Anticonvulsant hypersensitivity syndrome associated with carbamazepine administration: Case series.

Hypersensitivity reactions are common adverse drug reactions (ADRs) associated with antiepileptics. Carbamazepine is one of the routinely prescribed drugs for the treatment of epilepsy and neuropathic pain. ADRs due to carbamazepine range from mild maculopapular rash to severe anticonvulsant hypersensitivity syndrome (AHS). AHS is the triad of fever, rash, and internal organ involvement occurring 1-8 weeks after exposure to an anticonvulsant (1 in 1,000 to 10,000 exposures). Spontaneously reported three cases of AHS-drug hypersensitivity reactions induced by carbamazepine are discussed here. Seven to ten days after starting therapy, patients developed maculopapular skin rashes, fever and liver or kidney involvement. The causal relationship between drug and ADR was found to be 'certain' in one case and 'probable' in other two cases with both WHO-UMC and Naranjo causality assessment scale. All the three cases show category 4a according to Hartwig's severity scale as ADR was the cause for hospital admission. On assessing preventability of ADRs by modified Schumock and Thorntons' scale, one case was falling into category of 'definitely preventable' and other two were 'not preventable'. AHS is rare but serious reaction with carbamazepine which requires vigilant monitoring by physicians to avoid major consequences.

In-silico analysis for RNA-interference mechanism of α-synuclein to treat Parkinson's disease.

Parkinson's Disease (PD) causing mutations in α-synuclein gene are ALA30PRO, GLU46LYS and ALA53THR. The conformational changes in proteins with respect to all the three mutations were analysed. These were used to predict the structures of Short Interfering RNA (siRNA) antisense strand and siRNA region. The siRNA binds with the argonaute protein forming RNA Induced Silencing Complex (RISC). Then, siRNA antisense-strand was attached to RISC. The structure of dicer (RNase-III-enzyme) cleaves double-stranded RNA (dsRNA) into two siRNA-strands. Incorporation of single siRNA-strand into RISC guides to pair with the complementary α-synuclein target-messenger RNA (mRNA) thereby enabling it to cleave the target.

Receptor-based pharmacophore tool for design and development of next-generation drugs.

Drug discovery is an intricate process in which new drugs are designed or discovered. A pharmacophore is an essential ensemble of steric and electronic features for drug discovery, which is necessary to ensure optimal interactions with a specific target structure and to trigger its biological response. Here we present our innovative approach: the Receptor-Based Pharmacophoric Tool (RBPT), a transparent user friendly GUI sphere that generates pharmacophores using the structure of the target protein at the specified binding site. The pharmacophore generated for the specified binding site of a target can be used in virtual screening and for further studies.

Discovering novel carriers for oral insulin tablets: a pharmacoinformatics approach.

Insulin is used medically to treat Type 1 diabetes mellitus most commonly injected subcutaneously for human beings. The realisation that insulin injections have become a part of life can be extremely harrowing for many diabetic patients. Using insulin therapeutically is not a new practice, but still delivery methods to make the process more bearable have not gained widespread prominence as of yet. Oral delivery of insulin in tablet form has always been a significant challenge for pharmaceutical researchers. This study is a prospect of oral insulin tablet through pharmacoinformatics approach.

Percutaneous Radiofrequency Rhizotomy in Treatment of Trigeminal neuralgia: A Prospective Study.

