Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents.

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

Lipid profile of population of central region of Nepal.

This study was conducted to know the status of Lipid profile in people of central region of Nepal. This study was conducted in College of Medical Sciences & Teaching Hospital, Bharatpur, Nepal from February 2009 to March 2010 which is situated in central region of Nepal. A total of 870 cases, out of which 512(58.85%) male and 358(41.14%) female were included and study was carried out using data retrieved from the register maintained in the Department of Biochemistry. The variables collected were age, sex, lipid profile which includes total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C) & low density lipoprotein-cholesterol (LDL-C). The data was analyzed using excel 2007 and Statistical Package for the Social Sciences (SPSS) 16.0. The total mean±SD of TC, TG, HDL-C, LDL-C were found to be 164.87±49.49, 157.56±79.78, 33.59±11.10, 97.79±40.68 respectively. Total Cholesterol, HDL-C & LDL-C were found to be statistically significant whereas TG was statistically insignificant between male and female. In both male and female, TG & LDL-C were higher in the age group of 21-40 years whereas HDL-C was higher in the age group of >61 years in both the group. Total cholesterol (TC) level was higher in the age group of 21-40 years in male while in female in the age group of 41-60 years. Desirable level of TC was observed in 78.50% of the total subjects while the normal TG, LDL-C were observed in 56.55%, 81.49%, respectively. Very high levels of TC, TG, LDL-C were observed in 4.94%, 0.34% & 1.6% of the total population studied, respectively. More percentage of female (27.65%) had higher HDL-C level than in male (15.62%). High triglycerides (TG) level is the commonest lipid abnormality in our study. HDL-C level was increase with increasing in age. Clinical evaluation can be made according to this study.

Implementing self sustained quality control procedures in a clinical laboratory.

INTRODUCTION: Quality control is an essential component in every clinical laboratory which maintains the excellence of laboratory standards, supplementing to proper disease diagnosis, patient care and resulting in overall strengthening of health care system. Numerous quality control schemes are available, with combinations of procedures, most of which are tedious, time consuming and can be "too technical" whereas commercially available quality control materials can be expensive especially for laboratories in developing nations like Nepal. Here, we present a procedure performed at our centre with self prepared control serum and use of simple statistical tools for quality assurance. METHODS: The pooled serum was prepared as per guidelines for preparation of stabilized liquid quality control serum from human sera. Internal Quality Assessment was performed on this sample, on a daily basis which included measurement of 12 routine biochemical parameters. The results were plotted on Levey-Jennings charts and analysed with quality control rules, for a period of one month. RESULTS: The mean levels of biochemical analytes in self prepared control serum were within normal physiological range. This serum was evaluated every day along with patients' samples. The results obtained were plotted on control charts and analysed using common quality control rules to identify possible systematic and random errors. Immediate mitigation measures were taken and the dispatch of erroneous reports was avoided. CONCLUSIONS: In this study we try to highlight on a simple internal quality control procedure which can be performed by laboratories, with minimum technology, expenditure, and expertise and improve reliability and validity of the test reports.

A study of correlation between vitreous potassium level and post mortem interval.

Present study was undertaken to study the correlation of potassium level of vitreous humor with time since death. Vitreous was collected from 150 medicolegal autopsy cases between August 2000 to March 2001 in Bharatpur Hospital, Bharatpur, Chitwan, Nepal. There was a linear increase in vitreous potassium level with rise of postmortem interval. This indicates that rise in potassium levels after death has a strong correlation with the PMI.

Biologically active substituted benzodiazepines and their effect on cardiovascular and central nervous system.

Some substituted 1,5-benzodiazepine derivatives (including a spirocyclopentane moiety) were synthesized (Table I) and evaluated for their hypotensive and CNS activities respectively. The compounds which showed promising cardiovascular activity also exhibited marked anti-depressant action (Table II,III,IV). All the compounds showed higher ALD50 value.

Cardiovascular effects of novel imidazoline congeners.

2-Aryl-4,5-bis(diphenyl)-1-(N-acetyl hydrazide)-1,3-imidazoline (IIb1-4) was prepared by the reaction of ethyl chloro acetate and hydrazine hydrate with 2-Aryl-4,5-bis (diphenyl)-1H-imidazoline (I a1-4), which on further substitution with aryl/heterocyclyl aldheyde gave 2-Aryl-4,5-bis (diphenyl)-1-(4-substituted hydrazone)-1,3-imidazoline (III Ca-i). This was again cyclised to oxadiazole in the presence of ferric chloride and glacial acetic acid yielded 2-Aryl-4,5-bis(diphenyl)-1-(2-substituted-1,3,4-oxadizole)-1,3-imi dazoline (IV da-i). These compounds were screened for hypotensive activity and an attempt were made to get the site of action of these compounds.

