Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment.

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity.

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.

Validation of PAS Kinase, a Regulator of Hepatic Fatty Acid and Triglyceride Synthesis, as a Therapeutic Target for Nonalcoholic Steatohepatitis.

Hyperactivation of sterol regulatory element binding protein 1c (SREBP-1c), which transcriptionally induces expression of enzymes responsible for lipogenesis and triglyceride (TG) formation, is implicated in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) pathogenesis. Posttranslational SREBP-1c maturation and activation is stimulated by the protein per-arnt-sim kinase (PASK). knockout mice are phenotypically normal on a conventional diet but exhibit decreased hypertriglyceridemia, insulin resistance, and hepatic steatosis on a high-fat diet.

Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study.

Background: Intramuscular immunisation with a vaccine composed of three recombinant Helicobacter pylori antigens-vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), and neutrophil-activating protein (NAP)-prevented infection in animal models and was well tolerated and highly immunogenic in healthy adults. We aimed to assess the efficacy of the vaccine in prevention of a H pylori infection after challenge with a CagA-positive strain (BCM 300) in healthy volunteers.

Methods: In this randomised phase 1/2, observer-blind, placebo-controlled, single-centre study, healthy non-pregnant adults aged 18-40 years who were confirmed negative for H pylori infection were randomly assigned (3:4) to three intramuscular doses of either placebo or vaccine at 0, 1, and 2 months.

GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study.

Rationale: GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans.

Methods: Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs.

Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives.

Unlabelled: Patients and families living with metabolic disorders face challenging dietary and drug treatment regimens. On the hypothesis that poor palatability, volume and frequency of drug/formula administration contribute to treatment non-adherence and hyperammonemic episodes, a survey was conducted of patient, caregiver (CG) and physician perspectives on treatments used in urea cycle disorders (UCD).

Methods: A paper and online survey assessed experience with UCD medications, medical foods and dietary supplements.

Protein and calorie intakes in adult and pediatric subjects with urea cycle disorders participating in clinical trials of glycerol phenylbutyrate.

Background: Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals.

Objective: To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys.

Design: Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB.

Fasting Blood Ammonia Predicts Risk and Frequency of Hepatic Encephalopathy Episodes in Patients With Cirrhosis.

Background & Aims: There is controversy over the use of measuring blood levels of ammonia (NH3) in the management of patients with overt hepatic encephalopathy (HE).

Methods: We performed a retrospective analysis of data from a randomized, double-blind study of 178 patients with cirrhosis given glycerol phenylbutyrate (an NH3-lowering agent) or placebo for 16 weeks. Blood samples were collected at baseline and on study days 7 and 14 and NH3 levels were measured.

Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials.

Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.

Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire.

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

Purpose: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.

Methods: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.

Results: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.

Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes.

Objective: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs).

Study Design: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth.

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.

Unlabelled: Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events.

Glycerol Phenylbutyrate in Patients With Cirrhosis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous Ammonia Concentration.

Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6 mL (6.

Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate.

Objectives: To examine ammonia levels, pharmacokinetics, and safety of glycerol phenylbutyrate (GPB; also referred to as HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs).

Study Design: This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hour blood and urine sampling on NaPBA and again on a phenylbutyric acid-equimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD.

Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.

Unlabelled: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively.

Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults.

Background: Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominate in the USA and Canada. We describe the first in humans clinical trial of this prophylactic HCV vaccine.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

Unlabelled: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis.

Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control.

Unlabelled: Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia.

Methods: An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA.

Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study.

Introduction: Helicobacter pylori infection is among the most common human infections and the major risk factor for peptic disease and gastric cancer. Immunization with vaccines containing the H pylori vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), and neutrophil-activating protein (NAP), alone or in combination, have been shown to prevent experimental infection in animals.

Aim: We sought to study the safety and immunogenicity of a vaccine consisting of recombinant VacA, CagA, and NAP given intramuscularly with aluminium hydroxide as an adjuvant to noninfected healthy subjects.

Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial.

Background/aims: Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesized in the liver whose levels decrease sharply in liver cirrhosis.

Methods: We conducted a randomized double-blind placebo-controlled clinical trial to evaluate the effect of subcutaneous administration of IGF-I (20 microg/kg/day with dose escalation to 50-100 microg/kg/day) for 4 months in patients with alcoholic or primary biliary cirrhosis (PBC) and subnormal IGF-I levels. Eight alcoholics and one PBC entered the placebo group and seven alcoholics and two PBC the treatment group.

Blasts from the past.

With this issue of the JCI, we celebrate the 80th anniversary of the Journal. While 80 years is not a century, we still feel it is important to honor what the JCI has meant to the biomedical research community for 8 decades. To illustrate why the JCI is the leading general-interest translational research journal edited by and for biomedical researchers, we have asked former JCI editors-in-chief to reflect on some of the major scientific advances reported in the pages of the Journal during their tenures.

Thyroid hormone export varies among primary cells and appears to differ from hormone uptake.

We characterized T3 efflux in primary cultures of cells derived from human placenta, neonatal rat cardiac myocytes, and rat inner medullary collecting ducts (IMCD). The T3 efflux rate was highest in placenta cells, followed by ventriculocytes, atriocytes, and IMCD cells. Verapamil reversibly blocked [125I]T3 efflux in these cells in a manner that correlated with their T3 efflux rate.