Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.

OBJECTIVE--To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGN--Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. SETTING--Hospital and community based case-control and cohort studies. MAIN OUTCOME MEASURES--(a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. RESULTS--12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS--The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.     

Adverse Reactions to Daily and Intermittent Rifampicin Regimens for Pulmonary Tuberculosis in Hong Kong

This paper reports the nature, incidence, and severity of adverse reactions to regimens of rifampicin and ethambutol given once weekly, twice weekly, or daily and to a standard reserve regimen in a total of 330 Chinese failure patients who completed at least six months'' chemotherapy in a therapeutic comparison in Hong Kong.The adverse reactions which occurred on the regimens of intermittent rifampicin were termed cutaneous, abdominal, “flu”, and respiratory; in addition, purpura and abnormal liver function tests were encountered. There was an association of adverse reactions with the interval between doses and with the dose size of rifampicin, the highest incidence occurring with once-weekly rifampicin in high dosage. A procedure was developed for managing adverse reactions to intermittent rifampicin. Of 202 patients treated with intermittent rifampicin 60 developed adverse reactions, but in only 7 (3%) was it necessary to terminate the drug, though a further 10 (5%) were changed to daily rifampicin. On daily rifampicin, generalized hypersensitivity, cutaneous reactions, (one with purpura), and impaired liver function were encountered. Adverse reactions on the standard ethionamide, pyrazinamide, and cycloserine regimen were frequent and some were serious.     

放化疗对胃肠道的损伤以及微生态制剂防治的研究进展

肿瘤患者放化疗后不良反应较多,尤其是胃肠道反应.放化疗对胃肠道的损伤主要包括:严重损伤肠粘膜,造成肠黏膜免疫功能紊乱,以及肠道菌群失调,引发腹泻或便秘.研究发现,微生态制剂可用于防治放化疗对胃肠道的损伤,减少或避免不良反应的发生.     

Double-blind Cross-over Study of Ketoprofen and Ibuprofen in Management of Rheumatoid Arthritis

A double-blind cross-over study of ketoprofen (Orudis) 150 mg daily and ibuprofen (Brufen) 1,200 mg daily was carried out in 35 outpatients with rheumatoid arthritis. Results suggest that analgesic and anti-inflammatory activity of ketoprofen is superior to that of ibuprofen. Significantly greater pain relief (P < 0·05) and reduction in joint circumference (P < 0·01) was obtained with ketoprofen than with ibuprofen. Side effects of the drugs were comparable and not serious.     

Recognizing and reporting adverse drug reactions.

Although physicians in practice are most likely to see patients with adverse drug reactions, they may fail to recognize an adverse effect or to attribute it to a drug effect and, when recognized, they may fail to report serious reactions to the US Food and Drug Administration (FDA). To recognize and attribute an adverse event to a drug effect, physicians should review the patient''s clinical course, looking at patient risk factors, the known adverse reactions to the suspected drug, and the likelihood of a causal relationship between the drug and the adverse event-based on the temporal relationship, response to stopping or restarting the drug, and whether other factors could explain the reaction. Once an adverse drug reaction has been identified, the patient should be informed and appropriate documentation made in the patient''s medical record. Serious known reactions and all reactions to newly released drugs or those not previously known to occur (even if the certainty is low) should be reported to the FDA.     

Oncogenic GBX2 promotes the malignant behaviors of bladder cancer cells by binding to the ITGA5 promoter and activating its transcription

Functional & Integrative Genomics - In bladder cancer patients, metastasis after surgical resection and serious adverse reactions brought by cisplatin-based systemic chemotherapy make it urgent...     

Early postnatal ibuprofen and indomethacin effects in suckling and weanling rat kidneys

The use of indomethacin in preterm newborn infants with symptomatic patent ductus arteriosus is associated with compromised renal function. Ibuprofen has been shown to be as effective as indomethacin with fewer renal side effects. We examined the hypothesis that early postnatal ibuprofen has less adverse effects on neonatal rat renal prostanoids, COX-2 expression, and angiotensin II than indomethacin. Newborn rats received IP injections of human therapeutic doses of ibuprofen or indomethacin on the first 3 days of life. Control rats were treated with equivalent volume saline. Kidneys were assessed in suckling and weanling rats for prostanoids, COX-2 expression, and angiotensin II. In suckling rats, indomethacin suppressed PGE(2) and COX-2 expression, and increased PGF(2alpha), whereas ibuprofen increased COX-2 and angiotensin II. Although both NSAIDs suppressed 6-ketoPGF(1alpha) and TxB(2) levels in suckling rats, the effect was sustained in weanling rats with indomethacin. Our findings demonstrate that indomethacin exhibits more potent suppressive effects on renal COX-2 and vasodilator prostanoids which are important regulators of renal development and function. These long-term, sustained effects may explain in part, why indomethacin exerts more severe adverse renal effects than ibuprofen, when administered during early postnatal life.     

