Nonselective Beta-adrenergic Blocker Research Articles

Studies on Propranolol hydrochloride floating tablets formulated with different concentrations of Aegle marmelos gum

This research employs Aegle marmelos gum in various ratios as a natural polymer to formulate and assess Propranolol hydrochloride floating tablets. Because of its high solubility and permeability, propranolol hydrochloride, a non-selective beta-adrenergic receptor blocker, has a restricted bioavailability. Floating tablets are intended to improve the absorption and bioavailability of drugs by staying afloat in the stomach. Aegle marmelos gum (AMG) was used as a polymer in varied ratios to create distinct formulations. The tablets were then tested for a number of characteristics, including hardness, friability, drug content, in vitro buoyancy, and drug release profiles. The findings showed that the Aegle marmelos gum content had a major impact on the tablets' floating qualities and drug release characteristics.

In silico drug repurposing carvedilol and its metabolites against SARS-CoV-2 infection using molecular docking and molecular dynamic simulation approaches

The pandemic of coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a significant impact on the economy and public health worldwide. Therapeutic options such as drugs and vaccines for this newly emerged disease are eagerly desired due to the high mortality. Using the U.S. Food and Drug Administration (FDA) approved drugs to treat a new disease or entirely different diseases, in terms of drug repurposing, minimizes the time and cost of drug development compared to the de novo design of a new drug. Drug repurposing also has some other advantages such as reducing safety evaluation to accelerate drug application on time. Carvedilol, a non-selective beta-adrenergic blocker originally designed to treat high blood pressure and manage heart disease, has been shown to impact SARS-CoV-2 infection in clinical observation and basic studies. Here, we applied computer-aided approaches to investigate the possibility of repurposing carvedilol to combat SARS-CoV-2 infection. The molecular mechanisms and potential molecular targets of carvedilol were identified by evaluating the interactions of carvedilol with viral proteins. Additionally, the binding affinities of in vivo metabolites of carvedilol with selected targets were evaluated. The docking scores for carvedilol and its metabolites with RdRp were − 10.0 kcal/mol, − 9.8 kcal/mol (1-hydroxyl carvedilol), − 9.7 kcal/mol (3-hydroxyl carvedilol), − 9.8 kcal/mol (4-hydroxyl carvedilol), − 9.7 kcal/mol (5-hydroxyl carvedilol), − 10.0 kcal/mol (8-hydroxyl carvedilol), and − 10.1 kcal/mol (O-desmethyl carvedilol), respectively. Using the molecular dynamics simulation (100 ns) method, we further confirmed the stability of formed complexes of RNA-dependent RNA polymerase (RdRp) and carvedilol or its metabolites. Finally, the drug-target interaction mechanisms that contribute to the complex were investigated. Overall, this study provides the molecular targets and mechanisms of carvedilol and its metabolites as repurposed drugs to fight against SARS-CoV-2 infection.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

288 Propranolol Use in Adult Burn Patients: Results from a Multi-center Safety and Efficacy Trial

Abstract Introduction The hypermetabolic response induced by a large burn is associated with increased cardiac work, total body wasting, and impaired physical function, leading to delays in psychosocial recovery and reintegration into society, and persistence of chronic conditions. Modulation of this response could reduce long-term burn morbidity. Catecholamines drive burn-induced hypermetabolism, therefore clinicians have employed the non-selective beta-adrenergic receptor blocker propranolol to reduce cardiac stress and the hypermetabolic response. Here, in a masked, placebo-controlled study, we investigated the safety and efficacy of the administration of propranolol to adult burn patients during the acute hospitalization period. Methods Adults with large burns (n=157, mean 38 ± 15% TBSA) were enrolled at 13 participating centers. Subjects were randomized to receive placebo (n=75) or propranolol (n=82) with data collected for 72 and 79 subjects, respectively. Propranolol administration was initiated with an oral dose of 0.2 mg/kg dose and adjusted to decrease mean heart rate by 20%. The primary endpoint was effect on cardiac rate pressure product (CRPP), while the secondary endpoints included infections and survival. Adverse events were also tracked. Assessments were conducted between the time of consent and discharge, with a long-term follow-up visit occurring approximately 5 months post-burn on average. Results CRPP was significantly reduced with propranolol during the acute hospitalization period (p< 0.0001, Fig 1). The initial dose of propranolol adequately reduced heart rate in most patients. Infections were not different between cohorts. Cardiac complications (atrial arrhythmias, ventricular arrhythmias, cardiac arrest) occurred at similar rates for each group, as did additional complications (abdominal compartment syndrome, deep vein thromboses, pneumothorax, pulmonary embolus). Mortality was similar for both the placebo and propranolol cohorts. Post-discharge heart rates and blood pressures were similar in both groups at approximately 5 months following injury. Conclusions This study demonstrates that the short-term administration of propranolol to adults with large burns decreases CRPP without increasing complications, infections, or mortality. Furthermore, a safe dosing strategy was identified. This strategy may be effective for reducing acute cardiac stress and hypermetabolism. Future studies should focus on the effects of propranolol administration for longer periods, determining the effects on additional endpoints like the hypermetabolic response, pathologic scarring, long-term cardiac dysfunction, whether smaller burns benefit from the administration of propranolol.

