Theophylline-induced alteration in serum electrolytes and uric Acid of asthmatic children

Theophylline, (1,3-dimethylxanthine) is widely used as a smooth muscle relaxant, myocardial stimulant and a diuretic agent. The most frequent use of theophylline is in treatment of acute and chronic asthma as a bronchodilator. To determine the effect of Theophylline on serum electrolyte and uric acid, 21 asthmatic children (age range 1.5-7 years) with severe acute asthma and 25 patients with chronic asthma (5-15 years ) who were being treated with slow-release theophylline were enrolled in this study. Fifty age and sex matched normal children took part as control. Blood samples (5m1) were withdrawn before, during and after completion of the course of intravenous theophylline treatment (0.05-0.70 mg/kg/ hr). Sera obtained were used for analysis of K+, Na+, phosphorus, calcium and uric acid by RA-1000 automated analyzer and the following results were obtained: (1) After treatment, total serum calcium in acute asthmatic patients decreased significantly compared with controls (P<0.01); (2) serum phosphate and K+ levels of acute and chronic asthmatic patients after therapy decreased as compared with controls (P<0.01). (3) Post therapy increase in serum level of uric acid in acute and chronic asthmatic patients was statistically significant as compared with control (P<0.001). We conclude that the serum levels of phosphate, potassium, calcium and uric acid should he monitored in patient receiving theophylline especially during prolonged use and critical emergency cases.     

Ketotifen in the prophylaxis of extrinsic bronchial asthma. A multicenter controlled double-blind study with a modified-release formulation

In a placebo controlled double-blind multicenter trial, 245 patients with bronchial asthma (131 male and 124 female patients) between 6 and 51 years of age were treated in two parallel groups. A slow-release oral formulation containing 2 mg of ketotifen or placebo was administered daily for a duration of 12 weeks. Over a period of four weeks before the study, 94 percent of the patients had asthmatic attacks. 78 percent had cough, and 62 percent had nasal symptoms. In the group treated with slow-release oral ketotifen, there were 3.9 asthmatic attacks (range, 0 to 20) per week, and in the placebo group, there were 2.9 (range, 0 to 12) (mean values during four weeks prior to start of treatment). At the end of treatment, asthmatic attacks were significantly reduced in the group treated with slow-release oral ketotifen compared with placebo. Significant reduction was also evident for cough and sputum production, as well as nasal discharge and obstruction; however, slow-release oral ketotifen did not significantly improve pulmonary function indices when compared to placebo. The use of concomitant medication (beta-sympathomimetic drugs) was also significantly reduced in the group receiving slow-release oral ketotifen. The overall efficacy assessed by the investigators was "very good" and "good" in 76 percent of the group receiving slow-release oral ketotifen and 30 percent in the group receiving placebo (p less than 0.001). Tolerability rated by the investigators was "very good" and "good" in 90 percent of the group with slow-release oral ketotifen and in 96 percent of the group with placebo (p less than 0.10). The most frequent side effects were "mild" and "moderate" sedation, sleepiness and drowsiness reported in 44 percent of the patients receiving slow-release oral ketotifen and in 26 percent of the patients receiving placebo. This difference was statistically significant (p less than 0.01).     

Regulation of stromal cell-derived factor-1 and exhaled nitric oxide in asthmatic children following montelukast and ketotifen treatment

BACKGROUND: Montelukast and ketotifen are oral anti-allergy medications in asthmatic children. This study investigates the modulation effect of montelukast and ketotifen on children with intermittent to mild persistent asthma as demonstrated by the levels of peak expiratory flow (PEF), asthma scores (AS), exhaled nitric oxide (eNO) and plasma stromal cell-derived factor-1 (SDF-1) concentration in a randomized, prospective study. METHODS: Fifty asthmatic children were enrolled and received 8 weeks of treatment with oral montelukast sodium 5mg chewable tablet administered once daily, or 1mg ketotifen, and were followed for a 4-week post-treatment washout period. ENO concentration, AS and PEF were measured before, 2, 4, 6 and 8 weeks after initial treatment, and 4 weeks after cessation of treatment. RESULTS: Montelukast therapy was showed to improve AS, PEF and eNO within 2 weeks and remained the improvement during the treatment period. Montelukast also significantly decreased plasma SDF-1 levels after 8 weeks of treatment. In contrast, the ketotifen treatment revealed no significant effects in these clinical parameters until 4 and 6 weeks of the therapy, and did not suppress plasma SDF-1 levels after 8 weeks of treatment. To prove whether montelukast directly suppressed SDF-1 induction, we studied effects of montelukast on the LPS-induced SDF-1 expression and SDF-1-induced chemotaxis of monocytic (THP-1) cells. Montelukast, but not ketotifen, could suppress SDF-1 expression and its related chemotaxis on THP-1 monocytic cells. CONCLUSIONS: Leukotriene receptor antagonist, such as montelukast, may be a better non-steroid anti-inflammatory drug for mild childhood asthma in preventing airway inflammation.     