Historical perspectives and the future of adverse reactions associated with haemopoietic stem cells cryopreserved with dimethyl sulfoxide

A retrospective review of the published literature identified several hundred adverse reactions (e.g. nausea, chills, cardiac arrhythmias, neurological symptoms and respiratory arrest) associated with the transplantation of stem cells cryopreserved with dimethyl sulfoxide. The occurrences of these are generally accepted as commonplace, as the majority of reactions are transient, whilst a few patients may require clinical treatment. This exploratory study is a collation of the historical data and the expectations for the notification of serious adverse reactions. Outline information is presented on the development of related European Directives, some technical aspects of dimethyl sulfoxide and the sequential stages of preservation and administration.     

Evaluation of Spontaneous Reports of Adverse Reactions to Drugs

An adverse drug-reaction monitoring system based on spontaneous reporting to a central register of adverse reactions has been in operation for eight years. As a test of the validity of the reports and of the probability of causal relationship between drug and reaction a random sample of 82 cases were followed up in detail. The sample included 17 deaths, 26 serious reactions, and 39 reactions of moderate or only minor severity. Altogether 78% of the reactions were considered to be “probably” drug related and 13% “possibly” drug related. It is concluded that the reports are of value in the detection and evaluation of drug safety.     

Activation of a 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes by the anti-inflammatory agent ibuprofen

Human peripheral blood polymorphonuclear leukocytes (PMNs) metabolized [14C]arachidonic acid predominantly by lipoxygenase pathways. The major products were 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and 15-HETE. These and other lipoxygenase products, including their derived leukotrienes, have been implicated as mediators of inflammatory and allergic reactions. In human platelets, the nonsteroidal anti-inflammatory drug ibuprofen inhibited production of the cyclooxygenase product thromboxane B2 (I50 = 65 microM), whereas the lipoxygenase product 12-HETE was not appreciably affected even at 5 mM ibuprofen. The 5-lipoxygenase of human PMNs (measured by 5-HETE formation) was inhibited by ibuprofen but was about six times less sensitive (I50 = 420 microM) than the platelet cyclooxygenase. The unexpected observation was made that the human PMN 15-lipoxygenase/leukotriene pathway was selectively activated by 1-5 mM ibuprofen. Metabolites were identified by ultraviolet spectroscopy, by radioimmunoassay, or by retention times on high pressure liquid chromatography in comparison with authentic standards. The major product was 15-HETE; and in all of 19 donors tested, 15-HETE formation was stimulated up to 20-fold by 5 mM ibuprofen. Other identified products included 12-HETE and 15- and 12-hydroperoxyeicosatetraenoic acid. Activation of the 15-lipoxygenase by ibuprofen occurred within 1 min and was readily reversible. The effects of aspirin, indomethacin, and ibuprofen on the PMN 15-lipoxygenase were compared in six donors. Ibuprofen produced an average 9-fold stimulation of the enzyme, whereas aspirin and indomethacin resulted in an average 1.5- and 2-fold enhancement, respectively.     

Influences on older people’s decision making regarding choice of topical or oral NSAIDs for knee pain: qualitative study

Objective To explore the factors that influence older people’s decision making regarding use of topical or oral ibuprofen for their knee pain.Design Qualitative interview study nested within a randomised controlled trial and a patient preference study that compared advice to use oral or topical non-steroidal anti-inflammatory drugs (NSAIDs) for knee pain in older people.Setting 11 general practices.Participants 30 people aged ≥50 with knee pain. Results Participants’ decision making was influenced by their perceptions of the associated risk of adverse effects, presence of other illness, nature of their pain, advice received, and practicality. Although participants’ understanding of how the medications worked was sometimes poor their decision making about the use of NSAIDs seemed logical and appropriate. Participants’ model for treatment was to use topical NSAIDs for mild, local, and transient pain and oral NSAIDs for moderate to severe, generalised, and constant pain (in the absence of other more serious illness or risk of adverse effects). Participants showed marked tolerance and normalisation of adverse effects.Conclusion Participants had clear ideas about the appropriate use of oral and topical NSAIDs. Taking such views into account when prescribing may improve adherence, judgment of efficacy, and the doctor-patient relationship. Tolerance and normalisation of adverse effects in these patients indicate that closer monitoring of older people who use NSAIDs might be needed.     

