Β-blocking Agents Research Articles

β-Blocker Therapy in Veterans with Asthma or Chronic Obstructive Pulmonary Disease

To determine whether an association exists between health care resource use and beta-blocker therapy in patients with asthma or chronic obstructive pulmonary disease (COPD), and to determine whether any significant differences exist between type of beta-blocker agent administered and resource use. Retrospective cohort study. Three Veterans Administration (VA) databases with information from hospitals and clinics in Iowa and Nebraska. Patients. A total of 8390 veterans with a diagnosis of asthma or COPD receiving treatment with a beta-blocker or another cardiovascular agent. Clinic visits and hospital admissions for asthma or COPD that occurred in 2000-2001 were identified using electronic administrative data files. Analyses were adjusted for comorbidity and patient demographics. Mean patient age was 67 years, and 97% of the patients were men. In unadjusted analyses, patients taking beta-blockers had more hospital admissions, similar inpatient length of stay (LOS), and fewer outpatient clinic visits for asthma or COPD. In adjusted analyses, however, no difference was noted in the odds of hospital admission or in LOS, and patients had fewer clinic visits related to asthma or COPD. The hazard ratio for hospital admission for asthma or COPD during the observation year was similar for patients taking and not taking beta-blockers, and no difference was noted with selective versus nonselective beta-blockers. However, the hospital admission rate was lower with atenolol than metoprolol. Patients taking beta-blockers did not have more hospital admissions or clinic visits for their asthma or COPD than patients not taking these agents. When clinically indicated, beta-blockers-especially atenolol-should be considered for patients with asthma or COPD.

Prevention of Left Ventricular Remodeling With Granulocyte Colony-Stimulating Factor After Acute Myocardial Infarction

Experimental and clinical evidence has recently shown that pluripotent stem cells can be mobilized by granulocyte colony-stimulating factor (G-CSF) and may enhance myocardial regeneration early after primary percutaneous coronary intervention (PCI) management of acute myocardial infarction. Sustained or long-term effects of mobilized CD34-positive mononuclear stem cells, however, are unknown. Thirty consecutive patients with ST-elevation myocardial infarction undergoing primary PCI with stenting and abciximab were selected for the study 85+/-30 minutes after PCI; 15 patients were randomly assigned to receive subcutaneous G-CSF at 10 microg/kg body weight for 6 days in addition to standard care including aspirin, clopidogrel, an angiotensin-converting enzyme inhibitor, beta-blocking agents, and statins. In patients with comparable demographics and clinical and infarct-related characteristics, G-CSF stimulation led to sustained mobilization of CD34 positive mononuclear cells (MNC(CD34+)), with a 20-fold increase (from 3+/-2 at baseline to 66+/-54 MNC(CD34+)/microL on day 6; P<0.001); there was no evidence of leukocytoclastic effects, accelerated restenosis rate, or any late adverse events. Within 4 months, G-CSF-induced MNC(CD34+) mobilization led to enhanced resting wall thickening in the infarct zone of 1.16+/-0.29 mm (P<0.05 versus control), which was sustained at 1.20+/-0.28 after 12 months (P<0.001 versus control). Similarly, left ventricular ejection fraction improved from 48+/-4% at baseline to 54+/-8% at 4 months (P<0.005 versus control) and 56+/-9% at 12 months (P<0.003 versus control and paralleled by sustained improvement of wall-motion score index from 1.70+/-0.22 to 1.42+/-0.26 and 1.33+/-0.21 at 4 and 12 months, respectively), after G-CSF (P<0.05 versus baseline and P<0.03 versus controls). Accordingly, left ventricular end-diastolic diameter showed no remodeling and stable left ventricular dimensions after G-CSF stimulation, whereas left ventricular end-diastolic diameter in controls revealed enlargement from 55+/-4 mm at baseline to 58+/-4 mm (P<0.05 versus baseline) at 12 months after infarction and no improvement in diastolic function. Mobilization of MNC(CD34+) by G-CSF after primary PCI may offer a pragmatic strategy for improvement in ventricular function and prevention of left ventricular remodeling 1 year after acute myocardial infarction.

The effect and safety of carvedilol on the patients with chronic congestive heart failure

目的 观察β受体阻滞剂卡维地洛治疗慢性心力衰竭的临床疗效.方法采用随机和多中心研究方法,将60例心力衰竭患者随机平均分为两组,两组均给予心力衰竭常规治疗,A组加用卡维地洛.6个月随访其好转率,并比较治疗前后左室收缩内径(LVDs)、左室舒张内径(LVD)、左室射血分数(LVEF)变化.结果6个月后A组好转率(治愈率+好转率)为88%,B组好转率82.7%.两组LVDs、LVD、LVEF较治疗前均有显著改善(P＜0.05).结论卡维地洛在心力衰竭标准用药基础上治疗慢性心力衰竭是有效及安全的,可显著改善左室重塑。

Data feedback and clinical process improvement in acute myocardial infarction

Numerous reports have shown substantial undertreatment of acute myocardial infarction (AMI). The goal of this intervention study was to improve both the acute and discharge care of patients with AMI. Thirty-eight Tenet hospitals participated in a cardiac improvement collaborative called the Partnership for Change. Interventions included the implementation of a computerized concurrent data feedback system and the organization, staffing, and deployment of performance improvement teams at each hospital. Data were collected on 11 394 patients with AMI between January 1, 2001, and June 30, 2002. We calculated rates of treatments including aspirin (first 24 hours and at discharge), beta-blocking agent (first 24 hours and at discharge), reperfusion using thrombolysis (first 30 minutes) or percutaneous intervention (first 2 hours), angiotensin-converting enzyme inhibitor (at discharge), smoking cessation counseling (during hospital stay), and referral to a cardiac rehabilitation program (at discharge). Statistically significant increases were seen for all indicators. Aspirin use during the first 24 hours increased from 86.4% to 96.5% and use at discharge increased from 70.0% to 87.4%. The use of beta-blocking agents during the first 24 hours increased from 51.4% to 88.4% and use at discharge increased from 62.4% to 83.5%. Reperfusion during the first 2 hours increased from 25.9% to 35.3%. Discharge use of angiotensin-converting enzyme inhibitors increased from 29.3% to 43.3%. Smoking cessation counseling increased from 35.1% to 80.6%. Referral to a cardiac rehabilitation program increased from 16.9% to 41.7%. All P values were <.001. The implementation of a rapid-cycle computerized concurrent data feedback system along with on-site process improvement teams was associated with a substantial increase in the use of both acute and discharge treatments for AMI.

Hydrophilic interaction liquid chromatographic tandem mass spectrometric determination of atenolol in human plasma

A hydrophilic interaction liquid chromatographic method with tandem mass spectrometry for the determination of atenolol, a beta-blocking agent, in human plasma has been developed and validated over the curve range of 10--2000 ng/mL. The assay was based on protein precipitation followed by evaporation of the extraction solvent, reconstitution with acetonitrile, and chromatography on an Hypersil silica column (50 x 4.6 mm) using a low aqueous--high organic mobile phase. The mobile phase consists of 85% acetonitrile, 15% water, 0.5% acetic acid and 0.04% trifluoroacetic acid and runs isocratically at a flow rate of 2.0 mL/min. The column ef fluent was split so that 50% of it was transferred into the LC-MS/MS interface operated in positive electrospray ionization mode. The chromatographic run time was 2.0 min per injection. Atenolol and the internal standard, atenolol-d(7), showed a retention time of 1.0 min. The inter-day and intra-day precision and accuracy of the quality control samples were <5.3% relative standard deviation and <8.0% relative error, respectively. To explore the application of the current method for the analysis of other beta-blocking agents, propranolol and metoprolol were tested under the same chromatographic conditions with retention times of 0.68 and 0.75 min, respectively. The present method could be used for therapeutic drug monitoring, pharmacokinetic and drug--drug interaction studies of beta-blocking agents.

