Effects of autacoid inhibitors and of an antagonist on malaria infection in mice.
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The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 +/- 4.5 to 16.1 +/- 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 +/- 5.8 to 4.9 +/- 0.75%) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials. (+info)
Cutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin.
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Elevated levels of serotonin (5-hydroxytryptamine, 5-HT) are observed in the serum of asthmatics. Herein, we demonstrate that 5-HT functions independently as an eosinophil chemoattractant that acts additively with eotaxin. 5-HT2A receptor antagonists (including MDL-100907 and cyproheptadine (CYP)) were found to inhibit 5-HT-induced, but not eotaxin-induced migration. Intravital microscopy studies revealed that eosinophils roll in response to 5-HT in venules under conditions of physiological shear stress, which could be blocked by pretreating eosinophils with CYP. OVA-induced pulmonary eosinophilia in wild-type mice was significantly inhibited using CYP alone and maximally in combination with a CCR3 receptor antagonist. Interestingly, OVA-induced pulmonary eosinophilia in eotaxin-knockout (Eot-/-) mice was inhibited by treatment with the 5-HT2A but not CCR3 receptor antagonist. These results suggest that 5-HT is a potent eosinophil-active chemoattractant that can function additively with eotaxin and a dual CCR3/5-HT2A receptor antagonist may be more effective in blocking allergen-induced eosinophil recruitment. (+info)
Anti-shock effect of cyproheptadine in rabbit.
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Twenty four New Zealand rabbits were equally divided into a cyproheptadine (Cyp) treated group and a control group. Profound hemorrhagic shock was produced by exsanguination via carotid artery until mean arterial pressure (MAP) = 5.3 kPa (40 mm Hg) for a period of 90 min. After given Cyp 10 mg.kg-1, the MAP and central venous pressure (CVP) of the treated group rose obviously (P less than 0.01) and the mesenteric microcirculation improved markedly. After 1 h, all indices returned nearly to the preshock state. The survival rate 2 h after Cyp increased to 12 (P less than 0.01) in comparison with the control group (7). The results showed that Cyp, which dilates the vasculature and improves the microcirculation through blocking serotonin S2 and histamine H1 receptors, has a beneficial anti-shock effect. (+info)
Role of brain amines in the fetal hyperpyrexia caused by tranylcypromine in LiCl-pretreated rats.
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Tranylcypromine (TCP), a monoamine oxidase inhibitor, caused a fatal hyperpyrexia in rats pretreated with LiCl once a day for 4 days. Pretreatment with LiCl alone did not alter the level of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) in the brain. In fatal hyperpyrexia caused by LiCl plus TCP, the brain 5-HT and DA levels were increased, whereas the brain NE level was decreased. Reserpine and alpha-methyl-p-tyrosine completely prevented the hyperpyrexia, but FLA-63 did not show any effect. The hyperpyrexia was completely prevented by p-chlorophenylalanine (PCPA) given 72 hours before TCP but not by PCPA given 24 hours before TCP. Haloperidol and chlorpromazine, DA receptor blockers, inhibited the fatal hyperpyrexia, while cyproheptadine and methysergide, 5-HT receptor blockers, did not. These results suggest that DA plays an essential role in the hyperpyrexia induced by the combination of TCP and LiCl in rats, but the involvement of 5-HT is inconclusive. (+info)
Different neuroendocrine systems modulate pulsatile luteinizing hormone secretion in photosuppressed and photorefractory ewes.
