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Objective: to evaluate the influence of processes of lipid peroxidation, and antioxidant protection on the function of external respiration in children-residents of radioactive contaminated territories., Materials and Methods: There were examined children of school age, inhabitants of radioactive contaminated ter- ritories (RCT) without respiratory and pulmonary pathology, and patients with bronchial asthma (BA). Examination of the ventilation lung function was performed by the method of pneumotachography according to the analysis of the «flow-volume» loop. End products of lipid peroxidation (LPO), reacting with thiobarbituric acid (malondialde- hyde), enzymes-antioxidants - catalase, superoxide dismutase, glutathione peroxidase, glutathione transferase were studied to determine the signs of oxidative stress., Results: Examinations of ventilation lung function in children-residents of RCT without respiratory and pulmonary pathology showed no significant deviations of its parameters beyond the limits of physiological fluctuations; a decrease in bronchial patency at different levels of the bronchial tree was established in children with BA. An increased incidence of bronchial hyperreactivity was noted in both the patients with BA and those who did not have bronchopulmonary pathology. The absence of an increase in the content of LPO products (malondialdehyde) in blood serum of children-residents of RCT with increased activity of catalase and group of glutathione enzymes indi- cates the sufficiency of compensatory possibilities of antioxidant protection., Conclusions: Studies of correlation between the function of external respiration and markers of oxidative stress determined that the indices of bronchial patency directly correlate with the activity of enzymes-antioxidants of the glutathione group and inversely - with the content of the LPO products in children-residents of RCT. The frequency of bronchospasm inversely correlated with the activity of glutathione group antioxidants. There are inverse correla- tion of 137Cs content in the body with the activity of glutathione transferase and glutathione peroxidase., (Ye. I. Stepanova, I. Ye.Kolpakov, S. M. Alokhina, V. Yu. Vdovenko, V. M. Zyhalo, O. S. Leonovych.)

Objective: To determine the features of the nitrogen oxide metabolism and risk of developing endothelial dysfunc-tion in children with e-NOS 4a/4b gene polymorphism, who live under prolonged enter 137Cs to the body., Materials and Methods: There were examined 117 children-residents of radioactively contaminated territories and50 children of control group. The level of stable metabolites was defined in blood serum (NO2- and NO3-). The ther-mographic method was used to register the endothelium dependent reaction of the vascular bed to changes in theblood supply. The ventilation capacity of the lungs was evaluated using this method of pneumotachography.Polymorphism in intron 4 of the gene e-NOS was studied by the method of polymerase chain reaction. The contentof 137Cs in the body of children was determined using a human radiation counter Skrynner M-3., Results and Conclusions: In children-residents of radioactively contaminated territories with genotype 4a/4b com-paring to children who had genotype 4b/4b, the decrease in the nitric content of in the blood serum, the increase inthe thermographic index of the recovery period of blood circulation to the baseline level after occlusion test werenoted, that is indicative of the decreased NO-synthase active of vascular endothelium in the carriers of the minorallele a in the 4th intron of gene eNOS (genotype 4a/4b), and is a risk factor for development of endothelial dysfunc-tion. It was proved a decrease in the index of lung tissue elasticity and stretchability - FVC / NFVC of the lungs com-paring to children with genotype 4b/4b, there was a reduction of integral index of respiratory tract permeability -FEV1/NFEV1. The inverse correlation dependence between the presence of allele a in the genotype and the values ofFVC/NFVC of the lungs (r = -0.259; p <0.05) and FEV1/NFEV1 (r = -0.2267; p <0.05) was found. Signs of bron-chospasm were found in the carriers of the allele a in 1.5 times more often than in children-carriers of homozy-gotes from allele b., (Ye. I. Stepanova, I. Ye. Kolpakov, V. M. Zyhalo, V. Yu. Vdovenko, V. V. Vasylenko, O. M. Leonovych.)

In a 20-year-old woman with known asthma, anaphylactic bronchospasm induced a grave combined respiratory and metabolic acidosis (pH(a) 6.66) with marked hypoxaemia (S(a)O(2) 45%). The beneficial effects of the rightward shift of the oxyhaemoglobin dissociation curve on tissue O(2) unloading at such pH was more than offset by the negative effect on S(a)O(2) at the reduced P(a)O(2) (7.0 kPa) found in this patient. This case illustrates the detrimental effect of grave acidosis on arterial blood oxygen content at subnormal P(a)O(2) values, the beneficial effect of a supranormal P(a)O(2) on the S(a)O(2) in such patients, and the rapid remission rate of life-threatening acidosis and blood lactate after adequate ventilation and tissue oxygenation were secured. The initial treatment of the patient and clinically relevant considerations are discussed.

