A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.     

Treatment strategies for hypertension in patients with type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic, autoimmune disease that is characterized by total absence of insulin production. Hypertension is a common comorbidity in T1DM with complex pathophysiology, while it is also a well-recognized risk factor for the development of cardiovascular disease (CVD), as well as other microvascular diabetic complications.     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

肝内胆管癌转化治疗

肝内胆管癌（ICC）可切除率低，进展期ICC的治疗有效率不高，预后很差。转化治疗在多种晚期肿瘤中有一定的疗效，是目前晚期肿瘤治疗的研究热点。随着对ICC基因组的深入了解和新的治疗药物的开发及组合，基于系统化疗的联合治疗策略，精准靶向治疗，免疫检查点抑制剂等显示出较好的疗效，使得部分进展期ICC病人能降期转化手术，获得长期生存。     

多柔比星肾病肾损伤早期核因子-κB和血管紧张素ⅠⅡ的表达及关系探讨

目的　探讨在多柔比星 (阿霉素 )肾病综合征 (NS)幼年大鼠肾损伤过程中核因子 (NF) κB和血管紧张素ATⅠ、ATⅡ的表达及其相关性。方法　 4周龄雄性Wistar大鼠单侧肾切除加腹腔注射阿霉素造成NS模型 ,分别以免疫组织化学和原位杂交检测ATⅠ、ATⅡ和NF κB。结果　肾病组随着病变时间的延长 ,NF κB和ATⅠ、ATⅡ表达的强度和部位均呈增强趋势 ,治疗组在相同时间点则两者都有不同程度下调 (P <0 .0 5 )。结论　在阿霉素肾病损伤过程中NF κB和ATⅠ、ATⅡ起着介导作用。     

Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease

BACKGROUND: Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. AIM: The aim of the study was to assess the effects of statins, fibrates, or angiotensin-converting enzyme inhibitors (ACEIs) on fibrin clot properties. PATIENTS AND METHODS: In a randomized double-blind study, men with advanced CAD taking low-dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day(-1) (n = 13), atorvastatin 40 mg day(-1) (n = 12), fenofibrate 160 mg day(-1) (n = 12), and quinapril 10 mg day(-1) (n = 11) for 28 +/- 2 days. Moreover, CAD patients (n = 13) taking aspirin (75 mg day(-1)) for 8 weeks were studied after additional 4 weeks on an open-label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator-induced fibrinolysis were evaluated at baseline and after drug administration. RESULTS: Permeability increased following the administration of simvastatin (by 20%; P = 0.01), atorvastatin (by 22%; P = 0.001), fenofibrate (by 16%; P = 0.02), and quinapril (by 13%; P = 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post-treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). CONCLUSIONS: Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.     

The Bradykinin-potentiating peptides from venom gland and brain of Bothrops jararaca contain highly site specific inhibitors of the somatic angiotensin-converting enzyme

Pyroglutamyl, proline-rich oligopeptides, classically referred to as bradykinin-potentiating peptides (BPPs) are found in Bothrops jararaca venom, and are naturally occurring inhibitors of the somatic angiotensin-converting enzyme (ACE). The chemical and pharmacological properties of these peptides were essential for the development of captopril, the first active site directed inhibitor of ACE, currently used to treat human hypertension. ACE is a complex ectoenzyme of the vascular endothelium, possessing two catalytic sites, performing diverse specific roles. Recent advances concerning novel features of BPPs revealed that they might still contribute to a better understanding of the cardiovascular physiology and pathology. The molecular biology of the BPPs revealed that they are part of two distinct C-type natriuretic peptide precursors found in the venom gland and the brain of B. jararaca, each containing seven BPPs. In situ hybridization studies detected the presence of the corresponding mRNA precursor in snake brain regions correlated with neuroendocrine functions, such as the ventro-medial hypothalamus, the paraventricular nuclei, the paraventricular organ, and the subcommissural organ. In this article we discuss the large variety of homologous BPPs in B. jararaca venom and brain, its significance, and whether the BPPs could represent novel endogenous neuropeptides.     

Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.