Presence of lateral eye lens crystallins in the median eye of the american chameleon.

With the use of immunofluorescence techniques, gamma globulin antibody specific for the crystallins of Anolis carolinensis lateral eye lens was applied to sections through the median (parapineal) eye of Anolis carolinensis. Only the median eye lens exhibited fluorescence specific for the crystallins; other structures were negative. These results indicate that the lens of the reptilean median eye shares tissue-specific antigenic determinants with the lens of the lateral eye. This suggests a possible evolutionary relation between the two structures, based on biochemical, as well as previously reported anatomical, criteria.

Exploiting genomics to discover new antibiotics.

There is an urgent need to develop new classes of antibiotics to tackle the increase in resistance in many common bacterial pathogens. One strategy to develop new antibiotics is to identify and exploit new molecular targets and this strategy is being driven by the wealth of new genome sequence information now available. Additionally, new technologies have been developed to validate new antibacterial targets, for example, new technologies have been developed to enable rapid determination of whether a gene is essential and to assess the transcription status of a putative target during infection. As a result, many novel validated targets have now been identified and for some, appropriate high-throughput screens against diverse compound collections have been carried out. Novel antibiotic leads are emerging from these genomics-derived targeted screens and the challenge now is to optimize and develop these leads to become part of the next generation of antibiotics.

Simultaneous measurement of cardiac output and its distribution with microspheres in the rat.

The radioactive microsphere method was used to estimate simultaneoulsy the cardiac output and its distribution in the same rat by the use of an arterial reference sample obtained during microsphere distribution. Sufficient microspheres were injected so that all counted samples contained more than 400 spheres. No haemodynamic changes occurred during microsphere injection. The results for cardiac output of 253 +/- 11 ml/min per kg body weight agree with published estimates utilizing other techniques. The distribution of cardiac output also agrees with most published reports. This method should allow the rat to be conveniently used for certain haemodynamic studies when cardiac output and organ blood flow are necessary.

Reflex vagal withdrawal and the hemodynamic response to intravenous isoproterenol in the presence of beta-antagonists.

To investigate the contribution of reflex vagal tone to the hemodynamic response after intravenous isoproterenol, 12 healthy subjects received isoproterenol by both bolus injection and continuous infusion before and after atropine, and during intravenous infusion of the beta 1-selective antagonist atenolol and the nonselective beta-antagonist, propranolol. With bolus injections, atropine displaced the heart rate dose-response curve for atenolol to the right, implying reflex withdrawal of cardiac vagal tone, but did not alter the heart rate dose-response curve for propranolol. With continuous infusions of isoproterenol, atropine displaced the heart rate dose-response curves for both atenolol and propranolol to the left, implying the presence of a reflex increase rather than withdrawal in cardiac vagal tone. These reflex changes in cardiac vagal tone can be partly understood by changes in mean arterial pressure and pulse pressure. As the two methods of isoproterenol administration are associated with contrasting contributions from reflex vagal tone, dose ratios obtained for the displacement of the heart rate dose-response curve by beta-antagonists may differ.

Plasma concentrations and the time-course of beta blockade due to propranolol.

The effectiveness of intravenously administered propranolol in antagonizing the chronotropic effect of isoproterenol and exercise has been investigated, and has been found at all times to be a predictable function of its plasma concentrations according to the classical drug-receptor theory for competitive antagonism. The data show further that the relationship between effectiveness and time depends on the way in which antagonism is measured. If the dose ratio to isoproterenol (DR) is measured, then (DR-1) declines with time in parallel with drug concentration. On the other hand, if propranolol's effects are measured as percentage reduction in a given response, then this declines linearly with time, even though plasma concentrations decline exponentially. This fact explains why confusion has in the past arisen concerning the relationship of the duration of beta blockade and pharmacokinetic half-life.

Central effects of beta-adrenoceptor antagonists.

