Effect of a beta 2-agonist (broxaterol) on respiratory muscle strength and endurance in patients with COPD with irreversible airway obstruction.

The effect of broxaterol, a new beta 2-agonist, on respiratory muscle endurance and strength was studied in a double-blind, placebo-controlled, randomized crossover clinical trial in 16 patients with chronic obstructive pulmonary disease (COPD) with irreversible airway obstruction (FEV1 = 57.1 percent of predicted). One patient withdrew from the study because of acute respiratory exacerbation. Inspiratory muscle strength was assessed by maximal inspiratory pressure (MIP) and endurance time was determined as the length of time a subject could breathe against inspiratory resistance (target mouth pressure = 70 percent of MIP, Ti/Ttot = 0.4). Broxaterol (B) or placebo (P) was given orally for seven days at the dose of 0.5 mg three times a day with a washout period of 72 h between study treatments. Measurements were performed before administration of B or P and 2 h (six patients) or 8 h (nine patients) after the end of each treatment. No significant changes in FEV1 or FRC were observed after B or P suggesting that diaphragmatic length was maintained constant with each treatment. The MIP did not significantly change, while endurance time increased after B in the patients tested at 2 h (from 234.8 +/- 48.1 s to 284.0 +/- 48.0 s, p less than 0.05) and at 8 h (from 187.2 +/- 31.1 s to 258.2 +/- 40.4 s, p less than 0.005). No changes were observed after P. Minute ventilation, airway occlusion pressure (P0.1), integrated electromyographic activities of the diaphragm (Edi), and intercostal parasternals (Eic) (normalized to the value obtained during MIP) showed no change during the endurance run with different treatments. We conclude that in a group of COPD patients with irreversible airway obstruction, B significantly improves respiratory muscle endurance, and that this does not arise as a result of an effect on neuromuscular drive or pulmonary mechanics, but may be mediated by peripheral factors.

Copper, zinc and copper/zinc ratio in chronic pancreatitis and pancreatic cancer.

Serum copper and zinc levels and their ratio were evaluated in 48 control subjects, 29 patients with pancreatic cancer, 46 with chronic pancreatitis and 32 with extra-pancreatic diseases, with the purpose of ascertaining modifications in chronic pancreatic disease. Hepatic involvement and age were also investigated as possible factors influencing results. Cu/Zn ratio was found to be significantly increased in pancreatic cancer (2.66 +/- 0.16, mean +/- SE) as compared to controls (1.39 +/- 0.06, p less than 0.001), chronic pancreatitis (1.82 +/- 0.09. p less than 0.001) and extra-pancreatic diseases (1.81 +/- 0.18, p less than 0.001), but without practical clinical value. Serum zinc levels appear to decrease with age, while copper and Cu/Zn ratio increase. However, covariance analysis demonstrated that age does not play an important role in influencing copper and Cu/Zn ratio. A decreased liver synthetic function, at least in part age-related, seems to be an additional factor in decreasing serum zinc values.

Acute ventilatory and gas-exchange effects of a new beta-2 agonist, broxaterol, in asthmatics.

The ventilatory and gas-exchange effects of broxaterol, a new selective beta 2-adrenoceptor agonist, were investigated in ten asthmatics following intravenous administration of a single dose of 200 mcg. Broxaterol elicited a prompt and marked bronchodilating effect (increase in forced expiratory volume in one second and specific conductance), maintained at least up to the sixtieth minute. Minute ventilation and the mean expiratory flow did not increase significantly, the pattern of breathing showing a reduction of expiratory time, without modification of inspiratory time. On the other hand, occlusion pressure did not show any significant rise at all times of observation. Furthermore, the partial arterial oxygen and carbon dioxide pressures and alveolar-arterial difference in oxygen and physiological dead space remained unchanged, when measured at 20 min. The results demonstrated that broxaterol was an effective bronchodilating agent, also when rapidly injected, causing a prompt relief of bronchospasm. With respect to other beta 2-adrenoceptor agonists, this compound did not appear to increase minute ventilation or to induce an impairment of ventilation/perfusion ratio, at least after 20 min, when the bronchodilation was still evident. Finally, no side-effects or alterations of heart rate or blood pressure were reported.

Negligible metabolic effects of long-term oral treatment with a new beta 2-agonist: broxaterol.

