Response to nebulized ipratropium bromide and terbutaline in acute severe asthma.

Outpatient studies on asthmatics have shown that inhaled anti-cholinergic agents decrease in efficacy as FEV1 falls. To determine whether there are changes in response to inhaled anti-cholinergics during acute bronchoconstriction we have examined the effects of nebulized ipratropium and terbutaline in nine hospitalized patients recovering from acute severe asthma. At 6 a.m. each day throughout the admission, baseline PEFR was recorded. Ipratropium bromide, 1 mg, was nebulized and PEFR measured again 1 h later. Following this, terbutaline, 5 mg, was nebulized with further measurement of PEFR 15 min after nebulization. Results were analysed by paired t-tests. Mean baseline PEFR rose from 157 l m-1 on patients worst day to 300 l m-1 on their best day (P less than 0.01). Ipratropium improved mean PEFR by 55 l m-1 and 42 l m-1 on patients worst and best days respectively (P less than 0.01). Subsequent terbutaline improved mean PEFR on patients worst day by 23 l m-1 (P less than 0.01) but only by a non-significant 4 l m-1 on their best day (P = 0.09). Hence, ipratropium produced 96% of total bronchodilatation when baseline was highest, but achieved only 71% of total response when baseline was lowest, a highly significant change in response (P less than 0.01). We conclude that in acute severe asthma as baseline PEFR rises response to inhaled ipratropium improves, compared with total response to combined ipratropium followed by terbutaline.     

Once-daily sustained-release theophylline reduces diurnal variation in spirometry and symptomatology in adult asthmatics

In 22 adult asthmatics (mean age, 55.2 +/- 15.4 yr), we compared Uniphyl given once a day to Theo-Dur given twice a day using a randomized, double-blind, two-phase crossover trial. All patients demonstrated acute bronchodilator responsiveness (FEV1 increase greater than 15%) to inhaled salbutamol and were dependent upon both orally administered theophylline and inhaled salbutamol at time of entry. Each phase lasted 9 days, the first 2 days of which were a theophylline washout. Uniphyl was given once a day at 8 P.M. and Theo-Dur was given twice a day at 8 A.M. and at 8 P.M. For each patient, the total daily theophylline dose was the same during both phases. Asthma symptoms, drug side effects, and PEFR were recorded at 8 A.M. and at 4 and 8 P.M. each day. On Days 7, 8, and 9 of each phase, serum theophylline concentrations were measured and spirometry was performed at 8 A.M. and at 4 and 8 P.M. The results demonstrated significant differences in both pharmacokinetic and clinical efficacy between the 2 drugs. Uniphyl produced greater "peak" and lower "trough" theophylline concentrations than did Theo-Dur, although both lower "trough" theophylline concentrations than did Theo-Dur, although both drugs maintained concentrations within the accepted therapeutic range. In contrast to the pharmacokinetic findings, Uniphyl was associated with significantly less fluctuation in pulmonary function throughout the day, and the values at 8 A.M. for FEV1, PEFR, and wheeze demonstrated significant clinical efficacy in favor of Uniphyl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patterns of recovery of pulmonary functions in severe acute bronchial asthma

The recovery of pulmonary function were studied in fifty patients of acute bronchial asthma receiving a standard therapeutic regime. Sixty-two per cent of patients had achieved 50% of their total improvement in peak expiratory flow rate (PEFR) within 24 hours (fast responders) as against slow responders. Duration of asthma, characteristics of present exacerbation, mean pulse rate and presence of pulsus paradoxus on admission did not differ in fast and slow responders. The rise in PEFR within 4 hours of starting treatment was highly significantly correlated with a higher PEFR at 24 hours and a faster recovery. The mean arterial PaCO2 was higher (P less than 0.02) in slow responding group and they were slightly older (P less than 0.01), had lower mean FVC (P less than 0.01), mean FEV1 (P less than 0.02) and PEFR (P less than 0.001). The mean PaO2 of less than 80 mm Hg at 48 hours was more common in those with delayed recovery of PEFR.     

