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The impact of propranolol on nitric oxide and total antioxidant capacity in patients with resistant hypertension-evidence from the APPROPRIATE trial.
Ranasinghe, HN, Fernando, N, Handunnetti, S, Weeratunga, PN, Katulanda, P, Rajapakse, S, Galappatthy, P, Constantine, GR
BMC research notes. 2020;(1):228
Abstract
OBJECTIVES The objective was to assess the effect of propranolol on oxidative stress and anti-oxidant potential in patients with resistant hypertension as a secondary analysis of the APPROPRIATE trial. This randomized double blinded clinical trial recruited patients with resistant hypertension and allocated forty patients to propranolol and placebo in 1:1 ratio. The pro-oxidant state (nitrate and nitrite) was assessed using modified Griess assay. The total anti-oxidant capacity was measured using ABTS assay. RESULTS Analysis was performed for 18 patients from the propranolol group and 15 from the placebo group. A decline in end point ambulatory blood pressure (p = 0.031) and greater mean reduction in office SBP (29.7 ± 13.0 mmHg, p = 0.021) was noted in the propranolol arm. Nitrate and nitrite levels were lower at the end of a 90 day follow up period in both arms, with a greater mean reduction with propranolol. A significant increase in the AOC was noted in both arms with higher incremental value with Propranolol. The findings of this study do not demonstrate a statistically significant effect of propranolol on the oxidative stress/antioxidant balance in patients with resistant hypertension. The observed trends merit further evaluation.
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Association of Weight-Adjusted Caffeine and β-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery.
Roizenblatt, M, Dias Gomes Barrios Marin, V, Grupenmacher, AT, Muralha, F, Faber, J, Jiramongkolchai, K, Gehlbach, PL, Farah, ME, Belfort, R, Maia, M
JAMA ophthalmology. 2020;(8):819-825
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Abstract
IMPORTANCE Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. OBJECTIVES To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. DESIGN, SETTINGS, AND PARTICIPANTS This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). INTERVENTIONS Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. MAIN OUTCOMES AND MEASURES An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. RESULTS Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, -53.0; 95% CI, -99.3 to -6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, -12.0; 95% CI, -21.2 to -2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, -51.0; 95% CI, -77.6 to -24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, -16.0; 95% CI, -31.8 to -0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). CONCLUSIONS AND RELEVANCE The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.
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Thyrotoxicosis: Diagnosis and Management.
Sharma, A, Stan, MN
Mayo Clinic proceedings. 2019;(6):1048-1064
Abstract
Thyrotoxicosis is the clinical manifestation of excess thyroid hormone action at the tissue level due to inappropriately high circulating thyroid hormone concentrations. Hyperthyroidism, a subset of thyrotoxicosis, refers specifically to excess thyroid hormone synthesis and secretion by the thyroid gland. We performed a review of the literature on these topics utilizing published data in PubMed and MEDLINE. In this review, we discuss the more common etiologies of thyrotoxicosis, focusing on the current approach to diagnosis and management, new trends in those directions, and potential upcoming changes in the field.
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Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis.
Stritzke, A, Kabra, N, Kaur, S, Robertson, HL, Lodha, A
Journal of perinatology : official journal of the California Perinatal Association. 2019;(12):1584-1594
Abstract
OBJECTIVE To systematically assess the efficacy of oral beta blockage treatment in primary (before established) and secondary (in threshold stages) prevention of severe retinopathy of prematurity (ROP) in premature infants born ≤32 weeks gestational age. STUDY DESIGN Following the PRISMA guidelines, published literature was systematically assessed up to April 27, 2018. Trials and observational studies, in which beta blockage was used to prevent severe ROP (defined as stage ≥3, or requiring treatment) were included. Meta-analyses including random effects models were conducted to determine the overall effect of oral beta blockage on prevention of ROP. RESULTS Six studies (five clinical trials and one observational study) including 461 infants met inclusion criteria using propranolol. The pooled relative risk (RR) of severe ROP in the primary and secondary prophylaxis groups were 0.65 (95% CI 0.43-0.98, NNT = 7) and 0.48 (95% CI 0.35-0.65, NNT = 6) in RCTs, respectively. The RR of severe ROP in one observational study was 0.21 (95% CI 0.08-0.55) with a NNT of 3. There were low heterogeneity and publication bias. Side effects occurred in 8.4% of participants on propranolol. CONCLUSIONS Systematic assessment of studies showed that prophylactic oral propranolol appeared to be effective in preventing severe ROP in premature infants ≤32 weeks gestational age. Additional well powered, multinational, randomized control trials reporting on long-term outcomes are needed.
