A Stepwise Male Introduction Procedure to Prevent Inbreeding in Naturalistic Macaque Breeding Groups.

Male introductions into captive primate breeding groups can be risky and unsuccessful. However, they are necessary to prevent inbreeding in naturalistic breeding groups. The procedure used to introduce new individuals may affect the success and influence the risks associated with group introductions. At the Biomedical Primate Research Centre (BPRC) in Rijswijk, the Netherlands, male rhesus macaque (Macaca mulatta) introductions into naturalistic social groups with a matrilineal structure and without a breeding male achieve relatively high success rates. This paper describes the male introduction procedure used at the BPRC. Males are stepwise familiarized with and introduced to their new group, while all interactions between the new male and the resident females are closely monitored. Monitoring the behaviour of the resident females and their new male during all stages of the introduction provides crucial information as to whether or not it is safe to proceed. The BPRC introduction procedure is widely applicable and may improve the management of captive primate groups in any housing facility worldwide. Thus, the careful introduction management can minimize the risk associated with male introductions and enhance the welfare of captive primates.

Factors determining male introduction success and long-term stability in captive rhesus macaques.

The entrance of new males into non-human primate groups bears high social risk, yet migration is necessary to prevent inbreeding. Males are not always accepted in their new group. In the wild, males may increase the likelihood of successful group entry by choosing a new group based on their own and the group's characteristics. Understanding whether these characteristics also determine a male's ability to enter captive groups is crucial to improve introduction management. This study aims to identify which factors determine male introduction success (i.e. male stays in the group for at least 4 weeks) and long-term stability (i.e. the male does not cause considerable behavioural problems after success) after male introductions in captive groups of rhesus macaques (Macaca mulatta), creating one-male groups. We studied 64 male introductions at the breeding colony of the Biomedical Primate Research Centre in Rijswijk, The Netherlands. 49 (77%) introductions were successful, with the male obtaining a long-term stable social position in the group in 38 (59%) introductions. Introductions of males that reached at least prime age, into groups with more adult females, but without pregnant females were most successful. Moreover, long-term stability was highest when males were heavier, were at least 3.5 years old when they were first removed from their natal group, and groups had few matrilines and no pregnant females were present. Males should be introduced at the time they would naturally immigrate, when they are strongest. Moreover, groups should consist of few large matrilines, as observed in the wild, with philoatric females and males that are removed at natural age. Our study highlights the importance of composing naturalistic groups and mimicking natural migration patterns to maintain long-term stable breeding groups in captivity.

Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.

BACKGROUND: Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS: Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS: Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 µmol/24 h) and ~8 times higher in T2DM (1786.0 µmol/24 h) than with placebo (HVs: 386.93 µmol/24 h; T2DM: 220.00 µmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS: Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).

A low TSH profile predicts olanzapine-induced weight gain and relief by adjunctive topiramate in healthy male volunteers.

Second generation antipsychotics, like olanzapine (OLZ), have become the first line drug treatment for patients with schizophrenia. However, OLZ treatment is often associated with body weight (BW) gain and metabolic derangements. Therefore, the search for prospective markers for OLZ's negative side effects as well as adjunctive treatments to inhibit these has been of major interest. The aim of this study was to investigate in healthy male volunteers (age: 36 ± 11 years; BW: 84 ± 12 kg; BMI=25.5 ± 2.5) whether adjunctive topiramate (TPM) administration opposes OLZ-induced weight gain over the course of 14 days treatment. In addition, we investigated behavioral, endocrine and metabolic characteristics as underlying and potentially predictive factors for weight regulation and/or metabolic derangements associated with OLZ and TPM treatment. While adjunctive TPM indeed reduced OLZ-induced weight gain (P<0.05, Mann-Whitney U), behavioral/metabolic/endocrine characteristics of OLZ treatment were not affected by TPM. Using multiple regression analysis, BW gain was the key factor explaining metabolic disturbances (e.g., plasma insulin- LDL interaction: P<0.01, R(2)=.320), and cumulative food intake during treatment was the best denominator of BW gain (P<0.01, R(2)=.534). Neither TPM treatment, nor its circulating levels, contributed to variation observed in ΔBW. In a second multiple regression analysis, we observed that a low baseline thyrotropin profile (TSHAUC) before the start of drug treatment was associated with an increase in ΔBW over the course of drug treatment (P<0.05, R(2)=.195). Adding TSHAUC as covariate revealed that adjunctive TPM treatment did attenuate OLZ induced BW gain (P<0.05, ANCOVA). Further exploration of the circulating thyroid hormones revealed that individuals with a low plasma TSH profile were also those that were most sensitive to adjunctive TPM treatment blocking OLZ-induced ΔBW gain. Others have shown that OLZ-induced BW gain is associated with improvement in brief psychiatric rating scores (BPRS); adjunctive TPM treatment may be a solution specifically for those subjects susceptible to OLZ-induced rapid weight gain who-on a therapeutic level-benefit most of OLZ treatment.

