K. Nandakumar

Hepatoprotective activity of alcoholic and aqueous extracts of leaves of Tylophora indica (Linn.) in rats

Objective: To investigate the hepatoprotective activity of alcoholic (ALLT) and aqueous (AQLT) extracts of leaves of Tylophora indica (asclepiadaceae) against ethanol-induced hepatotoxicity. Materials and Methods: Leaf powder of Tylophora indica was successively extracted with alcohol and water. Preliminary phytochemical tests were done and the LD Departments of Pharmacology for both extracts determined. The hepatoprotective activity of the ALLT and AQLT were and *Pharmaceutical Chemistry, assessed in ethanol-induced hepatotoxic rats. V. L. College of Pharmacy, Results: The ALLT showed presence of alkaloids, carbohydrates, steroids, saponins and Raichur, India triterpenes, while alkaloids, carbohydrates and saponins were present with AQLT. The ALLT did not produce any mortality even at 5000 mg/kg while LD

Anti-inflammatory activity of Terminalia paniculata bark extract against acute and chronic inflammation in rats

ETHNOPHARMACOLOGICAL RELEVANCE Terminalia paniculata Roxb. (Family-Combretaceae) is a wild tree commonly used in traditional ayurvedic medicine for the treatment of inflammation of parotid glands and in menstrual disorders. AIM OF THE STUDY To explore the folk use of Terminalia paniculata on pharmacological grounds to evaluate the scientific basis of anti-inflammatory activity. MATERIALS AND METHODS The anti-inflammatory activity of Terminalia paniculata was studied against carrageenan-induced hind paw edema, air pouch inflammation and complete Freunds adjuvant (CFA)-induced arthritis in rats. The aqueous extract of Terminalia paniculata bark (TPW) was administered at the concentrations of 100, 200 and 400mg/kg body weight. RESULTS TPW showed significant (p<0.05) anti-inflammatory activity by reducing the edema volume in carrageenan-induced paw edema in rats. Further, TPW (400mg/kg) also reduced the carrageenan-induced leukocyte migration (50.92 ± 5.71%) and myeloperoxidase activity (49.31 ± 5.24%) in air pouch exudates. TPW (200mg/kg) exhibits anti-rheumatic and analgesic activities by improving the altered haematological milieu (ESR, CRP, RF, WBC, RBC and Hb) and also by inhibiting the flexion scores and radiographic changes in CFA-induced arthritis. This extract also had significant (p<0.05) effects on the occurrence of secondary lesions compared to CFA control. CONCLUSIONS Terminalia paniculata bark may be a potential preventive or therapeutic candidate for the treatment of chronic inflammation and arthritis.

Isolation of anxiolytic principle from ethanolic root extract of Cardiospermum halicacabum.

Cardiospermum halicacabum roots have been used traditionally for the treatment of epilepsy and anxiety disorders. The purpose of this study was to characterize the putative phytoconstituents present in the ethanolic root extract having anxiolytic activity using an elevated plus-maze (EPM) and light dark transition model. Control mice were orally treated with an equal volume of vehicle (4% gum acacia), and positive control mice were treated with diazepam (1mg/kg). In the EPM test, out of pool of 19 master fractions (MF) only MF-14, 16 and 17 significantly (30mg/kg, p<0.05, p<0.01 and p<0.001) increased the number of entries in the open arm. MF-14, 16 and 17 (10, 20 and 30mg/kg) had also increased the time spent by mice in illuminated part of the box significantly (p<0.05, p<0.01 and p<0.001), as compared to control. However, significant changes (p<0.05, p<0.01 and p<0.001) were recorded in other parameters, e.g., rearing, time spent in the closed arm and dark zone in both the models. These results suggested that C. halicacabum root is an effective anxiolytic agent. The phytoconstituent responsible for the observed central effects was isolated from MF-14 and identified as well-known compound, Cardiospermin, a cyanogenic glucoside.

Vasorelaxant effect in rat aortic rings through calcium channel blockage: a preliminary in vitro assessment of a 1,3,4-oxadiazole derivative.