Evidence for antiaggressive property of some calcium channel blockers.

The effect of calcium channel blockers on foot shock induced (aggression (FSA) were studied in mice. Verapamil, (10, 20 and 40 mg kg-1 i.p.) diltiazem (20 and 40 mg kg-1 i.p.) and nifedipine (25 and 50 mg kg-1 i.p.) significantly reduced fighting episodes. Diltiazem and nifedipine blocked the amphetamine induced facilitation of FSA, while verapamil blocked both amphetamine as well as physostigmine induced facilitation of FSA. These findings suggest that calcium channel blockers possess antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism.

Modification of reserpine-induced emetic response in pigeons by alpha 2-adrenoceptors.

In the present study, an attempt has been made to elucidate the role of alpha 2-adrenoceptors in reserpine-induced emesis in pigeons. Reserpine was found to induce dose-dependent emesis and a 500 micrograms kg-1 dose was found to be the 100% emetic dose. alpha 2-adrenoceptor agonists clonidine and alpha-methylnoradrenaline inhibited the reserpine induced emesis. Out of the two selective alpha 2-adrenoceptor antagonists idazoxan and yohimbine, only the latter induced a dose-dependent emesis. However, both the drugs potentiated reserpine-induced emesis and antagonised its inhibition by clonidine. Prior depletion of monoamines by reserpine also blocked the emetic response of reserpine. These observations indicate that release of monoamines is responsible for its emetic response in pigeons which is modulated by presynaptic alpha 2-adrenoceptors in a predictable manner.

Evidence for a central component in the cardiovascular effects of calcium channel blockers.

The possibility of a central component in the cardiovascular effects of peripherally administered calcium channel blockers has been explored through a comparison of the effects observed after intravenous (i.v.) and intracisternal (i.c.) administration of verapamil and diltiazem in chloralose-anesthetized and artificially ventilated cats. Both agents produced relatively greater effects after i.c. than after i.v. administration. The bradycardiac effect following i.c. as well as i.v. administration was totally abolished by bilateral cervical vagotomy, and the hypotensive effect was attenuated by this procedure. The results strongly suggest the existence of a central component in the cardiovascular effects of both agents.

Protection against gastric ulcer by verapamil.

The effect of verapamil, a calcium channel blocker, was studied against stress (cold restraint), aspirin and pylorus ligation induced gastric ulcers in rats. Verapamil inhibited ulcerogenic response and ulcer index in all the three types of ulcers. Verapamil also decreased total and free gastric acidity without changing gastric secretory volume.

Opioid and non-opioid central cardiovascular effects of ketamine.

The cardiovascular responses to ketamine injected intracisternally were examined in chloralose anaesthetized cats. Blood pressure and heart rate were recorded at different time intervals after intracisternal injection of drug or saline vehicle. The low doses of ketamine (0.5 or 1.0 mg) elicited dose dependent increase in blood pressure and heart rate. In contrast the high dose of ketamine (4 mg), produced a fall in blood pressure and heart rate. The cardiovascular response elicited by the low dose was naloxone insensitive and completely blocked by haloperidol, but not by dopamine antagonist pimozide. The vasodepressor and bradycardiac effect of the 4 mg dose was naloxone antagonizable. These data show that excitatory cardiovascular effects of the low dose result from a naloxone resistant site while in high doses an inhibitory effect is elicited by action at naloxone sensitive opiate receptors.

Central alpha-adrenoceptor influence over the cardiovascular reflexes activated by veratrine.

Intravenous veratrine induced alterations in cardiovascular parameters in cats were used as a tool for assessing the influence of central alpha-adrenoceptors over reflex adjustments in the heart rate and blood pressure. Blockade of central alpha 2-adrenoceptors with idazoxan or yohimbine, inhibited, while their activation by clonidine, as also blockade of alpha 1-adrenoceptors, with prazosin, potentiated the veratrine induced bradycardia. The hypotensive effect was relatively unaltered by these treatments. Low doses of clonidine potentiated the veratrine-induced bradycardia. It appears that alpha 2-adrenoceptor mechanisms exert greater control over the reflex regulation of heart rate than over reflex control of blood pressure.

Sulphinpyrazone and the platelet serotoninergic mechanism in ischaemic heart disease.

