Selective PI3Kδ inhibitors,a review of the patent literature

Introduction: Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is the first kinase involved in, and a key component of, the PI3K/Akt/mTOR signalling pathway, and is significantly upregulated in many cancers. However, four distinct isoforms of PI3K are known with different expression patterns and different pathophysiological roles. The PI3Kδ isoform is expressed in leukocytes and has been implicated as a potential target in the development of selective inhibitors for the treatment of haematological malignancies and various inflammatory diseases.

Areas covered: This review briefly covers the understanding of the four PI3K isoforms and their roles and the inhibitors selective for either one or two isoforms that have been identified to date. It then focuses upon progress in the identification of selective PI3Kδ inhibitors focusing upon the original efforts at ICOS/Calistoga that led to the initial clinical candidates such as CAL-101. After assessing the patent filings from these companies, it considers filings from other players and how they have sought to explore similar, and structurally distinct, scaffolds in their search for selective inhibitors, and how different companies appear focused on either oncological or anti-inflammatory uses for their inhibitors.

Expert opinion: The impact of the work at ICOS is highlighted by the fact that prior to their disclosure of selective leads, no patent applications claiming selective PI3Kδ inhibitors had been filed by other companies. This disclosure, followed by the first filings by Piramed, led to an upsurge in interest with a large cluster of filings published in 2008 while half the relevant applications were published in 2010 or 2011. These efforts, and the initial clinical data on CAL-101, the leading PI3Kδ inhibitors, have also prompted a number of commercially significant deals. In addition to an increasing number of filings, the entry into the clinical development of more selective PI3Kδ inhibitors should stimulate a better understanding of the role of this specific kinase isoform.     

New phosphatidylinositol 3-kinase inhibitors for cancer

Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins important to cancer development or survival. The PI3K signaling axis is an important pathway involved in myriad human malignancies. Inhibition of this axis is a promising therapeutic approach for several cancers.

Areas covered: This article reviews current literature and recent conference proceedings to analyze the rationale for targeting PI3K and its downstream effectors in cancer. Preclinical and clinical results of several PI3K and PI3K–mammalian target of rapamycin (mTOR) inhibitors in early clinical trials, as single agents and in combination with other drugs, are discussed. Thus far, clinical results have been mixed.

Expert opinion: The clinical utility of PI3K and PI3K–mTOR inhibitors will depend on appropriate selection of patients. Mutations in the PI3K pathway may predict sensitivity to PI3K inhibition but they are not reliable biomarkers at this point. Efforts to define predictive biomarkers will probably be the key to finding therapeutic uses for this novel class of anticancer agents.     

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D₂) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.

Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT_2A system in schizophrenia are reviewed. The implications of a combined D₂ and 5-HT_2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT_2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT_2A receptor antagonists for the treatment of schizophrenia.

Expert opinion: 5-HT_2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT_2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT_2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.     

MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms

Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.     

大孔树脂纯化柽柳总黄酮工艺的研究

目的 研究D-101大孔吸附树脂分离纯化柽柳总黄酮的工艺条件. 方法 以柽柳总黄酮为指标,对上样量、吸附时间、洗脱速度、乙醇浓度和上样药液pH进行考察. 结果大孔树脂分离柽柳总黄酮的最佳工艺条件为上样量15 mL,pH 6～7,吸附30 min,流速3 BV.h^-1,乙醇浓度70%,乙醇用量3 BV. 结论 D-101大孔吸附树脂能有效分离纯化柽柳总黄酮.     

Korero te kai o te Rangatira: Nutritional wellbeing of Māori at the pinnacle of life

Aim: To provide a succinct overview of the historical food eating patterns of Māori, the indigenous population of New Zealand, by examining the dietary practices of older Māori, and the significance of these practices for their health and wellbeing. Method: A historical review of food sources that provided pre‐colonisation eating patterns of Māori was developed. Full engagement of older Māori was sought in the design and implementation of a longitudinal study of ageing ‘Life and Living to Advanced Age: A Cohort study in New Zealand’, (LILACS NZ) referred to in the present review. A cross‐sectional pilot study, which included older Māori aged 75 to 79 years, provided detail of traditional foods currently utilised in Northland and the Bay of Plenty regions. For the main study, local Māori providers conducted the research processes and the longitudinal cohort study (LILACS NZ) was implemented. Nutritional assessment included nutrition screening at baseline and detailed assessment using the repeated multiple pass, 24‐hour recall method for each participant in a 12‐month follow up. Results: A wide range of foods were utilised prior to European contact. Similar traditional food was used in Northland and Bay of Plenty regions and these traditional foods were found to be valued and frequently used by older Māori. Those able to access important traditional foods on a regular basis had a significantly better nutrition status. Those who had less regard for the importance of traditional foods to practise their culture tended to be at higher nutrition risk. Screening identified over half of older Māori to be at high nutrition risk. Most participants viewed traditional foods to be very important and were able to eat these on a regular basis. Conclusion: Research shows the impact of colonisation resulted in displacement of traditional foods from the diets of older Māori and this has been accompanied by higher nutrition risk. Food is an important cultural activity for Māori and Māori elders need to be supported to increase their consumption of traditional foods. Further investigations will examine the dietary patterns and nutrient intake of older Māori in relation to health and wellbeing.     

