Influence of renin-angiotensin system blockades on vascular access survival in patients on maintenance hemodialysis.

INTRODUCTION: Results on the association between the use of renin-angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. METHODS: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). RESULTS: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. CONCLUSIONS: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear.

Cardiovascular outcomes of ß-blocker-calcium channel blocker initial dual therapy vs. other initial dual therapies in Chinese patients with hypertension: A real-world retrospective study.

This retrospective study compared cardiovascular (CV) outcomes between initial ß-blocker (BB) + calcium channel blocker (CCB) dual therapy ("B + C") and other initial dual therapies in Chinese newly diagnosed hypertensive patients. In this study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received any initial optimal dual therapy recommended by the Chinese hypertension guideline were included. 1:2 propensity score matching (PSM) was used to balance baseline characteristics between patients receiving B + C and patients receiving other initial dual therapies ("Others"). The primary outcome was major adverse cardiovascular events (MACE) that occurred from January 01, 2012 to December 31, 2017, consisting of non-fatal stroke, non-fatal myocardial infarction (MI), non-fatal chronic heart failure (CHF), and all-cause death. Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. After the PSM, 6227 patients receiving B + C and 12 454 patients receiving Others were included. Compared to patients receiving Others, patients receiving B + C had a significantly lower risk of MACE (hazard ratio [HR] 0.85; 95% confidential interval [CI] 0.78-0.92; p < .001), non-fatal stroke (HR 0.89; 95% CI 0.81-0.98; p = .018) and non-fatal CHF (HR 0.74; 95% CI 0.63-0.86; p < .0001). Additionally, differences in risks of non-fatal MI and all-cause death between the 2 treatment cohorts were not statistically significant. In conclusion, BB + CCB initial dual therapy was associated with a lower risk of MACE, stroke, and CHF than other optimal initial dual therapies recommended by the Chinese hypertension guideline in Chinese newly diagnosed hypertensive patients.

Diferencias de género en la titulación de fármacos de pacientes con insuficiencia cardiaca y fracción de eyección reducida del ensayo ETIFIC / Gender differences in drug titration among heart failure patients with reduced ejection fraction in the ETIFIC trial

Introducción y objetivos El tratamiento óptimo disminuye la mortalidad y hospitalizaciones por insuficiencia cardiaca (IC) en pacientes con IC y fracción de eyección reducida. En los ensayos clínicos las mujeres estuvieron infrarrepresentadas y no fueron evaluadas específicamente. Este estudio buscó comparar la seguridad y efectividad de titulación (ajuste de dosis) de fármacos en mujeres y varones. Métodos Estudio post hoc de género del ensayo aleatorizado multicéntrico ETIFIC. Se incluyeron pacientes hospitalizados con IC de novo y fracción de eyección reducida. Proceso estructurado de titulación en unidades de IC. Objetivo principal: la dosis relativa media de bloqueadores beta (% de la dosis objetivo) alcanzada por mujeres frente a varones. Objetivos secundarios: dosis relativas medias de otros fármacos de IC, eventos adversos y resultados clínicos a 6 meses. Resultados Se incluyeron 320 pacientes, 83 (25,93%) mujeres y 237 (74,06%) varones. (76 frente a 213 analizados). Media±desviación estándar de dosis relativa de bloqueadores beta mujeres frente a varones: 62,08±30,72% frente a 64,4±32,77%; diferencia −2,32%; IC95%, −10,58-5,94; p=0,580, antagonistas del receptor de mineralocorticoides 79,85±27,72% comparado con 67,29±31,43%; p=0,003, sin diferencias significativas en dosificación de otros fármacos. El análisis multivariante no encontró diferencias significativas. Mortalidad cardiovascular 1 (1,20%) frente a 3 (1,26%), p=1 y 0 hospitalizaciones por IC (0,00%) frente a 10 (4,22%), p=0,125. Conclusiones En un análisis post hoc del ensayo ETIFIC de titulación en IC no encontramos diferencias de género significativas en dosificación, mortalidad cardiovascular y hospitalizaciones por IC (AU)

Introduction and objectives Optimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men. Methods This post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months. Results A total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean±standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08%±30.72% vs 64.4%±32.77%, with a difference of−2.32% (95%CI,−10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85%±27.72% vs 67.29%±31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P=1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P=.125. Conclusions In a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations (AU)

A transcription factor is the target of propranolol treatment in infantile hemangioma.

