Cardiac lesions induced by neuroleptic drugs in the rabbit

Belhani, Dalila; Frassati, Dominique; Mégard, R.; Tsibiribi, Panayota; Bui‐Xuan, Bernard; Tabib, A.; Fanton, Laurent; Malicier, D.; Descotes, Jacques; Timour, Quadiri

doi:10.1016/j.etp.2005.09.003

Cited by 31 publications

(19 citation statements)

References 26 publications

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“…Inflammatory infiltrate, myocyte necrosis and coagulation necrosis have been observed in myocarditis (Kishimoto and Hiraoka, 1994). The histological lesions observed in the present study are the same as those previously described in rabbits treated with the combination levomepromazine + risperidone (Belhani et al, 2006) as well as those found at necropsy in several schizophrenic patients treated with levomepromazine that died suddenly (Frassati et al, 2004). However, no ventricular hypertrophy was observed in the present study: there was no statistically significant difference in the weight of hearts between control and treated animals.…”

Section: Discussionsupporting

confidence: 85%

“…Thus, Frassati et al (2004) suggested a causative role of neuroleptics in 13 of 14 psychiatric patients with sudden death. Indeed, dilated cardiomyopathy, left ventricle hypertrophy, mitral pro-risperidone (1 mg kg −1 once every other week) as this dose regimen closely mimics currently recommended treatment of human psychotic patients and was previously shown to induce marked histological changes in the heart of treated rabbits (Belhani et al, 2006). In addition, selenium tissue concentrations were measured in the heart, liver and kidneys of treated and control animals, and the hearts were examined histologically.…”

Section: Introductionmentioning

confidence: 99%

“…In a previous experimental study, myolysis, interstitial and endocardial fibrosis, leukocytic infiltrate and necrosis were observed in rabbits treated with neuroleptics for 90 days, and the combination levomepromazine + risperidone was found to be the most cardiotoxic treatment regimen (Belhani et al, 2006). Selenium deficiency has been demonstrated to play a role in various cardiovascular diseases (Nève, 1991(Nève, , 1996Peretz et al, 1991).…”

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confidence: 96%

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Role of selenium in heart lesions produced by neuroleptics in the rabbit

Vaillant

Turrel

Bost

et al. 2007

J of Applied Toxicology

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Organic and/or functional heart lesions sometimes resulting in sudden death have been described in psychiatric patients treated with neuroleptics. As selenium has been suggested previously to play a role in the development of such lesions, the present study was undertaken to determine whether a correlation could be found between heart lesions induced by neuroleptics and changes in blood selenium as well as myocardial tissue concentrations in the rabbit. Twelve NZW adult rabbits were treated intramuscularly with both levomepromazine (3 mg kg(-1) day(-1)) and risperidone (1 mg kg(-1) once every other week) for 3 months, and compared with 12 saline-treated controls. Blood samples were drawn before and at the end of the study. Tissue samples from the heart, liver and kidneys were obtained at the end of treatment, and the hearts were examined histologically. Heart lesions including disorganization of cardiac fibers, myolysis, interstitial and endocardial fibrosis, and necrosis were noted in treated animals, but not in controls. There was a 20% decrease in selenium blood levels and a 50% decrease in selenium myocardial tissue levels in treated animals compared with controls (P < 0.001). In contrast, no differences in selenium levels in liver and kidneys were found across the experimental groups. These results suggest a possible correlation between selenium depletion and neuroleptics-induced heart lesions.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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confidence: 96%

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Role of selenium in heart lesions produced by neuroleptics in the rabbit

Vaillant

Turrel

Bost

et al. 2007

J of Applied Toxicology

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“…We observed experimentally the development of myocarditis with a number of neuroleptics including amisulpride, haloperidol, levomepromazine, olanzapine, risperidone as well as combinations of levomepromazine and haloperidol or risperidone (Belhani et al, 2006). Indeed, global ventricular hypertrophy was found in rabbits treated with olanzapine and chiefly the combinations levomepromazine-haloperidol and levomepromazine–risperidone; necrosis with amisulpride and haloperidol; endocardial fibrosis with levomepromazine; but no marked lesions with risperidone.…”

Section: Mechanisms Involved In Sudden Deaths Of Cardiac Originmentioning

confidence: 99%

Sudden Death of Cardiac Origin and Psychotropic Drugs

Timour¹,

Frassati²,

Descotes³

et al. 2012

Front. Pharmacol.

