基于AMPK/mTOR通路的天然产物抗大肠癌研究进展

大肠癌是严重危害人类健康的常见恶性消化系统肿瘤之一,目前临床上大肠癌的主要治疗手段是手术结合放化疗,但往往伴随着多种副作用。与此同时,越来越多的天然产物表现出良好的抗大肠癌活性,有望成为新型大肠癌治疗候选药物。AMP依赖的蛋白激酶(AMPK)是细胞内能量代谢的中心枢纽,可以通过抑制其下游靶标哺乳动物雷帕霉素靶蛋白(mTOR)而调控肿瘤细胞生长、增殖等。近年来,越来越多的研究显示一些天然产物能够通过调控AMPK/mTOR通路而发挥其抗大肠癌活性。围绕AMPK/mTOR信号通路在大肠癌中的作用及基于此通路的抗大肠癌天然产物的研究进展进行综述。

     

CNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesics

fMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system‐specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are “normal.” Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential “translational tool” in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23–41, 2007. © 2007 Wiley‐Liss, Inc.     

Genetic disposition to addictive disorders--current knowledge and future perspectives

It is well established that addictive disorders have a strong genetic background. Multiple, and in part interacting, genes are likely to be responsible for the disease phenotype, making the search for underlying alleles a challenging and complicated task. Linkage analyses and association studies have failed to unequivocally identify underlying genes. Conversely, genome sequencing and the systematic search for polymorphic marker loci have yielded dense chromosome maps so that, along with automated genotyping, the identification of individual genes will soon become possible. Initial results provide hints that regulators of gene expression might play an important role in addiction.     

The clinical usefulness of agonist-antagonistic opioid analgesics in chronic pain

The mixed agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Pentazocine, the first and most widely used of this group of drugs has two major limitations: by mouth it is not a strong analgesic, but is closer in efficacy to the peripherally acting drugs aspirin and paracetamol than the weak opioids; and its use is associated with psychotomimetic side effects in 10–20 percent of patients. The weak opioid analgesics codeine and dextropropoxyphene are more effective and better tolerated than pentazocine.

Buprenorphine is the most useful of the agonist-antagonists in chronic pain patients. It is potent, long-acting (6–9 h) and effective when given sublingually. However, it has a limited effective dose range and produces the same side effects as morphine-like drugs, possibly more frequently at equianalgesic doses. It may be used in the treatment of cancer pain, or in patients with chronic arthritides or other forms of chronic non-cancer pain who require a potent conventional analgesic, as an alternative to the weak opioids or to morphine in low doses.

Nalbuphine and butorphanol are only available for parenteral administration which means that their usefulness in the treatment of chronic pain is limited. Meptazinol is restricted by its manufacturers to ‘short term’ treatment and there is little information on its use in chronic pain patients.     

Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping

Depending upon the UDP glucuronosyltransferase 1A1 (UGT1A1) genotype, patients are more or less susceptible to the risk of severe toxicity of irinotecan. As the US FDA-approved label of irinotecan (CPT-11, Camptosar) has been recently revised to include UGT1A1 genotype among potential risk factors for toxicity, it is expected that UGT1A1 genotyping will be increasingly used in patients undergoing irinotecan treatment. At present, the label states that *28/*28 (7/7) genotype patients are at higher risk of neutropenia and should be treated at a lower dose of irinotecan. Although effective alternative drugs (i.e., oxaliplatin) exist for metastatic colorectal cancer (the main indication of irinotecan), recent studies have confirmed that irinotecan has an important place in the management of this disease. We feel that now is the time for addressing questions around the UGT1A1*28 testing that many oncologists might have had but remained unanswered. For example, does the test have adequate sensitivity/specificity? Can the test results be effectively utilized to guide therapy of metastatic colorectal cancer patients? Is it possible that the *1/*1 (6/6) patients are underdosed? How can the genetic prediction of irinotecan toxicity be improved? Is the UGT1A1*28 test fully predictive of the UGT1A1 deficiency in patients who are not of Caucasian origin? Clinicians and investigators interested in a discussion of each of these points could find this article a useful source.     

Genetic and genomic predictors of anti-TNF response

The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.     

Genetic predictors of therapeutic response to clozapine: current status of research

Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients. Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.     

