[Place and role of safety pharmacology in drug development]. / Place et rôle de la pharmacologie de sécurité dans le développement des médicaments.

SUMMARY: Safety pharmacology is a key regulatory step for drug development and approval. Prior to phase I, the effects of a drug candidate should be evaluated and characterized on vital functions (cardiovascular, respiratory and central nervous system) according to good laboratory practice standards. For cardiovascular evaluation, effects on blood pressure and electrocardiogram should be explored with a particular emphasis on ventricular repolarization prolongation, a major risk factor for life-threatening arrhythmias, like "torsades de pointe". Global behaviour, motor activity, reflexes and body temperature should be evaluated in animals. A dedicated study is necessary for respiratory function evaluation. All of these studies should be conducted after single administration of the compound administered by the anticipated clinical route. Dependence potential and abuse liability should be characterized for innovative drugs and/or drugs acting on the central nervous system. Evidence for adverse effects at discovery stage with high throughput systems is becoming a key step of decision-making process for pharmaceutical industry. Therefore, determination of the safety margin, risk/benefit ratio analysis and investigation of adverse effects are major decisional elements for providing safety reassurance to patients. Safety of patients will also be improved through modelling methodologies allowing a safer transposition of experimental pharmacology results to clinical pharmacology.

Nucleotides of tRNA governing the specificity of Escherichia coli methionyl-tRNA(fMet) formyltransferase.

In Escherichia coli, the free amino group of the aminoacyl moiety of methionyl-tRNA(fMet) is specifically modified by a transformylation reaction. To identify the nucleotides governing the recognition of the tRNA substrate by the formylase, initiator tRNA(fMet) was changed into an elongator tRNA with the help of an in vivo selection method. All the mutations isolated were in the tRNA acceptor arm, at positions 72 and 73. The major role of the acceptor arm was further established by the demonstration of the full formylability of a chimaeric tRNA(Met) containing the acceptor stem of tRNA(fMet) and the remaining of the structure of tRNA(mMet). In addition, more than 30 variants of the genes encoding tRNA(mMet) or tRNA(fMet) have been constructed, the corresponding mutant tRNA products purified and the parameters of the formylation reaction measured. tRNA(mMet) became formylatable by the only change of the G1.C72 base-pair into C1-A72. It was possible to render tRNA(mMet) as good a substrate as tRNA(fMet) for the formylase by the introduction of a limited number of additional changes in the acceptor stem. In conclusion, A73, G2.C71, C3.G70 and G4.C69 are positive determinants for the specific processing of methionyl-tRNA(fMet) by the formylase while the occurrence of a G.C or C.G base-pair between positions 1 and 72 acts as a major negative determinant. This pattern appears to account fully for the specificity of the formylase and the lack of formylation of any aminoacylated tRNA, excepting the methionyl-tRNA(fMet).

Cellular pharmacology of potassium channel openers in vascular smooth muscle.

Potassium channel opening is a physiological mechanism which excitable cells exploit to maintain or restore their resting state. Thus drugs that open vascular potassium channels have the potential to restrain or prevent contractile responses to excitatory stimuli or clamp the vessel in a relaxed condition. Hence, potassium channel openers, such as aprikalim and levcromakalim, relax agonist precontracted vascular preparations in vitro and lower systemic and regional vascular resistances in intact animals. Glibenclamide, a blocker of ATP sensitive potassium (KATP) channels, antagonises these effects. The main vasorelaxant mechanism of the potassium channel openers is to increase the potassium efflux through opening plasmalemmal potassium channels, which repolarises and/or hyperpolarises the membrane. This effect lowers the opening probability of voltage dependent calcium channels, restrains agonist induced calcium release from intracellular sources through inhibition of inositol trisphosphate formation, decreases the sensitivity of intracellular contractile elements to calcium, and accelerates the clearance of intracellular calcium via the Na+/Ca+ exchanger. Experimental evidence indicates that mechanisms not linked to potassium channel opening may also contribute to the potassium channel opener induced vasorelaxation; these remain to be clearly defined (for example, inhibition of the refilling of intracellular calcium stores). Potassium channel openers displace the binding of 3H-P1075, a potent potassium channel opener, in myocytes and intact rings from the rat aorta. In patches from vascular myocytes, potassium channel openers primarily open a small conductance (10-20 pS) KATP channel which is gated by [ATP]i and particularly by nucleotide diphosphates and magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a cytotoxic T-lymphocyte alveolitis in human immunodeficiency virus-infected patients.