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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. There are three kinds of risk factors: physiological (e.g., low cardiac rate of sportsmen), physiopathological (e.g., hepatic insufficiency, hypothyroidism) and “therapeutic” (due to interactions between psychotropic drugs and other medicines). Association of pharmacological agents may increase the likelihood of SCDs either by (i) a pharmacokinetic mechanism (e.g., increased torsadogenic potential of a psychotropic drug when its destruction and/or elimination are compromised) or (ii) a pharmacodynamical mechanism (e.g., mutual potentiation of proarrhythmic properties of two drugs). In addition, some psychotropic drugs may induce sudden death in cases of pre-existing congenital cardiopathies such as (i) congenital long QT syndrome, predisposing to torsade de pointes that eventually cause syncope and sudden death. (ii) A Brugada syndrome, that may directly cause ventricular fibrillation due to reduced sodium current through Nav1.5 channels. Moreover, psychotropic drugs may be a direct cause of cardiac lesions also leading to SCD. This is the case, for example, of phenothiazines responsible for ischemic coronaropathies and of clozapine that is involved in the occurrence of myocarditis. The aims of this work are to delineate: (i) the risk of SCD related to the use of psychotropic drugs; (ii) mechanisms involved in the occurrence of such SCD; (iii) preventive actions of psychotropic drugs side effects, on the basis of the knowledge of patient-specific risk factors, documented from clinical history, ionic balance, and ECG investigation by the psychiatrist.

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“…It was learned that his complaints of gingival swelling had appeared at least 10 years before beginning nifedipine medication at the age of 25, indicating that the present GO was induced not only by nifedipine, but also by a combination of some other previously prescribed drugs, including antipsychotic and/or other drugs for internal diseases (Table 1). It was reported that the drugs for mental diseases--such as haloperidol, levomepromazine, mianserin *possible association with pulmonary (21), cardiac (22) or gingival fibrosis (1,3,5,(17)(18) or biperiden--which were prescribed to the patient could cause cardiac or pulmonary fibrosis (Table 1) (21-22). However, the medication was not decreased or changed at all after consultation with his physician.…”

Section: Clinical Historymentioning

confidence: 99%

A case report of multiple-drug-induced gingival overgrowth with TIMP-3 over-expression

et al. 2008

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A case of multiple-drug-induced gingival overgrowth (GO) in a 46-year-old male is reported. The patient exhibited severe gingival enlargement throughout the entire mandible and maxilla with a history of multiple medications for psychiatric and internal diseases. A gingivectomy specimen was examined pathologically and further analyzed using immunohistochemical and molecular biological methods for the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Histologically, the gingival overgrowth was due to fibrous granulation tissue with hyperplastic collagen bundles and squamous epithelia, and the lesion was pathologically diagnosed as drug-induced gingival hyperplasia. An enhanced transcript level for TIMP-3 but reduced levels for MMPs and cathepsin L were quantitatively determined by RT-PCR. TIMP-3 was strongly immunohistochemically localized in fibroblasts and endothelial cells. DNA invader genotyping revealed that the patient carried one GO-related allele (α2 integrin +807C). These findings showed that, in this GO case, collagen accumulation in the gingival granulation tissue was associated with decreased MMPs and increased TIMP-3 expression, which was suggested to be synergistically induced by simultaneous and multiple medications, including nifedipine and antipsychotic drugs.

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Cardiac lesions induced by neuroleptic drugs in the rabbit

Cited by 31 publications

References 26 publications

Role of selenium in heart lesions produced by neuroleptics in the rabbit

Role of selenium in heart lesions produced by neuroleptics in the rabbit

Sudden Death of Cardiac Origin and Psychotropic Drugs

A case report of multiple-drug-induced gingival overgrowth with TIMP-3 over-expression

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