الفهرس 
Introduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Summary and Conclusion
Second-generation (atypical) antipsychotics have been substantially used in treatment of psychiatric disorders during the past decade. Although the cardiovascular toxicity of conventional antipsychotics is well-established, the cardiovascular profile of members of the atypical class is a subject of investigation. Some drugs, such as olanzapine, pose known metabolic and cardiovascular risk. On the other hand, the ‘newer’ atypical antipsychotic aripiprazole has been shown to have an adverse effect profile comparable to that of placebo. A significant weight gain on administration of aripiprazole was, however, observed in a long-term double-blind controlled trial. Regarding cardiovascular toxicity, several case reports have linked development of hypertension with commencement of aripiprazole therapy. This adverse effect of the drug was observed from as early as the first dose. Moreover, a 24-month study reported significant increase in both systolic and diastolic blood pressures as well as significant mild increase in QTc interval. Earlier reports, however, tend to associate orthostatic hypotension with the use of antipsychotic drugs. This conflict might echo the lack of systematic evaluation of the comparative safety and tolerability of this agent.
Aripiprazole is the first atypical antipsychotic with potent partial agonist activity at D2 and 5-HT1A receptors. Efficacy of aripiprazole, as well as its undesirable effects, is attributed, in part, to its effect on serotonergic receptors. These receptors are involved in either modulation of blood pressure or change in cardiac rhythm, or both.
Aim of the Work:
The aim is to study the cardiovascular adverse effects upon acute graded dosing and chronic administration of aipiprazole, correlating the outcome effect to serotonergic receptors through using a serotonergic blocker (cyproheptadine) and comparing the outcome results to that of chronically administered olanzapine.
Study Design:
In the present study, 117 Male Wistar rats were used. They were divided into 12 groups:
Animal Groups:
I. Acute Study:
The acute study consisted of 6 groups, 9 animals each:
Group 1: Control vehicle-treated animals, Group 2: ARI-treated group with the dose 1 mg/kg i.p., Group 3: ARI-treated group with the dose 3 mg/kg i.p., Group 4:
ARI-treated group with the dose 10 mg/kg i.p., Group 5: Cyproheptadine treated group with the dose 10 mg/kg i.p., Group 6: Cyproheptadine pretreated with the dose of 10 mg/kg i.p., followed by ARI with the dose of 10 mg/kg i.p.
The outcome measures were:
(a) Systolic blood pressure using the tail-cuff technique 60 and 90 minutes after injection for each animal.
(b) ECG was done for each animal after anesthesia and QTc interval was calculated.
(c) Invasive blood pressure for measurement of systolic, diastolic and mean BP using P23XL (Viggo Spectramed Inc.) pressure transducers two hours after injection for each animal.
II. chronic Study:
The chronic study consisted of 6 groups, [group (1) consists of 18 animals, while the other groups consist of 9 animals each].
The drugs were administered daily for 21 days i.p. The volume of injected drugs i.p. was 2 - 3.5 mL/kg. All groups received i.p. injections including either drug treatment or vehicle throughout the experiment.
Group 1: Control vehicle-treated group (18 animals), divided into 2 sub-groups: (a) 9 animals treated with 2.5% tween 80 i.p.,(b) 9 animals treated with 0.0001% acetic acid i.p., Group2: OLA-treated group with the dose 10 mg/kg i.p., Group 3: ARI-treated group with the dose 6 mg/kg i.p., Group 4: Cyproheptadine treated group with the dose 10 mg/kg i.p., Group 5: Cyproheptadine pretreated group with the dose of 10 mg/kg i.p., followed by OLA with the dose of 10 mg/kg i.p. , Group 6:Cyproheptadine pretreated group with the dose of 10 mg/kg i.p., followed by ARI treated with the dose of 6 mg/kg i.p.
The outcome measures were:
• Systolic blood pressure using the tail-cuff technique on the days 1, 7, 14 and 21 of the study.
• Body weight using 3-digit electronic balance on the days 1, 7, 14 and 21 of the study.
• ECG was done for each animal after anesthesia and QTc interval was calculated.
• Evaluation of the ex-vivo aortic reactivity using isolated aortic ring which is then assessed for PHE cumulative dose contraction and ACh cumulative dose relaxation for each animal