Cetuximab, its clinical use and future perspectives

Increase in the expression of epidermal growth factor receptors (EGFRs) has been observed in many tumours. EGFR overexpression usually correlates with a more advanced stage of the disease, a poorer prognosis and a worse chemotherapy response. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been extracellular domain receptor inhibition, using monoclonal antibodies. In this review, we summarize the current status as well as what is likely to be the future use of monoclonal antibodies directed against EGFR. We have focussed on cetuximab being the most developed one. It has been mainly studied in colorectal cancer, and the major portion of this review will focus on all the research that has been carried out on this tumour. Clinical development of cetuximab is also important in head and neck cancer and in lung cancer. Interesting studies have been carried out in pancreatic, gastric, oesophageal and ovarian tumours, as well as in malignant gliomas.     

Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma

Introduction: Based on extensive preclinical data and abundant evidence for clinical activity, vascular endothelial growth factor receptor (VEGFR) inhibitors are currently standard of care for metastatic renal cell carcinoma (mRCC). Axitinib is one of the most selective molecules in the class of anti-angiogenic agents, which confers an optimal profile between its safety and anti-cancer activity spectrum.

Area covered: In this review, the authors discuss the different stages that lead to the approval of axitinib in the clinic as well as the current perspectives for its clinical use with other promising therapies in mRCC such as immune checkpoint inhibitors and vaccines.

Expert opinion: In 2015, axitinib has emerged as one of the major agents used in mRCC. Based on robust preclinical data, this highly specific VEGFR inhibitor continues to be evaluated in different indications, including the adjuvant setting but also sequential administration with other molecularly targeted agents or combinations with immune therapies.     

The cognitive and psychomotor effects of opioid analgesics

Twelve subjects (8 male) took part in a randomised double blind four way crossover design study comparing four treatments: (i) morphine sulphate 10 mg, (ii) morphine sulphate 15 mg, (iii) lorazepam 1 mg (positive control) and (iv) placebo. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam produced a marked impairment in the tests of attention and memory. CFFT was reduced from 1–4 h but this only reached significance at 4 hours. The subjective measures suggested impaired alertness but this did not reach significance. The effects of morphine were less dramatic; both doses of morphine produced significant impairment at 1 hour on tests of secondary memory retrieval (delayed word recall and picture recognition sensitivity). CFFT was reduced for the whole observation period (6 h) achieving statistical significance at 4 hours. Morphine 15 mg produced a significant improvement in accuracy on the choice reaction time test at the 2, 4 and 6 h assessments. These results show minimal impairment of cognitive and psychomotor function after single oral doses of morphine and with possible improvement in one test. Further studies are required to examine the effect of repeated doses.     

阿片类药物在癌痛治疗中的应用

癌痛是肿瘤患者最常见的症状。癌痛管理是肿瘤综合治疗的重要组成部分,良好的疼痛控制可以增加患者对抗肿瘤治疗的依从性,提高患者及家属的生活质量。合理使用阿片类药物,选择正确的阿片类药物,正确的给药途径和给药间隔是癌痛治疗成功的关键。本文介绍了阿片类药物的分类和作用机制,详细分析了口服给药途径、经黏膜/皮肤给药途径、静脉/皮下给药途径、轴索镇痛等4类给药途径的优缺点及临床应用,为临床医护人员合理使用阿片类药物提供指导。     

Simvastatin: present and future perspectives

Simvastatin is lipophilic statin with a short half-life that is primarily metabolized by CYP450 3A4. At doses of 5 – 80 mg, simvastatin lowers LDL cholesterol by 25 – 50%. Simvastatin has been shown to reduce the risk of cardiovascular disease by 35% and overall mortality by up to 30% over 5 years. The recommended starting dose of simvastatin 40 mg is approved as a lipid-lowering agent and for all high-risk patients, including those with cardiovascular disease and diabetes, regardless of the baseline LDL level. Simvastatin dose should be adjusted in those receiving CYP3A4 inhibitors, gemfibrozil, or ciclosporin, amiodarone, or in those with severe renal insufficiency. Coformulation of simvastatin with ezetimibe is now available, and coformulation with extended release niacin is under development.     

Simvastatin: present and future perspectives

Simvastatin is lipophilic statin with a short half-life that is primarily metabolized by CYP450 3A4. At doses of 5 - 80 mg, simvastatin lowers LDL cholesterol by 25 - 50%. Simvastatin has been shown to reduce the risk of cardiovascular disease by 35% and overall mortality by up to 30% over 5 years. The recommended starting dose of simvastatin 40 mg is approved as a lipid-lowering agent and for all high-risk patients, including those with cardiovascular disease and diabetes, regardless of the baseline LDL level. Simvastatin dose should be adjusted in those receiving CYP3A4 inhibitors, gemfibrozil, or ciclosporin, amiodarone, or in those with severe renal insufficiency. Coformulation of simvastatin with ezetimibe is now available, and coformulation with extended release niacin is under development.