Home nebulizers in severe chronic asthma

Twenty-four outpatients who continued to have severe chronic asthma despite attending a chest clinic were studied. All were already using inhaled beta-agonists from a pressurized aerosol and regular inhaled corticosteroids. Nineteen were on long-term oral corticosteroids. Comparison was made between their symptoms and peak expiratory flow rate (PEFR) during 4 weeks on their usual treatment and the following month when they were also given 5 mg terbutaline night and morning by nebulizer. During the second month the symptom score for nocturnal asthma improved by 30% (P less than 0.01), for daytime wheeze by 23% (P less than 0.025) and shortness of breath by 15% (P less than 0.01). The prebronchodilator morning and evening PEFR increased by 8% (P less than 0.025) and 10% (P less than 0.01) respectively. A dose-response study with inhaled terbutaline in six patients before and after 4 weeks of nebulizer treatment showed no evidence of a decline in response. Home nebulizers produced considerable overall improvement. Because of variations in individual responses a monitored trial of the type which we have used is desirable before a decision is made on long-term treatment.     

Real and pseudo late asthmatic reactions after submaximal exercise challenge in patients with bronchial asthma. A new definition for late asthmatic responses after exercise challenge

The late asthmatic reaction after exercise challenge remains a controversial issue. In this study, 21 patients recorded peak expiratory flow rate (PEFR) on two control days without performing exercise. There was no difference between both control days when PEFR at 1 h was compared with baseline PEFR and when PEFR at 4 to 13 hours was compared with baseline PEFR. After analyzing variation coefficients of baseline PEFR on a control day and exercise day, PEFR was not allowed to differ more than 15.3 percent in the same patient when comparing exercise day and control day for the late fall in PEFR in the study. In 17 of 81 patients, a late asthmatic reaction after exercise challenge was present when PEFR fall was greater than or equal to 20 percent compared with baseline PEFR value. In eight of the 17 patients, a real late asthmatic reaction to exercise challenge was present with a PEFR fall greater than or equal to 20 percent on at least three successive time points and who had a PEFR fall greater than or equal to 20 percent compared with corresponding clocktime on a control day. The late asthmatic reaction to exercise challenge is characterized not as a nonspecific epiphenomenon, but as a fall in PEFR of greater than or equal to 20 percent compared with baseline PEFR value and with corresponding clocktime on a control day on at least three successive time points. Graphic illustration of airway responses following exercises may facilitate the detection of a late asthmatic response.     

Effect of clomifene on thyroid function in normal men.

To study the effect on thyroid function 100 mg of clomifene citrate was given once a day to two groups of healthy male volunteers for 5 and 12 consecutive days, respectively. In both groups serum concentrations of TSH, thyroxine, triiodothyronine, T3 resin uptake test and thyroid hormone binding proteins were measured before, during and after oral administration of clomifene. The effect of clomifene treatment was evaluated in Group 1 by means of serum FSH and LH measurements. Further in Group 2 the serum TSH response to iv TRH (200 microgram) was also investigated. The mean per cent elevations in serum concentrations of FSH and LH were 145 and 200, respectively. In Group 1 a small but statistically significant decrease within reference limits in triiodothyronine (P less than 0.01) and free thyroxine index (P less than 0.02) was found on day 4 of clomifene. On day 5 a slight increase in TSH was observed (P less than 0.05). In Group 2 the response of TSH to TRH showed a non-significant increase after 5 days and a significant increase (P less than 0.01) after 12 days of clomifene. Eight days after discontinuation of the drug the response was restored to normal. No changes in the thyroid hormone binding proteins in serum could be demonstrated. Though the observed changes were slight, they indicate that clomifene exerts an influence directly on the thyroid function.     