臨床における薬学の展開―１５年の軌跡―

In this review, we outline the new developments in pharmaceutical practice, education and research achieved by the Department of Pharmacy of the University of Tokyo Hospital in the 15 years from 1990 to 2004.In pharmaceutical practice, we created 1) a computer-aided total dispensing system linked to a system for the efficient examination of prescriptions, a parallel dispensing system for countable and uncountable drugs incorporating several automatic dispensing support devices, and a drug usage consultation system for outpatients using Drug Information Sheets, Drug Information Cards and leaflets, and 2) a total dispensing system for injectable drugs including those for intravenous hyperalimentation (IVH) for inpatients and home parenteral nutrition (HPN).In the area of new dosage forms, we developed several original non-commercial, high level medications designed to improve the QOL of patients, such as buprenorphine sublingual tablets and suppositories and retinoic acid aqueous gel ointment. We also started providing consultation to patients in wards and support for raising the quality of medical treatment, and created a drug information system for medical staff and patients. Other achievements were the development of a therapeutic drug monitoring system (TDM) for organ transplantation and a total clinical research trial management system based on new GCP.In the area of education, we created a pharmaceutical education program for bed-side training (BST) for undergraduate students of the Faculty of Medicine and a training program on pharmaceutical practice for undergraduate students of the Faculty of Pharmaceutical Sciences. We also developed a practical training program for newly graduated trainee pharmacists and a continuing education program for post-graduate pharmacists.In the area of clinical research, we review the following four major projects : 1) Drug interactions between the new quinolone antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs), 2) PK/PD analysis of QT prolongation induced by drugs for non-cardiovascular diseases, 3) Quantitative evaluation of pharmacological effects and adverse effects of β-blocking agents based on the receptor occupancy theory, and 4) Clinical research on genotyping of drug metabolizing enzymes for the purpose of creating tailor-made treatments.

Heart Rate Reduction: A Potential Target for the Treatment of Myocardial Ischaemia

Because most of myocardial perfusion takes place during diastole, reducing the heart rate is likely to have anti-ischaemic effects. The present paper reviews the role of heart rate in relation to coronary artery disease outcome, as well as ways to reduce heart rate in the clinical setting. Nonpharmacological intervention, and particularly exercise training, has a definite effect on both heart rate reduction and the prevention of myocardial ischaemia. The protective role of β-blockers after acute myocardial infarction is amply documented; their anti-ischaemic efficacy appears to be attributable to their effect on heart rate, but also to their role in cardiac inotropism. Recently, the If (funny) current inhibitor ivabradine, which has a potent heart rate reduction effect without any haemodynamic effect has demonstrated anti-ischaemic efficacy in a randomised trial versus placebo, as well as in trials where it showed an effect similar to that of the conventional anti-ischaemic agents amlodipine and atenolol. In addition, such an agent, which does not influence myocardial contractility, might be particularly valuable in the setting of myocardial stunning or acute left ventricular failure at the acute stage of myocardial infarction. However, only future studies will determine whether isolated heart rate reduction will have the same protective efficacy as that of β-blocking agents in secondary prevention after myocardial infarction.

Nonselective β-blocking agent improves the outcome of cardiopulmonary resuscitation in a rat model

Postresuscitation myocardial dysfunction has been recognized as a leading cause of early death after initial successful resuscitation. Recent experimental and clinical studies have indicated that the beta-adrenergic effect of epinephrine significantly increases the severity of postresuscitation myocardial dysfunction. The fact that beta-adrenergic stimulation increases myocardial oxygen consumption during ventricular fibrillation is an important implication with respect to both the exogenous in terms of pharmacologic interventions during cardiopulmonary resuscitation and the endogenous as the result of intense sympathetic activation of cardiovascular collapse. Earlier experimental evidence has indicated that oxygenation improved by beta-blockade and beta1-blocking agent did offset the adverse effect of epinephrine. This prompted us to investigate the effect of beta-blockade on both exogenous and endogenous beta stimulation in an established rat model. Prospective, randomized, controlled study. Animal research laboratory. Male Sprague-Dawley rats. In this series of studies, propranolol was administrated before ventricular fibrillation as a pretreatment combined with epinephrine treatment during precordial compression and then alone in a prolonged cardiac arrest setting. Improved postresuscitation myocardial dysfunction (cardiac index, dP/dt40, -dP/dt) was observed with propranolol, a nonselective beta-adrenergic blocker, in pretreated animals such that the beneficial effects were associated with better postresuscitation survival. Nonselective beta-blockade improved the outcome of cardiopulmonary resuscitation in a rat model and deserves further evaluation in settings of cardiopulmonary resuscitation.

