Low-dose almitrine bismesylate in the treatment of hypoxemia due to chronic obstructive pulmonary disease.

STUDY OBJECTIVE: Assessment of acute and chronic effects of low-dose almitrine bismesylate (AB) in stable chronic obstructive pulmonary disease (COPD). STUDY DESIGN: Oral administration of AB, 25 mg three times a day, for 6 months in all patients. Pulmonary function, blood gases, and peripheral nerve conduction velocity were measured at baseline and after long-term administration of AB. In addition, oral pharmacokinetics and effects on pulmonary circulation at rest were studied in half of the patients. Intravenous pharmacokinetics were measured after a single intravenous dose of 60 mg of AB 3 months before the start of oral AB treatment in the other seven patients. SETTING: Outpatient clinic of a community hospital in a coal mining district in southwest Germany. PATIENTS: Fourteen patients with clinically stable COPD and hypoxemia. RESULTS: Acute effects of AB were as follows: a significant increase in arterial oxygen tension (PaO2) from 61 +/- 7 mm Hg to 74 +/- 8 mm Hg (p < 0.001), a decrease in arterial carbon dioxide tension (PaCO2) from 41 +/- 8 mm Hg to 38 +/- 7 mm Hg (p < 0.01), a rise of pH from 7.45 +/- 0.04 to 7.48 +/- 0.04 (p < 0.01), and a transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mm Hg (not significant). After long-term treatment, once tissues were saturated with almitrine, improvement in gas exchange persisted with a PaO2 of 70 +/- 10 mm Hg (p < 0.001) and a PaCO2 of 39 +/- 6 mm Hg (not significant) without elevation of pH (7.45 +/- 0.04) or of pulmonary artery pressure (26 +/- 8 mm Hg). The terminal half-life of AB was 56 +/- 45 days after a single intravenous administration, and 55 +/- 16 days after long-term oral dosing. None of the patients developed clinically manifest peripheral neuropathy. Impaired asymptomatic peripheral motor nerve function was prevalent in 4 (29 percent) of the patients and remained unchanged during long-term AB administration. However, asymptomatic impairment of motor nerve conduction velocity developed in two patients with inadequate high AB plasma levels despite low-dose therapy. Both patients were known to have additional conditions predisposing for neuropathy. CONCLUSIONS: Low-dose AB therapy, 75 mg daily, resulted in sustained elevation of arterial oxygen tension in hypoxemic patients with COPD. Although pulmonary artery pressure increased transiently after the first dose, it remained unchanged with long-term treatment despite persistent improvement of pulmonary gas exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of the responses of endothelin-1 to exhaustive physical exercise under simulated high-altitude conditions with acute hypoxia.

To assess whether acute alveolar hypoxia leads to the release of endothelin-1 (ET) in vivo, ET, cortisol (CORT), and lactate (LA) levels were determined in 15 healthy subjects at rest and during exhaustive incremental cycle ergometry on two separate test days. The subjects were to breathe a gas mixture with reduced O2 content ([H] fraction of inspired O2, 0.14) on one day and normal air on the other (N). Modified responses of LA and CORT to exhaustive incremental cycle ergometry on the H day indicated elevated anaerobic tissue metabolism and increased physical stress. With acute alveolar hypoxia, the response of ET to exhaustive physical labor was found to be augmented.

Increase of serum insulin and stable c-peptide concentrations with exhaustive incremental graded exercise during acute hypoxia in sedentary subjects.

