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Journal Club

Journal Club. Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH.

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Journal Club

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  1. Journal Club MeijvisSC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jun 11;377(9782):2023-30. PiccinniC, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011 Jun;34(6):1369-71. 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文 Matsuda, Masafumi 2011年6月16日8:30-8:55 ８階　医局

  2. ニューモシスチス肺炎に対する使用 成人市中肺炎診療ガイドライン　2007年

  3. 成人市中肺炎診療ガイドライン　2007年

  4. Department of Internal Medicine (S C A Meijvis MD, W J W Bos MD, Prof D H Biesma MD), Department of Pulmonology (H Hardeman MD, Prof J C Grutters MD), Department of Medical Microbiology and Immunology (G T Rijkers PhD, H van Velzen-Blad MSc, G P Voorn MD), and Department of Clinical Pharmacy (E M W van de Garde PhD), St Antonius Hospital, Nieuwegein, Netherlands; Department of Internal Medicine, GelderseVallei Hospital, Ede, Netherlands (H H F Remmelts MD, R Heijligenberg MD); Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, Netherlands (E M W van de Garde); Department of Intensive Care Medicine, OnzeLieveVrouweGasthuis, Amsterdam, Netherlands (H Endeman MD); and Division Heart and Lungs (J C Grutters) and Department of Internal Medicine (H H F Remmelts, D H Biesma), University Medical Centre Utrecht, Utrecht, Netherlands Lancet 2011; 377: 2023–30

  5. Background Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation.

  6. Methods In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerisedrandomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640.

  7. Figure 1: Study profile *Eg, pregnant or breastfeeding.

  8. http://pda.ahrq.gov/clinic/psi/psicalc.asp

  9. Findings Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4–5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6・5 days (IQR 5・0–9・0) in the dexamethasone group compared with 7・5 days (5・3–11・5) in the placebo group (95% CI of difference in medians 0–2 days; p=0・0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemiacompared with 35 (23%) of 153 controls (p<0・0001).

  10. SUMMARY Our study shows that a 4-day course of 5 mg dexamethasone reduces length of hospital stay in patients admitted for community-acquired pneumonia. The faster decline in concentrations of C-reactive protein and interleukin-6 that we noted in patients given dexamethasone compared with controls support the notion that dexamethasone reduces the systemic inflammatory response. Although serious adverse events were rare, the benefits of corticosteroids should be weighed against the potential side-effects.

  11. Interpretation Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in nonimmunocompromised patients with community-acquired pneumonia.

  12. Panel: Present understanding of systemic inflammation in sepsis and acuterespiratory distress syndrome Activated glucocorticoid receptor α —via downregulation of nuclear factor-κB —is most important physiological inhibitor of inflammation, affecting thousands of genes involved in stress-related homoeostasis At cellular level, patients with dysregulatedinflammation have inadequate glucocorticoid receptor-mediated down regulation of inflammatory transcription factor nuclear factor-κB, despite often having increased concentrations of circulating cortisol (systemic inflammation-associated glucocorticoid resistance) Systemic inflammation-associated glucocorticoid resistance can be reversed by increasing glucocorticoid receptor α activation with quantitatively adequate and prolonged glucocorticoid supplementation In patients with sepsis and acute respiratory distress syndrome, much evidence supports a strong association between prolonged down regulation, induced by glucocorticoid treatment, of the inflammatory response and improvement in organ physiology Even short treatment with glucocorticoid is associated with downregulation of glucocorticoid receptor concentrations in most cell types and adrenal insufficiency; without 6–9 days’ tapering, rebound systemic inflammationis common and associated with substantial clinical deterioration Published Online June 1, 2011 DOI:10.1016/S0140- 6736(11)60777-0

  13. Message/Comments ステロイドは肺炎の標準治療！? （真菌はダメだと思いますが。） ただし、退院してからどうなるか？慎重に今後も評価が必要らしい。 肺炎でどんどんステロイド治療がされると、血糖管理コンサルトが増えるのではないか？また減量後のリバウンドとか副腎不全とかも心配。

