Leukotriene D4 Receptor Research Articles

Can montelukast sodium be an alternative treatment in the treatment of interstitial cystitis?

The leukotriene D4 receptors have been detected in human bladder detrusor myocytes, and they can play the role of interstitial cystitis etiology. Our study aims to explain the role of mast cells histologically and immunohistochemically in the pathogenesis and the effectiveness of montelukast that leukotriene D4 receptor antagonist in the treatment of interstitial cystitis. Twenty-four Wistar albino adult female rats were used. Group 1 (n = 8): control (sham) group, Group 2 (n = 8): interstitial cystitis group, and Group 3 (n = 8): treatment group. Groups 2 and 3 rats were administered 75 mg/kg cyclophosphamide four times every three days intraperitoneally. The rats in the treatment group were started on montelukast sodium as 10 mg/kg, 1 × 1/day per orally after the last administration of cyclophosphamide and were given for 14 days. Mast cells in the bladder tissues were examined histologically, and the presence of IL-6, 8, VEGF, and TNF alpha was examined immunohistochemically. Thin transitional epithelium, loose connective tissue, weak smooth muscle bundles, and signs of chronic inflammation were observed in the interstitial cystitis group. Regenerated transitional epithelium, intact basement membrane, compact lamina propia, thick smooth muscle bundles, and rare inflammatory cells were observed after the treatment with the montelukast. Mast cells were decreased in bladder tissue after treatment. IL-6, IL-8, VEGF, and TNF alpha levels were significantly decreased after treatment. We found that inflammatory mediators were significantly reduced after treatment with montelukast in the interstitial cystitis group. Montelukast can be used as an effective drug in the treatment of interstitial cystitis.

Understanding the pathophysiological changes via untargeted metabolomics in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease caused by anew strain of the coronavirus. There is limited data on the pathogenesis and the cellular responses of COVID-19. In this study, weaimedto determine the variation of metabolites between healthy control and COVID-19 via the untargeted metabolomics method. Serum samples were obtained from 44 COVID-19 patients and 41 healthy controls. Untargeted metabolomics analyses were performed by the LC/Q-TOF/MS (liquid chromatography quadrupole time-of-flight mass spectrometry) method. Data acquisition, classification, and identification were achieved by the METLIN database and XCMS. Significant differences were determined between patients and healthy controls in terms of purine, glutamine, leukotriene D4 (LTD4), and glutathione metabolisms. Downregulations were determined in R-S lactoglutathione and glutamine. Upregulations were detected in hypoxanthine, inosine, and LTD4. Identified metabolites indicate roles for purine, glutamine, LTD4, and glutathione metabolisms in the pathogenesis of the COVID-19. The use of selective leukotriene D4 receptor antagonists, targeting purinergic signaling as a therapeutic approach and glutamine supplementation may decrease the severity and mortality of COVID-19.

Montelukast Efficiency in Improving the Deleterious Gastrointestinal Effects of Dexamethasone in Rats

Abstract Background: Montelukast and dexamethasone are used in combination in the treatment of asthma. Treatment by steroids resulted in gastric mucosa weakening enhancing the occurrence of ulcer in addition to its effect on the motility and contractility of gastrointestinal tract. Aim of Study: The present study was designed to evaluate the anti-ulcer effect of montelukast, a selective leukotriene (LT) D4 receptor antagonist compared to famotidine and its effect on the motility and contractility of the small intestine in gastric ulcer induced by dexamethasone and aggravated by cold stress. Material and Methods: Adult male rats were divided into 5 groups: The first received normal saline. The other groups were given dexamethasone intraperitoneally (4mg/kg/day) for 5 days. The third group received famotidine 40mg/kg/day while the fourth and fifth groups received montelukast 30 and 60mg/kg/day orally respectively thirty minutes after dexam-ethasone. At the end, rats were exposed to cold stress then sacrificed to extract the stomachs and intestines to determine gastric ulcer score and intestinal transit then the response of small intestine to acetyl choline was recorded. Then the stomachs were divided for histopathological and biochemical studies. Results: Dexamethasone treatment resulted in ulceration of gastric mucosa, increased intestinal transit, diminished intestinal contraction and increased oxidative stress. The group treated with montelukast 60mg/kg/day showed a sig-nificant decrease in mean gastric ulcer score, intestinal transit but increase of intestinal contractility. All treated groups showed significant MDA decrease, improved histopathological picture of the stomach while the two montelukast treated groups showed significant increase in SOD. Conclusion: Montelukast with high dose shows a prom-ising role in eliminating the undesirable effects induced by corticosteroids especially if associated with stress.

