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A sensitive monoclonal antibody, 3G10, derived from a mouse immunized with an immunogen of salbutamol hapten conjugated to keyhole limpet hemocyanin was developed against β-agonists, with a view to establishing a rapid gold nanoparticle immunochromatographic strip. The antibody displayed a 50% inhibitory concentration (IC50) of 1.04 ng/mL for salbutamol and simultaneously detected nine other β-agonists (clenbuterol, cimatero, brombuterol, mabuterol, terbutaline, clenpenterol, carbuterol, mapenterol, pirbuterol) with uniform cross-reactivity. The immunochromatographic strip had cut-off values of 5 ng/mL for salbutamol and clenbuterol, 20 ng/mL for cimaterol, brombuterol and mabuterol, and 50 ng/mL for terbutaline, clenpenterol, carbuterol, mapenterol and pirbuterol. The collective advantages of the newly developed strip, such as high affinity, sensitivity and rapidity, support its utility in detecting β-agonists from actual biological samples, such as urine.

In the search for new effective positive inotropic agents for the treatment of congestive heart failure (CHF), interest has focused mainly on two groups of agents namely adrenoceptor agonists and drugs inhibiting phosphodiesterase. Common for drugs belonging to both groups is that their positive inotropic effects seem to involve an increase in the intracellular concentration of cyclic AMP. Drugs acting by stimulation of beta 1- and/or beta 2-adrenoceptors (e.g. dopamine, dobutamine, prenalterol, pirbuterol, salbutamol, terbutaline, fenoterol) have initial beneficial effects, but seem to be ineffective for long-term treatment. This has been suggested to be due to desensitization of the beta-adrenoceptors, and means, if this effect can be definitely established, that beta-adrenoceptor stimulation should be restricted to the acute treatment of CHF. Among drugs inhibiting phosphodiesterase, sulmazole, amrinone, milrinone, and fenoximone all have been shown to improve cardiac performance in patients with CHF during short-term treatment. However, results of long-term treatment with most of these drugs seem less encouraging. It has been suggested that these drugs may not be an effective approach to treatment of patients with CHF, since even if it is possible to achieve short-term gains, the long-term effects on the myocardium may be detrimental. Their ultimate place in the treatment of CHF remains to be established.

Summary Objective : To address the utility of the forced oscillation technique (FOT) in assessing bronchodilator responsiveness compared with forced expiratory volume in 1s (FEV 1 ). Methods : This is a retrospective analysis of consecutive 126 patients with a clinical history of asthma without any other lung diseases at a pulmonary function testing laboratory. The following measurements were obtained three times each, before and after two doses of pirbuterol 0.2mg inhalation: the respiratory resistance at 5Hz ( R rs5), the mean respiratory resistance between 5 and 20Hz ( R rs5–20), and the mean respiratory conductance (Grs5–20) by FOT and the FEV 1 by spirometer. These measurements were transformed into dimensionless subject-specific effect-size " d -scores" by dividing them by the estimated pooled within-subject standard deviation. Results : Descriptive statistics for each value were the following [mean baseline value (±sd), Δ value (pre- minus post value), and d -score ( P value compared to FEV 1 )]: Grs5–20 (Ls −1 kPa −1 ) [1.79±0.53, Δ =+0.39, d =2.64 ( P R rs5–20 (kPaL −1 s) [0.60±0.16L, Δ =−0.10, d =2.56 ( P =0.001)], R rs5 (kPaL −1 s) [0.78±0.25, Δ =−0.16, d =2.52 ( P 1 (L) [1.90±0.64, Δ =−0.20, d =1.83]. The higher d -score of Grs5–20, R rs5–20 and R rs5 compared to FEV 1 indicates that these are better indicators for bronchodilator response than FEV 1 . The percentages of subjects exhibiting change in the expected direction after bronchodilator were not significantly different between each value: R rs5 (85.7%), R rs5–20 (83.3%), Grs5–20 (83.3%), and FEV 1 (83.3%) [ P >0.05]. Conclusions : Several forced oscillation measures, namely Grs5–20, R rs5–20 and R rs5, are more accurate and sensitive for detecting bronchodilator response than FEV 1 in patients with asthma.