Drugs that stimulate adrenergic receptors are expected to affect glucose and lipid metabolism. Therefore, it was deemed to be of interest to assess whether the new selective beta 2-adrenoceptor agonist, broxaterol, exerts any metabolic effect. Broxaterol has been evaluated in 21 patients, 18 men and 3 women, aged 34 to 80 years, with a diagnosis of reversible obstructive airways disease. Broxaterol was administered orally at doses of 0.5 mg thrice daily for 1-12 months, according to an open design. In addition to metabolic parameters (plasma glucose, insulin, high and low density lipoprotein-cholesterol, triglycerides, free fatty acids, glycerol, sodium, potassium), arterial pH, partial arterial oxygen and carbon dioxide pressure, lung function tests--forced expiratory volume in one second (FEV1), maximum mid-expiratory flow (MMEF75-25) and specific airways conductance (SGaw)--heart rate and blood pressure were assessed at baseline and after 1, 2, 3, 4, 5, 6, 9, 12 months of treatment. No statistically significant change from baseline was observed in the levels of plasma glucose, cholesterol, triglycerides, or free fatty acids. Plasma levels of insulin, glycerol and sodium only increased in the first three months of treatment; a slight hypokalaemia was also observed during the same period. The bronchodilation (significant increase in FEV1, MMEF75-25, SGaw) was maintained throughout the study; no hospital admission was necessary. Tremor, palpitations and restlessness were reported in six patients; no significant changes in heart rate and blood pressure were observed. The data suggest that the metabolic effects of long-term treatment with oral broxaterol can be considered as very negligible.

[Structural changes demonstrable by optic and electron microscopy in cellular and support components of nevi in the phase of neoplastic transformation and their therapeutic treatment]. / Modificazioni strutturali evidenziabili al microscopio ottico ed elettronico delle componenti cellulari e di sostegno dei nevi in fase di trasformazione neoplastica e loro trattamento terapeutico.

The mole can transform itself in melanoma. The transformation is caused in some's opinion by congenital cells, in some's opinion by external elements (metabolic, physical, caustic, etc.). The authors lean to external causes metabolic, physical caustic) and they consider useful the chirurgical and radiant treatment.

[Type-II orofaciodigital syndrome. Description of a case]. / Sindrome oro-facio-digitale tipo II. Descrizione di un caso.

There are at least four different types of Oro-facial-digital syndromes. The features of type II are bilateral polydactyly of hands, peculiar face with normal skin, hair, and intelligence. It is due to an autosomal recessive gene. We report a case of Oro-facio-digital syndrome in a four year old girl with a peculiar face and polydactyly of hand and feet, born from normal non consanguineous parents. Her mother was pregnant at the time of observation and came for an evaluation of the recurrence risk. The pregnancy was monitored by ultrasonography.

Effects of broxaterol and theophylline on fatigued canine diaphragm in vivo. A randomized, controlled study.

Since broxaterol, a new beta 2-agonist, has been shown to improve contractility of fatigued canine diaphragm in vitro, a controlled, randomized study was designed to assess its effects on fatigued canine diaphragm in vivo, and compare these to the expected inotropic effects of aminophylline. Diaphragm fatigue was induced in 21 dogs using electrophrenic stimulation at 20 Hz until transdiaphragmatic pressure (Pdi) at 20 Hz was reduced to about 50% of its original value. After stabilization of fatigue, animals were randomized in three groups. Aminophylline-treated animals received an intravenous bolus of 20 mg/kg, broxaterol-treated animals were given an initial bolus of 100 micrograms/kg, and control animals obtained an equal load of saline. After 3 h, aminophylline-treated animals and broxaterol-treated animals received a second dose of 20 mg/kg and 200 micrograms/kg, respectively, whereas control animals received a second dose of saline. Pdi was measured every 30 min for 6 h. At therapeutic serum levels, theophylline did not affect Pdi at any stimulation frequency compared with control conditions. In contrast, broxaterol administration resulted in a significant (p less than 0.05) and long-lasting increase in Pdi at low stimulation frequencies. Pdi at 20 Hz thus increased by 20 +/- 16% 90 min after the first bolus, and by 36 +/- 18% 90 min after the second dose. We conclude that (1) broxaterol promotes recovery of low-frequency fatigue in a dose-dependent way, and (2) theophylline does not improve the force output of fatigued canine diaphragm in vivo.

Bronchodilation and beta 2-selectivity of broxaterol in asthmatics: a crossover, single-blind, terbutaline- and placebo-controlled study.