A T8 lymphocyte alveolitis occurs in HIV-positive patients, even in the absence of any lung infections or tumors. Using the monoclonal antibody (MAb) D44, the CD8+ T cells can be further subdivided into two functional subsets of cytotoxic T lymphocytes (CTL; CD8+, D44+) and suppressor T cells (CD8+, D44-). A dual fluorescence analysis of alveolar and peripheral lymphocytes has been used in HIV-positive patients without lung infections or tumors to reveal a dramatic increase in alveolar T8 lymphocytes (83%), compared to peripheral values (52%), which was mainly composed (89%) of CD8+ D44+ CTLs. Functional studies confirmed the cytolytic activity of these phenotypically defined alveolar CTLs on autologous alveolar macrophages used as target cells, excluding a natural killer-like activity. An immuno-enzyme analysis concomitantly revealed the co-expression of the p18 HIV antigen and the CD4 molecule on the autologous alveolar macrophages. These data suggest that CTL alveolitis occurs during HIV infection and is directed against HIV-infected alveolar macrophages which are presumably the targets of the locally recruited lung CTLs.

Molecular recognition governing the initiation of translation in Escherichia coli. A review.

Selection of the proper start codon for the synthesis of a polypeptide by the Escherichia coli translation initiation apparatus involves several macromolecular components. These macromolecules interact in a specific and concerted manner to yield the translation initiation complex. This review focuses on recent data concerning the properties of the initiator tRNA and of enzymes and factors involved in the translation initiation process. The three initiation factors, as well as methionyl-tRNA synthetase and methionyl-tRNA(f)Met formyltransferase are described. In addition, the tRNA recognition properties of EF-Tu and peptidyl-tRNA hydrolase are considered. Finally, peptide deformylase and methionine aminopeptidase, which catalyze the amino terminal maturation of nascent polypeptides, can also be associated to the translation initiation process.

Extensive T8-positive lymphocytic visceral infiltration in a homosexual man.

Lymphocytic visceral infiltration has recently been noted in association with lymphadenopathy-associated virus infection. A homosexual man, who had clinical and immunologic features of the acquired immune deficiency syndrome (AIDS)-related complex, is described. The patient presented not only with peripheral blood lymphocytosis but also with extensive lymphocytic infiltration involving lungs, lymph nodes, nerves, muscles, and esophagus. Lymphocyte subset immunostaining analysis showed that the lymphocytes were T8-positive. Thirty months after the clinical onset of the disease, no evidence of progression to AIDS was seen. Moreover, clinical improvement was observed, even though the patient did not receive long-term treatment. The clinical history of this patient suggests that lung T8-positive lymphocytic infiltration is associated with an increased risk of infectious episodes such as pneumonia and bronchitis.

Long-term results of monthly inhaled pentamidine as primary prophylaxis of Pneumocystis carinii pneumonia in HIV-infected patients.

PURPOSE: To evaluate the long-term efficacy and safety of inhaled pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus (HIV). PATIENTS: Two hundred thirty-two HIV-infected patients with a CD4 cell count below 20% of the total lymphocyte count were given aerosolized pentamidine once every 4 weeks for more than 3 months. Pentamidine aerosols were administered at the hospital under medical supervision. Prevention of bronchospasm was carried out using inhaled salbutamol. RESULTS: Mean duration of prophylaxis was 15.9 months. Eleven patients (4.7%; [95% confidence interval 2% to 7.4%]) developed PCP. Probability to remain free of PCP is 95.6% at 12 months, 94% at 18 months, and 88% at 24 months. Mean delay between the onset of the prophylaxis and the occurrence of PCP for the 11 patients was 12.9 months (range: 4 to 26 months). No major side effect was observed, and minor side effects (cough, acute dyspnea) were infrequent. CONCLUSION: The efficacy and tolerance of aerosolized pentamidine as shown in our study support its use as primary prophylaxis against P. carinii in HIV-infected patients.

