The late 20th century witnessed the novel discovery of "Nitrergic" or "Nitroxidergic" innervation of the vascular smooth muscles, their role as a vasodilator in cerebral, ocular and penile vasculature, as well as their reciprocal action to adrenergic vasoconstriction. The identification of this nerve as a postganglionic parasympathetic nerve, the discovery of autonomic efferent nerves where Nitric oxide (NO) is the neurotransmitter (NTM) to blood vessels, its physiological role in the control of smooth muscle tone, and the pharmacological implications of NO have been reviewed. This will aid an in-depth analysis of vascular dysfunctions and the development of strategic pharmacotherapeutic interventions with time.

The lipid-lowering actions of statins are well known. However, recent studies provide compelling evidence that the clinical benefits of statin therapy may also be attributed to mechanisms independent of their cholesterol-lowering effects. These non-lipid-lowering (pleiotropic) effects of statin therapy are believed to include antiinflammatory actions, property to reverse endothelial dysfunction by decreasing LDL oxidation and increasing nitric oxide bioavailability. Their antioxidant actions, ability to provide plaque stability, favorable coagulation profile, ability to prevent platelet aggregation and normalize sympathetic outflow as well as their antiproliferative and immunosuppressive properties also contribute to the non-lipid-lowering effects. These pleiotropic effects shown by statin therapy offer many advantages over the currently available drugs for dyslipidemias. These additional benefits not only find therapeutic application in cardiovascular disorders but also in many other disease states.

The new generation of analgesics and antiinflammatory drugs, namely, the selective inhibitors of cyclooxygenase-2 (COX-2) enzymes, popularly known as Coxibs, have become a very popular class of drugs because of their gastro-sparing property. Coxibs were the widely prescribed drugs (nearly 8 million people round the globe take these drugs) until the recent setback with rofecoxib, which was withdrawn from the market by the innovator due to increased risk of heart attacks and strokes observed with its long-term use. The withdrawal of this popular NSAID has not only caused a great setback in the global market of coxibs but has also questioned the ethics involved in the toxicity testing and sharing of information with the end users of this new class of drugs. This article briefly reviews the developments in coxib theory, the clinical efficacy and safety of these agents in the light of the latest cardiovascular concerns.

OBJECTIVE: To investigate the in vivo mutagenic effects of ribavirin in mice. METHODS: Mice were injected (i.p.) 20, 100, or 200 mg/kg ribavirin (single exposure) for bone marrow micronucleus, peripheral blood micronucleus and bone marrow chromosome aberration tests. Five treatments of 200 mg/kg ribavirin was given (i.p.) for sperm morphology test. The tests were performed as per the standard procedures. RESULTS: Ribavirin induced significant number of micronucleated polychromatic erythrocytes (MNPCEs) at 24, 48 and 72 h following the exposure with more effects at 24 h (p<0.05-0.001). Micronucleated PCEs were more at 48 h in lower dose-levels and at 72 h in highest dose-level in the peripheral blood (p<0.05-0.001). Ribavirin induced structural chromosomal damage hence producing the fragments for the micronucleus formation. Ribavirin decreased the PCE%, P/N ratio and the mitotic index indicating that it prevents cell division in mouse bone marrow. Ribavirin also decreased the testis weight and induced the formation of abnormal sperms. CONCLUSION: Ribavirin is a potent mutagen and cytotoxic agent in mice in vivo. Further, it also induces point mutations in germ cells yielding abnormal sperms. The genotoxic effects of ribavirin are not exerted in a dose-dependent pattern in mouse.

OBJECTIVE: To investigate the effect of lyophilized aqueous extract of pericarps of Sapindus trifoliatus (ST) in various in vitro and in vivo inflammatory models. METHODS: ST was studied for its in vitro inhibitory activity against 5-lipoxygenase (5-LO), cyclo-oxygenase (COX), leukotriene B4 (LTB4) and nitric oxide synthase (NOS). At doses 20 and 100 mg/kg, i.p. ST was evaluated in acute pedal inflammation induced by carrageenan, histamine, serotonin and zymosan in rats and mice. Further, the effect of topical application of the extract (1 mg and 5 mg) on ear inflammation induced by various inflammatory agents like -O-tetradecanoyl-phorbol 13-acetate (TPA) or capsaicin or arachidonic oxazolone or dinitrofluorobenzene (DNFB) was also investigated. RESULTS: In vitro evaluation of the extract revealed its inhibitory activity against the major inflammatory mediators 5-LO, COX, LTB4 and NOS. The extract significantly inhibited the pedal inflammation produced by carrageenan, histamine, serotonin and zymosan. Further, topical application of ST significantly inhibited the ear inflammation induced by acute and multiple applications of TPA and acute application of capsaicin or arachidonic acid. However, the extract failed to inhibit ear inflammation induced by oxazolone or DNFB. CONCLUSION: ST has antiinflammatory activity possibly mediated through 5-LO and COX pathways.