Unlabelled: Wheezy bronchitis can be the first sign of bronchial asthma thus wheezy bronchitis is under special supervision and its etiologic factors are especially analyzed among infants and young children. Due to diagnostic difficulties in this age group allergic inflammation markers are taken into consideration in aspect of recurrent bronchitis prevention. Such marker is eosinophillic cationic protein (ECP). ECP is released from eosinophilles during the late phase of allergic reaction. The aim of the study was to assess ECP concentrations among infants and young children with wheezy bronchitis., Material and Methods: Ninety-four patients with wheezy bronchitis between 1 month and 36 months old were included into the study (47 with the first episode and 47 with at least third episode). Forty-three patients hospitalized due to other causes, from the same age group (these patients haven't already had any wheezy bronchitis) were included into the control group. Among all patients concentrations of ECP were evaluated (among patients from the study group in the acute phase of the disease) by fluoroimmunoenzymatic method (FEIA) with the use of UniCAP 100 set (Pharmacia & Upjohn Diagnostics AB)., Results: Statistically significant differences of ECP concentrations in blood plasma during wheezy bronchitis among infants and young children in correlation to the control group and higher concentrations were observed among patients with wheezy bronchitis. No statistically significant differences were observed in aspect of ECP concentrations between patients with the first episode and patients with recurrent wheezing. No influence of family history of allergy nor symptoms of allergy were observed whereas higher concentrations of ECP were observed among patients with higher level of CRP CONCLUSION: ECP isn't a good marker of prediction of reccurrent wheezing

Background: Patients undergoing pulmonary resection are thought to be at high risk for the development of postoperative pulmonary complications (PPCs), and these complications may lead to serious morbidity. The purpose of this study was to identify the factors associated with postoperative pulmonary complications in patients undergoing lung cancer resection and to determine the effect of PPCs on survival., Methods: The study involved a retrospective review of 635 patients who had undergone curative resection for lung cancer. The patient group included 504 males (79.4%), and the overall mean age was 61.3 years. Patients were classified as those who had experienced PPCs (PPCs group, n = 105, 16.5%) or those who had not (no-PPCs group, n = 530, 83.5%)., Results: The surgical procedures performed were 101 pneumonectomies (15.9%), 505 lobectomies (79.5%), and 29 lesser resections (4.6%). Cancer types comprised 330 squamous cell carcinomas (52.0%), 255 adenocarcinomas (40.2%) and 50 others (7.8%). Univariate analysis showed that the following factors were predictors for PPCs: male sex, erythrocyte sedimentation rate, preoperative serum fibrinogen level, pulmonary function, chronic obstructive pulmonary disease, smoking, double primary cancer, and surgical duration. Multivariate logistic regression showed that preoperative serum fibrinogen level (p < 0.001), surgical duration (p < 0.0001) and being male (p = 0.02) were significant predictors of PPCs. Overall survival 3 years after surgery was 68.2% in no-PPCs group and 38.8% in PPCs group (p < 0.0001). Regardless of tumor staging, overall survival differed significantly between PPCs and no-PPCs groups, whereas disease-free survival did not., Conclusions: Higher preoperative serum fibrinogen levels, longer surgical duration, and being male were the predictive factors for PPCs in surgical candidates. The development of PPCs was linked to a shortened overall survival.

Right ventricular strain is a source of troponin elevation in some patients with acute pulmonary embolism. Acute and/or severe obstructive airway disease could lead to a sudden increase in pulmonary arterial pressure and right ventricular afterload. We report a case of troponin I elevation in a 40-year-old woman who presented with acute severe bronchospasm and had a negative evaluation for coronary artery disease.