Hypoxia was shown to reduce insulin concentrations at rest and during exercise. However, some studies have also demonstrated increases in the hormone associated with arterial desaturation. This study was conducted in order to decide [1] whether acute alveolar hypoxia increased or decreased the circulating insulin levels, and [2] to elucidate whether interactions of insulin with other hormones were of relevance in this respect. Glucose (GLU), insulin (INS), c-peptide (CP), adrenaline and noradrenaline (CATs), atrial natriuretic peptide (ANP) and cortisol (CORT) as well as the capillary blood gases were determined in 15 healthy fasting male volunteers (age: 26.2 +/- 2.8 years, body mass index: 22.4 +/- 2.7 kg.m-2). On two separate test days the subjects breathed, in random order, either normal air (N) or a gas mixture with reduced oxygen content (H; FIO2: 0.14). Measurements were made at rest as well as during an incremental cycle exercise in a supine position (increments of 6 min and 50 W) at 100 W and 150 W, at volitional exhaustion (N: 227 +/- 36 W; H: 200 +/- 32 W) as well as in the 5th min of recovery. Arterial desaturation was seen throughout on H-day. At rest all hormones and GLU were normal and showed no influence of H. During exercise INS remained constant on N-day, increased on H-day and was significantly higher with H than with N, most pronounced at 150 W and at volitional exhaustion with 20%, respectively. For CP and GLU no significant exercise-induced changes were seen on either test day and no influence of H was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal modifications in patients admitted to an internal intensive care unit for acute hypoxaemic respiratory failure.

To clarify which endocrine modifications can be observed in acute hypoxaemic respiratory failure, 15 severely ill male patients [PAT; median age: 61 (range: 48 years); median height: 173 (range: 12) cm; median mass: 73 (range 31) kg] were investigated immediately upon admission to an intensive care unit (ICU) for this clinical disorder. Before starting treatment, the blood gases were measured and a number of selected hormones with special relevance for an ICU setting were determined. These are known to be modified by acute hypoxaemia in healthy subjects and to possess glucoregulatory properties, or an influence upon cardiocirculation or the vascular volume regulation: insulin, cortisol, adrenaline, noradrenaline, atrial natriuretic peptide, renin, aldosterone, angiotensin converting enzyme, and endothelin-I (ET). To elucidate whether potential endocrine changes resulted from acute hypoxaemia alone, the underlying disease, or unspecific influences connected with the ICU setting, all measurements were compared to those of a completely healthy reference group (REF) with comparable acute experimental hypoxaemia. The latter state was achieved by having the REF breathe a gas mixture with the oxygen content reduced to 14% (H). In the REF, neither the medians nor the distribution of endocrinologic measurements were modified significantly by acute hypoxaemia. In the PAT, the medians were increased considerably, yet with a slight diminution of ET. The distribution of individual values was considerably broader than in the REF with H. In conclusion, considerable increases in the means of the above hormones, with the exception of ET, can be registered in severely ill patients admitted to ICUs with acute hypoxaemic failure. However, such modifications cannot be considered attributable exclusively to acute arterial hypoxaemia. The underlying clinical disorders, such as septicaemia or an unspecific endocrine epiphenomenon, including severe and not only hypoxaemic stress, seem to be predominant.

[Apolipoproteins and lipoproteins with differing physical activity and performance capability]. / Apolipoproteine und Lipoproteine bei unterschiedlicher körperlicher Aktivität und Leistungsfähigkeit.

In 216 healthy subjects (74 endurance trained persons, 87 variably trained subjects and 55 sedentary individuals) the behaviour of triglycerides, total cholesterol, lipoproteins and apolipoproteins in blood serum - all in relation to physical performance capacity - were determined in the early morning under fasting conditions. HDL-/total cholesterol (%) as well as the ratios LDL/HDL and Apo A1/Apo A2 proved to have the highest selectivity. Only marginal differences or none at all between the groups were found for Apo B, Apo A2 and total cholesterol. In an analysis of correlation the strongest relation with physical performance was found for HDL-/total cholesterol (%), Apo A1/Apo A2, Apo A1 and LDL/HDL. No significant correlations were found for total-cholesterol, Apo B and Apo A2. When the influence of age and body weight was excluded in an analysis of partial correlation Apo A1 showed the strongest relation to physical performance. The relevant partial correlations for Apo A1/Apo A2, HDL-cholesterol and HDL-/total cholesterol (%) were found to be weaker. With regard to the influence of increased physical activity on the human lipid metabolism it was concluded that the determination of lipoproteins can be significantly supplemented by the determination of apolipoproteins. The behaviour of Apo A1 and Apo A1/Apo A2 indicates that enhanced physical activity increases the vasoprotective HDL2 subfraction.