The central effects of atenolol, a cardioselective beta-adrenoceptor antagonist, were investigated in six healthy men. Two flash-fusion threshold (2FFT), simple reaction time (SRT), digital copying (DCT), symbol-digit modalities (SDMT), and Gibson's spiral maze tests (GSMT) and mood rating scales for tension, alertness, depression, detachment, and anxiety were used. Each subject took 50, 100, 200, and 400 mg atenolol and identical placebo orally in a randomized, double-blind, crossover study and the psychomotor tests were performed at 0, 2, 3, 5, and 8 hr. 2FFT was prolonged at 3 hr after all doses and at 2 and 5 hr with 100, 200, and 400 mg. The maximum effect was achieved with 200 mg and mean 2FFT correlated with mean plasma atenolol concentration. SRTs were prolonged after all doses at between 2 and 5 hr. The DCT and the retest gain of the SDMT were both lower than after placebo at 2 hr with 100, 200, and 400 mg. The time taken to perform the GSMT was not altered by active drug, but the number of errors was lower at 2 hr with 100 and 200 mg. The self-rating mood scales showed a subjective decrease in tension 2 hr after 400 mg. The results show that atenolol exerts central effects in man.

Erythrocyte cation transport and age: effects of digoxin and furosemide.

The uptake of rubidium 86 (86Rb) by human erythrocytes was measured at various ages. Effects of digoxin and furosemide on this process were examined and, in the case of digoxin, related to its numbers of specific cellular binding sites. There were no significant effects of age on absolute cellular Rb uptake, digoxin-sensitive Rb uptake, or numbers of cellular binding sites for digoxin, but the ability of digoxin to inhibit digoxin-sensitive 86Rb uptake increased with age. The ability of furosemide to inhibit digoxin-insensitive 86Rb uptake did not change with age. Results suggest a dynamic contribution to altered sensitivity to digoxin in elderly persons.

Effects of thyroid dysfunction on propranolol kinetics.

Propranolol kinetics was studied in six hyperthyroid and six hypothyroid patients who received single oral and intravenous doses of propranolol when they had thyroid dysfunction and again when they had become euthyroid. Change in thyroid status from hyperthyroid to euthyroid produced no change in the elimination half-life (t 1/2) of oral propranolol (3.2 +/- 0.5 to 4.1 +/- 0.7 hr), the oral clearance (38.4 +/- 7.3 to 27.4 +/- 2.4 ml/min/kg), the elimination t 1/2 of intravenous propranolol (2.5 +/- 0.3 to 3.5 +/- 0.7 hr), and the apparent volume of distribution (4.8 +/- 0.4 to 3.8 +/- 0.5 l/kg). The systemic clearance of propranolol, however, was greater when the patients were hyperthyroid (20.8 +/- 2.5 ml/min/kg) than when they had become euthyroid (11.7 +/- 1.7 ml/min/kg). The elimination t 1/2 after oral propranolol was longer in the hypothyroid (3.7 +/- 0.5 hr) than in the euthyroid state (2.0 +/- 0.1 hr). No other changes were observed in the kinetic parameters measured when these hypothyroid patients had become euthyroid. Adequate beta-adrenoceptor blockade in hyperthyroid patients may require higher propranolol dosage than expected.

Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade.

Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.

Plasma binding and the affinity of propranolol for a beta receptor in man.

The effects of plasma drug binding on the relationship between propranolol concentration and the antagonism of isoproterenol tachycardia have been investigated in 8 normal subjects and 8 hypertensive patients. During chronic intravenous infusion of propranolol giving a narrow range of total plasma concentrations (22.5 to 50 ng/ml), there was, at best, a poor correlation with effects. On the other hand, there was excellent correlation between efficacy and free drug concentration, which fitted the predictions of the receptor theory of competitive antagonism. The true affinity constant for the binding of propranolol to its receptor can be calculated in terms of free drug concentration (KAfree) and was found to vary 2-fold compared to the affinity constant in terms of total plasma concentration (KAtotal) which varied 4-fold, the greater variation being due to plasma binding differences. Compared to normal subjects, KAfree and KAtotal were smaller in hypertensive subjects, implying lesser sensitivity to the drug, and plasma propranolol binding was greater. There was no difference in KAfree between high- and low-renin essential hypertensives, but KAtotal was smaller in the high-renin group due to increased plasma binding which did not reach statistical significance. It is concluded that the effect of propranolol on heart rate is a predictable function of free drug concentration in man and that the contribution of individual variation in receptor sensitivity to differences in oral dosage requirement is minor compared to that of variations in bioavailability.

