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Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review).
Liu, M, Liu, H, Chen, J
Oncology reports. 2018;(3):901-911
Abstract
An uncontrolled cell cycle is an obvious marker of tumor cells. The G1‑S phase is an important restriction point in the normal cell cycle, but in cancer cells the restriction function is reduced, leading to uncontrolled cell proliferation. Two cyclin‑dependent kinases (CDKs), CDK4 and CDK6, play a crucial role in the G1‑S phase transition. Inhibitors of CDK4/6 are presently the subjects of numerous studies, and PD 0332991, an inhibitor of CDK4/6, has been used to treat hormone receptor (HR)‑positive, advanced‑stage breast cancer. This inhibitor has also been studied in other cancers, such as lung cancer. In this review, we will discuss the regulation of the normal cell cycle transition from G1 to S phase, the most promising inhibitor of CDK4/6, PD 0332991, as applied in different cancers, and finally we propose a mechanism of acquired resistance as well as the incredible potential for CDK4/6 inhibitors in the treatment of cancer. Briefly, we assert that, going forward, a new treatment pattern for cancer may be a combination therapy with a cell cycle inhibitor and a molecular targeted drug.
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Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes.
Tan, X, Hu, J
Expert opinion on pharmacotherapy. 2016;(9):1285-93
Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon(TM)) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise. AREAS COVERED This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed. EXPERT OPINION Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.
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3.
Targeting CDK4/6 in patients with cancer.
Hamilton, E, Infante, JR
Cancer treatment reviews. 2016;:129-38
Abstract
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer.
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4.
New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine.
Orsolini, L, Tomasetti, C, Valchera, A, Iasevoli, F, Buonaguro, EF, Vellante, F, Fornaro, M, Fiengo, A, Mazza, M, Vecchiotti, R, et al
Expert review of neurotherapeutics. 2016;(5):483-95
Abstract
Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, partial agonist at the 5-HT1A and 5-HT1B receptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings.
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[New developments in the antiarrhythmic therapy of atrial fibrillation].
Ravens, U
Herzschrittmachertherapie & Elektrophysiologie. 2014;(1):41-6
Abstract
Atrial fibrillation often affects elderly people with cardiovascular disease and takes a progressive course with increasing resistance to treatment. For the latter, electrical and structural changes (remodelling) seem to be responsible that are directly related to the high excitatory rate in the atria. Therapeutic strategies for atrial fibrillation consist of (i) treating the underlying cardiovascular disease, (ii) re-establishing sinus rhythm and (iii) reducing ventricular rate. Rapid pharmacological or electrical cardioversion is expected to prevent remodelling. Classical antiarrhythmic drugs are notoriously ineffective and burdened with serious cardiac and extracardiac side effects so that there is an urgent need for effective and safe novel compounds. In this review the three recently introduced drugs dronedarone, vernakalant and ranolazine are discussed with respect to the use in atrial fibrillation. Other new antiarrhythmic agents are still in the developmental phase and aim at atria-selective mechanisms thereby excluding ventricular proarrhythmic effects. The mechanisms of action will be discussed in the context of the present understanding of the pathophysiology of onset and maintenance of atrial fibrillation.
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6.
[Cognitive dysfunctions in depression - underestimated symptom or new dimension?].
Jarema, M, Dudek, D, Czernikiewicz, A
Psychiatria polska. 2014;(6):1105-16
Abstract
Cognitive deficits constitute an integral part of clinical picture of depression, but often not enough attention has been paid to these deficits, mainly because of the presumption that they are secondary to typical depressive symptoms. It is considered that cognitive impairment is one of the main causes of depressive patients' poor functioning. Cognitive deficits are observed already in the first depressive episode. They may correlate with the severity of depression, with the patient's age and level of education. They may persist regardless of the improvement of depression during treatment. Cognitive deficits in depression are divided into "cold" which are not related to emotions, and "hot" - related to emotions. The "cold" deficits are supposed not to respond to antidepressants and seem to persist even in clinical remission. Vortioxetine is a novel antidepressant with a unique mechanism of action: it acts through the serotonine reuptake inhibition, but works also as 5HT(1A) agonist, as well as partial agonist of the 5HT(1B) receptor and antagonist of the 5HT(1D), 5HT(3) and 5HT(7) receptors. In preclinical studies vortioxetine showed the normalization of serotoninergic, noradrenergic, and dopaminergic transmission, additionally through GABA-ergic and glutaminergic effects. It has antidepressive property, it proved to be efficacious in various types of depression (severe, depression with anxiety, and depression in elderly); it also proved to be efficacious in those patients who did not respond sufficiently to SSRIs and SNRIs treatment. Vortioxetine is also beneficial for cognitive functions in depressed patients.
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The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials.