A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children.

BACKGROUND: Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study. METHODS: Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5-8 mg/kg (dry syrup) or 100-200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2. RESULTS: A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/minvs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/minvs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/minvs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences. CONCLUSIONS: The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children.     

Psychological change associated with theophylline treatment of asthmatic children: a 6-month study.

Theophylline has been associated with a variety of behavioral side effects in asthmatic children. This study was a 6-month investigation of the relationship between theophylline treatment and psychological changes in 8 to 16 year old asthmatic children. Included were a group receiving theophylline (n = 19), a control group not receiving theophylline (n = 44), and a nonasthmatic control group (n = 24). The three groups had similar age, socioeconomic status, and IQ. The two groups of children with asthma demonstrated greater emotional dysfunction, characterized by tendency toward withdrawal and depression, than the nonasthmatic control group. Each of five assessment appointments (baseline and 1 week, 1 month, 3 months, and 6 months after beginning theophylline treatment) included measures of pulmonary function, attention, impulsivity, memory, fine motor control, activity level, self-reported mood, and parental observation of difficult behavior. Pulmonary functions were lower in the theophylline group at baseline but improved significantly after commencement of theophylline therapy. Over the 6-month interval, children in the theophylline group demonstrated improved scores on a laboratory measure of attention, while their parents reported increased conduct problems and hyperactivity. On the whole, psychological score changes were subtle, and no other between-group differences emerged in the remaining laboratory measures.     

A comparative study of the effects of ketotifen, disodium cromoglycate, and beclomethasone dipropionate on bronchial mucosa and asthma symptoms in patients with atopic asthma

Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa. We compared the effects of ketotifen, disodium cromoglycate (DSCG), and beclomethasone dipropionate (BDP) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma. In this 12-week parallel study, 32 patients were randomly allocated to either the ketotifen group (2 mg day-1, n = 13), DSCG group (8 mg day-1, n = 9) or BDP (400 micrograms day-1, n = 10). Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Before and after treatment, pulmonary function and bronchial responsiveness to methacholine were evaluated, and fibreoptic bronchoscopy and biopsy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils (EG2), mast cells (AA1), and T cells (CD3, CD4, and CD8). Our clinical findings showed significant improvement in symptom score and bronchial responsiveness (P < 0.01) each) in all groups. Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group (P < 0.05, both groups). PEF significantly increased in the DSCG group in comparison to the ketotifen (P < 0.01) and BDP (P < 0.05) groups, FEV1% increased significantly in the DSCG (P < 0.01) and BDP (P < 0.05) groups in comparison to the ketotifen group. Compared with their baseline values, treatment significantly decreased EG2+ activated eosinophils, and CD3+ and CD4+ T cells, in each group (P < 0.01). Both the DSCG (P < 0.05) and the BDP groups (P < 0.01) exhibited significant decreases in AA1+ mast cell count, but this was not observed in the ketotifen group. Comparing before- and after-treatment values, only the DSCG group exhibited a significant decrease in the number of CD8+ T cells (P < 0.01). Ketotifen, DSCG, and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients; and both the DSCG and BDP groups had better clinical responses than the ketotifen group.     

