Colonic treatments and targets: issues and opportunities

The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.     

Pharmacogenetics and personalised medicine

The traditional concern of pharmacogenetics was Mendelian (monogenic) variation, which visibly affected some drug responses. Pharmacogenetics was broadened by the observation that multifactorial genetic influences, in conjunction with environmental factors, usually determine drug responses. Variability of gene expression, a new theme of the science of genetics, also affects pharmacogenetics; for example, enhanced enzyme activity does not necessarily indicate a mutation, but may be the consequence of a drug-induced enhancement of gene expression. Methodological advances permit the conversion of pharmacogenetics into the broad practice of pharmacogenomics; this improves the possibility of identifying genetic causes of common diseases, which means establishing new drug targets, thereby stimulating the search for new drugs. While the main medical effect of pharmacogenetics was an improvement of drug safety, pharmacogenomics is hoped to improve drug efficacy. On the way to personalized medicine, we may stepwise improve the chances of choosing the right drug for a patient by categorizing patients into genetically definable classes that have similar drug effects (as, for example, human races, or any population group carrying a particular set of genes). It is wise to expect that, even after we have reached the goal to establish personalized medicine, we will not have eliminated all uncertainties.     

EMR documentation of physician–patient communication following genomic counseling for actionable complex disease and pharmacogenomic results

Genomic risk information for potentially actionable complex diseases and pharmacogenomics communicated through genomic counseling (GC) may motivate physicians and patients to take preventive actions. The Ohio State University‐Coriell Personalized Medicine Collaborative is a randomized trial to measure the effects of in‐person GC on chronic disease patients provided with multiplex results. Nine personalized genomic risk reports were provided to patients through a web portal, and to physicians via electronic medical record (EMR). Active arm participants (98, 39% female) received GC within 1 month of report viewing; control arm subjects (101, 54% female) could access counseling 3‐months post‐report viewing. We examined whether GC affected documentation of physician–patient communication by reviewing the first clinical note following the patient's GC visit or report upload to the EMR. Multivariable logistic regression modeling estimated the independent effect of GC on physician–patient communication, as intention to treat (ITT) and per protocol (PP), adjusted for physician educational intervention. Counselees in the active arm had more physician–patient communications than control subjects [ITT, odds ratio (OR): 3.76 (95% confidence interval (CI): 1.38–10.22, p < 0.0094); PP, OR: 5.53 (95% CI: 2.20–13.90, p = 0.0017). In conclusion, GC appreciably affected physician–patient communication following receipt of potentially actionable genomic risk information.     

Gorgan (Turkmen in Iran) HLA genetics: transplantation,pharmacogenomics and anthropology

HLA class I and II alleles have been studied in a population from Gorgan (North East Iranian city bordering Turkmenistan). This population is composed of mainly Turkmen who speak Oghuz Turkish language. Comparison of Gorgan people HLA profile has been carried out with about 7984 HLA chromosomes from other worldwide populations; extended haplotypes and three dimension genetic distances have been calculated by using neighbor-joining and correspondence relatedness analyses. Most frequent extended HLA haplotypes show a Siberian/Mediterranean admixture and closest populations are Chuvashians (North Caspian Sea, Russia) and other geographically close populations like Siberian Mansi, Buryats and other Iranians. New extended HLA haplotypes have been found, such as: A*31:01-B*35:01-DRB1*15:01-DQB1*03:01, A*01:01-B*35:01-DRB1*03:01-DQB1*02:01. Relationships of Turkmen with Kurgan (Gorgan) archaeological mounds, Scythians and Sarmatians are discussed. This study is also useful for a future transplantation Gorgan waiting list, Gorgan HLA and disease epidemiology and HLA pharmacogenomics.     

肿瘤药物基因组学的研究进展

药物基因组学是一门从基因水平预测药物疗效及毒性的新兴学科,旨在阐释药物疗效和毒性的个体差异,指导个体化用药,尽量避免药物不良反应和耐药现象的发生。肿瘤药物基因组学的主要研究对象是人体内与抗肿瘤药物反应相关的生物标志物,包括药物代谢酶、药物作用靶标以及药物转运体等。生物标志物的基因多态性是导致药物反应因人而异的关键因素,单核苷酸多态性则是基因多态性的一种重要形式。本文通过总结肿瘤生物标志物的基因多态性,分析抗肿瘤药物在药效、毒性和耐药方面的个体化差异,探讨肿瘤药物基因组学的研究进展,为临床用药提供参考。     

Pharmacogenomics and serotonergic agents: research observations and potential clinical practice implications

Abstract  Pharmacogenomics of serotonin are potentially relevant in research and clinical practice. There are few proven examples of the importance of pharmacogenetics of serotonin-modifying agents used in functional gastrointestinal or motility disorders. Drug metabolism is dependent on function of the cytochrome P450 enzymes, such as 2D6 and 3A4. Genetic variations in transporters and translation mechanisms have been associated with responses to treatment in irritable bowel syndrome and in obesity. Research on the impact of polymorphisms of key proteins on the pharmacokinetics and pharmacodynamics of drugs that alter serotonin-mediated signalling will assist in explaining diverse responses to those drugs and ultimately improve clinical practice, individualizing medicine.     

后基因组时代的医药研究前沿

对后基因组时代医药前沿进行简略的介绍，它们包括：化学生物学、预防药学、疾病基因组学、药理基因组学、蛋白质组学、药理蛋白质组学和环境基因组学。对化学信息学、生物信息学、计算机模拟技术亦有提及。     

Unfavourable expression of pharmacologic markers in mucinous colorectal cancer

Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety. The reason for this disparity is unclear, but may result from a differential response to adjuvant chemotherapy. We examined known molecular markers for response to common chemotherapy in these two histological subtypes. In all, 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome. Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed. Quantitative expression levels of drug pathway genes were determined using TaqMan RT-PCR (5-fluorouracil (5-FU): TYMS, DPYD, ECGF1; oxaliplatin: GSTP1 (glutathione S-transferase pi), ERCC1 and 2; irinotecan: ABCB1, ABCG2, CYP3A4, UGT1A1, CES2, TOP1). Mucinous tumours significantly overexpressed both TYMS and GSTP1 relative to nonmucinous tumours and patient-matched normal mucosa. No significant differences in expression of the remaining markers were found. Mean follow-up was 20 months; 17 patients had recurrent disease. Among patients receiving 5-FU, those with mucinous tumours experienced shorter disease-free survival (DFS) than those with nonmucinous tumours (median DFS 13.8 vs 46.5 months, P=0.053). Mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. Likewise, DFS may be decreased in patients with mucinous tumours who receive 5-FU. The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer.     

Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p=2 × 10⁻⁵) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p<0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p<0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol–reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p<0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility.