Effect of Secondary Prevention Medication on the Prognosis in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) has been and remained a puzzling clinical entity. The role of secondary prevention therapy in patients with MINOCA remains unclear. This study aimed to evaluate the associations between secondary prevention medications and outcomes in patients with MINOCA. A total of 259 patients with MINOCA were consecutively enrolled. Basic information and medication of patients were assessed. We defined major adverse cardiovascular events as the primary end point and angina rehospitalization as the secondary end point. Logistic regression models were used to assess the correlation between treatment and outcomes. The proportion of statins, aspirin, clopidogrel, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB), and ß-blocker used at admission was 88.8%, 86.9%, 84.6%, 51.7%, and 61.4%, respectively. At discharge, patients with MINOCA were less likely to be released on statins, aspirin, clopidogrel, ACEI/ARB, and ß-blocker. The use of secondary prevention medications was significantly lower at 2 years of follow-up with the most significant reductions being clopidogrel 29.4%, ACEI/ARB 39.0%, and aspirin 42.3%. About 19.1% of patients with MINOCA suffered adverse events during the follow-up period. Adverse events risk decreased when statins and ACEI/ARB were used, whereas the risk of adverse events was not lower in patients with aspirin, clopidogrel, and ß-blocker. In conclusion, patients with MINOCA were less likely to receive secondary prevention medications at the time of discharge and early discontinuation of medications at the time of follow-up. Statins and ACEI/ARB were the only medications substantially associated with lower adverse events; by comparison, aspirin, clopidogrel, and ß-blocker seem to have no impact on prognosis.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

Relative Performance of Propensity Score Matching Strategies for Subgroup Analyses.

Postapproval drug safety studies often use propensity scores (PSs) to adjust for a large number of baseline confounders. These studies may involve examining whether treatment safety varies across subgroups. There are many ways a PS could be used to adjust for confounding in subgroup analyses. These methods have trade-offs that are not well understood. We conducted a plasmode simulation to compare relative performance of 5 methods involving PS matching for subgroup analysis, including methods frequently used in applied literature whose performance has not been previously directly compared. These methods varied as to whether the overall PS, subgroup-specific PS, or no rematching was used in subgroup analysis as well as whether subgroups were fully nested within the main analytical cohort. The evaluated PS subgroup matching methods performed similarly in terms of balance, bias, and precision in 12 simulated scenarios varying size of the cohort, prevalence of exposure and outcome, strength of relationships between baseline covariates and exposure, the true effect within subgroups, and the degree of confounding within subgroups. Each had strengths and limitations with respect to other performance metrics that could inform choice of method.

The effect of labetalol and nifedipine MR on blood pressure in women with chronic hypertension in pregnancy.

AIM: To compare the blood pressure (BP) lowering effects of labetalol and nifedipine modified release (MR) in hypertensive pregnant women. We also investigated the effect on the heart rate (HR) and determined the proportion of time spent in target. METHODS: This was an exploratory study. Women with chronic hypertension taking either labetalol or nifedipine were offered 24-h ambulatory blood pressure monitoring (ABPM). Sleep, wake and drug ingestion times were self-reported. An indirect response model was used to analyse the systolic BP (SBP), diastolic BP (DBP) and HR time-series; the effect of gestation and type of drug was evaluated. RESULTS: Forty-eight women were recruited: 24 in each group. There was no difference in clinical characteristics. In women taking nifedipine there was a positive association between the dose of nifedipine and pre-dose BP p = .002, this was not present in the labetalol group. There was a difference between the drug effects on both the SBP and DBP time-series (p = .014). In comparison to labetalol, there was less variation in day time BP in those women prescribed nifedipine. Women on labetalol spent a larger proportion of time with their DBP below target (<80 mmHg). The HR dynamics were qualitatively different, a stimulatory effect was found with nifedipine compared to an inhibitory effect with labetalol. CONCLUSION: There are significant and important differences between the BP lowering effects of nifedipine and labetalol. A large randomised control trial is required to investigate the relationship between BP variability and time in target on pregnancy outcomes.

Retrospective review of the use of as-needed hydralazine and labetalol for the treatment of acute hypertension in hospitalized medicine patients.