Clinical pharmacologic observations on atenolol, a beta-adrenoceptor blocker.

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of a series of single doses of atenolol reduced an exercise tachycardia. After a 200-mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half-life of 6.36 +/- 0.55 hr: 43 +/- 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a significant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recovered from the urine, and the clearance was 97.3 ml/min. Comparison of AUC O leads to chi after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half-life, area under the plasma concentration-time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.

Antiarrhythmic effects of a lidocaine congener, tocainide, 2-amino-2',6'-propionoxylidide, in man.

Eight patients with frequent premature ventricular contractions (PVCs) were given single oral doses of 2-amino-2', 6'-propionoxylidide hydrochloride (APX), a lidocaine congener, to investigate the drug's efficacy, toxicity, and pharmacokinetics. Of the 7 patients receiving more than 100 mg, 5 demonstrated at least 60% reduction in PVCs in the 5-hour period following one of the doses; the responsiveness to APX was similar to that observed when intravenous lidocaine was given to the same patients. There were side effects of transient dizziness, lightheadedness, and nausea in 3 patients 20 to 30 min after doses of 400 to 800 mg; slightly smaller doses in 2 of these patients retained efficacy without side effects. There were no effects on arterial blood pressure, heart rate, or the electrocardiogram of normally conducted beats. Laboratory values remained within normal limits, although the hemoglobin level and hematocrit showed a small but significant fall probably related to repeated blood sampling during the study. Drug plasma levels at 1 and 2 hr after administration and the area under the plasma concentration-time curve were proportional to dose, and the drug disappeared with a mean elimination half-life of 14.7 +/- 1.7 hr (mean +/- SD). Plasma levels resulting in suppression of PVCs ranged from 1 to 5 mug/ml. A mean of 39.7 +/- 12.4% of an orally administered dose was recovered unchanged in 48-hr urine collections. Comparison of the present results with those previously obtained after intravenous administration of APX indicates that oral bioavailability of the drug was essentially complete. APX appears to be a promising orally effective antiarrhythmic drug with suitable pharmacokinetic characteristics to warrant studies designed to establish dosage regimens for chronic therapy.

Regulated gene expression in Staphylococcus aureus for identifying conditional lethal phenotypes and antibiotic mode of action.

Selectively regulating gene expression in bacteria has provided an important tool for studying gene function. However, well-regulated gene control systems have been restricted primarily for use in laboratory non-pathogenic strains of bacteria (e.g. Escherichia coli, Bacillus subtilis). The development of analogous systems for use in bacterial pathogens such as Staphylococcus aureus would significantly enhance our ability to examine the contribution of any given gene product to pathogen growth and viability. In this report, we adapt, examine and compare three regulated gene expression systems in S. aureus, which had previously been used in B. subtilis. We demonstrate that all three systems function and exhibit titratable induction, together covering a dynamic range of gene expression of approximately 3000-fold. This dynamic range correlates well with the physiological expression levels of cellular proteins. Importantly, we show that one of these systems, the Spac system, is particularly useful for examining gene essentiality and creating specific conditional lethal phenotypes. Moreover, we find that titration of selective target gene products using this system allows direct demonstration of antibiotic mode of action.

Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma.

