Retinoic Acid 2012

8/22/2019 Retinoic Acid 2012

1/6

8 SUPPLEMENT TO JAPI febr uary 2012 VOL. 60

IntroductionTh thick clod cov ov th ndstnding opthophsiolog o Chonic Ostctiv PlmonDiss (COPD) is nviling pidl nd this hs contitdsignicantly to recent drug development and is likely to do sovn in th t. Psistnt xpos to n inhld iitnt likcigaree smoke, biomass smoke or industrial smoke leads toactivation of several inammatory pathways which contributeto the pathology of COPD in multiple ways.1-3 Ths iitntsactivate macrophages in the respiratory tract which then releasemultiple chemotactic factors to aract neutrophils, monocytesand T lymphocytes. These cells release a baery of proteinscalled as chemokines and cytokines which get involved in thevarious complex inammatory and destructive pathways leading

to chronic bronchitis and emphysema. Moreover, the steroidswhich arrest asthmatic inammation quite eectively are foundto be disappointingly less potent in COPD. As a ray of hope, theinammatory process in COPD, has the potential to be inhibitedat dierent stages of its pathway. Hence, recent drug discoveryhas focused on intervention of these pathways by inhibiting oneof the steps. However, real challenge lies in developing suchdrugs that are not only eective, but also safe. 2-4

anoth impotnt mchnism implictd in th pthognsisof COPD is oxidative stress. Physiologically, the load of oxidants

is lncd th lvls o nti-oxidnts in th lng. Whn th

oxidant load exceeds the anti-oxidant response, it is known asoxidative stress. This oxidative stress fuels the inammationin COPD and also contributes to airway remodeling andmphsm. Oxidtiv stss is lso ccsd o contiting tosteroid resistance in COPD. This knowledge has stimulated wideintst in th dvlopmnt o potnt nti-oxidnts.5-7

Emerging TherapyIn this review article, we discuss the recent advances taken

place in the development of newer drugs for managing ChronicOstctiv Plmon Diss.

Smoking CessationSmoking csstion is th onl intvntion tht hs n

shown to aenuate the progression of disease (FEV1 decline) inCOPD. However, aempts by smokers to quit smoking end upmo commonl in ils thn sccss. To ssist smoks insmoking cessation, several drugs have recently been developedsuccessfully. Drugs like Bupropion and Varenicline have beenused as Nicotine replacement therapy (NRT) which has beenshown to double the chances of smoking cessation in thosewho aempt it.

Currently, research is focusing on development of antibodiesagainst the free nicotine circulating in the blood, in order to formntign-ntiod complxs. Ths ntign-ntiod complxsbeing unable to cross the blood-brain barrier would not be able

to stimulate the nicotine receptors and will thus make smokingnon-njol (fig 1). Plimin slts o l clinicltrials support a benecial eect of this approach (Figure 2).Nicotine-Qbeta, CYT002-NicQb and NicVAX are currently threesch vccins nd dvlopmnt. Th comintion o ctiv ndpssiv immniztion m lso good sttg.8,9

Newer Bronchodilatorsbonchodiltos th min st o COPD mngmnt

as they improve symptoms and quality of life signicantlyminl mpting th tppd i thogh dilttion o thdistal airways. Thus bronchodilators provide symptomatic reliefonl nd do not ncssil modi th diss pocss. Shot

Newer Therapies for Chronic Obstructive PulmonaryDisease

Rahul Kodgule*, Abhijit Vaidya**, Sundeep Salvi***

*Senior Research Fellow, Chest Research Foundation, Pune; **PojctManager, Cipla Ltd., Mumbai; ***Director, Chest Research Foundation,Marigold Complex, Kalyani Nagar, Pune 411014, Maharashtra

