Porsolt and Partners Pharmacology

Sainte-Foy-lès-Lyon, France

Porsolt and Partners Pharmacology

Sainte-Foy-lès-Lyon, France
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Castagne V.,Porsolt and Partners Pharmacology | Moser P.,Porsolt and Partners Pharmacology | Roux S.,Porsolt and Partners Pharmacology | Porsolt R.D.,Porsolt and Partners Pharmacology
Current Protocols in Pharmacology | Year: 2010

The development of antidepressants requires simple rodent behavioral tests for initial screening before undertaking more complex preclinical tests and clinical evaluation. Presented in the unit are two widely used screening tests used for antidepressants, the forced swim (also termed behavioral despair) test in the rat and mouse, and the tail suspension test in the mouse. These tests have good predictive validity and allow rapid and economical detection of substances with potential antidepressant-like activity. The behavioral despair and the tail suspension tests are based on the same principle: measurement of the duration of immobility when rodents are exposed to an inescapable situation. The majority of clinically used antidepressants decrease the duration of immobility. Antidepressants also increase the latency to immobility, and this additional measure can increase the sensitivity of the behavioral despair test in the mouse for certain classes of antidepressant. Testing of new substances in the behavioral despair and tail suspension tests allows a simple assessment of their potential antidepressant activity by the measurement of their effect on immobility. Copyright © 2010 John Wiley & Sons, Inc.


Lynch J.J.,Abbott Laboratories | Shek E.W.,Abbott Laboratories | Castagne V.,Porsolt and Partners Pharmacology | Mittelstadt S.W.,Abbott Laboratories
Brain Research Bulletin | Year: 2010

The metabolic-related hormone, leptin has been suggested for clinical use as an anticonvulsant based upon data generated from in vitro and in vivo non-human studies. However, a number of other non-human experiments have demonstrated proconvulsant activity for leptin. The current study investigated potential pro- and anticonvulsant effects of leptin during exposure to either glutamate (the major endogenous excitatory neurotransmitter) or three subtype-selective glutamate receptor agonists (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kainate). Male C57BL/6JRj mice were pretreated with leptin (0.1-10. mg/kg, i.p.) and then administered doses of the glutamate receptor agonists (i.p.) that had been previously shown to result in clonic convulsions in approximately half of the animals tested. Leptin had no clear convulsant-related effects with either glutamate or AMPA, but it exhibited dose-related, proconvulsant activity (decreased latency to first occurrence of various convulsion-related signs, and increased percentage of animals exhibiting such signs) with both NMDA and kainate. The proconvulsant effects of leptin observed during the current study suggest that a cautious approach should be taken when administering leptin to individuals who may be prone to seizures. © 2010 Elsevier Inc.


Moser P.,Porsolt and Partners Pharmacology | Wolinsky T.,Porsolt and Partners Pharmacology | Castagne V.,Porsolt and Partners Pharmacology | Duxon M.,Porsolt and Partners Pharmacology
Journal of Pharmacological and Toxicological Methods | Year: 2011

Preclinical assessment of drug abuse and dependence has been the subject of several recent regulatory guidelines. Both the European and US authorities recommend a tiered approach and are generally aligned on the methods which should be used. The first tier simply compares the pharmacology of the novel substance to known drugs of abuse. The second tier aims to identify abuse and dependence liability more directly. The most direct approach to assessing reinforcing properties is the i.v. self-administration procedure. Unfortunately there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties or pharmacokinetics (PK). Indeed, the choice of training substance, species and procedural parameters can radically affect the outcome. Apart from the lower cost of the rat, the primate presents several advantages for self-administration studies (potentially greater similarity to humans in behavioral effects, active doses and PK). Although it does not measure abuse liability directly, drug discrimination is a powerful method for assessing the similarity of a test substance to a known drug of abuse. In this procedure an animal uses the interoceptive effects of the substance as the discriminative stimulus to determine which of two responses to make. For certain classes of substance, such as hallucinogens acting via the 5-HT 2A receptor, discrimination is the only procedure currently able to identify them. Drug dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, many factors (duration and frequency of drug treatment, dose/exposure levels, duration of observation after discontinuation) can complicate interpretation. Telemetry may represent a novel approach which allows continuous observation of somatic and behavioral parameters during drug withdrawal thereby increasing sensitivity. Presently available tools can identify essentially all substances known to cause abuse or dependence with little risk of false positives. It remains unclear how effective these models will be with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models remains very high. © 2010 Elsevier Inc.


Goineau S.,Porsolt and Partners Pharmacology | Rompion S.,Porsolt and Partners Pharmacology | Guillaume P.,Porsolt and Partners Pharmacology | Picard S.,Porsolt and Partners Pharmacology
Toxicology and Applied Pharmacology | Year: 2010

Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100mg/kg p.o.) or morphine (30mg/kg i.p.) under varying conditions (100% air versus 5% CO2-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations. © 2010 Elsevier Inc.


Kalk P.,Charité - 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.


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.


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.


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.


PubMed | Porsolt and Partners Pharmacology
Type: | Journal: Current protocols in pharmacology | Year: 2012

The vigilance-controlled quantified EEG can be used either as a safety, or as a discovery pharmacology procedure. Put strategically into the preclinical development process of a drug, it can be useful for making the decision about the future research direction to be taken. The experimental approach described in this unit is based on the rat EEG. Even though there are considerable differences in function and structure between human and rat brain, the EEG response to psychoactive drugs and convulsants is similar in the two species. Thus, the rat EEG is generally a reliable predictor for human CNS drug effects.


PubMed | Porsolt and Partners Pharmacology
Type: | Journal: Current protocols in pharmacology | Year: 2012

Abnormalities of cardiac rhythm are one of the most common clinical problems in cardiology and arise as the result of either disorders of cardiac impulse formation or conduction, or a combination of both. It has been established that some classes of drugs, such as tricyclic antidepressants (e.g., imipramine), cardiac glycosides (e.g., digoxin), and Class I or Class III antiarrhythmic drugs (e.g., quinidine or amiodarone) can produce electrocardiographic toxicity in humans. It is therefore highly advisable to assess the effect of any new compound in this respect, during the early phases of drug development. This unit presents a protocol to detect the electrocardiographic toxicity of compounds in the anesthetized guinea pig.

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