Comparison of peak expiratory flow rate and FEV1 in assessing bronchomotor tone after challenges with occupational sensitizers

Bronchial responses to occupational sensitizers measured by peak expiratory flow rate (PEFR) and forced expiratory volume in 1 s (FEV1) during late reactions (between 90 minutes and 8 hours after exposure) were compared in two groups of 88 subjects who had undergone specific inhalation challenges in the laboratory. The first group had what was considered a positive reaction (a fall of at least 15 percent in FEV1) whereas the second group's reaction was interpreted as negative (fall in FEV1 less than 15 percent). Although the correlation in terms of percentage of change from baseline values was statistically significant, the correspondence was poor. PEFR proved far less sensitive than FEV1 in detecting a reaction. Whereas the mean maximum change in FEV1 overall was 27 percent, the mean maximum change in PEFR at the same time interval was only 16 percent. Moreover, individual correlations between the percentage of change in FEV1 and PEFR were satisfactory (r2 greater than 0.80) in only 32/88 subjects (36 percent). No subject who was considered to have a negative challenge according to FEV1 had a change in PEFR greater than 20 percent. We therefore conclude that changes in PEFR are far less sensitive than changes in FEV1 in detecting responses during late reactions to occupational sensitizers.     

Comparative study of anticholinergic and betamimetic agents in the treatment of asthma attacks

Four regimens of bronchodilatation therapy administered on 2 consecutive days were tested in 4 randomly selected groups of 6 asthmatic patients: 1) intravenous atropine + inhaled oxitropium bromide; 2) intravenous atropine alone; 3) intravenous salbutamol + inhaled salbutamol; 4) intravenous salbutamol alone. On the second day the treatments were crossed over, i.e. the groups which had received the intravenous + inhaled treatment on the first day received the same drug in i.v. form alone and vice versa. The intravenous doses of atropine and salbutamol were 0.5 mg each administered over 1 hour, and those of oxitropium and salbutamol aerosol were 100 mcg hourly for 6 hours. In addition, all patients received methylprednisolone 20 mg i.v. on each day of the study. Peak expiratory flow rate (PEFR), heart rate (HR) and arterial pressure were recorded before treatment, then hourly for 6 hours. All 4 regimes produced significant improvement in PEFR (P less than 0.01). Bronchodilatation was not significantly different in the 4 groups, but improvement was markedly better when intravenous injections were associated with inhalations. No side-effects were recorded with the anticholinergic drugs, whereas a slight but significant increase in HR (P less than 0.05) was observed with the adrenergic drug. This study suggests that anticholinergic agents provide a therapeutic alternative for severe acute asthma when beta 2-adrenergic stimulants cannot be used.     

Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism

Magnesium (Mg) deficiency in man may result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D]. To determine whether these changes are due to selective Mg depletion, we studied 26 normal subjects before and after a 3-week low Mg (less than 1 meq/day) diet. This diet induced Mg deficiency, as demonstrated by a fall in pre- to postdiet serum Mg levels from 0.80 +/- 0.01 to 0.61 +/- 0.02 mmol/L (P less than 0.001), an increase in Mg retention from 11 +/- 4% to 62 +/- 4% (P less than 0.001), and a fall in red blood cell free Mg2+ from 205 +/- 10 to 162 +/- 7 microM (P less than 0.001). Serum calcium (Ca) fell significantly from 2.36 +/- 0.02 to 2.31 +/- 0.03 mmol/L (P less than 0.05), and serum 1,25-(OH)2D fell from 55 +/- 4 to 43 +/- 3 pmol/L (P less than 0.05). PTH secretion was impaired, as demonstrated by a fall or no change in serum PTH in 20 of 26 subjects despite a fall in the serum Ca and Mg. In addition, an iv injection of Mg in eight subjects after the diet resulted in a significant rise in PTH from 15 +/- 2 to 19 +/- 2 ng/L (P less than 0.01), whereas a similar injection given to six of the subjects before the diet resulted in a significant fall from 28 +/- 5 to 13 +/- 3 ng/L (P less than 0.001). The fall in serum 1,25-(OH)2D may be due to both the decrease in PTH secretion and a renal resistance to PTH. PTH resistance was suggested, as no increase in serum 1,25-(OH)2D was observed in the six subjects in which the PTH concentration rose by mean of 68% after the diet. Also, the rise in serum 1,25-(OH)2D after a 6-h human PTH-(1-34) infusion was significantly less after Mg deprivation. The results demonstrate that mild Mg depletion can impair mineral homeostasis and may be implicated as risk factor for osteoporosis in disorders such as chronic alcoholism and diabetes mellitus, in which Mg deficiency and osteoporosis are both common.     

