Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K+-channels, the late Na+-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca2+-activated K+-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development.
Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy. 相似文献
Areas covered: In this review, we discuss ENaC structure and function and its role in CF lung disease and focus on ENaC inhibition as a potential therapeutic target to rehydrate CF mucus. We also discuss the failure of the first generation of pharmacological inhibitors of ENaC and recent alternate strategies to attenuate ENaC activity in the CF lung.
Expert opinion: ENaC is an attractive therapeutic target to rehydrate CF ASL that may serve as a monotherapy or function in parallel with other treatments. Given the increased number of strategies being employed to inhibit ENaC, this is an exciting and optimistic time to be in this field. 相似文献
Area covered: The purpose of this narrative review is to explore the important roles of the sodium pump α1 subunit in glioblastoma and analyze its potential therapeutic applications.
Expert opinion: Expression of the sodium pump α1 subunit in glioblastoma tissues is generally higher than that in normal tissues. Sodium pump α1 subunit-mediated pivotal antiglioblastoma signaling pathways have been reviewed, and their impact on the sensitivity of glioblastoma cells to anticancer drugs has recently been clarified. In addition, various pharmacologically optimized sodium pump inhibitors have recently reached early clinical trials, and explorations of sodium pump α1 subunit inhibitors may hold promise for the development of stratification strategies in which patients are treated based on their isoform expression status. 相似文献
Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed.
Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited. 相似文献
Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.
Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM. 相似文献
Areas covered: Herein, the authors focus specifically on sotagliflozin (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database.
Expert opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study. 相似文献
Areas covered: This review is focused on spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors.
Expert opinion: Generally, privileged structure-based optimizations have emerged as an effective approach to discover newly antiviral agents. More generally, due to the similar Mg2+ catalytic active centers of endoribonucleases, some divalent metal ion chelators were found to be versatile binders targeting multiple metalloenzymes. Therefore, privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological activities, or to provide effective ligands for multiple targets by modifying the existing active compounds. 相似文献
Areas covered: In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D.
Expert opinion: The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2–0.5% (2–6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research. 相似文献
Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase.
Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A.
Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners. 相似文献
Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.
Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.
Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other. 相似文献
Areas covered: A search for phase 1 and 2 acne treatment trials in the US National Institutes of Health database of clinical trials and the European Medicines Agency database with the key words ‘acne’ and ‘treatment’ was carried out, on 6 January 2017.
Expert opinion: The detected trials mostly investigate topical agents that may act via sebosuppressive effects, antimicrobial properties or anti-inflammatory actions. The compounds under investigation include olumacostat glasaretil, cortexolone 17α-propionate, stearoyl-CoA desaturase 1 inhibitors, agents affecting the melanocortin system, omiganan, and minocycline. Systemic studied anti-acne drugs include finasteride, biologics, low dose anti-inflammatory antibiotics, and leukotriene B4 inhibitors. 相似文献
Research design and methods: This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.
Results: After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10–3 to 14.3 ± 9.0 × 10–3 and from 23.2 ± 14.9 × 10–3 to 13.7 ± 5.4 × 10–3, respectively (both p < 0.01 vs. baseline).
Conclusions: These findings indicate that ipragliflozin might have a beneficial effect on beta-cells. 相似文献
Methods: We conducted post hoc analyses of the results of a 52-week open-label study of Japanese type 2 diabetes mellitus patients treated with 100 or 200 mg canagliflozin. Patients were divided into four subgroups according to their baseline body mass index (BMI): group I, BMI < 22 kg/m2; group II, BMI ≥ 22 to < 25 kg/m2; group III, BMI ≥ 25 to < 30 kg/m2 and group IV, BMI ≥ 30 kg/m2.
Results: The overall safety was similar among the four BMI subgroups, although there were slight differences in terms of the incidences of hypoglycemia, asymptomatic hypoglycemia, female genital infections and proportions of patients with total ketone body levels exceeding 1000 μmol/l at any time for both canagliflozin doses. Hemoglobin A1c, fasting plasma glucose and body weight decreased significantly from baseline to week 52 at both canagliflozin doses. The changes in hemoglobin A1c, and fasting plasma glucose were not significantly different among the four BMI subgroups for either dose.