Interferon therapy induces the improvement of lung function by inhaled corticosteroid therapy in asthmatic patients with chronic hepatitis C virus infection: a preliminary study

STUDY OBJECTIVES: Several reports have suggested that subsets of asthmatic patients with chronic viral infection fail to respond to corticosteroid therapy. Therefore, this study was designed to determine that asthmatic patients with chronic hepatitis C virus (HCV) infection fail to improve lung function by inhaled corticosteroid therapy, and that interferon (IFN) therapy against HCV is effective for such patients. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Forty asthmatic patients with chronic HCV infection. INTERVENTIONS: After a 4-week run-in period, all asthmatic patients received therapy with inhaled beclomethasone dipropionate (BDP), 400 micro g twice daily for 6 weeks. After the first study, all asthmatic patients continued to receive inhaled BDP, and 30 HCV-positive asthmatic patients received IFN-alpha therapy for 6 months. MEASUREMENTS AND RESULTS: Prebronchodilator and postbronchodilator FEV(1) values were examined after a 4-week run-in period, after 6 weeks of BDP therapy, and at 1 year from the end of IFN therapy. After a 4-week run-in period as well as after 6 weeks of BDP therapy, there were no significant differences in either prebronchodilator or postbronchodilator FEV(1) values among the three groups. However, 1 year after the end of IFN therapy, the mean prebronchodilator and postbronchodilator FEV(1) values were significantly higher in the IFN responder group (n = 11) [prebronchodilator FEV(1), 1.93 L (SD, 0.13 L); postbronchodilator FEV(1), 2.28 L (SD, 0.15 L)] than in the IFN nontreatment group (n = 10) [prebronchodilator FEV(1), 1.78 L (SD, 0.10 L); p = 0.01; postbronchodilator FEV(1), 2.07 L (0.13 L); p = 0.005] or the IFN nonresponder groups (n = 19) [prebronchodilator FEV(1), 1.79 L (SD, 0.15 L); p = 0.006; postbronchodilator FEV(1), 2.07 L (SD, 0.18 L); p = 0.002]. Moreover, prebronchodilator and postbronchodilator FEV(1) values were significantly higher only in the IFN responder group at 1 year after the end of IFN therapy than after the 4-week run-in period (prebronchodilator FEV(1), p = 0.028; postbronchodilator FEV(1); p = 0.002) or after 6 weeks of BDP therapy (p = 0.016 and p = 0.004, respectively). CONCLUSIONS: Our findings suggest that chronic HCV infection in asthmatic patients is associated with impaired responses to inhaled BDP therapy and that intervention with IFN reverses such responses only in the IFN responder group.     

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children.

The effect over time of regular treatment with montelukast (MNT) in inhibiting exercise-induced bronchoconstriction (EIB) has never been evaluated in children. The aim of the present study was to examine the preventive effect of MNT against EIB in children at different time-points over a 4-week treatment period. Thirty-two asthmatic children (aged 6-12 yrs) were enrolled in a double-blinded, randomised, parallel group design to receive a 4-week treatment with MNT (5 mg chewable tablets administered once daily in the evening) or placebo. Exercise challenge was performed at baseline and after 3, 7 and 28 days of treatment, 20-24 h after dosing. MNT was significantly more protective than placebo against EIB at each time. The mean percentage drop of forced expiratory volume in one second (FEV1) was 24.6, 13.6, 12.0 and 11.6 for MNT, and 24.4, 22.4, 21.8 and 21.0 for placebo, at baseline and after 3, 7 and 28 days, respectively. For each drug, no significant difference in the percentage drop of FEV1 was found between different days. Regular treatment with montelukast provided significant protection against exercise-induced bronchoconstriction in asthmatic children over a 4-week period with no tolerance to the bronchoprotective effect.     

The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: a pilot study

We explored the additive effect of titrated oral theophylline in patients with stable chronic obstructive pulmonary disease (COPD) who received both tiotropium, 18mug od, and formoterol, 12mug bid. Thirty-six patients with moderate-to-severe COPD were enrolled in this two-period trial. They were initially treated with formoterol+tiotropium for 4 weeks. After this first period, they were divided in two groups of 18 patients. Both groups continued with the initial treatment for further 4 weeks, but the first group received also placebo whereas the second group received oral theophylline. The combination therapy with formoterol+tiotropium induced a significant improvement in mean predose FEV(1) and FVC at the end of the first period, and a significant reduction in dyspnea score as measure by a visual analogic scale and in use of rescue salbutamol. The second period of treatment elicited a significant further improvement in lung function and reduction in dyspnea score and salbutamol use in both groups. On the contrary, differences in improvements in FEV(1) and FVC and reduction in dyspnea score and salbutamol use between theophylline and placebo arms at the end of the second treatment period were not significant, although 5 patients reported an important relief in dyspnea during the theophylline administration period. These findings question the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, but also indicate the possibility that some of them can benefit from theophylline because of a symptomatic improvement.     