Propranolol is a nonselective ß-adrenergic receptor (AR) blocker that has been the first-line therapy for problematic infantile hemangioma (IH), the most frequent childhood vascular tumor. Although IHs are benign and eventually regress spontaneously, at least 15% of patients require treatment. Despite the extensive use of propranolol for IH treatment, its mode of action remains unclear. In this issue of the JCI, Seebauer et al. investigated the cellular and molecular consequences of propranolol treatment on IH vascular tumor formation in a murine model of IH. The efficacy of propranolol was independent of its ß-AR blocker activity and was attributable to the direct targeting of the transcription factor SOX18, which, in turn, reduced hemangioma blood vessel formation. We believe these results will guide clinical translation for the use of more efficient and safer therapies for IH and possibly for other vascular anomalies in which SOX18 plays a role.

Antipsychotics Use Is Associated With Greater Adherence to Cardiometabolic Medications in Patients With Schizophrenia: Results From a Nationwide, Within-subject Design Study.

BACKGROUND: People with schizophrenia/schizoaffective disorder (schizophrenia) die early, largely due to cardiovascular-related mortality. Antipsychotics are associated with lower mortality. We aimed to explore whether antipsychotic use can reduce discontinuation of medications for cardiovascular risk factors and diseases ("cardiometacolic drugs"), using a within-study design controlling for subject-related factors. METHODS: Persons diagnosed with schizophrenia between 1972 and 2014, aged <65 years at cohort entry were identified in Finnish national databases. Four subcohorts were formed based on cardiometabolic drug use during the follow-up period, 1996-2017, namely statin (n = 14,047), antidiabetic (n = 13,070), antihypertensive (n = 17,227), and beta-blocker (n = 21,464) users. To control for subject-related factors, including likelihood of adherence as a trait characteristic, we conducted a within-subject study comparing the risk of discontinuation of each cardiometabolic drug during periods on vs off antipsychotics within each subject. We also accounted for number of psychiatric and nonpsychiatric visits in sensitivity analyses. RESULTS: In 52,607 subjects with schizophrenia, any antipsychotic use vs nonuse was associated with decreased discontinuation risk of antidiabetics (adjusted hazard ratio [aHR] = 0.56, 95% confidence interval [CI] = 0.47-0.66), statins (aHR = 0.61, 95%CI = 0.53-0.70), antihypertensives (aHR = 0.63, 95%CI = 0.56-0.71), and beta-blockers (aHR = 0.79, 95%CI = 0.73-0.87). Antipsychotics ranking best for discontinuation of all cardiometabolic drug categories were clozapine (aHR range = 0.34-0.55), followed by olanzapine (aHR = 0.43-0.71). For statins, aHRs ranged from aHR = 0.30 (95%CI = 0.09-0.98) (flupentixol-long-acting injectable (LAI) to aHR = 0.71 (95%CI = 0.52-0.97) (risperidone-LAI), for anti-diabetic medications from aHR = 0.37 (95%CI = 0.28-0.50) (clozapine) to aHR = 0.70 (95%CI = 0.53-0.92) (quetiapine), for antihypertensives from aHR = 0.14 (95%CI = 0.04-0.46) (paliperidone-LAI) to aHR = 0.69 (95%CI = 0.54-0.88) (perphenazine), for beta-blockers from aHR = 0.55 (95%CI = 0.48-0.63) (clozapine) to aHR = 0.76 (95%CI = 0.59-0.99) (perphenazine-LAI). The decreased risk of discontinuation associated with antipsychotic use somewhat varied between age strata. Sensitivity analyses confirmed main findings. DISCUSSION: In this national database within-subject design study, current antipsychotic use was associated with substantially decreased risk of discontinuation of statins, anti-diabetics, antihypertensives, and beta-blockers, which might explain reduced cardiovascular mortality observed with antipsychotics in people with schizophrenia.

The Effect of Intravenous and Oral Beta-Blocker Use in Patients with Type B Thoracic Aortic Dissection.

