CHEST MEDICINE BY WAHEED SHOUMAN

4. What is the treatment of bronchial asthma? SABA LABA ICS Anticholinergics Antileukotriens IGE antagonists PDEI Anti-mediators Anti-inflammatory Interleukin antagonists Others

5. What is the treatment of COPD? SABA LABA ICS Anticholinergics Antileukotriens!!!!!!! IGE antagonists!!!!!!! PDEI Anti-mediators Anti-inflammatory Interleukin antagonists!!!!!!!! Others

7. Onoue et al, Expert Opin. Drug Deliv. (2009) 6(8):793-811

8. Hansel and Barnes Lancet 2009; 374: 744–55

10. Nicotine vaccine ,when nicotine is coupled to a carrier protein, it is possible to induce antibody formation to nicotine

11. The antibodies in the circulation then bind nicotine reversibly

12. The binding, however, greatly slows delivery of nicotine to the brain, reducing its addiction potential. Clinical trials with nicotine vaccine are currently underway, and early studies show promiseRennard, 2011

14. FDA declined to approve rimonabant because of concerns for potential suicide riskRennard, 2011

15. LABA Long-Acting Beta-Agonist LABA LiberaAccademia Belle Arti LABA Lubbock Area Baptist Association LABA Latin American Business Association LABA Leicestershire Asian Business Association LABA Los Angeles Business Advisors LABA Lebanese Alliance for Breastfeeding Action LABA Litchfield Area Business Association LABA Los Angeles Bowling Association LABA Latin American Boxing Association LABA Lancaster Avenue Business Association LABA Laboratory Animal Breeders Association LABA A Chinese Festival in mid-January

17. O’Donnell et al, Respiratory Medicine (2011) 105, 1030e1036

18. O’Donnell et al, Respiratory Medicine (2011) 105, 1030e1036

20. Raghavan et al, Current Opinion in Pharmacology 2011, 11:204–210

21. Compared with placebo, NVA237, 50 mg (Novartis) used through DPI (breezhaler) showed significant and sustained bronchodilatory efficacy in patients with mild, moderate or severe COPD Fogarty et al, Respiratory Medicine (2011) 105, 337e342

22. Arformoterol (Brovana, nebulization) Hanania et al, COPD: Journal of Chronic Obstructive Pulmonary Disease,2010, 7:17–31

24. LAMA Or LAAC Abbreviate as you can A title for a Tibetan teacher of the Dharma Los Angeles Modern Auctions Los Angeles Music Academy An animal Local Authority Members Association

27. Manufacturers of these inhalers could stop selling them prior to these deadlines

29. Aclidinium is rapidly hydrolysed in human plasma, unlike other currently available antimuscarinics including tiotropium. This results in very low and transient systemic exposure, suggesting a reduced potential for class-related systemic side effectsDevelopmental Status UK: Phase III Clinical Trials EU: Phase III Clinical Trials US: Pre-registration (Filed) Genuair® is a multi-dose dry powder inhalation device

31. CORTICOSTEROIDS They treat All Untreatable, When You Can't add any More, Add Steroids

33. The maintenance use of inhaled corticosteroids has been shown in several trials to decrease the incidence of acute COPD exacerbations by 12–25%

34. This effect is more pronounced in patients with more severe disease and those with a history of recurrent exacerbationsHanania and Sharafkhaneh, 2009

35. PDE4 Inhibitors Which Isozyme

38. Trials with cilomilast in COPD reported a reduction in inflammatory markers in bronchial biopsies (i.e. CD8+ T cells and CD68+ macrophages) and modest improvement in FEV1, quality of life and reduction in COPD exacerbation

39. The use of PDE-4 inhibitors during an acute exacerbation of COPD has not been evaluated

40. The anti-inflammatory effect of PDE4 inhibitors raises the possibility that they could alter the natural history of COPDHanania and Sharafkhaneh, 2009

42. The sub-type PDE4D appears to be particularly important in mediating this response

43. Cilomilast has some selectivity for PDE4D. As a result, its maximally tolerated dose may be limited and may be sub-optimal.Cilomilast is 15mg twice oral tab(Ariflo, GSK)

44. Roflumilast, which is not selective among the PDE4 species, may be slightly more effective clinically in contrast to theophyllineRennard, 2011

46. Based on the existing large body of clinical data, the efficacy of roflumilast is well established and the place of this type of compound in COPD therapy is quite well delineated.

