Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy.

Objective: To review the pharmacology, efficacy, and safety of the selective transthyretin inhibitor tafamidis for transthyretin amyloid cardiomyopathy (ATTR-CM). Data Sources: A PubMed (1966 to October 2019) and ClinicalTrials. gov search was conducted using the keywords tafamidis, Fx-1006A, Vyndaqel, and Vyndamax. Additional articles were identified from references. Study Selection and Data Extraction: We included English-language clinical studies evaluating the pharmacology, efficacy, or safety of tafamidis in humans for ATTR-CM. Data Synthesis: Tafamidis binds to the thyroxine-binding sites of the transthyretin tetramer and inhibits its dissociation into monomers, which is the rate-limiting step in the amyloidogenic process. Treatment with tafamidis was significantly associated with a significant reduction in mortality, lowered cardiovascular-related hospitalizations, less functional decline, and improved transthyretin stabilization compared with placebo. Additionally, tafamidis was found to have fewer adverse events, with no difference found compared with placebo. Relevance to Patient Care and Clinical Practice: Historically, symptomatic management for ATTR-CM was the only option, and the treatment of the underlying disease was limited to liver or heart transplantation. Tafamidis is the first medication approved for the treatment of ATTR-CM and the only medication that showed a reduction in all-cause mortality and cardiovascular-related hospitalizations in patients with amyloidosis. However, the role of tafamidis in patients with the New York Heart Association class III/IV heart failure or mutated transthyretin remains unclear. Conclusion: Tafamidis is an effective and safe oral medication for the treatment of the cardiomyopathy of transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

The Effect of Ranolazine on Glycemic Control: a Narrative Review to Define the Target Population.

Ranolazine is an anti-anginal medication that reduces the sodium-dependent calcium overload via the inhibition of the late sodium current. After its approval for the treatment of chronic angina in 2006 in the USA, ranolazine has been reported to have several pleiotropic effects on various cardiac conditions, such as atrial fibrillation, ventricular arrhythmias, diastolic and microvascular dysfunction, and pulmonary arterial hypertension. Recently, several studies reported some promising results on the potential benefits of ranolazine on glycemic control. Though the mechanism of the antihyperglycemic effect is still unknown, ranolazine may exert the effect through ß cell preservation, inhibition of glucose secretion, and enhancement of insulin secretion in a glucose-dependent manner. Given the increased risk of cardiovascular disease in patients with diabetes, it will be useful if one medication can simultaneously improve chronic angina and diabetes. Therefore, ranolazine could be a favored choice among other anti-anginal agents for patients with comorbidity of chronic angina and diabetes mellitus. In this review, we summarize the available data from clinical studies and provide valuable insight into defining the target population for the antihyperglycemic effect of ranolazine.

Molecular cloning of the crustacean hyperglycemic hormone (CHH) precursor from the X-organ and the identification of the neuropeptide from sinus gland of the Alaskan Tanner crab, Chionoecetes bairdi.

Crustacean hyperglycemic hormone (CHH) secreted from sinus glands primarily elicits hyperglycaemia in crustaceans. CHH is particularly important for energy metabolism during environmental and physiological stress as animals switch to anaerobiosis. CHH has been purified from multiple brachyuran crab species to date, but not from the cold water Tanner crab, Chionoecetes bairdi, a species found in Alaskan coastal waters. The purpose of molecular cloning the C. bairdi CHH precursor and identification of its neuropeptide form in sinus glands is to establish tools to further study cold water crab metabolic physiology. Cold water crabs such as those in the genus Chionoecetes are a good model for understanding the role that climate change and associated water temperature changes might have on metabolic physiology. CHHs in sinus glands of C. bairdi were purified using reverse-phase HPLC and were identified as CHH with an enzyme-linked immunosorbent assay (ELISA) using cross-reacting Callinectes sapidus and Carcinus maenas CHH antisera. The bioactivity of CHH was further assessed using a homologous assay by injecting CHH into eyestalk ablated C. bairdi and measuring subsequent rise in circulating glucose. The full length cDNA (1944bp) of C. bairdi CHH was determined by PCR using degenerate primers cloning and 5', 3' rapid amplification of cDNA ends (RACE). A phylogenetic analysis of deduced amino acid sequences from six brachyuran crab species showed C. bairdi CHH most closely related to the majid crab, Libinia emarginata (P55688). Future studies will enable us to compare metabolic physiology and requirements of cold water C. bairdi with the warm water crab C. sapidus.

Extended Duration Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Peripheral Arterial Disease: A Meta-Analysis.

BACKGROUND: Patients with peripheral arterial disease (PAD) undergoing percutaneous coronary intervention (PCI) are at elevated risk of ischemic and bleeding events. However, the optimal duration of dual antiplatelet therapy (DAPT) after PCI in patients with PAD remains unclear. METHODS: A systematic literature search was performed through June 2017 using PubMed, EMBASE and Cochrane databases with the following key terms: "dual antiplatelet therapy", "P2Y12 inhibitor", "myocardial infarction", "percutaneous coronary intervention", "stent", "peripheral arterial disease", and "ankle-brachial index". The analysis was restricted to randomized trials published in English in patients with PAD receiving extended DAPT (> 12-month) after PCI. Overall analysis was performed using Review Manager 5.3 with the Mantel-Haenszel method. RESULTS: Two randomized controlled trials involving 895 patients were included in this review. Compared to the placebo group, there was no statistical significance in the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients receiving extended DAPT (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.37 - 1.57; P = 0.46). The results were associated with substantial heterogeneity (I2 = 71%, P = 0.07). Extended DAPT was not significantly associated with increased moderate/severe bleeding events (OR 1.63, 95% CI 0.84 - 3.18; P = 0.15; I2 = 0%, P = 0.59). The extended DAPT was associated with 82% relative risk reduction in the events of definite/probably stent thrombosis. CONCLUSIONS: Among patients with PAD, extended DAPT after PCI resulted in a non-significant difference in ischemic and bleeding events compared to placebo, respectively. The routine use of extended DAPT in this cohort should be carefully evaluated.