ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis.

Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor ziritaxestat failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162 and NCT03733444), two identically designed phase III studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).

Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.

Design, Setting, And Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries).

Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships.

A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease.

Purpose: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED).

Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response.

Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin-2 (IL-2) signaling in a population of T cells during an immune response by combining in silico modeling and single-cell measurements in vitro. We demonstrate that IL-2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL-2 signaling within the population.

[ST elevation in the initial phase of myocardial infarct--a sequela of acute coronary occlusion of an expression of neurohumorally-induced metabolic processes?].

The artificial coronary artery occlusion results immediately in ST-segment elevation (ST-E), therefore the ST-E in acute myocardial infarction is considered to be the result of acute coronary occlusion. But in the early phase of myocardial infarction a significant correlation between ST-E and occlusion of the coronary artery does not exist. The early ST-E seems to be predominantly the consequence of sympathico-adrenergic induced metabolic processes in the ischemic myocardium.

[Destroying of antigenicity and influencing the immunochemical reactivity of hepatitis B virus antigens (HBsAg, HBcAg and HBeAg) through disinfectants--a proposed method for testing (author's transl)].

So far, hepatitis B virus cannot be grown in tissue cultures. Consequently, the inactivating effect of disinfectants upon the infectivity of hepatitis B virus could only be insufficiently investigated. Investigations using the only suitable test animal, the chimpanzee, are associated with substantial efforts and high cost and are also limited in their extent.

[Beta-receptor blockader therapy in the acute stage of myocardial infarct pathophysiological basis].

The causal connection between the coronary occlusion and the necrosis of the myocardium, as it is verified again and again, is not unequivocal. The favourable effects of the beta-receptorblockers in the acute phase of the infarction of the height of the ST-elevations, the later levels of the CPK and the prognosis of the patients plead for the essential causal importance of the catecholamines in the infarctional process. The catecholamines have an effect on the myocardium increasing the contraction and dissipating oxygen.

[beta-Receptor blockers in the early stage of myocardial infarction with left ventricular failure (author's transl)].

In infarct-induced acute left ventricular failure, beta-receptor blockers are considered to be contraindicated. On the assumption that in left ventricular pumping failure in the early stages of the infarction there is a state of functional hypercontractility of the myocardium, we accordingly treated infarction in its early stage with the beta-blocker talinolol (Cordanum). Digitalis glycosides were not used in the acute phase.

[Significance of clinical and functional diagnostic findings for the physical rehabilitation ability of the patients with heart infarct].

In 75 patients with condition after myocardial infarction or chronic ischaemic heart disease, respectively, was tested to what extent from clinical and functional-diagnostic findings prognostic estimations concerning the regaining of a cardiocirculatory functional capacity corresponding to age are possible by a complex rehabilitation programme. A daily ergometer training lasting eight weeks which was individually dosed was in the centre of rehabilitation. It was shown that from the findings of ergometry with permanent ECG-registration the effect of rehabilitation, as a rule, can be predicted.

Sporadic bovine meningo-encephalitis-isolation of a paramyxovirus.

Isolation of a viral agent (107) directly from brain explants of a 15-month-old heifer with symptoms of a sporadic encephalomyelitis is described. The virus shares properties with the paramyxovirus family. It grows in a variety of cell cultures from different species, and induces nuclear and cytoplasmic inclusion bodies in infected cells.