Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach

Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the ‘common arm’ approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a ‘common’ carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.     

Receptor pharmacogenetics: relevance to CNS syndromes

Pharmacogenetic research dedicated to the investigation of inherited factors that influence drug response has produced exciting results over the past decade. Adding to the knowledge that genetic variation in metabolic enzymes may cause drug-related adverse reactions, recent studies indicate that variation in neurotransmitter receptors can also be the cause of treatment failure. In addition, recent studies have attempted to use genetic information for the prediction of treatment outcome. The aim of this review is to summarize the most significant findings in pharmacogenetic research in relation to CNS drugs and to outline how these studies could lead to the individualization of drug treatment.     

他汀的药物基因组学研究进展

他汀类药物在冠心病整体防治中起重要地位。某些候选基因的多态性可以预测他汀治疗的效果或不良反应,本文综述了药物基因组学研究在他汀类药物使用的进展,为他汀类药物的个体化使用提供参考依据。     

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug‐related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug‐related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.     

Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen‐activated protein kinase kinase 1/2, and antagonists to Ca²⁺ and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca²⁺ release, calmodulin and mitogen‐activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen‐activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal‐regulated kinase 1/2 and Ki‐67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal‐regulated kinase pathway plays a key role.     

Emerging drugs in the management of hypertension

Hypertension is a global health problem, affecting developing and developed countries alike. Most patients with hypertension are undiagnosed, and most diagnosed patients are either untreated or inadequately treated. Randomised controlled trial evidence suggests diuretic therapy for hypertension is as effective as newer drugs in reducing cardiovascular events. There is good evidence for the use of specific classes of drugs in hypertensive patients with a variety of associated clinical conditions, but for uncomplicated cases, the current emphasis in hypertension management is on blood pressure lowering rather than drug class. Individual patients vary in their responses to different drug classes, and optimal therapy for the individual is determined by trial and error. Pharmacogenomics may assist in tailoring therapy for individuals in the future. Emerging drugs include newer members of classes already established in clinical practice, for example, angiotensin II receptor antagonists, aldosterone receptor antagonists, calcium antagonists and centrally acting drugs; newer fixed-dose combination therapies; and more novel therapies, for example, endothelin (ET) receptor antagonists, activators of nitric oxide (NO)-sensitive guanylyl cyclase and vasopeptidase inhibitors.     

药物基因组学研究进展

同一种药物对患有相同疾病的不同患者疗效不同是临床上常见的一种现象 ,以往的观点认为这是由于药代动力学的差异造成的。最近的研究表明 ,药效学原因所产生的差异更为广泛和显著 ,而药效学差异大多源于基因的差异。为此 ,提出了“药物基因组学”这个全新的概念。1　药物遗传学与药物基因组学药物遗传学 (ｐｈａｒｍａｃｏｇｅｎｅｔｉｃｓ)的概念是 2 0世纪5 0年代由ＦｒｉｅｄｒｉｃｈＶｏｇｅｌ[1] 首先提出的 ,它研究包括药物在内的外界化学物质 (尤其是有毒外源物质 )引起机体反应 (主要指毒性和不良反应 )的遗传多样性。在ＲＦＬＰ和…     

药物基因组学与高血压病的药物选择

药物基因组学是研究遗传学与药物反应的相互关系。本综述了药物基因组学的基本概念、高血压病和抗高血压药物反应异质性、与药物新陈代谢相关的基因、个体化治疗等方面的应用情况。对不同个体高血压相关基因、基因影响抗高血压药物治疗对血压作用的药物动力学等的研究，不仅为药物治疗的分子机制提供了新的思路，也可明确血压水平相关基因的个体差异及其在高血压发生中的重要作用。