Long-term oral carvedilol in chronic heart failure

The long-term β-blockade strategy with carvedilol, metoprolol succinate or bisoprolol is now strongly recommended to reduce the rates of mortality and morbidity in patients with chronic heart failure (CHF). Although the benefits observed with such drugs are viewed as a class effect, theoretically, carvedilol might be superior to the other two agents, considering its unique pharmacological profile, which includes a more comprehensive antiadrenergic activity and potentially relevant ancillary properties. So far, carvedilol has been proven to be effective and safe in a broader range of CHF patients than metoprolol and bisoprolol. Moreover, a recent large clinical trial has shown a significantly greater survival benefit with carvedilol as directly compared with metoprolol tartrate. Therefore, carvedilol may be the preferred β-blocking agent to treat patients with CHF.

Molecular Design and Development of Potassium Channel Blockers

AbstractFor Abstract see ChemInform Abstract in Full Text.

Commentary on the Carvedilol or Metoprolol European Trial (COMET)

β-Adrenergic blockade is commonly and successfully used to treat chronic heart failure. Until recently, few data were available on which to base selection of a particular β-blocking agent. The Carvedilol or Metoprolol European Trial (COMET) provides evidence that β-blockers are not interchangeable. The trial compared carvedilol, a nonselective β-blocker with α-adrenergic blocking and numerous ancillary activities, with metoprolol tartrate. In comparison to metoprolol tartrate, significant reductions in all-cause mortality and cardiovascular mortality were observed with carvedilol. These data indicate that cardiovascular benefit may be obtained from switching patients from metoprolol tartrate to carvedilol.

Molecular Design and Development of Potassium Channel Blockers

During the past decade, much attention has been directed toward the development of potassium channel blockers, which were expected to be a novel type of antiarrhythmic agent. Pharmacological screening for new cardiovascular agents led us to discover the potassium channel blocking activity of MS-3579 which we originally prepared as a β-blocking agent. Since MS-3579 lacks potency as a class III agent and its (aryloxy) propanolamine moiety was thought to be the typical β-blocking pharmacophore, we decided to manipulate this moiety to diminish β-blocking activity and potentiate class III activity. In this paper we introduce the development of Nifekalant Hydrochloride, which selectively modulates potassium channel and homogeneously prolongs the transmembrane action potential duration (APD) and consequently, refractoriness, without slowing intercardiac condition, and can terminate reentry. Nifekalant Hydrochloride was approved and launched as the first class III antiarrhythmic agent, developed in Japan.

Cardioprotection by Carvedilol: Antiapoptosis is Independent of β-Adrenoceptor Blockage in the Rat Heart

Carvedilol, a beta-blocking agent with beta-blocking properties is now widely used for the treatment of congestive heart failure. In addition to its beta-adrenergic receptor blockage, antiapoptotic effects have been demonstrated in experimental animals. The cardioprotective effects of carvedilol and its hydroxylated analogue BM-91.0228 were tested with regard to their infarct-limiting and antiapoptotic properties in an experimental infarct model in the rat heart. Anesthetized rats were subjected to either 30 (groups 1 to 3) or 60 minutes (groups 4 to 6) of coronary artery occlusion followed by 30 minutes of reperfusion. Groups 1 and 4 served as the control; groups 2 and 5 received intravenous Carvedilol (1 mg/kg) and groups 3 and 6 received intravenous administration of BM-91.0228 (1 mg/kg), respectively, 5 minutes prior to coronary occlusion. Infarct sizes were measured by triphenyltetrazolium chloride staining. In situ visualization of apoptosis was measured by nick end labeling. Carvedilol reduced infarct size after 30 minutes of coronary occlusion compared to controls (8.7% +/- 2.7% versus 27.3% +/- 3.4%, P <.001), while BM-91.0228 showed no significant infarct size reduction (23.7% +/- 5.9%, NS). Neither Carvedilol (36.9% +/- 3.9%) nor BM-91.0228 (42.4% +/- 3.6%) reduced infarct size after 60 minutes of coronary occlusion compared to controls (47.7% +/- 3.9%, NS). Carvedilol reduced apoptosis after 30 minutes (4.9% +/- 1.3% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (11.7% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. BM-91.0228 reduced apoptosis after 30 minutes (7.3% +/- 1.4% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (13.4% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. Carvedilol is cardioprotective by preventing ischemia-perfusion-induced necrosis and apoptosis of cardiomyocytes. The antiapoptotic effects of Carvedilol are independent of its beta-adrenoceptor blocking effects, but its effects might be caused by antioxidant properties and by modulation of the signalling pathway.