The study was undertaken on the basis of several reports in the literature that relaxation of vascular smooth muscles is a good treatment strategy in hypertension, angina and other cardiovascular disorders. Oxadiazoles have been reported to have effect on vascular smooth muscles and calcium influx. The goals of our current in vitro study were to investigate the effect of a 1,3,4-oxadiazole derivative on vascular smooth muscles in rat aorta, and to elucidate the associated signaling pathway. NOX-1 induced a relaxation of vascular smooth muscles in both endothelium intact and denuded rat aortic rings precontracted with norepinephrine or phenylephrine or KCl. NOX-1 also significantly antagonized cumulative dose-response effect of norepinephrine, phenylephrine, KCl or calcium with reduction in submaximal contractions. Verapamil, an L-type of calcium channel blocker, effectively attenuated phenylephrine and calcium induced contractions in aortic rings. Incubation with NOX-1 and verapamil did not significantly alter the dose-response curve of phenylephrine or calcium compared to verapamil treatment alone indicating L-type Ca2+ channel blockage leads to loss of NOX-1 activity. Hence it can be concluded NOX-1 exhibited vasorelaxant action by inhibiting calcium influx from extracellular space to intracellular space through L-type of calcium channels.

Naringin and Rutin Alleviates Episodic Memory Deficits in Two Differentially Challenged Object Recognition Tasks

Background: Cognitive decline or dementia is a debilitating problem of neurological disorders such as Alzheimers and Parkinsons disease, including special conditions like chemobrain. Dietary flavonoids proved to be efficacious in delaying the incidence of neurodegenerative diseases. Two such flavonoids, naringin (NAR) and rutin (RUT) were reported to have neuroprotective potential with beneficial effects on spatial and emotional memories in particular. However, the efficacy of these flavonoids is poorly understood on episodic memory, which comprises an important form of autobiographical memory.Objective: This study objective is to evaluate NAR and RUT to reverse time-delay-induced long-term and scopolamine-induced short-term episodic memory deficits in Wistar rats. Materials and Methods: We have evaluated both short-term and long-term episodic memory forms using novel object recognition task. Open field paradigm was used to assess locomotor activity for any confounding influence on memory assessment. Donepezil was used as positive control and was effective in both models at 1 mg/kg, i.p. Results: Animals treated with NAR and RUT at 50 and 100 mg/kg, p.o. spent significantly more time exploring novel object compared to familiar one, whereas control animals spent almost equal time with both objects in choice trial. NAR and RUT dose-dependently increased recognition and discriminative indices in time-induced long-term as well as scopolamine-induced short-term episodic memory deficit models without interfering with the locomotor activity. Conclusion:We conclude that, NAR and RUT averted both short- and long-term episodic memory deficits in Wistar rats, which may be potential interventions for neurodegenerative diseases as well as chemobrain condition.

Highly active antiretroviral therapy induced adverse drug reactions in Indian human immunodeficiency virus positive patients

Objective To assess the incidence, severity pattern, causality, predictability and preventability of adverse drug reactions (ADRs) and to identify risk factors for adverse drug reactions in highly active antiretroviral therapy. Methods Enrolled patients were intensively monitored for ADRs to highly active antiretroviral therapy. Predictability was assessed based on history of previous exposure to the drug or literature incidence of ADRs. Preventability was assessed using Schumock and Thornton criteria and severity was assessed using modified Hartwig and Siegel scale. Multivariate logistic regressions were used to identify the risk factors for ADRs. Results Monitoring of 130 retropositive patients by active pharmacovigilance identified 74 ADRs from 57 patients. Anemia and hepatotoxicity were the most commonly observed ADRs. The organ system commonly affected by ADR was red blood cell (21.4%). The ADRs were moderate in 77% of cases. Type A reactions (77%) were more common. A total of 10.8% ADRs were definitely preventable. The incidence rate of ADRs (65.9%) was highest with Zidovudine + Lamivudine + Nevirapine combination. A total of 84% interruptions to highly active antiretroviral therapy were due to toxicity. CD4 less than 200 cells/μl, female gender and tuberculosis were observed as risk factors for ADRs. Conclusion Incidence of ADRs in intensively monitored patients was found to be 43.8%. Anemia in HIV patients is an influential risk factor for occurrence of ADRs. With the increasing access to antiretroviral in India, clinicians must focus on early detection and prevention of ADRs to highly active antiretroviral therapy.

Study of β-Adrenoreceptor Antagonistic Activity of DPJ 904 in Rats

β-Adrenoreceptor antagonistic activity of a newly synthesized compound was evaluated in vivo by measuring the mean arterial blood pressure and heart rate of urethane-anesthetized rats treated with isoprenaline. In vitro β1-, β2- and β3-antagonism was studied using isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively, in comparison to isoprenaline response. DPJ 904 (1, 3 and 10 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardia response in anesthetized rat. DPJ 904 (1, 3 and 10 mg/kg, i.v.) significantly inhibited both the tachycardial effects and hypotensive response induced by isoprenaline. DPJ 904-antagonized isoprenaline induced positive chronotropic effects of isolated rat right atria and a uterine relaxant effect indicating β1- and β2-blockade. The parallel shift to the right of the concentration-response curve of isoprenaline in the presence of DPJ 904 in KCl (30 mmol/l) induced contraction of the rat colon suggesting that DPJ 904 also possessed β3-adrenoreceptor antagonistic activity. The selectivity to β1-adrenoreceptor was nearly 20.5 times greater than to β2-adrenoreceptor. The present study indicates that DPJ 904 possesses β-adrenoreceptor antagonistic activity with slightly more affinity to the β1-adrenoreceptor subtype.