Effects of the addition of nedocromil sodium to maintenance bronchodilator therapy in the management of chronic asthma.

STUDY OBJECTIVES: To assess the efficacy and safety of nedocromil sodium metered dose aerosol as an adjunct to sustained-released theophylline therapy in adult theophylline-dependent asthma patients and to examine the ability of nedocromil sodium to substitute for theophylline. DESIGN: Randomized double-blind placebo-controlled parallel group study. Two-week baseline, eight-week treatment period. SETTING: Out-Patient Clinic. PATIENTS: Sequential sample of 35 adult chronic asthmatic patients maintained on a regimen of sustained-release theophylline (dose range, 400 to 800 mg daily) and on-demand inhaled beta 2-bronchodilators. All patients completed the study. INTERVENTIONS: 2 x 2-mg nedocromil sodium metered dose aerosol twice daily or matching placebo randomly allocated after two-week baseline. Theophylline dose reduced by half or one third after four weeks of test treatments, then stopped for final two weeks. Use of inhaled beta 2-bronchodilators permitted throughout trial period. MEASUREMENTS AND RESULTS: The following results were in favor (statistically significant findings, p less than 0.05) of nedocromil sodium compared with placebo: all diary card efficacy variables (nighttime asthma, morning tightness, daytime asthma, cough, twice daily peak expiratory flow [PEF], inhaled beta 2 use) during all periods of assessment (weeks 1 to 2, 3 to 4, 5 to 6, and 7 to 8) with the exception of cough and nighttime beta 2 use during weeks 1 to 2; patient and clinician opinion of treatment efficacy (end of weeks 4 and 8); ability to reduce the theophylline dose; clinician assessment of asthma severity at the end of the study, and clinic FEV1 at weeks 4, 5, 6, and 8. One placebo-treated patient reported transient moderately severe nausea and taste loss. No clinically significant changes were seen in the laboratory data. CONCLUSION: Nedocromil sodium, 4 mg twice daily, conferred significant benefit when added to sustained-release theophylline therapy. The results suggest that nedocromil sodium may permit a reduction in theophylline dosage and possibly substitute for theophylline in previously dependent patients.     

Intervention at lower blood pressure levels to achieve target goals in type 2 diabetes: PRADID (PResión Arterial en DIabéticos tipo Dos) study

BACKGROUND: Arterial hypertension greatly increases the risk of cardiovascular disease, renal insufficiency, and retinopathy in patients with type 2 diabetes. Epidemiological studies all document a reduced risk for the aforementioned consequences at a blood pressure (BP) lower than 130/80 mmHg. For this reason, lower target BPs are recommended by recent guidelines committees. A lower threshold BP for treatment, also proposed in guidelines, could facilitate the attainment of the recommended target BP. However, little data exist on the efficacy and safety of starting pharmacological therapy in type 2 diabetic patients exhibiting high-normal BP (HNBP) or the first stage of isolated systolic hypertension previously considered as borderline isolated systolic hypertension (BISH). OBJECTIVE: To determine the antihypertensive efficacy and safety of the fixed-dose combination of the non-dihydropiridine calcium channel blocker (CCB) and ACE inhibitor verapamil SR/trandolapril 180/2 mg (V + T), versus trandolapril 2 mg (T), versus placebo (P) in previously untreated type 2 diabetic patients diagnosed as having HNBP or BISH. METHODS: Multicentric, double-blind, placebo-controlled study with a 16-week follow-up in three groups totalling 438 participants. The primary end-point was to attain the recommended guideline goal of a systolic BP (SBP) value lower than 130 mmHg in all patients and a diastolic BP (DBP) value lower than 85 mmHg in HNBP. Participants were randomized (2:2:1) to verapamil V + T, T, or P. Doses were doubled at week 8 if BP was not controlled. RESULTS: Both active groups were more effective than placebo to decrease SBP and DBP. The mean difference in SBP from placebo was 7.1 mmHg (3.3-10.9, 95% confidence interval (CI); P < 0.001) for T and 7.8 mmHg (3.9-11.6, 95% CI; P < 0.001) for V + T, with no statistical difference between both active groups. Combined treatment (V + T) decreased DBP by 4.6 mmHg (2.3-6.9, 95% CI; P < 0.001) more than placebo and 2.1 mmHg (0.3-4.0, 95% CI; P = 0.021) more than T. At the end of the study, 36.5% in the T group, 37.8% in the V + T group, and 14.9% (P = 0.009, P versus V + T and T) had attained the primary end-point. No significant difference was found between T and V + T with regard to the percentage of good control for SBP, but the control rate on the DBP (DBP < 85 mmHg) was significantly higher in the V + T group (88.8%), when compared with T (79.1%) or P (63.5%) (P = 0.002). Withdrawal rates due to adverse effects did not differ among trandolapril alone (9.4%), the combination (11.7%) and placebo (8.1%). CONCLUSION: Antihypertensive treatment is more effective than placebo for controlling SBP and DBP in previously untreated participants with type 2 diabetes exhibiting low threshold BP values. Combination therapy with verapamil SR/trandolapril was more effective than trandolapril alone for controlling DBP.     

Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone

Older men, particularly those with low serum testosterone (T) levels, might benefit from T therapy to improve bone mineral density (BMD) and reduce fracture risk. Concerns exist, however, about the impact of T therapy on the prostate in older men. We hypothesized that the combination of T and finasteride (F), a 5 alpha-reductase inhibitor, might increase BMD in older men without adverse effects on the prostate. Seventy men aged 65 yr or older, with a serum T less than 12.1 nmol/liter on two occasions, were randomly assigned to receive one of three regimens for 36 months: T enanthate, 200 mg im every 2 wk with placebo pills daily (T-only); T enanthate, 200 mg every 2 wk with 5 mg F daily (T+F); or placebo injections and pills (placebo). Low BMD was not an inclusion criterion. We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry. Prostate-specific antigen (PSA) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate. Fifty men completed the 36-month protocol. By an intent-to-treat analysis including all men for as long as they contributed data, T therapy for 36 months increased BMD in these men at the lumbar spine [10.2 +/- 1.4% (mean percentage increase from baseline +/- SEM; T-only) and 9.3 +/- 1.4% (T+F) vs. 1.3 +/- 1.4% for placebo (P < 0.001)] and in the hip [2.7 +/- 0.7% (T-only) and 2.2 +/- 0.7% (T+F) vs. -0.2 +/- 0.7% for placebo, (P < or = 0.02)]. Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip. After 6 months of therapy, urinary deoxypyridinoline (a bone-resorption marker) decreased significantly compared with baseline in both the T-only and T+F groups (P < 0.001) but was not significantly reduced compared with the placebo group. Over 36 months, PSA increased significantly from baseline in the T-only group (P < 0.001). Prostate volume increased in all groups during the 36-month treatment period, but this increase was significantly less in the T+F group compared with both the T-only and placebo groups (P = 0.02). These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men. In addition, the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels.     

Theophylline induces a reduction in circulating interleukin-4 and interleukin-5 in atopic asthmatics.

Theophylline, a known phosphodiesterase inhibitor, has been widely used as an additional bronchodilator in asthmatic patients who are not adequately controlled on high-doses of inhaled steroids. However, there is growing evidence that theophylline may also have anti-inflammatory or immunomodulatory effects in asthma. This study investigated whether theophylline administration has an impact on serum levels of interleukin (IL)-4 and IL-5 in asthmatic patients. Eight asymptomatic patients aged 30+/-1.5 yrs (mean +/- SEM) with mild atopic asthma were given a single daily dose of theophylline 150 mg or placebo in an on (theophylline)-off (placebo)-on (theophylline)-off (placebo) protocol with a 3-week duration of each on- or off- interval. Determination of serum IL-4 and IL-5 was done at baseline for all subjects and on the last day of each 3-week interval for the patients under study. Serum IL-4 levels were: 35+/-6 (baseline), 19+/-3 (on-1 interval), 29.5+/-4 (off-2), 15+/-2 (on-3) and 26+/-4 pg x mL(-1) (off-4), while IL-5 levels were 27+/-5, 18+/-4, 28+/-5, 17+/-4 and 28+/-5 pg x mL(-1), respectively. Spirometry was unchanged during the study and serum theophylline levels at the end of the two on-periods were 4.5+/-0.05 and 4.2+/-0.07 microg x mL(-1), while all patients remained asymptomatic. In conclusion, the administration of a low, single, daily dose of oral theophylline in asymptomatic patients with mild atopic asthma seems to reduce circulating interleukin-4 and interleukin-5.     

