No abstract

An unfortunate subset of hypertensive patients develops resistant hypertension in which optimal doses of three or more first-line antihypertensive drugs fail to sufficiently control blood pressure. Patients with resistant hypertension represent a high-risk and difficult-to-treat group, and such patients are at amplified jeopardies for substantial hypertension-related multi-organ failure, morbidity, and mortality. Thus, there is a pressing requirement to better improve blood pressure control through the pharmaceutical generation of novel classes of antihypertensive drugs that act on newer and alternative therapeutic targets. The hyperactivity of the brain renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of hypertension in various experimental and genetic hypertensive animal models. In the brain, angiotensin-II is metabolized to angiotensin-III by aminopeptidase A (APA), a membrane-bound zinc metalloprotease enzyme. A large body of evidence has previously established that angiotensin-III is one of the main effector peptides of the brain RAS. Angiotensin-III exerts central stimulatory regulation over blood pressure through several proposed mechanisms. Accumulating evidence from preclinical studies demonstrated that the centrally acting APA inhibitor prodrugs (firibastat and NI956) are very safe and effective at reducing blood pressure in various hypertensive animal models. The primary purpose of this study is to narratively review the published phase I–II literature on the safety and efficacy of APA inhibitors in the management of patients with hypertension. Moreover, a summary of ongoing clinical trials and future perspectives are presented.

Purpose: The standard of care for treatment of celiac disease (CD) is a stringent lifetime gluten-free diet (GFD), which is very challenging. Larazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of CD. We endeavored to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) which studied the efficacy and safety of larazotide acetate in patients with CD. Methods: We examined four databases from inception to 20-August-2020 using related keywords. We identified all relevant RCTs and judged their risk of bias. We pooled continuous outcomes as mean difference and dichotomous outcomes as risk ratio with 95% confidence interval under fixed-effects meta-analysis model. Results: Four RCTs met our eligibility criteria, comprising 626 patients (larazotide acetate, n=465, placebo, n=161). Three and two studies reported outcomes of patients undergoing gluten challenge and GFD, respectively. For change in lactulose-to-mannitol ratio, the overall effect estimate did not reveal a significant difference between larazotide acetate and placebo groups. For change in total gastrointestinal symptom rating scale (GSRS), subgroup analysis showed that larazotide acetate significantly yielded better symptomatic improvement in the gluten challenge but not gluten free subgroup. Similar finding was found for change in celiac-disease GSRS (CD-GSRS) favoring the gluten challenge over gluten free subgroup. When compared to placebo, larazotide acetate favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge. Other AEs were comparable between both treatment groups. Conclusions: Larazotide acetate is well-endured and superior to placebo in alleviating gastrointestinal symptoms.

Dialogic reading (DR) is an evidence-based interactive shared reading intervention. This systematic review investigated the effect of DR interventions on the communicative initiations and responses of children with autism, an area of great difficulty for most individuals with autism. More precisely, the paper aimed to (a) describe the characteristics of DR interventions, (b) evaluate the outcomes and effectiveness of DR interventions, and (c) synthesize the quality of the studies. Nine experimental studies were included in the review in which the original DR intervention or adapted versions of it were examined. All studies provided strong to adequate research report strength. Although the review showed inconsistent effects of the interventions on the communicative initiations and responses of children with autism, it concluded that DR can be a promising and beneficial shared reading intervention.