  14. ピオグリタゾンは癌を予防する？ Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. Wang Y, James M, Wen W, Lu Y, Szabo E, Lubet RA, You M. Mol Cancer Ther. 2010 Nov;9(11):3074-82. Epub 2010 Nov 2. Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of colon cancer liver metastasis. Takano S, Kubota T, Nishibori H, Hasegawa H, Ishii Y, Nitori N, Ochiai H, Okabayashi K, Kitagawa Y, Watanabe M, Kitajima M. Anticancer Res. 2008 Nov-Dec;28(6A):3593-9. Antidiabeticthiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Galli A, Ceni E, Crabb DW, Mello T, Salzano R, Grappone C, Milani S, Surrenti E, Surrenti C, Casini A. Gut. 2004 Nov;53(11):1688-97. Pioglitazone Shows Promise for Oral Cancer Prevention Laird Harrison International Association of Dental Research (IADR) 89th General Session and Exhibition: Abstract 945. Presented March 17, 2011. 膵臓、肝臓、大腸、肺、口腔癌　によいらしい？

  15. eight vs19 cases per 10 000 person-years PROactive study (45mg/day) Vol.3 No.6 2011/6 月刊糖尿病 ● 102-7

  16. http://www.afssaps.fr/

  17. Fate of Takeda’s Actos to be assessed by UK regulators this week By Kirsty Barnes in London Published: June 13 2011 15:51 | Last updated: June 13 2011 15:51 http://www.ft.com/cms/s/2/106e2f74-93a9-11e0-922e-00144feab49a.html#ixzz1PC79uFodThe UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) will meet this week to discuss the fate of Takeda Pharmaceutical’s (TYO:4502) diabetes blockbuster pioglitazone (Actos) in the UK, a source told BioPharm Insight. An MHRA spokesperson confirmed that a meeting will be held on Thursday and possibly Friday to discuss the Actos situation, although the specific agenda remains confidential. Following this, the European regulator, the Committee for Medicinal Products for Human Use (CHMP), will meet on 20 June to assess the matter, the source said. The MHRA spokesperson confirmed this. In an emailed statement, Takeda noted that a pan-European review of pioglitazone is ongoing within the European Medicines Agency (EMA) and Takeda is fully cooperating with the EMA on its review and has provided all data available to it to all regulatory authorities worldwide. On Thursday the French Health Products Safety Agency (AFSSAPS) announced the suspension of the use of drugs containing pioglitazone (Actos and Competact). Germany has since taken the same decision, it has been reported. This follows an announcement by the US Food and Drug Administration (FDA) in September 2010 that pioglitazone was under review by the agency after possible associations with a heightened risk of bladder cancer were identified in preliminary findings of a 10-year study sponsored by Takeda. The source explained that this because pioglitazone stimulates the peroxisome proliferator-activated receptor (P-PAR) gamma and alpha receptors and this bladder growth promotion is a class property of alpha/gamma agonists in rodents.

  18. 09/06/2011 Update on ongoing European review of pioglitazone–containing medicines Suspension of use of these medicines in France while Europe-wide review continues The European Medicines Agency (EMA) has been informed by the French Medicines Agency (Afssaps) of its decision to suspend the use of pioglitazone-containing medicines in France (Actos, Competact), while awaiting the outcome of the ongoing European review on the benefits and risks of these antidiabetic medicines. This decision by the French authority follows receipt of results of a retrospective cohort study carried out in France which became available today. These results appear to suggest an increased risk of bladder cancer with pioglitazone. The EMA’s Committee for Medicinal Products for Human Use (CHMP) started a European review of pioglitazone-containing medicines in March 2011 to investigate the signal of a possible increased risk of bladder cancer with pioglitazone. The CHMP is currently reviewing all relevant data, including data from pharmacoepidemiological studies, non-clinical and clinical data, post-marketing reports of bladder cancer and published data to assess their impact on the balance of benefits and risks of these medicines. The Committee will now also assess the results of the French study and its potential impact on the use of these medicines across the whole EU. The CHMP will discuss this issue at their next meeting on 20-23 June 2011 and recommend appropriate actions as necessary. While this review is ongoing the CHMP is not recommending any changes to the use of pioglitazone-containing medicines. The Agency will make further announcements as soon as new information becomes available. Notes The European review of the centrally authorised pioglitazone-containing medicines Actos, Glustin, Competact, Glubrava and Tandemact and the occurrence of bladder cancer is being conducted in the context of a formal review, initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004, on 16 March 2011. The French targeted epidemiological study is a retrospective cohort study conducted by the French health insurance (Caisse National d’AssuranceMaladie) following antidiabetic patients taking antidiabetic medicines between 2006 and 2009.

