Nonclinical evaluation of immunological safety in Göttingen Minipigs: The CONFIRM initiative.

There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Göttingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates.

Safety profile of etifoxine: A French pharmacovigilance survey.

Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine-related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs.

Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions?

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia.

Decrease in factor V activity in patients treated with azathioprine or 6-mercaptopurine.

Background And Objective: A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care.

Imiquimod and pulmonary embolism: a case report.

Bilateral pulmonary embolism possibly related due to topically applied imiquimod is reported in a 47-year-old male patient with no evidence of risk factors.

Analytical findings of an acute intoxication after inhalation of methoxetamine.

Methoxetamine (MXE) is increasingly used and abused, as it is frequently presented as being safer than ketamine, and legal. Cases of only MXE consumption being associated with the occurrence of seizures are rarely reported. A single MXE intoxication case by inhalation is described concerning a 21-year-old man, not known to be epileptic, who was found collapsed in his bedroom, supposedly after an epileptic seizure.

Safety evaluation of a whey protein fraction containing a concentrated amount of naturally occurring TGF-β2.

TM0601p is a whey protein isolate derived from cow milk, containing a concentrated amount of transforming growth factor β2 (TGF-β2), and is intended for nutritional use in infants and adults. In vivo and in vitro studies have been performed to evaluate the safety of this product. In a 13-week toxicity study, treatment of adult Sprague-Dawley rats by gavage at up to 2000mg/kg/day did not result in any significant findings other than minor non-adverse changes in urinary parameters in females.

Effects of amlodipine and perindoprilate on the structure and function of mitochondria in ventricular cardiomyocytes during ischemia-reperfusion in the pig.

The aim of this study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochondria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were measured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindoprilate. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial permeability transition pores.

Protective effects of ranolazine and propranolol, alone or combined, on the structural and functional alterations of cardiomyocyte mitochondria in a pig model of ischemia/reperfusion.

Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion.

Immunotoxic effects of cyclophosphamide and cyclosporine in the dog.

Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily.

Translational immunologic safety evaluation: a perspective.

Although translational research is a rapidly evolving area of biomedical sciences, translational immunologic safety evaluation has so far attracted only very limited attention. Assays and animal models have been developed to identify immunotoxic hazards related to immunosuppression, but less attention has been paid to immunostimulation, hypersensitivity, and autoimmunity. Some of these assays and models are recommended by regulatory bodies, even though it is as yet unsure to what extent they can predict the potential of, or lack of, new chemical entities and drug candidates for inducing significant immunotoxic effects.

Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs.

Aims: The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs.

Methods: Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared.

Ivabradine but not propranolol delays the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial metabolic energy status.

Objective: Heart rate reduction (HRR) has shown a beneficial impact on the prevention of ventricular fibrillation, which could be explained by increased myocardial blood flow and preservation of mitochondrial structure. Here, we assessed the HRR impact on time to onset of ventricular fibrillation (TOVF) and myocardial metabolic energy status.

Methods And Results: An acute myocardial ischaemia was induced in pigs until ventricular fibrillation onset and TOVF was then measured.

Development of a Delayed-Type Hypersensitivity (DTH) Model in the Cynomolgus Monkey.

Although a T-dependent antibody response (TDAR) assay is generally recommended as the first-line immune function assay in nonclinical immunotoxicity evaluation, second-line assays such as delayed-type hypersensitivity (DTH) to measure cell-mediated responses can provide helpful additional information. In this study, male Cynomolgus monkeys were injected intramuscularly either once or twice with 1 mg Keyhole Limpet Hemocyanin (KLH) or twice with a commercially available tetanus vaccine (40 IU tetanus toxoid + 0.06 mg aluminum hydroxide).

Involvement of neuroleptic drugs in selenium deficiency and sudden death of cardiac origin: study and human post-mortem examination.

The involvement of psychotropic drugs in sudden deaths has been highlighted. The objective of this work was to establish a link between selenium levels in heart tissue, psychotropic treatment and sudden death. Selenium levels were measured by electrothermal atomic absorption spectroscopy post-mortem in heart, brain and liver.

Etifoxine-induced acute hepatitis: a case series.

Objective: Etifoxine is approved for the treatment of psychosomatic manifestations of anxiety. Several cases of acute hepatitis have been recently notified to the French pharmacovigilance centres. Our aim was to review all relevant cases of etifoxine hepatitis.

Sudden death of cardiac origin and psychotropic drugs.

Mortality rate is high in psychiatric patients versus general population. An important cause of this increased mortality is sudden cardiac death (SCD) as a major side-effect of psychotropic drugs. These SCDs generally result from arrhythmias occurring when the posology is high and may attain a toxic threshold but also at dosages within therapeutic range, in the presence of risk factors.

Safety immunopharmacology: evaluation of the adverse potential of pharmaceuticals on the immune system.

The ICH S6R1 and S8 guidelines define a general framework for the immunotoxicity evaluation of biotechnology-derived pharmaceuticals and human pharmaceuticals, respectively. As severe and unpredicted adverse events dramatically showed in the recent years that the immune system is a critical aspect of drug safety, this framework needs to be revisited to enhance the prediction of nonclinical immune safety evaluation. Safety immunopharmacology is deemed to contribute to this awaited improvement by enabling early screening of the potential for drug candidates to induce unexpected immunosuppressive and immunostimulatory effects as well as nonimmune-mediated hypersensitivity reactions.

Piribedil-induced sleep attacks in patients without Parkinson disease: a case series.

Background: Sleep attacks were initially described in 1999 in patients with Parkinson disease (PD) treated by dopamine agonists (DAs). Because the respective role of DAs or PD-induced excessive daytime sleepiness is still unclear, reports of sleep attacks in non-PD patients treated with DA would support the specific role of these drugs. Piribedil, a nonergot dopamine D2/D3 agonist with alpha(2)-noradrenergic properties, is indicated in the treatment of PD as well as in patients with circulatory disorders.

Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion.

Aims: We showed previously that ivabradine (IVA), a selective inhibitor of the cardiac pacemaker I(f) current, achieved protection against ischaemia-induced ventricular fibrillation (VF) in pigs by increasing the VF threshold (VFT). This was correlated to the heart rate reduction (HRR), the limitation of monophasic action potential shortening and the reduction of the hypoxic area. This study investigated myocyte ultrastructure and regional myocardial blood flow (RMBF), potentially involved in these cardioprotective effects of IVA.

5-Fluorouracil-induced Tako-Tsubo-like syndrome.

Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported.

Salbutamol misuse or abuse with fatal outcome: a case-report.

Salbutamol is a short-acting agonist of the β(2) adrenergic receptors sometimes misused or abused, which can result in various cardiovascular adverse effects. We report one case of fatal salbutamol misuse or abuse in a 36-year-old poorly controlled female asthmatic patient with a past medical history of alcoholism and a recent smoking cessation. She died shortly after hospital admission following acute dyspnea and sudden collapse at home.

Critical review of preclinical approaches to evaluate the potential of immunosuppressive drugs to influence human neoplasia.

Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models.