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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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[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 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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Update on evidence for treatment with ranolazine in stable angina.
Carbone, F, Montecucco, F, Mach, F
Swiss medical weekly. 2013;:w13874
Abstract
Chronic angina represents a major burden for public health systems because of its poor prognosis and its high treatment costs. Ranolazine is an emerging drug recently approved for the treatment of this disease. The main molecular mechanism underlying ranolazine-mediated beneficial effects has been identified as inhibition of the late Na+ current during the action potential, which potentially improves oxygen consumption, diastolic dysfunction and coronary blood flow. Moreover, this particular mechanism of action also confers on ranolazine a potential antiarrhythmic effect. The aim of this review is to update the evidence for ranolazine treatment in chronic angina and discuss its therapeutic perspectives based on the most recent clinical and experimental studies.
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New treatment options for late Na current, arrhythmias, and diastolic dysfunction.
Maier, LS
Current heart failure reports. 2012;(3):183-91
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Abstract
The late Na current is of pathophysiological importance for the heart. Ranolazine is an innovative anti-ischemic and antianginal agent that inhibits the late Na current, thereby reducing the Na-dependent Ca-overload, which improves diastolic tone and oxygen handling during myocardial ischemia. In addition, ranolazine seems to exert beneficial effects on diastolic cardiac function. Moreover, there are experimental and clinical data about its antiarrhythmic properties. A beneficial atrial selectivity of ranolazine has been suggested that may be helpful for the treatment of atrial fibrillation. The purpose of this review article is to discuss possible future clinical indications based on novel experimental and preclinical results and the significance of the available data.
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The patient with chronic ischemic heart disease. Role of ranolazine in the management of stable angina.
Di Monaco, A, Sestito, A
European review for medical and pharmacological sciences. 2012;(12):1611-36
Abstract
Ischemic heart disease (IHD) is a major cause of death in Western Countries and accounts for very high costs worldwide. In this review we discussed the pathogenesis, symptoms, diagnosis, prognosis and management of chronic IHD. In particular, we discussed about the percutaneous coronary interventions and coronary artery bypass grafting, as well as to clinical trials that evaluated the advantages of one approach versus another. Pharmacological treatment is among major objectives of the review and for each class of therapeutic agents an evaluation of well-conducted clinical trials is provided. The most important drug classes in IHD treatment are betablockers, calcium channel blockers, nitrates, antiplatelet agents, and ACE-inhibitors. In addition to these agents, also new treatment options are evaluated in patients with stable IHD. Ranolazine, in particular, is a innovative anti-anginal drug with a great successful in the management of patients with refractory angina. A pharmacological as well as clinical profile of this drug is provided.
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Dysregulation of bone remodeling by imatinib mesylate.
Vandyke, K, Fitter, S, Dewar, AL, Hughes, TP, Zannettino, AC
Blood. 2010;(4):766-74
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Abstract
Imatinib mesylate is a rationally designed tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Although the efficacy and tolerability of imatinib are a vast improvement over conventional chemotherapies, the drug exhibits off-target effects. An unanticipated side effect of imatinib therapy is hypophosphatemia and hypocalcemia, which in part has been attributed to drug-mediated changes to renal and gastrointestinal handling of phosphate and calcium. However, emerging data suggest that imatinib also targets cells of the skeleton, stimulating the retention and sequestration of calcium and phosphate to bone, leading to decreased circulating levels of these minerals. The aim of this review is to highlight our current understanding of the mechanisms surrounding the effects of imatinib on the skeleton. In particular, it examines recent studies suggesting that imatinib has direct effects on bone-resorbing osteoclasts and bone-forming osteoblasts through inhibition of c-fms, c-kit, carbonic anhydrase II, and the platelet-derived growth factor receptor. The potential application of imatinib in the treatment of cancer-induced osteolysis will also be discussed.
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Aripiprazole versus other atypical antipsychotics for schizophrenia.
Komossa, K, Rummel-Kluge, C, Schmid, F, Hunger, H, Schwarz, S, El-Sayeh, HG, Kissling, W, Leucht, S
The Cochrane database of systematic reviews. 2009;(4):CD006569
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Abstract
BACKGROUND In many countries of the industrialised world second generation (atypical) antipsychotics have become first line drug treatments for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of other second generation antipsychotics. OBJECTIVES To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY We searched the Cochrane Schizophrenia Group Trials Register (March 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA We included all randomised trials comparing oral aripiprazole with oral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. MAIN RESULTS The review currently includes four trials with 1404 participants on two out of eight possible comparisons - aripiprazole versus olanzapine and aripiprazole versus risperidone. The overall number of participants leaving the studies early was considerable (38.5%), limiting the validity of the findings, but with no significant differences between groups. Aripiprazole was less efficacious than olanzapine in terms of the general mental state (PANSS total score: n=794, 2 RCTs, MD 4.96 CI 1.85 to 8.06), but it was associated with fewer side-effects such as cholesterol increase, weight gain, sedation and prolactin associated side-effects. Compared with risperidone there was no difference in efficacy (PANSS total score: n=372, 2 RCTs, MD 1.50 CI -2.96 to 5.96). Dystonia, QTc abnormalities, prolactin and cholesterol increase were less frequent in the aripiprazole group, while tremor was more frequent in the aripiprazole group compared with those allocated risperidone. AUTHORS' CONCLUSIONS Aripiprazole may be somewhat less effective than olanzapine, but more tolerable in terms of metabolic effects and sedation. There is no evidence for a difference in efficacy compared to risperidone, but for better tolerability in terms of dystonias, cholesterol prolactin increase and QTc prolongation. Randomised evidence comparing aripiprazole with other second generation antipsychotic drugs is currently not available.
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Imatinib-induced tumor lysis syndrome: report of a case and review of the literature.
Chang, H, Shih, LY
Chang Gung medical journal. 2008;(5):510-4
Abstract
Imatinib is a selective tyrosine kinase inhibitor which acts on breakpoint cluster region-Abelson fusion gene (BCR-ABL) positive leukemia including all phases of chronic myeloid leukemia and acute lymphoblastic leukemia. It may induce rapid apoptosis and subsequent tumor lysis syndrome. Only 3 cases of imatinib-induced tumor lysis syndrome have been reported. We herein described an additional patient with BCR-ABL (ela2) positive acute lymphoblastic leukemia who developed tumor lysis syndrome after 10-day treatment with imatinib. Experience in the current case suggests that preventive measures for tumor lysis syndrome, including allopurinol and hydration, should be taken for patients with high leukemia burden who receive imatinib therapy, and parameters of tumor lysis should be monitored in the early phase of therapy.
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Monitoring treatment of chronic myeloid leukemia.
Baccarani, M, Pane, F, Saglio, G
Haematologica. 2008;(2):161-9