INTRODUCTION: Trigeminal neuralgia (TN) often called as "Tic douloureux" is a syndrome characterized by paroxysmal facial pain, is one of the most painful and debilitating craniofacial pain disorders. The controversy regarding the etiology and treatment of TN still exists. OBJECTIVE: To evaluate the effectiveness of percutaneous radiofrequency rhizotomy (PRR) for TN, after failure of pharmacological management. METHOD: A nonrandomized, non comparative, descriptive, in vivo study of 15 patients with TN of maxillary and mandibular divisions of trigeminal nerve and patients with pain refractory to pharmacological management were done. It was performed as an O.P.D procedure. A routine follow up was done in all cases for 1 year. RESULTS: In a total of 15 patients, 8 female and 7 male patients were enrolled for the study. Early pain relief (immediately, postoperatively to 6 month) classified as excellent or good (successful), occurred in 12 of 15 patients (80 %). Fair or poor pain relief (unsuccessful) occurred in three patients (20 %).There was no mortalities and no major morbidity. SUMMARY: It was found that surgical treatment with PRR is a safe and effective way to manage patients with TN in whom pharmacologic therapy is either ineffective or not tolerated, with low side effects which are well tolerated.

In-silico analysis and QSAR studies of tacrine hybrids with ubiquitin ligase on Alzheimer's disease.

Ubiquitin ligase was an important protease in the pathogenesis of Alzheimer's Disease (AD). Currently, a handful of drugs were available and they are at best only able to offer some relief from symptoms. Cure for this disease is currently not available. Tacrine hybrids show inhibitory activities to the ubiquitin ligase. The three-dimensional quantitative structure?activity relationship (3D QSAR) models and in-silico studies would be useful in developing new drug leads against Alzheimer's disease. The objective of this work involves the designing of new substances, with potential inhibitory activity over AcetylCholinesterase Enzyme (AChE), using rational drug design strategies.

Effect of Withania somnifera on forced swimming test induced immobility in mice and its interaction with various drugs.

The objective of the present study was to evaluate the antidepressant action of Withania somnifera (WS) as well as its interaction with the conventional antidepressant drugs and to delineate the possible mechanism of its antidepressant action using forced swimming model in mice. Effect of different doses of WS, fluoxetine and imipramine were studied on forced swimming test induced mean immobility time (MIT). Moreover effect of WS 100 mg/kg, i.p. was observed at different time intervals. Effect produced by combination of sub therapeutic doses of WS with imipramine (2.5 mg/kg, i.p.) as well as fluoxetine (2.5 mg/kg, i.p.) were also observed. Effect of WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) were observed in mice pretreated with reserpine (2 mg/kg, i.p.) and clonidine (0.15 mg/kg, i.p.). Effects of prazosin (3 mg/kg, i.p.) or haloperidol (0.1 mg/kg, i.p.) pre-treatment were also observed on WS induced decrease in MIT. WS produced dose dependent decrease in MIT. Maximum effect in MIT was observed after 30 min of treatment with WS 100 mg/kg, i.p. Combination of WS (37.5 mg/kg, i.p.) with imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) also produced significant decrease in the MIT. Clonidine and reserpine induced increase in MIT, was significantly reversed by treatment with WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.). Pre-treatment with prazosin but not haloperidol, significantly antagonized the WS (100 mg/kg, i.p.) induced decrease in MIT. It is concluded that, WS produced significant decrease in MIT in mice which could be mediated partly through a adrenoceptor as well as alteration in the level of central biogenic amines.

Comparative study of beta-adrenoceptor blocking efficacy of two formulations of esmolol in vivo and in vitro.

The objective of the present study was to compare the cardiovascular beta-blocking activity of two different formulations of esmolol. Spontaneously beating guinea-pig isolated atria and the heart rate and blood pressure of anaesthetized cat were employed in the study to compare the beta-blocking efficacy of the two formulations of esmolol using isoprenaline as an agonist. In guinea-pig isolated atria the standard esmolol formulation (Brevibloc) reduced basal atrial rate more significantly than the indigenously formulated esmolol (test formulation). Both the formulations produced similar parallel rightward shift of cumulative concentration response curves of isoprenaline with closely comparable pA2 values. In anaesthetized cats, only indigenous esmolol formulation significantly decreased basal heart rate. Both the formulations did not modify the basal blood pressure and isoprenaline-induced fall in blood pressure, despite significantly blocking isoprenaline-induced tachycardia. It is suggested that both the formulations produced similar degree of beta-1 adrenoceptor blocking activity.

