Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey

OBJECTIVE: To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. METHODS: The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. RESULTS: All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. CONCLUSIONS: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.     

The Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Healthcare Workers with Pre-Existing Psychiatric Conditions

Psychiatric Quarterly - Both healthcare workers (HCWs) and psychiatric patients during the COVID-19 pandemic appear to have elevated prevalence of psychiatric symptoms, but little is known about...     

Suppression of ongoing experimental allergic encephalomyelitis in DA rats by novel peptide drug,structural part of human myelin basic protein 46–62

Previously, we demonstrated that autoantibodies (AAb) in multiple sclerosis (MS) reveal site-specific binding and cleavage toward myelin basic protein (MBP) epitope library. We have found several fragments of MBP immunodominant in terms of AAb binding. Here, we applied these peptides to DA rats with induced protracted relapsing experimental allergic encephalomyelitis (EAE) most closely related to MS. DA rats with EAE induced by syngenic spinal cord homogenate in complete Freund's adjuvant were treated by nasal route with human MBP 46–62, 81–102, 124–139, 147–170, and Copaxone®. MBP 124–139 and 147–170 displayed only mild therapeutic effects but MBP 46–62 significantly reduced EAE, reflected by lower clinical scores and shorter EAE duration compared to controls.     

Crohn''s Disease of the Colon

Retroperitoneal lumbocrural abscess occurred in 12 patients of 231 with Crohn's colitis or ileocolitis. Although all patients with this complication fell within the group of 175 ileocolitis patients, at least four originated in fistulous tracts of the colon. Eleven of the 12 abscesses developed spontaneously as the first major complication of the disease. The prominent clinical features included pain radiating down the thigh, hip joint flexion, difficulty in walking, hydronephrosis and hydroureter. Internal and external fistulas were significantly more common in the abscess group of 12 patients than in the 219 patients without retroperitoneal abscess. Radiological evidence of granulomatous disease was found in all patients; fistulous tract formation was characteristic and the development of extraperitoneal gas bubbles, in four patients, pathognomonic of abscess with gast-forming organisms. In the presence of established retroperitoneal abscess, the surgical sequence suggested is drainage synchronous with, or followed by diversion and ultimately definitive resection. Resection with anastomosis should not be carried out in the presence of an acute inflammatory process with frank abscess or free pus communicating with the peritoneal cavity. The spontaneous development of retroperitoneal abscess is a serious development in the natural history of Crohn's (ileo) colitis. It frequently heralds the first of a series of operative procedures to deal with the abscess. It sequels are enterocutaneous fistulas and further extension of the disease process.     

Self‐Adhesive Resin Cements—Part II

This is the second part of a two‐part piece on self‐adhesive resin cements; Part I was presented in the previous issue of the Journal. Here in Part II, the specific topics concerning self‐adhesive cements are clinical performance, post‐cementation sensitivity, and cementation of endodontic posts.