Gastroprotective effect of leukotriene receptor blocker montelukast in alendronat-induced lesions of the rat gastric mucosa.

Ayanoglu-Dulger G.

Department of Pharmacology, School of Pharmacy, Marmara University, Istanbul, Turkey. gokselsener hotmail.com

Alendronate causes serious gastrointestinal adverse effects. We aimed to investigate if montelukast, a leukotriene receptor antagonist, is protective against this damage. Rats were administered 20 mg/kg alendronate by gavage for 4 days, either alone or following treatment with montelukast (10 mg/kg). On the last day, following drug administration, pilor ligation was performed and 2 h later, rats were killed and stomach, liver and kidney tissues were removed. Gastric acidity, gastric tissue ulcer index values and malondialdehyde (MDA); an end product of lipid peroxidation, and glutathione (GSH) levels; a key antioxidant, as well as myeloperoxidase (MPO) activity; an indirect marker of tissue neutrophil infiltration were determined, and the histologic appearance of the stomach, liver and kidney tissues were studied. Chronic oral administration of alendronate induced significant gastric damage, increasing myeloperoxidase activity and lipid peroxidation, while tissue glutathione levels decreased. Similarly, in the alendronate group MDA levels and MPO activities of liver and kidney tissues were increased and GSH levels were decreased. Treatment with montelukast prevented the damage as well as the changes in biochemical parameters in all tissues studied. Findings of the present study suggest that alendronate is a local irritant that causes inflammation through neutrophil infiltration and oxidative damage in tissues, and that montelukast is protective against this damage by its anti-inflammatory effect.

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[Effect of montelukast on the apoptosis of lymphocytes in asthmatic rats and its molecular mechanism]

[Article in Chinese]

Liu C.

Department of Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China.

OBJECTIVE: To investigate the effect of montelukast(MK) on the apoptosis of lymphocytes and the associated molecular mechanism in asthmatic rats in vivo and in vitro. METHODS: The asthmatic model was established by sensitizing and challenging SD rat with ovalbumin (OVA). Forty male SD rats were randomly divided into control group, asthma group, MK-treated group and Dexamethason (DXM)-treated group. T lymphocytes were labeled with CD(4)+ and CD(8)+ antibodies and then labeled with TdT-mediated dUTP nick end labeling (TUNEL) to detect apoptotic cells, and immunohistochemical staining of Fas antigen (CD95) was performed to detect Fas positive cells. The influences of MK on apoptosis and Fas antigen spontaneous expression on CD(4)+ / CD(8)+ lymphocytes in vivo and in vitro were assayed. RESULTS: The apoptosis rates of T lymphocytes from peripheral blood and lung tissue of asthmatic rats pre-treated by MK were significantly elevated as compared with those in normal control and asthma groups. In vitro culture MK was found to induce in dose- and time-dependent manner the apoptosis of peripheral blood lymphocytes pre-treated with OVA. A synergic effect of MK and DXM was demonstrated, i.e. MK in 10(-6) mol/L concentration markedly promoted the induction of apoptosis and expression of Fas antigen by 10(-6) mol/L DXM. CONCLUSION: MK could induce apoptosis of peripheral blood and lung lymphocytes (mainly CD(4)+) in asthmatic rats, which may be mediated by Fas system. The induction of apoptosis of lymphocytes by MK may contribute to anti-inflammation mechanisms. Furthermore, a synergic effect of MK and DXM on the induction of apoptosis of lymphocytes might exist.

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Examination of 209 drugs for inhibition of cytochrome P450 2C8.

Obach RS.

Pharmacokientics, Pharmacodynamics,, and Drug Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Groton, CT 06340, USA.

Cytochrome P450 2C8 is involved in the metabolism of drugs such as paclitaxel, repaglinide, rosiglitazone, and cerivastatin, among others. An in vitro assessment of 209 frequently prescribed drugs and related xenobiotics was carried out to examine their potential to inhibit CYP2C8. A validated sensitive, moderate-throughput high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay was used to detect N-desethylamodiaquine, the CYP2C8-derived major metabolite of amodiaquine metabolism, using heterologously expressed recombinant CYP2C8 (rhCYP2C8) and pooled human liver microsomes. The 209 drugs were first tested at 30 muM for their ability to inhibit rhCYP2C8. Forty-eight compounds exhibited greater than 50% inhibition and were further evaluated for measurement of IC50. The six most potent inhibitors (IC50 <1 microM) from this set were measured for IC50 in pooled human liver microsomes, and the most potent inhibitor identified was the leukotriene receptor antagonist, montelukast (IC50 = 19.6 nM). Inhibitors of CYP2C8 were identified from a wide variety of therapeutic classes, with no single class predominating. Other potent inhibitors included candesartan cilexetil (cyclohexylcarbonate ester prodrug of candesartan), zafirlukast, clotrimazole, felodipine, and mometasone furoate. Seventeen moderate inhibitors of rhCYP2C8 (1 < IC50 < 10 microM) included salmeterol, raloxifene, fenofibrate, ritonavir, levothyroxine, tamoxifen, loratadine, quercetin, oxybutynin, medroxyprogesterone, simvastatin, ketoconazole, ethinyl estradiol, spironolactone, lovastatin, nifedipine, and irbesartan. These in vitro data were used along with clinical pharmacokinetic information in predicting potential drug-drug interactions that could occur by inhibition of CYP2C8. Although almost all drugs tested are not expected to cause drug interactions via inhibition of CYP2C8, montelukast was identified as being of concern as a potential inhibitor of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2C8 is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.