BACKGROUND: Beta-blockers have become the cornerstone for medical management in patients with chronic type B aortic dissection (TBAD). However, the effect of being on and/or receiving intravenous beta-blockers during hospitalization on outcomes of surgical repair of TBAD is not fully described. We sought to investigate this association during open surgical repair (OSR) and endovascular (Endo) intervention for nontraumatic TBAD. METHODS: The Premier Healthcare Database was inquired (June/2009-March/2015). Patients with nontraumatic isolated TBAD were identified via ICD-9-CM diagnosis and procedural codes. Patients with codes that indicated TAAD were excluded. In-hospital mortality, cardiac complications (CHF, MI, arrythmia) and stroke were evaluated. Log binomial regression analyses with bootstrapping were performed to assess the relative risk of adverse outcomes. RESULTS: A total of 1,752 were admitted for OSR (54.3%) and Endo (45.7%) TBAD repair. Use of oral beta blocker (BB) was 16.0% in OSR and 56.4% in Endo groups. In each arm, patients on BB were more likely to be diabetic, on aspirin or statin and more likely to receive additional IV BB than nonBB patients. There was no significant difference in age, sex, race, or prior history of CHF between BB and nonBB groups. Mortality was proportionally lower in patients on BB in OSR group (7.9% vs. 16.7%; P = 0.006) and Endo (3.3% vs. 9.2%; P < 0.001). The adjusted relative risk for mortality and stroke were significantly lower in oral BB recipients compared with none [aRR (95% CI): 0.53 (0.32-0.90) and 0.46 (0.25-0.87); both P ≤ 0.02]. IV metoprolol was the only IV BB that reduced mortality [aRR (95% CI): 0.62 (0.46-0.85); P = 0.003]. A dose of ≤10 mg was associated with significant mortality reduction: 6.3% (3.0-9.5%) compared with 8.1% (4.6-11.6%) in no IV BB group. Cardiac complications were not affected by BB use. CONCLUSIONS: For patients with nontraumatic TBAD, use of oral BB was associated with significant protection against in-hospital mortality and stroke following repair. Metoprolol was the only Intravenous BB type associated with improved survival. Further research is warranted to elucidate the effect of beta-blockers on the long-term surgical outcomes of TBAD.

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking ß-blockers.

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (Pint = 0.043 and Pint = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.

In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment.

Most common intraocular pressure (IOP) reduction regimens for the management of glaucoma include the topical use of eye drops, a dosage form that is associated with short residence time at the site of action, increased dosing frequency, and reduced patient compliance. In situ gelling nanofiber films comprising poly(vinyl alcohol) and Poloxamer 407 were fabricated via electrospinning for the ocular delivery of timolol maleate (TM), aiming to sustain the IOP-lowering effect of the ß-blocker, compared to conventional eye drops. The electrospinning process was optimized, and the physicochemical properties of the developed formulations were thoroughly investigated. The fiber diameters of the drug-loaded films ranged between 123 and 145 nm and the drug content between 5.85 and 7.83% w/w. Total in vitro drug release from the ocular films was attained within 15 min following first-order kinetics, showing higher apparent permeability (Papp) values across porcine corneas compared to the drug's solution. The fabricated films did not induce any ocular irritation as evidenced by both the hen's egg test on chorioallantoic membrane and the in vivo Draize test. In vivo administration of the ocular films in rabbits induced a faster onset of action and a sustained IOP-lowering effect up to 24 h compared to TM solution, suggesting that the proposed ocular films are promising systems for the sustained topical delivery of TM.

Implication of Ivabradine Therapy in Up-Titrating Beta-Blocker Dose in Patients with Systolic Dysfunction.

Ivabradine, which reduces heart rate (HR) without affecting sympathetic nerve activity, improves mortality and morbidity in patients with systolic dysfunction. However, its impact on up-titrating a concomitant beta-blocker dose in such a cohort, via increasing cardiac output and blood pressure and improving tolerability to beta-blockers, remains unknown. In this single-center, prospective, randomized control trial, patients with systolic dysfunction, defined as left ventricular ejection fraction < 50%, sinus rhythm, heart rate > 75 bpm, systolic blood pressure between 90 and 110 mmHg, and New York Heart Association functional class III or IV, who are refractory to up-titration of a beta-blocker due to symptomatic hypotension, dizziness, or worsening heart failure, were assigned to the 20 ivabradine arm or the 20 conventional therapy arm and followed-up for 6 months. The primary outcome is the daily dose of beta-blocker at 6-months follow-up. The secondary outcomes are echocardiographic parameters including overlap between E-wave and A-wave in transmitral diastolic filling flow, plasma B-type natriuretic peptide level, 6-minute walk distance, and heart failure readmission rate. By conducting this study, we hope to demonstrate the clinical benefit of ivabradine therapy in up-titrating beta-blockers and improving clinical outcomes in patients with systolic dysfunction.

