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Le Genest Saint Isle, France

Picard S.,University of Caen Lower Normandy | Goineau S.,Porsolt and Partners Pharmacology | Guillaume P.,Porsolt and Partners Pharmacology | Henry J.,University of Caen Lower Normandy | And 2 more authors.
Cardiovascular Toxicology | Year: 2011

Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core battery mandatory studies. This critical review aims at discussing the usefulness, relevance, advantages, and limitations of some preclinical in vivo, in vitro, and in silico models, with high predictive values and currently used in supplemental safety studies. © 2011 Springer Science+Business Media, LLC. Source

Kalk P.,Charite - Medical University of Berlin | Kalk P.,Institute of Pharmacology | Sharkovska Y.,Institute of Pharmacology | Sharkovska Y.,University of Potsdam | And 16 more authors.
Hypertension | Year: 2011

Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by ≤46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media:lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-β1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-β1 expression. Copyright © 2011 American Heart Association. All rights reserved. Source

Porsolt R.D.,Porsolt and Partners Pharmacology | Moser P.C.,Porsolt and Partners Pharmacology | Castagne V.,Porsolt and Partners Pharmacology
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-D-aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/ memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics. Source

Tricot S.,CNRS Sea, Molecules and Health | Mimouni V.,CNRS Sea, Molecules and Health | Rompion S.,Porsolt and Partners Pharmacology | Froger C.,Porsolt and Partners Pharmacology | And 3 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2010

In this study, we investigated the effect of a high n-3 fatty acid diet (eicosapentaenoic and docosahexaenoic acids) in Zucker obese and lean rats on blood pressure in association with physiological parameters, serum biochemistry and oxidative stress analysis. After 150 days of treatment, dietary fish oil supplementation in Zucker obese rats (9 months of age) reduces bodyweight gain and serum triglyceridemia and nitrite levels, increases serum glucose and angiotensin converting enzyme activity, but does not alter blood pressure, cholesterol levels and serum markers of oxidative stress (malondialdehyde, glutathione), compared to the Zucker rats fed control diet. According to these results, we can consider that after 150 days of treatment, fish oil is not enough to regulate parameters involved in the metabolic syndrome, such as cholesterolemia and blood pressure, in a 9 month-old genetically type-2 diabetes rat. © 2010 Elsevier Ltd. Source

Moser P.,Porsolt and Partners Pharmacology | Wolinsky T.,Porsolt and Partners Pharmacology | Duxon M.,Porsolt and Partners Pharmacology | Porsolt R.D.,Porsolt and Partners Pharmacology
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Nonclinical assessment of drug abuse and dependence is the subject of several recent regulatory guidelines, which are generally aligned on the methods to be employed. The most direct approach to assessing reinforcing properties of a drug is the self-administration procedure whereby animals can initiate intravenous injections of the test substance, something they readily do with prototypic drugs of abuse. Complications arise because there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties, or pharmacokinetics. Moreover, the choice of training substance, species, and procedural parameters can radically affect the outcome. Apart from the lower cost of rats, primates present several advantages for self-administration studies with similarity to human pharmacokinetics in particular. The most powerful method for assessing similarities between a test substance and a prototypic drug of abuse is the drug discrimination procedure. In contrast to self-administration, drug discrimination is pharmacologically very specific, often reflecting functional activity at receptor level. Dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, interpretation can be complicated by factors such as duration and frequency of administration and observations as well as the choice of end points. Telemetry allows continuous observation of multiple parameters during withdrawal, thereby increasing sensitivity. Presently available tools identify all substances known to cause abuse or dependence, with little risk of false-positives. It remains unclear, however, how predictive these models are with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models is remarkably high. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. Source

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