It has been suggested that airway eosinophilic inflammation is associated with the severity of exercise-induced bronchospasm (EIB). Blood eosinophils are known to be an indirect marker of airway inflammation in asthma. The aim of this study is to investigate that a simple and easy blood test for blood eosinphil counts may predict the severity of EIB in asthma. Seventy-seven men with perennial asthma (age range 18-23 years) were included. Lung function test, skin prick test, and blood tests for eosinophils counts and total IgE levels were performed. Methacholine bronchial provocation test and, 24 h later, free running test were carried out. EIB was defined as a 15% reduction or more in post-exercise FEV1 compared with pre-exercise FEV1 value. Atopy score was defined as a sum of mean wheal diameters to allergens. EIB was observed in 60 (78%) of 77 subjects. Asthmatics with EIB showed significantly increased percentages of eosinophils (P<0.01), log eosinophil counts (P<0.001), and atopy scores (P<0.05) and decreased log PC20 values (P < 0.05) compared with asthmatics without EIB. Asthmatics with eosinophils of > 700 microl(-1) (36.9 +/- 12.7%) had significantly greater maximal % fall in FEV1 after exercise than asthmatics with eosinophils of < 350 microl(-1) (24.7 +/- 16.6%, P <0.05). Blood eosinophil counts > 350 microl(-1) yielded the specificity of 88% and positive predictive value of 93% for the presence of EIB. When a multiple regression analysis of maximal % fall in FEV1 according to log eosinophil counts, log PC20, log IgE and atopy score was performed, only blood eosinophil counts were significant factor contributing to the maximal % fall in FEV1 after exercise. These findings not only suggest that a simple blood test for eosinophils may be useful in the prediction of the severity of EIB, but also reinforce the view that airway eosinophilic inflammation may play a major role in EIB in asthma.

For the early institution of anti-asthma treatment, reliable markers distinguishing the children with asthma from children with virus-associated wheeze are needed. Serum eosinophilic cationic protein (ECP) has been suggested as a marker correlating with the intensity of eosinophilic inflammation. We have studied 27 children (age 3 to 35 months) admitted with acute bronchial obstruction. Each child had been followed for 12 months after the first episode and then assigned to one of two groups (asthma or non-asthma) based on the clinical course. Serum ECP (s-ECP) was taken at the acute episode and again at least 6 months later, when the child was completely symptom-free. Serum ECP was analyzed using the Pharmacia CAP ECP FEIA immunofluorescence system. Mean s-ECP during the acute episode was 26.5 micrograms/L (5.5-69) in the asthma group (n = 14) and 9.7 (5.2-17 micrograms/L) in the non-asthmatics (n = 13), p < 0.01. There was no difference in the s-ECP analyzed during the symptom-free period. Elevated values of serum ECP taken during, but not outside, the acute episodes of bronchial obstruction may be helpful in predicting the development of bronchial asthma in young children with acute obstructive episodes.

The issue of hypercoagulability in acute asthmatic attacks is controversial. This may be due to lack of an appropriate test to monitor overall coagulation. Current hematologic tests do not account for the cellular fraction of blood that has procoagulant activity. Our study uses a clotting assay called the modified recalcification time test that is performed with whole blood to ensure the contribution of all chemical and cellular mediators in the coagulation process, particularly tissue factor. Venous blood samples were obtained from 12 adult patients with acute exacerbation of asthma or chronic obstructive pulmonary disease and compared with samples from 12 age-matched healthy control subjects. By use of the modified recalcification time, the presence of a relative hypercoagulable state was demonstrated in patients with acute bronchospasm. Furthermore, there is an identifiable difference in modified recalcification time value between the patients with acute attacks who required hospital admission versus those discharged from the emergency department.

Induction of anaesthesia with thiopental sometimes causes bronchospasm. Although the mechanism by which thiopental induces bronchospasm may involve cholinergic stimulation, direct spastic effect and histamine release, the spastic effects of thiopental have not been comprehensively defined. In this study, we have assessed the effect of thiopental on in vivo airway smooth muscle tone using direct visualization method with a superfine fibreoptic bronchoscope as previously reported. Twenty-one mongrel dogs were anaesthetized with pentobarbital (30 mg kg-1) and paralysed with pancuronium (200 micrograms kg-1 h-1). The trachea was intubated with a tube that had a second lumen for insertion of the bronchoscope (od: 2.2 mm) to continuously measure bronchial cross-sectional area. The tip of the bronchoscope was placed between the second and third bronchial bifurcation of the right lung. The dogs were allocated to three groups of seven: group T, A+T, H+T. In group T, thiopental 0 (saline), 0.1, 1.0 and 10 mg kg-1 was given i.v. In group A+T, saline i.v., 5 min later atropine 0.1 mg kg-1 i.v., and 5 min later thiopental 10 mg kg-1 was administered. In group H+T, bronchoconstriction was produced with histamine 10 micrograms kg-1 i.v. followed by infusion at 500 micrograms kg-1 h-1. Thirty minutes later, thiopental 0, 1.0 and 10 mg kg-1 were given. Arterial blood sampling was performed for measurement of plasma catecholamines and histamine. In group T, thiopental significantly reduced bronchial cross-sectional area (maximally by 28.7 (5.6% at 0.5 min after thiopental 10 mg kg-1), which returned to the baseline in 3 min, while any changes in plasma concentrations of catecholamines and histamine were not observed except norepinephrine level at 1 min following thiopental 10 mg kg-1 i.v. Atropine pretreatment completely prevented thiopental-induced bronchospasm in group A+T. In group H+T, thiopental 10 mg kg-1 transiently but significantly decreases bronchial cross-sectional area. Therefore, the present study indicates that the mechanism of thiopental bronchospasm may result from cholinergic nerve stimulation.

