The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study.

BACKGROUND: Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis. METHODS: The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment. RESULTS: In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment. CONCLUSION: Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS. GOV IDENTIFIER: NCT02203149.

Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons.

Na+-coupled carboxylate transporters (NaCs) mediate the uptake of tricarboxylic acid cycle intermediates in mammalian tissues. Of these transporters, NaC3 (formerly known as Na+-coupled dicarboxylate transporter 3, NaDC3/SDCT2) and NaC2 (formerly known as Na+-coupled citrate transporter, NaCT) have been shown to be expressed in brain. There is, however, little information available on the precise distribution and function of both transporters in the CNS. In the present study, we investigated the functional characteristics of Na+-dependent succinate and citrate transport in primary cultures of astrocytes and neurons from rat cerebral cortex. Uptake of succinate was Na+ dependent, Li+ sensitive and saturable with a Michaelis constant (Kt) value of 28.4 microM in rat astrocytes. Na+ activation kinetics revealed that the Na+ to succinate stoichiometry was 3:1 and the concentration of Na+ necessary for half-maximal transport was 53 mM. Although uptake of citrate in astrocytes was also Na+ dependent and saturable, its Kt value was significantly higher (approximately 1.2 mM) than that of succinate. Unlabeled succinate (2 mM) inhibited Na+-dependent [14C]succinate (18 microM) and [14C]citrate (4.5 microM) transport completely, whereas unlabeled citrate inhibited Na+-dependent [14C]succinate uptake more weakly. Interestingly, N-acetyl-L-aspartate, which is the second most abundant amino acid in the nervous system, also completely inhibited Na+-dependent succinate transport in rat astrocytes. The inhibition constant (Ki) for the inhibition of [14C]succinate uptake by unlabeled succinate, N-acetyl-L-aspartate and citrate was 15.9, 155 and 764 microM respectively. In primary cultures of neurons, uptake of citrate was also Na+ dependent and saturable with a Kt value of 16.2 microM, which was different from that observed in astrocytes, suggesting that different Na+-dependent citrate transport systems are expressed in neurons and astrocytes. RT-PCR and immunocytochemistry revealed that NaC3 and NaC2 are expressed in cerebrocortical astrocytes and neurons respectively. These results are in good agreement with our previous reports on the brain distribution pattern of NaC2 and NaC3 mRNA using in situ hybridization. This is the first report of the differential expression of different NaCs in astrocytes and neurons. These transporters might play important roles in the trafficking of tricarboxylic acid cycle intermediates and related metabolites between glia and neurons.

Transport characteristics of N-acetyl-L-aspartate in rat astrocytes: involvement of sodium-coupled high-affinity carboxylate transporter NaC3/NaDC3-mediated transport system.

We investigated in the present study the transport characteristics of N-acetyl-L-aspartate in primary cultures of astrocytes from rat cerebral cortex and the involvement of NA+-coupled high-affinity carboxylate transporter NaC3 (formerly known as NaDC3) responsible for N-acetyl-L-aspartate transport. N-acetyl-L-aspartate transport was NA+-dependent and saturable with a Michaelis-Menten constant (Km) of approximately 110 microm. NA+-activation kinetics revealed that the NA+ to-N-acetyl-L-aspartate stoichiometry was 3 : 1 and concentration of Na+ necessary for half-maximal transport (KNA m) was 70 mm. NA+-dependent N-acetyl-L-aspartate transport was competitively inhibited by succinate with an inhibitory constant (Ki) of 14.7 microm, which was comparable to the Km value of NA+-dependent succinate transport (29.4 microm). L-aspartate also inhibited NA+-dependent [14C]N-acetyl-L-aspartate transport with relatively low affinity (Ki = 2.2 mm), whereas N-acetyl-L-aspartate was not able to inhibit NA+-dependent aspartate transport in astrocytes. In addition, Li+ was found to have a significant inhibitory effect on the NA+-dependent N-acetyl-L-aspartate transport in a concentration-dependent manner. Furthermore, RT-PCR and western blot analyses revealed that NaC3 is expressed in primary cultures of astrocytes. Taken collectively, these results indicate that NaC3 expressed in rat cerebrocortical astrocytes is responsible for NA+-dependent N-acetyl-L-aspartate transport. This transporter is likely to be an essential prerequisite for the metabolic role of N-acetyl-L-aspartate in the process of myelination.