Reversibility tests in chronic obstructive airways disease: their predictive value with reference to benefit from domiciliary nebuliser therapy

The role of short-term tests of reversibility in selecting patients with COAD for long-term nebuliser therapy is uncertain. In a double-blind placebo-controlled crossover study we have examined the correlation between short-term reversibility and response to a home nebuliser. We studied 20 patients with severe COAD (mean age 66, mean FEV1 0.81 l) and little reversibility (less than 20% increase in FEV1 post-inhaled salbutamol 200 micrograms and less than 25% increase in peak expiratory flow rate, PEFR, on oral steroids). PEFR, spirometry, lung volumes and airways conductance were recorded before and 1 h after a mixture of nebulised ipratropium 0.5 mg and fenoterol 1.25 mg. Patients then recorded twice-daily PEFR at home while they received nebulised ipratropium plus fenoterol, or saline placebo, four times a day for three week blocks using a double-blind cross over protocol. Mean PEFR on home nebuliser rose from 164 l m-1 (placebo) to 196 l m-1 (ipratropium plus fenoterol), paired t-test P = 0.0001. Correlation coefficients between short-term response for PEFR, spirometry and lung volumes, and improvement in home PEFR on nebulised ipratropium plus fenoterol, were all poor (R = -0.37-0.35, P = 0.83-0.11). We conclude that in severe COAD, reversibility tests of PEFR, spirometry and lung volumes do not correlate with response to a home nebuliser. Home measurements of PEFR are probably the best objective method of assessing response to a home nebuliser in such patients.     

Effect of spironolactone on renal prostaglandin excretion in patients with liver cirrhosis and ascites

The effect of spironolactone on the urinary excretion of prostaglandins was studied in patients with liver cirrhosis and ascites. Patients were kept in bed and given a sodium-restricted diet for at least 4 days before spironolactone treatment was considered. Starting from the 5th day of protocol, patients were treated with this diuretic if their spontaneous weight loss had been less than 600 g during the 2 previous days. Patients were distributed in groups according to weight loss during the first 4 days on diuretic therapy: Group I (high responders), II (medium responders) and III (low responders). Group I patients showed higher basal values (4th day of protocol) of urinary sodium (P less than 0.02) and urinary 6-keto-PGF1 alpha (P less than 0.02) than the other patients, but there were no significant differences in the basal excretion rates of PGE2 nor TXB2 among the groups. The therapeutic requirement for spironolactone treatment in patients from Group I was delayed as compared with the other two groups (P less than 0.001) due to the fact that their spontaneous weight loss took place over a long period. For all patients, spironolactone administration produced a significant increase in 6-keto-PGF1 alpha excretion (P less than 0.01) without affecting significantly urinary elimination of PGE2 nor TXB2. A close relationship was found between the spironolactone-induced increments in urinary sodium and urinary 6-keto-PGF1 alpha excretion (r = 0.74, P less than 0.001). It is suggested that the ability of the kidney to synthetize prostacyclin can influence the natriuretic response to spironolactone therapy in patients with liver cirrhosis.     

Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir

Zanamivir is a potent and specific inhibitor of influenza A and B virus neuraminidase, that is now approved for the treatment, and is currently under development for the prophylaxis of influenza. To assess the safety of this drug in asthmatics, 13 subjects with mild/moderate asthma [forced expiratory volume in 1 sec (FEV1)> or =70% predicted, reversibility of FEV1 to salbutamol > or =15%, concentration of methacholine causing a drop of 20% in the FEV1 (PC20FEV1)< or =8 mg ml(-1)], were recruited to a double-blind, randomized, placebo controlled, two way cross-over study. Subjects received 10 mg zanamivir as a dry powder (2 x 5 mg blisters via a Diskhaler Sovnn Plastics Ltd., Berkshire, U.K.), or a matching placebo, twice daily on day 1 and then four times daily from day 2 to day 14, in two separate periods separated by a washout period of 7 days. PC20FEV1 to methacholine was determined pre-study, on day 1 after the evening dose and on day 14 after the last dose of the study drug. FEV1 was measured pre-study and at regular intervals on days 1 and 14. Laboratory safety tests were performed on days 1, 7 and 15. Morning and evening peak expiratory flow rate (PEFR) and any adverse events were recorded in a diary card. Eleven subjects completed the study. One was withdrawn due to non-compliance, and one due to an adverse event that occurred during the placebo period. On day 1 the geometric mean PC20 for zanamivir was 36% lower than for placebo [ratio to placebo 0.64, (90% CI 0.44, 0.93)] and on day 14 this was 33% lower with zanamivir [ratio to placebo 0.67 (90% CI 0.38, 1.15)]. Both these confidence intervals were within the pre-defined interval of 'no clinically significant effect' of 0.25-4 (i.e. a change of two doubling doses of methacholine PC20FEV1 which was considered clinically significant). The time weighted mean FEV1 was 0.15 l (5.4%) lower for zanamivir on day 1 compared to placebo (90% CI 0.03, 0.28; P=0.050) and 0.01 l higher compared to placebo on day 14 (90%CI -0.12, 0.10; P=0.912). The day 1 changes were not associated with any significant symptoms or requirement for rescue bronchodilator therapy. Furthermore there was no apparent treatment difference over the 14 day dosing period in FEV1 data (90% CI: -0.11, 0.05, P=057). The mean morning PEFR was 4 l min(-1) less for zanamivir than for placebo (90% CI: -11, 3) and mean evening PEFR was 9 l min(-1) less (90% CI: -24, 5). The study treatments were well tolerated by the subjects with no clinically significant adverse events attributable to zanamivir treatment. Zanamivir inhaled as a dry powder does not significantly affect the pulmonary function and airway responsiveness of subjects with mild/moderate asthma and therefore its use in such patients subjects is not precluded.     

THE EFFECT OF AMIODARONE ON THYROXINE KINETICS

Amiodarone was given by daily intraperitoneal injection (10 mg/kg body weight) to a group of 11 New Zealand white rabbits. Over 6 weeks there were significant increases (P less than 0.01) in plasma total T4 concentration (43 +/- 8 to 60 +/- 13 nmol/l; mean +/- 1 SD) and rT3 concentration (0.12 +/- 0.06 to 0.31 +/- 0.16 nmol/l) and a significant fall in total plasma T3 (2.3 +/- 0.3 to 1.7 +/- 0.2 nmol/l). The plasma clearance of T4 in rabbits treated with amiodarone for 6 weeks was significantly reduced relative to controls (64 +/- 25 vs 109 +/- 19 ml/kg per day, P less than 0.01) but the production rate was unchanged (3.8 +/- 1.8 vs 3.7 +/- 1.4 nmol/kg per day). In the amiodarone treated animals the increased plasma T4 concentration was entirely accounted for by the reduced clearance. It is inferred that the normal output of T4 by the thyroid is pituitary dependent and that TSH secretion is sustained in the presence of hyperthyroxinaemia because of amiodarone induced partial inhibition of T4 utilization by the thyrotroph.     

