Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI.

The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n = 24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n = 13). An intravenous infusion of budesonide was used as a reference. The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler and P-MDI, respectively; and, using the second method, 32% and 18%, respectively. The results of the present study indicate that administration of budesonide via Turbuhaler gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.

Cancer risk in asthmatic subjects selected from hospital discharge registry.

We wanted to study cancer risk in asthmatic subjects. With the use of central health registries, a cohort of 64,346 patients, treated in hospital with an asthma diagnosis, was followed with respect to cancer development. The observed numbers of different types of cancer were compared with the expected numbers, estimated from population data, with consideration taken to patient age, sex, survival, and the year of diagnosis. In general, a marked reduction of cancer incidence (2 out of 3 of the expected numbers) was found, with the exception of two cancer types: cancer of the respiratory tract and cancer of endocrine glands. A more noticeable reduction in cancer risk was seen for multiple myeloma, malignant melanoma, mammary cancer, uterine body cancer, and stomach cancer. The causes of this "protective effect" are not indicated by the present analysis, and need further study.

Intravenous infusion of enprofylline with an exponentially decreasing drug concentration in acute asthma.

Nine patients (3 women), aged 29-78 years, with acute asthma were treated with the antiasthma xanthine, enprofylline, in an open-design study without a reference drug. Enprofylline was administered intravenously (i.v.) over 2 h with an exponentially decreasing concentration. This alternative infusion system was found to be simple to handle. All patients but one reached a therapeutic plasma concentration of enprofylline within 20 min, but with a lower peak plasma, concentration as compared to what previously has been found with a conventional i.v. injection of the same amount of drug. The plasma concentration of enprofylline remained on a stable and therapeutic level over the 2-h observation period. The effect on lung function was comparable to that found in other controlled trials with enprofylline. A system for i.v. administration of drugs with an exponentially decreasing concentration as an alternative to manually given i.v. injections should be further evaluated.

Comparison of neurokinin A and substance P on cardiovascular and airway function in man.

The airway and cardiovascular effects of intravenous neurokinin A (NKA) and substance P (SP) were compared in six normal subjects. Both SP and NKA increased skin temperature (SkT) and heart rate (HR), but SP was more potent than NKA by factors of 6 and 20 respectively. No change in systolic blood pressure (BP) occurred with either peptide, but diastolic BP fell significantly with SP infusion. SP caused bronchodilation and NKA bronchoconstriction. NKA and SP have differing physiological roles and may activate different receptor populations.

Reproducibility of heart rate changes following adenosine infusion in man.

The change in heart rate following infusion of adenosine in healthy human subjects was studied on two occasions. Adenosine produced a significant, dose-related increase in heart rate. Tachyphylaxis to this effect of the naturally occurring nucleoside did not occur. There was a tendency for prolonged infusion to cause a greater increase in heart rate, but this did not reach significance.

Sensory neuropeptide effects in human skin.

1 Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% of maximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection of CGRP upon the response to SP although there was a tendency for an enhancement of the wheal response. 5 The H1-histamine antagonist terfenadine (60 mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered. 6. Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances. 7. These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo-oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NK, receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.

Effects of adenosine on autonomic control of heart rate in man.

Six healthy subjects (two female) aged 23-40 years participated in a double-blind randomized cross-over study to investigate autonomic mechanisms involved in the chronotropic effect of adenosine in conscious man. Adenosine was infused in increasing doses following saline, propranolol (0.2 mg kg-1 body weight) or propranolol (0.2 mg kg-1 plus atropine (0.04 mg kg-1). Heart rate and blood pressure were measured supine, on standing and during a Valsalva manoeuvre. Plasma catecholamines were measured in the supine and standing positions. Following saline, adenosine (up to 120 micrograms kg-1 min-1) caused a dose-related increase in heart rate (mean +/- SD maximum increase 18 +/- 8 bpm; P less than 0.01). The change in heart rate with adenosine after propranolol (12 +/- 9 bpm; P less than 0.05) did not differ significantly from the corresponding change following saline but was abolished by propranolol plus atropine, which, in turn, was associated with a mean maximum decrease in heart rate of 5 +/- 3 bpm (P less than 0.01). The increase in heart rate during the initial 30 s on standing was augmented with adenosine compared with saline (16 +/- 5 bpm; P less than 0.01). A significant increase in plasma noradrenaline on standing was also found with adenosine compared with saline (6.37 +/- 2.86 vs. 4.77 +/- 1.79 nmol 1(-1); P less than 0.05). The heart rate response to the Valsalva manoeuvre was not affected by adenosine. These results suggest that the positive chronotropic effect of infused adenosine in conscious man may in part be caused by an inhibition of cardiac vagal tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrasting effects of two xanthines, theophylline and enprofylline, on the cardio-respiratory stimulation of infused adenosine in man.