Effect of ß-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet ß-blockers are commonly used in HFpEF despite the lack of robust evidence. OBJECTIVES: This study aimed to evaluate the effect of ß-blocker withdrawal on peak oxygen consumption (peak Vo2) in patients with HFpEF and chronotropic incompetence. METHODS: This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with ß-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) ß-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo2 and percentage of predicted peak Vo2 (peak Vo2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. RESULTS: The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo2 and peak Vo2% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo2 and peak Vo2% increased significantly after ß-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively). CONCLUSIONS: ß-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. ß-blocker use in HFpEF deserves profound re-evaluation. (ß-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39).

Blockade of beta adrenergic receptors protects the blood brain barrier and reduces systemic pathology caused by HIV-1 Nef protein.

Combination antiretroviral therapy (cART) targets viral replication, but early viral protein production by astrocytes may still occur and contribute to the progression of HIV-1 associated neurocognitive disorders and secondary complications seen in patients receiving cART. In prior work with our model, astrocytic HIV-1 Nef expression exhibits neurotoxic effects leading to neurological damage, learning impairment, and immune upregulation that induces inflammation in the lungs and small intestine (SI). In this follow-up study, we focus on the sympathetic nervous system (SNS) as the important branch for peripheral inflammation resulting from astrocytic Nef expression. Male and female Sprague Dawley rats were infused with transfected astrocytes to produce Nef. The rats were divided in four groups: Nef, Nef + propranolol, propranolol and naïve. The beta-adrenergic blocker, propranolol, was administered for 3 consecutive days, starting one day prior to surgery. Two days after the surgery, the rats were sacrificed, and then blood, brain, small intestine (SI), and lung tissues were collected. Levels of IL-1ß were higher in both male and female rats, and treatment with propranolol restored IL-1ß to basal levels. We observed that Nef expression decreased staining of the tight junction protein claudin-5 in brain tissue while animals co-treated with propranolol restored claudin-5 expression. Lungs and SI of rats in the Nef group showed histological signs of damage including larger Peyer's Patches, increased tissue thickness, and infiltration of immune cells; these findings were abrogated by propranolol co-treatment. Results suggest that interruption of the beta adrenergic signaling reduces the peripheral organ inflammation caused after Nef expression in astrocytes of the brain.

Benefits of prescribing low-dose digoxin in atrial fibrillation.

INTRODUCTION: The role of digoxin (cardiac glycoside) in controlling the heart rate (HR) for the treatment of atrial fibrillation (AF) patients has not been explored in depth. METHODS: To contribute to the limited data, our team conducted retrospective analysis of the clinical records of 1444 AF patients. We divided the AF patients into two groups, wherein group 1 patients were treated with beta-blockers (BB), low-dose digoxin, and an anticoagulant (vitamin K antagonist/factor-IIa inhibitor/factor-Xa inhibitor), and group 2 patients were treated with just BB and an anticoagulant. Our objectives were to compare the impact of combination therapy of BB and digoxin on the resting HR in patients with permanent AF and the patients' quality of life (QOL) at periodic intervals. RESULTS: The findings of our study showed a better control of the resting HR rate (<110bpm) and an improved QOL among the group 1 patients when compared with group 2 patients. CONCLUSION: Our findings are indicative of the favorable clinical outcomes that resulted from the addition of a low-dose of digoxin to the AF treatment regimen. However, larger studies/trials elucidating the outcomes of AF patients treated with the dual rate control therapy are required, to clarify the role of digoxin, guide the choice of agents, and standardize the AF treatment protocol.

The association between developing Parkinson's disease and ß-Adrenoceptor acting agents use: A systematic review and meta-analysis.

