Clinical Medicine Insights: Therapeutics

Recent developments in the treatment of seizure disorders have been focused on medications with novel mechanisms of action. One such medication is perampanel, a first-in-class, noncompetitive, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist recently approved for the adjunctive treatment of partial seizures in patients 12 years of age and older when other antiepileptic medications have failed. The drug has demonstrated efficacy in several clinical trials, and appears to exert its anti-seizure activity in a dose-dependent manner. The drug has a half-life of approximately 105 hours suggesting the medication might be a logical option for individuals who have difficulty with adherence to medications that require multiple daily doses. Because of changes in serum concentration when enzyme-inducing antiepileptic drugs are employed concurrently, escalations in the initial dose of perampanel are recommended. Adverse events reported with perampanel use tend to be mild to moderate. However, psychiatric side-effects, including hostility and aggressive behavior, have been noted in some patients resulting in the inclusion of a warning on the Food and Drug Administration (FDA) approved labeling.

Michele A. Faulkner

Clinical Medicine Insights Therapeutics

Perampanel for the Control of Drug-Resistant Partial-Onset Seizures in Patients 12 years and Older

12岁及以上患者药物难治性部分发作性癫痫的普瑞巴林控制

Kidney cancer is the most lethal of the genitourinary malignancies. Prior to the advent of cytokine-based immunotherapy 25 years ago, surgery was the only viable treatment for advanced renal cell carcinoma (RCC). Adjuvant therapy with interferon and interleukin-2 revolutionized the treatment paradigm, although responders were too often uncommon. The mid-portion of the last decade saw born a new class of drugs aimed at the angiogenesis/VEGF pathway, common to most clear-cell RCC. The latest FDA-approved compound in this class has promised to yield equal or better first-line efficacy as its predecessors while, perhaps, providing better tolerability. Here we review the available data at present regarding pazopanib.

Taylor Y. Lu

Edward N. Rampersaud

Pazopanib-the Latest First-Line Standard of Care Targeted Kinase Inhibitor for the Treatment of Advanced Renal Cell Carcinoma

帕唑帕尼——晚期肾细胞癌一线治疗靶向激酶抑制剂的最新标准

The identification of the ubiquitin–proteasome system as a new therapeutic target has been one of the most recent successes in cancer treatment. The development and clinical approval of the first-in-class proteasome inhibitor, bortezomib has revolutionized the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). In MM, bortezomib is now integrated in induction, conditioning, consolidation, maintenance, and salvage treatment protocols. Bortezomib-based regimens provide high remission rates and confer significant survival advantage compared to conventional chemotherapy in both the bone marrow transplant and non-transplant setting. In MCL, overall response rates in patients who have received at least one prior therapy range from 30 to 45%, even in chemotherapy resistant patients. Clinical trials to further improve the sequencing of bortezomib-containing combination therapies are ongoing. Until recently, intravenous injection was the standard route of bortezomib administration. However, severe adverse side effects, peripheral neuropathy in particular, were observed in up to 16% of MM patients and up to 54% of MCL patients treated with intravenous bortezomib, with grade 3 and 4 in 11 and 12% of patients, respectively. Moreover, complete remission rates, if at all, are low and duration of response is short both in MM and MCL. These limitations may be overcome by changing the method of bortezomib administration as well as by rationally combining bortezomib with other therapeutic agents. Indeed, recent data demonstrate that subcutaneous bortezomib administration is non-inferior to intravenous administration, with an improved systemic safety profile, good local tolerance, and a more convenient route of administration. Based on these data, subcutaneous bortezomib injection was approved as a supplemental new drug application for all approved indications in MM and MCL after at least one prior therapy. More than 30 clinical trials in MM and MCL are currently ongoing to evaluate the efficacy and safety profile of subcutaneous bortezomib also in induction, maintenance, and salvage therapy.

