Prescribing proton pump inhibitors: is it time to pause and rethink?

Proton pump inhibitors (PPIs) are among the most widely used agents in the world. The prevalence of reflux disease is increasing, as is the incidence of oesophageal adenocarcinoma, a complication that is strongly correlated with chronic reflux disease. Although these agents are generally safe, a number of potential side effects have been described and a careful assessment of the risks and benefits of PPI therapy is required in all patients being prescribed long-term therapy. Overutilization of PPIs is a problem in clinical practice and needs further attention. PPI use has been associated with osteoporosis and bone fracture, hypomagnesaemia, the development of gastric polyps, enteric infections, interstitial nephritis and pneumonia. Patients on long-term therapy should be periodically evaluated for the indications for continued therapy. Despite widespread publicity in the lay press, and regulatory guidance regarding a number of associations, the evidence for serious side effects is poor and the risk of confounding remains a real possibility for many associations. Patients are more concerned about the absolute risk of developing a complication than a relative risk. The absolute risk of all the complications attributed to PPIs is low and patients who need long-term PPI therapy need a clear discussion of the available data on the risk of therapy and also a discussion of the risk of continued reflux.     

Hsp90β inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy

The loss of glutamate transporter-1 (GLT-1) is associated with temporal lobe epilepsy (TLE). A recent study reported that Hsp90β interacted with GLT-1 and recruited it to 20S proteasome for degradation. Therefore, inhibiting Hsp90β may be a new strategy for treating epilepsy. So far, no studies have shown whether the inhibition of Hsp90β had therapeutic effects on absence epilepsy. Using a model of absence epilepsy, we demonstrated that 17-allylamino-17-demethoxygeldanamycin (17AAG) and Ganetespib (STA9090) had no therapeutic effect. Although this is a negative result, it also has a meaningful exploration value for whether Hsp90 inhibitors have therapeutic effects on other epilepsy types.     

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D.

Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension.

Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.     

Identification of CFTR activators and inhibitors: chance or design?

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl(-) channel expressed in various epithelial cells, and is a pharmacological target for activators and inhibitors. Activators are useful for the pharmacotherapy of cystic fibrosis, specifically for those mutations that affect CFTR protein by reducing its ability to stay in the open state. Conversely, inhibitors are potentially useful to treat secretory diarrhoea caused by enterotoxins, as the CFTR is the main route for Cl(-) flux in the intestine. Recently, a variety of potent modulators of the CFTR Cl(-) channel activity have been identified by high-throughput screening of a large collections of small molecules. The identification of CFTR activators and inhibitors with novel chemical scaffolds might help with the rational design of compounds with improved pharmacological properties.     

Combination therapy of sodium–glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: rationale and evidences

No single antidiabetic agent can correct all the pathophysiologic defects manifested in type 2 diabetes mellitus (T2DM) and, therefore, multiple agents are often required to achieve optimal glycemic control. Combination therapies, having different mechanisms of action, not only have the potential to complement their action, but may possess the properties to counter the undesired compensatory response. Recent finding suggests that sodium–glucose co-transporter-2 inhibitors (SGLT2i) increase endogenous glucose production (EGP) from liver, due to the increase in glucagon which may offset its glucose-lowering potential. In contrast, dipeptidyl peptidase-4 inhibitors (DPP4i) decrease glucagon and EGP. Especially in the light of this finding, combination therapies with SGLT2i and DPP4i are particularly appealing, and are expected to produce an additive effect. Indeed, studies find no drug–drug interaction between SGLT2i and DPP4i. Moreover, significant reduction in glycated hemoglobin has also been observed. This article aims to review the efficacy and safety of combination therapy of SGLT2i and DPP4i in T2DM.     

Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?

Mitogen-activated protein kinase (MAPK) signaling pathway, one of the most important signaling pathways in eukaryotic organism, is involved in multiple cellular events such as cell growth, differentiation, and apoptosis. MAPK is of great importance to the normal function of organisms, while its dysfunction results in various diseases. So far, inhibitors specifically against each subfamilies of MAP kinase have been developed, while more endeavors are needed to discover the compounds selectively targeting a particular subfamily member. Most of the kinase inhibitors exert their functions in an ATP-competitive way or a non-ATP-competitive way. Further studies on the effective mechanism of the MAPK inhibitors and their therapeutic roles in the treatment of diseases are helpful for the illumination of MAP kinase function, the development of novel inhibitors, and the therapy of diseases caused by the dysfunction of the MAPK pathway.     

Protein kinase CK2 inhibitors: emerging anticancer therapeutic agents?

Protein kinase CK2 is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. A number of structurally unrelated CK2 inhibitors, tested on a variety of cells derived from tumours, including lymphomas, leukaemias, multiple myeloma and prostate carcinoma, display a pro-apoptotic effect which is roughly proportional to their in vitro inhibitory potency. In the present review we summarize the most recent discovery of potent and selective CK2 inhibitors and their prospective as future anticancer agents.     

p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

COPD represents a major respiratory disorder, causing significant morbidity and mortality throughout the world. While therapies exist for COPD, they are not always effective, and many patients experience exacerbations and morbidity despite current therapies. Study of the molecular mechanisms involved in the underlying physiological manifestations of COPD has yielded multiple new targets for therapeutic intervention. In this review, we discuss signaling pathways involved in COPD pathogenesis and review clinical studies of p38 MAPK inhibitors, TNFα inhibitors, and IKK2 inhibitors as potential COPD therapies.     

Weight loss differences seen between glucagon-like peptide–1 receptor agonists and sodium–glucose cotransporter–2 inhibitors for treatment of type 2 diabetes

BackgroundWeight loss is an advantageous quality for diabetic medications because it can improve insulin sensitivity and glucose control and reduce cardiovascular risk factors and comorbidities. Glucagon-like peptide–1 (GLP-1) receptor agonists and sodium–glucose cotransporter–2 (SGLT-2) inhibitors are both preferred agents for use after metformin therapy, and both cause modest weight loss.ObjectiveThe aim of this study was to evaluate the difference in weight loss between GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes (T2D).MethodsThis was a retrospective study that was conducted at a level 3 patient-centered medical home in Buffalo, NY. The participants were adults with T2D treated with either a GLP-1 receptor agonist or an SGLT-2 inhibitor, in addition to background diabetes medications, between January 1, 2012, and September 20, 2017. The outcome measures included the median weight loss after 6 months of consecutive therapy compared between the 2 antidiabetic classes and the median differences in blood pressure, glycosylated hemoglobin (A1C) levels, and renal function markers compared between the 2 classes.ResultsA total of 73 patients were included in the final analysis, with 31 receiving SGLT-2 inhibitors and 42 receiving therapy with GLP-1 receptor agonists. The SGLT-2 inhibitor cohort presented a median weight loss of –2.80 kg (interquartile range [IQR] –5.40 to –1.50), and the GLP-1 receptor agonist cohort presented a median weight loss of –1.15 kg (IQR –3.38 to 0.975) (P = 0.014). There were no statistically significant differences in A1C levels, blood pressure, or renal function markers.ConclusionSGLT-2 inhibitors, when used in combination with background diabetes regimens, can lead to more statistically significant weight loss than GLP-1 receptor agonists without compromising renal function.