Fig. 1a : Mechanism of nicotine action

Brain

Blood-Brain

Barrier

Nicotne

Nicotne bound to

Nicotne - Receptors

Blood

Fig. 2 : Continuous abstinence rate in smokers after immunization

Fig. 1b : Immunization mechanism against nicotine

Brain

Blood-Brain

Barrier

Antigen-

antibody

Complex

Unbound

receptors

Blood

P=0.174P=0.004

P=0.920 P=0.920

Ab: Antibody

40.3%

32.1% 32.1% 31.3%

56.6%

60%

50%

40%

30%

20%

10%

0%

-10%

Smokingabstainers(%)

VaccinatedSub ects

High Abresponders

Medium Abres onders

Low Abres onders

Placebo


2/6

SUPPLEMENT TO JAPI febr uary 2012 VOL. 60 9

acting-bronchodilators have met with serious problems of non-complinc to th ttmnt cs o th discomot csd mltipl dosing. This hs ld to th dvlopmnt o longacting- and ultra long acting-bronchodilators which producesustained bronchodilation lasting for 12-24 hours. This allowsfor once-daily or twice-daily dosing which improves patientcomplinc.

Ultra Long Acting MuscarinicAntagonists (ultra-LAMA)

Ultra-LAMAs are presently the best treatment available forCOPD. The action of ultra-LAMAs like Tiotropium is mediatedby good selectivity (for blocking) for and slow dissociationom M

3receptors in the lungs. They not only have beer and

sustained bronchodilatory eect but recently they also havebeen shown to have anti-inammatory properties. It appearsthat LAMAs reduce the rate of exacerbation in COPD patientsand hence, have the potential to partially halt progress of thediss nd impov motlit.10,17

Aclidinium, glycopyrronium, darotropium, TD-4208,CHF5407, QAT-370, GSK-573719, Dexpirronium and RBx343E48F0 are some of the ultra-LAMAs under development.aclidinim is st cting. rcnt clinicl tils hv cstd

dot on onc-dil dosing o clidinim nd tils to invstigtecacy and safety of twice-daily dosing are underway. The otheronchodiltos ing vltd in clinicl tils.9-16

Ultra long acting 2agonists (ultra-

LABA)Ultra-LABAs have duration of action that lasts for at least 24

hours. Carmoterol, indacaterol, milveterol, vilanterol, olodaterol,LAS100977, PF610355, JNJ39758979, Slignin- o indol-containing

2-agonists, UK-503590 and Compound X som

of the ultra-LABAs currently under development. Carmoterol,indacaterol, vilanterol, LAS100977 are faster acting comparedto salmeterol. Indacaterol, a promising ultra-LABA has been

ppovd in eop nd uSa o onchodilto ttmnt.Large clinical trials have shown that indacaterol may be beerthan salmeterol, formoterol and tiotropium in increasing troughFEV1 in COPD patients at doses of 150 and 300 mg and therewas no evidence of tachyphylaxis. In asthma milveterol has beenfound to be safe and well-tolerated, with ecacy comparableto salmeterol. Its role in COPD is yet unexplored. Vilanterol isanother ultra-LABA in clinical trials, and has been found to besafe and eective in both asthma and COPD patients.9-16

Th dposition o inhld dg into th lngs is sll lssthan 30%. However, using a formulation process like Modulitetechnology, the drug deposition of carmoterol has been shownto impovd p to 41%.9

Novel CombinationsSome COPD patients respond well to LAMAs and some

to LABAs depending on various factors including variablepdominnc o t-dngic o mscinic cptos inthese patients. Using a combination of the two may solve thepolm o sch vition in spons to onchodiltos.Furthermore, LAMAs and LABAs have been shown to havesynergistic eects.13,18 Since, these combinations are more likely

to be used in severe or very severe COPD cases, addition of asteroid or anti-inammatory drug would make sense, as steroids likl to dc th xctions in ths ptints.19 Varioussuch triple drug combinations are presently available or would vill soon in th mkt.

