The cysteinyl leukotriene D4 receptor antagonist montelukast for the treatment of interstitial cystitis.

Bouchelouche P.

Department of Urology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.

PURPOSE: The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease. We examined the efficacy of the cysteinyl leukotriene 1 receptor antagonist montelukast for treating patients with interstitial cystitis and detrusor mastocytosis. MATERIALS AND METHODS: Ten women in whom interstitial cystitis was diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases criteria and who also had detrusor mastocytosis with a minimum of 28 mast cells per mm.2 muscle tissue were included in this study. Patients received a single dose of montelukast daily for 3 months. The efficacy of treatment was determined by 24-hour urinary frequency, nocturia and pain using visual analog scales. RESULTS: After 1 month of montelukast treatment there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the 3 months of treatment. After 3 months 24-hour urinary frequency had decreased from 17.4 to 12 voidings (p = 0.009), nocturia had decreased from 4.5 to 2.8 (p = 0.019) and pain had decreased from 46.8 to 19.6 mm. on a visual analog scale (p = 0.006). No side effects were observed during treatment. CONCLUSIONS: Montelukast treatment resulted in significant improvement in urinary frequency and pain. Its efficacy for decreasing urinary frequency and pain imply a role of leukotriene receptor antagonists for managing interstitial cystitis but further placebo controlled clinical studies are needed.

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Leukotriene Modifier Therapy for Mild Sleep-Disordered-Breathing in Children.

Gozal D.

Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.

Background- Children with mild sleep-disordered-breathing (SDB), who may not be recommended for adenotonsillectomy (T&A), frequently exhibit neurocognitive and behavioral morbidity, and may benefit from alternative therapeutic interventions such as leukotriene modifier therapy. Methods- 24 children with SDB completed an open label intervention study for 16 weeks with daily montelukast therapy. Sleep studies and adenoid size estimates from lateral x-ray films of the neck were obtained prior to and following treatment. In a parallel study, adenoid and tonsillar tissues from children with obstructive sleep apnea (SA) or recurrent throat infections (RI) were subjected to qPCR, immunohistochemistry and western blotting for gene and protein expression of leukotriene receptors LT1-R and LT2-R, and for concentrations of LTB4 and LTC4/D4/E4. Results- Montelukast treatment induced significant reductions in adenoid size and respiratory-related sleep disturbances, which were absent in 16 children with SDB who did not receive treatment. LT1-R and LT2-R mRNA were similarly abundant in adenoid tissues, but increased LT1-R and LT2-R protein expression and higher levels of LTB4 and LTC4/D4/E4 emerged in children with SA. Conclusions- Oral therapy with a leukotriene modifier appears to be associated with improved breathing during sleep. Double blind, placebo controlled trials will be needed to corroborate current findings and solidly establish anti-inflammatory strategies, such as leukotriene modifiers, as therapeutic alternatives in children with SDB too mild to justify referral for T&A.

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Bronchoprotective effects of single doses of salmeterol combined with montelukast in thermally induced bronchospasm.

McFadden ER Jr.

Center for Academic Clinical Research, Case Western Reserve University School of Medicine, Department of Medicine of MetroHealth Medical Center, Cleveland, OH 44109, USA.

STUDY OBJECTIVES: Salmeterol (S) and montelukast (M) individually inhibit the obstructive consequences of thermal stimuli such as exercise and hyperventilation (HV), but there is no information on whether these drugs can interact positively. DESIGN: Randomized trial. SETTING: University teaching hospital. PARTICIPANTS: Atopic asthmatic patients with sensitivity to thermal provocations. INTERVENTIONS: Eleven asthmatic patients generated stimulus-response curves to isocapnic HV while breathing frigid air without any interventions and then after pretreatment with 42 mug of S, 10 mg of M, and the combination. The order of testing was randomly determined. MEASUREMENTS AND RESULTS: Minute ventilation (Ve) was increased in 20-L increments until FEV(1) fell >or= 15%. Measurements were obtained before and 1 h after drug administration, and then again 5 min after each bout of HV. In the nonintervention trial, the provocation commenced after the patients presented to the laboratory. In the control challenge, the mean (+/- SEM) FEV(1) decreased 24.6 +/- 1.7% from baseline. S and M both increased the mean prechallenge FEV(1) significantly (S, 10.4 +/- 1.7% [p < 0.01]; M, 4.1 +/- 1.3% [p = 0.02]; S + M, p = 0.01). The combination of S + M produced greater bronchodilatation (mean improvement, 12.4 +/- 2.3%) than M alone (p = 0.004), but not greater than S alone (p = 0.80). Both drugs blunted the obstructive response similarly (protection: M, 34.6 +/- 15.1%; S, 60 +/- 8.7%; p = 0.13). The benefits added arithmetically with the combined regimen (protection with S + M, 84.9 +/- 5.5%; p = 0.01 vs S alone; p = 0.003 vs M alone). CONCLUSION: These data indicate that the concurrent administration of single standard doses of S and M appears to provide greater protection against thermal stimuli than does either drug alone. Further experimentation will be required to ascertain whether the combination will provide additional clinical benefits to patients over those of the single agents.

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Burn-induced oxidative injury of the gut is ameliorated by the leukotriene receptor blocker montelukast.

Yegen BC.

Department of Pharmacology, School of Pharmacy, Marmara University, 34668 Haydarpasa, Istanbul, Turkey.

There is increasing evidence that oxidative stress has an important role in the development of multiorgan failure after major burn injury. In the present study, we investigated whether the leukotriene receptor blocker montelukast is protective against burn-induced injury of the gut. Under brief ether anaesthesia, shaved dorsum of the rats was exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10 s. Montelukast (10 mg/kg) or saline was administered intraperitoneally immediately after and at the 12th hour of the burn injury. Rats were decapitated 24 h after burn injury and the skin samples, as well as tissue samples from stomach, ileum and colon, were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Tissues were also examined microscopically. Tumor necrosis factor-alpha (TNF-alpha) and lactate dehydrogenase (LDH) were assayed in serum samples. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, serum TNF-alpha and LDH were elevated in the burn group as compared to control group. On the other hand, montelukast treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by thermal trauma. Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on burn-induced gastrointestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism.

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Preventive treatment of headaches.

Silberstein SD.

Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA. Stephen.Silberstein jefferson.edu

PURPOSE OF REVIEW: To review recent advances in preventive headache treatment. RECENT FINDINGS: Migraine may be a progressive disorder. Aggressive treatment may stop progression. Propranolol, the beta-blocker, and the anticonvulsant topiramate are effective for migraine prevention. Feverfew, montelukast and acupuncture have not proven effective. SUMMARY: New drugs and other treatment strategies expand the spectrum of preventive migraine treatments.

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