47. However some other issues remain to be clarified, including the safety profile and the systemic anti-inflammatory effects of roflumilast in COPDAntoniu, International Journal of COPD 2011:6 147–155

48. Pooled analysis of two large 12-month studies confirms that roflumilast 500 µg once daily improves lung function, reduces COPD symptoms and the rate of moderate or severe exacerbations, and increases time to onset of moderate or severe exacerbations in patients with severe-to-very-severe COPD receiving concomitant LABAs. Bateman et al , ERJ, doi: 10.1183/09031936.00178710, 2011

49. Gross et al, COPD: Journal of Chronic Obstructive Pulmonary Disease,2010,7:141-153

51. Other rare side effects include; insomnia, anxiety, nervousness, and depression, suicidal ideation

52. In doses > 100mg/kg, it has a pro-inflammatory properties.

53. Roflumilast has been evaluated as an inhaled formulation in a rat model of OVA-induced asthma and its anti-inflammatory and bronchodilator effects have been demonstrated.Antoniu, International Journal of COPD 2011:6 147–155

55. While active orally, theophylline derivatives have been found to be locally irritating, although modestly effective as inhaled bronchodilators .

56. PDE4 inhibitors may be effective by the inhaled routeRennard, 2011

59. Furthermore, two more recent US clinical trials compared fluticasone/salmeterol (250/50 μg bid) to salmeterol (50 μg bid). Fluticasone/salmeterol combination, compared to salmeterol, reduced the rate of moderate to severe COPD exacerbation by 30% during the 1-year study follow-upHanania and Sharafkhaneh, 2009

61. Rates of COPD exacerbations did not differ between the two study arms.

62. However, the fluticasone/salmeterol arm had a lower rate of systemic steroid-requiring exacerbation episodes while subjects on tiotropium had fewer antibiotic-requiring exacerbationsHanania and Sharafkhaneh, 2009

64. Combined formoterol and tiotropium (Tiomate or Duova)

65. Relovair (fluticasonefuroate + vilanteroltrifenatate,GSK) Long-acting beta agonist (LABA) in combination with the once-a-day inhaled corticosteroid (ICS), fluticasonefuroate (FF) Developmental Status UK: Phase III Clinical Trials EU: Phase III Clinical Trials US: Phase III Clinical Trials

68. There is insufficient evidence to determine if triple therapy is superior to the LAAC + LABA treatment regimenGaebel et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:206–243, 2011

70. PDE5 INHIBITORS BE CAREFUL ALERT, IT IS NOT TRUE ASSASSIN

72. Pulmonary vasoconstriction serves to maintain ventilation-perfusion balance, and preserve oxygenation, pulmonary vasodilators also have the potential to worsen oxygenation.

73. Whether pulmonary vasodilator drugs will prove useful to treat patients with COPD remains to be determinedRennard, 2011

74. PDEI5 Inhibitors of PDE5, which catalyze the degradation of cyclic GMP, relax vascular smooth muscle. They may also reduce pulmonary arterial pressure and may have utility in pulmonary hypertension but whether improved cardiac output will be offset by worsening ventilation-perfusion matching by these agents (or any other pulmonary vasodilators) remains to be determined Rennard, 2011

75. ANTI-INFLAMMAORY DRUGS INFLAMMAORY DISEASE, BUT NO ANTI-INFLAMMAORY DRUG HAS A ROLE, EVEN IN THE NEAR FUTURE. THERE MUST A MISTKE, SURE THERE IS

77. This is even more important, since exacerbations can also be significantly reduced by non anti inflammatory treatments, namely long-acting bronchodilators and lung volume reduction surgeryBeeh and Glaab, COPD: Journal of Chronic Obstructive Pulmonary Disease,2009, 6:395–403

79. A recently published prospective study using infliximab in stable COPD patients failed to reveal any beneficial effects for this agent when used over six months