Six normal male subjects, ages 28-40 years, were studied on separate days during increasing infusions with adenosine, 40-120 micrograms kg-1 min-1, before and during infusions of two xanthine derivatives, theophylline (mean plasma concentration 9 mg l-1) and enprofylline (mean plasma concentration 3 mg l-1). The study was double-blind, randomized, placebo controlled. Cardio-respiratory variables were measured non-invasively. Adenosine by itself increased heart rate (P less than 0.05), skin temperature (P less than 0.05), resting minute ventilation (P less than 0.01) and decreased estimated Pa, CO2 (P less than 0.01). Compared with placebo enprofylline increased heart rate (P less than 0.05) and shifted the heart rate and ventilation dose-response curves of adenosine upwards (P less than 0.05 and P less than 0.02, respectively). Theophylline did not by itself affect heart rate but significantly (P less than 0.05) reduced the heart rate response to adenosine. Compared with placebo theophylline caused a small increase in minute ventilation (P less than 0.05) and flattened the dose-response curves of the effects of adenosine on ventilation (P less than 0.01) and Pa, CO2 (P less than 0.01). Theophylline also reduced abdominal and chest discomfort caused by adenosine permitting significantly (P less than 0.05) higher infusion rates of adenosine. These findings suggest that, with equipotent bronchodilating plasma concentrations, theophylline can inhibit while enprofylline augments some cardio-respiratory stimulant effects of infused adenosine in man.

Circulatory and respiratory effects of infused adenosine in conscious man.

1. The nucleoside, adenosine, was infused into six conscious healthy male subjects at rates up to 100 micrograms kg-1 min-1. 2. Compared with a control 0.9% saline infusion, adenosine in all subjects caused dose dependent increases in heart rate, skin temperature and minute ventilation with corresponding falls in PaCO2, estimated transcutaneously. 3. There were no changes in systemic blood pressure, airways resistance (measured by forced partial expiratory manoeuvres), or plasma catecholamines. At the top infusion rates subjects experienced tolerable chest and abdominal discomfort. 4. These findings conflict with some previous studies in anaesthetised man and animals, in which higher doses of adenosine and its long acting analogues have caused hypotension and central respiratory depression. 5. Although some of these changes may have been due to symptoms, the cardiovascular changes may have been due to a vasodilator action and the respiratory stimulation may have been due to an action on peripheral chemoreceptors.

Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole.

In a single blind randomized study, eight normal subjects (23-40 years) received on two separate days adenosine as a constant i.v. infusion with doses increasing from 0.005-0.1 mg kg-1 min-1 following either i.v. dipyridamole 0.4 mg kg-1 per 10 min or a corresponding volume of saline. Heart rate, blood pressure and skin temperature were measured. Following saline all subjects tolerated adenosine 0.07 mg kg-1 min-1, six also tolerated 0.09 mg kg-1 min-1. Both heart rate and skin temperature increased with adenosine in a dose-related manner. Thus, adenosine 0.09 mg kg-1 min-1 was associated with an increase in heart rate (mean +/- SD) from baseline before saline with 16 +/- 10 b.p.m. (P less than 0.01) and an increase in skin temperature with 1.3 +/- 0.8 degrees C (P less than 0.02). Dipyridamole, which inhibits the cellular uptake of adenosine was associated with a change in heart rate similar to that induced by adenosine. Furthermore, when adenosine was infused following dipyridamole the changes in heart rate and skin temperature were potentiated as compared with adenosine following saline. Thus, following dipyridamole an increase in heart rate with 15 b.p.m. above baseline was obtained with 0.005 mg kg-1 min-1 of adenosine as compared with 0.08-0.09 mg kg-1 min-1 of adenosine following saline. Blood pressure did not change in any of the studies. Exogenous adenosine in man has a dose-related positive chronotropic effect and a local dilatory effect in the skin microcirculation. Dipyridamole potentiates the cardiovascular effects of infused adenosine in man.