Cognitive effects of short-term manipulation of serum sex steroids in healthy young men

We examined the effects of sex steroids on cognitive functioning by exogenously manipulating circulating T levels in a group of healthy young men. Thirty-two men were randomized to receive 8 wk of treatment including: 1) im T enanthate 100 mg/wk plus daily oral placebo (T); 2) im placebo/wk plus 125 microg daily oral levonorgestrel (LNG); 3) im T enanthate 100 mg/wk plus 125 microg daily oral LNG (T + LNG); 4) im placebo/wk plus daily oral placebo. Cognitive functions were assessed at baseline and twice during treatment. Serum T and E2 levels were significantly increased in the T and T + LNG groups compared with baseline (P < 0.01) and T levels were significantly decreased in the LNG group (P < 0.05). Verbal memory significantly decreased in the LNG group (P < 0.01) and was maintained by coadministration of T in the T + LNG group. Divided attention was unaffected in the LNG group but improved significantly in the T + LNG group. In summary, decreased serum T levels induced by LNG or direct effects of the progestin, LNG, adversely affects verbal memory in normal young men. These results suggest that short-term changes in sex steroid levels have effects on cognitive function in healthy young men.     

Six-week trial of nebulized flunisolide nasal spray: Efficacy in young children with moderately severe asthma

This study evaluated the clinical efficacy of nebulized flunisolide nasal solution (Nasalide®) in young children with moderately severe asthma. Twenty-two asthmatic children, ages 12–72 months, completed this double-blind placebo-controlled study. After a 6-week observation period, 18 patients were paired according to asthma severity. One child from each pair was randomized to flunisolide, the other to placebo; 4 patients were independently randomized. Placebo or drug was then administered for 6 weeks. Throughout the study, symptoms, drug usage, and analog scales reflecting asthma severity and family disruption were recorded in a diary. Multiple regression analysis was used to compare the flunisolide and placebo groups in regard to the amount of improvement demonstrated from the observation to the active periods of the study. Analog scores of asthma severity and family disruption, albuterol aerosol use, and systemic corticosteroid use fell roughly 40% from baseline in the flunisolide group. This improvement was significant compared to the placebo group. We conclude that 1 ml (250 μg) of nebulized flunisolide nasal spray solution, administered three times daily, reduced the severity of asthma symptoms, and the need for both albuterol aerosol and systemic corticosteroid therapy in young children with moderately severe asthma during a 6-week trial. Longer term studies are warranted. Pediatr. Pulmonol. 1997; 24:397–405. © 1997 Wiley-Liss, Inc.     

Comorbid major depressive disorder as a prognostic factor in cocaine-abusing buprenorphine-maintained patients treated with desipramine and contingency management

Depression is common among patients who abuse both opiates and cocaine, and its treatment has had mixed success. This study compares buprenorphine-maintained patients with lifetime major depressive disorder (MDD, N = 53) with those never depressed (ND, N = 96) on cocaine and opiate-free urines during a 12-week outpatient double-blind, placebo-controlled, randomized clinical trial. The 149 subjects were assigned to four groups: 1) desipramine (DMI) + contingency management (CM); 2) DMI + noncontingency management (NCM); 3) placebo + CM; and 4) placebo + NCM. Depression assessments included Hamilton Depression Rating Scale, Center for Epidemiological Studies Depression Inventory, and Structured Clinical Interview for DSM-IV interview for diagnosis of lifetime MDD. Urine toxicologies were performed thrice weekly and the CES-D was performed monthly. The MDD group had a larger proportion of females (45% vs 21%, P = 0.02) and were more likely to be married (13.2% vs 7.3%, P = 0.02) than the ND group. Treatment retention did not vary by depression status. Hierarchical Linear Modeling found that depressive symptoms decreased comparably across the four treatment groups. Although participation in CM improved drug-free urines more for patients with MDD than for the ND group (Z = 2.44, P = 0.01), treatment with DMI was significantly more efficacious for the ND group than for the MDD group (Z = -2.89, P = 0.003). These results suggest that patients with MDD may respond better to behavioral treatments such as CM than to desipramine plus buprenorphine. The ND cocaine-abusing, opiate-dependent patients may be more responsive to the anticraving effects of DMI.     

