Köln, Universiẗat, Diss., 2004.

Propranolol (PROP) is a β-blocker prescribed mainly to treat human cardiac diseases but with its wide usage it often makes its way into the aquatic environment. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The 48 h LC50 was 21.6 mg/L, well above environmental levels (0.00059 mg/L). Embryos/larvae continuously PROP-exposed had decreased and increased transcript levels of the β1-adrenoceptor at 1 dpf and 5 dpf, respectively. Stressed, PROP-exposed zebrafish had reduced testosterone and estradiol levels and exhibited less anxiety behaviours than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length (0.0006 mg/L PROP) and mass (20 mg/L PROP). Changes in cholesterol and testosterone levels occurred in PROP-exposed fish. Thus PROP-exposure alters developmental patterns and CA-regulated process that are essential for normal behaviours and responses to stress, and at least some of these changes persist in the adult zebrafish.

Propranolol (PROP) is a β-blocker prescribed mainly to treat human cardiac diseases but with its wide usage it often makes its way into the aquatic environment. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The 48 h LC50 was 21.6 mg/L, well above environmental levels (0.00059 mg/L). Embryos/larvae continuously PROP-exposed had decreased and increased transcript levels of the β1-adrenoceptor at 1 dpf and 5 dpf, respectively. Stressed, PROP-exposed zebrafish had reduced testosterone and estradiol levels and exhibited less anxiety behaviours than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length (0.0006 mg/L PROP) and mass (20 mg/L PROP). Changes in cholesterol and testosterone levels occurred in PROP-exposed fish. Thus PROP-exposure alters developmental patterns and CA-regulated process that are essential for normal behaviours and responses to stress, and at least some of these changes persist in the adult zebrafish.

Propranolol (PROP) is a β-blocker prescribed mainly to treat human cardiac diseases but with its wide usage it often makes its way into the aquatic environment. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The 48 h LC50 was 21.6 mg/L, well above environmental levels (0.00059 mg/L). Embryos/larvae continuously PROP-exposed had decreased and increased transcript levels of the β1-adrenoceptor at 1 dpf and 5 dpf, respectively. Stressed, PROP-exposed zebrafish had reduced testosterone and estradiol levels and exhibited less anxiety behaviours than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length (0.0006 mg/L PROP) and mass (20 mg/L PROP). Changes in cholesterol and testosterone levels occurred in PROP-exposed fish. Thus PROP-exposure alters developmental patterns and CA-regulated process that are essential for normal behaviours and responses to stress, and at least some of these changes persist in the adult zebrafish.

Beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided in asthma over risk of bronchospasm which may vary according to drug selectivity and duration of administration. This thesis attempts to quantify the risk of beta-blocker and NSAID exposure in asthma by synthesising clinical trial evidence and conducting observational studies using linked electronic medical records. As part of this thesis, three systematic reviews of clinical trials were conducted evaluating: the prevalence of aspirin-exacerbated respiratory disease (AERD); risk of selective NSAIDs/COX-2 inhibitors in people with AERD; and risk of acute beta-blocker exposure in people with asthma. Electronic primary care data from the Clinical Practice Research Datalink (CPRD) was used to define a cohort of people with active asthma, measure the prevalence of beta-blocker and NSAID prescribing, and perform a series of nested case control studies evaluating asthma death, asthma hospitalisation and primary care asthma exacerbations (PCAE). A self-controlled case-series was performed for PCAE as well. Based upon work in this thesis, the prevalence of AERD in people with asthma was around 9%. Selective NSAIDs triggered respiratory symptoms in 8% of people with AERD whilst no significant changes in lung function or symptoms occurred with COX-2 inhibitors. Acute non-selective beta-blocker exposure caused a significant mean fall in FEV1 of 10%, a significant increase in respiratory symptoms in around 1 in 13 and a non-significant increase in falls in FEV1 of ≥20% in around 1 in 9. Acute selective beta-blocker exposure caused a significant mean fall in FEV1 of 7%, significant falls in FEV1 of ≥20% in around 1 in 8 and a non-significant increase in respiratory symptoms in around 1 in 33. The prevalence of selective beta-blocker prescribing in asthma rose by around 200% over the 12 year period whilst the prevalence of non-selective beta-blocker prescribing rose by around 90%. Changing trends in NSAID prescribing occurred over the 12 year period with COX-2 inhibitors now rarely prescribed. Using the nested case control design, both incident and high-dose non-selective beta-blocker exposure was associated with significantly increased risk of asthma morbidity (hospitalisation and PCAE). In contrast, no significant increased risk of asthma morbidity occurred with any type of selective beta-blocker exposure. Consistent findings were seen for PCAE using the self-controlled case series. No significantly increased risk was seen with different oral NSAIDs apart from weak evidence of an association between asthma death and non-selective NSAID exposure which is unlikely to be causal. Significant numbers of people with asthma are prescribed beta-blockers and NSAIDs. Evidence from clinical trials and observational studies demonstrate that non-selective beta-blockers significantly increase asthma morbidity with risk appearing to vary according to dose and duration of administration. Although selective beta-blockers have the potential to cause significant changes in lung function, no significant increase in asthma morbidity was observed in observational studies. Although around 9% of asthmatics may be susceptible to NSAIDs, no strong evidence was found to suggest that the current practice of NSAID prescribing increases asthma morbidity. At the same time, COX-2 inhibitors are infrequently prescribed despite apparently being well tolerated by people with AERD.

For more than half a century cardiovascular disease has been the leading cause of death in the United States.  Aging, hypertension, and obesity are major risk factors for cardiovascular disease and clearly associated with arterial stiffness.  Arterial stiffness generates higher afterloads and diminishes coronary perfusion thereby causing ventricular hypertrophy and ischemia.  Importantly, arterial stiffness is an independent predictor of cardiovascular disease risk and all-cause mortality.   Current strategies such as inhibition of angiotensin II or angiotensin converting enzyme, reduction of smooth muscle tone, blood volume, or inflammatory mediators, and improving glucose homeostasis are effective destiffening options.  Nebivolol, a third generation beta-blocker, has unique vasodilatory characteristics and may be particularly efficacious as a destiffening agent.  Only a few studies have addressed this issue while relying on indirect, blood pressure-dependent stiffness indices precluding clear understanding of study outcomes.  There remains a need to determine the potential utility of nebivolol therapy as an arterial destiffening strategy.   Thus, we hypothesized that the combination of nebivolol and lifestyle modification would reduce central arterial stiffness in middle-aged and older hypertensive adults more than either intervention alone.  To test this hypothesis, we randomized 45 hypertensive adults to receive lifestyle modification, nebivolol, or combination for 12 weeks.  β-stiffness index, pulse wave analysis, and arterial compliance were measured at baseline and following the intervention.  No baseline differences in variables of  interest were observed between groups.  In contrast to our hypothesis, lifestyle modification, nebivolol, and combination groups had similar (P>0.05) reductions in beta-stiffness index (-1.87±0.83; -2.03±0.60; and -2.51±0.90 U), respectively, while carotid-femoral pulse wave velocity declined only in the nebivolol and combination groups.   Our findings suggest combination of nebivolol and lifestyle modification reduces arterial stiffness to a similar degree as either intervention alone in middle-aged and older hypertensive adults.  Further studies are needed to determine if the changes in arterial stiffness continue to occur or remain clinically significant over longer durations. / Ph. D.

Techn. Universiẗat, Diss., 2005--München.

