Antivirals in medical biodefense.

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha- and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). AIM: To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. METHODS: In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. RESULTS: In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP-A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP-B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). CONCLUSIONS: Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.

Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species.

The pharmacokinetics of moxifloxacin was investigated in NMRI mice, Wistar rats, rhesus monkeys, beagle dogs, Göttingen minipigs and healthy human volunteers after i.v. and oral administration of moxifloxacin-HCl (single doses of moxifloxacin 9.2 mg/kg bodyweight) in animals and 100 mg moxifloxacin (1.4 mg/kg bodyweight p.o. and 1.2 mg/kg bodyweight i.v.) in humans. The plasma concentration vs time courses of the unchanged compound (determined by HPLC) and the derived pharmacokinetic parameters were used to evaluate the absorption process, to compare the pharmacokinetics in these species and to perform an interspecies scaling. The results of the pharmacokinetic investigations indicate a clear dependence on the species. Moxifloxacin is absorbed quickly (rats, dogs, humans > monkeys): the major portion of the dose reached the systemic circulation within the first 2 h. In the minipig absorption was slower. Bioavailability was high to moderate (91-52%) in all species. Protein binding (f(u)) was low (55-71%) in all species. The volume of distribution at steady state (Vss) was medium to large (2.0-4.9 L/kg) in all species. There were considerable differences in maximum concentrations (C(max,norm), 0.430-0.070 kg/L) and in AUCnorm values (oral, 6.18-0.184 kg x h/L; i.v., 7.51-0.237 kg x h/L). Total body clearance (CL) decreased with increasing bodyweight (4.21-0.132 L/(h x kg)). The mean residence time (MRT) decreased with decreasing bodyweight (15-0.88 h). The half-life (t(1/2)) decreased with decreasing bodyweight (oral, 12-1.3 h, i.v., 13-0.93 h). There was moderate to low renal excretion (i.v., 20-6.2%), the renal clearance, (CL(R)) was in the range 0.615-0.0222 L/(h x kg). Regarding the pharmacokinetic parameters determined after oral administration, the dog was most similar to the human in terms of Cmax, AUC and t(1/2). There was good correlation between bodyweight and CL (coefficient of correlation (r) = 0.959), Vss (r = 0.990) and MRT (r = 0.943). On the basis of preclinical studies a terminal half-life appropriate for once-daily dosing in humans was predicted and confirmed by Phase I data.