Jonathan A. Leff

Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction

BACKGROUND Montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta(2)-receptor agonist, each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction (EIB) in short-term studies. Direct comparisons between these agents in long-term studies are limited. OBJECTIVE We sought to compare montelukast and salmeterol in the long-term treatment of EIB. METHODS One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1) of at least 18% were randomized (double-blind) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks. Exercise challenge was repeated at day 3, week 4, and week 8 after randomization near the end of the dosing interval for both drugs. The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1) at week 8. RESULTS Montelukast was effective in treating EIB without inducing tolerance and provided superior (P </=.001) protection than salmeterol at weeks 4 and 8, with comparable protection at day 3. The frequency of respiratory clinical adverse events (P =.046) and discontinuations because of clinical adverse events (P =.052) were less with montelukast. CONCLUSION The effect of montelukast was greater than that of salmeterol in the chronic treatment of EIB over a period of 8 weeks in patients with mild asthma as demonstrated by effect size, maintenance of effect, and fewer respiratory clinical adverse events during the study period. Montelukast may be a better alternative to salmeterol as a controller agent for the chronic treatment of EIB.

Serum antioxidants as predictors of the adult respiratory distress syndrome in septic patients

Adult respiratory distress syndrome (ARDS) can develop as a complication of various disorders, including sepsis, but it has not been possible to identify which of the patients at risk will develop this serious disorder. We have investigated the ability of six markers, measured sequentially in blood, to predict development of ARDS in 26 patients with sepsis. At the initial diagnosis of sepsis (6-24 h before the development of ARDS), serum manganese superoxide dismutase concentration and catalase activity were higher in the 6 patients who subsequently developed ARDS than in 20 patients who did not develop ARDS. These changes in antioxidant enzymes predicted the development of ARDS in septic patients with the same sensitivity, specificity, and efficiency as simultaneous assessments of serum lactate dehydrogenase activity and factor VIII concentration. By contrast, serum glutathione peroxidase activity and alpha 1Pi-elastase complex concentration did not differ at the initial diagnosis of sepsis between patients who did and did not subsequently develop ARDS, and were not as effective in predicting the development of ARDS. Measurement of manganese superoxide dismutase and catalase, in addition to the other markers, should facilitate identification of patients at highest risk of ARDS and allow prospective treatment.

Lack of Benefit of Methotrexate in Severe, Steroid-Dependent Asthma: A Double-Blind, Placebo-Controlled Study

OBJECTIVE To determine the effect of low-dose methotrexate in asthmatic patients on steroid use, asthma symptom scores, pulmonary function, airway reactivity, blood cellular components, and immunoglobulin E levels. DESIGN A randomized, double-blind, parallel, placebo-controlled, 13-week clinical trial with follow-up of patients in an open trial of methotrexate at the conclusion of the double-blind study. SETTING An asthma care outpatient clinic. PATIENTS From February 1988 to March 1990, 19 patients with severe, steroid-dependent asthma were enrolled in the study. Two of these patients were excluded from analysis. INTERVENTIONS Patients were administered methotrexate or placebo intramuscularly, to assure complete absorption, once weekly during the 13-week study. RESULTS Patients on methotrexate and placebo both significantly decreased their steroid dose by 39.6% (95% CI, 25.1% to 54.1%, P = 0.001) and 40.2% (CI, 17.9% to 67.4%, P = 0.003), respectively. Pulmonary function did not differ significantly between the methotrexate and placebo groups. In addition, airway reactivity and symptom scores were unchanged on methotrexate or placebo. No significant toxicities were seen during the course of the 13-week blinded study, but one patient on methotrexate and prednisone in the follow-up period developed Pneumocystis carinii pneumonia and died. Despite continuing methotrexate for up to 1 year, and increasing methotrexate to 30 mg weekly, no significant benefit of methotrexate on asthma control could be shown. CONCLUSION Our study does not support the use of methotrexate in the treatment of severe asthma.