A purposeful analysis of home and foreign literature has been made, its results being inconsistent with generally accepted notion of a bronchial spasm as a pathogenetic sign and so impossible to be logically interpreted. The analysis supports the supposition on the possibility of the manifestation of the expiratory bronchial spasm as a compensatory-adaptative mechanism directed to increase the intrathoracic pressure, alveolar-capillary diffusion of oxygen and oxygenation of the aerated blood in the case of hypoxemia. Results of examination of 30 miners with the expiratory bronchial permeability in the presence of the hypoxic and load-induced hypoxemia give grounds to confirm existence of the breathing regulation mechanism and to elaborate a differential approach for estimation of the bronchial spasm in patients with pulmonological diseases.

The effect of ketamine on bronchospasm during mechanical ventilation was evaluated in a prospective, placebo-controlled, double-blind trial. Fourteen mechanically ventilated patients with bronchospasm were randomly allocated to either ketamine 1 mg/kg or saline placebo. In the ketamine-treated patients, PO2 increased from 10.5 (+/- 0.5) kPa to 16.4 (+/- 2.7) kPa (P < .05), whereas PO2 in the placebo-treated patients remained unchanged. The PCO2 was constant in the ketamine group, although it increased from 5.6 (+/- 0.9) kPa to 6.1 (+/- 0.9) kPa in the placebo group (P < .05). The pulmonary stethoscopic bronchospasm improved immediately after the administration of ketamine, whereas the thoracic compliance remained unchanged. In conclusion, the ketamine-treated patients showed an improvement by stethoscopic examination, in PO2 and in PCO2, suggesting that ketamine might be useful in the treatment of bronchospasm during mechanical ventilation. However, further studies are required to decide whether ketamine should be considered the drug of choice in patients with severe bronchospasm during ventilator treatment.

The mechanism of enterosorption positive influence on the course of bronchospastic condition was studied on the model of allergic bronchospasm. The using of the sorbent (polyphepan) during the period of sensitization of rats prevented the beginning of bronchospasm or reduced its extent. The results of investigation proved that a decrease the of biogenic amines concentration in biological liquids and tissues depending on their transport and sorption in intestine is one of the main mechanisms of enterosorption.

The effect of intravenous theophylline on the outcome of inhospital treatment of acute bronchospasm has been assessed, comparing the results achieved by computer-assisted dosing, designed to achieve and maintain a serum theophylline level of 16 micrograms.ml-1 (10 patients) with those of unaided physicians (15 control patients). The outcome measures compared were clinical improvement, peak expiratory flow rate and serum theophylline concentration. Loading doses of theophylline in the control and computer groups were: 167 and 437 mg, respectively. Initial serum theophylline concentrations, measured 20 min after the loading dose, were 13.6 and 17.0 micrograms.ml-1 in the control and computer groups, respectively. In patients who had not received theophylline prior to admission, loading doses and initial concentrations were: 200 mg and 9.4 micrograms.ml-1 in the control group (n = 5) versus 613 mg and 15.7 micrograms.ml-1 in the computer group (n = 4), respectively. During maintenance therapy, serum theophylline concentrations were kept in the therapeutic range (10-20 micrograms.ml-1) throughout 51% and 77% of the hospitalisation period, in the control and computer groups, respectively. There were no differences between the two groups in the rate or extent of clinical improvement or in change in peak expiratory flow rate. The computer assisted theophylline dosing regimen outperformed that of the unaided physicians in achieving and maintaining therapeutic serum theophylline concentrations in acute bronchospasm. There was no correlation between clinical outcome and serum theophylline concentration, but this may have been due to the small sample size and modest difference in serum theophylline between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the incidence of the late reaction of the bronchi in patients with atopic asthma the following methods of the provocation with atopic asthma the following methods of the provocation were applied: a) exercise test, b) a 3-minute ventilation with cold air and c) inhalation of the distilled water Disturbances of ventilation were assessed spirographically. An emphasis was also on the activity of NCF in the blood serum following the applied provocation tests. It was found that the late bronchospasm followed the exercise test in about half of the examined patients (48%). It was less frequent after hyperventilation with cold air (33%) and inhalation of the distilled water (38%). Bronchospasm was accompanied by the increase in NCF activity in the blood serum. The late bronchospasm after provocation tests in asthmatics is a real fact, not depending on the accidental ventilation disorders.

