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.

Class of 2012 Abstract / Specific Aims: During pre-hospital transport, trauma patients may be given a long-acting neuromuscular blocker (NMB) to facilitate endotracheal intubation or to prevent movement. The purpose of this study was to determine the rate of long-acting NMB use and evaluate the concurrent use of sedatives. Methods: This was a retrospective cohort study conducted in a tertiary care, academic emergency department of trauma patients aged 18-89 years who were intubated in the pre-hospital setting. The primary outcome was to determine the rate of long-acting NMB use. The use of post- intubation sedatives was compared between the groups using Wilcoxon rank-sum test or Fisher’s exact test, using an a priori alpha level of 0.05 for all analyses. Main Result: A total of 51 patients were included in final analyses. All patients received etomidate or midazolam for intubation. 86% (n=44) received succinylcholine, 10% (n=5) were given rocuronium and 4% (n=2) did not receive a NMB. After intubation, 75% (n=38) received an additional long-acting NMB to prevent movement (vecuronium (n=22) or rocuronium (n=16)) . Overall, 82% (n=42) of patients received a long- acting NMB during transport. There was no difference in the rate of post-intubation sedative use between groups (79% versus 67%, respectively, p=0.42). The long-acting NMB group received midazolam less promptly after intubation (16 versus 7 minutes, respectively, p=0.04). Conclusions: The use of long-acting NMB is common during the pre-hospital transport of trauma patients. Some of these patients may not be given sedatives or have delays in receiving sedatives following intubation and be at risk of being paralyzed without sedation.

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.

Zugl.: Giessen, Universiẗat, Diss., 2008.

Zugl.: Giessen, Universiẗat, Diss., 2008.

Class of 2012 Abstract / Specific Aims: During pre-hospital transport, trauma patients may be given a long-acting neuromuscular blocker (NMB) to facilitate endotracheal intubation or to prevent movement. The purpose of this study was to determine the rate of long-acting NMB use and evaluate the concurrent use of sedatives. Methods: This was a retrospective cohort study conducted in a tertiary care, academic emergency department of trauma patients aged 18-89 years who were intubated in the pre-hospital setting. The primary outcome was to determine the rate of long-acting NMB use. The use of post-intubation sedatives was compared between the groups using Wilcoxon rank-sum test or Fisher’s exact test, using an a priori alpha level of 0.05 for all analyses. Main Result: A total of 51 patients were included in final analyses. All patients received etomidate or midazolam for intubation. 86% (n=44) received succinylcholine, 10% (n=5) were given rocuronium and 4% (n=2) did not receive a NMB. After intubation, 75% (n=38) received an additional long-acting NMB to prevent movement (vecuronium (n=22) or rocuronium (n=16)) . Overall, 82% (n=42) of patients received a long-acting NMB during transport. There was no difference in the rate of post-intubation sedative use between groups (79% versus 67%, respectively, p=0.42). The long-acting NMB group received midazolam less promptly after intubation (16 versus 7 minutes, respectively, p=0.04). Conclusions: The use of long-acting NMB is common during the pre-hospital transport of trauma patients. Some of these patients may not be given sedatives or have delays in receiving sedatives following intubation and be at risk of being paralyzed without sedation.

Betaxolol, a long-acting β-adrenergic blocker that enters the central nervous system, was examined for therapeutic effects on the persistent anxiety of anxiety disorders. Prior studies of β-blockers examined only agents that were short-acting or did not enter the brain. Betaxolol was administered to 31 patients in open trials. Of 13 outpatients, 11 had generalized anxiety disorder (GAD) and 2 had adjustment disorder with anxiety. Five with GAD had concurrent panic disorder. Of 18 inpatients, 16 had GAD and 2 had adjustment disorder with anxiety. Betaxolol doses were increased until the patient responded or declined further dosage. Severity was rated on a 4-point global scale. Before betaxolol, all were moderately or severely ill. In all patients with panic disorder panic attacks stopped within 2 days (p < 0.001). Anxiety decreased to no more than marginally ill in 85% of outpatients (p < 0.0001) and all inpatients (p < 0.0001). Betaxolol doses were usually 5 mg once or twice daily; four inpatients took 10 to 20 mg twice daily. In sum, betaxolol administration was rapidly followed by improvements that were easily noticed by the doctor, even in patients with longstanding anxiety and obsessive-compulsive personality disorder. Preliminary observations in posttraumatic stress disorder are similar.