A double blind study in 25 patients with ischaemic heart disease and 20 matched healthy controls examined the effect of sulphinpyrazone on the uptake of serotonin by platelets and the basal concentrations of serotonin in platelets. Uptake was measured using tritium labelled serotonin and basal concentrations estimated spectrophotofluorometrically. Serotonin uptake was significantly increased both in the patients with chronic stable angina of effort and in those with a history of myocardial infarction six months or more previously. Sulphinpyrazone reduced serotonin uptake from 94.25 (SE 8.65) to 57.86 (5.37) cpm/10(8) platelets after 24 weeks of treatment in the group with stable angina and from 137.45 (16.26) to 68.08 (8.38) cpm/10(8) platelets in the myocardial infarction group. Raised basal concentrations in the two groups were also reduced by sulphinpyrazone. Placebo had no effect on serotonin uptake or basal concentrations in either group of patients. The ability of sulphinpyrazone to inhibit uptake and reduce basal concentrations of serotonin in patients with ischaemic heart disease may be yet another mechanism through which this drug exerts its beneficial antiplatelet effect.

Role of medullary cholinoceptors in baroreflex bradycardia.

Cholinergic receptors present in three medullary nuclei namely, the nucleus tractus solitarii (NTS), nucleus ambiguous (AMB) and the dorsal motor nucleus of the vagus nerve (DMV) have been studied with regard to their role in regulation of heart rate (HR), blood pressure (BP) and baroreceptor reflex activation induced bradycardia in cats. Microinjection of carbachol into NTS was without effect while administration of carbachol or pilocarpine into AMB and DMV elicited dose related decrease in HR without affecting BP. These effects were completely antagonized by ethylbenztropine. Bilateral muscarinic cholinoceptor blockade of either AMB or DMV, with ethylbenztropine, produced a partial inhibition of the baroreflex bradycardia while intracisternal ethylbenztropine completely abolished this reflex response. Involvement of muscarinic cholinoceptors of AMB or DMV in baroreflex mediated adjustments of HR is therefore suggested.

An analysis of the alpha-adrenoceptor modulation of vasomotor tone at the level of lateral medullary pressor area (LMPA).

Microinjection of noradrenaline and clonidine into lateral medullary pressor area (LMPA) of chloralose anaesthetized cats produced dose dependent decrease in blood pressure without affecting heart rate, while phenylephrine did not elicit any cardiovascular response. Selective alpha 2-adrenoceptor antagonists idazoxan and piperoxan, microinjected locally, blocked the effects of the agonists but prazosin and phenoxybenzamine, which are relatively selective for alpha 1-adrenoceptors, failed to do so. Clonidine did not elicit any response in guanethidine pretreated cats but noradrenaline microinjected into LMPA of these animals induced a pressor response which was blocked by prazosin pretreatment. It is concluded that catecholaminergic fibres impinging upon this area inhibit the activity of the inhibitory second order baroreceptor neurone by activating alpha 1-adrenoceptors while alpha 2-adrenoceptors situated presynaptically on these inhibitory catecholaminergic nerve terminals are responsible for the manifestation of the hypotensive effect of clonidine and exogenously administered noradrenaline.

Nucleus locus coeruleus: evidence for alpha 1-adrenoceptor mediated hypotension in the cat.

Microinjection of noradrenaline or phenylephrine into the nucleus locus coeruleus of cats induced a dose dependent and long lasting hypotension. Clonidine was required in a dose of 1 microgram for eliciting a significant hypotension while its lower doses (up to 500 ng) failed to elicit any significant cardiovascular alteration. The effects on heart rate evoked by these agents were insignificant. Microinjection of alpha-adrenoceptor antagonists prazosin, piperoxan and RX 781094 per se did not evoke any significant cardiovascular effects and only prazosin pretreatment showed dose dependent antagonism of the hypotensive effect of clonidine. Piperoxan was required in four times higher dose (20 micrograms) to partially antagonize the clonidine induced hypotension. RX 781094, a selective alpha 2-adrenoceptor antagonist, however, even up to a dose of 20 micrograms (four times that of prazosin) did not alter the effect of clonidine. Similar pattern of antagonism was also seen for noradrenaline and phenylephrine. The results demonstrate the presence of alpha 1-adrenoceptors in the nucleus locus coeruleus, the activation of which leads to a fall in blood pressure.

An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat.

Electrical stimulation of locus coeruleus (LC) and subcoeruleus (SC) elicited an increase in heart rate (HR) and blood pressure (BP). Adrenergic neurone blockade in the posterior hypothalamus with guanethidine and also bilateral adrenalectomy completely blocked the LC stimulation induced cardiovascular responses. The cardiovascular responses elicited by electrical stimulation of SC were, however, unaffected by the former and only partially inhibited by the latter. It is suggested that the LC stimulation-evoked rise in HR and BP is mediated by catecholamine release from the adrenal medulla due to an activation of the hypothalamic-adrenal axis. The cardiovascular responses elicited by stimulation of SC are mainly due to activation of the sympathetic preganglionic neurones and are further augmented by the adrenal catecholamine release.