Progressive increases in serum catalase activity in advancing human immunodeficiency virus infection

We found that serum from individuals with Acquired Immunodeficiency Syndrome (AIDS) had more (p less than .05) catalase activity (31.5 +/- 5.2 U/mL) than serum from healthy control subjects (7.3 +/- 0.8 U/mL). Moreover, serum catalase (but not glutathione peroxidase) activity increased progressively with advancing human immunodeficiency virus (HIV) infection (i.e., AIDS greater than symptomatic infection greater than asymptomatic infection greater than controls). Increases in serum catalase activity correlated with increases in serum hydrogen peroxide (H2O2) scavenging ability and reached levels which decreased exogenous H2O2-mediated injury to cultured endothelial cells without altering neutrophil bactericidal activity or mononuclear cell cytotoxicity in vitro. Serum catalase activity correlated with serum lactate dehydrogenase (LDH) activity but did not appear to be a consequence of erythrocyte (RBC) hemolysis since RBC fragility and serum haptoglobin levels were comparable in HIV-infected and control subjects. Increases in serum catalase activity may reflect and/or compensate for systemic glutathione and other antioxidant deficiencies in HIV-infected individuals.

Effect of vitamin E deficiency and supercritical fluid aerosolized vitamin E supplementation on interleukin-1-induced oxidative lung injury in rats

We hypothesized that alterations in lung vitamin E levels would impact the development of acute oxidative lung injury. We found that dietary induced deficiency of vitamin E diminished lung tissue levels of vitamin E and increased lung leak following intratracheal administration of interleukin-1 (IL-1) to rats. Conversely, rats administered vitamin E directly to the lungs as an inhaled aerosol (0.3-3 microns particles) formed by supercritical fluid aerosolization (SFA) had increased lung tissue vitamin E levels and decreased IL-1 induced lung leak compared to control rats. Lung myeloperoxidase (MPO) activities, reflecting neutrophil concentrations, were increased in rats given IL-1 intratracheally compared to rats given saline intratracheally but were not different for control or vitamin E depleted rats. Lung MPO activities in rats given IL-1 intratracheally were slightly higher in SFA vitamin E treated rats than in control rats. Our results suggest that vitamin E levels affect susceptibility to IL-1 induced, neutrophil-dependent lung injury. We speculate that supercritical fluid aerosol (SFA) delivery of vitamin E can rapidly increase lung vitamin E levels and decrease acute oxidative lung injury.

Catalase and hydrogen peroxide cytotoxicity in cultured cardiac myocytes

We examined the role of intracellular catalase activity in modulating hydrogen peroxide (H2O2)-induced cytotoxicity in cultured chick embryo cardiac myocytes. Injury was quantitated by release of lactate dehydrogenase (LDH). Application of 1.5 mM H2O2 to myocytes caused LDH release beginning at 2 h. Inactivation or inhibition of catalase with aminotriazole or sodium azide increased LDH release but did not cause earlier release. Free catalase which entered or became associated with myocytes, but not catalase bound to agarose beads, which did not enter or become associated with myocytes, was protective. Separate experiments demonstrated that myocyte catalase activity decreased by 27% between 1 and 4 h of H2O2 exposure. Treatment with aprotinin, a protease inhibitor, prevented the H2O2-induced fall in catalase activity at 4 h but treatment with deferoxamine, an iron chelator, had no effect on catalase activity. Thus, with exposure of cardiac myocytes to H2O2, the magnitude of the cytotoxicity is modulated by endogenous or cell associated exogenous catalase. It is proposed that in addition to excessive accumulation of H2O2, a reduction intracellular catalase activity may be required before substantial cell injury occurs during H2O2 exposure. Activation of proteases may cause the reduction in catalase activity in this setting.

Increased serum catalase activity in rats subjected to thermal skin injury

We found that: rats subjected to thermal skin injury (burn) had increased serum hydrogen peroxide (H2O2) scavenging activity, serum catalase activity, erythrocyte (RBC) fragility, and edematous lung injury (lung leak) when compared to sham-treated rats. Serum H2O2 scavenging activity was inhibited by addition of sodium azide, a catalase inhibitor. Treatment of rats with the oxygen radical scavenger, dimethylthiourea (DMTU), decreased RBC fragility and lung leak but did not alter increased H2O2 scavenging or catalase activity of serum from rats subjected to skin burn. We conclude that increased serum catalase activity is a consequence of thermal skin injury and that increased serum catalase activity may be a mechanism that modulates H2O2-dependcnt processes following skin burn.