Non-Selective Beta-Adrenergic Blocker Propranolol: A Life Saving Drug for Hospitalized Patient with Traumatic Brain Injury in Intensive Care Unit

Background: Traumatic Brain Injury (TBI) is the most common cause of death under the age of forty. This in turn results in intracranial injury in about 90% of the cases from least-income countries. The majority of patients admitted to the Intensive care Unit (ICU) had trauma which is managed by preventive strategies and to combat the secondary hit stimulated by the primary hit International guidelines have formed a protocol to be applied in patients with TBI for the better outcome and to increase the survival rate.
 Objectives: The aim of this study was to determine the importance of beta-adrenergic blocker propranolol in patients admitted with TBI.
 Methodology: The literature search was conducted to find recent articles related to the aim of the study to analyze the significance of beta-blocking agent propranolol in TBI.
 Results: Paroxysmal Sympathetic Hyperactivity (PSH) occurs within 24 hours of TBI in patients with Glasgow Coma Scale (GCS ≤ 8). In patients who are agitated or in restlessness propranolol is the drug of choice to reduce hyperactivity. Several studies reported that using beta-adrenergic blocking agents decreases the mortality rate and current studies started focusing on the primary initiation of propranolol and also reported side-effects associated in TBI.
 Conclusion: Early administration of Non-selective beta-adrenergic blocker propranolol will continue to be the standard prophylactic pharmacotherapeutic method as it limits the risk of sympathetic storming in high-risk patients with TBI.
 Keywords: Traumatic Brain Injury (TBI), Propranolol, Beta-adrenergic blocker, Paroxysmal Sympathetic Hyperactivity (PSH).

Propranolol: A migraine prophylactic since the 1960s

IntroductionPropranolol was the first non-selective beta-adrenergic blocker to be developed. Initially it was used in the treatment of cardiovascular diseases, but since the 60's it has been used in the prevention of migraine.ObjectiveThe objective of this study was to know the history of propranolol and its use as a migraine prophylactic.MethodsThis study was an integrative literature review using articles with historical data on propranolol, from its origin in cardiology to its indication in the preventive treatment of migraine.ResultsPropranolol was described in 1962 for the treatment of cardiovascular diseases. In the same decade, it was prescribed for the preventive treatment of migraine and, recently, included in the consensus of the Brazilian Headache Society.ConclusionAlthough propranolol was initially synthesized for the treatment of heart disease, it has proved to be an effective drug in preventing migraine attacks.

Cerebellar repetitive transcranial magnetic stimulation versus propranolol for essential tremor.

