Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new ketotifen research articles will be listed here shortly after becoming available to us.
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Medical research on ketotifen
Effect of Mast Cell Stabilizers in Hyperhomocysteinemia-induced Cardiac Hypertrophy in Rats.
J Cardiovasc Pharmacol. 2008 Jun; 51(6): 596-604
Singh AP, Singh M, Balakumar P
The present study has been designed to investigate the effect of sodium cromoglycate and ketotifen, mast cell stabilizers in hyperhomocysteinemia-induced cardiac hypertrophy in rats. METHODS:: Rats were administered L-methionine (1.7 g/kg/day PO) for 8 weeks to produce hyperhomocysteinemia. Sodium cromoglycate (24 mg/kg/day IP) and ketotifen (1mg/kg/day IP) treatments were started from first day of administration of L-methionine and continued for 8 weeks. The development of cardiac hypertrophy was assessed in terms of measuring mean arterial blood pressure (MABP), ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content, and LV collagen content. Further, the oxidative stress in heart was assessed by measuring lipid peroxidation, superoxide anion generation, and reduced glutathione (GSH). Moreover, the cardiomyocyte diameter and LV mast cell density were determined using hematoxylin-eosin and toluidine blue staining, respectively. RESULTS:: The L-methionine administration produced hyperhomocysteinemia, which significantly increased MABP, oxidative stress, and density of mast cells and consequently produced cardiac hypertrophy by increasing cardiomyocyte diameter, LVW/BW, LVWT, LV protein and collagen content. However, sodium cromoglycate and ketotifen treatments significantly attenuated hyperhomocysteinemia-induced oxidative stress and pathological cardiac hypertrophy without significantly altering MABP. Moreover, sodium cromoglycate and ketotifen treatments did not affect serum homocysteine levels. CONCLUSIONS:: Thus, it may be concluded that hyperhomocysteinemia-induced cardiac hypertrophy is associated with an increase in oxidative stress and density of mast cells in heart. Sodium cromoglycate and ketotifen may have attenuated hyperhomocysteinemia-induced pathological cardiac hypertrophy, possibly by reducing oxidative stress and preventing the degranulation and increase in density of mast cells.
Nihon Shinkei Seishin Yakurigaku Zasshi. 2008 Apr; 28(2): 75-83
Nakao K, Ikeda K, Kurokawa T, Togashi Y, Umeuchi H, Honda T, Okano K, Mochizuki H
In atopic dermatitis patients, pruritus is a severe symptom that is difficult to treat. It is previously reported that TRK-820, a kappa-opioid receptor agonist, reduces murine scratching behavior induced by an intradermal injection of histamine or substance P or an intracisternal injection of morphine. It is also reported that TRK-820 ameliorates the intractable pruritus in hemodialysis patients. However, it is still unclear whether TRK-820 possesses antipruritic effects on the pruritus in dermatitis patients. Therefore, the effect of TRK-820 on scratching behavior in NC/Nga mice maintained in a conventional environment, an animal model of atopic dermatitis, was examined. Oral TRK-820 (10-100 microg/kg) inhibited the scratching behavior but did not affect the locomotor activity. On the other hand, ketotifen (3-30 mg/kg, po), an antihistamine, did not attenuate the scratching behavior. TRK-820 showed the highest selectivity and activity for kappa-opioid receptor among all human opioid receptors. Release of various inflammatory mediators from a variety of cells and activity of nitric oxide synthase were not altered by TRK-820. This compound showed much lower affinities for other receptors than that for opioid receptors. These results suggest that TRK-820 is effective against antihistamine-resistant pruritus in atopic dermatitis patients via the kappa opioid receptor.
Exp Toxicol Pathol. 2008 May 29;
Sánchez-Patán F, Aller MA, Cuellar C, Rodero M, Corcuera MT, Nava MP, Gómez F, Blanco MD, Guerrero S, Anchuelo R, Muñiz E, Alonso MJ, Teijón JM, Arias J
Experimental early prehepatic portal hypertension induces an inflammatory exudative response, including an increased infiltration of the intestinal mucosa and the mesenteric lymph nodes by mast cells and a dilation and tortuosity of the branches of the superior mesenteric vein. The aim of this study is to verify that the prophylactic administration of Ketotifen, a stabilizing drug for mast cells, reduces the consequence of splanchnic inflammatory response in prehepatic portal hypertension. Male Wistar rats were used: Sham-operated and with Triple Partial Portal Vein Ligation, which were subcutaneously administered poly(lactide-co-glycolide) acid microspheres with vehicle 24h before the intervention and SO and rats with Triple Partial Portal Vein Ligation, which were administered Ketotifen-loaded microspheres. Around 48h after surgery, the portal pressure was measured; the levels of chymase (Rat Mast Cell Protease-II) were assayed in the superior mesenteric lymph complex and granulated and degranulated mast cells in the ileum and cecum were quantified. Prophylactic administration of Ketotifen reduced portal pressure, the incidence of dilation and tortuosity of the superior mesenteric vein branches, the amount of Rat Mast Cell Protease-II in the superior mesenteric lymph complex and the number of activated mast cells in the cecum of rats with portal hypertension. In summary, the administration of Ketotifen reduces early splanchnic inflammatory reaction in the rat with prehepatic portal hypertension.