A New Method Using Pulmonary Gas-Exchange Kinetics To Evaluate Efficacy of β-Blocking Agents in Patients With Dilated Cardiomyopathy

The effects of beta-blocking agents on exercise tolerance in cardiopulmonary exercise testing (CPX) have not been fully identified. Because the negative chronotropic effects of these agents produce a sluggish increase in heart rate (HR) during CPX, exercise capacity is actually underestimated by methods that depend on HR-related variables such as peak oxygen uptake (O(2)) and anaerobic threshold (AT). The aim of this study was to clarify the efficacy of beta-blocking agents by means of O(2) kinetics, a parameter independent of HR, in patients with dilated cardiomyopathy (DCM). The exercise capacity of 12 patients (9 men and 3 women; mean +/- SD age, 54 +/- 12 years; New York Heart Association class I [n = 1], NYHA class 2 [n = 4], and NYHA class III [n = 6]) with DCM, who were treated with beta-blocking agents, was evaluated by CPX. O(2) was calculated from respiratory gas analysis on a breath-by-breath basis. Nine patients were treated with metoprolol (30 mg or 60 mg), two with carteolol (10 mg or 20 mg), and one patient with atenolol (25 mg). All patients showed a significantly favorable results (ie, improvement in symptoms of congestive heart failure). Peak O(2) (20.4 +/- 5.1 to 18.8 +/- 5.8 mL/min/kg), AT (12.7 +/- 3.5 to 12.1 +/- 2.1 mL/min/kg), and exercise time (4.8 +/- 2.2 to 4.5 +/- 2.1 s) were unchanged. The time constant of O(2) kinetics (tau) on response to constant low-dose work loading (warm up) decreased significantly (64 +/- 30 to 44 +/- 24 s; p < 0.01) and ejection fraction increased (30 +/- 14 to 44 +/- 15%, p < 0.01) significantly following treatment with beta-blocking agents. In spite of excluding two NYHA I patients, these changes were also statistically correlated. In the low level of exercise, tau was prolonged in patients with DCM. Although indexes of total exercise time and AT were not useful markers for clinical improvement in cardiac performance as assessed by echocardiography, measuring can validly assess the beneficial effects in heart failure treated with beta-blocking agents.

Heart failure in diabetic patients: Utility of β-blockade

Background: Congestive heart failure (CHF) occurs with increased frequency in patients with diabetes and carries a higher risk of morbidity and mortality compared with nondiabetic persons. Diabetic patients are more likely to suffer from CHF and its consequences because of hypertensive and ischemic heart disease and diabetic cardiomyopathy. Methods: Intensive combination therapy, directed at the different aspects of the pathophysiology of CHF in diabetes patients, results in improved outcomes. Improvement of glycemia, reduction of low-density lipoprotein cholesterol levels, tight control of blood pressure, and antiplatelet therapy have been all shown to decrease the morbidity and mortality associated with CHF in diabetic patients. β-blockade added to angiotensin-converting enzyme (ACE) inhibition has become an increasingly integral component of CHF therapy. Results: Improved outcome with β-blockade treatment is due to decreased incidence of both sudden death and pump failure and is of particular benefit to diabetic patients during and after myocardial infarctions complicated by systolic dysfunction. Conclusions: Based on retrospective analysis, β-blocking agents with vasodilating properties may provide additional benefits in diabetic patients because they may improve insulin sensitivity and vasorelaxation.