Propranolol, a nonselective beta-adrenergic blocker, has long been used as one of the standard treatments for essential tremor (ET). Repetitive transcranial magnetic stimulation (rTMS) has also been used for a long time as a substitution therapy for ET patients. The main aim of this study was to evaluate the antitremor effect of 1-Hz (low-frequency) cerebellar rTMS and compare it to the use of propranolol in ET patients. In this single-blinded, randomized, controlled pilot study, a total of 38 patients with ET were randomized into two groups. One group (n=20) received 1200 pulses of 1-Hz rTMS at an intensity of 90% of the resting motor threshold to the bilateral cerebellar region for 10days. Another group (n=18) received oral propranolol for 30 days. The initial dose was 30mg/day, which was increased to 60mg/day after 5days, then to 90mg/day on the 11th day, and continued thereafter for 20days. The Fahn-Tolosa-Marin (FTM) clinical scale was assessed at baseline and at days 5, 10, and 30 to evaluate tremor severity, specific motor tasks, and functional disability. Low-frequency rTMS of the cerebellum significantly improved tremor severity, specific motor tasks (writing, spiral drawing, and pouring), and FTM total scores on days 10 and 30. Nevertheless, we found no significant difference in functional disability at any point in time (p>.05). There were no statistically significant differences in FTM Part A, Part B, Part C scores and total scores of patients in propranolol group on days 5 and 10 compared with before treatment (p>.05). However, FTM total scores and FTM Part A, Part B, and Part C scores were significantly improved for patients when the dose of propranolol was 90mg/day on day 30. Our study showed that there was no statistically significant difference in the total FTM scores and FTM Part A, Part B, and Part C scores between rTMS and propranolol on days 5, 10, and 30 (p>.05). We conclude that both cerebellar low-frequency rTMS and propranolol could be effective treatment options for patients with ET, but it is not clear which method is more effective.

SHOCK FROM NADOLOL OVERDOSE: THE FIRST REPORTED CASE OF SUCCESSFULLY TREATED WITH CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT)

SHOCK FROM NADOLOL OVERDOSE: THE FIRST REPORTED CASE OF SUCCESSFULLY TREATED WITH CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT)

Activation of Sympathetic Nervous System Contributes to Erthroprotein Gene Upregulation by Hypobaric Hypoxia

Hypobaric hypoxia (HH) experienced at high altitude initiates a series of physiological adaptations to maintain homeostasis. One such adaptation is the activation of the Epo gene which encodes the glycoprotein hormone erythropoietin (EPO). Increased circulating EPO levels defend against HH by facilitating blood O2 transport through increasing red blood cell production. HH also increases blood pressure (BP) through activation of the sympathetic nervous system and the ensuing elevation of circulating catecholamine levels. The present study examined the role of sympathetic nerve activation in HH‐evoked Epo gene activation and elevated circulating levels of EPO. Studies were performed on adult, male wild‐type (WT) mice treated with 18 hours of HH (0.4 atmospheres), simulating low O2 condition experienced at high altitude. Our results showed increased renal Epo gene abundance and elevated plasma EPO levels. Remarkably, these responses were either markedly attenuated or absent in mice with selective ablation of adrenal medulla as well as after treatment with propranolol, a non‐selective beta‐adrenergic receptor blocker. Moreover, infusion of epinephrine alone activated renal Epo gene and elevated plasma EPO levels. These results suggest that sympathetic nerve activation and the ensuing increase in plasma epinephrine contribute to Epo gene activation by HH.

β-blockers in advanced cirrhosis: More friend than enemy

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.

Treatment with beta-blockers normalizes RyR2 phosphorylation and calcium spark activity in atrial myocytes from patients with atrial fibrillation

