Cost-Effectiveness of New Direct-Acting Antivirals to Prevent Post-Liver Transplant Recurrent Hepatitis.

Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen.

Management of treatment-naïve chronic hepatitis C genotype 1 patients: a cost-effectiveness analysis of treatment options.

New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients' selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1-F4 fibrosis, (ii) only F2-F4 and (iii) only F3-F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1-F4 strategy relative to F3-F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1-F4 strategy relative to F3-F4 was €1 818 679 (TVR IL28B-guided) and €1 866 437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization.

Protection against apoptosis by monoamine oxidase A inhibitors.

Several lines of evidence have been accumulating indicating that an important role may be played by mitochondrial homeostasis in the initiation phase, the first stage of apoptosis. This work describes the results obtained by using different inhibitors of monoamine oxidases (MAO), i.e. pargyline, clorgyline and deprenyl, on mitochondrial integrity and apoptosis. Both pargyline and clorgyline are capable of protecting cells from apoptosis induced by serum starvation while deprenyl is ineffective. These data represent the first demonstration that MAO-A inhibitors may protect cells from apoptosis through a mechanism involving the maintenance of mitochondrial homeostasis.

Studies on heterocyclic compounds: spiro [indole-3,2'-thiazolidine] derivatives. Antimicrobial activity of monohalogenated 3'-phenylspiro 3H-indole-3,2'-thiazolidine-2,4' (1H)-diones.

The following halogenated 3'-phenyl [3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione of general formula (A) were synthesized and screened for antimicrobial activity. (formula: see text) where: X = H (I, III, V, VII, IX, XI, XIII, XV), CH3 (II, IV, VI, VIII, X, XII, XIV, XVI); Y = H (I, II), 3-F (III, IV), 2-Cl (V, VI), 3-Cl (VII, VIII), 4-Cl (IX, X), 2-Br (XI, XII), 3-Br (XIII, XIV), 4-Br (XV, XVI). The synthetic approach involves the preparation of variously substituted Schiff-bases of indol-2,3-dione, which then are subjected to cyclocondensation with alpha-mercaptoalkanoic acids, to give spirothiazolidinones of type (A). The prepared compounds were screened against S. aureus, B. cereus, M. paratuberculosis, E. coli, S. typhi, Pr. mirabilis, Ps. aeruginosa, C. albicans, S. cerevisiae, A. niger by a disk-diffusion assay (Kirby-Bauer modified. The results of the antimicrobial screening showed that the prepared compounds exhibited varying degrees of activity against Gram-positive, Gram-negative bacteria, and fungi. 3-Fluoro-derivative (III) showed inhibitory activity especially toward S. aureus and C. albicans. Chloroderivatives (VII) and (VIII) showed broad-spectrum "in vitro" antimicrobial activity, and were especially inhibitory toward S. aureus, E. coli, and S. Typhi. Fluoro-derivative (IV) and bromo-derivatives (XIII) and (XIV) possessed marked antimicrobial activity against M. paratuberculosis.

Studies on heterocyclic compounds: spiro [indole-3,2'-thiazolidine] derivatives. II. Antimicrobial activity of halogenated 3'-phenylspiro 3H-indole-3,2'-thiazolidine -2,4 (1H)-diones.

The following polyhalogenated 3'-phenyl 3H-indole-3,2'-thiazolidine -2,4' (1H)-dione of general formula (A) were synthesized and screened for antimicrobial activity. (formula: see text) where: X = H (I, III, V, VII, IX, XI), CH3 (II, IV, VI, VIII, X, XII); Y = H (I, II), 2,4-F2 (III, IV), 2,4-Cl2 (V, VI), 3,4-Cl2 (VII, VIII), 2,6-Cl2 (IX, X), 2,4,6-Cl3 (XI, XII). The general synthetic route involves the preparation of variously substituted isatin-3-imines, which are subjected to cyclocondensation with thioglycolic acid to give compounds I, III, V, VII, IX, XI, or thiolactic acid to give compounds II, IV, VI, VII, X, XII. The prepared compounds were screened against S. aureus, B. cereus, M. paratuberculosis, E. coli, Pr. mirabilis, Ps. aeruginosa, C. albicans, S. cerevisiae, A. niger by a disk-diffusion assay (Kirby-Bauer modified). The results of the antimicrobial screening showed that the polyhalogenated derivatives of type (A) exhibited varying degrees of activity against Gram-positive, Gram-negative bacteria, and fungi. Compound (III) showed a significant activity toward A. niger, moreover compound (IV) was active toward C. albicans. Compound (IX) was very active toward S. typhi and Ps. aeruginosa. Compounds (VII), (IX) and (XII) were very active toward M. paratuberculosis.