In six COPD-affected horses, we analysed the factors responsible for the changes in pleural pressure (delta Pplmax) that occur during tidal breathing. Four-hundred-and-sixty-eight measurements of each parameter: pulmonary resistance (RL), dynamic elastance (Edyn), air flow rates, and the timing of breathing, were gathered during a trial of the bronchodilator pirbuterol. Data were placed into seven ranks, based on the magnitude of delta Pplmax; rank 1: 5-15; rank 2: 15-25; rank 3: 25-35; rank 4: 35-45; rank 5: 45-55; rank 6: 55-65; and rank 7 > 65 cm H2O. Up to rank 4 (45 cm H2O), the increase in delta Pplmax was due to increases in RL, Edyn, and inspiratory and expiratory air flow rates. Further increases in delta Pplmax were due to continuing increases in Edyn and flow rates with little change in resistance. The increase in inspiratory flow rates was the result of a decrease in inspiratory time. The large increase in peak expiratory flow could not be explained by the small decrease in expiratory time and must therefore be due to a change in breathing strategy as delta Pplmax increased. Changes in air flow rates as well as changes in RL and Edyn must be considered as reasons for a change in delta Pplmax when evaluating horses with COPD.

This paper reviews the impact of the use of technologically dissimilar beta-agonist aerosols--the Maxair Autohaler (pirbuterol acetate) breath-actuated aerosol and the traditional albuterol press-and-breathe inhaler-on the treatment costs of asthma. If, as clinical evidence would suggest, the breath-actuated aerosol is not only as effective as an albuterol inhaler with a spacer, but is easier to use and results in more optimal beta-agonist use by patients, then one might consider the hypothesis that patients possessing a breath-actuated inhaler would, ceteris paribus, experience lower asthma-related treatment costs-principally, those medical costs associated with fewer emergency room visits and hospitalizations. This hypothesis is considered from the perspective of a retrospective claims database study of patients who used one or the other beta-agonist inhaler exclusively. At the descriptive level, costs of treatment for patients using the press-and-breathe inhaler are estimated to be 16.5% greater than costs for patients using the breath-actuated inhaler. In the multivariate analysis, the presence of the breath-actuated inhaler (in a dummy variable analysis) was not only statistically significant (P0.05), but entered with the expected negative sign. Estimated cost impacts under various model specifications are consistent with the magnitude of the cost differences reported in the descriptive analysis. Total cost savings with the Maxair Autohaler ranged from 8.7% to 11.7%, with medical cost savings estimated at 14.6%.

See related article page 22 haps someday, but certainly not yet. Rather, we must consider the implications of this new knowledge for clinical care on a more empirical basis. Population studies identify increased risk from continuous scheduled use of β2-receptor agonists but don’t identify those individuals most at risk.3,4 The studies of β2-adrenoreceptor polymorphisms reviewed by Binaei et. al.2 suggest that it is a sub-population who may be most at risk because of down-regulation of the β2adrenoreceptor when there is repeated use of β2adrenoreceptor agonists. Despite the common practice of prescribing regularly scheduled use of shorter-acting β2-adrenoreceptor agonists such as albuterol, there is no therapeutic rationale for such continuous use. These agents are primarily indicated for as-needed use to relieve acute symptoms. The current standard of care further mandates that frequent use of a bronchodilator for relief of acute symptoms indicates the need for anti-inflammatory therapy. A short course of an oral corticosteroid is the agent of choice for an acute exacerbation associated with subresponsiveness to a β2-agonist, and an inhaled corticosteroid is the agent of choice for persistent symptoms of asthma.5 While the inhaled corticosteroids alone are often sufficient to control the daily symptoms of chronic asthma, not all patients are adequately controlled on conventional low doses, and higher doses are associated with progressive risk of small but measurable systemic effects that can include growth suppression in addition to suppression of the hypothalamic-pituitary axis in children.6 Data have demonstrated that the addition of Adrenoreceptor agonists have long been the agents of choice for relieving acute symptoms of asthma since the first report of epinephrine use for acute asthma in 1900. Considerable pharmacologic research has subsequently gone into the development of variations of these receptor agonists. The extraction of ephedrine from the ancient Chinese herb Ma Huang provided an oral alternative to epinephrine.1 The progressive alteration of the molecule to isoproterenol (isoprenaline), isoetharine, albuterol (salbutamol), metaproterenol (orciprenaline), terbutaline, bitolterol, and pirbuterol eventually permitted more specific targeting of the β2-adrenoreceptor and also longer duration of action than epinephrine. More recently, even longer acting β2adrenoreceptor agonists, salmeterol and formoterol, have been introduced, not for acute intervention but as maintenance therapy for chronic asthma. The manuscript by Binaei and colleagues2 in the issue of the Journal elegantly describes the current growing literature that relates polymorphisms in the β2-adrenoreceptor to both asthma severity and variability in the response to these pharmacological agents that have played such a major role in treating asthma over the years. Are we entering a brave new world where pharmacologic agents are chosen following pharmacogenetic analysis of the individual patient? Per