India leads competition in this respect by launching the rsttriple inhaler containing tiotropium, formoterol and ciclesonideis already available in India while such combinations arepsntl not th in most o th oth contis incldingeop nd uS.20 Som o th comintions in dvlopmntare: aclidinium+formoteroluticasone/budesonide, tiotropium+ formoterol Fluticasone /Budesonide, glycopyronium+formoterolmometasone, indacaterol+glycopyrronium (QVA-169),

olodaterol + tiotropium, milveterol/vilanterol + darotropium,cmotol + tiotopim nd omotol + dxpionim.9-16

One of the limitations of such approach is delivery of LAMAand LABA at dierent locations in the lung which reduces theirsngistic potntil. a novl ppoch o comining ths dgsin singl dim molcl holds pomis to dliv oth thdgs t sm loctions in od to hv mximm sngisticeect. Such molecules are known as dual-acting muscarinicantagonist-

2-agonist (MABA) bronchodilators. GSK-961081,

Bicyclohept-7-ylamine derivatives, THRX-200495, THRX-198321,LAS190792 and TD-5959 are some of the potential MABAscntl nd dvlopmnt.9,13

Anti-Infammatory DrugsDrugs that can reduce the lung inammation in COPD,safely and eectively, will undoubtedly be the drugs of choicefor managing COPD. Years of research to discover such wonderdg hs givn ith to som nti-inlmmto gnts oideas, which may not be as eective as desired but can be ofpgmtic s in clinicl pctic. Toiling sch to ndstndth molcl sons hind th nsponsivnss o COPDinammation to corticosteroids, has led to the understandingthat oxidative stress-mediated reduction in an enzyme known asHistone Deacetylase (HDAC) might be the culprit. Interestingly,theophylline has been shown to increase the cellular levels ofHDAC. Hence, it is thought that oral theophylline given in lowdoses may augment the anti-inammatory eect of inhaled

steroids. A study on theophylline with budesonide (ADC4022)hs ld n sccssll compltd.21-23

PDE4 InhibitorsPhosphodies terase -4 (PDE4) , an i soenzyme of

phosphodiesterase, is specifically expressed in many pro-inflammatory cells such as neutrophils, macrophages,eosinophils, mast cells and lymphocytes. As a consequence,slctiv PDe4 inhiition m hv inhiito ctspon vios inlmmto nd immnomodlto clls.Considering the problem of compliance with inhaled drugsand lack of availability of an eective anti-inammatory drug,oral PDE4 inhibitors hold great promise. Roumilast, a selective

PDE4 inhibitor, has been developed and approved as an anti-

Fig. 3 : Change in lung function parameters after treatment withrofumilast

60

40

20

0

-20

-40

-60

Placebo Roflumilast 250 mcg Roflumilast 500 mcg

Prebronchodilator FEV1 in ml


3/6


inammatory agent for COPD. In a multi-centric clinical trialRoumilast also improved FEV1 marginally, but signicantly inCOPD ptints ov nd ov tiotopim (fig 3).24-27 rcntlit hs n sggstd tht PDe4 inhiitos th st dd-ontherapy over LAMAs and LABAs for COPD.

A combination of the inhaled PDE4 inhibitor GSK256066(phase II) with a LAMA (potentially darotropium) in addition to,a LABA (either milveterol or Vilanterol) is also being explored.However, intolerable gastrointestinal side eects of present PDE4inhibitors have prompted development of specic PDE4B andPDe7 inhiitos (Tl 1).13

AntiproteasesProteases like matrix metalloproteinases (MMP), which are

released from macrophages, neutrophils and epithelial cells,digst lstin to cs mphsm. Slctiv MMP inhiitoslike AZ11557272, have been shown to prevent emphysema andairway thickening in guinea pigs. MMP-9 and MMP-12 inhibitors ing cntl invstigtd in Phs II nd Phs III clinicltrials and the results are awaited with interest. Midesteine

and BAY-71-9678 are few other elastase inhibitors that havecompltd phs I stdis.9-16