Arrhythmogenicity from combined bronchodilator therapy in patients with obstructive lung disease and concomitant ischemic heart disease.

Twenty-four patients (five women) aged 53-72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline (600 mg daily), enprofylline (600 mg daily) or placebo. The study was double-blind, randomized, triple-crossover with each regimen given for two weeks. Holter monitoring was used during 48 consecutive hours in each period. Compared with placebo, addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm (p less than 0.001). A small, but statistically significant (p less than 0.05) increase in mean hourly frequency of premature ventricular beats (PVBs) occurred with enprofylline as compared with placebo. However, in only two patients with enprofylline (and one patient with theophylline) the increase in PVBs was such that a clinically relevant proarrhythmic effect seems possible. Furthermore, ventricular tachycardia was not more frequently observed with any xanthine than with placebo. Thus, combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease. Holter monitoring is recommended to assess the individual patient's response to such therapy.

Bronchodilating plasma concentrations of enprofylline and theophylline have minor cardiovascular effects in man.

The cardiovascular effects with bronchodilating plasma concentration of theophylline (3.8-12.6 mg/l) and enprofylline (0.8-3.0 mg/l) were studied in six healthy male subjects by means of non-invasive procedures. With these plasma concentrations only minor effects were noted with regard to heart rate, blood pressure and systolic time intervals. However, both xanthines seem to have a vasodilating ability and a weak positive inotropic effect on the heart.

Short-term oral terbutaline does not induce myocardial hypertrophy in man.

Seven healthy male subjects, with an average age of 32 years, received 15 mg oral terbutaline daily for 14 days. Echocardiography was used to evaluate myocardial wall thickness. The terbutaline dose given resulted in plasma concentrations of terbutaline which improve lung function in asthmatic patients. Echocardiographic measurements were, however, unchanged during the study compared to pretreatment values. Thus, contrary to what has been reported in animal models, short-term terbutaline treatment in man does not seem to induce cardiac hypertrophy.

Aspects on "traditional" vasodilators in the treatment of chronic heart failure.

Vasodilator therapy of heart failure has through the last 5-10 years become a well established treatment. Traditionally these drugs have been classified after their primary site of action on the vascular beds. Thus drugs primarily acting on the arteriolar bed are called afterload-reducing agents and are exemplified by hydralazine. Drugs primarily acting on the venous bed have been called preload-reducing reducing agents and the typical example is nitroglycerin. Other drugs, like prazosin, act on both the arteriolar and venous vascular beds. The classification is, however, not as sharp as originally believed since preload- and afterload-reducing activities mix with each other. Treatment with vasodilators for chronic heart failure has mainly been advocated in patients with valvular regurgitation, ischemic heart disease and various types of dilated cardiomyopathies. It seems appropriate today to put some questions concerning vasodilator therapy for heart failure. Among such questions are: When in the natural history of congestive heart failure should vasodilator therapy be commenced? How effective is long-term administration of vasodilating drugs? May vasodilator therapy decrease mortality in congestive heart failure? What about the efficacy of new vasodilating drugs compared to more traditional ones? In the review of vasodilating drugs besides ACE inhibitors, these questions will be addressed.

Cardiac arrhythmias in patients with mild-to-moderate obstructive lung disease. Comparison of beta-agonist therapy alone and in combination with a xanthine derivative, enprofylline or theophylline.

Long-term ambulatory Holter-monitoring was used to evaluate the arrhythmogenic effects of beta 2-agonist therapy, alone and in combination with a xanthine derivative, theophylline or enprofylline. Twenty patients (mean age 51 years) with mild-to-moderate obstructive lung disease (bronchial asthma or chronic bronchitis), but without concomitant ischemic heart disease were studied. Compared with beta 2-agonist therapy alone, both combined regimens were associated with a small but significant increase in the frequency of ventricular arrhythmias. Few serious arrhythmias were observed, however, and the clinical significance of these findings is thought to be minor. Although adenosine has been suggested to have an antiarrhythmic effect, a difference between theophylline and enprofylline in the effect on adenosine (theophylline but not enprofylline being an adenosine antagonist) would appear to be of less cardiac relevance in patients without ischemic heart disease.

