Bronchial reactivity in asthmatic children at high and low altitude. Effect of budesonide.

Inhaled steroids may control bronchial inflammation in asthmatics exposed to allergens. In this study we evaluated whether prophylactic budesonide would prevent relapse of asthma in children re-exposed to offending allergens at sea level, after a period of antigen avoidance at high altitude. Thirty children received either budesonide (200 micrograms b.i.d.) or placebo (double-blind). Following a 4-wk baseline period and 2 wk of treatment at high altitude, children were treated for 3 mo at sea level. Methacholine challenge and pulmonary function studies were performed before and after baseline period, after the 2 wk of treatment in the mountain environment, and at the end of treatment. ECP serum levels were evaluated after the baseline period and at the end of treatment. PEFR and symptoms were recorded in a diary card during the study. The increase in methacholine provocative dosage was greater, although not significant (p = 0.096), in the budesonide than in the placebo group after the treatment at high altitude and remained higher at the end of the treatment (p = 0.04). ECP levels increased in both the groups with no significant difference. Our results confirm that budesonide, in addition to its efficacy in treating pre-existent airway inflammation, is effective in preventing the increase of reactivity in asthmatic children re-exposed to allergens.

[The feasibility and tolerability of prolonged treatment with low doses of heparin-calcium administered subcutaneously in infarct patients. A multicenter clinical study]. / Fattibilità e tollerabilità di un trattamento prolungato con basse dosi di eparina calcica per via sottocutanea in pazienti infartuati. Studio clinico multicentrico.

Practical feasibility and clinical tolerability of low dose heparin given subcutaneously for the prevention of reinfarction were evaluated in this open, multicentric trial of post-marketing surveillance. 309 investigators participated. 2830 evaluable patients (2090 M, 709 F, mean age 63 years) who had in the previous 2 years a myocardial infarction were treated subcutaneously with calcium heparin (Calciparina Italfarmaco, 0.5 ml prefilled syringe) at the daily dosage of 12.500 U. The foreseen treatment length was of 1 year; after 6 months of daily injections, calcium heparin could be taken for cycles of 30 days, with 10 day intervals. The enrolled patients resulted to be representative of the population affected with ischemic cardiopathy. One year treatment with calcium heparin was completed by 2040 patients (72.1%); about 1/4 of the patients did not complete the protocol. Patient's subjective decision to withdraw accounted for 46.3% of withdrawals; poor tolerability accounted for 15% of withdrawals (3.8% of total patients). Overall, 237 patients (8.4%) suffered from adverse reactions (353 complaints). Local reactions at the injection site accounted for 60% of total adverse reactions, involving 7.5% of total cases. To follow, allergic reactions (2.5%) and other different types of adverse reaction (incidence less than 0.5%). By analyzing the reactions that provoked drug withdrawal, no organ or function (e.g.: haemostasis) were found to be at risk during the heparin treatment. 64 patients died during the trial. These deaths were in prevalence due to cardiovascular diseases: ventricular fibrillation, cardiac failure, arterial thromboembolism (cardiac reinfarction, stroke).(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerability profile of the antiinflammatory compound imidazole salicylate: a metanalysis of safety data in 1408 patients.

In order to evaluate the incidence of side-effects (S.E.), the withdrawal rate and the type of S.E. of the new antiinflammatory agent imidazole salicylate, we performed an analysis of 33 clinical trials involving 1408 patients treated with 750 mg t.i.d. (tablets or solution) or 1000 mg b.i.d. (granulated powder), taking into account all the factors (treatment duration, pharmaceutical form, indications, etc.) that could influence the type and incidence of S.E. Slight and transient episodes of pyrosis or epigastric pain represented the great majority of S.E. The overall rate of withdrawal was 1.8%. According to the duration of therapy, the incidence of S.E. was: 2-3 days, 3.3%; 5-7 days, 5.6%; 10-14 days, 8.8%; 30 days, 10.2%. The pharmaceutical forms, the treated pathologies and the various experimental designs adopted (double-blind, open, etc.) did not influence the S.E. rate. With imidazole salicylate the overall incidence of S.E. was always lower than other NSAID's ranging from 10% to 64% of that observed with the reference drugs (other salicylates, ibuprofen, naproxen, flurbiprofen, piroxicam, diclofenac). In conclusion, this analysis showed a linear relationship between S.E. and exposure time up to 10-12 days, followed by a clear trend toward a plateau of 10% of S.E. with treatments up to 30 days. Therefore the risk-benefit ratio, particularly when compared with that of the reference drugs, seems to be very favourable.

Comparison of the protective effect and duration of action of orally administered clenbuterol and salbutamol on exercise-induced asthma in children.