Abstract Background Atrial fibrillation has been associated with an increase in ryanodine receptor (RyR2) phosphorylation and local calcium release (calcium sparks). Carvedilol, a nonselective beta-adrenergic receptor blocker also inhibits the cardiac ryanodine receptor (RyR2), but it has been suggested that the enantiomer R-carvedilol only inhibits RyR2 activity and hence has the potential to inhibit calcium sparks without affecting RyR2 phosphorylation. Purpose This study aimed to determine the ability of the enantiomers R- and S-carvedilol to reverse RyR2 phosphorylation at s2808 and calcium sparks induced by the β2-adrenergic agonist fenoterol, in order to determine the relationship between RyR2 phosphorylation at s2808 and calcium spark frequency, and to assess the efficacy of R- and S-carvedilol. Methods Human right atrial myocytes were isolated and subjected to immunofluorescent labelling of total and s2808 phosphorylated RyR2, or loaded with fluo-4 and subjected to confocal calcium imaging. Beta-adrenergic receptors were first activated with 3μM fenoterol and then inhibited by different concentrations of carvedilol R- or S-enantiomers. Results Incubation of myocytes with fenoterol increased the s2808/RyR2 ratio from 0.32±0.03 to 0.66±0.05 (n=18, p<0.001). Incubation with 0.1, 0.3, 1 or 3μM R-carvedilol in the presence of fenoterol changed the s2808/RyR2 ratio to 0.64±0.05, 0.44±0.04, 0.34±0.07 and 0.28±0.05 (p<0.01) respectively. For comparison 3μM S-carvedilol reduced the s2808/RyR2 ratio to 0.23±0.06 in myocytes from 5 patients (p<0.01). Confocal calcium imaging revealed that fenoterol increased the spark density from 0.28±0.04 to 1.24±0.25 events/s/1000μm2 (n=9, p<0.01) and addition of 0.1, 0.3, or 1μM R-carvedilol changed the frequency to 1.32±0.52, 0.38±0.05, and 0.15±0.05 events/s/1000μm2 (p<0.01) respectively. Analysis of atrial myocytes from patients without atrial fibrillation revealed that the s2808/RyR2 ratio was similar in 25 patients treated with beta-blockers (0.39±0.04) and 57 that did not receive beta-blockers (0.44±0.03, p=0.33) while the s2808/RyR2 ratio was significantly smaller in 16 patients with atrial fibrillation receiving beta-blockers (0.43±0.08) than in 5 patients that did not (0.80±0.19, p<0.05). Conclusions R-carvedilol reverses the effects of beta-adrenergic stimulation on s2808 phosphorylation and calcium sparks in human atrial myocytes, and treatment with beta-blockers reduces excessive RyR2 phosphorylation at s2808 in patients with atrial fibrillation to levels observed in those without the arrhythmia, pointing to beta-adrenergic receptors as a target for controlling RyR2 phophorylation and activity in atrial fibrillation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation & Spanish Ministry of Health and Consume

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

Long-term results of variceal bleeding management in 302 patients with chronic extrahepatic portal vein obstruction.

Treatment modalities of variceal bleeding or rebleeding for extrahepatic portal vein obstruction (EHPVO) are limited, and their long-term results and prognostic factors are unclear. This study aimed at assessing the long-term results of EHPVO treated with current recommendations and investigating the influencing factors. Between 2009 and 2016, 302 consecutive patients with EHPVO were included. Watch-and-wait policy was applied for those with no (n=59) or small varices (n=55), nonselective beta-adrenergic blocker and nonselective beta-adrenergic blocker plus endotherapy were for primary (n=115) and secondary prophylaxis (n=87), transjugular intrahepatic portosystemic shunt (TIPS) or combination therapy was for those with recurrent bleeding (n=92). The median follow up was 58.8months. The 1-, 3-, and 5-year cumulative rates were 3.6%, 19.2%, 32.3% for small varices development and 4.5%, 30.9%, 53.4% for large varices development. The 1-, 3-, and 5-year cumulative rates were 11.1%, 20.9%, and 34.9% for first variceal bleeding and 16.0%, 26.9%, and 33.6% for variceal rebleeding. For those with recurrent variceal bleeding, only TIPS (n=37, technical success rate: 90.2%) was associated with a reduced risk of variceal rebleeding (1-, 3-, and 5-year: 5.6%, 11.7%, and 21.9%). The 1-, 3-, and 5-year survival rates were 96.9%, 95.8%, and 91.9%. Prothrombotic factors and anticoagulation did not influence the risk of variceal bleeding, rebleeding, and survival. By applying the same variceal management as recommended for patients with liver cirrhosis, patients with non-cirrhotic EHPVO showed a similar development of varices and variceal bleeding. This is also true for the beneficial effect of TIPS to prevent rebleeding.

Complete atrioventricular block due to timolol eye drops: a case report and literature review

BackgroundTimolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block.Case presentationA 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (− 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup.ConclusionWe conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.

Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression

Propranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined. However, it is necessary to take into account all the properties of propranolol to select a drug that could be efficiently combined with. Propranolol was reported to block the late phase of autophagy. Hence, we hypothesized that in condition enhancing autophagy flux, cancer cells should be especially sensitive to propranolol. 2DG, a glycolysis inhibitor, is an anti-tumor agent having limited effect in monotherapy notably due to induction of pro-survival autophagy. Here, we report that treatment of cancer cells with propranolol in combination with the glycolysis inhibitor 2DG induced a massive accumulation of autophagosome due to autophagy blockade. The propranolol +2DG treatment efficiently prevents prostate cancer cell proliferation, induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics and aggravates ER stress in vitro and also suppresses tumor growth in vivo. Our study underlines for the first time the interest to take advantage of the ability of propranolol to inhibit autophagy to design new anti-cancer therapies.

