Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2)

Introduction While current standard of care (SOC) for idiopathic pulmonary fibrosis (IPF) slows disease progression, prognosis remains poor. Therefore, an unmet need exists for novel, well-tolerated agents that reduce lung function decline and improve quality of life. Here we report the design of two phase III studies of the novel IPF therapy, GLPG1690. Methods and analysis Two identically designed, phase III, international, randomised, double-blind, placebocontrolled, parallel-group, multicentre studies (ISABELA 1 and 2) were initiated in November 2018. It is planned that, in each study, 750 subjects with IPF will be randomised 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or placebo, once daily, on top of local SOC, for at least 52 weeks. The primary endpoint is rate of decline of forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are week 52 composite endpoint of disease progression or all-cause mortality (defined as composite endpoint of first occurrence of ≥10% absolute decline in per cent predicted FVC or all-cause mortality at week 52); time to first respiratory-related hospitalisation until end of study; and week 52 change from baseline in the St George’s Respiratory Questionnaire total score (a qualityof-life measure). Ethics and dissemination Studies will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peerreviewed publication. Trial registration numbers NCT03711162; NCT03733444

Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis

RATIONALE: Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-D-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model). OBJECTIVES: The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design. MATERIALS AND METHODS: Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation. RESULTS: Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN. CONCLUSIONS: The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells

Depósito e perdas de calda em sistema de pulverização com turboatomizador em videira Deposition and spray losses in an air-assisted sprayer system in grapevine

Grande parte dos viticultores da região Norte do Paraná pratica a condução da videira em caramanchão, com mais de 50 aplicações fitossanitárias em um único ciclo. O objetivo deste trabalho foi avaliar essas aplicações com turboatomizador assistido de ar no sistema de pulverização, por meio do depósito de calda nas folhas e perdas. O trabalho foi desenvolvido utilizando-se de cinco condições de aplicação, variando-se tamanho de gotas e volume de aplicação, com quatro repetições, em blocos casualizados. A avaliação do sistema foi feita com a aplicação de uma calda de cloreto de potássio (5%), sendo o depósito nas folhas medido pela condutividade elétrica, e as perdas, pela comparação entre volumes aplicado e recuperado nas folhas. Para todas as condições, as perdas foram superiores a 48%. Os maiores volumes aplicados apresentaram as maiores deposições, e gotas maiores apresentaram maior depósito e mesma perda em relação a gotas menores. Os menores volumes não diferiram com relação à deposição, destacando-se as condições gotas maiores a volume baixo e a testemunha utilizada pelo viticultor, que apresentaram as menores perdas. Os resultados demonstram que o turboatomizador é uma importante ferramenta para maximizar as operações de pulverização em uva, e as alterações na configuração das pontas de pulverização devem ser mais estudadas.<br>Winegrowers in the north of Paraná State carry on grapevines in arbour and pesticide applications could overcome more than fifty times in a cycle. The aim of this study was to evaluate the features of the air assisted sprayer application system by spray volume deposition and losses. Five treatments and four randomized blocks were used. The treatments varied the droplet size and application volume. The evaluation of the system was done with a 5% spray solution containing KCl being the leaves spray deposit measured through electric conductivity and the losses by the comparison among applied and recovered spray volumes on the leaves. For all of the conditions, the losses were above 48%, the conditions of larger volumes presented the largest depositions and larger droplets presented larger deposit and same loss in relation to smaller droplets. The smallest volumes did not differ regarding the deposition standing out the larger droplets to low volume conditions and the witness used by the winegrower (small droplets and low volume), that presented the smallest losses. The results demonstrate that the air-assisted sprayer is an important tool to maximize the pulverization operations in grape and the alterations of nozzles configuration should be better studied