INTRODUCTION: Parkinson's disease (PD) ranks the second most common neurodegenerative disease. Aside from genetic predisposition, many external factors such as traumatic brain injury and exposure of substances including pesticides also contribute to PD's pathogenesis. Many previous studies observed the association between the use of ß-adrenoceptor acting agents and risk of PD. OBJECTIVE: To conduct systematic review and meta-analysis to summarize whether the use of ß-agonist and ß-antagonist agents were associated with risk of PD. METHOD: We independently searched for published studies from EMBASE and MEDLINE databases from inception to February 2021. This meta-analysis includes 9 case-control studies and 1 cohort study meeting the eligibility criteria, with a total of 380,105 participants. RESULTS: Overall ß-antagonists use appeared to associate with increase PD risk with an odd ratio (OR) of 1.2 (95% CI 1.07-1.34). Propranolol and metoprolol had a statistically significant association with higher risk of PD: pooled OR was 1.67 (95% CI 1.22-2.29) and 1.07 (95% CI 1.03-1.1), respectively. On the other hand, ß-agonists significantly inverse association with PD risk with OR of 0.88 (95% CI 0.85-0.92). Salbutamol unexpectedly showed no statistical significance in reduced risk of PD with a pooled risk ratio of 1.0 (95% CI 0.87-1.16). CONCLUSION: Overall ß-antagonists, including propranolol and metoprolol, were associated with an increased risk of PD, in contrast to ß-agonists, which were associated with decreased the risk.

Beta-adrenergic glaucoma drugs reduce lymphatic clearance from the eye: A sequential photoacoustic imaging study.

Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect of 2 topical beta-adrenergic blockers, timolol and betaxolol, commonly used as glaucoma drugs, on lymphatic clearance of albumin from the aqueous humor to neck lymph nodes. Adult mice were treated with either topical timolol, a non-selective ß-blocker, 0.5% (n = 8), or topical betaxolol, a selective ß1-adrenergic blocker, 0.5% (n = 6) twice daily for 14 days and compared to respective control groups (n = 5 and n = 7). Changes in lymphatic clearance from the eye were assessed using a quantitative in vivo photoacoustic imaging approach. In all subjects, right eye and neck lymph nodes were longitudinally assessed by sequential photoacoustic imaging just prior to near-infrared dye injection into the anterior chamber of the eye, and 20 min, 2 and 4 h after injection. Repeat measurements of mean pixel intensities (MPIs) of right eyes and nodes were performed at all timepoints. The areas under the curves (AUC) were calculated and the AUC of the treated-group was compared to that of controls using the Mann-Whitney U test. The slopes of MPI of each region of interest over time were compared using the linear mixed model after adjusting for IOP decrease after treatment and other parameters such as sex and body weight. In the timolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.003), and significant decrease in slope of MPI compared with controls (P = 0.0025). In the betaxolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.02), and significant decrease in slope of MPI compared with controls (P = 0.0069). Topical treatment with timolol and betaxolol reduced lymphatic clearance of albumin from the aqueous humor to the neck lymph nodes. This finding may be relevant for the management of secondary glaucomas and inflammatory eye disease in which the clearance of accumulated proteins and antigen from the eye is important to disease recovery and sight protection. This study suggests that the beta-adrenergic system plays a role in the regulation of lymphatic clearance from the eye.

Design of ultra-fine carvedilol nanococrystals: Development of a safe and stable injectable formulation.

Carvedilol (CAR) is a strategic beta-blocker agent which its application has been limited by its very low water solubility. The present study describes a soluble form of drug based on nano-cocrystal (NCC) anti-solvent precipitation technique. The COSMOquick software was employed to select the optimum coformer (tartaric acid, TA) and organic solvent (acetone) relying on the enthalpy changes of cocrystallization and solubilization. Central Composite Design (CCD) considering the impact of CAR, TA, poloxamer 188 (stabilizer) concentrations, and anti-solvent/solvent ratio on CAR NCCs particle size (PS) could produce ultra-fine NCCs (about 1 nm). The lyophilization of NCCs investigating slow/fast freezing rates, various types and concentrations of cryprotectants and lyoprotectants indicated that PEG and trehalose (5 % w/vconcentration) under slow freezing rate could re-produce the initial PSs successfully. CAR NCCs indicated about 2000 fold increase in solubility compared with pure CAR. DSC and PXRD experiments proved that the formulations containing trehalose led to more crystalline and the ones comprising PEG led to more amorphous structures. Interestingly, the slow freezed PEG protected NCCs were physically stable for at least 18 months. In conclusion, the NCC technology could produce the first safe soluble form of CAR for treating hypertension urgencies easy for industrial scale-up.