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Vol. 39, No. 3, 2013 July September Original Paper
Antipsychotic Drugs And Salivary Leptin Levels
In Wistar Rats
RISTINA DUMITRESCU , CATALINA PISOSCHI , A. CAMEN 1Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova 2Department of Biochemistry, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova 3Department of Oral and Maxillo-Facial Surgery, Faculty of Dentistry, University of Medicine and ABSTRACT: Purpose. Mental dissorders such as psychosis, agitation, mania, dementia and bipolar disorder are
treated with variable doses of antipsychotics. However, these drugs are often associated with metabolic side effects
(weight gain), endocrine disruptions, diabetes mellitus and cardiovascular diseases.Unfortunately, a single reliable
predictor of weight gain has not been found, but a relation is to be mentioned between the levels of circulating leptin,
administration of antipsychotics and weight increase. The aim of this study was to assess the effects of exposure to
antipsychotics from both generations on the salivary leptin levels. Material and Methods. Salivary leptin was
determined by the ELISA technique, on three groups of male Wistar rats treated with haloperidole, haloperidole
decanoate and aripiprazole for 4 weeks.Results. The present study evidences a significant statistical difference
between the values of salivary leptin prior to and after the drug treatment with the first generation agents. Aripiprazole
produced no changes. Conclusions. The treatment with haloperidole and haloperidole decanoate induces an
increase in salivary leptin levels.
KEYWORDS antipsychotics, rats, salivary leptin, weight gain
The purpose of this study was to evidence Introduction
changes of salivary leptin levels during Since the introduction of chlorpromazine in the early 1950s, a large number of antipsychotics (neuroleptics) have been Material and Methods
discovered. In recent years the so-called atypical The study was done according with Directive neuroleptic drugs have also become available. [1]. The increasing use of atypical (second generation) antipsychotics has led to a greater Commitee from The University of Medicine and appreciation of not only the benefits of these drugs, but also of the spectrum of toxicity that 21 adult male Wistar rats were divided into three groups of seven (weight 225-240 g, age Typical drugs still play an important role in 70-80 days). For the 28 days period of the the treatment of psychotic disorders and offer a experiment, their weight was recorded a jeun, valid alternative to atypicals where atypicals are between 9.00 and 10.00 am for an adequate poorly tolerated. The essential difference dosing of the substances. All medications were between the two groups is the size of the therapeutic index in relation to extrapyramidal However, most second-generation - haloperidole (animals labeled from H1 to H7); antipsychotics, and to a lesser degree first- - haloperidole decanoate (animals labeled from generation antipsychotics, can produce adverse effects (such as substantial drug-induced weight - aripiprazole (animals labeled from A1 to A7); gain) that are a major factor in promoting poor Each animal had a unique record file and adherence to, and even discontinuation of, antipsychotic treatment on the one hand, and increasing the risk of metabolic syndrome and cardiovascular disease on the other [5-8]. technique, applied in humans, for collecting the These adverse effects could be explained by gingival crevicular fluid, as adapted for saliva a possible impact of antipsychotic drugs on collecting [9], for 30 sec, saliva was collected on peptide hormonal regulators of metabolic filter paper strips introduced in the oral cavity of control – leptin, ghrelin and adiponectin. the animal. Collecting was done prior to Maria Bogdan et al. - Antipsychotic Drugs and Salivary Leptin Levels in Winstar Rats beginning of drug administration, as well as 24 Discussion
hours after the last administration. The absorbed liquid was dilluted in 100μl phosphate-buffered possible, prevention, of major adverse effects of saline (PBS), the obtained samples being frozen antipsychotics and some other drugs used to treat mental illness is a topic of much debate, because a wide range of side effects may be encountered, especially the metabolic syndrome. Sandwich technique for biological assays of In 2001, Groschl identified salivary leptine in rodents, according to the indications of the healthy patients and the molecular form in manufacturer. The results were expressed in which it is excreted in the saliva [10]. ng/ml. Statistical analysis of the obtained results was based on average value±SD (standard circulating leptin during the administration of deviation) and the Mann-Withney U-test, the antipsychotic drugs, when increased values were correlations for p<0.05 being considered observed [11], and other investigations have shown correlations between the values of seric leptin and the weight increase in patients suffering from schizophrenia, subjected to Salivary leptin levels prior to the initiation of the treatment ranged between 0,1-0,4 ng/ml antipsychotics [12, 13]. Also under study, beside leptin, were other hormones present in the serum haloperidole; 0,21ng/ml for haloperidole (ghrelin, adiponectin, resistin), known as impacting the energetical balance through aripiprazole). In the end of the treatment, salivary leptin registered values between 0,2- Salivary leptin was determined in different 0,9ng/ml (0,54ng/ml) for the group treated with pathological situations, sometimes representing haloperidole, 0,2-0,6ng/ml (0,38ng/ml) for the a better alternative than determination of the one treated with haloperidole decanoate, and circulating leptin, because the method of leptin 0,1ng/ml -0,2ng/ml for aripiprazole group, collecting and determination in blood (plasma or serum) is quite difficult for the investigator and uncomfortable for the pacient, the risk of failure Table 1. Salivary Leptin levels (ng/ml)