Modification of the antihypertensive effect of indapamide by indomethacin.

Oral treatment with indapamide was found to reduce blood pressure of hypertensive rats but not of normotensive rats. Chronic indomethacin treatment had no effect on blood pressure of untreated normotensive and hypertensive rats. Also indomethacin did not modify the antihypertensive effect of indapamide excluding the direct involvement of PGs in the antihypertensive effect of indapamide. Vascular reactivity to pressor agents NA, ADR and ANG was significantly increased after indomethacin treatment. This may be due to the blockade of the actions of PG in modifying vascular reactivity to vasoconstrictor agents or may be a direct effect of indomethacin on calcium fluxes. Indapamide reduced the reactivity to NA and ANG in the presence of indomethacin suggesting that the antihypertensive effect of indapamide may be through a decrease in reactivity to pressor agents which is independent of increase in the synthesis of vasodilator PGs.

Cadmium-induced hypertension in rats.

Chronic cadmium chloride (CdCl2, 0.5 and 1.0 mg/kg, i.p.) treatment in female albino rats for 2 weeks resulted in elevation of blood pressure. In chronic CdCl2-treated rats the pressor responses to different doses of noradrenaline, angiotensin II and depressor responses to acetylcholine and isoprenaline were unaltered. In rat hindquarter preparation there was elevation of perfusion pressure and the sensitivity of vascular bed to noradrenaline was increased in the CdCl2-induced hypertensive rats. Complete bilateral adrenalectomy or chemical sympathectomy or treatment with captopril did not prevent the development of CdCl2-induced hypertension. Treatment with verapamil (15 mg/kg/day, p.o.) or nifedipine (10 mg/kg/day, p.o.) for 2 weeks prevented the development of hypertension with chronic CdCl2 treatment. It is suggested that chronic treatment of rats with CdCl2 induces hypertension. It is possible that cadmium mimics the calcium ion for the induction of hypertension in rats.

Effects of Abana, an Ayurvedic preparation, on rabbit atrium and intestine.

The effects of Abana, an Ayurvedic remedy, administered orally to rabbits was studied for its effects on isolated atria and intestine. Administration of Abana for 3 days increased the basal amplitude and reduced the responses of atria to isoprenaline and norepinephrine. Combined treatment with Abana and isoprenaline reduced this effect. It is possible that Abana treatment for 3 days has an action similar to that of chronic administration of isoprenaline (down regulation of beta receptors). A similar down regulation of beta receptors of smooth muscle of rabbit intestine also seems to occur. Abana pretreatment potentiated the inotropic responses of histamine and CaCl2. These effects may be due to a specific depressant effect of Abana on the adrenergic receptors and a direct sensitization of the atrium manifested by an increased response to CaCl2.

Investigation of some effects of levamisole on dog blood pressure.

The effects of levamisole were investigated on the blood pressure of anaesthetized dog. Levamisole (0.5 to 4.0 mg/kg) elicited a biphasic effect, an initial brief depressor response followed by a pressor response. The pressor response was dose-related and was blocked by phenoxybenzamine. The residual depressor response was blocked by propranolol. Repeated administration of a high dose of levamisole produced tachyphylaxis. The pressor response to levamisole was not modified by either reserpinization, acute bilateral adrenalectomy or pretreatment with cocaine, whereas pretreatment with dexamethasone, nialamide or pyroaallol shifted the dose-response curve to the right. Levamisole potentiated the pressor responses to noradrenaline, angiotensin and acetylcholine. The effects of levamisole are ascribed to inhibition of monoamine oxidase, catechol-O-methyl transferase, catecholamine uptake2 mechanism and cholinesterase.

Interactions of levamisole with some autonomic drugs on guinea-pig vas deferens.

