Maria Robuschi

Obstructive Sleep Apnea–Dependent and –Independent Adrenergic Activation in Obesity

No agreement exists as to the mechanisms responsible for the sympathetic hyperactivity characterizing human obesity, which has been ascribed recently to a chemoreflex stimulation brought about by obstructive sleep apnea rather than to an increase in body weight, per se. In 86 middle-age normotensive subjects classified according to body mass index, waist-to-hip ratio, and apnea/hypopnea index (overnight polysomnographic evaluation) as lean and obese subjects without or with obstructive sleep apnea, we assessed via microneurography muscle sympathetic nerve traffic. The 4 groups were matched for age, gender, and blood pressure values, the 2 obese groups with and without obstructive sleep apnea showing a similar increase in body mass index (32.4 versus 32.0 kg/m2, respectively) and waist-to-hip ratio (0.96 versus 0.95, respectively) compared with the 2 lean groups with or without obstructive sleep apnea (body mass index 24.3 versus 23.8 kg/m2 and waist-to-hip ratio 0.77 versus 0.76, respectively; P<0.01). Compared with the nonobstructive sleep apnea lean group, muscle sympathetic nerve activity showed a similar increase in the obstructive sleep apnea lean group and in the nonobstructive sleep apnea obese group (60.4±2.3 and 59.3±2.0 versus 40.9±1.8 bs/100 hb, respectively; P<0.01), a further increase being detected in obstructive sleep apnea subjects (73.1±2.5 bursts/100 heart beats; P<0.01). Our data demonstrate that the sympathetic activation of obesity occurs independently in obstructive sleep apnea. They also show that this condition exerts sympathostimulating effects independent of body weight, and that the obstructive sleep apnea–dependent and –independent sympathostimulation contribute to the overall adrenergic activation of the obese state.

Aspects of bronchial reactivity to prostaglandins and aspirin in asthmatic patients.

The behaviour of bronchial reactivity to PGF2alpha was studied in asthmatic patients under various experimental conditions. Premedication with aminophylline, i.v., and, to a lesser extent, with DSCG afforded a partial protection, while beclomethasone dipropionate was inactive under this point of view. Diftalone, a new non-steroid anti-inflammatory agent, was well tolerated in 9 aspirin-intolerant asthmatic patients, and did not modify the bronchial response to PGF2alpha which was found to be generally lower then that of other aspirin-tolerant asthmatic patients. PGE 1-2 and DSCG prevented the bronchospasm induced by inhalation or ingestion of acetylsalicylic acid in a small group of patients. Good protection was also reached with PGE1-2 in the exercise-induced bronchospasm.

Intolerance to Tartrazine in Aspirin-Induced Asthma: Results of a Multicenter Study

One hundred and fifty-six German, Italian and Polish patients with confirmed aspirin-induced asthma underwent open oral challenges with increasing doses of tartrazine up to 25 mg. All positive challenges were repeated under double-blind conditions. Only 4 of 156 patients (all Polish) had positive reactions in a double-blind test, as evidenced by a fall in FEV1 greater than 25% from baseline and corresponding clinical symptoms. Sixty-five patients who tolerated 25 mg tartrazine well received 50-3,000 mg tartrazine and none showed adverse reactions. Thus, intolerance to tartrazine appears to be rare among Central-European and South-European patients with aspirin-induced asthma, its frequency amounting to about 2.6%.

Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone–dependent asthma

BACKGROUND Inhaled lysine acetylsalicylate and furosemide exert a mutually potentiating protective activity on experimentally induced bronchoconstriction in asthma. OBJECTIVE Our purpose was to investigate the clinical effectiveness of combined treatment of asthma with inhaled lysine acetylsalicylate and furosemide. METHODS We performed a randomized, double-blind, crossover study in nine patients with chronic asthma requiring a high dose (2 mg/day) of inhaled beclomethasone for clinical control. Patients were treated with a combination of 720 mg inhaled lysine acetylsalicylate and 40 mg furosemide twice daily, or with matched placebo in addition to inhaled steroids. The dose of inhaled steroids was reduced by half every 15 days and eventually suspended unless a patients respiratory condition worsened. RESULTS During treatment with placebo, all patients had worsening of asthma at dosages of 1 or 0.5 mg/day beclomethasone (mean +/- SE, 833 +/- 83 micrograms/day). During combined treatment complete suspension of inhaled steroids in two patients and reduction to 0.5 to 0.25 mg in the remaining seven patients (mean, 250 +/- 72 micrograms/day) was achieved, with a mean reduction of 71% +/- 7%. Forced expiratory volume in 1 second, weekly peak expiratory flow rate, symptom score, and bronchodilator intake remained significantly better with combined treatment than with placebo. CONCLUSIONS Treatment with inhaled lysine acetylsalicylate and furosemide allows a considerable sparing of inhaled steroids without significant side effects in patients with severe asthma.