Effects of montelukast on human nasal mucosa.

Montelukast is a selective and orally active leukotriene D4 receptor antagonist often used in treating asthma and allergic rhinitis. Montelukast nasal spray was developed to avoid systemic adverse effects of the drug in vitro. However, the effects of montelukast on human nasal mucosa are not yet fully explored and potential nasal vascular side effects of the drug merit further exploration. First, the effects of montelukast on vasocontractile responses generated by smooth muscles in the vascular structures of human nasal mucosa were investigated directly in vitro. This study examined the effects of montelukast on human nasal mucosa in terms of mucosa resting tension, vasoconstriction caused by 10- 6 M methoxamine as a sympathetic mimetic, and electrically induced vasoconstrictions. The results indicated that addition of methoxamine to the incubation medium caused the nasal mucosa to vasocontract in a dose-dependent manner. Addition of montelukast at doses of 10- 5 M or above elicited a significant vasodilation response to 10- 6 M methoxamine-induced vasoconstriction. Montelukast could not inhibit electrical field stimulation-induced spike vasoconstriction. Moreover, increase in concentration of montelukast had minimal effect on basal tension of nasal mucosa. The study indicated significant vasodilation on human nasal mucosa under high concentrations of montelukast with a probable α-adrenoceptor antagonism. Hence, the nasal activity of α-adrenergic agonist nasal spray for nasal obstruction may be reduced in those using concomitant (oral or local spray) montelukast.

Role of Cysteinyl Leukotrienes in Allergic Rhinitis.

Cysteinyl leukotrienes (CysLTs) are lipid mediators that have been implicated in the pathogenesis of allergic rhinitis. Pharmacological studies using CysLTs indicate that two classes of receptor exist: CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R). The CysLT1R is a high-affinity leukotriene D4 receptor with lower affinity for leukotriene C4 that is sensitive to the CysLT1R antagonist currently used to treat asthma and allergic rhinitis. Our previous immunohistochemical and autoradiographic studies have demonstrated the presence of anti-CysLT1R antibodies labeled in eosinophils, mast cells, macrophages, neutrophils and vascular endothelial cells in human nasal mucosa. Furthermore, we have revealed that the novel radioactive CysLT1R antagonist [3H]-pranlukast bound specifically to CysLT1R in human inferior turbinates and its binding sites were localized to vascular endothelium and the interstitial cells. These data suggest that the major targets of CysLT1R antagonists in allergic rhinitis are the vascular bed and infiltrated leukocytes such as mast cells, eosinophils and macrophages. Clinical trials have demonstrated that CysLT1R antagonists are as effective as antihistamines for the treatment of allergic rhinitis; however, they are less effective than intranasal steroids. The use of CysLT1R antagonists in combination with antihistamines has generally resulted in greater efficacy than when these agents were used alone.

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors.

Senile plaques comprised of Aβ peptides are a hallmark of Alzheimer’s disease (AD) brain, as are activated glia that release inflammatory molecules, including eicosanoids. Previous studies have demonstrated that amyloid precursor protein (APP) and Aβ levels can be increased through activation of thromboxane A2-prostanoid (TP) receptors on neurons. We demonstrate that TP receptor regulation of APP expression depends on Gαq-signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gαq-linked prostaglandin E2 and leukotriene D4 receptors also regulate APP expression. Prostaglandin E2 and thromboxane A2, as well as total APP levels, were found to be elevated in the brains of aged 5XFAD transgenic mice harboring Aβ plaques and activated glia, suggesting that increased APP expression resulted from eicosanoid binding to Gαq-linked neuronal receptors. Notably, inhibition of eicosanoid synthesis significantly lowered brain APP protein levels in aged 5XFAD mice. These results provide new insights into potential AD therapeutic strategies.

Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo

The multidrug resistance protein 4 (MRP4) is a member of the ABCC subfamily of the adenosine triphosphate-binding cassette transporters that remove cyclic nucleotides from platelets and uptake ADP into dense granule in platelets. However, whether MRP4 directly involves platelet activation remains unclear. Thus, the aim of our study was to determine the detailed mechanisms underlying the regulation of MRP4 in platelet activation. Our results revealed that the MRP4 inhibitor MK571 inhibited collagen-induced platelet aggregation which was partially reversed by the PKA inhibitor H89, but not by the adenylyl cyclase (AC) inhibitor SQ22536 and the guanylyl cyclase (GC) inhibitor ODQ, suggesting that MK571 can prevent collagen-induced aggregation via a route independent of cyclic nucleotide production. In the present study, we found that MK571 inhibited collagen-induced ATP release and calcium mobilization. The phosphorylation of protein kinase C, JNK, and Akt was also inhibited by MK571, and electron spin resonance experiment showed that MK571 significantly reduced hydroxyl radical formation. Moreover, MK571 delayed platelet plug formation in vitro by a PFA-100 device, and delayed thrombus formation in mesenteric venules of mice irradiated by fluorescein sodium. However, previous studies have reported that MK571 also blocks MRP1 and leukotriene D4 (LTD4) receptor. Therefore, whether MK571 inhibits platelet activation through MRP1 or LTD4 receptor needs to be considered and further defined. In conclusion, in addition to blocking the transport of cyclic nucleotides, MRP4 inhibition may prevent thrombus formation in vitro and in vivo. Our findings also support the idea that MRP4 may represent a potential target for the development of novel therapeutic interventions for the treatment of thromboembolic disorders.

Montelukast: much more than an antiasthma drug

Montelukast (MK), a selective leukotriene D4 receptor antagonist, is used mainly to reduce eosinophilic inflammation in asthmatic patients. The primary objective of this mini-review is to describe novel additional targets for MK besides the lung and to highlight its antioxidant potential. Literature published between 2002 and 2013 was reviewed for significant antioxidant and anti-inflammatory properties of MK in various experimental models of inflammation rather than that in the airways of asthmatics. Evidence suggests the potential use of MK in many inflammatory diseases rather than asthma therapy.

Synthesis of Optically Active Thromboxane A2 and Leukotriene D4 Receptor Antagonists

Abstract Both (+)- and (−)-4-{[(2-{4-chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)-vinyl]phenyl}ethyl)thio]methyl}benzoic acid (1), Thromboxane A2 and Leukotriene D4 receptor dual antagonist were synthesized. Racemic methyl 4-({[2-amino-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate (2), and methyl 4-[({2-amino-1-[3-(1,3-dioxolan-2-yl)phenyl]ethyl}thio)methyl]benzoate (3) were derived from 2-(3-bromophenyl)-1,3-dioxolane (4). Compound 2 was resolved via di-p-toluoyl-d/l-tartaric acid salts to transform to (+)- and (−)-1, respectively. We also demonstrated that one optically active salt of compound 2 was converted to optically active (+)-1 without chromatography purification.

Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model

The effects of anti-ulcerogenic drugs are dependent on the increase in prostaglandin production and reduction in leukotriene production in the gastric mucosa. Montelukast is an anti-asthmatic drug, a selective reversible cysteinyl leukotriene D4 receptor antagonist. In this study, we aimed to evaluate the anti-ulcerogenic effect of montelukast and to investigate the relationship between its anti-ulcerogenic effect and polymorphonuclear leukocyte infiltration in the gastric tissues. Male Sprague-Dawley rats were separated into five groups. Distilled water (control group), famotidine (40 mg/kg), and montelukast (5, 10 and 20 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered to all the groups. Six hours later, the animals were sacrificed by decapitation. The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, and the stomachs were later evaluated histopathologically (polymorphonuclear leukocyte infiltration). Ulcer inhibition rates were as follows: famotidine 96.14% and montelukast 59.96%, 72.65% and 76.97% (5, 10 and 20 mg/kg, respectively). Montelukast (10 and 20 mg/kg) showed effects similar to those of famotidine histopathologically. In this study, it was observed that there was a relationship between the anti-ulcerogenic effect of montelukast and polymorphonuclear leukocyte infiltration in the gastric mucosa, and montelukast behaved as an anti-ulcerogenic drug both macroscopically and microscopically.