BACKGROUND: The aim of this study was to evaluate the use of as-needed (PRN) labetalol and hydralazine [intravenous (IV) or oral] in hospitalized medicine patients for the treatment of severe asymptomatic hypertension and to examine the potential negative outcomes associated with their use. METHODS: The electronic health record of 250 medicine patients hospitalized at the University of Colorado Hospital between November 2014 and April 2016 who received at least one dose of PRN IV or oral hydralazine or labetalol were retrospectively reviewed. The primary outcome was to describe the use of PRN antihypertensive medications in this population. RESULTS: A total of 573 PRN doses of antihypertensive medication were administered. Oral hydralazine was the most common (521 doses, 90.9%). A total of 36% of PRN administrations were given for a systolic blood pressure (SBP) <180 mmHg and diastolic blood pressure (DBP) <110 mmHg (cut-point for acute severe hypertension). No serious adverse events were related to PRN antihypertensive administration. Despite receiving at least one PRN antihypertensive medication during hospitalization, 40.8% of patients were not continued on their home antihypertensive medication(s) while hospitalized, and 62.4% of patients did not have their home regimens intensified at discharge. CONCLUSION: As-needed oral hydralazine is frequently prescribed for acute blood pressure lowering with administration thresholds often less than what are used to define acute severe hypertension. Many patients are prescribed PRN antihypertensive medication instead of being continued on their home regimens, and most patients do not have the intensity of their home regimens increased. Providers need to be educated about the use of PRN antihypertensive medication for the management of severe asymptomatic hypertension in the hospital setting.

Adrenergic blockers and the risk for common solid cancers: a case-control study.

Laboratory studies have suggested that adrenergic blockers may inhibit the proliferation and migration of cancer cells, but epidemiological evidence of their effect on cancer incidence has proven inconsistent. We therefore conducted a case-control study using the Clinical Practice Research Datalink to assess the effect of adrenergic blockers on the incidence of prostate, lung, bowel and breast cancers. From among patients aged 18 years or older who contributed at least 2 years of prospectively gathered data between 1 January 1987 and 31 December 2012, we selected incident cases of relevant cancers and controls, frequency matched 10 : 1 by age. Logistic regression was used to adjust effect estimates for age, sex, smoking, alcohol use, and a number of potentially confounding comorbidities and coprescriptions. A total of 18 968 colorectal, 19 082 lung, 21 608 prostate and 29 109 breast cancers were identified. We found no evidence of a protective effect of adrenergic blockade in lung and prostate cancers and found a slightly increased risk for colorectal and breast cancers in users. This was largely explained by the effects of confounding in multivariate analyses, with final odds ratio estimates for lung, colorectal, breast and prostate cancers of 0.99 [95% confidence interval (0.96-1.04)], 1.14 (1.09-1.18), 1.10 (1.06-1.14), and 1.01 (0.98-1.05), respectively, for ß-blocker exposure, and final odds ratio estimates for lung, colorectal and breast cancer of 1.03 (0.97-1.09), 1.13 (1.07-1.20), and 1.08 (1.00-1.17), respectively, for α-blocker exposure. We found no evidence to suggest that adrenergic blocker use prevents common cancers. Indeed, we found a slightly increased risk for colorectal and breast cancers, which may reflect residual confounding.

The therapy of Cushing's disease in adults and children: an update.

Cushing's disease (CD) is a rare endocrine disorder resulting from excessive production of adrenocorticotrophin hormone by a pituitary adenoma. The consequent hypercortisolaemia gives rise to characteristic features of the disease and its morbidities. Treatments aim to restore normal cortisol levels, provide long-term control of the disease and the tumour, and the improvement of patient well-being. The first line of treatment remains transsphenoidal surgery with remission rates of 65-90% in CD secondary to a pituitary microadenoma. Second-line treatment includes repeat surgery, radiotherapy, medical therapy, and bilateral adrenalectomy. The success rate of radiotherapy ranges from 46% to 74% and is probably independent of the mode of delivery of the radiation, but may take several years to become effective. Medical therapy is useful in acutely unwell patients or while awaiting radiotherapy to become effective. The most often-used medical agents include metyrapone and ketoconazole, which inhibit steroidogenesis; less often, centrally-acting drugs or a glucocorticoid receptor blocker are used, but experience with them is more limited. Bilateral adrenalectomy remains an important treatment option to control unresponsive severe hypercortisolism, particularly in patients with severe CD.The management of childhood CD does not differ from adult disease, with transsphenoidal surgery as successful as in adults but radiotherapy is more rapid in onset. Regardless of the age of the patient, Cushing's disease remains a challenge to the physician and requires a multidisciplinary approach to achieve the most desirable outcome.

Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function.

Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the ß-adrenergic (ß-adrenoceptor) and M2 muscarinic receptor. ß(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of ß(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human ß(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies.