Ambulatory monitoring and exercise testing in the evaluation of a new long-acting calcium ion antagonist KB-944 (Fostedil) for the treatment of exertional angina pectoris

The anti-anginal effects of KB-944 (Fostedil), a new calcium ion antagonist with a half life of approximately 23-28 hr, were evaluated in 20 patients with exertional angina pectoris in a placebo-controlled single-blind dose titration trial. Ambulatory monitoring and multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and after two 2-weekly periods of KB-944 therapy. The mean (+/- SEM) exercise time to the development of angina on treadmill walking increased from 6.9 +/- 0.4 min on placebo to 9.4 +/- 0.5 min on KB-944 100 mg/day (P less than 0.001) and 9.7 +/- 0.8 min on KB-944 200 mg/day (P less than 0.001 vs placebo and not significant vs KB-944 100 mg/day). The time to the development of 1 mm ST-segment depression of 5.3 +/- 0.4 min on placebo increased to 6.5 +/- 0.5 and 6.6 +/- 0.5 min on KB-944 100 and 200 mg/day, respectively (P less than 0.01 vs placebo). The heart rate at rest of 77 +/- 3 beats/min on placebo was reduced to 68 +/- 3 beats/min on KB-944 100 mg/day (P less than 0.001) and 71 +/- 2 beats/min on KB-944 200 mg/day (P less than 0.01). The maximal heart rate and the rate-pressure product were not altered by KB-944 therapy. One patient developed unstable angina during the treatment phase of KB-944 200 mg/day and was withdrawn. Five patients complained of dyspepsia and one of headache and lethargy during KB-944 200 mg/day. One patient developed ventricular tachycardia during treadmill testing while on KB-944 200 mg/day. The 24-hr ambulatory monitoring data confirmed the findings of exercise testing. KB-944 (Fostedil) in a dose of 100 mg once daily was well tolerated as compared to KB-944 200 mg once daily and both the doses were equally effective. The drug merits further evaluation for the treatment of exertional angina pectoris.     

Sodium restriction lowers high blood pressure through a decreased response of the renin system--direct evidence using saralasin

Twenty-nine patients with essential hypertension were studied while on their normal diets, on the 5th day of a high sodium diet (around 350 mmol/day) and on the 5th day of a low sodium diet (10 mmol/day). The fall in mean arterial pressure on changing from the high sodium to the low sodium diet was 9.0 +/- 1.6 mmHg and the rise in the plasma renin activity in the same period was 2.52 +/- 0.41 ng/ml/h, these two variables being significantly correlated (r = -0.45; P less than 0.02). An infusion of saralasin was given on the 5th day of the low sodium diet. A highly significant negative correlation was found between the fall in blood pressure on sodium restriction and the change in blood pressure with saralasin (r = -0.52; P less than 0.005); this correlation was still significant when corrected for the severity of the hypertension (r = -0.41; P = 0.03) while it became non-significant if controlled for plasma renin activity on the low sodium diet (r = -033; NS). These results provide direct evidence that the fall in blood pressure which is seen on reducing sodium intake in many patients with essential hypertension is, at least in part, directly mediated by the reactivity of the renin angiotensin system.     

A comparison of several agents with two delivery systems for the prevention of airway narrowing induced by nebulised pentamidine isethionate