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.     

Possible pathogenic pathways in the adverse clinical events seen following ivermectin administration to onchocerciasis patients.

BACKGROUND: Reactions are commonly associated with the chemotherapy of onchocerciasis. However unmanageable reactions are uncommon when ivermectin (Mectizan(R)) is used for the treatment of this infection, and this drug has proved to be a great improvement over previously used agents. Serious adverse events (SAE) nevertheless have occurred, and there is considerable concern about the negative effect such events may have on mass drug administration programs.This paper reviews the basic pathogenic mechanisms that can be involved in the destruction of microfilaria by chemotherapeutic agents. A central challenge to filarial chemotherapy is the need to remove parasites from biologically sensitive tissues, a more difficult medical challenge than eliminating nematodes from the gastrointestinal tract.Explanations for the etiology of the serious adverse reactions occurring with ivermectin treatment in specific geographic areas where there is coincident heavy Loa loa infections are hampered by a lack of specific pathological case material. Ways to investigate these possibilities are reviewed. Possible pathogenic mechanisms include embolic vascular pathology accompanied by local inflammation, blood brain barrier mdr1 abnormalities, and genetic predisposition to excessive inflammatory responses. CONCLUSION: It is important to keep ivermectin, and all its associated adverse clinical events, in perspective with the many other chemotherapeutic agents in general use - many of which produce serious adverse events even more frequently than does ivermectin. Currently available evidence indicates that the pathogenesis of the Loa-associated adverse reactions are probably related to inflammatory responses to microfilariae in specific tissues. However, the possibility of genetic predispositions to pathology should also be considered.     

Dyspnoea,asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN--Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation''s international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS--Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES--Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS--In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION--Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.     

Measles immunisation in children with allergy to egg.

OBJECTIVE--To examine the occurrence of adverse reactions to measles vaccine given as a single dose to children with egg allergy, and to determine if the administration of single dose to children with a positive result in an intradermal skin prick test with the vaccine is associated with adverse reactions. DESIGN--Review of results of immunisation and prospective study of 96 consecutively presenting children given intradermal skin testing with the vaccine. SETTING--Children''s allergy centre. SUBJECTS--410 children sensitive to egg referred to the allergy unit for advice about measles immunisation. MAIN OUTCOME MEASURES--Nature and severity of reactions associated with the administration of measles vaccine. RESULTS--All children had a positive result in a skin prick test with egg white, and five had a positive result in a skin prick test with vaccine. Of 96 consecutive children, 46 had a positive result in an intradermal test with vaccine. After immunisation with a full dose (0.5 ml) of vaccine adverse reactions were associated with a mild reaction in four children, none of whom required treatment. Only one of the 46 children with a positive result in an intradermal vaccine skin test had a reaction associated with vaccine administration. None of the children with a positive result in a skin prick test with measles vaccine reacted to the vaccine. The rate of minor reactions to the vaccine not requiring treatment was 0.98% (95% confidence interval 0.27% to 2.48%) and serious reactions requiring treatment was 0% (0% to 0.9%). CONCLUSION--Children with IgE mediated allergic reactions to egg protein should be investigated and managed by practitioners with special knowledge in this subject. Measles immunisation should be performed in a setting where any adverse reactions can be dealt with appropriately. Skin tests and measles vaccine and desensitisation are not necessary.     