Cysteinyl leukotrienes mediate the response of submucosal ganglia from rat colon to bradykinin

The aim of the present study was to find out the mechanism by which the inflammatory mediator, bradykinin, induces an increase of the cytosolic Ca2+ concentration ([Ca2+]i) in enteric neurons. For this purpose, ganglia in the isolated submucosa from rat colon were loaded with the Ca2+-sensitive dye, fura-2, and were exposed to bradykinin (2·10−8mol/l). Under control conditions, the kinin evoked a transient increase in [Ca2+]i. Preincubation with quinacrine or arachidonyltrifluoromethylketone (AACOCF3), i.e. blockers of cytosolic phospholipase A2, prevented the raise of [Ca2+]i. This inhibition was mimicked by 5,8,11,14-eicosatetrayonic acid (ETYA), an inhibitor of cyclooxygenases as well as lipoxygenases, and by BWA4C, a selective inhibitor of lipoxygenases, whereas indomethacin was ineffective, suggesting the mediation of the kinin response by a lipoxygenase metabolite. Indeed, a leukotriene, leukotriene D4 (LTD4), mimicked the effect of bradykinin. The LTD4 receptor blocker, MK-571, inhibited the increase in [Ca2+]i evoked by LTD4 and by bradykinin. Consequently, bradykinin receptors in submucosal ganglia from rat colon are coupled to a stimulation of phospholipase A2, the release of arachidonic acid and the production of LTD4, which seems to be finally responsible for the change in the cytosolic Ca2+ concentration.

Montelukast Was Inefficient in Maintaining Steroid-Induced Remission in Adult Eosinophilic Esophagitis

Leukotriene D4 is produced by and functions as a chemotactic factor for eosinophils. Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilic infiltration, determining structural changes and dismotility symptoms. Montelukast, a selective leukotriene D4 receptor antagonist, has gained increasing consideration as a therapeutic agent for EoE. However, limited available information has shown that montelukast is not effective in reducing eosinophilic infiltration. Our paper aims at evaluating whether montelukast could be consider as a steroid-sparing therapy by assessing its efficacy in maintaining both clinical and histopathological remission achieved after topical corticosteroids in adult EoE patients. Eleven consecutively diagnosed adult EoE patients were prospectively studied. Esophageal biopsies were obtained before and after a 6-month treatment with fluticasone propionate 400 μg/twice a day. Immediately after that, montelukast 10 mg/day was instituted. A new endoscopy was foreseen after a new 3-month period, or as soon as the patients presented esophageal symptoms. Symptoms were assessed by using a questionnaire before and after fluticasone propionate treatment and after montelukast therapy. Eosinophils density into the esophageal epithelium and lamina propria was significantly reduced after a 6-month treatment with topical steroids (P = 0.003) and increased to levels similar to baseline level into the first 3 months after treatment with montelukast. Baseline symptom scores significantly decreased after treatment with topical steroids (P = 0.003) and increased again after montelukast therapy, but baseline levels improved. Montelukast was not efficient in maintaining the histopathological or clinical response achieved by topical steroids in adult EoE patients.

Characterization of the Cysteinyl Leukotriene 2 Receptor in Novel Expression Sites of the Gastrointestinal Tract