Inactivation of xanthine oxidase by hydrogen peroxide involves site-directed hydroxyl radical formation

The mechanism of xanthine oxidase (XO) inactivation by hydrogen peroxide (H2O2) and its biologic significance are unclear. We found that addition of increasing concentrations of H2O2 progressively decreased xanthine oxidase activity in the presence but not the absence of xanthine in vitro. Inactivation of XO by H2O2 was also enhanced by anaerobic reduction of XO by xanthine. Inactivation of XO by H2O2 was accompanied by production of hydroxyl radical (.OH), measured as formation of formaldehyde from dimethylsulfoxide (DMSO). In contrast, addition of H2O2 to deflavo XO did not produce .OH. Inactivation of XO by H2O2 was decreased by simultaneous addition of the .OH scavenger, DMSO. However, inactivation of XO by H2O2 and formation of .OH were not decreased following addition of the metal chelator. DETAPAC, and/or the O2 scavenger, superoxide dismutase. The results suggest that inactivation of XO by H2O2 occurs by production of .OH following direct reduction of H2O2 by XO at the flavin site.

Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline

Low-dose methotrexate (MTX) therapy has been recently proposed as alternative therapy for patients with severe steroid-requiring asthma. Several questions have been raised regarding the mechanism of action, including alteration of pharmacokinetics of two medications used in these patients, specifically, glucocorticoids and theophylline. To address this question, pharmacokinetic studies were performed at baseline and after 6 weeks of treatment with either intramuscular MTX or placebo (folic acid). Plasma concentrations of theophylline were measured by fluorescence polarization immunoassay (TDx, Abbott Diagnostics, Abbott Park, Ill.). Prednisolone, methylprednisolone, and cortisol concentrations were measured by high-performance liquid chromatography. Fifteen adults were enrolled in the double-blind, placebo-controlled trial. No change in prednisolone pharmacokinetic parameters was found. Theophylline clearance decreased an average of 19% in patients randomized to receive MTX, from 48.0 +/- 2.0 ml/hr/kg to 38.9 +/- 3.6 ml/hr/kg (p less than 0.05). This change resembles change observed with theophylline and phenobarbital clearance in which a high degree of interpatient variability is observed. The most likely explanation for the change in theophylline clearance is inhibition of hepatic microsomal enzyme activity. Three patients complained of adverse effects, and dosage was reduced in one patient. The variable effect of MTX on theophylline clearance indicates that theophylline concentration monitoring should be performed in patients receiving both drugs.

Pharmacokinetics of low-dose methotrexate in adult asthmatics.

Several reports have been published on the disposition of methotrexate (MTX) when given in low dosages, but none in asthmatic patients. To address this matter, pharmacokinetic studies were performed in nine patients with severe, steroid‐requiring asthma (ages 18–76 yrs) after the sixth weekly intramuscular dose of MTX. Theophylline pharmacokinetic studies were also performed at baseline prior to the start of MTX treatment and at the time of the MTX studies. Total systemic clearance of MTX, given as mean (SD), was 122.6 (25.1) ml/minute, volume of distribution at steady state 0.49 (0.2) L/kg, half‐life 3.1 (0.3) hours, mean residence time 5.0 (0.6) hours, and renal clearance 89.1 (36.3) ml/minute. These values are similar to those previously reported for other patient populations receiving low‐dose MTX. Eight of these patients were evaluated for changes in theophylline pharmacokinetics. Theophylline clearance at week 6 decreased an average of 19% from baseline and correlated inversely with total MTX clearance. Percentage change in theophylline clearance from baseline was inversely correlated with MTX nonrenal clearance, but was not statistically significant. This finding may indicate competition for clearance pathways between MTX and theophylline.