PURPOSE: The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo, given twice daily, in patients with mild to moderate asthma. PATIENTS AND METHODS: Seven asthmatic patients, age 34 +/- 5 years were evaluated. Mean forced expiratory volume in 1 second (FEV1) (% predicted) at entry was 58 +/- 5%. After at least 2 weeks run-in without beta 2-agonist therapy, patients were randomized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks, in a double-blind, crossover design. Dose-response curves (DRC) to eformoterol (cumulative dose 6 micrograms to 126 micrograms) for airways and systemic beta 2-responses were constructed at the end of each treatment period. Responses were measured at baseline, 30 minutes after each dose, and for 6 hours after the last dose. In addition, in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period. RESULTS: There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1: 0.16 L (95% CI -0.04 to 0.36) and forced expiratory flow (FEF25-75): 0.27 L/sec (95% CI -0.08 to 0.62). The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly (P < 0.05) attenuated after chronic therapy with eformoterol compared with placebo. The mean differences between eformoterol and placebo for delta FEV1 were as follows: peak: 0.26 L (95% CI 0.09 to 0.43), and at 6 hours: 0.39 L (95% CI 0.20 to 0.58). Corresponding values for delta FEF25-75 were as follows: peak: 0.41 L/sec (95% CI 0.10 to 0.71), 6 hours 0.52 L/sec (95% CI 0.22 to 0.82). Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo. There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo. CONCLUSIONS: Our results suggest that chronic therapy with eformoterol produces (1) tachyphylaxis to its bronchodilator response, which was greatest at 6 hours after the last dose, (2) tachyphylaxis of extrapulmonary beta 2-mediated responses, and (3) subsensitivity of in vitro beta 2-adrenoceptor function.

Prior treatment with diuretic augments the hypokalemic and electrocardiographic effects of inhaled albuterol.

PURPOSE: High doses of inhaled albuterol produce substantial improvements in bronchodilatation but are associated with dose-related systemic side effects including hypokalemia and hypomagnesemia. Concomitant diuretic therapy also produces these metabolic sequelae and may therefore precipitate cardiac arrhythmias in patients taking this combination of drugs. The purpose of this study was to investigate the electrocardiographic (ECG) effects of high-dose inhaled albuterol, and to evaluate whether potentiation occurs with bendrofluazide. PATIENTS AND METHODS: Ten normal subjects (mean age [+/- SEM]: 29 +/- 2 years, four women, six men) received seven days of treatment with either bendrofluazide 5 mg or identical placebo in a single-blind, randomized, cross-over design, with a 10-day washout period. After each treatment period, responses (potassium, magnesium, ECG) to cumulative doubling doses of inhaled albuterol (100 micrograms to 2,000 micrograms) were measured. RESULTS: Baseline potassium levels (mean and 95% confidence intervals) were lower after pretreatment with bendrofluazide compared with placebo (3.07 mmol/L [2.89 to 3.25 mmol/L] versus 3.78 mmol/L [3.62 to 3.93 mmol/L]; p less than 0.001). The combination of bendrofluazide and albuterol produced a lower absolute level of potassium than did placebo and albuterol: (2.72 mmol/L [2.50 to 2.95 mmol/L] versus 3.18 mmol/L [3.09 to 3.27 mmol/L]; p less than 0.001). Mean (+/- SEM) potassium fell to a lower level with bendrofluazide and albuterol in women than in men (2.45 +/- 0.04 mmol/L versus 2.90 +/- 0.13 mmol/L; p less than 0.005). Albuterol alone produced a small but significant fall in magnesium (0.842 mmol/L [0.815 to 0.869 mmol/L] to 0.789 mmol/L [0.757 to 0.820 mmol/L]; p less than 0.001), but no further change after bendrofluazide. Pretreatment with bendrofluazide increased the frequency (p less than 0.001) and amplitude (p less than 0.05) of U waves due to albuterol. Albuterol also attenuated T-wave amplitude (p less than 0.001) and prolonged the Q-Tc interval (p less than 0.001), with no additive effect from bendrofluazide. ST-segment depression (p less than 0.001) occurred in five subjects who inhaled albuterol. CONCLUSION: These findings show that treatment with bendrofluazide augments the hypokalemic and ECG effects of high-dose inhaled albuterol. The arrhythmogenic potential of this interaction may be important in patients with acute exacerbations of chronic airflow obstruction, who have concomitant hypoxemia and ischemic heart disease.