  19. アクトスは昨年度全世界で3879億円を売り上げた武田の最主力製品アクトスは昨年度全世界で3879億円を売り上げた武田の最主力製品

  20. the Department of Pharmacology, University of Bologna, Bologna, Italy; Metabolic Diseases & Clinical Dietetics, Department of Clinical Medicine, University of Bologna, Bologna, Italy. Diabetes Care 34:1369–1371, 2011

  21. OBJECTIVE—To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications. RESEARCH DESIGN AND METHODS—Case/noncasebladder cancer reports associated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR). RESULTS—Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug reaction pairs (pioglitazone, 31; insulin, 29;metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was indicative of a definite risk for pioglitazone (4.30 [95%CI 2.82–6.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively). CONCLUSIONS—In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies.

  22. The ratio cases/ noncases for each drug were compared with the ratio of cases/noncases for all other antidiabetic drugs. Stratified analyses weighed the influence of male sex and old age. The possible effect of notoriety bias was tested by a year-by-year analysis. Epi Info 3.4.3-2007 software (Centers for Disease Control and Prevention, Atlanta, GA) was used for statistical analyses. EXAMPLEPRR(proportional reporting ratio)

  23. EXAMPLEROR(Reporting odds ratio )

  24. Diabetes Care 34:1369–1371, 2011

  25. risk factors cigarette smoking, urinary tract infections, occupational exposure to aromatic amines occupational exposure to polycyclic aromatic hydrocarbons drugs (e.g., cyclophosphamide) the systematic use of glucocorticoids

  26. The ROR analysis has several limitations: generic under-reporting, over reporting generated by notoriety bias, dependence on the drug-marketing period (Weber effect), missing or misspelled data lack of information on patients’ habits (smoking) or occupational risks. Prescription number and actual use? Prescription bias ?

  27. notoriety bias may have contributed to part of the association between pioglitazone use and bladder cancer, we also observed a significant relationship in 2004, which preceded publication of the PROactivestudyand label revision. Therefore, we do not believe that our findings can be explained by notoriety bias alone. A greater use of pioglitazone could also have influenced this result.

  28. The Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; The Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; the Division of Research, Kaiser Permanente Northern California, Oakland, California; the Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania. Diabetes Care 34:916–922, 2011

  29. OBJECTIVE—Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes.

  30. RESEARCH DESIGN AND METHODS—This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≧40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time dependent variable. Cox regression–generated hazard ratios (HRs) compared pioglitazone use with non pioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking.

  31. Data are n (%) orr median (range) unless otherwise indicated.N/A, not applicable. *All comparisons have P values ,0.01 except female sex (P = 0.46). †Creatinine$1.4 mg/dL for women and$1.5 mg/dL for men. ‡History of urinary tract infections, urolithiasis, incontinence, and other bladder or urethral conditions. §Low income defined as median household income in census block below the cohort average ($59,000). ¶Includes newly diagnosed patients and patients who newly enrolled in KPNC with an existing diagnosis of diabetes.

  32. RESULTS—The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9–1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of ＞24 months of therapy, there was an increased risk (1.4 [1.03–2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage.

  33. CONCLUSIONS—In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.

  34. Message/Comments ROR(reporting odds ratio) という指標の妥当性はやはり検討が必要なのでは。 Kaiser Permanente Northern California diabetes registry を見るにしても、処方の時に処方した人に対してバイアスが入るのでどこまで信用できるかは不明。 これらのデータから新規処方の禁止はないと感じるが．．．フランスとドイツということと、時期的に、また以前のランタス騒ぎを考えると、政治的な要素が入っているのではないかとも噂されている。

  35. http://www.theheart.org/article/1237021.do

  36. http://www.theheart.org/article/1228257.do

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