What can we learn from consumer reports on psychiatric adverse drug reactions with antidepressant medication? Experiences from reports to a consumer association.

BACKGROUND: According to the World Health Organization (WHO) the cost of adverse drug reactions (ADRs) in the general population is high and under-reporting by health professionals is a well-recognized problem. Another way to increase ADR reporting is to let the consumers themselves report directly to the authorities. In Sweden it is mandatory for prescribers to report serious ADRs to the Medical Products Agency (MPA), but there are no such regulations for consumers. The non-profit and independent organization Consumer Association for Medicines and Health, KILEN has launched the possibility for consumers to report their perceptions and experiences from their use of medicines in order to strengthen consumer rights within the health care sector. This study aimed to analyze these consumer reports. METHODS: All reports submitted from January 2002 to April 2009 to an open web site in Sweden where anyone could report their experience with the use of pharmaceuticals were analyzed with focus on common psychiatric side effects related to antidepressant usage. More than one ADR for a specific drug could be reported. RESULTS: In total 665 reports were made during the period. 442 reports concerned antidepressant medications and the individual antidepressant reports represented 2392 ADRs and 878 (37%) of these were psychiatric ADRs. 75% of the individual reports concerned serotonin-reuptake inhibitor (SSRI) and the rest serotonin-norepinephrine reuptake inhibitor (SNRI). Women reported more antidepressant psychiatric ADRs (71%) compared to men (24%). More potentially serious psychiatric ADRs were frequently reported to KILEN and withdrawal symptoms during discontinuation were also reported as a common issue. CONCLUSIONS: The present study indicates that consumer reports may contribute with important information regarding more serious psychiatric ADRs following antidepressant treatment. Consumer reporting may be considered a complement to traditional ADR reporting.

Safety and pharmacokinetic studies of silodosin, a new α1A-adrenoceptor selective antagonist, in healthy Chinese male subjects.

The objectives of the study were to assess the safety and pharmacokinetics of silodosin capsules in 82 healthy male Chinese subjects. To evaluate the safety after single-dosing escalation, 40 subjects were equally divided into 4 groups (2, 4, 8, 12 mg) by a randomized, double-blind and placebo-controlled design. To assess the pharmacokinetics after single-dosing, 30 subjects were equally divided into 3 groups (4, 8, 12 mg). To assess the safety and pharmacokinetics via multiple-dosing, 12 subjects were included as a group (4 mg once daily at day 1 and day 7; 4 mg twice daily at day 2 through day 6). The safety observations showed that mild adverse events, including postural hypotension, dizziness, and headache, were observed. After single-dosing at doses of 4, 8, and 12 mg, the mean area under the concentration-time curve from 0 to 36 h (AUC(0-36)) values were 136.82±46.38, 270.17±54.66, and 474.63±108.50 µg/l·h and the mean maximal silodosin concentration in plasma (C(max)) values were 26.70±7.48, 48.47±12.35, and 94.07±22.59 µg/l, respectively. After multiple-dosing, the C(max) value at day 7 was 33.84±19.54 µg/l, and the AUC(0-24) value at day 7 was 193.19±68.96 µg/l·h. The accumulation ratio of the AUC value was 1.55 by comparing the multiple-dosing with the single-dosing. It is concluded that silodosin is safe and tolerated in healthy Chinese male subjects at the dosing levels used in this study. The mean C(max) and AUC values of silodosin increased proportionally with dose escalation, showing characteristics of linear pharmacokinetics.

[Clinical pharmacology and electrophysiological properties of dronedarone]. / Klinisch-pharmakologisches und elektrophysiologisches Profil von Dronedaron.

Dronedarone is a benzofuran derivative structurally similar to amiodarone but non-iodinated. The agent was systematically developed with the aim to maintain the antiarrhythmic potency of amiodarone while reducing the extracardiac side effects of the drug. Dronedarone is less lipophilic compared to the mother compound, which manifests in a substantial lower time to steady state (4-8 days compared to 1-3 weeks with amiodarone), and a more rapid elimination (half life 25-30 hours). Dronedarone has antiarrhythmic properties of all Vaughan-Williams classes. Among other channel blocking effects, It blocks sodium ion channels at higher stimulation frequency, prolongs the cardiac action potential, and has properties of a calcium channel blocker. Further, dronedarone has non-competitive antiadrenegic effects. No reverse use dependence has been documented at higher heart rate. These effects explain the antiarrhythmic and rate control properties of dronedarone in patients with atrial fibrillation.