Background Although both beta-adrenergic agonists and anticholinergic agents are widely used in the treatment of patients with COPD, they influence the pulmonary circulation and ventilation differently. We compared the effects of these two agents on gas exchange and distribution of ventilation in COPD. Methods Pirbuterol and ipratropium bromide were administered by inhalation via a metered-dose inhaler to 12 and 14 patients with COPD, respectively, in a randomized, double-blind fashion. Pulmonary function tests, arterial blood gas levels, heart rate, resting minute ventilation (V¨ E ), physiologic dead space volume to total ventilation ratio (VD/Vt) and oxygen consumption (V¨o 2 ) were measured prior to and then 5, 15, 30, and 60 min after administration of the respective drugs. The changes in these measurements after administration of the two drugs were analyzed and compared with each other. Results The pulmonary function test measurements showed similar improvement after administration of both drugs. Heart rate fell in both groups. After administration of pirbuterol, the alveolar-arterial oxygen pressure difference (P[A-a]O 2 ) and V¨ E rose significantly and the rise in FEV 1 showed a negative correlation with the fall in PaO 2 . In contrast, the use of ipratropium bromide did not produce these effects, but resulted in a fall in V¨o 2 and a rise in VD/Vt . Conclusion Pirbuterol and ipratropium are equally effective bronchodilators in COPD. Pirbuterol results in a significant rise in P(A-a)O 2 and resting V¨ I . Ipratropium does not affect these measurements and seems to reduce the oxygen cost of breathing. The results suggest significant differences between the effects of the two agents on gas exchange, ventilation, and V¨o 2 which could be of clinical significance.

In a double-blind trial the effects on ventilatory function (FEV1), heart rate and blood pressure of oral pirbuterol and oral salbutamol in various single doses were studied in ten patients with chronic asthma. Pirbuterol (15 mg) and salbutamol (4 mg) produced equal peak levels of bronchodilatation. There was no significant difference in the mean rise in heart rates caused by the two drugs, and no other significant side-effects were noted.

Proper coordination of inhalation and MDI canister activation is an important determinant of availability of medication to airways and subsequent clinical response. We compared coordination of terbutaline and pirbuterol MDIs by evaluating clinical effects, deposition in a model of the human upper airway, rate of aerosol settling in a tank, and particle size distribution. The maximum clinical effects and least deposition in the upper airway occurred when both MDIs were activated at onset of inhalation. When MDIs were activated before inhalation, pirbuterol was less affected than terbutaline. Pirbuterol MDI aerosol is slightly smaller than terbutaline MDI aerosol. The results of this study strongly suggest that both clinical and airway model differences noted were due, at least in part, to smaller size of pirbuterol aerosol.

Study objective: Patients with acute asthma often have difficulty using a conventional metered-dose inhaler. The Maxair Autohaler (3M Pharmaceuticals; St. Paul, MN) is a hand-held breath-actuated device developed to help patients coordinate drug administration. The study objective is to compare the efficacy of the Autohaler with inhaled β-agonist administered by wet nebulizer in treating acute asthma exacerbations. Design: Parallel, randomized, placebo-controlled clinical trial. Setting: Emergency department (ED) of a university-affiliated hospital. Participants: Patients aged 18 to 55 years presenting to the ED with acute asthma and an FEV 1 40 to 70% on hospital arrival. Interventions and measurements: Patients were given either six puffs of the Maxair Autohaler (1,200 μg pirbuterol) plus saline solution by nebulizer (active Autohaler group) or six puffs placebo by Autohaler plus 2,500 μg albuterol via nebulizer (active nebulizer group). Treatment was repeated at 30 and 60 min, with clinical evaluation performed before each treatment and again at 120 min. At 120 min, the protocol was completed. Results: Twenty-four patients were enrolled, with 5 excluded because of protocol violations. Baseline FEV 1 percent predicted values for the active Autohaler group were 53% vs 51% for the active nebulizer group (p=not significant [NS]). At time 120 min, values were 66% for Autohaler and 64% for nebulizer (p=NS). The average time to administer Autohaler was 2.9 min, vs 9.1 min for nebulizer. No patient was excluded because of the inability to use the Autohaler device adequately. Conclusion: In patients with moderate asthma exacerbations, similar improvements in pulmonary function are obtained when β-agonists are given by either the Maxair Autohaler or a wet nebulizer device. (CHEST 1998; 114:766–770) Abbreviations: ED=emergency department; MDI = metered-dose inhaler