In 10 patients of chronic bronchitis culture of mononuclear cells were performed. Supernatant was applied in inhalation. Bronchospasm was not observed in spastic bronchitis patients but it was present in asthmatic patients. In 50% of chronic bronchitis patients the inhalation test to histamine was positive.

Dietary factors may influence inflammatory and antioxidant activity, and hence the development of chronic respiratory symptoms. To examine this hypothesis, the authors analyzed data from the Second National Health and Nutrition Examination Survey (NHANES II). NHANES II was conducted on a sample representative of the civilian, noninstitutionalized US population, which included 9,074 white and black adults aged 30 years or older. Dietary factors were derived from serum levels and from a 24-hour dietary recall questionnaire. The authors examined the relations of these dietary factors to the presence of currently active respiratory symptoms. The relation of serum vitamin C, dietary vitamin C intake, dietary fish intake, the ratio of dietary sodium to dietary potassium, and the ratio of serum zinc to serum copper to the respiratory symptoms of bronchitis and wheezing was assessed. Initially, nutrient-specific logistic regression analysis was performed, controlling for age, race, sex, calories, and pack-years of cigarette smoking. When multiple nutrients and total caloric intake were considered for each respiratory symptom outcome, bronchitis was negatively associated with serum vitamin C and with the serum zinc:copper ratio and was positively associated with the sodium:potassium ratio. Wheezing was negatively associated with serum vitamin C, niacin, and the serum zinc:copper ratio. Interactions between nutrients and smoking status were not significant. These data suggest that several dietary constituents may influence the occurrence of respiratory symptoms in adults, independently of cigarette smoking.

We studied the effects of prostacyclin (PGI2) on the airway responses to platelet-activating factor (PAF) in a randomized and crossover study in eight normal subjects. PGI2 or diluent (glycine buffer) was continuously infused on 2 separate days. Two breaths of PAF (21 micrograms) were inhaled three times every 15 minutes and airflow at 30% of vital capacity from partial flow-volume curves (Vp30) was measured. PGI2 (4 ng/kg/min) had no effect on Vp30 or blood pressure, whereas heart rate increased from 70.3 +/- 3.9 to 73.7 +/- 4.0 beats/min (mean +/- SEM; p less than 0.01). Two subjects did not complete the study because of transient hypotension. PGI2 had no effect on PAF-induced bronchoconstriction with maximal decreases in Vp30 of 42.0 +/- 8.0% (p less than 0.01) during PGI2 and 49.8 +/- 14.2% (p less than 0.02) during diluent infusion. Ex vivo platelet aggregation to PAF (10(-9) to 10(-7) mol/L) was significantly inhibited by PGI2. Circulating neutrophils decreased from 4.7 +/- 0.9 x 10(9)/L to 1.5 +/- 0.3 x 10(9)/L (p less than 0.05) 5 minutes after the first PAF inhalation during diluent infusion, whereas there was no significant change with PGI2. Thus, PGI2 does not influence PAF-induced bronchoconstriction in man despite causing marked inhibition of ex vivo PAF-induced platelet aggregation and preventing the fall of neutrophils.

The effect of the plasma obtained before and after graded submaximal exercise was examined in 10 bronchial asthma patients with the syndrome of asthma of physical effort (APE) by means of fluorescent exploration using the cation probe 4-(p-demethylaminostyryl)-1-methylpyridinum and rat thymocytes as a test system. Four normal donors and five bronchial asthma patients without the APE syndrome were used as control. The plasma of patients with the APE syndrome, obtained after physical exercise, brought about a decrease of the number of fluorescent cells. In APE patients, the coefficient of the drop of thymocyte fluorescence amounted to 0.65 +/- 0.04, that in the control group to 1.1 +/- 0.08 (p less than 0.01). It is assumed that after physical exercise in the plasma of APE patients, there may occur factor depolarizing the membrane of thymocytes, which is likely to play a substantial role in the pathogenesis of the afterload bronchospasm.

Blood serum theophylline concentrations were studied in 6 volunteers and 8 patients with bronchospastic syndrome by using an enzyme immunological assay with a commercial kit "Fedesim" (USA) at intravenous and oral administration of euphylline in a dose of 5 mg/kg. The maximal concentration at intravenous injection of euphylline was reached in volunteers in 15 minutes, at oral administration--in 90 minutes, and in patients--somewhat later.