Protective activity of inhaled nonsteroidal antiinflammatory drugs on bronchial responsiveness to ultrasonically nebulized water

Relatively high doses of oral aspirin are needed to afford a significant protective effect against the bronchial obstructive reaction to ultrasonically nebulized distilled water (UNDW) in asthmatic patients. Sodium salicylate at similar doses and indomethacin at normal dose afford no protection. The present study was undertaken to assess the protective activity of these drugs taken by inhalation. Thirteen asthmatic patients performed two UNDW challenges 20 minutes and 24 hours after inhalation of 900 mg lysine acetylsalicylate (L-ASA) or placebo. The volume of UNDW causing a 20% fall in FEV1 (UNDW PD20) was calculated by linear interpolation on the dose-response curve. UNDW response after placebo was not significantly different from the preliminary test (PD20 4.3 +/- 0.7 and 4.1 +/- 04 ml, respectively, mean +/- SE), whereas after L-ASA, UNDW PD20 increased to 17 +/- 2.7 ml (p < 0.01 vs placebo) and remained significantly increased after 24 hours. In another group of 12 patients under the same experimental conditions, an equivalent dose of inhaled sodium salicylate caused no effect. Finally, in a third group of asthmatic patients pretreatment with inhaled indomethacin at two dose levels (6 patients, 25 mg; 10 patients, 50 mg) resulted in a significant dose-related protective effect. These findings indicate that inhaled indomethacin and especially L-ASA exert against UNDW-induced bronchoconstriction a potent protective effect, which appears to be mediated by inhibition of local prostaglandin synthesis in the airways. This fact could have therapeutic implications.

Protective effect of inhaled lysine acetylsalicylate on allergen-induced early and late asthmatic reactions ☆ ☆☆ ★

Conflicting results have been reported on the effect of non-steroidal antiinflammatory drugs on allergen-induced asthmatic responses. The aim of this study was to investigate the effect of inhaled lysine acetylsalicylate (LASA) on the early and late allergen-induced responses. We studied 16 patients with mild, stable asthma who had an early asthmatic response and 10 patients with a dual (early and late) response. Each patient underwent two challenges with a single dose of allergen assessed in a preliminary test, after inhalation of either 720 mg of LASA in 4 ml of saline solution or placebo, according to a randomized, double-blind protocol. Allergen-induced hyperreactivity to methacholine was measured in six patients from each of the early and the dual response groups 2 hours and 24 hours after the challenge, respectively. In the patients with early response, the maximum fall in FEV1 after challenge was 24% +/- 1% after inhalation of placebo and 14% +/- 2% after inhalation of LASA (p < 0.005). No protection was observed in four patients who received the drug orally instead of by inhalation. In the patients with a dual response, the maximum FEV1 decrease during the early response was 27% +/- 2% after placebo and 21% +/- 2% after LASA (p < 0.025). During the late response (between 3 and 8 hours), the maximum decrease in FEV1 was 28% +/- 4% after placebo and 16% +/- 4% after LASA (p < 0.005). In both groups allergen challenge caused a significant reduction in methacholine PD20 after treatment with placebo but not with LASA. Without allergen challenge, LASA had no effect on methacoline reactivity. We conclude that inhaled LASA significantly reduces both the early and the late asthmatic response to allergen challenge and that it prevents the allergen-induced airway hyperresponsiveness that follows these responses.