80. the long-term safety of this agent was questioned in this study, as the incidence of malignancy was higher in the treated patients compared with placeboHanania and Sharafkhaneh, 2009

82. Each vial contains 100mg. Vial dissolved in 10ml sterile water and then dissolved in 250 ml 0.9% normal saline and infused in not less than 2 hours. Give H2 blocker and antihistaminic with or without steroids as premedications. Every 3-8 weeks

84. Theophylline: A deficiency in HDAC2 has been reported in COPD patients. The ability of theophylline to increase HDAC2 activity, therefore, raises the possibility that theophylline may have an important anti-inflammatory action, particularly, in combination with glucocorticoidsRennard, 2011

86. Selectins are the adhesion molecules that enable the attachment and “rolling” of leucocytes on the vascular endothelium, the first step in the neutrophil inflammatory response. Bimosiamose is taken daily by inhalation through a novel nebulizer device and is in two phase II studies. Gross, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:136–138, 2011

88. In an accepted clinical model of ozone challenge, inhalation of Bimosiamose led to a broad and favorable significant anti-inflammatory effect.

89. Revotars latest cross-over Phase II study investigated the anti-inflammatory effect of Bimosiamose inhaled twice daily over four weeks. Treatment with Bimosiamose resulted in a broad anti inflammatory effect as well as a trend in lung function improvement in COPD patients.http://www.revotar.de/copd.htm, 28/7/2011

91. Arriva has inhaled ilomastat “a potent, broad spectrum inhibitor of matrix metalloproteinases that has been shown to be active in an animal model of cigarette smoke-induced emphysema”.HunninghakeGM, et al. NEJM 2009;361:2599–608 Gross, COPD: Journal of Chronic Obstructive Pulmonary Disease,2010, 7:307–309

93. NF-kB is activated in macrophages and epithelial cells of COPD patients. It regulates expression of chemokines like IL-8, TNF-α and other inflammatory cytokines, and some of the metalloproteinases.

94. NF-kB proteins are present in the cytoplasm in association with inhibitory proteins that are known as inhibitors of NF-kB (IκBs)Hanania and Sharafkhaneh, 2009

96. However, IKK inhibitor did not reduced the inflammatory cell burden in COPD modelHanania and Sharafkhaneh, 2009

98. It has a significant anti-inflammatory effect by suppressing NF-kB. The role of curcumin in COPD is not clear but is currently being evaluatedHanania and Sharafkhaneh, 2009

99. RESVERATROL Resveratrol (3,5,4’-trihydroxystilbene) is a polyphenolic molecule found in the skins of red fruits such as grapes, and is one of the compounds in red wine It has antioxidant, antineoplastic and anti-inflammatory properties Resveratrol inhibited both basal and stimulated cytokine release by bronchoalveolarlavage (BAL) fluid macrophages from cigarette smokers and patients with COPD The identification of its mechanisms of action and its role in COPD requires further study Hanania and Sharafkhaneh, 2009

101. Importantly, several of the intermediates between mevalonate and cholesterol play an important role in regulation of signaling processes. It appears that statins, by inhibiting the production of mevalonate, may have anti-inflammatory actions patients treated with statins had lower risk of mortality as well as hospitalization.

102. This was true for both cardiac events and for COPD-related events

103. The same benefits, with lesser significance were found with ACEIs and ARBsRennard, 2011

105. Improvements in pulmonary hemodynamics may represent an addition to the growing list of potential benefits of statin use in COPD.

106. In multiple regression analysis, statin use was associated with a 4.2 mmHg (95% CI: 2 to 6.4, p=<0.001) lower PAWP and a 2.6 mmHg (95% CI: 0.3 to 4.9, p=0.03) reduction in mPAP independent of PAWPReed et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:96–102, 2011

107. ANTI LEUKOTRIENS YES MAY BE NO

109. MK-0633, was in development by Merck and completed a phase II trial in late 2009. However, neither the primary outcome, trough FEV1 in the last week of a 12-week RTC, nor any of the secondary outcomes were different between treatmentsBernstein JA, et al. Respir Med. 2011;105:392-401