Technetium-99m-DTPA aerosol and gallium-67 scanning in pulmonary complications of human immunodeficiency virus infection.

We retrospectively compared the results of 67Ga chest scans and 99mTc-DTPA aerosol clearance measurements with those of fiberoptic bronchoscopy in 88 patients infected with the human immunodeficiency virus. Of 100 investigations, a pulmonary infection was diagnosed in 39, mainly Pneumocystis carinii pneumonia and a noninfectious disorder was found in 42, mainly Kaposi's sarcoma and lymphocytic alveolitis. Gallium scans and DTPA clearance were abnormal respectively in 74% and 92% of infectious complications, and in 12% and 60% of noninfectious disorders. In 10 cases, DTPA clearance was accelerated, while chest x-ray, arterial blood gases and even gallium scanning were normal. A value of DTPA clearance greater than 4.5%.min-1 was both sensitive and specific for the diagnosis of Pneumocystis carinii pneumonia. The gallium scan was always normal in bronchopulmonary Kaposi's sarcoma. We conclude that in symptomatic patients: (1) DTPA clearance measurements are useful for detecting lung disease when chest x-ray and/or PaO2 are normal and (2) a gallium scan is indicated to distinguish progressive Kaposi's sarcoma from a superimposed second process when radiological abnormalities of pulmonary Kaposi's sarcoma are present.

Human immunodeficiency virus-related lymphocytic alveolitis.

We observed 276 HIV-infected patients to determine the frequency, degree, and clinical presentation of the lymphocytic alveolitis in different stages of HIV disease, and also to identify the lymphocyte subsets involved. In 154 patients with proved lung infections or tumors (group A), bronchoalveolar lavage fluid showed lymphocytosis in 78 percent of cases. In 122 subjects (31 AIDS and 91 HIV-infected non-AIDS patients) without evidence of lung tumor or infection (group B), lymphocytic alveolitis was seen in 72 percent of cases. In 61 of 88 (69 percent) group B lymphocytic patients, we observed respiratory symptoms or diffuse interstitial opacities; however, we also observed such alveolitis in 27 of 46 (59 percent) group B patients free of respiratory symptoms and abnormality of chest x-ray film. This alveolitis was seen not only in AIDS or ARC patients but also at earlier stages of HIV infection. T-lymphocyte analysis showed a large majority (40 to 93 percent) of CD8 positive lymphocytes in the 37 patients tested. A dual fluorescence analysis revealed, in 18 subjects, that those cells were phenotypically cytotoxic (CD8 + D44 +). These findings suggest that, regardless of HIV-infection stages and of opportunistic lung infections, a CD8-positive T-lymphocyte alveolitis may be present in HIV-infected patients and could be responsible for cough, dyspnea, interstitial pneumonitis, and abnormalities of pulmonary function tests.

Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans?