Background We considered that β 2 -adrenergic stimulation may dilate resistance coronary vessels by opening ATP-sensitive potassium (K ATP ) channels, thereby triggering NO formation. Methods and Results In conscious instrumented dogs after β 1 -adrenergic blockade, intracoronary (IC) injections of acetylcholine (ACh), nitroglycerin (NTG), and pirbuterol (PIR), a selective β 2 -adrenergic agonist, were performed before and after blockade of NO formation with IC N ω -nitro- l -arginine methyl ester (L-NAME, 50 μg·kg −1 ·min −1 ×12 minutes) or blockade of K ATP channels with IC glibenclamide (25 μg·kg −1 ·min −1 ×12 minutes followed by 2 μg·kg −1 ·min −1 ). PIR (50.0 ng/kg) increased coronary blood flow (CBF) by 32±6 from 43±7 mL/min and by only 11±2 ( P P ATP channels, caused dose-dependent increases in CBF that were partially inhibited by L-NAME. In experiments in which CBF was controlled, the fall in distal coronary pressure caused by PIR was less after L-NAME or glibenclamide than before. Conclusions β 2 -Adrenergic dilation of resistance coronary vessels involves both the opening of K ATP channels and NO formation. L-NAME antagonized lemakalim responses consistent with a link between the opening of K ATP channels and NO formation in canine resistance coronary vessels.

Aerosol administration of bronchodilators to horses is recommended for treatment of certain airway diseases such as 'heaves'. We have developed a novel, hand-held, metered-dose inhaler and we sought to determine the bronchodilator efficacy of the beta 2 adrenoceptor agonist pirbuterol delivered by this device to horses affected with 'heaves'. To induce airway obstruction, 6 heaves-susceptible horses were stabled, bedded on straw and fed hay. When the maximum change in pleural pressure during tidal breathing (delta Pplmax) was greater than 20 cmH2O on 2 consecutive days, pulmonary function was measured before and 5, 10 and 30 min, as well as 1, 2, 3, 4, 5, 6 and 7 h after administration of aerosol pirbuterol. Pirbuterol was administered using a metered canister and the hand-held delivery device that was inserted into the left nostril. Either vehicle or pirbuterol acetate (400, 600, 800, 1200 or 1600 micrograms) was administered to each horse. Relief of airway obstruction indicated by changes in pulmonary function was observed within 5 min after administration of both vehicle and pirbuterol. Significant decreases in delta Pplmax and pulmonary resistance (RL) and an increase in dynamic compliance (Cdyn) persisted for the 7 h duration of the experiment. Comparison of the effect of vehicle and pirbuterol at each time period showed that pirbuterol decreased RL and delta Pplmax significantly for up to 1 h. The optimal dose was determined to be 600 micrograms. Immediate response to treatment, magnitude of drug effect and lack of side effects indicated that aerosol pirbuterol is an effective and safe bronchodilator in horses with 'heaves'. The hand-held, metered-dose aerosol delivery device was very convenient and extremely effective and is, therefore, recommended for delivery of therapeutic aerosols to horses.