Ibuprofen Overdose—A Prospective Study

Of 61 cases of ibuprofen overdosage reported consecutively to the Rocky Mountain Poison and Drug Center from September 1985 through April 1986, 16 were excluded because of incomplete follow-up or concurrent medication ingestion. A toxic reaction developed in 7 (16%) of the remaining 45 patients. Nausea, vomiting, abdominal cramps, mild central nervous system depression, coma, tachycardia, apnea, metabolic acidosis with or without respiratory alkalosis, hematemesis, and oliguric renal failure were noted. Two of six adults had a toxic reaction, and one died. Among pediatric patients, 5/39 (13%) had a toxic reaction. Of patients whose ibuprofen ingestion was less than 104 mg per kg, none became ill. All patients in whom the time of ingestion was known (six of seven) and who had a toxic reaction did so within four hours of ingestion. An ibuprofen overdose, although usually benign, can occasionally produce serious toxicity.     

Commercially viable resolution of ibuprofen

Ibuprofen belongs to the non-steroidal anti-inflammatory drug (NSAID) family known as profens. Studies demonstrate that (S-ibuprofen is 160 times more potent than (R-ibuprofen in vitro, while the accumulation of (R-ibuprofen can cause serious side effects such as gastrointestinal pain. Candida rugosa lipase was used to enantioselectively esterify racemic ibuprofen with decan-1-ol and butan-1-ol in cyclohexane with an enantiomeric ratio (E) of 130 and 46, respectively, in up to 46% conversion. Separation by bulb-to-bulb distillation of (R)-ibuprofen and unreacted alcohol from the corresponding (S)-alkyl ibuprofen ester was possible for the decyl but not the butyl case. The enantioselective hydrolysis of (S)-alkyl ibuprofen esters with the same biocatalyst in aqueous phosphate buffer was twice as slow for the decyl alcohol versus the butyl example. The combined environmentally friendly enantioselective esterification and hydrolysis of ibuprofen insured the isolation of (S)-ibuprofen with a greater than 99% enantiomeric excess.     

布洛芬联合甲硝唑对慢性牙周炎龈沟液中细胞因子的影响

目的:研究布洛芬联合甲硝唑对慢性牙周炎的疗效和对龈沟液中细胞因子的影响。方法:选择2013年1月~2015年12月在我院进行诊治的慢性牙周炎患者82例,随机分为两组,观察组给予布洛芬联合甲硝唑治疗,对照组给予甲硝唑治疗,比较两组的临床疗效、龈沟液中细胞因子的变化和抗氧化作用。结果:观察组的有效率为82.93%(34/41),明显高于对照组的65.85%(27/41)(P0.05);两组治疗后的龈沟出血指数、牙菌斑指数、附着水平和牙周袋深度均明显降低(P0.05),且观察组降低的更为明显(P0.05);两组治疗后的超敏C反应蛋白、肿瘤坏死因子、白介素-6和白介素-8水平均明显降低(P0.05),且观察组降低的更为明显(P0.05);两组治疗后的超氧化物歧化酶和谷胱甘肽过氧化物酶水平均明显升高(P0.05),丙二醛和一氧化氮水平均明显降低(P0.05),且观察组更为明显(P0.05);两组不良反应发生率相比无明显差异(P0.05)。结论:布洛芬联合甲硝唑对慢性牙周炎疗效显著,可以有效降低炎症水平,减少自由基损伤,有助于牙周组织的重建及恢复。     

同步放化疗治疗中晚期宫颈癌的临床效果分析

目的：子宫颈癌（Cervical Cancer）是女性生殖系统常见的恶性肿瘤,严重影响女性的身体健康及生活质量。本研究通过观察单纯放疗与同步放化疗治疗中晚期宫颈癌的临床效果,探讨治疗宫颈癌的最佳方式,为后续临床研究提供参考。方法：选取我院2008年1月-2009年6月收治的中晚期宫颈癌患者124例,随机分为同步放化疗组和单纯放疗组,每组62例。单纯放疗组采取腔内或腔外照射的方式进行放射治疗,而同步放化疗组在此基础上采用多烯紫杉醇＋顺铂（DP）方案进行治疗。观察并比较两组患者的近期临床疗效、毒副反应发生率及随访情况。结果：同步放化疗组的治疗总有效率、毒副反应发生率均高于单纯放疗组,但患者经对症处理后均获得改善;同步放化疗组三年生存率高于单纯放疗组,差异均具有统计学意义（P〈0．05）。结论：在中晚期宫颈癌的临床治疗中,对患者实施放射治疗的同时选择合理的药物及给药方案进行化疗具有明显的近期疗效,患者的毒副反应可耐受,且治疗后的生存率较高,值得临床推广应用。