Cytokine InhibitorsTNF- (Tumour Necrosis Factor-) is a key mediator of

inlmmtion inclding sstmic inlmmtion in COPD.Iniximab, an inhibitor of TNF-, has been clinically testedand was however, not been found to be of any clinical benetin COPD. Oth ctokins tht ing tgtd psntl oinhibition include interleukin (IL)-1, IL-6 and IL-7. Tocilizumab,a potent inhibitor of IL-6, is yet to be tested in COPD patients.Ths dgs still in th dvlopmnt phs.9-16

Chemokine antagonistsThe chemotactic effects of chemokines CXCL8, CXCL1

and CXCL5 on neutrophils and monocytes are mediated bya common receptor, CXC receptor (CXCR)-2. ADZ8309, anoral CXCR1/2 antagonist has shown to inhibit neutrophilinammation in humans. Antagonists have also been developedfor other important chemokine receptors like CXCR3 andCXCR5. SCH-527123 and GSK656933 have already completedphs I stdis.9-16

TGF- InhibitorsTransforming growth factor (TGF)- plays a key role in

brosis of small airways, which is a major cause of progressiveFEV1 decline and reduced exercise capacity in COPD patients.SD-280, a TGF- inhibitor has been developed. However, thereare long-term concerns about inhibition of TGF-.9-16

Nuclear factor-kB inhibitorsNcl cto-kb is tnsciption cto tht pls k

role in COPD inammation by regulating the expression ofCXCL8 and other chemokines, TNF- and other inammatorycytokines, as well as MMP9. Therefore, inhibition of NF-kB by

inhibition of the inhibitor of NF-kBkinase (IKK)-2 seems to bea promising therapeutic option. Several (IKK)-2 inhibitors arecntl nd dvlopmnt.9-16

p38 MAP Kinase inhibitors:p38 mitogn-ctivtd potin kins (p38 MaP kins)

is ctivtd clll stss nd glts th xpssion oIL-8, TNF- and MMPs, proteins involved in driving COPDairway inammation. Inhaled formulations of p38 MAP kinaseinhibitors, currently in the development phase, are GSK681323and GSK856553.9-16

PI3K InhibitorsPhosphoinositol 3-kinases (PI3Ks) are involved in the

inammatory process, specically in neutrophil recruitmentand activation. PI3K- and PI3K- have been targeted forinhiition nd svl sch inhiitos cntl in l dgdvlopmnt phs.9-16

PPAR AgonistsPoxisom Polito-ctivtd rcptos (PPars)

mil o lignd-ctivtd ncl homon cptos longingto the steroid receptor super-family. Recently, PPAR- andPPAR- have demonstrated immunomodulatory properties.PPAR- agonists also inhibit TGF- and hence may be helpful inpreventing brosis. The PPAR agonists currently being studied

for therapeutic use in COPD are rosiglitazone and SB 219994.9-16

Table 1 : Common adverse events recorded in rofumilast trial

Placebo n=280Rofumilast

250 mcg n=576 500 mcg n=555

Patients experiencing 1 adverse event 174 (62%) 382 (66%) 370 (67%)

COPD xction 65 (23%) 135 (23%) 113 (20%)

Nsophngits 19 (7%) 42 (7%) 46 (8%)

Dih 6 (2%) 28 (5%) 50 (9%)upp spito tct inction 14 (5%) 27 (4%) 23 (4%)

Ns 2 (1%) 16 (3%) 27 (5%)

Fig. 4 : Oxidant-Antioxidant Imbalance

-Cigarette smoke

-Air pollutants

-Neutrophils

-Macrophages

-mucin-glutathione-uric acid-proteins-alphatocopherol-ascorbic acid


4/6


Endoplasmic

Reticulum

O2 O2.-

NADH/NADPH Oxidase

Xanthine oxidase

Lipooxygenase

Cyclooxygenase

P450 monooxygenase

Mitochondrial oxidation

phosphorylation

Superoxide

anion

H2O2

Hydrogen

peroxide

Superoxide

dismutase

OH-

Fenton

Reaction/

Haber Weiss

Reaction

Oxidative Stress

- DNA damage

-Oxidize proteins

(enzymes, histones)