Clenbuterol (C), a long-acting beta 2-selective bronchodilator was compared with salbutamol (S) in exercise-induced asthma (EIA) at two premedication time levels. Sixteen asthmatic children with EIA living at an altitude of 1,750 m were treated with C (0.001 mg/kg) and S (0.12 mg/kg), administered randomly in a double-blind cross-over study 90 and 300 minutes before exercise tests of running on a treadmill for 6 minutes. Pulmonary functions were evaluated prior to the administration of the drugs and immediately before, at the end of, and 2, 5, 10, 15, 20, and 25 minutes after exercise tests. In the preliminary screening exercise test the mean fall of FEV1 was 41.1%, but it was 21.0% and 27.1% after S and 21.9% and 19.9% after C administered 90 and 300 min prior to the test, respectively. Salbutamol administered 300 minutes before the test was statistically less effective than the same drug administered 90 minutes before the test or C administered 300 minutes before the test. Therefore, we can conclude that clenbuterol provides a more lasting protection than salbutamol in EIA.

Bronchodilating activity of oral clenbuterol in asthmatic children after single administration of different dosages.

The dose-response activity of clenbuterol, a new long-acting beta 2-agonist, was evaluated in 12 children aged 5 to 11 years with moderate to severe asthma. The study was a double-blind cross-over comparison of three oral dose levels: 0.5, 1.0, and 1.5 micrograms/kg and placebo all in the form of syrup. Pulmonary function, heart rate, blood pressure, and tremor were evaluated at 30, 60, 90, and 120 min, then hourly for 8 hr, following the ingestion of the drug. The bronchodilating effect of clenbuterol, evaluated as percentage changes in expiratory flow rates was significantly different from placebo. The overall fall-off in the effect of 1.0 micrograms/kg and 1.5 micrograms/kg doses after 8 hr was small. The results of the 1.0 micrograms/kg dose often overlapped those of the 1.5 micrograms/kg dose, suggesting that a single 1.0 micrograms/kg dose of clenbuterol is most advisable in children, assuring the most favorable risk/benefit ratio. Even the highest dose of clenbuterol caused only a marginal increase in tremor, not statistically different from that induced by placebo.

Oral clenbuterol and procaterol. A double-blind comparison of bronchodilator effects in children with chronic asthma.

In a double-blind crossover study, clenbuterol at a dose of 0.75 micrograms/kg, procaterol at a dose of 1.5 micrograms/kg, and placebo, all administered orally, were compared for bronchodilation efficacy. Twelve children aged from 6 to 13 years, with moderate to severe asthma, participated in the trial. Pulmonary function, heart rate, blood pressure, and tremor were evaluated at 30, 60, 90, and 120 minutes and then hourly for 8 hours after administration. Both clenbuterol and procaterol induced a significant change over their baseline values for all the pulmonary function parameters considered. For clenbuterol, the same was also observed in comparison with placebo, while for procaterol this was true only for FEV1 and FEF25-75, while no difference resulted from FVC and PEF. Mild and transient tremor was the only side effect observed. Oral clenbuterol and procaterol were both demonstrated to be safe and effective. However, at the doses studied, clenbuterol had a significantly higher bronchodilator activity lasting up to 8 hours.

Oral beta 2-selective adrenergic bronchodilators.

Oral beta 2-agonists (carbuterol, pirbuterol, procaterol, bitolterol, clenbuterol) are drugs widely used as bronchodilators. The efficacy and selectivity of bronchodilators drugs depend on their intrinsic pharmacological properties and on the route of administration. The characteristics of the oral route are easy usage, precise dosage and assured effects. Consequently, disadvantages (delayed onset of action, more frequent side-effects) and the indications, (patients with severe chronic airways obstruction, nocturnal asthmatic attacks, and children and elderly subjects) are clearly evident. The most recent beta 2-agonists have an efficient and prolonged bronchodilating action with well-known side-effects. In order to control drug efficiency in a large population and identify type and degree of adverse reactions, a post-marketing surveillance study was programmed for clenbuterol. The results available confirms that long-term treatment with oral clenbuterol is an effective and safe therapeutical approach. During long-term treatment, tachyphylaxis (a diminished responsiveness) develops. This complex biological phenomenon can be studied, in several ways i.e. functional response of target-organ, appropriate biochemical-metabolical indices, and functional evaluation of the cellular beta-receptors in vitro. Also in the light of evaluation of serum levels of cyclic nucleotides (cyclic adenosine and guanosine monophosphates) it appears that the clinical importance of tachyphylaxis is mild and that chronic therapy with beta 2-agonists is safe and effective when used in selected patients.