Banon, D, Filion, KB, Budlovsky, T, Franck, C, Eisenberg, MJ
The American journal of cardiology. 2014;(6):1075-82
Abstract
Despite the use of traditional antianginal medications (i.e., β blockers, calcium channel blockers, and nitrates) and revascularization therapies, symptoms of chronic stable angina pectoris (CSAP) persist in ≥25% of patients. The objective of this systematic review was to synthesize the available evidence from randomized controlled trials (RCTs) of ranolazine for the treatment of CSAP. We systematically searched the Cochrane Register of Controlled Trials, EMBASE, and MEDLINE through July 2013 for RCTs comparing ranolazine with placebo or antianginal medications administered as part of usual care for the management of CSAP. End points of interest included exercise stress test performance (duration, time to angina, and time to ST-segment depression), frequency of angina attacks/week, nitroglycerin use/week, and quality of life. We identified 7 RCTs (n = 3,317) of patients with CSAP due to coronary artery disease. Comparators included placebo, amlodipine, and atenolol. All but 1 trial showed a statistically significant improvement in all 3 exercise stress test parameters with ranolazine compared with placebo. Ranolazine also reduced angina frequency and nitroglycerin use compared with placebo. These findings were consistent whether or not patients were also prescribed traditional antianginal pharmacotherapy. In conclusion, ranolazine reduces anginal symptoms among patients with symptomatic CSAP despite their use of traditional antianginal medications.
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The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors.
DeCaprio, JA, Duensing, A
Current opinion in oncology. 2014;(4):415-21
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Abstract
PURPOSE OF REVIEW Although most gastrointestinal stromal tumors respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), complete remissions are rare and the majority of patients achieve disease stabilization. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically. RECENT FINDINGS Although imatinib induces apoptosis in a subset of gastrointestinal stromal tumor cells, it leads to a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex (DP, p130/RBL2, E2F4 and MuvB), a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A was shown to enhance imatinib-induced gastrointestinal stromal tumor cell death. SUMMARY Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses.
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A review of real-world data on the effects of aripiprazole on weight and metabolic outcomes in adults.
Citrome, L, Kalsekar, I, Baker, RA, Hebden, T
Current medical research and opinion. 2014;(8):1629-41
Abstract
BACKGROUND Metabolic abnormalities observed with atypical antipsychotic treatment may be specific to each antipsychotic medication. The association between atypical antipsychotics and risk factors for cardiovascular disease prompted the American Diabetes Association (ADA) and the American Psychiatric Association (APA) to issue a consensus statement that categorized aripiprazole and ziprasidone as atypical antipsychotics with a lower likelihood of metabolic abnormalities. OBJECTIVE The aim of the current systematic review was to evaluate real-world studies (i.e. observational/naturalistic and open-label studies) assessing the risk for weight gain, dyslipidemia, glucose abnormalities, and diabetes mellitus in adult patients receiving treatment with atypical antipsychotics, with a specific focus on aripiprazole. METHODS A systematic PubMed search for articles published between 1 January 2000 and 4 October 2011 was performed using the following search terms in the title and abstract: aripiprazole, atypical, glucose, insulin, cholesterol, triglycerides, diabetes, hemoglobin A1c, weight, body mass index, and hyperlipidemia. RESULTS Twenty-two peer-reviewed articles were found that assessed the metabolic effects associated with aripiprazole treatment, including studies from small observational trials to large databases (n = 15 to n > 1,700,000). Thirteen articles reported observational or naturalistic studies, and nine were open-label trials evaluating weight gain, dyslipidemia, glucose abnormalities, and the risk of developing diabetes in adult patients receiving treatment with aripiprazole. Compared with other atypical antipsychotics, aripiprazole was either less likely to have an impact or had a comparable impact on weight gain and dyslipidemia; the degree of effect appeared to be dependent on study design. In addition, there was less risk of diabetes mellitus with aripiprazole compared with most other atypical antipsychotic agents. CONCLUSIONS Consistent with data from randomized controlled studies, the current review of observational/naturalistic and open-label studies suggests aripiprazole may be associated with a lower risk than other commonly used atypical antipsychotics for metabolic adverse events in adults, consistent with the ADA/APA consensus statement.
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Use of ranolazine in the prevention and treatment of postoperative atrial fibrillation in patients undergoing cardiac surgery.
Tsu, LV, Lee, S
The Annals of pharmacotherapy. 2014;(5):633-7
Abstract
OBJECTIVE To determine the evidence for use of ranolazine for treatment and prevention of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. DATA SOURCES A literature search of MEDLINE (1946 to January 2014) was conducted, using the search terms ranolazine, atrial fibrillation, and cardiac surgery. A search of reference citations was conducted to identify additional references. STUDY SELECTION AND DATA EXTRACTION Clinical trials investigating the use of ranolazine for POAF were included in the review. DATA SYNTHESIS Three clinical trials were reviewed; 2 trials, 1 retrospective and 1 prospective, compared ranolazine with amiodarone or usual care for prevention of POAF and demonstrated a significant decrease in the incidence of POAF without increasing the incidence of postoperative complications. A third prospective trial used ranolazine in combination with amiodarone for the treatment of POAF and demonstrated a significant reduction in the time required to convert patients from atrial fibrillation to normal sinus rhythm compared with amiodarone alone. CONCLUSIONS In these current small trials, ranolazine appears to be a safe and efficacious therapeutic alternative for the treatment and prevention of POAF in patients undergoing cardiac surgery. However, larger randomized controlled trials are needed before ranolazine should be considered for the treatment or prevention of POAF. It is an attractive option compared with current treatments for this indication-primarily β-blockers and amiodarone-because ranolazine has minimal effects on heart rate and blood pressure.