-Oxidize lipids

-Apoptosis

-Neutrophil

sequestration

-Inactivation of anti-

proteases

- Steroid

unresponsiveness

-Transcription of

proinflammatory

cytokines

Mitochondria

Generaton of oxidant radicals

and effects of oxidatve stress

Fig. 5 : Reactive oxygen species generation and its eects

Mean change in eCO from baseline

MeanchangeineCO(inppm)

MeanchangeinFEV1

(inMililiters)

N-Acetyl Fluticasome N-Acetyl Fluticasome

Mean change in FEV1 from baseline

0

-0.2

-0.4

-0.6

-0.8

-1

-1.2

120

100

80

60

40

20

0

-20

-40-1.087

-0.4347113

-31

p=0.017

Fig. 6: Outcomes of clinical trial using higher dose NAC

AntioxidantsOxidative stress arising out of oxidant-antioxidant imbalance,

contributes quite signicantly to the pathophysiology of COPDin multiple ways (Figures 4 and 5). N-Acetyl-Cysteine (NAC) isone of the most widely used and tested anti-oxidants. NAC hasbeen shown to reduce both local as well as systemic oxidativestss. Som stdis hv dmonsttd tht NaC dcsbronchial hypersecretion, prevents the decline in FEV1 and helpsdc th nms o COPD xctions.5,28

In our own study (unpublished data) comparing high doseNAC (1200 mg OD) with inhaled uticasone in a randomized,double blind study in 23 subjects with moderate-to-severe COPD,we found a signicant reduction of exhaled carbon monoxide

(which is a biomarker for oxidative stress) by 1.09 ppm in NACgroup against 0.43 ppm decrease in the uticasone group aftera 4 weeks treatment. Intriguingly, this was accompanied byan increase in FEV1 by 112ml in NAC group against a 30mlreduction in the uticasone group (Figure 6). This suggests thatin high doss NaC dcs oxidtiv stss nd m ld tomild bronchodilation, an added advantage over corticosteroids.However, the results are needed to be conrmed by large scalemlti-cntic clinicl til.29

Several anti-oxidants like N-acestelyn (NAL), N-isobutyryl-cysteine (NIC), erdosteine, procysteine and carbocysteine arecurrently under development. As against NAC, eective inhaledpption o ths nti-oxidnts cn dvlopd mking it

possible to deliver them in higher doses locally. NAL has beentested in clinical trials and was well tolerated. Erdosteine hasdditionl popt o dcing ctil dhsivnss sggst-ing potntil s to pvnt ctil xctions. NIC is lsseective and procysteine more toxic.5,28

NRF-2 ActivatorsNuclear factor erythroid-2 related factor 2 (NRF2), a

transcription factor, induces antioxidant expression, thusinhibiting oxidative stress. Plant products 6-methylsulnylhexylisothiocyanate (6-HITC) found in Japanese horseradish,sulforaphane isolated from broccoli and wasabi are the NRF-2ctivtos cntl ing stdid.30,31

StatinsSttins o 3-hdox-3-mthlgltl conzm-a

(HMG-CoA) are used widely as lipid lowering agents. However,recently statins have been found to have anti-inammatory,antioxidant, anti-thrombogenic and vascular function-restoringctions. rtospctiv stdis indict tht sttins might impovall-cause mortality, deaths from COPD, respiratory-relatedurgent care, COPD exacerbations, intubations for exacerbationsof COPD, exercise capacity and lung function decline in COPDpatients. Lipophilic statins such as atorvastatin and simvastatinare thought to be more eective than the hydrophilic pravastatin.

However, statins have been inadequately studied and needth vltion in ojctiv clinicl tils o th cn sd in th mngmnt o COPD.32-34

Regenerative TherapiesPsntl COPD is mngd onl smptomticll nd

is a progressive disease. Any drug/therapy that restores thedstod lvol tiss m ctll vs th diss.

