Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance.

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.

Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with existing congeners.

Since carbapenems and cephalosporins have been suggested to induce convulsive side effects through an inhibitory action on the central gamma-aminobutyric acid (GABA)-mediated inhibitory transmission, the present study evaluated the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4thiomorpholin ylcarbonyl)pyrrolidin-3-thio]-l-methylcarbapen-2-em-3- carboxylic acid (DK-35C) in in vitro and in vivo experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro experiments, their abilities to inhibit [3H]muscimol (5 nM) binding to GABA(A) receptors were measured using crude synaptic membranes prepared from the rat cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of the specific binding, were 0.6 for imipenem, 1.8 for cefazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35C induced convulsions in a dose-dependent manner in rats. The doses (nmol/rat) of the antibiotics which induce convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK-35C and >3000 for meropenem. In the mouse pentylenetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating enhancement of the convulsive activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked effects on the convulsive activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using rats, and suggest that DK-35C may possess a relatively weak convulsive activity mediated through an interaction with GABA(A) receptors.