PRIMARY OPEN-ANGLE GLAUCOMA IN ONCOLOGIC PATIENTS

Актуальность. Снижение зрительных функций при глаукоме неблагоприятно сказывается на качестве жизни онкологических больных. Но и сама злокачественная опухоль, как и методы ее лечения, могут вызывать прогрессирование глаукомы.

From Eye Drops to ICU, a Case Report of Three Side Effects of Ophthalmic Timolol Maleate in the Same Patient.

Timolol Maleate (also called Timolol) is a nonselective beta-adrenergic blocker and a class II antiarrhythmic drug, which is used to treat intraocular hypertension. It has been reported to cause systemic side effects especially in elderly patients with other comorbidities. These side effects are due to systemic absorption of the drug and it is known that Timolol is measurable in the serum following ophthalmic use. Chances of life threatening side effects increase if these are coprescribed with other cardiodepressant drugs like calcium channel or systemic beta blockers. We report a case where an elderly patient was admitted with three side effects of Timolol and his condition required ICU admission with mechanical ventilation and temporary transvenous pacing. The case emphasizes the need of raising awareness among physicians of such medications about the potential side effects and drug interactions. A close liaison among patient's physicians is suggested.

An observational study of bimatoprost 0.01% in patients on prior intraocular pressure-lowering therapy: the Canadian Lumigan(®) RC Early Analysis Review (CLEAR) trial.

PurposeTo evaluate the ocular hyperemia and intraocular pressure (IOP)-lowering efficacy of bimatoprost 0.01% in subjects with elevated IOP due to primary open-angle glaucoma (POAG) or ocular hypertension (OHT) in a real-world clinical setting.Subjects and methodsThis open-label, 12-week, observational study was conducted at 67 centers in Canada. Subjects with elevated IOP due to POAG or OHT instilled bimatoprost 0.01% as monotherapy once daily. Ocular hyperemia was graded by the investigator at baseline, week 6, and week 12 using a standardized photographic 5-point grading scale. Change in IOP from baseline was also evaluated at these time points. This analysis includes the subgroup of 268 subjects who had been previously treated with latanoprost 0.005%, bimatoprost 0.03%, travoprost 0.004%, and travoprost 0.004% with SofZia™ or nonselective beta-adrenergic receptor blockers prior to the study.ResultsAfter 12 weeks of treatment with 0.01% bimatoprost, ocular hyperemia was graded as none-to-mild hyperemia (grades 0, +0.5, or +1) for 94.1% of subjects and as moderate-to-severe hyperemia (grades +2 or +3) for 5.9%. No statistically significant shifts in ocular hyperemia ratings were observed at week 12 for any of the prior IOP-lowering therapies except bimatoprost 0.03%, in which 20.8% of subjects experienced an improvement. The mean percentage change from baseline IOP at week 12 following the switch to bimatoprost 0.01% monotherapy ranged from −2.3%±17.3% to −26.3%±12.4%. Furthermore, the decreased mean percentage change from baseline IOP was statistically significant across all prior IOP-lowering medications, except for bimatoprost 0.03% at the 6- and 12-week visits and travoprost 0.004% at the 6-week visit.ConclusionThis observational study demonstrates that bimatoprost 0.01% was well tolerated among POAG and OHT subjects who switched from prior IOP-lowering medication. Furthermore, a switch in ocular hypertensive treatment to bimatoprost 0.01% was associated with an additional 10%–15% reduction in IOP.

Blood pressure lowering efficacy of nonselective beta-blockers for primary hypertension.