Stem CellsInfusion with allogenic mesenchymal stem cells offer

hope, as they have the potential to regenerate alveolar tissueby themselves or by secreting growth hormones, specically,

vasculo-endothelial growth factor (VEGF). However, lodgingof the pulmonary blood vessels with the infused stem cells(oiztion) lding to tl otcom is n ndnilpossibility. Trials investigating the ecacy and safety of stemcells in COPD patients are underway.

Retinoic AcidRetinoic acid is known to increase alveolar septation during

lung development. All-trans-retinoic acid has been shownto indc gntion o th tminl spito tct ndreverse elastase induced emphysema. However, this was notsstntitd clinicl til vlting hlth stts on CTdnsit.9-16

Anti-ageing Therapyaccmlting DNa dmg csd oxidtiv stss is

hllmk o ccltd ging. accltd ging hs nimplictd in th pthognsis o COPD nd is mditdby inactivation of Silent Information Regulator Two (SIR2)protein-1 or sirtuin1 (SIRT1). Resveratrol, found in grapeskin, seeds and nuts, activates SIRT1, and is being studied asa possible therapeutic agent for COPD. New SIRT1 activatorsunder development are SRT1720, SRT501 and SRT2104. Thesemolcls mn tims mo potnt thn svtol.5,28,35

Apart from new drug discoveries, a lot of research is takingplace to discover new devices, formulation strategies and drug


5/6


Table 2: Summary of newer therapies for COPD

. Smoking Csstion 1. Vaccines:. Nicotin-Qt. CyT002-NicQc. NicVAX

. bonchodiltos 1. Ultra long acting -2 agonists:. Cmotol. Indctol

c. Milvtold. GSK-642444e. BI-1744-CLf. Saligenin or indole containing -2

gonistsg. UK-503590h. Compound X

2. ult long cting nti-mscinic gnts:. aclidinim omidb. Glycopyrronium bromidec. TD-4208d. QaT-370e. CHF 5407. Dotopim omidg. dxpionim

c. Novl comintions: 1. MABA (Muscarinic-antagonist- -2-gonist):a. GSK-91081. bicclohpt-7-lmin divtivs

2. LABA and ICS:. Cmotol nd dsonid. fomotol nd momtson

(Mff258)c. fomotol nd ciclsonidd. Indctol nd momtson

(QMF-149)e. Indacaterol and QAE-397 (a novel

coticostoid)f. Fluticasone furoate and GSK-642444

3. LABA, LAMA and anti-inammatorycomponds:

a. Tiotropium, salmeterol anduticasone/ciclesonide

b. Indacaterol, glycopyrronium andmomtson

c. Milveterol, darotropium anduticasone furoate

d. GSK-642444, dartropium anduticasone furoate

d. PDe4 Inhiitos 1. Roumilast2. Cilomilst

e. Anti-Inammatorydgs:

1. Ctokin Inhiitos :a. Iniximab (Anti-TNF). Tocilizm

2. Chmokin ntgonists:a. ADZ8309: CXCR1/2 antagonistb. Anti-CXCR3c. Anti-CXCR5

3. TGF- Inhibitors:. SD-280

4. antipotss:. Mimstt: Non-slctiv MMP

Inhiitob. AZ11557272: Dual MMP-9/MMP-12

Inhiito5. Dgs o impoving stoid sistnc:

a. Low dose theophylline. anti-oxidnts

6. Nuclear factor-kB inhibitors7. p38 MAP Kinase inhibitors8. PI3K Inhibitors9. PPAR Agonists:

. rosiglitzonb. SB 219994

. anti-oxidnts 1. N-ctl cstin (NaC) divtivs:a. N-acestelyn (NAL). N-isotlcstin (NIC)

c. edostind. Pocstin. Cocstin

2. Nrf-2 activtos:a. 6-methylsulnylhexyl isothiocyanate

(6-HITC). Slophn

g. Sttins Statins being studied for eects on COPD:. Simvsttin. atovsttinc. Pvsttin