[Ergometry procedures independent of body weight in children with special reference to blood pressure behavior in stress]. / Körpergewichtsunabhängige Ergometrieverfahren bei Kindern unter besonderer Berücksichtigung des Belastungsblutdruckverhaltens.

UNLABELLED: For the purpose of investigating differences in terms of gender and methodology, a group of 80 healthy children engaged in leisure-time sport activities (male: n = 50; 10.9 +/- 1.1 years; female: n = 30; 11.5 +/- 1.1 years) was divided into 3 groups, which were then subjected to different ergometric procedures. In group I, boys and girls were compared in a bicycle ergometry in an upright seated position. In group II, a bicycle ergometry in upright seated position was compared with a bicycle ergometry in a supine position. In group III, a bicycle ergometry in upright seated position was compared with a treadmill exercise. Bicycle ergometry was started at 25 W; workload was increased in steps of 25 W every 3 min until the children felt exhausted. RESULTS: No differences with respect to gender were found for maximum oxygen uptake, maximum heart rate and maximum lactate. The relevant parameters were also similar on submaximal levels of exercise intensity. All children reached a degree of thorough physical exhaustion at heart rates close to 200 X min-1. As in adults, maximum oxygen uptake decreased in the following order: treadmill exercise greater than bicycle ergometry in upright seated position greater than bicycle in supine position. Systolic and diastolic blood pressure on the various levels of exercise were lower than among adults.(ABSTRACT TRUNCATED AT 250 WORDS)

Physical performance and serum potassium under chronic beta-blockade.

Various publications have described a beta 2-receptor regulated potassium transport system in the cellular membrane of human skeletal muscle. To examine the suggestion that serum potassium alterations are among the causes of premature muscular fatigue during physical exercise under pharmacological blockade of beta-receptors, we have compared the influence of sustained blockade with a beta 1-selective blocker and a nonselective beta-blocker on the levels of serum potassium before, during and after a physical exercise test. 63 healthy physical education students received in random order and under double blind conditions either 100 mg Metoprolol (beta 1-selective) or 80 mg Propranolol (non-selective), or placebo daily for 3 months. Serum potassium was measured before, during (at 150 Watt and at the end of exercise) and after a bicycle exercise with a stepwise increase in work loads. After three months of beta-blocker treatment serum potassium levels during exercise were significantly higher than in control subjects receiving the placebo, and it took longer for the serum potassium levels to return to the resting level in the beta-blocker treated subjects. At rest, however, the levels were not found to be statistically different. In the subjects receiving Propranolol the post-exercise serum potassium levels were higher than in the subjects receiving Metoprolol. Three days after cessation of the medication these differences were no longer perceptible. Our findings confirm the existence of a beta-receptor regulated potassium transport system in human skeletal muscle and indicate that the transmembranous potassium transport in human skeletal muscle is predominantly regulated via beta 2-receptors, although beta 1-receptors seem also to be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects on physical performance of intrinsic sympathomimetic activity (ISA) during selective beta 1-blockade.