Effects of prostaglandin E1α cyclodestrin treatment on endothelial dysfunction in patients with systemic sclerosis

Objective Systemic sclerosis (SSc) is characterized by an altered nitric oxide (NO): endothelin I ratio and by endothelial dysfunction. Aims To verify the effects of prostaglandin E1 (PGE1) α-cyclodestrin treatment on endothelial function, quantified as flow-mediated dilation (FMD) of the radial artery. Methods In 16 women with SSc (age 57 ± 2.7 years, means ± SE) in whom a diagnosis of SSc had been made several years earlier (7.1 ± 1.2 years), FMD was evaluated by an echotracking technique on the radial artery, using trinitroglycerin vasodilation as a non-endothelial measure of the vessels ability to increase its diameter maximally. FMD was evaluated after 4 months washout period and after 4 months cyclic infusion of PGE1 α-cyclodestrin. Expired NO was measured at the same time. Results PGE1 α-cyclodestrin cyclic infusions did not modify systolic and diastolic blood pressure, heart rate or trinitroglycerin radial artery vasodilation. On the other hand, it induced a marked and significant increase in FMD of the radial artery, which was also accompanied by an increase in blood flow and expired NO. Conclusions Endothelial dysfunction and reduced FMD associated with SSc are improved by cyclic treatment with PGE1 α-cyclodestrin. This effect occurs together with a concomitant increase in expired NO, suggesting its direct positive influence on endothelial function. It may also partly explain the clinical beneficial effect of the drug in SSc.

Control of the Bronchial Tone

The tone of airway smooth muscle is the functional expression of a dynamic equilibrium between various excitatory and inhibitory mechanisms. On the excitatory side, the vagal reflex mechanism, mainly activated by central airway irritant receptors, is the most important. Bronchial epithelium plays a pivotal role in the regulation of the responsiveness of these receptors. Cholinergic responses of the bronchial muscle are mediated by muscarinic (M2) receptors. On the inhibitory side, the main mechanism is the adrenergic one: beta 2-receptors are mainly stimulated by circulating adrenaline. A dense population of beta 2-receptors has recently been observed in bronchial epithelium. Nonadrenergic-noncholinergic mechanisms--both excitatory and inhibitory--participate in the regulation of bronchial motor tone, but their role in man is still to be defined. Nonsteroidal anti-inflammatory drugs do not modify bronchial motor tone; thus, in this respect, at least in physiological conditions, a modulatory function of the prostaglandin system can be excluded. Probably the same applies to leukotrienes, but for a definite answer, specific antagonists are needed.

Prevention of fog-induced bronchospasm by high doses of ipratropium bromide in asthmatics.

In 12 adult asymptomatic, relatively stable adult asthmatics the protective effect of 3 doses (200, 1,000 and 2,000 micrograms) of ipratropium bromide against bronchospasm induced by an ultrasonic mist of distilled water was functionally (sRaw, FEV1) assessed. Ipratropium bromide and placebo were administered as an inhalation powder via a special inhaler in random order and under double-blind conditions at the same time on 4 usually consecutive days 90 min prior to the challenge. A considerable protective effect (clearly inferior, in any case, to that previously observed by us with fenoterol) was demonstrated (% protection approximately equal to 50) without any striking difference among the 3 doses. Mouth dryness (dose-related) was the sole complaint in some patients.

Prevention of Fog-Induced Bronchospasm by Duovent and Its Components (Fenoterol, Ipratropium Bromide) in Asthmatics

16 hyperreactive asthmatics were challenged with an ultrasonic mist of H2O at the same time of day on 4 usually consecutive days 2 h after premedication with placebo, fenoterol (200 micrograms), ipratropium bromide (80 micrograms) and Duovent (fenoterol 200 micrograms + ipratropium bromide 80 micrograms), given in random order and double-blind conditions. The challenge test consisted of 3 exposures of 30, 60 and 120 s with 4-min intervals. Specific airway resistance (sRaw) was measured under basal conditions and 1, 2 and 3 min after each exposure. FEV1 was measured under basal conditions and immediately after the last sRaw measurement. Fenoterol afforded a good protection; ipratropium bromide alone was ineffective but enhanced the protective effect of fenoterol when the two drugs were given in combination (Duovent). A similar effect was also observed after a second challenge performed 1 h (9 patients) or 3 h (6 patients) after the first one, which was performed 2 h after premedication.