The cardiac action potential results from a dynamic balance between inward depolarising Na+ and Ca2+ currents and outward K+ repolarising currents. During a cardiac cycle, the resultant of repolarisation phase from all ventricular cells is represented by the QT interval of the surface ECG. Congenital long QT syndrome (LQTS) is characterised by polymorphic ventricular tachycardia sometimes with twisting QRS morphology (torsade de pointes) which, although usually self-limiting, can result in sudden cardiac death. Acquired LQTS can be induced by a variety of drugs, including some nonsedative histamine H1 receptor antagonists (astemizole, terfenadine). The Committee for Proprietary Medicinal Products of the European Union has recently proposed studying the action potential in in vitro heart preparations as a preclinical test for predicting the propensity of noncardiovascular drugs to induce malignant QT prolongation in humans. The effects of several histamine H1 receptor antagonists on the electrically evoked action potential have been evaluated in rabbit Purkinje fibres. In this preparation, astemizole (0.3 to 10 micromol/L) prolongs the duration of the action potential measured at the level where repolarisation is 90% complete (APD90). This effect is dependent on drug concentration, incubation time, pacing frequency and K+ or Mg2+ concentration. Astemizole also markedly depresses the rate of rise of the action potential (Vmax). Terfenadine showed qualitatively similar, but quantitatively smaller, effects in this model. The histamine H1 receptor antagonists cetirizine, ebastine, carebastine, loratadine and fexofenadine do not significantly affect APD90 at 1 micromol/L, but cetirizine and carebastine prolong it slightly at 10 micromol/L. In conclusion, in rabbit Purkinje fibres, astemizole and terfenadine produce adverse electrophysiological effects at concentrations which may be achieved in the human myocardium in certain clinical situations. APD90 lengthening induced by carebastine and cetirizine is minor and occurs at concentrations that are very unlikely to be encountered clinically, since these drugs, in contrast to astemizole and terfenadine, do not accumulate in the myocardium. Direct extrapolation of preclinical results to humans requires great caution, since malignant QT prolongations by terfenadine and astemizole are extremely rare clinical events. However, since prolongation of the QT interval often precedes the development of torsade de pointes, any significant delay in cardiac repolarisation produced by noncardiovascular drugs in preclinical, and particularly in clinical, studies should, in general, be considered to indicate a potential cardiac risk in humans. Its significance should subsequently be evaluated in appropriate studies in patients with conditions known to predispose to arrhythmias.

Lack of effect of atrial natriuretic factor on the tone induced in rat portal vein by platelet-activating factor.

The spontaneous myogenic activity of the isolated rat portal vein was inhibited by atrial natriuretic factor or by sodium nitroprusside. These compounds were not effective on the tone induced by PAF-acether or carbachol. 8-Bromo cyclic GMP and dibutyryl cyclic AMP inhibited myogenic activity and reduced the agonist-induced contractions. Only dibutyryl-cyclic AMP significantly inhibited the PAF-acether-induced contractile responses. These results indicate that the tone induced by PAF-acether can be used to discriminate between drugs which selectively increase cyclic nucleotide levels.

Different regulation of vascular tone by angiotensin II and endothelin-1 in rat aorta.

The effects of moderate cooling and of phenylarsine oxide on the contraction induced by two vasoactive peptides, angiotensin II (AII) and endothelin (ET-1), were investigated on endothelium-free rings of rat aortas. At 37 degrees C, the contraction induced by AII (0.1 microM) was transient. This decline in tension is unlikely to be due to rapid degradation of AII. In contrast, ET-1 (10 nM) induced a slowly developing and sustained contraction similar to the one observed with phorbol 12-13 dibutyrate (PDB, 22 nM). Moderate cooling (25 degrees C) significantly potentiated and prolonged the effect of AII but reduced the velocity of the ET-1 and PDB contraction, although the rate of the phenylephrine (1 microM) response remained unchanged. Phenylarsine oxide (100 microM) reduced the decline in tension in response to AII but inhibited the contraction elicited by ET-1 and PDB. In rings incubated in calcium-free medium (37 degrees C), AII induced a phasic contraction. This was followed by a second phasic contraction after calcium (2.5 mM) had been restored to the bath. The intensity of this second contraction decreased as the time between AII and calcium injection increased. This method, using regression analysis, permitted us to determine the time taken to reduce the contraction by half (4.8 min; r: 0.96), which may reflect the half-time of receptor sequestration. In calcium-free medium, the contractions induced by ET-1 and PDB were slow and sustained. Thus, rapid AII-receptor internalization leads to a short-term regulation of vascular tone whereas activation of protein kinase C by ET-1 may induce a long-term regulation.

Endothelium independent protective effect of NG-monomethyl-L-arginine on endotoxin-induced alterations of vascular reactivity.