心复康丸对压力超负荷大鼠心肌miRNA-21的影响

目的:观察心复康丸对压力超负荷大鼠所致的心肌肥厚和心室重构的干预作用,并研究其作用机制是否影响心肌组织miRNA-21的表达。方法:雄性Wistar健康大鼠采用腹主动脉缩窄的方法,复制大鼠心肌肥厚和心室重构的模型,随机分为模型组,依那普利组(1.04 mg·kg~(-1)·d~(-1)),心复康丸低、高剂量组(52,208 mg·kg~(-1)·d~(-1))和假手术组,每组20只。分别于术后8,12周采用超声心动评价心功能二尖瓣水平收缩期左室后壁厚度(LVPWs),收缩末期左室容积(LV Vols)及左心室射血分数(LVEF);免疫组织化学法检测心肌组织中Fas,Fas L蛋白表达的变化;实时荧光定量-聚合酶链式反应(Real-time PCR)检测心肌组织miRNA-21 mRNA表达的改变。结果:术后8周,与正常组比较,各手术模型组大鼠LVPWs水平显著升高,LV Vols,LVEF水平显著降低,心脏肥大指数显著增加,心肌组织Fas与Fas L蛋白含量显著增加,miRNA-21 mRNA的表达显著升高(P0.01);与模型组比较,心复康丸低、高剂量组和依那普利组能明显降低LVPWs水平,明显升高LV Vols,LVEF水平,明显降低心脏肥大指数,明显降低心肌组织Fas与Fas L蛋白的表达,显著提高miRNA-21 mRNA的表达,心复康丸高剂量较为显著(P0.05,P0.01)。术后12周,与正常组比较,各手术模型组大鼠LVPWs水平显著升高,LV Vols,LVEF水平显著降低,心脏肥大指数显著增加,心肌组织Fas与Fas L蛋白含量显著增加,miRNA-21 mRNA的表达显著升高(P0.01);与模型组比较,心复康丸低、高剂量组和依那普利组能明显降低LVPWs水平,明显升高LV Vols,LVEF水平,明显降低心脏肥大指数,明显降低心肌组织Fas与Fas L蛋白的表达,显著提高miRNA-21 mRNA的表达(P0.05,P0.01)。结论:心复康丸改善压力超负荷大鼠心功能的作用可能与促进miRNA-21 mRNA的表达,调控Fas,Fas L蛋白,抑制细胞凋亡有关。     

复方脑得生中总黄酮纯化工艺研究

目的研究复方脑得生中总黄酮的最佳纯化工艺。方法采用正交设计和单因素试验法,以总黄酮的洗脱率和含量为指标,考察利用D-101树脂富集、纯化复方脑得生中总黄酮的工艺条件及参数。结果优选纯化工艺为：上样溶液浓度0．1g／mL,流速2aV／h,树脂径高比1：7;吸附后,先用5BV的水洗脱,再用5BV40％乙醇洗脱。所得提取物中总黄酮的含量为80．57％,总黄酮转移率达83．76％。结论优选纯化工艺得到的总黄酮含量高,工艺简单,适宜工业化生产。     

黄芪注射液中黄芪总皂苷的含量测定

目的：建立黄芪注射注中黄芪总皂苷含量测定的新方法。方法：采用大孔吸附树脂吸附分离,以5％得草醛冰醋酸溶液和高氯酸为显色剂,比色法测定,测定波长为536nm。结果：在10－50μg.ml^-1浓度范围内,线性关系良好,平均回收率为98．04％,RSD＝1．7％。结论：方法简便,结果可靠。     

Smokers have varying misperceptions about the harmfulness of menthol cigarettes: national survey data

Objective : To describe the prevalence of menthol use and perceptions of relative harmfulness among smokers in an ethnically diverse population where tobacco marketing is relatively constrained (New Zealand). Methods : The New Zealand (NZ) arm of the International Tobacco Control Policy Evaluation Survey (ITC Project) utilises the NZ Health Survey (a national sample). From this sample we surveyed adult smokers, with Wave 2 (n=923) covering beliefs around menthol cigarettes. Results : Agreement with the statement that “menthol cigarettes are less harmful than regular cigarettes” was higher in smokers who were: older, Māori, Pacific, Asian, financially stressed and had higher levels of individual deprivation. Most of these associations were statistically significant in at least some of the logistic regression models (adjusting for socio‐economic and smoking beliefs and behaviour). In the fully‐adjusted model this belief was particularly elevated in Pacific smokers (adjusted odds ratio [aOR] = 7.36, 95% CI = 1.92 – 28.27) and also in menthol smokers (aOR = 4.58, 95% CI = 1.94–10.78). Most smokers in this study (56%), and especially menthol smokers (73%), believed that menthols are “smoother on your throat and chest”. Conclusion : Various groups of smokers in this national sample had misperceptions around the relative harmfulness of menthols, which is consistent with most previous studies. Implications : This evidence, along with a precautionary approach, supports arguments for enhanced regulation of tobacco marketing and tobacco ingredients such as menthol.