production are slightly increased when the stimulation is initiated with serum from infected subjects this observation suggests that the efficiency of the opsonic activity determines the metabolic response of the cells. The ability of PMN to produce a normal respiratory burst depends upon both humoral and... 

Israel-Biet D, Labrousse F, Tourani J-M, Sors H, Andrieu J-M, Even P Elevation of IgE in HIV-infected subjects a marker of poor prognosis. J Allergy Clin Immunol 1992 89 68-75. 

Wang T, Yin Z, Zhang Z et al (2009) Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of l-(4-benzoylpiperazin-l-yl)-2-(4,7-dimethoxy-l//-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects. J Med Chem 52 7778-7787... 

---