Selective β1-adrenoreceptor blocking activity of newly synthesized acyl amino-substituted aryloxypropanolamine derivatives, DPJ 955 and DPJ 890, in rats

The in‐vivo β‐adrenoreceptor antagonistic activity of test compounds DPJ 955 and DPJ 890 was assessed against β‐adrenoreceptor agonist (isoprenaline) induced tachycardia in anaesthetized rats. The selectivity to block isoprenaline responses on different β‐adrenoreceptor subtypes (β1, β2 and β3) of the test compounds was carried out on isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively. Intravenous injection of isoprenaline alone in anaesthetized rats caused hypotension and tachycardia. DPJ 955 or DPJ 890 alone produced a fall in mean arterial pressure and bradycardia in a dose‐dependent manner. Administration of isoprenaline to anaesthetized rats pre‐treated with test compounds significantly blocked both the tachycardial and hypotensive responses induced by isoprenaline. The test compounds shifted the concentration response curves of isoprenaline towards the right for isolated rat right atrial preparations, rat uterus and rat colon, indicating β1, β2 and β3 adrenoreceptor blockade, respectively. The selectivity ratio for β1/β‐adrenoreceptors to DPJ 955 and DPJ 890 was 64.6 and 83.2, respectively. DPJ 890 was more potent in blocking β1‐adrenoreceptors and was more selective towards β1 receptors than to other β‐adrenoreceptor subtypes. In conclusion, DPJ 955 and DPJ890 have β‐adrenoreceptor blocking activity with high selectivity for the β1‐adrenoreceptor subtype.

β-Blocking activity of PP-34, a newly synthesized aryloxypropanolamine derivative, and its cardioprotective effect against ischaemia/reperfusion injury in laboratory animals

β‐Adrenoceptor antagonists are widely used in cardiovascular medicine. However, the main side effect of these drugs is due to antagonism of β2‐adrenoceptors in the airways, resulting in broncho‐spasm. Therefore, more cardioselective β‐blockers have been developed to offer a lower side effect profile. We have studied a new aryloxypropanolamine derivative (PP‐34) with more cardioselectivity and efficacy against ischaemia/reperfusion injury in rats. Oxalate salts of 1‐(tert‐butylamino)‐3‐(5‐tert‐butylaminomethyl‐2‐methoxyphenoxy) propan‐2‐ol (PP‐34) is a novel β‐adrenoceptor antagonist. In‐vitro studies in rat isolated right atria, guinea‐pig trachea and rat distal colon preparations were carried out to investigate the potency of PP‐34 towards different β‐adrenoceptor subtypes. pA2/pKB values of PP‐34 for β1, β2, and β3 adrenoceptor were 7.89 ± 0.15, 6.13 ± 0.09 and 6.30 ± 0.19, respectively. The β1/β2 selectivity ratio calculated was in the order of PP‐34 > atenolol > propranolol. Pre‐ischaemic administration (20 min before coronary occlusion) of PP‐34 (0.3 or 1 mg kg−1) showed cardioprotective effects against ischaemia/reperfusion injury in rats and significantly reduced arrhythmias, infarct area and necrosis induced by ischaemia/reperfusion injury. The efficacy of PP‐34 was found to be greater then atenolol. In conclusion, PP‐34 is a cardioselective β‐adrenoceptor antagonist, possessing potent anti‐arrhythmic and cardioprotective effects against ischaemia/reperfusion injury in rats.

Experimental animal models to induce cardiac arrhythmias

Cardiac arrhythmias are of different types based on their mechanism and origin. The information gathered from animal studies has been instrumental in devising diagnostic and therapeutic strategies; so different animal models are needed for different types of arrhythmias. The origin and mechanism underlying clinical arrhythmias are of considerable significance, since knowledge of these processes may provide a basis for successful therapy. Various animal models that encompass different types of arrhythmias are reviewed. This review classifies various experimental models according to their origin, which are mainly supraventricular and ventricular. Also included are various transgenic animal models for arrhythmias.