Clinical efficacy of hydralazine in chronic heart failure: one-year double-blind placebo-controlled study.

In a placebo-controlled trial 62 patients with chronic congestive heart failure (CHF) (New York Heart Association class III) had hydralazine (149 +/- 11 mg daily) or placebo added to conventional therapy. During 12 months' follow-up 27 patients dropped out, 15 of 32 in the hydralazine group and 12 of 30 among the control subjects. The 1-year mortality rate was 28% in the hydralazine group compared to 27% in the control group. Symptomatic improvement was noted in both groups; however, it was gradually more pronounced in the actively treated group with a statistically significant difference between the two groups at month 12 (p less than 0.05). The hydralazine patients increased their exercise capacity 25%, from 53 +/- 3 watts at month 0 to 67 +/- 4 watts at month 12 (p less than 0.01). No improvement in exercise capacity took place in the placebo group. A significant improvement in chest x-ray examination was found with hydralazine (p less than 0.01) in contrast to a significant deterioration among the control subjects (p less than 0.05). Thus, we conclude that hydralazine used in chronic CHF has beneficial clinical effects during long-term treatment.

Improved cardiac performance during exercise following hydralazine treatment in chronic heart failure.

Nine male patients with stable chronic heart failure of different etiology and optimally treated with digoxine and diuretics were given hydralazine, 50 mg b.i.d., during three months. Hemodynamic parameters were evaluated during upright submaximal exercise. An increase in cardiac index due to an increased stroke volume was noted following the first dose of hydralazine. After three months' treatment, cardiac index was further increased. The arteriovenous oxygen difference was initially unchanged, but significantly decreased following long-term treatment. These findings may indicate different effects of hydralazine acutely and after long-term treatment. It is suggested that the initial increase in blood flow is directed mainly to regions other than the exercising muscles, while more blood is directed to the muscles after long-term treatment. A possible mechanism to explain this postulated difference is discussed.

Cardiovascular effects of two different xanthines in healthy subjects. Studies at rest, during exercise and in combination with a beta-agonist, terbutaline.

The haemodynamic response to two xanthines, enprofylline and theophylline, was studied in 6 healthy male volunteers at rest, during exercise and in combination with the beta 2-agonist, terbutaline. At rest the haemodynamic effects of both xanthines were small and were qualitatively different from each other. While theophylline exerted a "pressor" response, enprofylline seemed to have arterial dilating ability. During exercise both xanthines as compared to placebo were associated with a higher heart rate and in general with increased systolic blood pressure. In combination with terbutaline enprofylline and theophylline both increased systolic blood pressure more than placebo, i.e. they augmented the positive inotropic effect of terbutaline. The systolic blood pressure was higher after theophylline than enprofylline despite their equipotent bronchodilator activity. This may reflect different inotropic effects of the xanthines as well as a difference in their influence on the response to adenosine.

A comparison of the acute and long-term hemodynamic effects of ventricular inhibited and atrial synchronous ventricular inhibited pacing.

Sixteen patients treated with a noninvasively programmable pacemaker were examined after a prolonged period of ventricular inhibited (VVI) and atrial synchronous ventricular inhibited (VDD) pacing. Maximal working capacity was determined by bicycle ergometry. Atrial and ventricular rates, brachial artery cuff pressure and breathing rate were determined at rest and during exercise. There was a mean increase in working capacity of 24% with VDD compared with VVI pacing (p less than 0.001). Thirteen of the patients were catheterized. During VDD pacing, cardiac output was significantly higher, particularly during exercise (+/- 32%) due to the capability of heart rate increase and despite a substantial compensatory stroke volume increase during VVI pacing. Arteriovenous oxygen difference was much higher during VVI pacing, reaching 164 +/- 14 ml/l during the highest work load, while the corresponding level during VDD pacing was 140 +/- 14 ml/l (p less than 0.001). During exercise, arterial blood lactate was significantly higher during VVI than during VDD pacing. Heart size was significantly smaller, 568 +/- 98 vs 530 +/- 96 ml/m2 BSA (p less than 0.05), during VDD pacing a questionnaire was completed by the patients to evaluate subjective symptoms and pacemaker preference. This part of the study favored the VDD mode of pacing. The conclusion of this study is that VDD pacing is superior to VVI pacing.