The beta3-adrenoceptor as a therapeutic target: current perspectives.

beta(3)-Adrenoceptors (beta(3)-ARs) are located not only on the plasma membrane of both white and brown adipocytes, but also exist in human heart, gall bladder, gastrointestinal tract, prostate, urinary bladder detrusor, brain and in near-term myometrium. They are now recognized as an attractive target for drug discovery and several efforts have been made in this field to understand their function and regulation in different human tissues. The aim of this review is to highlight the functional role of beta(3)-ARs as well as to discuss their potential for drug development.

Drug-induced urinary incontinence.

Physiological urinary continence depends on many factors that are potentially vulnerable to adverse drug effects, which may lead to incontinence. In principle, drugs could cause incontinence by lowering bladder outlet resistance and/or by increasing intravesical pressure, which disrupts the normal pressure relationship between the bladder and urethra and leads to urinary leakage; other possibilities include disturbances of central nervous control of voiding or an overproduction of urine. While many drug groups could theoretically induce urinary incontinence based upon pathophysiological considerations, evidence demonstrating a cause-effect relationship between drug usage and incontinence is sparse. Drug classes in which induction of incontinence has been proposed include alpha(1)-adrenoceptor antagonists, antipsychotics, benzodiazepines, antidepressants and hormone replacement therapy in postmenopausal women. However, other drug classes are not innocent in terms of causing urinary incontinence and physicians are well advised to closely monitor patients for the occurrence of incontinence after new prescriptions and/or major dosage changes.

alpha(1)-Adrenergic receptor antagonists and the iris: new mechanistic insights into floppy iris syndrome.

Understanding the role of adrenergic receptors in iris biology has gained widespread interest due to the recently described intraoperative floppy iris syndrome sometimes encountered during cataract surgery. alpha(1)AR-mediated iris dilator smooth muscle contraction occurs via alpha(1a)ARs whereas alpha(1b)ARs mediate iris arteriolar contraction. Because alpha(1)AR antagonists are first-line therapy for benign prostatic hyperplasia and lower urinary tract symptoms, more elderly patients requiring cataract surgery now receive these drugs. After reviewing intraoperative floppy iris syndrome, strengths/weaknesses of supporting data, and reviewing iris biology, a case is made that rather than being drug specific (alpha(1)AR antagonists), intraoperative floppy iris syndrome may represent the "tip of the iceberg." Relaxed iris dilator muscle resistant to adrenergic agonists should be expected with clinical drugs shown to relax the iris dilator (e.g., antagonists at alpha(1)AR, endothelin-A, angiotensin receptors, nitric oxide donors such as nitrates), and/or diseases associated with endothelial dysregulation (e.g., congestive heart failure, diabetes, hypertension). Rather than a rare, unexpected, unpredictable syndrome due to one drug, a careful medical history should elucidate intraoperative floppy iris syndrome predisposition. Just as anticoagulants are discontinued prior to elective surgery, conservative management of elderly patients suggests discontinuation of drugs that relax iris dilator muscle, in consultation with the patient's primary physician, should be considered prior to cataract surgery.

[Neurological manifestations in critically ill patients]. / Manifestaciones neurologicas del paciente en estado critico.

AIMS: To describe the pathophysiology, diagnosis and clinical manifestations of the neurological complications that critically ill patients often develop in intensive care units, and to discuss their treatment and prognosis, in the light of the most significant contemporary literature. DEVELOPMENT: The most frequent complication suffered by critically ill patients is sepsis, with encephalopathy as the main manifestation, and this has a direct effect on their prognosis. Polyneuropathy of the critically ill patient is linked to sepsis, as the main precipitating factor, as well as to the presence of high levels of glucose, which plays an important role in deciding whether mechanical ventilation can be withdrawn or not. Myopathy of the critically ill patient is related to the use of fluorinated steroids and neuromuscular blockers, which are frequently administered to these patients. All these entities represent a significant diagnostic challenge for the physician and are accompanied by important sequelae that continue after the patient's discharge from hospital, as well as myopathies and neuropathies associated to the use of drugs that are commonly administered to critically ill patients. It is therefore necessary to be familiar with the pathophysiology of the damage and with the associated factors, if a suitable diagnostic approach is to be employed. CONCLUSIONS: The incidence of these pathologies and their complications makes them important conditions that require a swift, accurate diagnosis so that treatment can be established early on and a prognosis can also be determined.