Evaluation of the role of adrenergic agents as bronchodilators started at the beginning of the century. In 1900, Solis-Cohen discovered a bronchodilator substance derived from the adrenal glands, later identified as epinephrine (adrenaline) [SolisCohen 1900]. A Chinese compound, ephedrine, was then introduced in 1924 for asthma treatment. In 1948, Ahlquist described (Xand ~-adreno­ receptors, and a ~-selective agent, isoprenaline (isoproterenol), was synthetised (Ahlquist 1948). Following the description of subclasses of ~­ receptors, ~I and ~2 (Lands et al. 1967), a new category of agents with ~2-adrenoreceptor specificity was developed, including salbutamol (albuterol), terbutaline, fenoterol, rimiterol and pirbuterol. They provided more prolonged bronchodilator effects, lasting over 4 to 6 hours, with no or minimal cardiac stimulation. They were followed by other agents such as procaterol and bitolterol, which are similar to salbutamol in the magnitude and duration of the bronchodilatation provided (Petty et al. 1988). More recently, ~2-agonists with a prolonged duration of action were synthesised, such as bambuterol, salmeterol and formoterol (Johnson 1991a; LOfdahl 1990). Nonselective ~-adrenoceptor agents are no longer recommended in the treatment of asthma, but even the selective short-acting ~2-agonists have been recently reported to induce untoward effects during regular use, leading to close scrutiny of ~2-selective agents with long (> 12 hour) durations of action (Kuitert 1992; LOfdahl & Svedmyr 1991; Nelson et al. 1991; Page & Costello 1992; Skorodin 1993; Spitzer et al. 1992). In this review, the pharmacological properties, clinical efficacy and adverse effects of these 2 categories of ~2agonists are compared and discussed, to better define their therapeutic usefulness in treating asthma. The properties of ~2-agonists are summarised in table 1.

Pirbuterol is a selective beta-2 adrenergic agonist that is indicated for the treatment of bronchospasm in patients with asthma. Traditionally, the most common form of administration of the beta-2 agonist is by inhalation from a pressurized metered-dose inhaler. The purpose of this study was to compare the bronchodilator efficacy and safety of two inhalations (400 micrograms) of pirbuterol delivered by a breath-actuated aerosol (BAA) with that of two inhalations of a matching placebo. Patients were studied on each of two study days with a baseline electrocardiogram and sequential pulmonary function testing for 6 hr. Fourteen patients completed the study. The mean age was 32 years, with a range of 21-56 years. Most of these individuals had had asthma for more than 5 years. The mean percent increase in FEV1 was 41.2% for pirbuterol compared to 25.4% for placebo (p = 0.0038). The duration of improvement of > 15% over baseline was 4.5 hr for the pirbuterol group compared to 1.8 hr for the placebo group (p = 0.0022). There was no difference between the groups with respect to onset of action or time to reach peak effect. There was no significant difference between treatments with respect to any cardiovascular parameter. We conclude that pirbuterol in the BAA device produced significantly more bronchodilatation than did placebo with respect to its peak effect, duration of effect, and percentage change from baseline. Therefore, we feel that pirbuterol administered through the BAA device is a safe, effective means of treating both acute and chronic asthma.

Background: Despite widespread acceptance of metered-dose inhalers (MDIs) in the treatment of asthma, many patients fail to operate these devices correctly. Inability to properly coordinate activation with onset of inhalation is regarded as the major factor in suboptimal MDI therapy. Methods: We evaluated Autohaler Inhalation Device (3M Pharmaceuticals, St. Paul, Minn.), a breath-activated MDI that is typically activated at a triggering flow rate of approximately 0.5 L/sec. We compared bronchodilator effect of pirbuterol acetate (Maxair), inhaled from Autohaler and a standard MDI, under conditions that ensured optimal technique in 20 patients with asthma. Spirometric variables (forced expiratory volume in 1 second [FEV 1 ], forced expiratory flow between 25% and 75% of vital capacity [FEF 25–75 ], forced vital capacity [FVC]) were measured before and at 15, 30, 60, and 90 minutes after two inhalations of full inspiratory reserve volume for each device. Results: Both devices produced significant and similar bronchodilation. Mean FEV, increased 32% above baseline 60 minutes after use of Autohaler and 31 % after use of a standard MD1. Similar changes were noted in FEF 25–75 and FVC for the two devices. Differences between devices for all spirometric variables were not statistically significant. Conclusion: Autohaler provides a promising alternative to the standard MD1 by overcoming breath-hand discoordination.

A survey of four inhaled beta-agonist agents was evaluated as a means of selecting the optimum agent for chronic therapy in patients with stable COPD. Eighteen patients completed as protocol of prebronchodilator and postbronchodilator spirometry utilizing albuterol, metaproterenol, pirbuterol, and terbutaline daily in random order. Subsequently, each patient received treatment with either the greatest or least response-invoking agent for four weeks, followed by a second interval with the opposite agent. At the end of each interval, the results of repeat spirometry, arterial blood gas determinations, 12-min walks, dyspnea questionnaires, and self-monitored peak expiratory flow rates were recorded. Use of the greatest response-invoking agent resulted in significantly larger prebronchodilator and postbronchodilator FEV, and FVC. No other study factor was significantly different. Acute bronchodilator surveys may have a role in medication selection in view of the improvement in spirometric volumes.