The effects of NG-monomethyl-L-arginine (NMMA), a specific inhibitor of nitric oxide (NO) synthesis was tested on the endotoxin-induced alterations of alpha-adrenoceptor function. In isolated aorta, there was no significant difference in the tension induced by phenylephrine (PE, 10 microM) on rings removed from control and endotoxin injected rats (10 mg/kg, ip). However, a lack of tonicity of the contraction was observed in rings of shocked rats (8 +/- 2.9 and 86 +/- 4.6% relaxation at 105 min for sham and shocked rings respectively). The gradual tension decrease to PE was more potent in rings possessing endothelial cells. However, in both preparations, the loss of tonicity was significantly inhibited by NMMA (30 microM). In endothelium-free rings, L-arginine (100 microM) potentiated the loss of tonicity to PE and reversed the inhibitory effect of NMMA. NMMA, like methylene blue, was also able to restore the PE-contraction. The results indicate that the endotoxin-induced alterations of vascular reactivity may be due, in part, to NO formation from L-arginine independent of the endothelium.

Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias.

Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na+, K+ and Ca2+) entering and leaving the cytosol mainly via transmembrane channels. Na+ and Ca2+ carry inward depolarising currents (INa, ICa) whereas K+ carries outward repolarising currents (Ito, IKr, IKS and IK1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as IKr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index > 30, calculated as ratio of IC50 against IKr over ED50 determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.

In vivo and in vitro effects of cicletanine in spontaneously hypertensive rats.

Oral treatment for 2 weeks with cicletanine [1,3-dihydro-6-methyl-7-hydroxy-3-(4-chloro-phenyl)furo(3,4-c)pyridine] at 30 mg/kg/day delayed the onset of hypertension in spontaneously hypertensive rats (SHR) (15.7 mmHg, p less than 0.001). This antihypertensive effect was increased when the animals were maintained on a high-salt diet (40.8 mmHg, p less than 0.001). The ability of cicletanine to alter calcium movements in phenylephrine (PE)- and angiotensin II (ANGIO)-triggered contraction was tested on isolated SHR aorta. PE (1 microM) and ANGIO (0.1 microM) induced a phasic contraction in calcium-free medium due to intracellular calcium release. Upon addition of calcium (2.5 mM) a second sustained (PE) or biphasis (ANGIO) contraction was observed. This second contraction was dependent on extracellular calcium influx. Cicletanine (0.1-0.3 mM) both reduced the phasic (77%, p less than 0.001 for PE; 68%, p less than 0.05 for ANGIO with cicletanine 0.3 mM) and the second contraction elicited by the two agonists (27%, p less than 0.001 for PE; 84%, p less than 0.001 for ANGIO with cicletanine 0.3 mM). These results suggest that in addition to its stimulatory effect on prostaglandin, a direct vascular action of cicletanine could also be involved in the antihypertensive properties of the drug.

In vitro cardiovascular antihistamine properties of cicletanine in comparison with diphenhydramine.

Cicletanine (CIC) (pA2: 7.0) was found to be as potent as diphenhydramine (DIPH) (pA2: 7.2) in competitively inhibiting histamine-induced contraction of isolated rabbit aorta. Both CIC (pA2: 7.3) and DIPH (pA2: 7.5) similarly shifted histamine-induced endothelium-dependent relaxation of isolated rat aorta to the right. The similarity of results (in terms of pA2 values) indicates that in spite of their opposite responses on vascular tone, the H1 receptors on rabbit and rat aortae may be similar. DIPH was found to be as potent as cocaine in potentiating the chronotropic action of noradrenaline on isolated right atria, whereas CIC was without effect. The ability of DIPH to inhibit the noradrenaline uptake at the neuronal membrane seems to be independent of its H1-receptor antagonism potency. Finally, the furopyridine framework of CIC does not elicit the cocaine-like activity of the oxyethylamine residue of DIPH.

[Effect of cicletanine on a sudden death model in dogs]. / Effet du ciclétanine sur un modèle de mort subite chez le chien.

Cicletanine is a new antihypertensive agent. In view of its various pharmacological properties and of the different factors involved in sudden death, cicletanine was tested on an ischaemia-reperfusion model in anaesthesized dogs. In these experiments myocardial reperfusion induced ventricular fibrillation in 87 p. 100 of the cases, where as only 20% of those animals who received cicletanine 20 mg/kg intravenously 15 minutes before the 30 minute coronary occlusion developed ventricular disorders (p less than 0.001 vs controls). Moreover, cicletanine showed good antiarrhythmic activity during occlusion (total number of arrhythmias: 73.0 +/- 23.15 in treated animals, as against 293.4 +/- 40.03 in controls; p less than 0.05). Thus, antihypertensive treatment with cicletanine may prevent some of the cardiovascular risks associated with arterial hypertension.

