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: NCT0102325

Shape and Volume Restoring Phenomena in Human Erythrocyte Suspension under Low Ion Strength Conditions

In this study, the earlier used method to measure the dynamics of shape changes in red blood cells (RBCs), based on an analysis of light fluctuations in the suspension, was modified to allow for the simultaneous recording of cell volume changes after appropriate recalculation of the raw absorbance and shape index data. With this improved methodology, we investigated the morphological and volume responses triggered by cell environment changes. In a low ionic strength medium (LIS), the characteristic triphasic shape changes (morphological response, MR) were accompanied with a gradual shrinking of the cells without any re-swelling phase. The addition of hyperosmotic NaCl during the terminal MR phase restored the discoid RBC shape inducing cell swelling resembling regulatory volume increase. The cell volume was greater than that before salt addition; however, it was lower than the initial isotonic cell volume. This re-swelling phase was inhibited by the external DIDS, acetozolamide and bicarbonate, and was slightly dependent upon pH ranging from 5 to 7.2. The analysis shows that chloride-induced re-swelling cannot be directly explained by the reversion of OH or HCO3 gradients which drive the Cl inside the cells against the concentration gradient, and indicates the significant role of the external bicarbonate ions in shape and volume responses in LIS

DEVELOPMENT OF THEORETICAL APPROACHES TO PHARMACEUTICAL CARE IMPROVEMENT CONSIDERING THE MODERN REQUIREMENTS OF HEALTH-CARE SYSTEM IN UKRAINE

Objective: The objective of this research was to formulate the theoretical approaches to the improvement of pharmaceutical care considering the modern requirements of the public health system in Ukraine.Methods: The analysis of pharmaceutical care has been performed using policy triangle†model. The pharmaceutical care policy model has been developed by applying the process approach.Results: The model of pharmaceutical care as a structural element of the national health policy has been developed. This model describes mechanisms by which the content, context, and process of the pharmaceutical care policy are influenced by the content, context, and process of the national health policy. Furthermore, we have defined the actors of the pharmaceutical care policy which are groups and organizations of various levels involved in the formation and development of the pharmaceutical care policy. Then, the structure of the pharmaceutical care policy has been elaborated. This policy is integrated into the national health-care system and is adapted to the good pharmacy practice requirements. The center of the policy is a process of pharmaceutical care delivering. The inputs, outcomes, management, and resources that are required for the pharmaceutical care process and provided by the actors have been identified. The data streams within this structure demonstrate implementation of the key elements of the pharmaceutical care process: Patient involvement, patient counseling and education, interprofessional collaboration, documentation of interaction, and follow-up. Furthermore, the mechanism of continual education and increasing of the professional level has been described in this structure.Conclusion: Proposed framework provides a comprehensive view of pharmaceutical care as a structural element of the national health policy considering new trends of the Ukrainian health system. The proposed model of the pharmaceutical care policy allows policy-makers to address all critical-to-quality aspects and stakeholders' needs

Phytochemical Profile and Pharmacological Activity of the Dry Extract From Arctostaphylos Uva-ursi Leaves Modified with Phenylalanine

Diseases of the urinary tract and kidneys occupy a leading place in the structure of diseases all over the world. Arctostaphylos uva-ursi leaves are one of the most widely used types of medicinal plant materials (MPM) with diuretic and uroantiseptic action. However, a decoction from the leaves of Arctostaphylos uva-ursi has certain disadvantages: the duration of the manufacturing process of the dosage form, the lack of standardization before use, the inaccuracy of dosage and the short storage time of the dosage form, which leads to a low complementarity of this remedy, therefore, the development of standardized extracts from this raw material is relevant.The aim. The aim of the research was a phytochemical study of a phenylalanine-modified dry extract from the leaves of Arctostaphylos uva-ursi to establish the possibility of creating a new diuretic drug.Materials and methods. The object of the study was dry extract from the leaves of Arctostaphylos uva-ursi, modified with phenylalanine. Phytochemical studies of phenolic compounds and saponins were carried out by HPLC and spectrophotometry. Determination of diuretic activity was carried out according to the method of E.B. Berkhina on outbred rats. Determination of the anti-inflammatory activity of the obtained extracts was carried out by the method of carrageenan edema in white rats. The study of the antibacterial activity of the extracts was carried out by the method of diffusion into agar.Results. In the extracts obtained by HPLC, phenol glycoside (arbutin), 2 phenol carboxylic acids (gallic and ellagic), 6 flavonoids, 8 saponins were identified and their quantitative content was determined. Among flavonoids, hyperoside and catechin were dominant; among saponins, ursolic acid, uvaol, and lupeol were dominant. In the obtained extracts, the content of the main groups of phenolic compounds was determined by spectrophotometry.Dry extract of Arctostaphylos uva-ursi, modified with phenylalanine, showed pronounced diuretic, anti-inflammatory and antimicrobial (in relation to St. aureus, E. coli, P. vulgaris, P. aeruginosa, B. subtilis and C. albicans) activity.Conclusions. The chemical composition, diuretic, antimicrobial and anti-inflammatory activity of dry extract from Arctostaphylos uva-ursi leaves modified with phenylalanine were determined. The obtained dry extract is noted for better solubility, bioavailability and pharmacodynamics, therefore it is a promising substance for creating new drugs in various dosage form

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

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). (Hepatology 2014;59:1073‐1083

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 pleuri sy 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