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(1/1501) Kinetic analysis of drug-receptor interactions of long-acting beta2 sympathomimetics in isolated receptor membranes: evidence against prolonged effects of salmeterol and formoterol on receptor-coupled adenylyl cyclase.

The long-acting beta2 sympathomimetics salmeterol and formoterol have been presumed to exert their prolonged action either by binding to an accessory binding site ("exo-site") near the beta2 adrenoceptor or by their high affinity for beta2 adrenoceptors and correspondingly slow dissociation. Whereas most studies with salmeterol had been done in intact tissues, which have slow diffusion and compartmentation of drugs in lipophilic phases, that restrict drug access to the receptor biophase, we used purified receptor membranes from rat lung and disaggregated calf tracheal myocytes as model systems. Binding experiments were designed to measure the slow dissociation of agonists by means of delayed association of (-)-[125I]iodopindolol. Rat lung membranes were pretreated with high concentrations of agonists (salmeterol, formoterol, isoprenaline) before dissociation was induced by 50-fold dilution. Half-times of association of (-)-[125I]iodopindolol remained unchanged compared with untreated controls, indicating that dissociation of agonists occurred in less than 2 min. Adenylyl cyclase experiments were designed to determine the on and off kinetics of agonists to beta2 adrenoceptors by measuring the rate of receptor-induced cyclic AMP (cAMP) formation. Experiments were performed in tracheal membranes characterized by high Vmax values of cAMP formation. Adenylyl cyclase activation occurred simultaneously with the addition of the agonist, continued linearly with time for 60 min, and ceased immediately after the antagonist was added. Similarly, when receptor membranes were preincubated in a small volume with high salmeterol concentrations, there was a linear increase in cAMP formation, which was immediately interrupted by a 100-fold dilution of the reaction mixture. This militates against the exo-site hypothesis. On the other hand, dissociation by dilution was much less when membranes were preincubated with a large volume of salmeterol at the same concentration, indicating that physicochemical effects, and not exo-site binding, underlie its prolonged mode of action.  (+info)

(2/1501) Reversal of severe pulmonary hypertension with beta blockade in a patient with end stage left ventricular failure.

A 52 year old man with severe chronic left ventricular failure (New York Heart Association class IV) was considered unsuitable for cardiac transplantation because of high and irreversible pulmonary vascular resistance (PVR). In an attempt to produce symptomatic improvement, metoprolol was cautiously introduced, initially at 6.25 mg twice daily. This was slowly increased to 50 mg twice daily over a two month period and continued thereafter. After four months of treatment the patient's symptoms had improved dramatically. His exercise tolerance had increased and diuretic requirements reduced to frusemide 160 mg/day only. Assessment of right heart pressures was repeated and, other than a drop in resting heart rate, there was little change in his pulmonary artery pressure or PVR. His right heart pressures were reassessed showing a pronounced reduction in pulmonary artery pressure and a significant reduction in PVR, which fell further with inhaled oxygen and sublingual nitrates. He was then accepted onto the active waiting list for cardiac transplantation. A possible mechanism of action was investigated by assessing responses to beta agonists during treatment. Not only was there pronounced improvement in PVR but it was also demonstrated that beta receptor subtype cross-regulation may have contributed to the mechanism of benefit.  (+info)

(3/1501) As-required versus regular nebulized salbutamol for the treatment of acute severe asthma.

Current British guidelines for the administration of beta2-agonists in acute severe asthma recommend regular nebulized therapy in hospitalized patients, followed by as-required (p.r.n.) use via hand-held devices after discharge. Since beta2-agonists do not possess anti-inflammatory activity in vivo, and are thus unlikely to influence the rate of recovery from an asthma exacerbation, it was hypothesized that patients given the short-acting beta2-agonist salbutamol on an as-required basis after admission to hospital would recover as quickly as those on regular treatment, but with potential reductions in the total dose delivered. Forty-six patients with acute severe asthma were randomly assigned to either regular prescriptions of nebulized salbutamol or to usage on a p.r.n. basis, from 24 h after hospital admission. The primary outcome measures were length of hospital stay, time to recovery, and frequency of salbutamol nebulization from 24 h after admission to discharge. Secondary outcome measures were treatment side-effects (tremor, palpitations), and patient satisfaction. Length of hospital stay was reduced in those patients allocated to p.r.n. salbutamol (geometric mean (GM) 3.7 days) versus regular salbutamol (GM 4.7 days). Time taken for peak expiratory flow to reach 75% of recent best was the same in both groups. There was a highly significant reduction in the number of times nebulized therapy was delivered to the p.r.n. group (GM 7.0, range 1-30) compared with the regular treatment group (GM 14.0, range 4-57; p=0.003; 95% confidence interval for ratio of GMs 1.29-3.09). In addition, patients reported less tremor (p=0.062) and fewer palpitations (p=0.049) in the p.r.n. group. Of the patients in the p.r.n. group who had received regular nebulized therapy on previous admissions (n=12), all preferred the p.r.n. regimen. Prescribing beta2-agonists on a p.r.n. basis from 24 h after hospital admission is associated with reduced amount of drug delivered, incidence of side-effects, and possibly length of hospital stay. This has implications for the efficient use of healthcare resources.  (+info)

(4/1501) The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects.