Development and characterisation of a novel and rapid lung eosinophil influx model in the rat.
Pulm Pharmacol Ther. 2008 Apr 7;
Werner-Klein M, Göggel R, Westhof A, Erb KJ
Eosinophils play a major role in the development and severity of asthma. Robust and rapid preclinical animal models are desirable to profile novel therapeutics inhibiting the influx of eosinophils into the airways. To develop a rapid, airway eosinophil recruitment model in the rat, Brown-Norway (BN) rats were immunised with ovalbumin (OVA)/alum on day 0, 1 and 2 and challenged with OVA aerosol on day 5 and 6. On day 7 bronchoalveolar lavage fluid (BALF) was analysed for eosinophil numbers, eosinophil peroxidase (EPO) activity and cytokines. Lung sections were also examined. The immunised animals showed a strong selective influx of eosinophils into the airways correlating with enhanced EPO activity, Interleukin (IL-4), IL-5 and monocytes chemo attractant protein levels in the BALF in comparison to sham-sensitised rats. In addition the immunised rats developed goblet cell metaplasia in the lung and showed OVA specific IgG1 and IgE levels in the serum but no airway hyperreactivity after metacholine challenge. Airway inflammation was suppressed by applying the steroids Budesonide (intra tracheally) and Prednisolone (per orally), Roflumilast a phosphodiesterase-4 inhibitor, and the H1 receptor antagonists Epinastine and Ketotifen. Montelukast, a Leukotriene receptor antagonist and Chromoglycate, a mast cell stabiliser, had no effect in this model. In summary, in this novel preclinical rat model therapeutics expected to inhibit the development of airway eosinophilia can rapidly be tested.
Int Immunopharmacol. 2008 Jul; 8(7): 1049-55
Youssouf MS, Kaiser P, Singh GD, Singh S, Bani S, Gupta VK, Satti NK, Suri KA, Johri RK
An immunopharmacological profile of 2, 7-dimethyl-3-nitro-4H pyrido [1,2-a] pyrimidine-4-one (P-I) has been investigated using in vitro and in vivo models representing various features of Type I allergy. P-I prevented compound 48/80-mediated histamine release from rat peritoneal mast cells. A promising anti-inflammatory activity of P-I was evident in active paw anaphylaxis (mice) and carragenan-induced paw edema (rat). P-I inhibited eosonophil accumulation and eosinophil peroxidase activity in bronchoalveolar lavage fluid from ovalbumin challenged balb/c mice: in these animals blood levels of IL-5, and CD4(+) T cells also remained attenuated. A promising bronchorelaxant effect of P-I was observed in histamine-contracted guinea pig tracheal chain via its antagonism to H1 receptor. These findings were compared with some known compounds (ketotifen, cetirizine and promethazine). The anti-histaminic, anti-inflammatory and bronchorelaxant activities of P-I has been discussed in context with its potential profile as an anti-allergic and anti-asthmatic agent.
J Pharmacol Sci. 2008 May; 107(1): 66-79
Hishinuma S, Sato Y, Kobayashi Y, Komazaki H, Saito M
We evaluated changes in the binding properties of sedative and non-sedative histamine H1-receptor antagonists induced by internalization of H1 receptors in intact human U373 MG astrocytoma cells. Internalization of H1 receptors was induced without their degradation by treatment with 0.1 mM histamine for 30 min at 37 degrees C, and then the intact cell binding assay was performed at 4 degrees C. The binding properties of [3H]mepyramine, a cell-penetrating radioligand for H1 receptors, were not changed by histamine pretreatment. Displacement curves for sedative H1-receptor antagonists (diphenhydramine, chlorpheniramine, promethazine, ketotifen, azelastine and oxatomide) against [3H]mepyramine binding were not changed by histamine pretreatment. In contrast, the displacement curves for non-sedative H1-receptor antagonists (mequitazine, bepotastine, olopatadine, epinastine, carebastine, desloratadine and fexofenadine) were changed by histamine pretreatment: two types of changes, i.e. a rightward shift in the monophasic curve or an increase in the proportion of the low affinity component of the biphasic curve, were prevented under hypertonic conditions, in which clathrin-mediated receptor internalization is known to be inhibited. Thus, internalization-mediated changes in the binding properties of H1-receptor antagonists were well correlated with their sedative and non-sedative behaviors, which might confirm their permeability through the biomembrane and possibly the blood brain barrier.