The dose of aerosol pirbuterol that could be administered safely to ponies (weight approximately 200 kg) was determined by observation for sweating, trembling and excitement and measurement of heart and respiratory rates during cumulative administration of the drug. Sweating, trembling and excitement were first observed following a dose of 2,400 micrograms and became more severe at 3,200 micrograms. These effects were accompanied by an increase in heart rate but not a change in respiratory rate. When 3200 micrograms was administered without prior administration of lower doses, side effects were trivial. This dose was therefore tested for its bronchodilator activity. Pulmonary function was evaluated in ponies that developed airway obstruction ('heaves') when housed in a barn and fed hay. Measurements were made when ponies were in clinical remission (Period A) and during an acute attack of airway obstruction (Period B). At Period A, pirbuterol had no effect on pulmonary function. Barn housing increased pulmonary resistance and decreased dynamic compliance. At Measurement Period B, pirbuterol administration significantly reduced pulmonary resistance and increased dynamic compliance and minute ventilation. These changes were significant 5 min after drug administration and lasted for the 30 min duration of the study. Vehicle administration had no effect on pulmonary function. It was concluded that aerosol pirbuterol has few undesirable side effects and is an effective bronchodilator in ponies with recurrent airway obstruction.

The IOP-lowering effect of pirbuterol, a beta-2 adrenergic agonist, was studied in rabbits. In normotensive rabbits, pirbuterol 0.5% eye drops reduced IOP by 20-25%. In ocular hypertensive rabbits (by glucose 5% venous infusion), pirbuterol reduced IOP by 20% (0.1% concentration) to 40% (0.5% and 1% concentration). A slight decrease in the effect was noticed after seven days of treatment.

Heart failure is a syndrome with distinct clinical signs and symptoms. The severity of cardiac failure and a deterioration in functional capacity can be determined by a progressive exercise test and by the noninvasive determination of maximum oxygen uptake. In patients with severe cardiac failure refractory to medica therapy, particularly those with cardiomyopathy or ischemic heart disease, survival is seriously compromised, resembling the most serious malignancy. Cardiotonic agents may be useful in improving the quality of life, provided that they are effective and are given sufficiently early in the course of the disease. Dobutamine given intravenously augments cardiac performance and improves renal function in patients with very advanced disease refractory to multiple diuretics; long-term survival, however, remains dismal. Amrinone appears to be a promising agent for the long-term treatment of chronic cardiac failure; the utility of pirbuterol, an oral catecholamine analog, remains to be determined.

We compared the initial and long-term effects of the beta-adrenergic agonist pirbuterol in 12 patients with chronic congestive heart failure. The drug's initial effect was a 35 per cent increase in cardiac index, but there was no significant change in heart rate or mean arterial pressure. After one month of therapy, the mean cardiac index and ejection fraction had returned to base-line values, and no clinical effect was evident in most patients. This apparent tolerance was not accompanied by changes in heart rate, blood pressure, or body weight, and it occurred in the presence of therapeutic drug levels during long-term therapy. The density of beta-adrenergic receptors on lymphocytes from patients treated with pirbuterol was significantly depressed as compared with that of patients with heart failure of comparable severity but not treated with pirbuterol. We conclude that tolerance to the hemodynamic and clinical effects of pirbuterol develops during long-term administration; this tolerance may be related to a decrease in myocardial or vascular beta-adrenergic receptors or both.

We studied a new synthetic "selective" beta 2 catecholamine, pirbuterol (PBL), in eight conscious, chronically instrumented dogs. PBL was administered as 10-minute intravenous infusions of 0.125, 0.5, 2, 4, and 8 μg/kg/min. At 2 μg/kg/min, changes from control (all significant at p 2 and beta 1 effects, and compared with isoproterenol at doses that give equivalent increases in myocardial contractility, PBL produced less increase in an index of myocardial oxygen consumption in three of the four dogs studied. On the basis of these data PBL may be useful for treating low CO syndromes without provoking myocardial ischemia.

A selected ion monitoring assay has been developed to measure plasma levels of the bronchodilator pirbuterol in animals and man. Pirbuterol is extracted from plasma with acetone + potassium carbonate and after further purification is converted to its trimethylacetyl derivative. With the use of the stable isotope labeled internal standard, pirbuterol-d9, precisions of 10% and 6% were achieved at plasma concentrations of 1 and 20 ng ml-1, respectively. The synthesis of the deuterium labeled internal standard is described.

