Effects of apricitabine and other nucleoside reverse transcriptase inhibitors on replication of mitochondrial DNA in HepG2 cells.

Several nucleoside reverse transcriptase inhibitors are associated with mitochondrial toxicity resulting from inhibition of DNA polymerase-gamma. This study compared the effects on mitochondrial DNA of apricitabine (previously referred to as AVX754 or SPD754), a novel cytidine analogue under development for the treatment of human immunodeficiency virus (HIV)-1 infection, and other reverse transcriptase inhibitors. Human HepG2 hepatoblastoma were cultured for up to 16 days with test compounds at concentrations of 0.3-300 microM. Mitochondrial DNA replication was assessed by means of a duplex nucleic acid sequence-based amplification technique, which measures the ratio of the number of mitochondrial DNA copies to the number of genomic DNA copies. Apricitabine and tenofovir had no effect on the mitochondrial DNA content. In contrast, alovudine, zalcitabine, didanosine and stavudine markedly reduced mitochondrial DNA content, whereas abacavir, emtricitabine, lamivudine and zidovudine produced slight increases in mitochondrial DNA, which may reflect an adaptive cellular response to mitochondrial dysfunction. These results suggest that apricitabine shows a favorable mitochondrial toxicity profile, which is important for long-term clinical use. Further studies are warranted to define the clinical implications of these findings.

[Rubella immunization with HPV77DE5 and RA 27/3 vaccines of 11 to 16-year-old girls: studies of antibody formation and antibody resistance after 4 and 8 years]. / Die Rötelnschutzimpfung mit HPV77DE5- und RA 27/3-Impfstoffen von 11-16 Jahre alten Mädchen: Untersuchungen zur Antikörperentwicklung und Antikörperpersistenz nach 4 und 8 Jahren.

In the first prepubertal study 292 girls aged 11-15 years from 5 secondary schools were immunized with HPV77DE5 with the normal dose and 1/10 of it. The seronegative rate was 30.4%. HAI-antibody conversion occurred in 98.2 to 100%. The mean antibody titer in the two groups with 1:80 and 1:84 were 2 titer steps below the mean HAI-titer of the prevaccinal seropositive girls. The booster effect on the pre-existing titers was minimal. In the second prepubertal study with 625 girls aged 11-16 years from 3 gymnasiums 50.4% were seronegative. Of 312 seronegative girls, 56 had been immunized with HPV77DE5 s.c., 151 with RA 27/3 s.c. and 105 with RA 27/3 i.n. HAI-antibody conversion was observed in 98.2%, 100% and 100% respectively. The mean HAI-antibody titer following HPV77DE5 was +/- 2 titer steps, following RA 27/3 s.c. and RA 27/3 i.n. only 0.6 titer steps lower than the mean titer of the prevaccinal seropositive group. The individuals with a low prevaccinal antibody titer showed a significant but transient antibody booster response. Antibody titer controls 4 years post vaccination in 213 of the girls (160 prevaccinal seronegative, 53 prevaccinal seropositive) showed that all prevaccinal seronegatives had remained antibody-positive. The mean HAI-titer following HPV77DE5 was only slightly lower (1: 97) than 8-12 weeks post vaccination (1: 104) wereas the mean titers following RA 27/3 s.c. and i.n. showed a decline from 1: 158 to 1: 119 and from 1: 181 to 1: 111. The comparison of negative, low and higher HAI-antibody titers with neutralisation antibody titers in sera taken before, 8-12 weeks and 4 years after vaccination gave a perfect correlation between negative and positive results in both tests. Also 8 years post vaccination all vaccinees had remained seropositive. In comparison to the 4-year value, the geometric mean HAI antibody titer had dropped to somewhat lower levels of 1: 64, 1: 74 and 1: 64 respectively in the prevaccinal seronegative vaccinees so that no titer differences existed 8 years following vaccination in the different vaccine groups. Low positive HAI titers of 1: 16 were found in 3 of 23 (13%) in the HPV77DE5 group and in 2 of 76 (2.6%) in the RA 27/3 s.c. group but in none of 54 in the RA 27/3 i.n. group. The low positive HAI titer of 1: 16 could be confirmed in the HiG and ELISA IgG tests.(ABSTRACT TRUNCATED AT 400 WORDS)