Am J Physiol Heart Circ Physiol. 2008 Jun; 294(6): H2456-64
Santone DJ, Shahani R, Rubin BB, Romaschin AD, Lindsay TF
Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after HS and resuscitation (HS/R) with the administration of the MC stabilizers to prevent MC degranulation. Anesthetized male Sprague-Dawley rats were randomized to sham-operated control or HS/R groups and underwent 60 min of HS followed by 2 h of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline 15 min before shock. Hearts were excised following HS or 2 h of reperfusion, and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum beta-hexosaminidase. Hearts were excised at 0 min (before HS) and following 60 min of HS (before resuscitation) for a histological evaluation of MC density and degranulation. In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure (P < 0.05), contractility (P < 0.05), and relaxation (P < 0.05) compared with that of HS controls. Serum beta-hexosaminidase increased during HS/R and was inhibited by MC stabilization (P < 0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. The inhibition of MC degranulation can significantly improve cardiac function following HS/R.
Exp Eye Res. 2008 May; 86(5): 791-7
Sanchis-Merino ME, Montero JA, Ruiz-Moreno JM, Rodriguez AE, Pastor S
In order to compare the relative efficacy of topical antihistamines with balanced saline solution (BSS) and benzalkonium chloride (BC) in the early phase of allergic conjunctivitis in an animal model of ocular anaphylaxis, 96 male guinea pigs were sensitized with intraperitoneal egg albumin (EA) and aluminum hydroxide. Seventy-six animals were used for determination of Evans blue (EB) extravasation and 20 for clinical evaluation of the allergic response (redness, edema, discharge and itch-scratch response). Eighteen days after sensitization the animals were topically challenged by conjunctival instillation of EA and treated 15 min before and 15 min after challenge with commercially available drugs (ketotifen, ketotifen single dose units [SDU], olopatadine, azelastine, spaglumic acid and emedastine) and controls (BSS and BC). The animals used for EB quantification were anesthetized and received an intravenous injection of EB simultaneously to the topical challenge. The ocular extravasation of the colorant was determined by 620 nm absorbance spectrophotometry. The animals used for clinical evaluation were observed for clinical signs of the allergic reaction. EB ocular extravasation was significantly lower in the eyes treated by spaglumic acid and emedastine. The clinical scoring was consistent with EB extravasation, though the difference was not statistically significant. Spaglumic acid and emedastine seem to be the most useful drugs to reduce EB extravasation and allergic signs in an animal model of early phase allergic conjunctivitis.
Wound Repair Regen. 2008 Mar-Apr; 16(2): 226-33
Gallant-Behm CL, Hildebrand KA, Hart DA
Skin wound healing in Yorkshire pigs closely approximates human wound healing. Conversely, red Duroc pigs form fibroproliferative, hypercontractile scars. As mast cells have been implicated in several fibrotic conditions, the present study used these models to evaluate the potential role of mast cells in wound contraction and fibrosis. Immediately following the creation of full-thickness excisional wounds, the mast cell stabilizer ketotifen was used to treat both Yorkshire and red Durocs. Control red Durocs showed significantly more wound contraction than Yorkshires, both before and after reepithelialization. Ketotifen treatment significantly reduced the first phase of contraction in red Duroc wounds to a level equivalent to Yorkshire wounds, but had no detectable effect on the postepithelialization phase of contraction. Cessation of drug treatment after 10 weeks did not lead to resumption of excessive contraction in red Durocs, indicating that ketotifen blocked rather than delayed such contraction during a critical phase of healing. Ketotifen treatment also reduced the deposition of collagen within the red Duroc wounds, but did not affect Yorkshire wound contraction or collagen deposition. These results suggest that ketotifen may be an effective treatment for the reduction of excessive wound contraction and fibrosis in human cutaneous injuries, without affecting the normal healing process.
Eur J Pharmacol. 2008 Mar 31; 583(1): 92-6
Kim HJ, Kim H, Han ES, Park SM, Koh JY, Kim KM, Noh MS, Kim JJ, Lee CH
Sphingosylphosphorylcholine (SPC) is upregulated in the stratum corneum of atopic dermatitis patients by sphingomyelin deacylase. We conducted an investigation, both to confirm that intradermal injection of SPC elicits scratching in mice, and to elucidate the detailed mechanism of the SPC-induced itch-scratch response. Intradermal administration of SPC increased the incidence of scratching behavior in a dose-dependent manner. SPC-induced scratching could be suppressed, significantly, by the mu-opoid receptor antagonist, naltrexon, the vaniloid receptor agonist, capsaicin, and the histamine H1 receptor antagonist ketotifen. d-erythro SPC, one of the SPC stereotypes, could elicit the scratch response, but not l-threo SPC. Y-27632 (1 mg/kg, an inhibitor of Rho-associated protein kinase (ROCK)), was found to suppress SPC-induced scratching. Both the stereospecificity of SPC and the involvement of the Rho/ROCK pathway suggested that SPC-induced scratching is related to the receptor.