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Portal hypertension and its management in children.
Grammatikopoulos, T, McKiernan, PJ, Dhawan, A
Archives of disease in childhood. 2018;(2):186-191
Abstract
Portal hypertension (PHT), defined as raised intravascular pressure in the portal system, is a complication of chronic liver disease or liver vascular occlusion. Advances in our ability to diagnose and monitor the condition but also predict the risk of gastrointestinal bleeding have enabled us to optimise the management of children with PHT either at a surveillance or at a postbleeding stage. A consensus among paediatric centres in the classification of varices can be beneficial in streamlining future paediatric studies. New invasive (endoscopic and surgical procedures) and non-invasive (pharmacotherapy) techniques are currently used enabling clinicians to reduce mortality and morbidity in children with PHT.
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Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.
Filippi, L, Cavallaro, G, Berti, E, Padrini, L, Araimo, G, Regiroli, G, Bozzetti, V, De Angelis, C, Tagliabue, P, Tomasini, B, et al
BMC pediatrics. 2017;(1):165
Abstract
BACKGROUND Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.
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Carvedilol versus propranolol effect on hepatic venous pressure gradient at 1 month in patients with index variceal bleed: RCT.
Gupta, V, Rawat, R, Shalimar, , Saraya, A
Hepatology international. 2017;(2):181-187
Abstract
BACKGROUND AND AIMS Endoscopic variceal ligation (EVL) plus beta blocker is the mainstay treatment after index bleed to prevent rebleed. Primary objective of this study was to compare EVL plus propranolol versus EVL plus carvedilol on reduction of HVPG after 1 month of therapy. METHODS Patients of cirrhosis presenting with index esophageal variceal bleed received standard treatment (Somatostatin therapy f/b EVL) following which HVPG was measured and patients were randomized to propranolol or carvedilol group if HVPG was >12 mmHg. Standard endotherapy protocol was continued in both groups. HVPG was again measured at 1 month of treatment. RESULTS Out of 129 patients of index esophageal variceal bleed, 59 patients were eligible and randomized into carvedilol (n = 30) and propranolol (n = 29). At 1 month of treatment, decrease in heart rate, mean arterial blood pressure (MAP) and HVPG was significant within each group (p = 0.001). Percentage decrease in MAP was significantly more in carvedilol group as compared to propranolol group (p = 0.04). Number of HVPG responders (HVPG decrease >20 % or below 12 mmHg) was significantly more in carvedilol group (22/29) as compared to propranolol group (14/28), p = 0.04. CONCLUSION Carvedilol is more effective in reducing portal pressure in patients with cirrhosis with esophageal bleed. Though a larger study is required to substantiate this, the results in this study are promising for carvedilol. Clinical trials online government registry (CTRI/2013/10/004119). Trial registration number CTRI/2013/10/004119.
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Long-term survival in the randomized trial of drug treatment in mild to moderate hypertension of the Oslo study 1972-3.
Holme, I, Kjeldsen, SE
European journal of internal medicine. 2015;(2):123-6
Abstract
BACKGROUND In the Oslo cardiovascular study of 1972-3 a 5-year randomized trial in mild to moderate hypertension was performed. Several changes in treatment practices have been recommended since that time. We followed the mortality patterns up to 40 years. METHODS Invited to the Oslo study screening were 25,915 middle-aged men and 16,203 (63%) participated. Reexaminations were done to select suitable participants into the trial. Men had blood pressure 150-179/95-109 mm Hg and the active group (n=406) was treated with thiazides, alpha-methyldopa and propranolol versus untreated controls (n=379). Cox regression analysis was used for statistical analyses. RESULTS There was no trend towards reduction in total mortality by treatment. A nominally significant increase in risk of death at first myocardial infarction was observed in the trial treatment group across the follow-up period, HR=1.51 (1.01-2.25); (P=0.042). The excess risk developed rapidly during the first 15 years, but the gap between the groups diminished to a large extent during the next 15 years, but the curves stayed at a certain distance for the last 10 years. Cerebrovascular death tended to be non-significantly reduced, HR=0.85 (0.52-1.41). CONCLUSIONS Drug treatment of mild hypertensive men initiated in the 1970s did not reduce mortality at first MI or total mortality. However, during the period (late 1980s and whole 1990s), when large changes in hypertension treatment practices occurred into regimes with more use of combination therapies including metabolically neutral drugs at lower doses, beneficial effects on MI mortality could be observed.