Total energy expenditure assessed by salivary doubly labelled water analysis and its relevance for short-term energy balance in humans.

RATIONALE: The doubly labelled water (DLW) method is a stable isotopic technique for measuring total energy expenditure (TEE). Saliva is the easiest sampling fluid for assessing isotopic enrichments, but blood is considered superior because of its rapid exchange with body water. Therefore, we compared a large range of isotopic enrichments in saliva and blood, and related TEE in subjects with their ad libitum total energy intake (TEI). The relevance of these parameters to body weight and fat change over an 8-day interval was also assessed. METHODS: Thirty subjects underwent DLW analysis over either 8 or 14 days, during which time initial and final blood and saliva enrichments were compared. TEI was assessed by dieticians over the 8-day period only. Isotope ratio mass spectrometry was used for the measurement of δ(2)H and δ(18)O values. RESULTS: No discrepancies were observed between sampling fluids over a wide range of enrichments. During the 8-day period, average TEI exceeded TEE by ~5% or less. Using saliva as sampling fluid, TEI and TEI-TEE, but not TEE, were positively correlated to body weight change. TEI-TEE and physical activity EE (AEE), but not TEI, correlated, respectively, positively and negatively to changes in fat mass. CONCLUSIONS: The DLW method in humans can be reliably applied using saliva as sampling fluid. TEI-TEE as well as AEE contributes significantly to changes in fat mass over an 8-day period.

Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies.

PURPOSE: Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FINDINGS: In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-∞ (mean range 45.6-8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. IMPLICATIONS: Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.

Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients.

BACKGROUND AND AIMS: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following miravirsen dosing and to assess long-term safety in patients treated with miravirsen. METHODS: In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of miravirsen or placebo dosing. RESULTS: PR therapy was started in 14/36 patients of whom 12 had received miravirsen. SVR was achieved in 7/12 patients previously dosed with miravirsen. All patients dosed with 7mg/kg miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications. CONCLUSION: No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.

The Value of Desmethylclozapine and Serum CRP in Clozapine Toxicity: A Case Report.

Clozapine, an atypical antipsychotic, has proved to be superior to other antipsychotics in treating patients with refractory schizophrenia. An increased plasma clozapine level above the therapeutic window may be associated with serious adverse events including paralytic ileus. Clozapine toxicity may occur in association with infection or after drug overdose. In a medical emergency situation, differentiating between a toxic clozapine ingestion and an infection-induced toxicity might be hindered by associated CNS changes and by the clozapine modulation of the inflammatory process. This may delay prompt initiation of a tailored treatment strategy. Here, we report a case of paralytic ileus developed within the context of clozapine toxicity. Although the underlying cause of toxicity was not clinically obvious, giving antimicrobial therapy resulted in an improvement in the patient's clinical condition. This report indicates the value of serum levels of C-reactive protein and desmethylclozapine, major metabolite of clozapine, in the treatment of aetiologically unclear clozapine toxicity.

Somatosensory profiles but not numbers of somatosensory abnormalities of neuropathic pain patients correspond with neuropathic pain grading.

Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as 'definite', 'probable', 'possible' and 'unlikely' neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with 'probable' and 'definite' grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades. Of patients who were clinically diagnosed with neuropathic pain, only 60% were graded as 'definite' or 'probable', while 40% were graded as 'possible' or 'unlikely' neuropathic pain. Apparently, there is a mismatch between a clinical neuropathic pain diagnosis and neuropathic pain grading. Contrary to the expectation, patients with 'probable' and 'definite' grades did not have a greater number of abnormalities. Instead, similar numbers of somatosensory abnormalities were identified for each grade. The profiles of sensory signs in 'definite' and 'probable' neuropathic pain were not significantly different, but different from the 'unlikely' grade. This latter difference could be attributed to differences in the prevalence of patients with a mixture of sensory gain and loss and with sensory loss only. The grading system allows a separation of neuropathic and non-neuropathic pain based on profiles but not on the total number of sensory abnormalities. Our findings indicate that patient selection based on grading of neuropathic pain may provide advantages in selecting homogenous groups for clinical research.