Salmeterol is approximately eight times as potent as salbutamol for systemic effects. This may be because the drug is eight times more potent on receptors or there may be differences in systemic bioavailability. The systemic effects of salbutamol are limited by its fairly high first-pass metabolism, but the oral bioavailability of salmeterol is unknown. The contribution of the swallowed fraction of an inhaled dose of salmeterol to its systemic effects were analysed in a randomized, double-blind, crossover study. Twelve healthy subjects were given inhaled salmeterol 400 microg, inhaled salmeterol 400 microg plus oral activated charcoal or inhaled placebo plus oral activated charcoal on three separate days. Cardiac frequency (fC), Q-T interval corrected for heart rate (QTc), plasma potassium and glucose concentrations were measured for 4 h following the inhaled drug. Salmeterol with and without oral charcoal produced significant changes for all measures compared to placebo. The magnitude of effect following salmeterol alone was significantly greater than that following salmeterol plus charcoal for fC and glucose (mean (95% confidence interval) differences 8 (2-13) beats x min(-1), 0.59 (0.04, 1.13) mmol x L(-1), respectively) and nonsignificantly greater for QTc interval and potassium concentration. The differences between salmeterol given with and without charcoal suggest that 28-36% of the systemic response to salmeterol administered from a metered-dose inhaler are due to drug absorbed from the gastrointestinal tract. Thus, most of the systemic effects are due to the inhaled fraction of the drug.  (+info)

(5/1501) beta2-adrenoceptor agonists reduce the decline of rat diaphragm twitch force during severe hypoxia.

The aim of the present study was to investigate the in vitro effects of the short-acting beta2-adrenoceptor agonist salbutamol and the long-acting beta2-adrenoceptor agonist salmeterol on hypoxia-induced rat diaphragm force reduction. In vitro diaphragm twitch force (Pt) and maximal tetanic force (Po) of isolated diaphragm muscle strips were measured for 90 min during hyperoxia (tissue bath PO2 83.8 +/- 0.9 kPa and PCO2 3.9 +/- 0.1 kPa) or severe hypoxia (PO2 7.1 +/- 0.3 kPa and PCO2 3.9 +/- 0.1 kPa) in the presence and absence of 1 microM salbutamol or 1 microM salmeterol. During hyperoxia, salbutamol and salmeterol did not significantly alter the time-related decreases in Pt and Po (to approximately 50% of initial values). Salbutamol had no effects on Po or the Pt-to-Po ratio. Salmeterol treatment significantly reduced Po and increased the Pt-to-Po ratio during hyperoxia (P < 0.05 compared with control value). Hypoxia resulted in a severe decrease in Pt (to approximately 30% of initial value) and Po after 90 min. Both salbutamol and salmeterol significantly reduced the decline in Pt during hypoxia (P < 0.05). The reduction in Po was not prevented. Salbutamol increased Pt rapidly but transiently. Salmeterol had a delayed onset of effect and a longer duration of action. Addition of 1 microM propranolol (a nonselective beta-adrenoceptor antagonist) did not alter Pt, Po, or the Pt-to-Po ratio during hypoxia but completely blocked the inotropic effects of salbutamol and salmeterol, indicating that these effects are dependent on beta2-adrenoceptor agonist-related processes.  (+info)

(6/1501) Incorporating quality of life data into managed care formulary decisions: a case study with salmeterol.

Pharmacy and Therapeutics committees of managed care organizations have traditionally developed formularies by limiting the numbers and kinds of pharmaceuticals they purchase, with the goal of cutting costs. These attempts to manage pharmaceutical costs do not take into account the interrelationship of the costs of various components of care; thus, drug costs may decrease, but expenditures for utilization of other resources may increase. Cost-minimization and basic cost-effectiveness studies, on which many prior- authorization and formulary programs are based, only evaluate only the cost of the drug and its effectiveness. However, with the heightened competition in the healthcare market, emphasis is increasingly being laid on patient satisfaction and outcomes. Cost-utility analysis is a potentially superior pharmacoeconomic tool because it evaluate the effect of drug therapy on quality of life; however, data from such analyses are seldom readily available to the committees that evaluate a drug's potential effects on the entire healthcare system. The purpose of this review is to stress the importance of approaching formulary management from a wider perspective and to emphasize that the results of cost-utility studies should be proactively evaluated and incorporated into decisions regarding formularies. This is especially important for symptom-intensive diseases, such as asthma, in which the quality of life can be notably impaired. Cost-utility analyses should be conducted for all newer therapies, such as salmeterol, which are highly effective and which have a positive impact on quality of life, to determine the overall effect on the managed care plan's budget.  (+info)

(7/1501) Evaluation of the effect on heart rate variability of a beta2-adrenoceptor agonist and antagonist using non-linear scatterplot and sequence methods.

AIMS: To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac beta2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). METHODS: Under double-blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (beta2-adrenoceptor partial agonist), ICI 118,551 (specific beta2-adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates. RESULTS: Salbutamol reduced the long-term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time-domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], [mean difference [95% confidence intervals of difference]]). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*10(3) ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR-1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive deltaRR and deltaRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo -1890 [-2600, -1179]; the beat-to beat difference (deltaRRn+1) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination. CONCLUSIONS: Agonism at the cardiac beta2-adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re-balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the beta2-adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The beta2-adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the beta2-adrenoceptor in cardiovascular disease states warrants further investigation.  (+info)

(8/1501) Determination of salbutamol and detection of other beta-agonists in human postmortem whole blood and urine by GC-MS-SIM.

This paper details a sensitive and quantitative method for the determination of salbutamol and the detection of terbutaline, clenbuterol, fenoterol, and isoprenaline in postmortem human whole blood and urine. It describes solid-phase extraction using a XtrackT XRDAH515 column, formation of trimethylsilyl derivatives, and analysis by gas chromatography-mass spectrometry-selective ion monitoring.  (+info)