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. METHODS: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. LAY SUMMARY: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.

Histomorphological Study of a New Nasal Spray with Anti-inflammatory Properties Efficacy in Rabbits with Rhinosinusitis.

INTRODUCTION: The high world prevalence of rhinosinusitis (RS) initiates the ways of a favorable search for effective and safe medicines for its pathogenetic treatment. The important part of this process is the choice of the most comfortable dosage form, which will enhance therapeutic compliance and ensure the appropriate medicine efficacy and safety. AIM: To substantiate the efficacy of a new nasal spray with anti-inflammatory properties containing Enisamium Iodide (EI) at a concentration of 10 mg/mL by histomorphological study of the nasal cavity and paranasal sinuses mucosal in rabbits with experimental rhinosinusitis (ERS). METHODS: EI (nasal spray) was a test object. Sinupret® was a reference drug. ERS was induced in rabbits on the first day of the study by tamponade of the right half of the nasal cavity under general anesthesia. The study was performed using 24 rabbits (4 groups, 6 rabbits in each group). The histomorphological examination was performed on the 25th day of the study by the standard light microscopy methods. RESULTS: The histomorphological examination of EI 10 mg/mL (nasal spray) impact on RS in rabbits, which administered during 10 days intranasally, revealed the significant therapeutic effect presented by reduced inflammation signs in the epithelium of the nasal cavities and paranasal sinuses mucosal. Besides, the EI impact was not inferior to the reference drug Sinupret® in tablets. The study of the pharmacological properties of the EI (nasal spray) on ERS showed the high rate of onset of EI actions when used intranasally which was superior to the rate of actions of the reference drug Sinupret® (tablets) administered intragastrically. CONCLUSION: The EI (nasal spray) is a promising drug for a pathogenetic therapy of acute RS, which demands further pre-clinical and clinical studies aiming to substantiate its implementation to the clinical practice.

The hepatoprotective effect of the combination of glucosamine derivatives with quercetin against methotrexate-induced liver toxicity.

The article presents the results of the study of the combination of aminosugars - glucosamine hydrochloride (GA h/ch) and N-acetylglucosamine - with quercetin (Q) called GlukvamineTM as a corrector of hepatotoxicity induced by methotrexate (MTX). The study was conducted on a model of MTX-induced liver damage in rats. GlukvamineTM was studied in the dose of 82 mg/kg with daily intragastric administration for 10 days compared to the substance GA h/ch, which was administered intragastrically at a dose of 50 mg/kg, and the substance of Q, which was administered intragastrically in the dose of 20.5 mg/kg. The efficiency of the drugs was assessed by the general condition of the animals, the values of the liver mass coefficient, the biochemical parameters of the blood serum and the histological analysis of the liver tissue. The GlukvamineTM effect on rats with MTX-induced liver damage caused an improvement of their general condition, recovery of the functional state of the liver by biochemical indicators, and the results of the histological analysis indicated a decrease in hepatotoxicity of MTX. At the same time, GlukvamineTM has statistically significantly exceeded the effect of GA h/ch and Q by most parameters. Thus, GlukvamineTM is a promising effective and safe drug for pharmacological correction of the hepatotoxicity of MTX.

Nephroprotective effect of N-acetylglucosamine in rats with acute kidney injury.

The article presents the results of the study of the nephroprotective effect of N-acetylglucosamine (NAG) under the development of experimental acute kidney injury (AKI). The study was conducted on a model of acute glycerol nephrosis in rats. NAG was studied at a dose of 50 mg/kg at daily parenteral administration during 1 week compared to quercetin, which was administered intraperitoneally at a dose of 34 mg/kg. The efficiency of the drugs was assessed by the functional state of animals, the renal excretory function and the nitrogen metabolism indices. The NAG effect on rats with AKI caused a reduction of the mortality rate, an increase in diuresis, a reduction of proteinuria, an increase in creatinine and urea excretion, which indicates the normalization of the renal excretory function and nitrogen metabolism. At the same time, NAG has statistically significantly exceeded the effect of quercetin in the majority of indices and, therefore, the level of efficiency. Thus, NAG is an efficient agent for AKI treatment, which can be used at parenteral route of administration.

Introduction of open visiting policy in intensive care units in Ukraine: policy analysis and the ethical perspective.

Open visiting policy (OVP) in intensive care units (ICU) is considered a favorable visiting regime that may benefit patients and their family members as well as medical staff. The article examines the conditions and causes of OVP-making process in Ukraine and presents the ethical analysis of its implications with respect to the key stakeholders: ICU patients, family members, and medical staff. The OVP, established by the Ministry of Health in June, 2016, changes current approaches to the recognition of the role of families in critically ill patients' care dramatically; it does, however, have serious shortcomings. The analysis of risks and benefits showed that OVP does not adequately cater to the needs of all the key players-family members, patients, and medical staff. Moreover, there is no clear mechanism to control OVP implementation via feedback from all the key players (particularly patients and their families). These issues give rise to a concern that the implementation of OVP will die on the vine. In order to prevent this, a range of measures is required: the optimization of the ICU facilities and internal procedures, supervision of OVP implementation by policy-makers, training of medical staff, and providing family members with educational programs. Considering current shortcomings, it is crucially important to develop clear and consistent internal guidelines in hospitals that will guarantee the introduction of open ICU visiting and quality of critical care provisions.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

OBJECTIVES: To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). METHODS: Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. RESULTS: Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. CONCLUSIONS: MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01023256.

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. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. CONCLUSION: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).

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 (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4 (27.9) µmol/L (ULN ∼48 µmol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cmax of 144 [125] vs. 292 [224] µg/mL on 6 and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9 mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE.

UPLC-MS/MS method for bioequivalence study of oral drugs of meldonium.

A rapid and simple method based on ultra-performance liquid chromatography on a hydrophilic interaction chromatography column with tandem mass-selective detection (UPLC-MS/MS) to determine meldonium in human plasma was developed. The calibration curve acquired in the range of 10-6000 ng/mL had quadratic form. Method validation proved the conformity of its properties (selectivity, matrix effect, lower limit of quantification, accuracy, precision and recovery) with the established requirements. The stability tests necessary for bioanalytical studies were performed. For the first time, the method was successfully applied to the bioequivalence studies of generic and brand name oral drugs of meldonium in capsules. Based on data from 24 volunteers, it was determined that the mean pharmacokinetic curves of the drugs are characterized by a double peak profile.

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. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. CONCLUSION: GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.