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Selective inhibition of human cytochrome P4502C8 by montelukast.

Proctor WR.

Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.

The leukotriene receptor antagonist montelukast was examined for its inhibition of the human drug-metabolizing enzyme cytochrome P4502C8 (CYP2C8). Montelukast was demonstrated to be a potent inhibitor of CYP2C8-catalyzed amodiaquine N-deethylase, rosiglitazone N-demethylase, and paclitaxel 6alpha-hydroxylase in human liver microsomes. Inhibition was also observed when the reaction was catalyzed by recombinant heterologously expressed CYP2C8. The mechanism of inhibition was competitive, with K(i) values ranging from 0.0092 to 0.15 microM. Inhibition potency was highly dependent on the microsomal protein concentration. Increasing the microsomal protein concentration by 80-fold yielded a 100-fold decrease in inhibition potency. Preincubation of montelukast with human liver microsomes and NADPH did not alter the inhibition potency, suggesting that montelukast is not a mechanism-based inactivator. Montelukast was a selective inhibitor for human CYP2C8; inhibition of other human cytochrome P450 enzymes was substantially less. These in vitro data support the use of montelukast as a selective CYP2C8 inhibitor that could be used to determine the contribution of this enzyme to drug metabolism reactions. These data also raise the possibility that montelukast could have an effect on the metabolic clearance of drugs possessing CYP2C8-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.

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Effect of fluticasone propionate and salmeterol in a single device, fluticasone propionate, and montelukast on overall asthma control, exacerbations, and costs.

Dorinsky P.

Sharp Rees-Stealy Medical Group, San Diego, California 92101, USA. Richard.oconnor sharp.com

BACKGROUND: Inhaled corticosteroids are the most effective class of anti-inflammatory agents and are recommended for patients with persistent asthma. OBJECTIVE: To compare the effectiveness of (1) fluticasone propionate, 100 microg, and salmeterol, 50 microg; (2) fluticasone propionate, 100 microg; and (3) montelukast, 10 mg, as first-line maintenance treatment for persistent asthma. METHODS: Combined analysis of 4 clinical trials, 2 that compared fluticasone propionate-salmeterol with montelukast and 2 that compared fluticasone propionate with montelukast as initial asthma therapy. RESULTS: The 4 studies had a total of 1,910 patients 15 years or older with symptomatic asthma previously treated with inhaled short-acting beta2-agonists alone. At the end point, there were significantly greater increases in forced expiratory volume in 1 second with fluticasone propionate-salmeterol (0.57 L; P < or = .004) vs fluticasone propionate (0.48 L) and montelukast (0.31 L) and significantly greater increases in morning peak expiratory flow rate (84.9 L/min; P < .001) vs fluticasone propionate (56.0 L/min) and montelukast (36.1 L/min). Fluticasone propionate-salmeterol significantly increased the percentage of symptom- and rescue-free days and significantly reduced albuterol use vs fluticasone propionate and montelukast (P < or = .04 for both). Patients treated with fluticasone propionate and montelukast had 2.6 and 3.6 greater risk, respectively, of having an asthma-related exacerbation vs fluticasone propionate-salmeterol users. In addition, mean daily exacerbation costs per treated patient were dollars 0.41 for fluticasone propionate-salmeterol, dollars 4.60 for fluticasone propionate, and dollars 7.57 for montelukast, whereas mean daily costs per patient exacerbation for fluticasone propionate-salmeterol, fluticasone propionate, and montelukast were dollars 29, dollars 128, and dollars 154, respectively. CONCLUSIONS: Patients with symptomatic asthma previously treated with short-acting beta2-agonists only who require maintenance therapy are likely to have greater clinical benefits, lower risk of an asthma exacerbation, and reduced exacerbation-related costs when initiating therapy with fluticasone propionate-salmeterol vs fluticasone propionate or montelukast.

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