OBJECTIVE: Sulphur mustard (SM), chemically 2,2'-dichloro diethyl sulphide, is an incapacitating and extremely toxic chemical warfare agent, and causes serious blisters on contact with human skin. SM forms sulphonium ion in the body that alkylates DNA and several other macromolecules, and induces oxidative stress. The aim of this study was to evaluate the protective effect of Aloe vera L. gel against SM-induced systemic toxicity and skin lesions. MATERIALS AND METHODS: Aloe vera gel was given (250, 500 and 1000 mg/kg) orally to mice as three doses, one immediately after SM administration by percutaneous route, and the other two doses on the next two days. Protective index was calculated with and without Aloe vera gel treatment. Aloe vera gel was also given orally as three doses with 3 LD50 SM and the animals were sacrificed for biochemical and histological evaluation, 7 days after SM administration. In another set of experiment Aloe vera gel was liberally applied on the SM administered skin site and the animals were sacrificed after 14 days to detect its protective effect on the skin lesions induced by SM. RESULTS: The protection given by Aloe vera gel was marginal. 1000 mg/kg dose of Aloe vera gel gave a protection index of 2.8. SM significantly decreased reduced glutathione (GSH), oxidised glutathione (GSSG) and WBC count, and significantly increased malondialdehyde (MDA) level, RBC count and Hb concentration. Aloe vera gel offered protection only in the increase of MDA level by SM. Severe damage was observed in the histology of liver, spleen and skin following SM administration, and 1000 mg/kg of Aloe vera gel partially protected the lesions. However, topical application of Aloe vera gel showed better protection of the skin lesions induced by SM. CONCLUSION: The study shows that percutaneous administration of SM induces oxidative stress and oral administration of Aloe vera gel could only partially protect it. Topical application of Aloe vera gel may be beneficial for protecting the skin lesions induced by SM.

OBJECTIVE: To examine the relaxant effects of the macerated and aqueous extracts of Cuminum cyminum on the tracheal chains of guinea pig. MATERIALS AND METHODS: The relaxant effects of cumulative concentrations of macerated and aqueous extracts (0.25, 0.5, 0.75 and 1.0 g%) in comparison with saline and theophylline (0.25, 0.5, 0.75, and 1.0 mM) were examined on pre-contracted tracheal chains of guinea pigs under different conditions. RESULTS: In Group 1 experiments (contracted by KCl) only the last two concentrations of theophylline and the highest concentration of macerated extract showed significant relaxant effect compared to that of saline (P<0.001 and P<0.05 for theophylline and macerated extract respectively). The effects of the last two concentrations of theophylline in this group were significantly greater than those of the macerated and aqueous extracts (P<0.001). However, in Group 2 experiments (contracted by methacholine) both the extracts and theophylline showed concentration-dependent relaxant effect compared to that of saline (P<0.05 to P<0.001). The effects of the two last concentrations of both extracts were significantly lower than those of theophylline in Group 2 experiments (P<0.05 to P<0.001). In Group 3 (non-incubated, contracted by methacholine) the extracts of Cuminum cyminum did not show any relaxant effect of tracheal chains. The relaxant effects of macerated and aqueous extracts in Groups 1 and 3 were significantly lower than those of Group 2 (P<0.05 to P<0.001). However, the effects of different concentrations of theophylline obtained in Group 1 and 2 were not significantly different. There was a significant correlation between the effects and concentrations of theophylline in Groups 1 and 2, macerated extract in Groups 2 and 3 and aqueous extract in Group 1 (P<0.05 to P<0.001). CONCLUSION: These results show a potent relaxant effect of Cuminum cyminum on guinea pig tracheal chains which may be due to a stimulatory effect of the plant on β-adrenoceptors and/or an inhibitory effect on histamine H1 receptors.

OBJECTIVE: To study the skeletal muscle relaxant property of Chonemorpha macrophylla (CM). MATERIALS AND METHOD: The skeletal muscle relaxant effect of the alcoholic extract of CM was studied on isolated frog rectus abdominis muscle, isolated rat phrenic nerve diaphragm muscle preparation and in intact young chicks. The parameter studied in the isolated muscle or isolated nerve muscle preparations was the extent of inhibition of acetylcholine or electrically-induced contraction of skeletal muscles. In intact chicks, the drug was administered i.v. in wing veins and the onset, duration and nature of paralysis were recorded. In all the experiments, the effect of the drug was compared with that of gallamine and succinylcholine. RESULTS: The alcoholic extract of CM reduced the acetylcholine-induced contraction of isolated frog rectus abdominis and electrically stimulated contractions of rat phrenic nerve diaphragm in a dose-dependent manner. In unanaesthetized chicks, it produced spastic type of paralysis with extension of the neck and limbs. The effects were similar to the effects of succinylcholine but different from those of gallamine. CONCLUSION: The alcoholic extract of CM possesses skeletal muscle relaxant property. It produces depolarizing type of muscle paralysis similar to that produced by succinylcholine.

OBJECTIVE: To evaluate the potential dopaminergic and serotonergic receptor-mediated modulatory effect of the aqueous extract of Sapindus trifoliatus [(ST), (family: Sapindaceae)], a traditional phytomedicine used in the treatment of hemicrania (migraine), using animal models and receptor assays. MATERIALS AND METHODS: ST (at 20 and 100 mg/kg, i.p. doses) was evaluated for its effect on apomorphine-induced climbing behavior, 5-hydroxytryptophan (l-5-HTP)-induced serotonin syndrome, and MK-801-induced hyperactivity in mice. The radioligand binding studies for various receptors and enzymes were carried out (outsourced) using standard procedures at 250 µg/ml concentration of ST. RESULTS: ST significantly inhibited the apomorphine-induced climbing behavior, the l-5-HTP-induced serotonin syndrome and MK-801-induced hyperactivity in mice. In the receptor radioligand binding studies, ST exhibited affinity towards dopamine D2, 5-HT2A receptors. CONCLUSION: The results of the behavioral studies in mice indicate that ST modulated D2 and 5-HT2A receptor-mediated paradigms. The radioligand binding studies supported these observations, suggesting the possible involvement of dopaminergic and serotonergic mechanisms in the antimigraine activity of ST.