Klaus Podar

Efficacy of Subcutaneous Bortezomib in the Management of Patients with Multiple Myeloma or Relapsed Mantle Cell Lymphoma

皮下硼替佐米在多发性骨髓瘤或复发性套细胞淋巴瘤患者管理中的疗效

Since its first human use in 2005, the γ-cyclodextrin sugammadex (Org 25969) has had the potential to become the reversal agent of choice, for rocuronium- or vecuronium-induced neuromuscular blockade. Sugammadex binds to the aminosteroid neuromuscular blocker, encapsulating it and extracting it from the neuromuscular junction, effectively ceasing activity and allowing neuromuscular transmission to recover rapidly. Phases I–III and subsequent trials have found sugammadex to be safe and effective in a wide range of doses and for the reversal of a range of depth of muscle relaxation in healthy volunteers and a variety of disease states. Sugammadex use may allow refinement of anesthetic practice and improvement in surgical conditions, through the maintenance of deep neuromuscular blockade right to the end of surgery, with subsequent rapid reversal. Debate remains about the use of sugammadex in the treatment of rocuronium anaphylaxis and airway emergencies. The high price of sugammadex currently prohibits its routine use, but if the price falls, after expiry of its patent, it may become cost-effective as a readily available agent in certain specific clinical situations. Serious adverse reactions have occurred in less than 1% of patients and are most commonly because of hypersensitivity. No deaths have been reported, but caution is advised in neonates, pediatrics, and pregnancy where data are lacking.

Steven Lobaz

Mark Clymer

Mario Sammut

Safety and Efficacy of Sugammadex for Neuromuscular Blockade Reversal

Sugammadex用于神经肌肉阻滞逆转的安全性和有效性

Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca 2+ from the sarcoplasmic reticulum, and this Ca 2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance.

Elizabeth A. Woodcock

David R. Grubb

Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

心力衰竭的新型治疗靶点：磷脂酶Cβ1b-Shank3界面

Purpose: Direct oral anticoagulants (DOACs) have been shown to be as effective or superior to warfarin, but warfarin use remains constant. Knowledge regarding the patient population who have switched from a DOAC to warfarin is limited. The objective of this study was to identify clinical predictors which may influence a patient’s likelihood of switching from a DOAC to warfarin for atrial fibrillation (AF) or venous thromboembolism (VTE). Methods: In this single-center, case-control study, patients who switched from a DOAC to warfarin were compared with patients who remained on a DOAC. Baseline demographics were compared between the switch and control groups. Independent factors that increased the likelihood of switching from a DOAC to warfarin were analyzed using logistic regression. Results: A total of 150 patients were included in the control (n = 100) and switch (n = 50) groups. Patients switched from a DOAC to warfarin had more medications at baseline (9 [7, 13] vs 11 [8, 18], P = 0.009). The presence of heart failure (HF) increased the likelihood of switching (odds ratio [OR] = 3.95, confidence interval [CI] = 1.70-9.21, P = 0.002), and for every 10 mL/min increase in creatinine clearance (CrCl), the likelihood of switching decreased ( R = 0.89 [0.80-0.99], P = 0.026). Patients with pulmonary embolism (PE) were less likely to switch from a DOAC to warfarin (OR = 0.20, CI = 0.05-0.86, P = 0.031). Explicitly listed reasons for switching included left ventricular assist device (LVAD) implantation (20%) and valve replacement procedures (20%). Conclusion: Congestive HF was a clinical predictor associated with an increased likelihood of switching from a DOAC to warfarin. Anticoagulation therapy for PE and higher CrCl was associated with a decreased likelihood in switching from DOAC to warfarin.

Amber Rollins

Sarah Hanigan

Kristen Pogue

Elizabeth Renner

Geoffrey Barnes

Michael Dorsch

Identifying Clinical Predictors of Switching From Direct Oral Anticoagulants to Warfarin

识别从直接口服抗凝剂转换为华法林的临床预测因素

Objective: The objectives of this study are, first, to measure concordance between 5 different renal function estimates (methods) in terms of recommended drug doses, and, subsequently, to establish the potential for significant clinical differences between Cockroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations in dosing a specific medication, namely, meropenem. Design and setting: This study used a Monte Carlo simulation, and this is a computer–based study with no actual patient data. Patients: A total of 1200 and 8701 simulated cases to study the concordance for the 5 methods and the potential clinical significance of discordance between CG and MDRD, respectively, were chosen for the study. Methods: Simulated factors were age, sex, height, weight, serum creatinine, ethnicity, and albumin. We estimated the renal function using 5 formulas (ie, 10 combinations) including CG, MDRD, and Chronic Kidney Disease Epidemiology Collaboration (CKD–EPI). Next, the team evaluated concordance for each combination in dosing 22 drugs. Finally, our researchers reviewed and simulated data from the literature to show how CG versus MDRD use can result in clinically significant differences for meropenem. Results: Pairwise combinations yielded statistically significant differences ( P &lt; .0001) except for CG and MDRD ( P &lt; .5147). In addition, the highest concordance was for MDRD and CKD–EPI. Average discordance is in the range of 25% to 30% with the lowest being between CG and albumin–based estimates. Both CG and MDRD were largely discordant which can reach up to 40% with a drug like meropenem and may be associated with significant adverse outcomes. Conclusions: Both CG and MDRD in our simulation are statistically comparable. Clinically, nonetheless, they are significantly inconsistent in terms of recommended drug dosing. We encourage practical comparisons of outcomes for individual or groups of medications (eg, meropenem and antibiotics) empirically dosed in renal patients on the basis of equations used in distinct populations.