To investigate the beta 2-receptor selectivity of a new beta 2-adrenoceptor agonist, broxaterol, we compared the respiratory and cardiovascular effects of this compound with those of terbutaline and placebo. Twelve asthmatic patients were evaluated in a randomized, single blind, crossover study. A single dose of each study treatment (broxaterol 400 micrograms and terbutaline 500 micrograms was administered with metered dose inhalers. Measurements of lung function (vital capacity, forced expiratory volume in one second, airway resistance and specific airway conductance), heart rate and systolic/diastolic blood pressure were performed before and at 15, 30, 60, 120, 240 and 360 min after each study treatment. No significant difference was observed between broxaterol and terbutaline in VC, FEV1 and Raw changes, although a greater and significant increase in sGaw was found only with broxaterol. Significant increases in heart rate and systolic blood pressure were observed only with terbutaline. The results of this study suggest that broxaterol can promote a greater bronchodilator effect with less cardiovascular side effects than terbutaline, probably through a greater beta 2-receptor selectivity.

Broxaterol increases force output of fatigued canine diaphragm more than salbutamol.

We previously demonstrated that broxaterol enhanced recovery of fatigued canine diaphragm. The aim of this study was to compare the inotropic effects of salbutamol and broxaterol on fatigued canine diaphragm. Low-frequency fatigue was induced in 14 mongrel dogs by electrophrenic stimulation, which was continued until transdiaphragmatic pressure (Pdi) at 20 Hz was reduced by 50% or for 1 h. After stabilization of fatigue, the animals received a bolus (18.5 microg/kg) of either broxaterol or salbutamol, followed by a continuous infusion (0.43 microg/kg/min). A second bolus of 74.0 microg/kg, followed by a continuous infusion of 1.72 microg/kg/min, was given after 90 min. Both drugs significantly increased twitch Pdi. Twitch Pdi measured 90 min after the first and second doses of broxaterol increased by 28 +/- 23% and 42 +/- 34%, respectively, whereas the salbutamol-induced increase was clearly smaller (9 +/- 10% and 17 +/- 15%, respectively). Broxaterol increased Pdi at 20 Hz by 25 +/- 28% with the first dose and by 29 +/- 21% with the second dose. In contrast, salbutamol did not alter Pdi at 20 Hz. Neither drug affected Pdi at 100 Hz. We conclude that broxaterol promoted recovery of low-frequency fatigue of the canine diaphragm in vivo in a dose-dependent manner, whereas salbutamol only minimally improved force production by the fatigued diaphragm.

Early bronchodilating effect of a new oral beta-2-receptor agonist (broxaterol) in bronchial asthma.

In order to determine the bronchodilating activity and safety of two beta-2-receptor agonists, broxaterol and procaterol, compared with a placebo, 12 patients with reversible airway obstruction were tested in a double-blind cross-over study. The drugs were administered orally and the dosage of broxaterol was 0.5 mg, that of procaterol 0.05 mg. Measurements of forced expiratory volume in 1 s (FEV1), heart rate and blood pressure were performed before and 30, 60, 120, 240, 360, and 480 min after each treatment. Both drugs produced bronchodilation but broxaterol was statistically 30 min faster in producing this effect than procaterol (p less than 0.05). Moreover this effect for both drugs persisted significantly for up to 480 min compared with the effect of the placebo (p less than 0.005). There were no significant side effects with either drug. Heart rate and blood pressure did not show any changes in clinical significance for broxaterol or procaterol. In our study, broxaterol showed a faster bronchodilating effect than procaterol, and tolerance was the same for both drugs.

Effects of intravenous broxaterol on respiratory drive and neuromuscular coupling in COPD patients.

Broxaterol, a new selective beta 2-agonist, has been shown to exert inotropic effects on both fresh and fatigued canine diaphragm. We evaluated the effect of broxaterol on the activation and force output of the respiratory muscles in patients with chronic obstructive pulmonary disease (COPD). We studied 9 patients with moderate to severe COPD. Each patient was infused with saline and Broxaterol (200 micrograms) in saline alternately. We measured lung volumes, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), breathing pattern, P0.1, respiratory muscle EMG (diaphragm, EMGd, and parasternal, EMGp) and P0.1/EMGd ratio. Measurements were made under control conditions and at 15, 30, 60, and 120 min after each infusion. Broxaterol, but not saline, resulted in a slight but significant increase in vital capacity (VC), forced expiratory volume in one second (FEV1) and MIP, and a decrease in functional residual capacity (FRC). Breathing pattern did not change, while EMG significantly decreased, and P0.1/EMGd significantly increased in 5 of the 9 patients after broxaterol. These data seem to indicate that by partially unloading the respiratory muscles, broxaterol results in decreased muscle activation (EMG). Increase in chest wall neuromuscular coupling (P0.1/EMGd) may also be observed.