Bilateral sensory abnormalities in patients with unilateral neuropathic pain; a quantitative sensory testing (QST) study.

In patients who experience unilateral chronic pain, abnormal sensory perception at the non-painful side has been reported. Contralateral sensory changes in these patients have been given little attention, possibly because they are regarded as clinically irrelevant. Still, bilateral sensory changes in these patients could become clinically relevant if they challenge the correct identification of their sensory dysfunction in terms of hyperalgesia and allodynia. Therefore, we have used the standardized quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS) to investigate somatosensory function at the painful side and the corresponding non-painful side in unilateral neuropathic pain patients using gender- and age-matched healthy volunteers as a reference cohort. Sensory abnormalities were observed across all QST parameters at the painful side, but also, to a lesser extent, at the contralateral, non-painful side. Similar relative distributions regarding sensory loss/gain for non-nociceptive and nociceptive stimuli were found for both sides. Once a sensory abnormality for a QST parameter at the affected side was observed, the prevalence of an abnormality for the same parameter at the non-affected side was as high as 57% (for Pressure Pain Threshold). Our results show that bilateral sensory dysfunction in patients with unilateral neuropathic pain is more rule than exception. Therefore, this phenomenon should be taken into account for appropriate diagnostic evaluation in clinical practice. This is particularly true for mechanical stimuli where the 95% Confidence Interval for the prevalence of sensory abnormalities at the non-painful side ranges between 33% and 50%.

Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

BACKGROUND: The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. METHODS: This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8). RESULTS: In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group. CONCLUSIONS: Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7.

BACKGROUND: ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. METHODS: The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. RESULTS: Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log(10) IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-α was induced in non-responders. CONCLUSIONS: These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation.

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design.

BACKGROUND: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design. METHODS: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily). RESULTS: Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA decline was 0.6 log(10) IU/ml in the first 24 h in the single-dose protocol and 1.5 log(10) IU/ml after 6 days of PHX1766 dosing. CONCLUSIONS: An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction.

Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects.

PURPOSE: The aim of our study was to evaluate the pharmacology of vorapaxar (SCH 530348), an oral PAR-1 antagonist, in healthy volunteers. METHODS AND RESULTS: In two randomized, placebo-controlled studies, subjects received either single ascending doses of vorapaxar (0.25, 1, 5, 10, 20, or 40 mg; n = 50), multiple ascending doses of vorapaxar (1, 3, or 5 mg/day for 28 days; n = 36), a loading dose (10 or 20 mg) followed by daily maintenance doses (1 mg) for 6 days (n = 12), or placebo. Single 20- and 40-mg doses of vorapaxar completely inhibited thrombin receptor activating peptide (TRAP)-induced platelet aggregation (>80% inhibition) at 1 h and sustained this level of inhibition for ≥72 h. Multiple doses yielded complete inhibition on Day 1 (5 mg/day) and Day 7 (1 and 3 mg/day). Adverse events were generally mild, transient, and unrelated to dose. CONCLUSION: Vorapaxar provided rapid and sustained dose-related inhibition of platelet aggregation without affecting bleeding or clotting times.

Asenapine Safety, Tolerability, and Pharmacokinetics After Single and Multiple Doses in Healthy Volunteers.

This double-blind, placebo-controlled, randomized study is the first in healthy volunteers to describe the safety, tolerability, and pharmacokinetics of sublingual asenapine at therapeutic dosages. After a 2-day placebo run-in phase, healthy male volunteers received placebo or asenapine escalated to dosages of 3, 5, 10, or 15 mg bid. Another group received single doses (2 and 5 mg) 1 week apart. Serial blood samples were obtained for pharmacokinetic analysis. The single asenapine doses and multiple bid doses up to 10 mg were well tolerated. The most frequent treatment-emergent adverse events were somnolence, oral paresthesia, fatigue, headache, dizziness, and dyspnea. Clinically relevant abnormalities or trends in laboratory and vital signs measures, physical examinations, or electrocardiograms were not observed. Asenapine was rapidly absorbed, with a tmax of ∼1 hour, and was biphasically eliminated with a terminal elimination half-life of 20 to 30 hours. In the range of 3 to 10 mg bid, increases in plasma concentrations were less than dose proportional. Asenapine appears to be well tolerated at single doses up to 5 mg and multiple doses up to 10 mg bid and can be administered to healthy volunteers in clinical pharmacology studies using the dosing regimens described.

Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients.