[Effect of cicletanine on arrhythmia and intracellular sodium accumulation in the isolated rat heart during ischemia and reperfusion]. / Effet du ciclétanine sur les arythmies et l'accumulation intracellulaire du sodium du coeur isolé de rat au cours de l'ischémié et de la reperfusion.

The antiarrhythmic effects of cicletanine (CIC), a new antihypertensive drug, were studied on isolated hearts from SHR and WKY rats subjected to global normothermic ischaemia. The effects of CIC on variations in intracellular sodium concentration induced by ischaemia-reperfusion were measured. After a 14-day treatment with CIC in doses of 30 and 100 mg/kg/day, the results were as follows: in WKY rats the incidence of ventricular fibrillation (VF) was reduced from 91% in controls to 41% and 50% (p less than 0.05) and the incidence of ventricular tachycardia (VT) was reduced from 100% to 41% and 58% (p less than 0.05). In SHR rats the percentages of VF were 100% in controls and 17% (p less than 0.001) and 33% (p less than 0.01) respectively in treated animals. Similarly, the incidence of VT was reduced from 100% to 17% (p less than 0.001) and 25% (p less than 0.001) respectively. The effects of CIC were more pronounced on SHR rats than on WKY rats. CIC reduced the intracellular sodium accumulation induced by ischaemia and reperfusion. The antiarrhythmic activity of CIC seems to be correlated with its inhibitory activity on intracellular sodium accumulation.

[Interaction between angiotensin II and endothelin isoforms in the pithed rat]. / Interaction entre l'angiotensine II et les isoformes de l'endothéline chez le rat démédullé.

The 3 isoforms of endothelin (ET) (potent peptidic vasoconstrictor isolated from endothelial cells) induce biphasic pressor effects when given intravenously: a transient hypotension followed by a long-lasting hypertension. The aim of this work was to study the regulatory effect of vascular tone on ET-induced pressor responses in the pithed rat. After pithing, diastolic blood pressure (DBP) was elevated by continuous perfusion of angiotensin-II (AII) or methoxamine (MTX). When DBP was stabilized ET's isoforms (ET-1, ET-2, ET-3) were injected (1 nmol/kg). Solvent injection permitted to assess the stability of AII or MTX perfusions. Intravenous injections of ET induced a sharp hypotension which is more pronounced when initial DBP increased whatever the vasoactive substance used to elevate DBP. The maximal effects of each ET was identical but the hypotension is longer for ET-3 than for ET-1 and ET-2. The following hypertensive phase diminished when DBP increased but is strongly blunted in AII-supported rats when compared to MTX-supported rats. Furthermore, ET-3 appeared to be devoided of hypertensive effect in AII-supported pithed rats. These results indicate that AII is able to modulate ET-induced pressor response, whereas the initial hypotensive phase is only dependent of vascular tone.

[Effects of Ginkgo biloba extract on 2 models of experimental myocardial ischemia]. / Effets de l'extrait de Ginkgo biloba sur deux modèles d'ischémie myocardique expérimentale.

Ginkgo biloba extract, a free radical scavenger containing kaempferol and quercetin esters, which are potent radical scavengers, was studied on various models of cardiac ischaemia, both in vitro and in vivo. On the two in vitro models of ischaemia-reperfusion described (rat and guinea-pig hearts) Ginkgo biloba extract was without effect on cardiac functional parameters. However, it induced a significant decrease in the intensity of ventricular fibrillation during the reperfusion stage. On normal or hypertrophied heart in vivo, Ginkgo biloba extract provided effective protection against the electrocardiographic disorders induced by ischaemia. On the different models of global or localized ischaemia (followed or not by reperfusion), a decrease of arrhythmia without change in cardiovascular parameters was regularly noted.