Pharmacologic aspects of cardioselectivity in a beta-blocking drug.

Beta 2 adrenoceptors have been subdivided into beta 1 and beta 2 receptors, both by the varying response of different tissues to sympathomimetic amines and, more recently, by radioligand-binding techniques. It would appear that beta 1 receptors occur predominantly in the heart, whereas beta 2 receptors are found in lungs, peripheral blood vessels and uterus, and are also involved with glycogenolysis and glucagon and insulin secretion. In addition, the distribution of beta 1 receptors appears to relate to the density of sympathetic innervation of an organ or tissue, but tissues without sympathetic innervation are found to contain beta 2 receptors. Thus, beta 1 adrenoceptors may be considered as physiologically innervated receptors mediating responses to neuronally released norepinephrine, and beta 2 receptors as mediating responses to circulating catecholamines, particularly epinephrine. Radioligand-binding studies have also shown that the heart contains beta 2 receptors and the lung beta 1 receptors, but these are in the minority, and their role has not been identified. For many years, cardioselective beta 1-adrenoceptor antagonists have been available. This was considered to be a dose-dependent phenomenon but recent evidence has cast doubt on the concept that cardioselectivity is lost during dose increases within the therapeutic range. Nevertheless, even small doses of cardioselective drugs may show some beta 2-receptor antagonism, and may have adverse effects on patients with obstructive airways disease. Finally, nonselective drugs may result in a diastolic pressor effect in the presence of circulating catecholamines in contrast to the "vascular sparing" seen with cardioselective drugs.

Further observations on the cardiotoxicity of isoprenaline during hypoxia.

1 In dogs respired with 10% oxygen: 90% nitrogen, only five out of 16 dogs survived repeated intravenous doses of isoprenaline (either 0.5 or 1.0 mug/kg) and only one out of six dogs survived repeated isoprenaline inhalations from a pressurized aerosol.2 In dogs respired with 15% oxygen: 85% nitrogen, five out of six dogs survived repeated intravenous doses of isoprenaline (2.5 mug/kg).3 The fatal response in these animals consisted of a fall in heart rate, arterial and pulse pressures. Sinus rhythm persisted even after the arterial pressure had fallen, though occasionally a slow A-V nodal rhythm or irregular ventricular ectopic beats occurred. Ventricular fibrillation did not occur.4 Eight out of 10 dogs brought to the verge of a fatal response with 10% oxygen: 90% nitrogen and repeated doses of isoprenaline (2.5 mug/kg) were resuscitated by the administration of 100% oxygen and, when necessary, cardiac massage.5 A group of five dogs survived the combined effects of repeated doses of isoprenaline (2.5 mug/kg) and respiration with 10% oxygen: 90% nitrogen when the time interval between doses was 11 min, instead of the usual 5 minutes.6 Control of pH by infusion of sodium bicarbonate did not protect the dogs from the combined effects of hypoxia and repeated isoprenaline challenge.7 After a 60 min period of continuous isoprenaline infusion in dogs breathing room air, only one of 10 dogs survived artificial respiration with 10% oxygen: 90% nitrogen and repeated challenge with intravenous isoprenaline (1.0 mug/kg) at 5 min intervals. At the higher infusion levels of isoprenaline (0.1 and 1.0 mug kg(-1) min(-1)), two dogs out of four died after the hypoxic mixture was started but before any isoprenaline challenge was given.8 The possible relevance of these findings in dogs to the recently observed increase in mortality in young asthmatics is discussed.

Comparison of the effects of I.C.I. 50172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline and exercise.