Pirbuterol and salbutamol capsules were compared in a multi-centre, double-blind, crossover study. Pirbuterol 10 mg four times daily and salbutamol 4 mg four times daily produced a similar increase in peak expiratory flow rate, matched by the patients' subjective appreciation of decreased beathlessness. Both drugs produced the same incidence of tremor.

A mild exchange labeling procedure utilizing O-deuterated or O-tritiated t-butanol with sodium catalysis afforded isotope exchange in the α-hydrogen position of the amide N-t-butyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridyl)-2-hydroxy-acetamide, thereby extending the utility of this approach with ketones to poor enolizers that are base labile. Complete label retention accompanied the subsequent steps of reduction and debenzylation to 2-hydroxymethyl-3-hydroxy-6(l-hydroxy-2-t-butylaminoethyl)-pyridine dihydrochloride (pirbuterol hydrochloride)-2H or -3H, in 15-18% overall yield at the 4 mmole level. Deuterium incorporation was estimated to be 39%; a specific activity of 206 μc/mg was achieved by radiolabeling. A radiochemical and chemical purity of > 99.5% was established. Tritium label stability was demonstrated in aqueous media at acidic, neutral and basic pH.

The effects of beta-adrenoceptor down-regulation on rat left atrial responses to the full agonist isoproterenol and the partial agonists prenalterol and pirbuterol were studied. Atria from rats implanted with a mini-osmotic-pump subcutaneously delivering isoproterenol at 400 micrograms X kg-1 X h-1 for 4 days were 12-16 times less sensitive to isoproterenol than normal atria. Scatchard analyses indicated that the implantation of these mini-osmotic-pumps produced a 50% decrease in the number of beta-adrenoceptors in the ventricles with no alteration in the binding constant of [3H]dihydroalprenolol. Receptor down-regulation produced a parallel shift to the right of concentration-response curves to isoproterenol, and a complete suppression of responses to both partial agonists. The affinities of the partial agonists for the receptors were not altered; in desensitized atria the partial agonists were functional beta-antagonists blocking the responses to isoproterenol. The data are modeled by equations from classical receptor theory which predict the depression of responses to partial agonists with receptor down-regulation. These results are discussed with respect to the utility of prenalterol and pirbuterol in congestive heart failure since possible tachyphylaxis to these drugs with chronic usage could limit their value.

Two proposed methods are reported for the quantitation of pirbuterol hydrochloride, namely, (i) colorimetric and (ii) titrimetric methods. The colorimetric method is based on coupling betweem diazotized sulphanilamide and pirbuterol hydrochloride. Under the optimum conditions studied, the coupling product exhibits a maximum at 440 nm. Linear relation between absorbance, A, and concentration of pirbuterol hydrochloride is in the range 5–40 μgml−1. The mean percentage obtained for capsules (ExirelR −15 mg) was 100.8 ± 0.7 whereas mean percentage recovery obtained for the authentic drug was 100.5 ± 0.8. The titrimetric procedure involves bromination of authentic pirbuterol in acid medium and residual titration of excess bromine. The stoichiometry of the reaction was investigated and infra-red analysis, of the bromoderivative was carried out. When applied to capsules the bromometric method gave mean percentage of 100.18 ± 2.25.

Pirbuterol hydrochloride, an orally effective beta-adrenergic agonist, improves hemodynamic abnormalities in patients with congestive heart failure, but its effects on myocardial oxygen consumption (MVO2) and coronary blood flow have not been characterized. We studied the effects of 20-30 mg of oral pirbuterol on myocardial metabolic and hemodynamic parameters in 12 patients (six with coronary artery disease) with chronic CHF refractory to standard medical therapy. Pirbuterol induced an increase in cardiac index (1.7 +/- 0.1 to 2.3 +/- 0.2 l/min/m2, p less than 0.05) and a fall in systemic vascular resistance (1884 +/- 118 to 1391 +/- 69 dyn-sec-cm-5, p less than 0.01) 2 hours after administration. Pulmonary capillary wedge pressure fell from arterial and right atrial pressures did not change. Heart rate remained constant. Arterial-coronary sinus oxygen content difference narrowed (from 12.9 +/- 0.4 to 11.1 +/- 0.3 vol%, p less than 0.05), while no significant change occurred in MVO2. Myocardial oxygen extraction ratio and myocardial lactate extraction ratio did not change, and no patient developed angina or electrocardiographic evidence of myocardial ischemia. Patients with coronary artery disease had hemodynamic and myocardial metabolic responses similar to those without coronary artery disease. Pirbuterol effects substantial acute hemodynamic improvement in patients with chronic congestive heart failure without increasing requirements for coronary blood flow or myocardial oxygen delivery and without provoking myocardial ischemia.