Effects of therapy with β-blocker agents on myocardial perfusion and outcome

Effects of therapy with β-blocker agents on myocardial perfusion and outcome

Heart rate and pulse pressure amplification in hypertensive subjects

Background Although mean blood pressure (MBP) remains unmodified along the arterial tree, pulse pressure (PP) increases physiologically from the central to the peripheral arteries. Amplification of PP is known to be influenced by heart rate (HR), but the impact of this alteration has never been tested in patients with hypertension. Methods A total of 712 hypertensive subjects, either treated or untreated, were divided into three classes of HR level. Carotid and brachial systolic blood pressure (SBP), carotid augmentation index, a marker of wave reflections, and carotid–brachial PP amplification were measured using applanation tonometry. Results Independent of age, sex, and antihypertensive drugs, subjects with HR >80 beats/min were characterized, in comparison with those with lower HR, by reduced carotid SBP, PP, and augmentation index, resulting in a significant increase in PP amplification. In men but not in women, this pattern was associated with higher values of brachial SBP and DBP and by higher incidences of elevated glycemia and atherosclerotic alterations. In the male population, PP amplifications was, independent of HR, associated with the presence of β blocking agents (negative association) and elevated plasma glucose. Conclusions Hypertensive men and women with high HR have significant PP amplifications, principally because of reduced central SBP and disturbed wave reflections. β-blocking agents and plasma glucose independently alter PP amplification in men but not in women. Whether these opposite patterns influence the gender difference in cardiovascular risk should be prospectively studied.

PH dependence of the hydrophobicity of β-blocker amine compounds measured by counter-current chromatography

The octanol–water partition coefficients ( P oct) of 17 antiadrenergic β-blocker compounds were determined by counter-current chromatography (CCC). Since CCC uses a biphasic liquid system, the octanol–water liquid system was used with essentially an octanol stationary phase and aqueous buffer mobile phase. The P oct coefficients were obtained directly without any extrapolation. The measured P oct values were in the 0.0015–4070 range ( −2.8< log P oct <3.6 ). Since the β-blocking agents are ionizable compounds, the P oct values obtained were strongly dependent on the aqueous-phase pH. The apparent P oct coefficients of the β-blockers were determined at three different pH values (∼3, 7 and 11) using 0.01 M ammonium phosphate buffers saturated with octanol. A model allowed us to obtain the molecular and ionic P oct value using the solute p K a with these three experimental octanol–water coefficients. Often, the P oct coefficients of the molecular forms obtained with the CCC method differ significantly from computed literature values and/or experimental values obtained by extrapolation. Relationships between biological properties and hydrophobicity were also examined.

Identification of isopropyl substituted β-blocking agents in human urine by gas chromatography and tandem mass spectrometry

A method for the sensitive detection of isopropyl substituted β-blocking agents in human urine is presented. The sample preparation step involves enzymatic hydrolysis, solid phase extraction and derivatisation withN-methyl-N-trimethylsilyl-trifluoroacetamide. The instrumental analysis was performed using gas chromatography-mass spectrometry with an ion trap mass spectromeler. The mass spectrometer was operated in the scan as well as in the MS-MS mode.

Antiadrenergic therapy of chronic heart failure: surprises and new opportunities.

The great British-American scientist-philosopher Alfred North Whitehead divided progress into three stages, the second of which was termed precision, in which the “right ways and wrong ways” of an original idea are elucidated.1 During this period, reinterpretation of the basic idea occurs and is essential to progress. Whitehead’s message is that important ideas are dynamic instruments that are constantly changing as new and usually unexpected information becomes available. This is why tests of particular hypotheses, including those tested in Phase III clinical trials, are often unsupportive, and why therapeutic paradigms constantly change. Within such an ephemeral milieu, the key to ultimate success is to view each unexpected or negative result as an opportunity for constructing and testing even more novel and valuable hypotheses within the framework of the general idea, to ascend to the final stage where progress can be “generalized.”1 Whitehead’s philosophical legacy is impressively in play in the area of antiadrenergic therapy of chronic heart failure (CHF). The unarguable basic idea is that the biologically powerful adrenergic compensatory mechanism plays a critical role in the natural history of CHF. It is the details or nuances within the general paradigm that continue to change, and lately, surprisingly so. As recently reviewed,2 the importance of dysfunctional adrenergic activation in CHF was first elucidated by work performed by Braunwald’s group at the National Institutes of Health in the 1960s. Among other things, this early work provided the first evidence of marked adrenergic activation in CHF. However, on the basis of reduction in myocardial tissue norepinephrine, and the short-term effects of large doses of antiadrenergic agents,3 the overall interpretation was that adrenergic support was deficient in CHF. This view prevailed for 10 to 15 years, and it contributed to the original logic behind developing Type III phosphodiesterase inhibitors …