The effect of montelukast on bronchial hyperreactivity in preschool children

INTRODUCTION: The effect of montelukast therapy on bronchial hyperreactivity (BHR) as measured by the methacholine challenge test in preschool children has not yet been reported. OBJECTIVE: To determine the effect of montelukast (4 mg/d) on BHR as evaluated by a provocative concentration of a substance causing a 20% fall in FEV(1) (PC(20)) values in preschool asthmatic children. PATIENTS: A total of 26 preschool children (8 girls) aged 3.3 to 6.0 years (mean [+/- SD] age, 4.7 +/- 0.8 years) with mild asthma. DESIGN: Double-blind randomized, placebo controlled, crossover study. Each child received 4 weeks of treatment with 4 mg of either montelukast or placebo separated by a 2-week washout period. Primary outcomes were PC(20) values and the stage number (triple dose) at which FEV(1) values dropped by 20%(.) Post-montelukast therapy PC(20) was compared to those for the post-placebo period. RESULTS: Following 4 weeks of montelukast treatment, the mean PC(20) was 4.79 +/- 4.69 mg/mL, while after 4 weeks of placebo the mean PC(20) was 2.07 +/- 2.37 mg/mL (p = 0.001). The montelukast/placebo ratio for PC(20) was 2.56 with a 95% confidence interval (CI) of 1.71 to 3.99. The median difference in stage was one triple dose with a 95% CI of 0.5 to 1.5. CONCLUSIONS: Four weeks of treatment with montelukast resulted in a decreased BHR compared with placebo.     

Effect of ketotifen on childhood asthma: a double-blind study

Ketotifen was administered orally, for 3 months, to 40 children aged 3-14 years with chronic extrinsic asthma of moderate severity in a double-blind placebo-controlled study. A significant clinical improvement with concomitant reduction of antiasthmatic drugs was found in the group receiving the active drug compared with the placebo group (p less than 0.05). The continued administration of ketotifen in an open study to a group of 21 children comprised of patients belonging to both groups (active-placebo) for a period of 15-18 months resulted in disappearance of symptoms in 10 children (47.6%) and moderate improvement in 7 (33.3%).     

Different IL-5 and IFN-γ Production from Peripheral Blood T-Cell Subsets in Atopic and Nonatopic Asthmatic Children

Defective Th1 and enhanced Th2-type cytokine responses have been implicated in the development of atopic disease. However, the immunopathology of nonatopic asthma, especially in children, remains unclear, and there have been few studies to compare the cytokine profile in peripheral blood T-cell subsets between atopic and nonatopic asthmatic children. To document whether atopic asthmatic children have a cytokine imbalance and to compare the cytokine profile between atopic and nonatopic asthmatic children, we investigated the interleukin (IL)-5-producing and interferon (IFN)-γ-producing T-cell subsets from peripheral blood mononuclear cells (PBMC). The percentages of IFN-γ-producing CD4⁺ and CD8⁺ T cells from atopic asthmatic children were decreased, but those in nonatopic asthmatic children were not decreased. In both groups of asthmatic children, the percentages of IFN-γ-producing CD4⁺ T cells were inversely correlated with the peripheral blood eosinophils and had a significant correlation with airway responsiveness (PC₂₀). Thus, we found that the mechanism underlying allergic inflammation of nonatopic asthma is not simple a Th1/Th2 cytokine imbalance. Considering the inverse relationship between IFN-γ-producing CD4⁺ T cells and eosinophilia or airway hyperresponsiveness, IFN-γ from CD4⁺ T cells may play an important role in allergic inflammation and airway hyperresponsiveness in asthmatic children.