Combinations of a pyrimidine containing nnrti with rt inhibitors
A technology of inhibitors and reverse transcriptase inhibition, which is applied in the direction of medical preparations containing active ingredients, antiviral agents, active ingredients of heterocyclic compounds, etc., can solve problems such as increased risk, increased drug burden, poor solubility, etc.
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Embodiment 1
[0113] Example 1: Pharmacokinetics of E-TMC278
[0114] A double-blind, randomized, placebo-controlled phase I study was designed to evaluate the safety, tolerability and in vitro pharmacokinetics of a single dose of compound E-TMC278 in healthy male volunteers. Oral doses of 12.5, 25 and 50 mg were formulated in PEG400 and taken with a standard meal. Pharmacokinetic results are shown in Table 4.
[0115] The pharmacokinetic results of another double-blind, randomized, placebo-controlled phase I study are also reported in Table 4. This study had 4 dosing periods to evaluate the effect of single 100 mg and 200 mg oral doses of compound E-TMC278 on healthy male subjects. Safety, tolerability, pharmacokinetics in subjects, and pharmacokinetics in vitro. The randomization was such that 6 subjects received the same dose of compound E-TMC278 and 3 subjects received placebo at each time period. There is an interval of about 14 days between each dosing period.
[0116] Table 4 d...
Embodiment 2
[0119] Example 2: Virological description of compound E-TMC278
[0120] In a cell-based assay, the compound E-TMC278 was tested using HIV's natural host cells. MT-4 cells (a cell line of human T cells) were infected with HIV-1 (wild type or mutant) and exposed to different concentrations of antiviral compounds in the presence of 10% fetal bovine serum. Cytotoxicity was determined in parallel with the antiviral activity so that the selectivity of the antiviral effect could be assessed. Active compounds must cross the cell membrane in order to interfere with the replication steps within the cell.
[0121] After four days of incubation at 37°C, the tetrazole-based The automated colorimetric assay for assessing the viability of HIV and mock-infected cells. This method allows calculation of the 50% inhibitory concentration (IC50), IC90, and 50% cytotoxic concentration (CC50) for inhibiting viral cytopathic effects. The ratio of CC50 / IC50, also known as the selection coeffici...
Embodiment 3
[0134] Example 3: Determination of compound E-TMC278 for prevention of intimacy through sexual intercourse or partner-related intimacy An in vitro model of the ability to contract HIV infection
[0135] For example, in one model monocyte-derived dendritic cells (MO-DCs) were infected with the monotropic HIV strain Ba-L at 10 -3 The multiplicity of infection (MOI) was 2 hours for infection. After infection, cells were washed 6 times and resuspended in 10% BCS at 400.000 cells / ml. Autologous CD4(+) T cells were purified from the lymphocyte fraction of the same eluate as the MO-DC and cultured at 2x10 6 A concentration of cells / ml was used (MO-DC / CD4(+)T ratio of 1 / 5).
[0136] Serial dilutions of compounds of formula (I) (test compounds) were added to co-cultures of MO-DC / CD4(+) T cells. Each experiment was performed in a 96-well plate, where each well contained 50 μl MO-DC, 50 μl CD4(+) T cells and 100 μl test compound. Half of the medium, with the test compound, was re...
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