h. rgntiv thpis 1. rtinoic cid:. all-tns-tinoic cidb. 9-cis-retinoic acid

2. Stm clls

i. anti-ging thp 1. SIrT1 activtos:. rsvtol. SrT1720c. SrT501d. SrT2104

j. Inhltion dvics New carrier systems:1. Mtix pticl ci omltions

(sing chitosn)2. Liposomes: Poly-lactide-co-glycolide

(PLGA)3. Polmic Nno-pticls4. Absorption enhancers: surfactant,

fay acid, taurochlorate, saturatedpolyglycolysed glyceride, trihydroxy bileslt nd hlonic cid

5. Cclodxtins: Cclospoin a

dliv gnts s psnt dvics nd dg dliv sstms l to dliv onl mginl mont o th dg to thdsid potion o th lng.12

althogh th xciting novl thpis m tk som timto reach practicing physicians, it is encouraging to realize thatour COPD patients will be receiving more eective and safettmnt in n t (Tl 2). W m soon mk thinammation in COPD respond to therapy. By then, smokingcsstion mins th most impotnt intvntion nd longacting-bronchodilators the most eective symptom-relievers.

References1. Sundeep S Salvi, Peter J Barnes. Chronic obstructive pulmonary

diss in non-smoks. Lancet 2009;374:73343.

2. William MacNee, and Rubin M. Tuder. New Paradigms in thePthognsis o Chonic Ostctiv Plmon Diss I. ProcAm Thorac Soc 2009;6:527531.

3. Leonardo M. Fabbri, Fabrizio Luppi, Bianca Beghe, and Klaus F.r. updt in Chonic Ostctiv Plmon Diss 2005.AmJ Respir Crit Care Med 2006;173:10561065.

4. Barnes PJ. Mediators of Chronic Obstructive Pulmonary Disease.Pharmacol Rev 2004;56:515-548.


6/6


5. Irfan Rahman. Review: Antioxidant therapeutic advances in COPD.Ther Adv Respir Dis 2008;2:351-74.

6. William MacNee. Oxidants/Antioxidants and COPD. Chest2000;117;303S-317S.

7. Z. Kluchov, D. Petrov1, P. Joppa, Z. Dorkov, R. Tkov.The Association between Oxidative Stress and Obstructive LungImpairment in Patients with COPD. Physiol Res 2007;56:51-56.

8. Jacques Cornuz. A Vaccine against Nicotine for Smoking Cessation:A Randomized Controlled Trial. PLoS ONE 3(6): e2547. doi:10.1371/jonl.pon.0002547

9. Carola Seifart and Claus Vogelmeier. Emerging drugs in chronicostctiv plmon disss. expt Opinion. Emerging Drugs2009;14:181-194

10. Peter J. Barnes. Emerging Pharmacotherapies for COPD. Chest2008;134;1278-1286

11. Peter J. Barnes. Future Treatments for Chronic ObstructivePlmon Diss nd Its Comoiditis. The Proceedings of theAmerican Thoracic Society 2008;5:857-864

12. Satomi Onoue, Shinger Misaka, Yohei Kawabata and ShizuoYamada. New treatments for chronic obstructive pulmonary diseaseand viable formulation/device options for inhalation therapy. ExpertOpin. Drug Deliv 2009;6:793-811.

13. Matera MG, Page CP, Cazzola M. Novel bronchodilators for thettmnt o chonic ostctiv plmon diss. Tnds inPharmacological Sciences 2011;1-12. Article in Press.

14. M. Cazzola and M.G. Matera. Emerging inhaled bronchodilators:n pdt.Eur Respir J2009;34:757769.

15. M Cazzola and MG Matera. Novel long-acting bronchodilators forCOPD and Asthma. British Journal of Pharmacology 2008;155:291299

16. Jean Bourbeau and Malcolm Johnson. New and ControversialThpis o Chonic Ostctiv Plmon Diss. Proc AmThorac Soc 2009;6:553554,

17. D.J. Powrie et al. Effect of tiotropium on sputum and seruminammatory markers and exacerbations in COPD. Eur Respir J2007;30:472478.