111. Using montelukast, Significant improvements in FVC, FEV1, PaO2 and St. George’s Respiratory Questionnaire (SGRQ) scores (p < 0.05) were observed in the montelukast group with no comparable improvements in the placebo groupWoodruff et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:21–29, 2011

112. ANTI-OXIDANTS IN THE LUNGS, WHAT IS OXIDIZED HAS GONE WITH THE WIND

114. Similarly, there was no effect on rate of COPD exacerbations in the study as a whole. There was, however, a reduction in exacerbation frequency in subjects who were not concurrently treated with glucocorticoidsRennard, 2011

117. Sibenadet (ViozanTM), an agonist on the D2 dopaminergic receptor, works through this pathway and is also a beta2 agonist leading to cough suppression and bronchodilatation. This was not sustained in long term studiesRennard, 2011

119. Anabolic androgens have been shown to result in increased muscle mass.

120. The clinical benefits of the two interventions remain controversialRennard, 2011

122. Tesamorelin is an analogue of human GHRH

123. Tesamorelin is undergoing a trial as a treatment for weight loss in severe COPDGross, Journal of COPD, The COPD Pipeline XI (August 2011)

124. Rivaroxban Rivaroxban is a once-daily oral direct factor Xa inhibitor that has been developed to avoid the need for regular INR measurements Gross, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:244–247, 2011

126. However, a recent meta-analysis concluded that consistent evidence across multiple important outcomes which clearly demonstrates clinical benefit does not existHanania and Sharafkhaneh, 2009

127. OMALIZUMAB If it works, it is not neither COPD nor Xolair

129. The study is sponsored primarily by National Jewish Hospital and the primary outcome is the frequency of acute exacerbationsGross, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:244–247, 2011

130. Ram et al, Fitoterapia 82 (2011) 141–151

131. endobronchial therapy

133. Under general anesthesia, separate dual-lumen catheter instillations of a suspension of fibrinogen and a solution of thrombin are endobronchially placed in target airways, those that lead to hyperinflated lung regions Besides the expected lung volume changes, meaningful improvements in quality of life and 6-minute walk were obtained and maintained for 6 monthsCriner GR et al AJRCCM 2009; 179:791–8)

134. CELL THERAPY, STEM CELL AND NANOMEDICINE EVERY BREAK-THROUGH IDEA STARTED LIKE THIS THIS THE FUTURE MEDICINE

136. This experiment demonstrated that pulmonary emphysema was not, as was once believed, entirely irreversible.

137. These original experiments have been repeated in the mouse, but not in other speciesRennard, 2011

139. Retinoic acid acts on three intracellular receptors: RAR-ɑ, RAR-β and RAR-γ.

140. It appears that the RAR-γ receptor may be particularly important in stimulating new alveolar wall formation.

141. RAR-γreceptor have been developed and are undergoing clinical trials both in patients with a-1PI

142. deficiency-associated emphysema and in smokers with normal levels of a-1 PI with emphysemaRennard, 2011

144. One possible mechanism to account for this difference would be the persistence of a stem/progenitor cell population capable of responding to retinoic acid and inducing the formation of new alveolar wall in rodents.

145. This raises the possibility that lung regeneration in the human may be facilitated by concurrent cell-based therapiesRennard, 2011

147. Granulocyte colony stimulating factorRennard, 2011

149. The primary outcome is spirometry at 12 months and did not show a significant change in the 4 subjects studied.

150. No adverse events were reported.Ribeiro-Paes et al. Int J of COPD 2011;6:63–71 DOI 10.2147/COPD.S15292

152. It is considered the pathway to personalized medicine

154. The good LABA MABA COMBINED THERAPY PDE4I MATRIX METALLOPROTEASE-12 INHIBITORS INHALED SELECTIN ANTAGONISTS

155. The bad Antileukotriens PDE5I Anti-IgE Smoking cessation methods Mucoactive drugs Weight gain interventions

156. The ugly Anti TNF drugs NF-kB antagonists Systemic anti selectins

157. The great promise Nano-based theranostics Anti-oxidants Cell therapy And to pray and say:

158. اللهم رب الناس أذهب البأس اشفِ أنت الشافي لا شفاء إلا شفاؤك ، شفاء لا يغادر سقما