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Trauma reactivation plus propranolol is associated with durably low physiological responding during subsequent script-driven traumatic imagery.
Brunet, A, Thomas, É, Saumier, D, Ashbaugh, AR, Azzoug, A, Pitman, RK, Orr, SP, Tremblay, J
Canadian journal of psychiatry. Revue canadienne de psychiatrie. 2014;(4):228-32
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OBJECTIVE In a previous, double-blind, placebo-controlled study, patients with posttraumatic stress disorder (PTSD) showed lower physiological response during script-driven traumatic imagery 1 week after receiving a single dose of propranolol given after the retrieval of a traumatic memory. We hypothesized that this effect would extend beyond 1 week using a modified treatment approach. METHOD Twenty-eight participants with PTSD read an account of their traumatic event once weekly for 6 consecutive weeks under the influence of open-label propranolol. One week and 4-months later, skin conductance, heart rate, and left corrugator electromyogram responses were measured while participants engaged in script-driven mental imagery of their traumatic event. Results from the 22 study participants were compared with results from treated and untreated participants in a previously published trial. RESULTS Most participants in our study were classified as non-PTSD cases at posttreatment and follow-up according to a psychophysiological discriminant function analysis. Posttreatment skin conductance and heart rate responses of the current (propranolol-treated) participants were lower than those of placebo participants from the previous study. No difference was observed between physiological responding measured posttreatment and at follow-up. CONCLUSIONS Low physiological responding during script-driven traumatic imagery after treatment extends up to 4 months, demonstrating the durability of the treatment effect's. Limitations include the absence of a placebo-controlled group and lack of physiological baseline measures. Despite these limitations, results point to the need for future trials examining the clinical efficacy of trauma reactivation plus propranolol, as it has the potential to become a novel, cost- and time-effective treatment for PTSD.
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MALDI-TOF MS imaging of controlled release implants.
Kreye, F, Hamm, G, Karrout, Y, Legouffe, R, Bonnel, D, Siepmann, F, Siepmann, J
Journal of controlled release : official journal of the Controlled Release Society. 2012;(1):98-108
Abstract
MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) imaging is used to characterize novel lipid implants allowing for controlled drug delivery. Importantly, this innovative technique provides crucial information on the inner structure of the implants before and after exposure to the release medium and does not require the addition of marker substances. Implants were prepared by extrusion at room temperature. Thus, in contrast to hot-melt extruded systems, the risks of drug inactivation and solid state transformations of the lipid matrix former are reduced. Hydrogenated/hardened soybean oil and glyceryl tristearate were studied as lipids and propranolol hydrochloride and theophylline as drugs, exhibiting significantly different solubility in water. The implants were also characterized by optical microscopy, differential scanning calorimetry, water uptake and lipid erosion studies, mathematical modeling as well as in vitro drug release measurements. Importantly, broad spectra of drug release patterns with release periods ranging from a few days up to several months could easily be provided when varying the initial drug content and type of lipid, irrespective of the type of drug. The diameter of the implants can be as small as 1mm, facilitating injection. MALDI-TOF MS imaging revealed homogeneous macroscopic drug distributions within the systems, but steep drug concentration gradients in radial and axial direction at the lower micrometer level, indicating drug- and lipid-rich domains. As the implants do not significantly swell, local irritation upon administration due to mechanical stress can be expected to be limited. Good agreement between experimentally measured and theoretically calculated drug release kinetics revealed that diffusional mass transport plays a major role for the control of drug release from this type of advanced drug delivery systems.