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The objective of this study was to determine whether two photoperiod regimens that induce anestrus in the ewe-short-day photorefractoriness (SDPR) and long-day photosuppression (LDPS)--act by different neuronal mechanisms. In separate experiments, ovary-intact (INTACT), ovariectomized (OVX), and ovariectomized estradiol-treated (OVX + E) ewes were subjected to three different photoperiodic regimens that resulted in reproductive quiescence: (1) exposure to long days (16L:8D), which caused photosuppression (INTACT, n = 9; OVX, n = 6; OVX + E, n = 5; (2) prolonged exposure to short days (10L:14D)), which caused photorefractoriness (INTACT, n = 10; OVX, n = 6; OVX + E, n = 5); (3) exposure to natural photoperiod, which induced seasonal anestrus (INTACT, n = 11; OVX, n = 6; OVX + E, n = 5). Effect of photoregimen was monitored by measuring progesterone or LH. Drug challenges were made after two sequential estrous cycles were missed in INTACT ewes, after mean LH concentrations dropped below 1 ng/ml in OVX + E ewes, and after LH interpulse intervals increased in OVX ewes. Effects of drug on LH pulse pattern were determined by taking blood samples at 12-min intervals for 8 h after i.v. diluent injection; then for 8 h after i.v. injection of cyproheptadine, a serotonin antagonist (3 mg/kg); and again 7 days later after i.v. injection of diluent or pimozide, a dopamine antagonist (0.25 mg/kg). Cyproheptadine had little effect except to decrease (p = 0.05) mean LH in INTACT anestrous ewes and decrease (p less than 0.01) pulse amplitude in OVX + E SDPR ewes. Pimozide did not affect LH pulse frequency in LDPS ewes. However, pimozide increased LH pulse frequency (p less than 0.005) and mean concentrations (p less than 0.005) in SDPR OVX + E ewes, whereas it suppressed LH pulse frequency (p less than 0.05) and amplitude (p less than 0.03) in SDPR INTACT and SDPR OVX ewes. The results suggest that (1) the role of the dopaminergic system differs in SDPR and LDPS ewes, and that different neuronal systems may effect SDPR and LDPS, (2) the effect of pimozide in SDPR ewes is altered by ovarian steroids, and (3) the serotonergic system has relatively little role in regulating pulsatile LH secretion in any of the three different states of anestrus. (+info)
Antipruritic and antierythema effects of ascomycete Bulgaria inquinans extract in ICR Mice.
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The effect of ethanol extract obtained from Bulgaria inquinans on the scratching behavior and vascular permeability changes induced by compound 48/80, histamine and serotonin in ICR mice was studied. The extract dose-dependently inhibited scratching behavior induced by compound 48/80 and serotonin. A significant inhibition was observed at doses of 300 and 600 mg/kg when Bulgaria inquinans extract was administered orally. However, no inhibitory effect was observed on the histamine-induced scratching behavior by the extract, even at a dose of 600 mg/kg. In addition, it also inhibited the increase in the vascular permeability induced by compound 48/80 and serotonin at doses of 300 and 600 mg/kg; however, it failed to inhibit the increased vascular permeability induced by histamine, even at a dose of 600 mg/kg. Bulgaria inquinans extract showed a potent inhibitory effect on histamine release induced by compound 48/80. These results suggest that Bulgaria inquinans extract is effective in cutaneous pruritus and erythema, which were probably mediated by inhibiting the release of histamine from mast cells and antagonizing the effect on serotonin. (+info)
Acute anticholinergic poisoning in children.
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We report two cases of unintentional poisoning with anticholinergic agents. The first patient, a 7-year-old girl, was prescribed four different medications by a general practitioner for treatment of abdominal colic and diarrhoea. All drugs had anticholinergic properties. The second patient, a 16-month-old boy, ingested his mother's cyproheptadine tablets. Both children presented with central and peripheral symptoms and signs compatible with acute anticholinergic syndrome. They recovered spontaneously following intravenous fluid replacement and close observation. Gastric lavage was also performed on the boy. Poisoning with cholinergic antagonists in children is a potentially serious hazard in Hong Kong. It may be avoided by careful prescribing on the part of general practitioners and safe storage of all medicinal products in the home environment. (+info)
New antihistamines: a critical view.
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OBJECTIVES: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES OF DATA: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSION: On the basis of the evidence on H1 antihistamines, none of them deserve the title "third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS. (+info)