The metabolic, hormonal and haemodynamic effects of oral pirbuterol, a new beta 2-adrenoceptor agonist, were studied acutely (n = 19) and after 3 months treatment (n = 11) in patients with severe heart failure receiving chronic frusemide therapy. In the acute study fasted patients (n = 10) showed reductions in plasma K+ (P less than 0.005) and cortisol (P less than 0.01) and increases in plasma glucose (P less than 0.005), insulin (P less than 0.01), lactate (P less than 0.005) and pyruvate (P less than 0.0025). These acute changes were less in unfasted subjects (n = 9). Maximal increase in stroke volume occurred at approximately half the plasma pirbuterol concentration required for maximal effect on plasma insulin. Treatment with pirbuterol for 3 months was associated with sustained increases in stroke volume and fasting plasma glucose and insulin, but there was loss of all other acute metabolic effects. Despite concurrent frusemide and digoxin therapy acute hypokalaemia caused no adverse effects. Hypokalaemia did not occur with chronic pirbuterol administration.

We examined, in conscious dogs, the effects of beta-adrenergic stimulation on measurements of left circumflex coronary arterial diameter and blood flow and on calculations of late diastolic coronary resistance (LDCR) and left circumflex coronary internal cross-sectional area (CSA). Isoproterenol (0.1 microgram/kg) initially decreased mean arterial pressure by 25 +/- 2% (mean +/- SEM), and LDCR by 62 +/- 4%, and increased heart rate by 82 +/- 10%, left ventricular (LV) dP/dt by 79 +/- 12%, and mean coronary blood flow by 85 +/- 5%, while CSA rose slightly. The peak effects on CSA (24 +/- 2%) occurred later, along with decreases in mean arterial pressure (7.4 +/- 1.0%) and LDCR (25 +/-5.3%) and increases in coronary blood flow (14 +/- 2%), LV dP/dt (12 +/- 3%), and heart rate (24 +/- 4%). Pirbuterol (1.0 microgram/kg) induced changes that were qualitatively similar to those induced by isoproterenol. Prenalterol (20 micrograms/kg), a cardioselective beta 1-adrenergic receptor agonist, did not affect mean arterial pressure, but increased heart rate by 40 +/- 5%, LV dP/dt by 72 +/- 10%, mean coronary blood flow by 34 +/- 11%, and CSA by 26 +/- 3%, and decreased LDCR by 29 +/- 5+. Isoproterenol and pirbuterol, but not prenalterol, increased coronary sinus O2 content and decreased A-VO2 difference. After beta 1-adrenergic receptor blockade with atenolol (1 mg/kg), prenalterol no longer induced significant effects, whereas isoproterenol and pirbuterol decreased mean arterial pressure similarly to what was observed prior to blockade, but did not increase LV dP/dt, and induced attenuated increases in mean coronary blood flow, CSA, and decreases in LDCR. Thus, in the intact, conscious animal, large coronary arteries are regulated by beta-adrenergic mechanisms. Surprisingly, a major fraction of large coronary arterial dilation appeared to be either directly or indirectly due to beta 1-adrenergic receptor mechanisms, although beta 2-adrenergic effects were also significant.

Pirbuterol hydrochloride has been assayed in alkaline medium by using a fluorometric method to measure fluorescence intensity at 372 nm with excitation at 310 nm and by the ▵A method at 242 nm.The linearity ranges are 0.5-4 μg/mL and 10-50 μg/mL, respectively. An authentic pirbuterol HC1 sample was analyzed by nonaqueous potentiometric titration using 0.1N perchloric acid, and the results were compared with those for fluorometric and AA methods. The mean percent recoveries for the authentic sample were 98.72 ± 1.13 and 99.24 ± 0.85, respectively. When applied to commercial capsules containing 10 mg and 15 mg each, the fluorometric method gave mean percent recoveries of 101.11 ± 1.05 and 98.12 ± 0.93; the ▵A method gave mean percent recoveries of 100.57 ± 0.83 and 97.80 ± 0.75, respectively.