Thyroid storm (TS) is a rare life threatening endocrine emergency. Estimates for mortality rate for untreated TS ranges from 50%-90%[1,2].; however if managed appropriately, mortality drops to less than 20%[2]. Management can include glucocorticoids, propranolol, propylthiouracil(PTU) or methimazole and iodine solution. Each have established roles in controlling the hyperdynamic state in the storm. What is not well established is subclinical cardiomyopathy that may exist with chronic uncontrolled hyperthyroidism. We present a case in which propranolol, used appropriately, led to cardiovascular collapse during the management of a thyroid storm. 48 year old female with a medical history significant for hypertension presented with a 1 day history of severe dyspnea. On arrival vitals were: BP 177/103, pulse 127, RR 28 and pulse ox 92% on room air. She had anasarca and a GCS of 6. She was intubated for airway protection. Head CT was normal. Labs were sodium 128, bicarbonate 18, glucose 38, anion gap 14, lactic acid 5, leukocytes of 12000, Hb 7.3. ABG was pH 7.04, PCO2 45, PaO2 138 on 100% O2 at PEEP of 10, immediately after intubation. TSH was undetectable, FT4 was > 8ng/dL with FT3 of 11pg/mL. Echocardiogram showed EF of 45%, RV dilation and biatrial enlargement. She received glucocorticoids, PTU and oral propranolol. Shortly afterwards she became bradycardic, hypotensive then developed pulseless electrical activity (PEA) despite glucagon and aggressive IV fluids. ROSC was achieved after 8 minutes of ACLS protocol. Within minutes she became bradycardic and hypotensive again then became pulseless again despite glucagon and attempts at transcutaneous pacing. After ROSC with ACLS protocol, she was eventually stabilized with aggressive IV fluid, 5 vasopressors and a bicarbonate drip. That night, she had a third cardiac arrest. After ROSC, an emergency bedside laparotomy was performed for decompression of compartment syndrome. Her hospital course was complicated by hematologic abnormalities requiring multiple blood products, gastrointestinal blood loss, NSTEMI and dialysis dependent renal failure. The concept of thyrocardiac disease must be kept in mind when managing a thyroid storm. In long standing hyperthyroidism, the resulting cardiomyopathy is compensated by tachycardia and increased sensitivity to catecholamines [3]. This compensatory mechanism depends on tachycardia to maintains adequate cardiac output. Failure to consider this led to our therapeutic misadventure. Current management of TS includes the use of propranolol to lessen the adrenergic effect on the heart and to inhibit peripheral conversion of T4 to T3. This patient’s experience suggested that abrupt disruption of this compensatory state with beta blockade puts the body at risk for cardiovascular collapse. Until management guidelines are updated, it is imperative to for clinicians to avoid beta blockers or use short acting beta blockers with extreme caution when managing TS.

No description available.

A apnéia central do sono (ACS) está associada à insuficiência cardíaca (IC). Objetivos: analisar o comportamento do sono em pacientes com IC e ACS com IAH>15 por hora e a influência dos betabloqueadores sobre o sono. Métodos: os pacientes realizaram duas polissonografias, com nitroglicerina e placebo, ambos transdérmicos. Resultados: em média, houve aumento da saturação de oxigênio e redução dos despertares e da frequência cardíaca, quando os pacientes fizeram uso de nitroglicerina. A prevalência de ACS no grupo betabloqueador foi menor do que relata a literatura. Conclusão: a nitroglicerina teve impacto positivo sobre variáveis polissonográficas. O betabloqueador reduziu a prevalência de apnéia. / The central sleep apnea (CSA) is associated to heart failure (HF). Objectives: Analyze sleeping behavior in patients with HF and CSA with AHI > 15 per hour, and the influence of beta-blocker on the sleep. Methods: patients were submitted to two sleep studies, with transdermic nitroglycerine and placebo. Results: On the average, we observed improvement in oxygen saturation and reduction in awakening episodes and in heart rate when patients slept with nitroglycerin compared to placebo. The prevalence of CSA in patients taking beta-blocker was inferior to that described in medical literature. Conclusion: Nitroglycerin had positive impact on sleep variables. Beta-blocker reduced CSA prevalence.