Beta-blockers are one of the classes of drugs frequently used to treat hypertension. Quantifying the blood pressure (BP) lowering effects of nonselective beta-blockers provides important information that aids clinical decision making. To quantify the dose-related effects of nonselective beta-adrenergic receptor blockers (beta-blockers) on systolic blood pressure (SBP) and diastolic blood pressure (DBP) as compared with placebo in people with primary hypertension. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2013. Randomized, double-blind, placebo-controlled, parallel or cross-over trials. Studies had to contain a nonselective beta-blocker monotherapy arm with a fixed dose. Participants enrolled into the studies had to have primary hypertension at baseline. Duration of studies had to be between three and 12 weeks. Two review authors (GW and AL) independently confirmed the inclusion of studies and extracted the data. We included 25 RCTs that evaluated the BP lowering effects of seven nonselective beta-blockers in 1264 people with hypertension. Among the 25 RCTs, four were parallel studies and 21 were cross-over studies. Overall, nonselective beta-blockers lowered systolic BP and diastolic BP compared with placebo. Nonselective beta-blockers, in the recommended dose range, did not showed a convincing dose-response relationship by direct comparison. The once (1x) and twice (2x) starting dose subgroups contained the largest sample size. The estimate of BP lowering efficacy for nonselective beta-blockers by combining the 1x and 2x starting dose subgroup was -10 mmHg (95% CI -11 to -8) for systolic BP and -7 mmHg (95% CI -8 to -6) for diastolic BP (low-quality evidence). Nonselective beta-blockers starting at the 1x recommended starting doses lowered heart rate by 12 beats per minute (95% CI 10 to 13) (low-quality evidence). The dose-response relationship in heart rate was evident by both direct and indirect comparison. Due to imprecision, there was no clear evidence of an effect of nonselective beta-blockers on pulse pressure in any dose subgroups except for a small reduction with the 2x starting dose (-2.2 mmHg, 95% CI -3.7 to -0.7) (very low quality evidence). The point estimates in the 1x, four times (4x) and eight times (8x) starting dose subgroups were similar to the 2x starting dose subgroup. Therefore, it would appear that if nonselective beta-blockers do lower pulse pressure, the magnitude is likely to be about 2 mmHg. There were very limited data (two studies) on withdrawals due to adverse effects (risk ratio (RR) 0.84; 95% CI 0.38 to 1.82). In people with mild-to-moderate hypertension, nonselective beta-blockers lowered peak BP by a mean of -10/-7 mmHg (systolic/diastolic) and reduced heart rate by 12 beats per minute. Propranolol and penbutolol were the two drugs that contributed to most of the data for nonselective beta-blockers. This estimate is likely exaggerated due to the presence of extreme outliers and other sources of bias. If we removed the extreme outliers from the analysis, the estimate for non-selective beta-blockers was lower (-8/-5 mmHg (systolic/diastolic)). Nonselective beta-blockers did not show a convincing graded dose-response in the recommended dose range for systolic BP and diastolic BP, while higher dose nonselective beta-blockers provided greater reduction of heart rate. Using higher dose nonselective beta-blockers might cause more side effects, such as bradycardia, without producing an additional BP lowering effect. The effect of nonselective beta-blockers on pulse pressure was likely small, at about 2 mmHg.

Propranolol-induced relaxation in the rat basilar artery

Propranolol is a non-selective beta-adrenergic receptor blocker used in the treatment of cardiovascular diseases and migraine prophylaxis. Although it has been shown that propranolol dilates the peripheral arteries of rat, its action in the central nervous system vasculature has not been investigated. In this study, the effects of propranolol in rat basilar artery were investigated. Basilar arteries from male Wistar rats were examined in a myograph system. The relaxant effects of propranolol, pindolol, atenolol, pizotifen and methysergide were examined in basilar arteries precontracted by serotonin or PGF2α. Only propranolol and pizotifen induced vasorelaxations; the pD2 values were 5.23±0.13 and 5.94±0.03; respectively. The vasorelaxation induced by propranolol and pizotifen was not affected by endothelium or the presence of l-NOARG and/or indomethacin. The calcium channel blocking activity of propranolol and pizotifen was compared with that of nifedipine in a calcium free solution with high K+ (60mM) concentration. These drugs shifted the concentration–response curves of calcium induced contractions with pA2 values of 5.45±0.04; 7.14±0.09; and 9.22±0.06 respectively. The P2Y receptor agonist UTP was used to induce sustained and stable contractions in basilar artery segments. Nifedipine caused a marked, but an incomplete relaxation. Cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum calcium channels, but not propranolol or pizotifen abolished the remaining tonus after partial relaxations obtained with nifedipine.These results suggest that propranolol causes vasorelaxation by blocking the L-type voltage-gated calcium channels in the rat basilar artery.