The effects of levamisole on responses to various agonists were studied in guinea-pig vas deferens. Levamisole did not itself exhibit any contractile or relaxant effect on guinea-pig vas deferens but in the presence of levamisole the concentration-response curve of noradrenaline (NA) was shifted to the left and the maximal response was increased. Responses to field-stimulation at 5 and 10 Hz were potentiated by levamisole. Cocaine and denervation caused potentiation of NA responses and these enhanced responses remained unchanged in the presence of levamisole. Acetylcholine (ACh) responses were potentiated by levamisole whereas responses to histamine, KCl and methoxamine remained unaltered. These results suggest that levamisole does not have any action at postsynaptic alpha-adrenoreceptors. The increased responses to NA and ACh in the presence of levamisole may be due to its uptake1, blocking and anticholinesterase activities respectively.

Investigation of the muscle relaxant activity of nitrazepam.

Administered intravenously in decerebrate cats nitrazepam or diazepam (0.0625 to 0.5 mg/kg) produced dose-related inhibition of the ipsilateral extensor reflex. Nitrazepam (0.25 mg/kg i.v.) produced a significantly greater (P less than 0.001) inhibition than that produced by diazepam (0.25 mg/kg i.v.). Nitrazepam or diazepam (0.0625-4 mg/kg i.v.) had no effect on the contractions of directly stimulated (120 V, 5 msec, 0.1 Hz) quadriceps femoris muscle and on the contractions of tibialis anterior muscle produced by stimulating the cut peripheral end of the lateral popliteal nerve (8 V, 1.5 msec, 0.1 Hz). Nitrazepam or diazepam (0.125-0.5 mg/kg i.v.) produced dose-related depressor responses in cats anaesthetized with chloralose or pentobarbitone. Nitrazepam produced a depressor response at 0.0625 mg/kg dose while diazepam did not. The drugs did not appear to have any deleterious effect on the veins removed 6 hr after the first exposure to the drugs as evidenced by lack of histological changes. It is concluded that nitrazepam and diazepam produce central muscle relaxation by inhibiting polysynaptic pathways in the spinal cord. The potency of nitrazepam appears to be greater than that of diazepam. Definitive evidence has been provided that the peripheral neuromuscular or direct muscular actions are not involved in the muscular relaxation produced by the two drugs.

Role of opioidergic component in the antihypertensive effect of clonidine.

The role of opioidergic system in the antihypertensive effect of clonidine was investigated in albino normotensive and renal-DOCA-salt hypertensive models of rats. Clonidine (2.5, 5 and 10.0 micrograms/kg, iv) produced a dose-related depressor response. Yohimbine (2 mg/kg, ip) blocked the clonidine-induced responses in both normotensive and hypertensive rats. Naloxone (2 mg/kg, iv) blocked the clonidine-induced depressor responses in hypertensive rats, but not in normotensive animals. Morphine (0.11 mg/kg, iv) produced a depressor response in both normotensive and hypertensive rats. Yohimbine (1 mg/kg, iv) did not affect the hypotensive effect of morphine in normotensive or hypertensive rats, whereas pretreatment with naloxone significantly blocked the hypotensive effect of morphine in both groups of animals. It is concluded that the hypotensive effect of clonidine in hypotensive rats could be due to an opioidergic mechanism since it is blocked by both naloxone and yohimbine.

influence of Mg++ and reserpine on the reactivity of rat seminal vesicle to 5-hydroxytryptamine.