In 15 healthy, not specifically trained volunteers (age: 26.6 +/- 2.7 years) single equipotent doses of a selective beta 1-blocker with intrinsic sympathomimetic activity (ISA) (200 mg Epanolol-Visacor; V) and of a selective beta 1-blocker without ISA (100 mg Metoprolol; M) were compared with placebo (P) with respect to their influence upon physical performance capacity and metabolism in a random, double blind, cross-over experimental setting. The subjects underwent three step by step incremental treadmill tests and three treadmill endurance tests until volitional exhaustion. Maximum running speed and maximum oxygen uptake were used as measures of maximum performance capacity. Running speed and oxygen uptake related to individual anaerobic threshold, and running time and running distance in the endurance tests were used as measures of endurance capacity. Both maximum and endurance performances were reduced significantly by beta-blockade. No relevant differences were discerned between V and M. The uniform reduction in exercise heart rate with both beta-blockers demonstrated the application of equipotent doses. At rest, heart rate was significantly higher under V than under M. Carbohydrate metabolism was unaffected, both beta-blockers showing equal inhibition of lipolysis during exercise. We conclude that intrinsic sympathomimetic activity has no influence upon physical performance and metabolism during selective beta 1-blockade.

A 7-week follow-up study of the behaviour of testosterone and cortisol during the competition period in rowers.

Nine rowers (six men of the regional and three women of the national top class) participated in the study. During 7 consecutive weeks of the competition period serum testosterone (T), SHBG, cortisol (C) and urea were determined at the same time every morning under fasting conditions. From the concentrations of T and SHBG the free testosterone fraction (T/SHBG) was calculated, and from the concentrations of T and C the ratio of T/C was derived. The object of the investigation was to gather information on a potentially altered anabolic-catabolic hormone relationship dependent upon the intensity of the individual training periods. All rowers showed a continuous decrease in T, T/SHBG and T/C during the observation period. A week of regenerative training halted the decrease. In two of the oarsmen who discontinued their training after 2 and 3 weeks respectively, T, T/SHBG and T/C showed a normalization in the following weeks. In all subjects the concentrations of urea increased during the first 2 weeks and decreased during the subsequent weeks of intense training and competition. The findings suggest an increase in catabolic activity in periods of intensive physical strain, including competitions. Regenerative phases of training seem to reduce the anabolic-catabolic imbalance.

[The value of studies of pulmonary gas exchange during exercise for evaluation of reduced arterial oxygenation at rest in asymptomatic long-term smokers]. / Zur Bedeutung von Untersuchungen des Gasaustauschs unter Belastung für die Bewertung einer reduzierten arteriellen Oxygenierung in Ruhe bei asymptomatischen Langzeit-Rauchern.

The aim of this study was to elucidate extent and nature of an impairment of gas exchange after long time cigarette-smoking. Pulmonary gas exchange at rest as well as during steady state exercise and conventional lung function tests (LFTs) were studied in 32 clinically healthy, asymptomatic severe cigarette-smokers (S; 48.1 +/- 15.7 pack-years) and 32 healthy lifetime nonsmokers (N) between 40 and 60 years of age, respectively, individually matched for age, body height, body weight and gender. Pulmonary function tests of all subjects were within the limits of normal values. Except for a slight reduction of MEF25 in S (p < 0.05) and a slight increase of FRC (p < 0.05), the groups did not differ with respect to LFTs. At rest, however, S had markedly lower values for PaO2, TLO2, DCO and KCO, and higher values for AaDO2 and QVA/Qt. Resting measurements for VD/VE and PaCO2 did not differ between N and S. During ergometry PaO2 and TLO2 increased respectively; AaDO2 and QVA/Qt fell concomitantly with VD/VE and PaCO2. On termination of exercise no significant difference between N and S for the above variables could be discerned any longer. Our findings confirm that even in clinically healthy asymptomatic cigarette-smokers a distinct impairment of gas exchange is present. Their improvement during physical exercise primarily indicates the presence of reversible ventilation-perfusion mismatching and excludes relevant morphologic changes in the lung in these cases.

Influence of xamoterol, a partial beta 1-selective agonist, on physical performance capacity and cardiocirculatory, metabolic and hormonal parameters.

