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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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Treatment with propranolol of 6 patients with idiopathic aquagenic pruritus.
Nosbaum, A, Pecquet, C, Bayrou, O, Amsler, E, Nicolas, JF, Bérard, F, Francès, C
The Journal of allergy and clinical immunology. 2011;(5):1113
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Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study.
Schepke, M, Wiest, R, Flacke, S, Heller, J, Stoffel-Wagner, B, Herold, T, Ghauri, M, Sauerbruch, T
The American journal of gastroenterology. 2008;(5):1152-8
Abstract
OBJECTIVES Angiotensin II receptor antagonists have been shown to moderately lower portal pressure in some patients with cirrhosis but may have adverse effects on kidney function. This study aimed at comparing the effects of a combined treatment using irbesartan plus propranolol with propranolol monotherapy on portal pressure and kidney function in patients with cirrhosis. METHODS Thirty-two patients were included (Child A/B/C: 13/18/1, etiology: 16 alcohol, 13 viral, 3 other; bilirubin 1.4 +/- 1.1 mg/dL, creatinine 0.86 +/- 0.20 mg/dL, baseline hepatic venous pressure gradient 18.7 +/- 5.3 mmHg). All patients received 20 mg propranolol b.i.d. Additionally, they randomly received either placebo (N = 15) or irbesartan (step-up dosage titration up to 300 mg/d, N = 17). Patients were followed at weekly intervals, re-evaluation of hepatic venous pressure gradient (HVPG) was performed after 8 wk. RESULTS One patient in the propranolol/irbesartan group was excluded due to variceal bleeding. No other adverse events occurred. Portal pressure declined in both groups (propranolol/irbesartan group 19.6 +/- 1.5 mmHg to 16.6 +/- 1.2 mmHg, P= 0.037, propranolol/placebo group 17.8 +/- 1.1 mmHg to 15.1 +/- 1.2 mmHg, P= 0.019). Sodium excretion significantly increased in the propranolol/irbesartan group (from 122 +/- 20 mmol/d to 230 +/- 23 mmol/d, P= 0.045), but not in the propranolol/placebo group. CONCLUSIONS Combination treatment of propranolol plus irbesartan is well tolerated in cirrhotic patients when titrating the angiotensin II antagonist in a step-up manner, and it increases sodium excretion in patients with compensated or moderately decompensated cirrhosis. Addition of irbesartan has no effect on portal pressure.
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Sodium Valproate versus Propranolol in paediatric migraine prophylaxis.
Ashrafi, MR, Shabanian, R, Zamani, GR, Mahfelati, F
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2005;(5):333-8
Abstract
In a randomized clinical trial the effect of Sodium Valproate in pediatric migraine prophylaxis was compared with that of Propranolol. One hundred and twenty patients with common migraine (migraine without aura) aged from 3 to 15 years who met the defined criteria enrolled into the study. Randomly the patients were divided in two groups of A and B, treating with sodium Valproate and Propranolol, respectively. Three phases of baseline period (phase I), titration and adjustment period (phases II) and fixed -dose treatment period (phase III) have been designed. A total of 57 patients in group A, and 58 patients in group B completed all phases of the trial. Seventy two percent of patients in group A and 69% of patients in group B have responded to Sodium Valproate and Propranolol, respectively, as a reduction of more than 50% in headache frequency per month. Further more both drugs have shown efficacy in reducing the severity and duration of headache and also better response to rescue medications (p value <0.01). There was no significant difference in all previously mentioned therapeutic effects between two groups (p value <0.05).
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The effect of propranolol on glyceryltrinitrate-induced headache and arterial response.
Tvedskov, JF, Thomsen, LL, Thomsen, LL, Iversen, HK, Williams, P, Gibson, A, Jenkins, K, Peck, R, Olesen, J
Cephalalgia : an international journal of headache. 2004;(12):1076-87
Abstract
Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.