塞来昔布结合结肠镜下息肉切除术治疗家族性腺瘤性息肉病患者的疗效

目的观察服用塞来昔布结合肠镜下息肉切除术对家族性腺瘤性息肉病(FAP)患者结直肠腺瘤消退的影响。方法 12例根据家族史并经结肠镜检查和组织病理学检查确诊的家族性腺瘤性息肉病患者,随机分为塞来昔布联合结肠镜治疗组和结肠镜治疗组,每组6例。塞来昔布联合结肠镜治疗组患者,行内镜下高频电凝、电切治疗结束后即口服塞来昔布800 mg/d,疗程为12个月;结肠镜治疗组患者每4个月行结肠镜下息肉切除术,疗程为12个月。两组患者均每4个月复查结肠镜1次,观察腺瘤的数目、类型。结果塞来昔布联合结肠镜治疗组于治疗后4、8、12个月腺瘤消退率分别为89.0%、93.1%和97.8%,而结肠镜治疗组分别为87.9%、86.9%和81.8%,两组比较差异有统计学意义(P<0.05)。结论塞来昔布联合结肠镜治疗可使家族性腺瘤性息肉病患者结直肠腺瘤保持长期显著消退状态,其治疗效果肯定,且优于单纯结肠镜下息肉切除的治疗方法。     

Cyclooxygenase 2: a molecular target for cancer prevention and treatment

Cyclooxygenase2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in several human cancers. Here, the potential utility of selective COX-2 inhibitors in the prevention and treatment of cancer is considered. The mechanisms by which COX-2 levels increase in cancers, key data that indicate a causal link between increased COX-2 activity and tumorigenesis, and possible mechanisms of action of COX-2 are discussed. In a proof-of-principle clinical trial, treatment with the selective COX-2 inhibitor celecoxib reduced the number of colorectal polyps in patients with familial adenomatous polyposis. Selective COX-2 inhibitors appear to be sufficiently safe to permit large-scale clinical testing and numerous clinical trials are currently under way to determine whether selective inhibitors of COX-2 are effective in the prevention and treatment of cancer.     

Celecoxib: a review of its use in the management of arthritis and acute pain

Celecoxib (Celebrex), the first cyclo-oxygenase (COX) 2-selective inhibitor (coxib) to be introduced into clinical practice, has been available for almost a decade. It is approved in one or more countries worldwide for the relief of the signs and symptoms of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (in patients aged > or =2 years) and ankylosing spondylitis (AS), the management of acute pain in adults, the treatment of primary dysmenorrhoea and the reduction in the number of adenomatous colorectal polyps in familial adenomatous polyposis.Celecoxib remains an effective and useful altenative to nonselective NSAIDs in the treatment of acute or chronic musculoskeletal pain. In the latter setting, it offers the prospect of improved gastrointestinal (GI) tolerability and, in patients not taking aspirin for cardioprophylaxis, a GI safety advantage. Currently available evidence of an increase in cardiovascular (CV) risk with celecoxib is inconsistent; any increase in risk is likely to be small and similar to that with nonselective NSAIDs. As with all NSAIDs, the potential GI, CV and renal risks of celecoxib must be weighed against the potential benefits in each individual; it is a rational choice for patients at low CV risk who require NSAID therapy, especially those at increased risk of NSAID-induced GI toxicity, but also those unresponsive to, or intolerant of, other NSAIDs. If selected, celecoxib, like all NSAIDs, should be used at the lowest effective dose for the shortest possible duration.     

Colon cancer: a role for cyclo-oxygenase-2-specific nonsteroidal anti-inflammatory drugs