In a double-blind, random, cross-over study, 14 healthy male volunteers received xamoterol 200 mg (Corwin; C) twice daily or placebo (P) for two seven-day medication periods to investigate effects on physical performance, cardiocirculatory parameters, metabolism and hormone levels during exercise. An oral glucose tolerance test (OGTT) was also done. C showed a positive inotropic effect up to an exercise intensity of 100 W, corresponding to a heart rate of about 100 beats.min-1. Chronotropic regulation of the heart remained unchanged, but the increase in systolic blood pressure was more pronounced and the catecholamines behaved as after P. From 150 W onwards, C exhibited beta-blocking properties; heart rate was reduced by up to 8 beats.min-1; systolic blood pressure remained unchanged; and the catecholamines showed a more pronounced increase than after P. Diastolic blood pressure behaved almost identically under all test conditions. With the exception of a slightly increased level of free fatty acids at rest, the parameters of physical performance, lipid and carbohydrate metabolism and the hormone levels under all conditions after C showed similar behaviour to that after as P. The findings indicate that physical performance capacity, cardiocirculatory system, metabolism and hormones were not negatively influenced by C.

Circulating leucocyte subpopulations in sedentary subjects following graded maximal exercise with hypoxia.

Ten healthy sedentary subjects [age, 27.5 (SD 3.5) years; height, 180 (SD 5) cm; mass, 69.3 (SD 6.3) kg] performed two periods of maximal incremental graded cycle ergometer exercise in a supine position. Randomly ordered and using an open spirometric system, one exercise was carried out during normoxia [maximal oxygen consumption (VO2max) = 38.6 (SD 3.5) ml.min-1.kg-1; maximal blood lactate concentration, 9.86 (SD 1.85) mmol.l-1; test duration, 22.6 (SD 2.7) min], the other during hypoxia [VO2max = 33.2 (SD 3.2) ml.min-1.kg-1; maximal blood lactate concentration, 10.38 (SD 2.02) mmol.l-1; test duration, 19.7 (SD 2.8) min]. At rest, immediately (0 p) and 60 min (60 p) after exercise, counts of leucocyte subpopulations (flow cytometry), cortisol and catecholamine concentrations were determined. At 0 p in contrast to normoxia, during hypoxia there was no significant increase of granulocytes. There were no significant differences between normoxia and hypoxia in the increases from rest to 0 p in counts of monocytes, total lymphocytes and lymphocyte subpopulations [clusters of differentiation (CD), CD3+, CD4+CD45RO-, CD4+CD45RO+, CD8+CD45RO-, CD8+CD45RO+, CD3+HLA-DR+, CD3-CD16/CD56+, CD3+CD16/CD56+, CD19+] as well as adrenaline, noradrenaline and cortisol concentrations. The counts of CD3-CD16/CD56(+)- and CD8+CD45RO(+)-cells increased most. At 60 p, CD3-CD16/CD56+ and CD3+CD16/CD56(+)-cell counts were below pre-exercise levels and under hypoxia slightly but significantly lower than under normoxia. We concluded that the exercise-induced mobilization and redistribution of most leucocyte and lymphocyte subpopulations were unimpaired under acute hypoxia at sea level. Reduced increases of granulocyte counts during the study and reduced cell numbers of natural killer cells and cytotoxic, not major histocompatibility complex-restricted T-cells, only indicated marginal effects on the immune system.

[Differential diagnostic significance of complex values of gas exchange during submaximal physical effort in patients with emphysema and pulmonary fibrosis]. / Zur differentialdiagnostischen Bedeutung von komplexen Kenngrössen des Gasaustauschs während submaximaler Körperarbeit bei Patienten mit Emphysem und Lungenfibrose.

The aim of this study was to clarify a) whether the behaviour of functional dead space ratio (VD/VE), alveolo-arterial difference of oxygen tensions (AaDO2) and the venous admixture ratio (QVA/Qt) differed at rest and during submaximal exercise, between patients with pulmonary emphysema and interstitial pulmonary fibrosis as well as from the respective findings in healthy controls, and b) whether a differentiation between these two diseases could be achieved by investigations of complex pulmonary gas exchange. Eleven patients with pulmonary fibrosis (F), which had been diagnosed by pulmonary biopsies, 11 patients with pulmonary emphysema (E) and 11 healthy controls (C) were subjected to conventional pulmonary function tests (PFTs: spirometry, bodyplethysmography, DCO) immediately followed by examinations of pulmonary gas exchange conducted at rest and during an incremental submaximal cycle spiroergometry (ERGO). With normal PFTs for C, vital capacity was diminished in F and the 1" timed vital capacity (FEV1) as well as Tiffeneau's index were reduced in E, while air way resistance and functional residual capacity were augmented in the latter group. In all patients the CO-diffusing capacity was lower compared to C, however, without differences between F and E. In both E and F, the arterial O2 tension were lower at rest as well as during ERGO when compared to C, whereas VD/VE, QVA/Qt and AaDO2 as well as the specific ventilation for O2 were higher, respectively. Alveolar ventilation was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipid profile of body builders with and without self-administration of anabolic steroids.

Twenty-four top-level body builders [13 anabolic steroid users (A); 11 non-users (N)] and 11 performance-matched controls (C) were examined to determine the effect on lipids, lipoproteins and apolipoproteins of many years of body building with and without simultaneous intake of anabolic steroids and testosterone. After an overnight fast, triglycerides (TG), total cholesterol (TOTC), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), the HDLC subfractions HDL2C and HDL3C, as well as apolipoprotein A-I (Apo A-I), apolipoprotein A-II (Apo A-II) and apolipoprotein B (Apo B) were determined. Both A and N, compared to C, showed significantly lower HDLC and higher LDLC concentrations, with the differences between A and C clearly pronounced. In a subgroup of 6 body builders taking anabolic steroids at the time of the study, HDLC, HDL2C, HDL3C, Apo A-I and Apo A-II were all significantly lower and LDLC was significantly higher than in a second subgroup of 7 body builders who had discontinued their intake of anabolic steroids at least 4 weeks prior to the study. In some single cases HDLC was barely detectable (2-7 mg.dl-1). The TG and TOTC remained unchanged. The present findings suggest that many years of body building among top-level athletes have no beneficial effect on lipoproteins and apolipoproteins. Simultaneous use of anabolic steroids results in part in extreme alterations in lipoproteins and apolipoproteins, representing an atherogenic profile. After discontinuing the use of anabolic steroids, the changes in lipid metabolism appear to be reversible.

Experimental acute hypoxia in healthy subjects: evaluation of systolic and diastolic function of the left ventricle at rest and during exercise using echocardiography.

To clarify whether or not systolic and diastolic function of the human left ventricle (LV) were decreased during acute hypoxia, at rest and with exercise, 14 healthy male volunteers [age 25.9 (SD 3.0) years, height 182.9 (SD 7.1) cm, body mass 75.9 (SD 6.9)kg] were examined using M-mode and 2D-mode echocardiography to determine the systolic LV function as well as Doppler-echocardiography for the assessment of diastolic LV function on 2 separate test days. In random order, the subjects breathed either air on 1 day (N) or a gas mixture with reduced oxygen content on the other (H; oxygen fraction in inspired gas 0.14). Measurements on either day were made at rest, several times during incremental cycle exercise in a supine position (6-min increments of 50 W, maximal load 150 W) and in 6th min of recovery. Corresponding measurements during N and H were compared statistically. Arterial O2 tension (PaO2) was normal on N-day. All subjects showed a marked acute hypoxia at rest [PaO2, 54.5 (SD 4.6) mmHg], during exercise and recovery on H-day. The latter was associated with tachycardia compared to N-day. All echocardiographic measurements at rest were within the limits of normal values on both test days. Ejection time, end-systolic and end-diastolic left ventricular dimensions as well as the thickness of left posterior wall and of interventricular septum showed no statistically significant influence of H either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)