Bronchial narrowing is the major side effect of inhaled nebulised pentamidine isethionate, used for the prophylaxis and treatment of Pneumocystis carinii pneumonia. Several agents and delivery systems were assessed for prophylaxis of bronchial narrowing in HIV-positive males receiving regular nebulised pentamidine isethionate. In a previous study we found the mean maximum fall in FEV1 with nebulised pentamidine alone to be 21%. FEV1 was measured before and after inhaling nebulised pentamidine, preceded by one of the following bronchodilator/immunoregulatory agents: Terbutaline metered dose inhaler (500 micrograms), nebulised salbutamol (5 mg), nebulised ipratropium bromide (500 micrograms), nebulised sodium cromoglycate (20 mg), and nedocromil sodium metered dose inhaler (4 mg). Each agent was administered once only to ten different subjects. Nebulised salbutamol gave most effective prophylaxis against bronchial narrowing induced by nebulised pentamidine (mean maximum fall in FEV1 = 5% vs. 21%, P less than 0.001). Terbutaline given by metered dose inhaler was significantly less effective than high dose terbutaline (10 mg) given by nebuliser, demonstrated in the previous study (mean maximum fall in FEV1 = 14% vs. 6%, P less than 0.05). Mean maximum falls in FEV1 for ipratropium bromide, sodium cromoglycate and nedocromil sodium were 16, 17 and 16%, respectively. High dose beta 2-agonists administered by nebuliser give more effective prophylaxis against nebulised pentamidine-induced bronchial narrowing than either lower doses given by metered dose inhaler, anticholinergics or immunoregulatory drugs.     

Inhibition of the morning cortisol peak abolishes the expected morning decrease in serum osteocalcin in normal males: evidence of a controlling effect of serum cortisol on the circadian rhythm in serum osteocalcin.

Osteocalcin (OC) in serum varies in a remarkably constant circadian rhythm with zenith at night and nadir in the morning. The factors controlling this rhythm are unknown, but several studies indicate that serum cortisol could be of major importance. We tested this hypothesis in a double-blind, placebo-controlled, cross-over study comprising 10 normal male volunteers (aged 23-31 yr) by measuring the response in serum OC and cortisol rhythms to a single dose of metyrapone (30 mg/kg body weight) administered at midnight. During placebo, serum cortisol consistently peaked early in the morning before 0730 h. Ingestion of metyrapone at 2400 h significantly postponed and flattened this peak (P less than 0.01). On both occasions, serum OC increased towards peak levels around 0300 h (P less than 0.01) with no overall differences in the OC profiles. However, when the serum OC time series were synchronized according to the individual cortisol nadirs, we found a significant (P less than 0.01) decrease in serum OC on the placebo day approximately 4 h after the cortisol nadir, whereas no significant changes (P greater than 0.50) were seen on the metyrapone day. Moreover, the mean serum OC level tended to be higher (P less than 0.10 in the interval 0-12 h, and P = 0.06 in the interval 4-8 h) on the metyrapone day compared with the placebo day. On the placebo day, the mean level of serum cortisol during the interval 0-4 h correlated inversely with the mean level of serum OC in the interval 4-8 h (r = 0.77, P less than 0.05). This relation was not found on the metyrapone day. In conclusion, administration of metyrapone, which reduced and postponed the early morning cortisol peak, abolished the normal morning decrease in serum OC. This strongly supports that changes in endogenous serum cortisol are of major importance for the circadian rhythm in serum OC.     

THE EFFECT OF MINOR INCREMENTS IN PLASMA THYROXINE ON HEART RATE AND URINARY SODIUM EXCRETION

We studied day/night (D:N) patterns of urinary sodium excretion and the 24 hour ambulatory electrocardiogram in seven normal subjects before and during the administration of T4. Thyroxine increased thyroid hormone levels within the normal range and inhibited the plasma TSH response to TRH. This was associated with a significant decrease in D:N sodium excretion (P less than 0.01) and D:N urine flow (P less than 0.01), a significant increase in mean nocturnal heart rate (P less than 0.01), and a lesser increment in mean daytime heart rate (P less than 0.05). These responses to small changes in thyroid hormone levels suggest that the anterior pituitary is not alone in recognising minor thyroid hormone excess. The clinical implication is that some patients with a normal T3 and T4 but an impaired TSH response to TRH might benefit from antithyroid treatment.     