UNLABELLED: Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log10 in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated. CONCLUSION: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients.

Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor.

BACKGROUND: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor. METHODS: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks. RESULTS: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment. CONCLUSIONS: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level.

Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients.

BACKGROUND & AIMS: The search for targeted anti-hepatitis C virus (HCV) drugs is driven by the adverse effect profile and limited efficacy of the current standard of care (pegylated interferon-alpha/ribavirin). In a first-in-human trial, we tested the safety, tolerability, and pharmacokinetics of the macrocyclic HCV NS3/4A protease inhibitor TMC435 in healthy volunteers, followed by HCV genotype 1-infected patients to assess antiviral activity. METHODS: The TMC435350-C101 study was a phase I, randomized, double-blind, placebo-controlled trial in 49 healthy volunteers, followed by an open-label, nonplacebo-controlled panel in 6 genotype 1 hepatitis C patients. Healthy volunteers received oral, single, ascending doses (up to 600 mg) or 5-day multiple ascending doses (200 mg twice daily or 100, 200, or 400 mg once daily). Patients received 200 mg once daily for 5 days. Pharmacokinetics and safety were evaluated for all panels, and plasma HCV-RNA levels were determined in patients. RESULTS: There were no serious adverse events, no grade 3 reactions, and no treatment-related discontinuations; pharmacokinetics supported a once daily dosing regimen. Plasma HCV-RNA levels dropped rapidly in all patients, with a median maximal reduction of 3.9-log(10) IU/mL and a median of 6 days to maximal reduction. The initial steep reduction of HCV-RNA (median 3.5-log(10) IU/mL at day 3) was followed by a more gradual decline that was maintained over the dosing period. No viral breakthroughs (>1-log(10) IU/mL HCV-RNA increase from nadir) were observed during treatment nor in the 3 days posttreatment; HCV-RNA returned to pretreatment levels by week 4. CONCLUSIONS: Once daily TMC435 given orally was generally safe and well tolerated and demonstrated potent antiviral activity.

Hypertensive crisis-induced electrocardiographic changes: a case series.

INTRODUCTION: Myocardial injury is one of the most notorious complications of a hypertensive crisis. Key electrocardiograph signs used to detect cardiac injury such as ST segment changes and cardiac arrhythmias usually indicate acute ongoing end-organ damage. Lack of early signs to predict end-organ damage might lead to a delay in the initiation of therapy and selection of the incorrect therapeutic strategy. CASE PRESENTATION: We describe five cases of tall, hyper acute symmetrical T-waves alone or accompanied by other electrocardiograph abnormalities in five healthy participants: three women aged 52, 60 and 62-years and two men aged 49 and 66-years, during a tyramine-monoamine oxidase-inhibitor interaction, phase I clinical trial. T-wave changes appeared early during the course of the hypertensive crisis and were attributed to subendocardial ischemia. The changes were transient and reverted to baseline in parallel with a fall in blood pressure. CONCLUSION: Recognition of tall symmetrical T-waves in early phases of hypertensive crisis heralds commencement of myocardial damage. This calls for prompt medical intervention to avoid an impending irreversible myocardial injury. It is our belief that these findings will add new insight into the management of hypertensive crisis and will open avenues of further investigation.

Reproducibility of 3.0 Tesla magnetic resonance spectroscopy for measuring hepatic fat content.

PURPOSE: To investigate reproducibility of proton magnetic resonance spectroscopy ((1)H-MRS) to measure hepatic triglyceride content (HTGC). MATERIALS AND METHODS: In 24 subjects, HTGC was evaluated using (1)H-MRS at 3.0 Tesla. We studied "between-weeks" reproducibility and reproducibility of (1)H-MRS in subjects with fatty liver. We also studied within liver variability and within day reproducibility. Reproducibility was assessed by coefficient of variation (CV), repeatability coefficient (RC), and intraclass correlation coefficient (ICC). RESULTS: The CV of between weeks reproducibility was 9.5%, with a RC of 1.3% HTGC (ICC 0.998). The CV in fatty livers was 4.1%, with a RC of 1.3% HTGC (ICC 0.997). Within day CV was 4.5%, with a RC of 0.4% HTGC (ICC 0.999). CV for within liver variability was 14.5%. CONCLUSION: Reproducibility of (1)H-MRS to measure HTGC for "between-weeks" measurements and in fatty livers is high, which is important for follow-up studies. Within liver variability displays a larger variation, meaning that liver fat is not equally distributed and during consecutive measurements the same voxel position should be used.