Thirty-three chronic asthmatic children and adolescents on predetermined doses of theophylline preparations who arrived at the Emergency Room with an acute episode of wheezing were evaluated to determine compliance, and if therapeutic plasma theophylline levels (PTLs) facilitate the effectiveness of epinephrine. Patients were divided into three groups based on the requirement of one, two, or three doses of epinephrine. In the total group of patient visits, only 25% took the theophylline preparations as prescribed. The poor responders group requiring three injections of epinephrine was characterized by the lowest compliance and the highest unacceptable PTLs. It appears that therapeutic PTLs enhance the response to epinephrine. The evaluation of compliance in case of epinephrine failure is recommended.

Plasma histamine in 8 normal subjects was measured before and after inhalation of carbachol to induce a 50% fall in specific airway conductance (SGaw). The measurements were repeated 5 min after inhalation of salbutamol or placebo. No significant change in plasma histamine occurred after placebo or carbachol inhalation, despite the persistent induced bronchospasm after the latter treatment. In contrast, plasma histamine was significantly increased from 0.25 to 0.43 ng/ml after salbutamol inhalation. Simultaneously, induced bronchospasm was relieved, from 51% to 103% of baseline SGaw. Thus, the relief of carbachol-induced bronchospasm by salbutamol was associated with a rise in plasma histamine. Since salbutamol itself is a potent inhibitor of mast cell degranulation and histamine release, the present findings suggest that histamine may be released and sequestered within the lungs during carbachol-induced-bronchospasm, and also that desequestration of bronchoconstrictor mediators accumulated at the point of contact of bronchial smooth muscle may contribute to the relief of bronchospasm by salbutamol.

Among the mediators involved in the pathophysiologic mechanisms that underly the reactions of the acute and delayed phases of bronchospasm induced by allergens in man, platelet-activating factor (PAF) could play an important role, in particular by its effects on platelets. In animals, inhalation or injection of PAF causes a platelet-dependent bronchoconstriction that is blocked by prior administration of an antiplatelet antiserum and accompanied by platelet accumulation in the pulmonary vessels. In man, inhalation of PAF causes a bronchospasm and induces a bronchial hyperreactivity. Abnormalities of platelet aggregation and the secretion into plasma of platelet factor 4 and beta-thromboglobulin have been described in patients with asthma during induced bronchospasm. Platelet functions have been studied in 15 patients with asthma before and after allergen bronchial provocation tests. There was no difference between platelet counts, plasma concentrations of platelet factor 4 and beta-thromboglobulin, and platelet aggregation induced by several agonists (adrenaline, arachidonic acid, or PAF) before and immediately after the allergen bronchial provocation test. There was no platelet pulmonary sequestration as studied with 111Indium-labeled platelets during 24 hours after the antigen challenge, and the life span of circulating platelets was normal. Our results do not support an important direct role for PAF in the pathophysiology of asthma. It is still possible that the current methodology is too insensitive to detect amounts of PAF in the circulation or that PAF is acting locally.

We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.

Bronchospasm following exercise is a phenomenon which occurs in most patients with reversible airway disease. The pathophysiologic mechanism leading to this bronchoconstriction with exercise has not yet been defined. Recently, prostaglandins have been implicated in the etiology of asthma. The purpose of this investigation was to determine changes in plasma prostaglandins occurring during exercise-induced asthma. Eight ambulant asthmatics were chosen for baseline pulmonary spirometry and peripheral venous blood prostaglandin E and F levels. The asthmatics were then exercised to 80% of their age-predicted maximal heart rate via a multistage branching treadmill protocol. At 5, 15, and 30 min following exercise, pulmonary spirometry was again performed and peripheral venous blood collected at the indicated times. Clinical bronchospasm as characterized by audible wheezing and greater than 15% decrease in FEV1 and MMEFR was obtained in all of the asthmatics. Peripheral PGE and PGF2alpha determinations following this exercise protocol were not altered significantly: (PGE: 0 min, 238; 5 min, 185; 15 min, 248; 30 min, 256 pg/ml); (PGF2alpha: 0 min, 50; 5 min, 24; 15 min, 25; 30 min, 17 pg/ml) (p less than 0.1). In summary, no significant change in peripheral blood prostaglandin E and F2alpha levels as determined by radioimmunoassay was noted at the time of exercise-induced bronchospasm.