Cysteinyl leukotrienes (cysLTs: LTC₄, LTD₄, and LTE₄) are pro-inflammatory lipid molecules synthesized from arachidonic acid. They exert their actions on at least two cysLT receptors (CysLT₁R and CysLT₂R). Endothelial expression and activation of these receptors is linked to vasoactive responses and to the promotion of vascular permeability. Here we track the expression pattern of CysLT₂R in a loss-of-function murine model (CysLT₂R-LacZ) to neurons of the myenteric and submucosal plexus in the small intestine, colonic myenteric plexus, dorsal root ganglia, and nodose ganglion. Cysteinyl leukotriene (LTC₄/D₄) stimulation of colonic submucosal venules elicited a greater permeability response in wild-type mice. In a dextran sulfate sodium-induced colon inflammation model, the disease activity index and colonic edema (measured by wet:dry weights and submucosal thickness) were significantly reduced in knockout (KO) mice compared to controls. Tumor necrosis factor-α levels in colon tissue were significantly lower in KO mice; however, myeloperoxidase activity was similar in both the KO and wild-type groups. Finally, patch-clamp recordings of basal neuronal activity of colonic-projecting nociceptive neurons from dorsal root ganglia (T9-13) revealed significantly higher excitability in KO neurons compared to wild type. These results suggest that a lack of neuronal expression of CysLT₂R in the murine colonic myenteric plexus attenuates colitis disease progression via a reduction in inflammation-associated tissue edema and increases neuronal sensitivity to nociceptive stimuli.

Detection of Leukotriene Receptor CysLT 1 R in Inflammatory Diseases by Molecular Imaging with Near-Infrared Fluorescence-Based Contrast Agents

As leukotriene D4 receptor CysLT1R upregulation is an early event in inflammatory processes, specific detection of CysLT1R via molecular imaging might be a promising diagnostic tool for inflammatory diseases. We coupled a specific anti-CysLT1R IgG antibody to near-infrared (NIR) hemicyanine fluorophore DY-734. The fluorophore was also coupled to unspecific rabbit-IgG antibody or corresponding Fab fragments. Expression of CysLT1R in HL-60 human promyelocytic leukemia cells in vitro could be proven by reverse transcriptase-polymerase chain reaction (PCR), real-time PCR, and flow cytometry. Detection of the probes by flow cytometry showed that CysLT1R*DY-734 probe binds distinctly stronger to HL-60 cells than IgG*DY-734. Induction of ear edema in mice was conducted to test signaling of the synthesized probes in vivo. A markedly higher fluorescence intensity was observed in the edematous region than in the healthy region by a whole-body imaging system. Semiquantitative analysis showed that CysLT1R*DY-734 and Fab-CysLT1R*DY-734 probes bind 1.9- and 1.2-fold stronger, respectively, than the unspecific probes. Biodistribution studies revealed an enrichment of full-length IgG probes in liver and spleen, whereas Fab-containing probes are mostly found in liver and kidneys. Taken together, we present an approach that might improve early diagnosis of inflammatory diseases in the long term.

Effects of montelukast on burn wound healing in a rat model

Montelukast, a selective cysteinyl leukotriene D4-receptor antagonist, is used in the treatment of asthma. In a rat model, our aim was to investigate the effects of montelukast, alone or in combination with topical antibiotics, on local burn wound healing. Rats were randomly allocated to four groups after local burn development: Group 1; rats were left to secondary healing without treatment, Group 2; a dose of 10 mg/kg montelukast was given by gastric gavage once a day for 10 days, Group 3; rats were treated with topical pomade (bacitracin neomycin sulphate), and Group 4; rats were treat with a combination of topical antibiotic and montelukast (10 mg/kg were given by gastric gavage once a day for 10 days). Skin biopsies were taken on days 3, 10, 14, and 20 relative to burn induction. Reepithelialization in the pomade and montelukast+pomade groups on the 10th day was significantly greater, in comparison with control and montelukast groups (p < 0.05). For the montelukast group, edema (on the 14th day) and angiogenesis, fibroblast proliferation, edema and macrophage infiltration (on the 20th day) were statistically improved in comparison with the control group (p < 0.05). For the montelukast+pomade group, angiogenesis, fibroblast proliferation and macrophage infiltration (on the 10th day), and angiogenesis, fibroblast proliferation, edema and macrophage infiltration (on the 14th and 20th days) were statistically improved in comparison with the control group (p < 0.05). In conclusion, montelukast was effective on burn wound healing. Moreover, the effect was amplified when combined with topical antibiotics applied in the early stage of burn wound healing.