1. The intravenous infusion of I.C.I. 50172 in doses up to 20 mg reduced, although not significantly, the increase in heart rate produced by the infusion of isoprenaline in healthy volunteers; the response to adrenaline was significantly reduced. The infusion of 1 mg propranolol abolished these responses2. After the pre-treatment of subjects with atropine or hexamethonium, I.C.I. 50172 produced a significant reduction in an isoprenaline tachycardia. This reduction was not competitive and did not exceed 50%.3. The intravenous injection of 4 mg I.C.I. 50172 reduced an exercise tachycardia; its effect was less than that of 4 mg propranolol. This difference became greater as the doses of the two drugs were increased. The dextro isomer of propranolol had no effect on the exercise tachycardia; I.C.I. 45763 reduced it to the same extent as propranolol.4. The intravenous injection of I.C.I. 50172 reduced the increase in heart rate produced by tilting a normal subject from the supine to 80 degrees head-up position. After the administration of atropine, I.C.I. 50172 almost abolished the response. In the presence of atropine, I.C.I. 50172 was as active as propranolol in reducing the increase in heart rate on tilting.5. The reason for the differences in the effects of I.C.I. 50172 on the increases in heart rate brought about by the three procedures is not clear.6. The increase in forearm blood flow produced by the infusion of isoprenaline into the brachial artery was not reduced by the intra-arterial administration of I.C.I. 50172.

The cardio-toxicity of isoprenaline during hypoxia.

1. The effects of the intravenous injection of isoprenaline on heart rate and arterial pressure has been studied in dogs artificially respired with room air or with 12% oxygen-88% nitrogen.2. In dogs breathing room air, isoprenaline in doses from 0.02 to 500 mug/kg increased heart rate and reduced arterial pressure. Ventricular fibrillation was produced in one out of three dogs given 250 mug/kg. This was the only dog breathing room air which was killed by isoprenaline.3. In dogs breathing room air the repeated intravenous injection at 5-min intervals of 2.5 mug/kg increased heart rate and reduced arterial pressure. No ill effects were produced by six doses.4. In dogs respired with 12% oxygen-88% nitrogen the PaO(2) was reduced from 84 to 38 mm Hg with no changes in PaCO(2). In these dogs death was produced by doses of isoprenaline which in dogs breathing room air produced normal responses.5. The fatal dose of isoprenaline (10-50 mug/kg) reduced heart rate and arterial and pulse pressures; sinus rhythm persisted until arterial pressure was less than 50 mm Hg. Ventricular fibrillation did not occur; death occurred from cardiac asystole.6. Death was produced in a similar way in dogs with hypoxaemia by giving four or five doses of isoprenaline (2.5 mug/kg) at 5-min intervals or by two doses of 25 mug/kg.7. The final reduction in arterial pressure during a fatal response resulted from a reduction in cardiac contractility.8. These lethal effects of isoprenaline could be prevented by pretreatment with propranolol.

A cohort study (with re-sampled comparator groups) to measure the association between new NSAID prescribing and upper gastrointestinal hemorrhage and perforation.

This cohort study examined the relationship between newly prescribed NSAIDs (none in the previous six months) and upper gastrointestinal hemorrhage and perforation in Tayside, Scotland. Exposure was classified by prescription duration. The study population consisted of the population of Tayside. A Comparator Group was chosen at random (within age and sex strata). Two hundred re-sampled comparator groups were created. Statistical analyses were carried out by Poisson regression (repeated for each of the re-samples). The analyses controlled for age, sex, prior hospitalization for upper gastrointestinal events, prior endoscopy, and the use of ulcer healing drugs. There were 78,191 subjects in the NSAID group, and 78,207 in each of the comparator groups. The increased risk with NSAIDs was only apparent for subjects without a history of upper gastrointestinal events; univariate rate ratio = 2.76 (1.90, 4.01). The final, re-sampled estimate of NSAID risk was rate ratio = 2.48 (1.87, 3.29).