Large bowel cancer is not only the third most frequent cancer in the world but is one of the most common human malignancies in Western countries, including North America. In recent years, multidisciplinary research in epidemiology, molecular biology, and laboratory animal model studies have contributed much to our understanding of the aetiology of this cancer; more importantly, it has enabled us to devise preventive strategies. Several epidemiological studies have detected a 40 to 50% decrease in risk of colorectal cancer in individuals who regularly use aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical trials with NSAIDs in patients with familial adenomatous polyposis have demonstrated that treatment with NSAIDs caused regression of pre-existing adenomas. Preclinical efficacy studies have provided scientifically sound evidence as to how NSAIDs act to retard, block, or reverse colonic carcinogenesis. Equally exciting are opportunities for effective chemoprevention with selective cyclo-oxygenase-2 inhibitors in a variety of animal models of colon cancer. Selective cyclo-oxygenase-2 inhibitors such as celecoxib have been proven to be effective chemopreventive agents against colonic carcinogenesis with minimal gastrointestinal toxicity. Our exploration of the multistep process of carcinogenesis has provided substantial insights into the mechanisms by which anti-inflammatory agents modulate these events. There is growing optimism for the view that realisation of preventive concepts in large bowel cancer will also serve as a model for preventing malignancies of the prostate and breast.     

Studies on the Development of Colon-targeted Delivery Systems for Celecoxib in the Prevention of Colorectal Cancer

The nonsteroidal anti-inflammatory drugs (NSAIDs) are found to be potential chemopreventive agents of colorectal cancer. Celecoxib, an NSAID with selective cyclooxygenase-2 inhibition, was proved to be effective for the prevention of colon cancer in patients with familial adenomatous polyposis (FAP) and sporadic polyps. In the light of this information, the present study was carried out to develop oral colon-targeting drug delivery systems for celecoxib using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for hardness, drug content and were subjected to in vitro drug release studies. The amount of celecoxib released from the matrix tablets at different time intervals was estimated by a HPLC method. Guar gum matrix tablets released only 2-4% of celecoxib in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets containing 20% of guar gum released another 37% of celecoxib after degradation by the colonic bacterial action. The matrix tablets containing 30% of guar gum released about 24% of celecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that the matrix tablets containing either 20 or 30% of guar gum are most likely to target celecoxib for local action in the colon. The guar gum matrix tablets of celecoxib showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40°C/RH 75% for 6 months. Differential scanning calorimetry (DSC) studies indicated no possibility of interaction between celecoxib and guar gum/other formulation excipients.     

塞莱昔布Celecoxib在预防家族性结肠息肉病术后复发的作用

目的探讨塞莱昔布对家族性结肠息肉病病人术后的肠息肉的防治作用。方法我们用小剂量塞莱昔布预防4例家族性结肠息肉病病人术后的十二指肠及小肠息肉的复发,剂量为200mg/天,疗程为18个月;之后,进行了三年随访观察,并将预防治疗方案和结果与国外报道的文献进行比较。结果这4例病人的三年随访观察表明,无十二指肠及小肠息肉的复发,且无心血管疾病的并发症和其他不良反应。结论塞莱昔布是一种有效的环氧化酶抑制剂,对家族性结肠息肉病病人术后的肠道息肉复发和心血管疾病的并发症有良好的预防作用,但应该使用小剂量、短疗程。     

Studies on the development of colon-targeted delivery systems for celecoxib in the prevention of colorectal cancer

The nonsteroidal anti-inflammatory drugs (NSAIDs) are found to be potential chemopreventive agents of colorectal cancer. Celecoxib, an NSAID with selective cyclooxygenase-2 inhibition, was proved to be effective for the prevention of colon cancer in patients with familial adenomatous polyposis (FAP) and sporadic polyps. In the light of this information, the present study was carried out to develop oral colon-targeting drug delivery systems for celecoxib using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for hardness, drug content and were subjected to in vitro drug release studies. The amount of celecoxib released from the matrix tablets at different time intervals was estimated by a HPLC method. Guar gum matrix tablets released only 2-4% of celecoxib in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets containing 20% of guar gum released another 37% of celecoxib after degradation by the colonic bacterial action. The matrix tablets containing 30% of guar gum released about 24% of celecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that the matrix tablets containing either 20 or 30% of guar gum are most likely to target celecoxib for local action in the colon. The guar gum matrix tablets of celecoxib showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. Differential scanning calorimetry (DSC) studies indicated no possibility of interaction between celecoxib and guar gum/other formulation excipients.     