Conclusion: Canagliflozin was tolerated in patients irrespective of their BMI at the start of treatment, although some caution may be needed. 相似文献
Areas covered: Here we cover the pre-clinical and clinical data for both for cyclin dependent kinase (CDK) and cell-cycle checkpoint inhibitors. While CDK inhibition can inhibit proliferation, checkpoint inhibitors can facilitate cell cycle progression in presence of DNA damage and can induce mitotic catastrophe.
Expert opinion: Though the preclinical data for cell cycle inhibitors in AML is compelling, the clinical translation so far has proven to be challenging. This is a reflection of the complexity of both, AML and cell cycle regulators. However, early introduction of cell-cycle active agents in combination with chemotherapy or targeted agents, identifying right sequence of use and identifying right biomarkers might pave the way into successful clinical translation. 相似文献
Areas covered: We discuss the recent insights into the tumor biology of UC, which may impact the prognosis as well as assist in developing precision medicine. This is followed by an overview of existing treatment including conventional chemotherapy as well as the trials that led to the recent approval of PD-1 and PD-L1 inhibitors. Ongoing phase II and phase III trials developing PD-1/PD-L1 inhibitors, CTLA-4 inhibitors and VEGF inhibitors as first-line therapy are discussed.
Expert opinion: The treatment paradigm for the first-line therapy of UC is expected to shift from conventional platinum-based combination chemotherapy towards novel therapy incorporating CPI immunotherapy. Finding the right combination of drugs in the appropriate disease setting and identifying the right patient population based on biomarkers are important questions to be answered. Another major challenge will be the financial burden associated with these new drugs. 相似文献
Areas covered: This review article summarizes the mPGES-1 inhibitors presented in patent literature from 2000 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo.
Expert opinion: The side effects of NSAIDs and COX-2 inhibitors on the gastrointestinal tract and the cardiovascular system showcase the urgent need for the discovery of novel potent and safe anti-inflammatory drugs. mPGES-1 inhibitors may present superior safety in comparison to existing anti-inflammatory drugs. The first synthetic inhibitor of mPGES-1 was reported in 2001 and up to now a variety of structurally different inhibitors has been developed. However, only recently two inhibitors entered clinical trials and none has reached yet the market. More preclinical and clinical studies on mPGES-1 inhibitors are needed to realize if indeed they may become novel agents for the treatment of inflammation and cancer. 相似文献
Areas covered: We discuss the use of α-glucosidase inhibitors, dipeptidyl-peptidase inhibitors, glucagon-like peptide 1 agonists, biguanides, thiazolidinediones and sodium glucose co-transporter 2 inhibitors in individuals with T1DM.
Expert opinion: Non-insulin therapies present a unique and exciting adjunctive treatment for individuals with type 1 diabetes. Although data are scarce, the classes of medications discussed help to lower glucose, decrease glycemic excursions and in some cases improve body weight, along with allowing dose reductions in total daily insulin. Glucagon-like peptide 1 agonists and sodium glucose co-transporter 2 inhibitors, in particular, have been demonstrated to provide clinical improvements in individuals with T1DM and we feel their use can be explored in obese, insulin-resistant patients with T1DM, those with frequent and significant glycemic excursions or individuals with persistently elevated hemoglobin A1c. 相似文献
Research design and methods: A total of 177 patients received 4 – 6 cycles of rituximab-based chemotherapy. The first cycle was given with standard schedule. In the second and subsequent cycles, RRI was initiated. Rituximab was administered as 20% of the dose infused in the first 30 min and the remaining 80% was given over 60 min. Benadryl and dexamethasone were given before infusions. Vital signs were measured at baseline and during infusion.
Results: In the first cycle, 48 patients experienced grade I – II infusion reactions and two patients showed grade III – IV infusion reactions. Six patients experienced infusion reactions during RRI. Two patients showed grade III infusion reactions to RRI and dropped out of the study. With a median follow up of 37.5 months, the 3-year overall survival and progression-free survival rates of the whole cohort were 93.1 and 81.1%, respectively.
Conclusions: Our preliminary observations suggested that RRI may be safe and feasible for patients with CD20+ NHL. 相似文献
Areas covered: The application claims the use of carbonic anhydrase activity modulators (inhibitors or activators) for treating allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis, or mast cell–mediated inflammation.
Expert opinion: Although there is a lack of essential biological data, this patent proposes a new type of applications for carbonic anhydrase inhibitors and deserves further studies. This may lead to new advances in the field of carbonic anhydrase with potential therapeutic implications in the management of type-2 inflammation. 相似文献
Methods: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.
Results: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.
Conclusion: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression. 相似文献