being quite high. But, saliva collecting from both humans and laboratory animals is much simpler, noninvasive, the results obtained being The levels of salivary leptin were measured over a 24 hr interval, the circadian rhythm being thus established, a correlation being also stated As to the animal weight, the average value between the leptin levels from saliva and plasma was of 229,85g in the group treated with haloperidole, comparatively with the initial The results of the present study, which average values of 232,00g; 228,35g, in the group applied the antipshychotic treatment to rats, treated with haloperidole decanoate, versus an evidence a significant statistical difference between the values of salivary leptin prior to and 230,57ng/ml for aripiprazole group versus the after the drug treatment with neuroleptics, in initial average values of 232,71ng/ml. (Table 2) haloperidole (p=0.032), and haloperidole decanoate groups (p=0.045), but not for the Table 2. Weight values (g)
aripiprazole group (p=1.000). As to the differences between the three groups, they are not statistically significant for haloperidole- haloperidole decanoate (p=0.236), only for aripiprazole-haloperidole (p=0.02) and for Haloperidole 231,14±3,42 228,35±2,57 aripiprazole-haloperidole decanoate (p=0.005). As for the animals’ body weight, the values registered no statistically significant differences for haloperidole group, but significant differences were observed for aripiprazole Vol. 39, No. 3, 2013 July September (p<0.05), and haloperidole decanoate (p<0.05) 6. Coccurello R., Moles Anna, Potential mechanisms groups, prior to and after the treatment. of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design, Pharmacology & Therapeutics treatment (4 weeks), the literature mentioning an interval of 3-20 weeks of antipsychotic drugs 7. Boyda H.N., Tse L., Procyshyn R.M., Honer W.G., Barr A.M., Preclinical models of antipsychotic modifications in the body weight of human drug-induced metabolic side effects, Trends in Pharmachological Sciences 2010; 31:484-497. subjects [2], the results support the idea that 8. Reynolds Gp., Kirk Sl., Metabolic side effects of some antipsychotics modifie salivary leptin antipsychotic drug treatment - pharmacological mechanisms, Pharmacology&Therapeutics 2010; 125:169-179. 9. Offenbacher S., Odle Bm., et all, The use of Conclusions
prostaglandin E2 levels as a predictor of The conducted experiment showed that, of periodontal attachment loss, J. Periodontal Res the three antipsychotic drugs that we studied, typical (haloperidole and haloperidole decanoate 10. Gröschl M, Rauh M, Wagner R, Neuhuber W, – retard formulation) and atypical (aripiprazole), Identification of leptin in human saliva, J Clin the salivary leptin levels were modified during the administration of the two neuroleptics 11. Iqbal Mm, Rahman A, Husain Z, Mahmud Sz, belonging to the first generation, higher values Ryan Wg , Feldman Jm, Clozapine: A Clinical Review of Adverse Effects and Management, Ann Determinations of salivary leptin should be continued on larger experimental groups and 12. Gorobets Ln (2008) Contribution of leptin to the over longer periods of time, for evidencing the formation of neuroleptic obesity in patients with possible body weight modifications in the schizophrenia during antipsychotic therapy, Bull Exp Biol Med., 146(3):348-50. 13. [entissi O, Epelbaum J, Olié Jp, Poirier Mf., Leptin and Ghrelin Levels in Patients With Schizophrenia References
During Different Antipsychotics Treatment: A 1. Page C., Curtis M., Walker M., Hoffman B., Review, J Clin Psych 2009, 29(3):304-306 Integrated Pharmacology, Third Edition, Mosby 14. [in H., Meyer Jm., Mudaliar S., Jeste Dv., Impact of atypical antipsychotic therapy on leptin, ghrelin 2. Aronson Jk., Meyler's Side Effects of Psychiatric and adiponectin. Schizophr Res. 2008, 100 (1- 3. Leucht S., Corves C., Arbter D., Engel Rr., Li C., 15. [eier U., Gressner Am., Endocrine regulation of Davis Jm., Second-generation versus first- energy metabolism: review of pathobiochemical generation antipsychotic drugs for schizophrenia: and clinical chemical aspects of leptin, ghrelin, a meta-analysis, Lancet, 2009, 373(9657):31-41. adiponectin and resistin., Clin Chem 2004, 50 (9): 4. Davis Jm., Chen N., Glick Id., A meta-analysis of the efficacy of second-generation antipsychotics, 16. Randeva Hs, Karteris E, Lewandowski Kc, Sailesh Arch Gen Psychiatry, 2003, 60(6):553-564. S, O’hare P, Hillhouse Ew., Circadian rhythmicity 5. Cohn Ta., Sernyak Mj., Metabolic monitoring for of salivary leptin in healthy subjects, Mol Genet patients treated with antipsychotic medications, Corresponding author: Maria Bogdan, University Assistant, PhD, Department of Pharmacology, Faculty of
Pharmacy, University of Medicine and Pharmacy of Craiova, 2-4 Petru Rares Street, 200349 Craiova,
Romania, e-mail: [email protected]



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