Cyclooxygenase as a target for colorectal cancer chemoprevention

Colorectal cancer (CRC) is one of the most common neoplasia in Western countries and the second leading cause of cancer-related death. The vast majority of cases belong to sporadic forms, whereas a small but relevant proportion of them corresponds to inherited disorders, i.e. familial adenomatous polyposis and Lynch syndrome. These individuals with germline mutations in cancer-promoting genes, along with those who had already developed a colorectal neoplasm, either adenoma or carcinoma, stand to benefit from chemopreventive interventions. A large body of evidence indicates that the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) can reduce the risk of CRC. Experimental studies have demonstrated that these drugs decrease the incidence of carcinogen-induced colon tumors in rodents, and several epidemiological investigations and therapeutic trials have also shown a 40-50% reduction in the risk of colorectal adenoma and cancer in individuals taking NSAIDs. Moreover, patients with familial adenomatous polyposis taking sulindac or celecoxib experience a reduction in adenoma size and number. The chemopreventive effects of NSAID are largely related to inhibition of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 overexpression is a frequent, but not universal event in colorectal neoplasms. Indeed, approximately 50% of adenomas and 80% of CRC express high levels of COX-2 mRNA and protein in neoplastic tissue. In this article, we will review the role of cyclooxygenase as a target for CRC chemoprevention, with special attention to the use of selective and non-selective COX-2 inhibitors in both individuals genetically predisposed and those who have already developed a colorectal neoplasm.     

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.     

A molecular rationale for the how, when and why of colorectal cancer screening

Colorectal cancer remains a leading cause of cancer-related mortality in the United States. Recently, colorectal cancer screening and colorectal cancer prevention have gained national attention. In response, the American Gastroenterological Association, the American College of Gastroenterology and the Agency for Healthcare Policy and Research have published recommendations for colorectal cancer screening and surveillance in patients with sporadic as well as hereditary forms of colorectal cancer. This review will focus on the basic molecular differences underlying the formation of carcinoma in patients with sporadic colorectal cancer, and the heritable syndromes of familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), and juvenile polyposis (JPS). By appreciating the molecular mechanisms underlying these four types of polyp cancer syndromes, the differences in clinical time course for progression from polyp to carcinoma and in current screening recommendations for patients with sporadic adenomas, FAP, HNPCC and JPS can be better understood.     

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.     

Familial polyposis coli: clinical manifestations, evaluation, management and treatment

Familial adenomatous polyposis (FAP) is an autosomal dominant, hereditary colon cancer syndrome that is characterized by the presence of innumerable adenomatous polyps in the colon and rectum. Gardner's syndrome is a variant of FAP, which in addition to the colonic polyps, also presents extracolonic manifestations, including desmoid tumors, osteomas, epidermoid cysts, various soft tissue tumors, and a predisposition to thyroid and periampullary cancers. Mutations of the APC gene are thought to be responsible for the development of FAP, and the location of the mutation on the gene is thought to influence the nature of the extracolonic manifestations that a given patient might develop. Though patients are often asymptomatic, bleeding, diarrhea, abdominal pain and mucous discharge frequently occur. Diagnostic tools include genetic testing, endoscopy, and monitoring for extra-intestinal manifestations. Currently, surgery is the only effective means of preventing progression to colorectal carcinoma. Restorative proctocolectomy with ileal pouch anal anastomosis (RPC/IPAA) with mucosectomy is the preferred surgical procedure, since it attempts to eliminate all colorectal mucosa without the need for an ostomy. Periampullary carcinoma and intra-abdominal desmoid tumors are a significant cause of morbidity and mortality in these patients after colectomy. Frequent endoscopy is needed to prevent the former, while there is no definitive treatment available yet for the latter. The following article presents a case and reviews the evaluation, management and treatment of Gardner's syndrome.     

结直肠癌伴发结肠息肉的临床分析

目的了解结直肠癌患者伴发结肠息肉的发生规律,探讨临床对结直肠癌伴发息肉的早期诊断及处理的策略。方法对67例结直肠癌患者的临床资料进行回顾性分析。结果 67例结直肠癌中有7例为复发性结直肠癌,于35例患者中检出息肉共95枚,其中22例有多发息肉;24例经组织病理活检,其中19例为腺瘤性息肉,1例出现癌变。结论结直肠癌伴发结肠息肉的比例较高,且多数为腺瘤性息肉,重视结直肠癌伴发息肉的处理是降低结直肠癌复发的重要措施。     

Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs

Celecoxib is an NSAID that was developed as a selective inhibitor of COX-2 and approved by the FDA for the treatment of various forms of arthritis and the management of acute or chronic pain. In addition, it was more recently approved as an oral adjunct to prevent colon cancer development in patients with familial adenomatous polyposis and is presently being investigated for its chemotherapeutic potential in the therapy of advanced cancers. However, in laboratory studies it was discovered that celecoxib was able to suppress tumor growth in the absence of any apparent involvement of COX-2, and additional pharmacologic activities associated with this drug were found. Intriguingly, the two pharmacologic effects, inhibition of COX-2 and suppression of tumor growth, were found to reside in different structural aspects of the celecoxib molecule and, therefore, could be separated. This dualism enabled the synthesis of close structural analogs of celecoxib that exhibited increased antitumor potency in the absence of COX-2 inhibition. In theory, such compounds should be superior to celecoxib for antitumor purposes because they might reduce gastrointestinal and cardiovascular risks and the life-threatening side effects that appear during the long-term use of selective COX-2 inhibitors. In this review, the authors present the status of preclinical development of anticancer analogs of celecoxib that are COX-2 inactive, with an emphasis on 2,5-dimethyl-celecoxib (DMC) and OSU-03012.     

Prevention of Aspirin against Recurrence of Polyposis after Operation on Patients with Familial Polyposis Coli

F amilial polyposis coli (FPC), also called familial adenomatous polyposis (FAP), is clinically characterized by hundreds of adenomatous polyp (AP) on the colorectal mucous membranes. This disease is a dominant chromosomal inheritance disease in both male…     

Low dose aspirin, COX-inhibition and chemoprevention of colorectal cancer

Chemoprevention of colorectal cancer involves the long-term use of pharmacologic agents that can prevent neoplasms from developing in the large bowel. This new approach requires major funding and human investments. Among the most widely studied agents for the chemoprevention of colorectal cancer, aspirin, the NSAIDs and COX-2 inhibitors seem to be the most promising. A large number of observational epidemiological studies show that regular use of aspirin and other NSAIDs is associated with a reduction in the risk of developing both colorectal adenomas and cancer. In addition, the prodrug sulindac reduces the growth of existing polyps in familial adenomatous polyposis (FAP). However, the dose, duration of effect and length of protection seen after cessation remain to be fully established. Furthermore, in view of previous discrepancies between the results of observational studies and randomized control trials (RCTs), it is crucially important to investigate the effects of aspirin by RCTs. RCTs investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than RCTs to investigate the effect on the incidence if colorectal cancer per se. Four RCTs of the effect of aspirin on adenoma recurrence are available. Other trials are currently underway.     

结直肠癌及肠道腺瘤性息肉患者肠道菌群失调情况及相关危险因素分析

目的 分析结直肠癌及结直肠腺瘤性息肉患者肠道菌群失调情况及相关危险因素.方法 选择海军总医院2015年1-12月收治的150例患者为研究对象,其中A组为早期结直肠癌,B组为结直肠腺瘤性息肉,C组为早期结直肠癌合并腺瘤性息肉,每组50例.分别于就诊时、术后(外科手术或肠镜下手术)1个月、3个月、6个月对患者肠道菌群进行检测,并分析各组肠道菌群失调危险因素.结果 3组在不同时间段肠镜活检样本中双歧杆菌(Bdb)和肠杆菌(EMB)计数比较差异均有统计学意义(P＜0.01).在相同时间点,3组间肠镜活检样本中Bdb计数比较差异均有统计学意义(P＜0.01).而在术后1个月时3组间肠镜活检样本中EMB计数比较差异有统计学意义(P＜0.05).同时3组肠道菌群失调发生率比较差异无统计学意义(P＞0.05).二分类Logistic回归分析提示BMI异常、服药史均为3组发生肠道菌群失调的危险因素(P ＜0.05,P＜0.01).此外年龄亦为B组肠道菌群失调的危险因素(P＜0.01).结论 肠道菌群失调在结直肠癌及结直肠腺瘤性息肉患者中表现出显著性差异,其中Bdb减少更为突出,进一步佐证肠道菌群失调在结直肠癌发生、发展中起到重要作用.     

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis

Celecoxib (Celebrex?) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties. In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400?mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis. Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs. Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800?mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs. Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.