UCB JO28 [( 2-[2-[4-(diphenylmethylene)-1-piperidinyl] ethoxy] ethoxy] acetic acid, hydrochloride) is derived from diphenylmethylene piperidine. Animal experiments have shown that it has spasmolytic properties for smooth muscle, particularly in the bronchi, as well as anti-Hl, anticholinergic and anti-serotonin activities. The degree of protection by JO28 against histamine and methacholine-induced bronchospasm has been investigated in 20 asthmatic patients with serious airways hyper-reactivity. Protection against histamine-induced bronchospasm was almost complete in 11 out of 12 patients, whereas protection against methacholine-induced bronchospasm, although clearly present in seven of eight patients, was less marked.

The present study describes a case of a 38-year-old nurse with asthma and probable sensitivity to sulfites. A double-blind challenge with sulfite and placebo was performed, pulmonary function tests were measured along with plasma levels of sulfites. A deficiency in sulfite-oxidase is suggested as the trigger mechanism of bronchospasm.

Plasma theophylline levels (mcg/ml) of 93 patients with a bronchopulmonary disease (asthma and chronic obstructive lung disease) who were on theophylline (normal or retarded) treatment, were determined on admission at the emergency ward because of acute bronchospasm. Our results show that theophylline blood levels were subtherapeutical in patients treated either with normal (2.1 +/- 0.8 mcg/ml) or retarded theophylline (9.6 +/- 1.3 mcg/ml). This was probably due to insufficient dosing and/or poor patient compliance. The necessity of monitoring this type of treatment is once again evident.

Fifteen adult chronic asthmatic patients were studied on 6 consecutive days of the second week of treatment with a new sustained release theophylline formulation, and 8 were again studied after three months on the same dosing regimen (375 mg b.i.d.). Serum theophylline concentrations were maintained in the therapeutic range (peak - 19.7 +/- 5.0 micrograms/ml; trough - 13.0 +/- 3.2 micrograms/ml) throughout the 12 hour dosing interval, and were greater than 75% of the peak concentration over 8.6 +/- 2.9 h. A degree of drug accumulation was evident in that the 1-h and 5-h levels rose from 12.2 +/- 4.1 and 4.5 +/- 4.8 micrograms/ml during the second week to 16.9 +/- 4.6 and 18.4 +/- 4.5 micrograms/ml, respectively, at three months. Between-patient differences accounted for 61%-71% of the total variation in steady state theophylline concentrations. After accounting for differences due to sampling time and assay error, unexplained random, within-individual variability amounted to 11%-18% of the total. Quantitative estimation of these components of variability may be incorporated into dosage forecasting methods based on single determinations of serum concentration.

Anaphylactic bronchoconstriction in passively sensitized guinea-pigs was induced by intravenous injection of antigen (ovalbumin). Five min after injection of the antigen, when the increase in airways resistance to overflow (bronchospasm) was maximum, the plasma levels of leukotrienes LTC4 and LTD4 had increased from undetectable levels of 0.280 and 1.423 ng/ml, respectively. Administration of 5-lipoxygenase inhibitors clearly suppressed the increase in the leukotriene levels concomitant with the suppression of bronchospasm.

This study examined the effectiveness of theophylline therapy in modifying exercise-induced bronchospasm (EIB) in children with perennial asthma and evaluated whether tolerance to theophylline developed with prolonged use. Twenty-one children between 7 and 16 years of age were studied by a standardized treadmill exercise test carried out before administration of theophylline, 90 minutes after administration of theophylline, and again after three weeks of round-the-clock theophylline treatment. Changes in forced expiratory volume at one second, forced expiratory flow between 25% and 75% of vital capacity, and peak expiratory flow rate were measured before and after each exercise test. Theophylline inhibited EIB in 20 of 21 subjects. There was considerable intersubject variation in the response to theophylline, however, ranging from complete inhibition in five subjects to no inhibition at all in one subject, even though theophylline controlled perennial asthma in all subjects, and all but one had theophylline levels between 10 and 22 microgram/ml when tested. On repeated testing after three weeks of therapy, no tolerance developed to theophylline. These findings suggest that EIB and perennial asthma may result from different causes and tha theophylline's ability to control asthma will not predict its effect on EIB. Subjects who have severe EIB should be retested after theophylline pretreatment of evaluate the effectiveness of therapy.