Divergent effects of antiprogesterone, RU 486, on progesterone, relaxin, and prolactin secretion in pregnant and hysterectomized pigs with aging corpora lutea

Porcine corpora lutea produce progesterone and relaxin during pregnancy and after hysterectomy. Peak amounts of relaxin are released into peripheral blood in both pregnant and hysterectomized animals on about day 113 (estrus = day 0 and term = 114), and this release coincides with an abrupt decrease in the progesterone concentration. RU 486, a progesterone receptor antagonist, was used to investigate the effects of interruption of progesterone binding to its receptor on luteal function and gonadotropin secretion of pigs with aging corpora lutea. RU 486 was administered orally to hysterectomized gilts (surgery on day 8) once a day (0800 h) on days 111-115 at two dosages (group 1, 2 mg/kg BW; group 2, 4 mg/kg BW). During 5 days of RU 486 treatment, plasma progesterone concentrations in both treated groups were markedly elevated (32 and 37 ng/ml for groups 1 and 2) compared with 22 ng/ml in the controls (group 3; P less than 0.01). PRL concentrations increased in both groups (9 and 13 ng/ml) and differed significantly from those of the controls (3 ng/ml) (P less than 0.04). RU 486 treatment delayed the time of relaxin peak to days 116.1 and 117.0 in groups 1 and 2 compared with day 114.1 in the controls (P less than 0.01). Pregnant gilts received RU 486 orally once a day (0800 h) at 4 mg/kg BW beginning on day 111 until parturition occurred. Parturition was induced on day 112.7 after only two RU 486 treatments compared with day 114.7 in the control group (P less than 0.01). Progesterone decreased abruptly from a pretreatment mean of 11 to less than 0.6 ng/ml during the 2 days that RU 486 was given compared with a shift from 12 to 6 ng/ml during the same period in the controls (P less than 0.01). The time of the relaxin peak was advanced to day 112.1 in RU 486-treated gilts compared with day 113.9 in the controls (P less than 0.01). Results from this study provide strong evidence that the antagonistic effect of RU 486 on progesterone receptor results in an abrupt increase in PRL and progesterone secretion in hysterectomized gilts with aging corpora lutea. In marked contrast with hysterectomized animals, the acute luteolytic effects of RU 486 depend on the presence of the uterus and/or conceptuses in the pig. Disruption of the regulatory loop of progesterone secretion by RU 486 alters the ability of corpora lutea to produce and release peak quantities of relaxin.     

The effect of prolonged submaximal warm-up exercise on exercise-induced asthma

The effect of a prolonged warm-up period of exercise on subjects with exercise-induced asthma (EIA) has been studied. Seven asthmatic subjects with known EIA were exercised according to two different protocols on two separate days, which were randomized. On Day A, subjects performed a standard 6-min treadmill run (S1A), which increased heart rate to 98% predicted maximum, followed 45 min later by an identical run (S2A). Refractoriness was demonstrated on the second exercise test, with a mean maximal fall in FEV1 of 29 +/- 3.1% and a PEFR of 32 +/- 2.8% after S2A, compared with a mean maximal fall in FEV1 of 46 +/- 2.6% and a PEFR of 51 +/- 4.0% after S1A. On Day B, subjects performed a 30-min treadmill run at a lower gradient (W1B), followed 21 min later by another standard 6-min treadmill test (S2B). W1B was followed by significantly less EIA (mean maximal fall in FEV1 of 17 +/- 5.4% and a PEFR of 21 +/- 6.3%) than followed S1A. Nevertheless, when subjects subsequently performed a standard 6-min run (S2B), significant refractoriness to bronchoconstriction, comparable to that observed after S2A, developed, with a mean maximal fall in FEV1 of 26 +/- 3.6% and a PEFR of 27 +/- 2.3% (p less than 0.05). We conclude that a warm-up period of exercise can induce refractoriness to EIA without itself inducing marked bronchoconstriction.