18. Becky J. Proskocil and Allison D. Fryer. 2-Agonist andAnticholinergic Drugs in the Treatment of Lung Disease. Proc AmThorac Soc 2005;2:305310

19. Douglas W Mapela, Judith S Hurleyb, Anand A Dalalc, ChristopherM Blancheed. The role of combination inhaled corticosteroid/long-acting -agonist therapy in COPD management. Primary CareRespiratory Journal 2010;ahead of print.

20. Barnes PJ. Triple inhalers for obstructive airways disease: will they sl? Expert Rev Respir Med 2011;5:297-300.

21. P J Barnes. Theophylline for COPD. Thorax 2006;61:742744.

22. Peter J. Barnes. Theophylline. New Perspectives for an Old Drug.Am J Respir Crit Care Med 2003;167:813818.

23. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD.AnnuRev Physiol 2009;71:451-64.

24. Peter M. A. Calverley et al. Effect of 1-Year Treatment withRoumilast in Severe Chronic Obstructive Pulmonary Disease.AmJ Respir Crit Care Med 2007;176:154161

25. Klaus F Rabe, Eric D Bateman, Denis ODonnell, Stephan Wie,Dirk Bredenbrker, Thomas D Bethke. Roumilastan oral anti-inammatory treatment for chronic obstructive pulmonary disease: ndomizd contolld til. Lancet 2005;366:56371

26. Victoria Boswell-Smith, Domenico Spina and Clive P. Page.Phosphodists inhiitos. British Journal of Pharmacology2006;147:S252-S257.

27. Giembycz MA, Field SK. Roumilast: rst phosphodiesterase-4inhiito ppovd o ttmnt o COPD. Drug Design,Development and Therapy 2010;4:147-58.

28. In rhmn. antioxidnt thpis in COPD. International Journalof COPD 2006;1:1529.

29. Brashier B, Ravindaran L, Kapoor S, Deshpande PK, Ghongane B,Madas S, Mandrekar S, Limaye S, Salvi S. Four weeks of treatment

with n-acetyl cysteine (NAC) (1200mg/day) reduces lung oxidativestss nd impovs lng nction in modt-to-sv COPDsjcts. European Respiratory Society Congress 2009;Abstract 2016.

30. Aruna Kode,1 Saravanan Rajendrasozhan,1 Samuel Caito,1 Se-RanYang,1 Ian L. Megson, and Irfan Rahman1. Resveratrol inducesgltthion snthsis ctivtion o N2 nd potcts ginstcigaree smoke-mediated oxidative stress in human lung epithelialclls.Am J Physiol Lung Cell Mol Physiol 2008;294:L478L488.

31. ysjio Moimits t l. a Slophn anlog Tht PotntlActivates the Nrf2-dependent Detoxication Pathway. The Journalof Biological Chemistry 2002;277:34563463.

32. Claudia C Dobler, Keith K Wong and Guy B Marks. Associationsbetween statins and COPD: a systematic review BMC PulmonaryMedicine 2009;9:32

33. eic M Motnsn Impct o sttins nd aCe inhiitos on motlitt COPD xctions. Respiratory Research 2009;10:45

34. B. John Mancini et al. Reduction of Morbidity and Mortalityby Statins , Angiotensin-Converting Enzyme Inhibitors, andangiotnsin rcpto blocks in Ptints With Chonic OstctivPlmon Diss. Journal of the American College of Cardiology2006;47:12,

35. Francine Z. Marques, M. Andrea Markus, Brian J. Morrisrsvtol: Clll ctions o potnt ntl chmicl thtconfers a diversity of health benets. The International Journal ofBiochemistry & Cell Biology 2009;41:21252128.

Documents

Retinoic Acid 2012