The effects of varying the concentration of Mg++ in the incubation medium on the contractile responses of rat isolated seminal vesicle to 5-hydroxytryptamine (5-HT) were investigated in the absence and presence of EDTA. Preparations incubated in Mg++-free and Mg++ excess media showed supersensitivity and subsensitivity to 5-HT respectively. In the presence of EDTA alterations in the sensitivity to 5-HT produced by varying the concentrations of Mg++ were comparatively less. Preparations obtained from reserpinized animals showed subsensitivity in normal and Mg++ excess media and supersensitivity in Mg++-free medium. In the presence of EDTA, reserpinized preparations showed slight supersensitivity in normal Mg++ medium, marked supersensitivity in Mg++-free medium and lesser subsensitivity in Mg++ excess medium. Probably EDTA by more effectively removing Mg++ from the membrane binding sites by chelation makes the membrane permeable to Ca++ leading to supersensitivity to 5-HT (observed only in the presence of EDTA). These results suggest that the failure of reserpine to induce supersensitivity to 5-HT in rat seminal vesicle may be due to an enhanced antagonism of Mg++ on Ca++ movements in this preparation due to the poor capacity of rat tissue to retain Ca++ (Krishnamurty and Grollman, 1976).

Blockade of 5-hydroxytryptamine-induced responses of rat seminal vesicle by lithium-possible mediation through calcium exchange..

Effect of lithium on the contractile responses of rat isolated seminal vesicle to 5-hydroxytryptamine (5-HT) were investigated by varying the Ca++ and Mg++ concentrations of the incubation medium in the absence and presence of EDTA. Preparations incubated in excess Ca++ (4.2 mM) or in Ca++-free Krebs solution showed decrease in sensitivity to 5-HT, whereas the responses to 5-HT were potentiated in Mg++-free incubation media and reduced in media containing excess Mg++. Rezerpinization failed to induce supersensitivity to 5-HT in any Mg++ concentration in the medium. However, reserpinized tissue in Mg++-free solution with EDTA showed increased sensitivity to 5-HT. Li+ inhibited responses to 5-HT. The inhibitory action of Li+ was augmented in medium lacking in Ca++ and was antagonized in media containing excess Ca++ (4.2mM). Li+ reduced the sensitivity and decreased maximum responses to 5-HT in any Mg++ concentration in the medium. In the presence of EDTA, the inhibition observed with Li+ in excess Mg++ (3.6 mM) medium was comparatively much less in both non-reserpinized and reserpinized preparations. Thus Li+ may be inhibiting responses to 5-Ht by block of influx of Ca++ or delayed efflux of Ca++ or inhibition of uptake of Ca++ or a combination of two or more of these effects.

Antagonism of calcium-induced contractions by some non-specific spasmolytics in depolarized smooth muscles.

The effects of papaverine MgCl2, cocaine, DNP, KCN and khellin on responses of some rabbit and rat tissues to CaCl2 were studied in vitro in a depolarizing medium. Guinea pig taenia coli preparation was used for comparison. In rabbit tracheal chain and vas deferens and guinea pig taenia coli preparations all spasmolytics shifted the concentration-response curves of CaCl2 to the right without affecting the maxima or slopes. In rat tracheal chain and vas deferens preparations all spasmolytics shifted the concentration-response curves of CaCl2 to the right. Furthermore all agents (except cocaine in tracheal chain preparations) depressed the maximum responses. The slopes were unaffected in either preparations. The initial competition and subsequent noncompetition observed in certain tissues is discussed in the light of the reported poor capacity of some tissues to retain Ca++ and the absence of releasable firmly bound Ca++ (11).

Studies on the sympathomimetic effects of guanoxan on smooth muscles of rat.

In anococcygeus muscle and vas deferens preparations of rat, guanidinomethyl-2-benzo-(1,4)-dioxane (guanoxan) potentiated responses to norepinephrine (NF) in concentrations which exerted a neurone blocking effect. The potentiation was significantly reduced in reserpinized preparations and was abolished in the presence of nialamide. The possible mechanisms of potentiation have been discussed. Higher concentrations of guanoxan produced concentration-related contractions. The contractions were significantly less in reserpinized preparations. Phentolamine both prevented and reversed the contractions while methysergide was ineffective in this respect. Thus the effect of guanoxan appears to be mediated through the activation of alpha-receptors by the released NE.