The leukotriene d4 receptor antagonist, montelukast, inhibits mast cell degranulation in the dermis induced by water avoidance stress

Cysteinyl leukotrienes play a part in inflammatory reactions such as asthma and inflammatory bowel diseases. The leukotrienes exert their actions by binding to and activating various receptors. Montelukast, a leukotriene receptor antagonist, which is used in the treatment of asthma has been shown to be effective in inhibiting the action or formation of leukotrienes. Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and seem to be related to infiltration and activation of mast cells that are releasing vasoactive and pro-inflammatory mediators. The aim of the present study was to investigate the effects of montelukast on the degranulation of mast cells in the dermis that is induced by water avoidance stress (WAS). Wistar albino rats were divided into four groups of 8 animals each. Control rats were injected with (1) the vehicle solution or (2) the montelukast solution in the absence of WAS. (3) the WAS group of rats was administered vehicle solution following WAS exposure for 2h daily for 5 days. (4) The WAS+ML group was administered montelukast 10mg/kg; i.p. following WAS exposure for 2h daily for 5 days. Dermal mast cell numbers were determined with toluidine blue and tryptase immunohistochemistry and observed using a light microscope. Numbers of both granulated and degranulated mast cells were significantly increased in the WAS group when compared to control rats. Montelukast treatment decreased the number of both mature granulated and degranulated mast cells in rats subjected to WAS. In conclusion, chronic montelukast treatment reduced WAS-induced infiltration and activation of mast cells in the dermis and may provide a useful therapeutic option in stress-induced skin disorders.

Effects of KP-496, a novel dual antagonist of leukotriene D4 and thromboxane A2 receptors on nasal blockage in guinea pig models of allergic rhinitis

KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis. Male Hartley guinea pigs were used. Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge. As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model). Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges. KP-496 may be clinically effective for nasal blockage in allergic rhinitis.

Gastroprotective and Antioxidant Effects of Montelukast on Indomethacin-Induced Gastric Ulcer in Rats

Montelukast, a selective reversible cysteinyl leukotriene D4-receptor (LTD4 receptor) antagonist, is used in the treatment of asthma. We have investigated alterations in the glutathione (GSH) and activity levels of antioxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione reductase (GR)] and myeloperoxidase (MPO), as markers of the ulceration process following oral administration of montelukast, lansoprazole, famotidine, and ranitidine, respectively, in rats with indomethacin-induced ulcers. In the present study, we found that 1) montelukast, lansoprazole, famotidine, and ranitidine all reduced the development of indomethacin-induced gastric damage, with this reduction occurring at a greater magnitude for montelukast, famotidine, and lansoprazole than for ranitidine; 2) montelukast and ranitidine both alleviated increases in the activity levels of CAT and GST enzymes resulting from gastric injury; 3) montelukast and ranitidine both ameliorated depressions in the GSH and activity levels of SOD and GR enzymes caused by indomethacin administration; and 4) all doses of montelukast, lansoprazole, and ranitidine decreased amplification of MPO activity resulting from induced gastric injuries. These results suggest that the gastroprotective effects of montelukast on indomethacin-induced ulcerations can be attributed to its ameliorating effect on oxidative damage and MPO activity.

Effects of KP-496, a Novel Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors, on Contractions Induced by Various Agonists in the Guinea Pig Trachea

A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496. The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea. KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea. These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

Gastric motor dysfunction: is eosinophilic mural gastritis a causative factor?

Delayed gastric emptying caused either by gastric motor dysfunction or by gastroparesis is a profoundly debilitating disorder. When unresponsive to medical therapy, patients may undergo radical surgery including near-total gastro-oesophageal, with varied symptomatic improvement. We describe two patients who presented with symptoms consistent with gastro-oesophageal reflux, unresponsive to medical management. After fundoplication both developed symptoms of profound gastric motor dysfunction and subsequently proceeded to near-total gastro-oesophageal with symptomatic improvement. Histological examination of both excised gastric specimens revealed eosinophilic mural gastritis. To our knowledge, these are the first cases to demonstrate the association of mural eosinophilia and symptomatic gastric motor dysfunction. We propose that patients with gastric motor dysfunction, refractory to medical management, progress to laparoscopy and mural biopsy before gastrectomy. This would allow histological analysis of the gastric wall, and in the event of a positive finding of mural eosinophilic gastritis would allow a trial of medical therapy that could include an eosinophilic stabilizer such as the leukotriene D4 receptor antagonist montelukast or intravenous corticosteroid therapy, which may alleviate the symptoms.