1 Pharmacological modulation of antigen-induced anaphylaxis in actively sensitized guinea-pigs with intravenously administered indomethacin (10 mg/kg), pyrilamine (2.0 mg/kg) and propranolol (0.1 mg/kg) resulted in a delayed onset, slowly developing bronchoconstriction indicative of a slow-reacting substance of anaphylaxis (SRS-A) response. 2 Measurements of pulmonary mechanics on the drug-pretreated animals challenged with ovalbumin demonstrated a more prominent effect on dynamic compliance than resistance. This is consistent with the more potent effects of SRS-A on peripheral rather than central airways. 3 The slowly developing bronchoconstriction obtained after treatment with indomethacin, pyrilamine and propranolol was inhibited by the standard SRS-A antagonist, FPL 55712 and the SRS-A synthesis inhibitors, phenidone, BW 755C and nordihydroguaiaretic acid. 4 Plasma SRS-A levels were determined in guinea-pigs following antigen challenge. The appearance of SRS-A in the plasma preceded the onset of bronchoconstriction and SRS-A levels remained elevated throughout its development. Coincident with the inhibition of bronchoconstriction by the SRS-A synthesis inhibitor, phenidone, was a dose-dependent reduction in plasma SRS-A. The intravenous ED50 in each case was 4 mg/kg. 5 This model of antigen-induced SRS-A-mediated bronchoconstriction should prove useful for the in vivo evaluation and development of therapeutics which regulate the synthesis of SRS-A.

The effect of a histamine releaser (48/80), an antigen (Ascaris suum extract) and of exogenous histamine infusion on antigen aerosol-induced bronchoconstriction was investigated in 24 mongrel dogs. During these substance infusions, the high values of arterial plasma histamine did not correlate with the degree of bronchoconstriction. Further, a severe bronchoconstriction with a relatively low arterial plasma histamine concentration was observed during antigen inhalation. During substance inhalation, a high local concentration of histamine is assumed to explain the increased bronchial "sensitivity" to actual plasma levels of histamine. Also, the responsiveness of the bronchial tree to antigen aerosol was observed to be reduced 90 min after induction of a strong histamine release. The importance of histamine in the first phase of immediate hypersensitivity is discussed.

We tested a new product containing aminophylline with 1,56% alcohol as therapy of bronchospasm in childhood to evaluate therapeutic activity, tolerance and adverse reactions. Authors confirm the usefulness of this product in childhood but dosage must be individualized with monitoring of theophylline blood levels.

In order to evaluate the efficacy of ventilation by high frequency transthoracic oscillation in obstructive lung disease, we studied 10 anesthetized and paralyzed rabbits during experimental bronchoconstriction. In order to generate body surface oscillation, the animals were placed in a body-box connected to a piston pump. Two frequencies were successively applied in random order: 1 Hz, representing "conventional" ventilation, and 5 Hz for high frequency ventilation. During the control period, the magnitudes of the oscillation were adjusted such that the tidal volumes thus produced yielded normocapnia (PaCO2 = 40 +/- 2 mmHg) for at least 3 min at each frequency. The same tidal volumes were then used after a bronchoconstriction induced by aerosolized carbachol. We obtained a severe and stable bronchoconstriction and oscillated the animals at 1 and 5 Hz at identical tidal volumes as those used during the control period. Identical at the 2 frequencies of oscillation during the control period, the rate of CO2 elimination with bronchoconstriction was significantly higher (p less than 0.05) at 5 Hz (15.9 +/- 3.3 ml/min) than at 1 Hz (14.2 +/- 3.9 ml/min); PaCO2 was also significantly lower at 5 Hz than at 1 Hz. Mean arterial PO2 was significantly higher (p less than 0.01) at 5 Hz (58 +/- 4 mmHg) than at 1 Hz (46 +/- 12 mmHg) during bronchoconstriction. Mean alveolararterial O2 pressure difference was significantly lower (p less than 0.01) at 5 Hz (49 +/- 13 mmHg) than at 1 Hz (59 +/- 11 mmHg). Only a minor increase in lung volume was found during high frequency ventilation, and no significant hemodynamic changes occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was undertaken to evaluate a method of prospectively estimating appropriate aminophylline infusion rates in acutely ill, hospitalized patients with bronchospasm. Steady-state serum theophylline concentrations (Css), clearances (Cl), and half-lives (t1/2) were estimated by the Chiou method using serum concetrantions obtained 1 and 6 h after the start of a constant-rate intravenous aminophylline infusion in 10 male patients averaging 57 years of age. Using an enzyme-multiplied immunoassay (EMIT) system for theophylline analysis, pharmacokinetic estimations were excellent for Css (r = 0.9103, p less than 0.01) and Cl (r = 0.9750, p less than 0.01). The mean estimation errors were 9.4% (range 0.8-21.5) for Css and 12.3% (range 1.3-28.0) for Cl. There was no correlation between patient age and Cl. This method is useful for rapidly individualizing aminophylline therapy in patients with acute bronchospasm.