Sabaa M Al Jasmi

Amer H Khan

Loai M Saadah

Syed Azhar Syed Sulaiman

Doaa Kamal Al Khalidi

Concordance Among Methods for Empiric Renal Drug Dosing: Meropenem as a Role Model for Clinical Superiority of Cockroft–Gault or Modification of Diet in Renal Disease

经验性肾药物剂量方法的一致性：美罗培南作为临床优势的模型——Cockroft-Gault或肾脏病饮食改良法

Peptic ulcer bleeding remains an important medical emergency. Important recent advances are reviewed. These include further support for a more restrictive transfusion strategy aiming for a target haemoglobin of 70-90 g/L. The Glasgow-Blatchford score remains the most useful assessment score for identifying the lowest risk patients suitable for outpatient management and predicting the need for intervention. Newer scores such as the AIMS65 and Progetto Nazionale Emorragia Digestive score (PNED) may be more accurate in predicting mortality. Pre-endoscopy erythromycin improves outcomes and is underused. A new disposable Doppler probe appears to provide more accurate determination of both rebleeding risk and the success of endoscopic therapy than purely visual guidance. Over-the-scope clips and haemostatic powders appear to have some role as endoscopic salvage therapies. Non- H. pylori, non-aspirin/non-steroidal anti-inflammatory drug (NSAID) ulcers contribute to an increasing percentage of bleeding peptic ulcers and are associated with a high rebleeding rate. The optimal management of these ulcers remains to be determined.

Ian LP Beales

Advances in the Therapy of Bleeding Peptic Ulcer

消化性溃疡出血治疗进展

Aldosterone receptor antagonists have recently been added to the American College of Cardiology/American Heart Association/Heart Failure Society of America 2017 guideline update for serving a role in the reduction in morbidity in patients with heart failure with preserved ejection fraction and an ejection fraction greater than 45%. This recent addition to the heart failure with preserved ejection fraction recommendations is supported by the findings of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist study. All trials with spironolactone or eplerenone in the treatment of patients with heart failure with preserved ejection fraction are reviewed for both cardiovascular morbidity and mortality and symptom improvement. Limited positive data exist on the role aldosterone receptor antagonists has on mortality and symptom improvement in patients with heart failure with preserved ejection fraction. Ongoing trials with angiotensin receptor neprilysin inhibitor and sodium-glucose co-transporter 2 inhibitors in patients with heart failure with preserved ejection fraction are reviewed. This review provides the current clinical and scientific data pertaining to the safety and efficacy of aldosterone receptor antagonists in patients with heart failure with preserved ejection fraction.

Joel C Marrs

Sarah L Anderson

Christian Gabriel

Role of Aldosterone Receptor Antagonists in Heart Failure With Preserved Ejection Fraction

醛固酮受体拮抗剂在射血分数保留的心力衰竭中的作用

Direct oral anticoagulants (DOACs) are indicated by the European Medicines Agency and US Food and Drug Administration for stroke prevention in patients with nonvalvular atrial fibrillation (AF). The role of DOACs in patients with AF and concomitant valvular heart disease (VHD) is less clear. Recent subanalyses of randomized controlled trials and meta-analyses have evaluated the role of DOACs in patients with AF and VHD. Patients with native aortic valve disease, tricuspid valve disease, or mitral regurgitation will be the primary focus as these represent the majority of VHD represented in the DOAC AF trials. Limited data exist on the role in patients with rheumatic mitral stenosis, mechanical heart valves, and mitral valve repair. This review provides the current clinical and scientific data pertaining to the safety and efficacy of DOAC use in patients with VHD.

Direct Oral Anticoagulant Use in Valvular Heart Disease

瓣膜性心脏病中的直接口服抗凝药物使用

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