future directions in copd management

Future directions in COPD management:The good the bad and the uglyBy Waheed ShoumanAssistant ProfessorChest MedicineZagazig University

What is the treatment of bronchial asthma?1. SABA2. LABA3. ICS4. Anticholinergics5. Antileukotriens6. IGE antagonists7. PDEI8. Anti-mediators9. Anti-inflammatory10. Interleukin antagonists11.Others

What is the treatment of COPD?1. SABA2. LABA3. ICS4. Anticholinergics5. Antileukotriens!!!!!!!6. IGE antagonists!!!!!!!7. PDEI8. Anti-mediators9. Anti-inflammatory10. Interleukin antagonists!!!!!!!!11.Others

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

Hansel and Barnes Lancet 2009; 374: 744–55

Smoking CessationNicotinic receptor partial agonists such as varenicline Nicotine vaccine ,when nicotine is coupled to a carrier protein, it is possible to induce antibody formation to nicotineThe antibodies in the circulation then bind nicotine reversiblyThe 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 promise

Rennard, 2011

RimonabantIt is a canabinoid receptor antagonist that alters release of gamma amino butyric acid release which, in turn, modulates the release of dopamine that is the main downstream mediator of nicotine effectsFDA declined to approve rimonabant because of concerns for potential suicide risk

Rennard, 2011

LABA Long-Acting Beta-AgonistLABA Libera Accademia Belle ArtiLABA Lubbock Area Baptist Association LABA Latin American Business AssociationLABA Leicestershire Asian Business AssociationLABA Los Angeles Business AdvisorsLABA Lebanese Alliance for Breastfeeding ActionLABA Litchfield Area Business AssociationLABA Los Angeles Bowling AssociationLABA Latin American Boxing AssociationLABA Lancaster Avenue Business AssociationLABA Laboratory Animal Breeders AssociationLABA A Chinese Festival in mid-January

Once-daily indacaterol (150-300mcg ) (Onbrez in Europe, Arcapta in USA) provided effective and sustained bronchodilation when given for 1 year to subjects with moderate to severe COPD, in association with decreased as-needed albuterol use and reduced exacerbations. Indacaterol was well tolerated

Chapman et al Chest 2011;140;68-75

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

Indacaterol (150mcg once daily)is a more effective bronchodilator than salmeterol and formoterol and that it is at least as effective as tiotropium

Kornmann, et al, Eur Respir J 2011; 37: 273–279

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

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

Arformoterol (Brovana, nebulization)

Hanania et al, COPD: Journal of Chronic Obstructive Pulmonary Disease,2010, 7:17–31

R-BambuterolThe R- enantiomer of bambuterol, a longacting beta-2 selective adrenergic agent, entered a Phase I trial in ChinaIt has shown greater efficacy and fewer side effects compared to [racemic] bambuterol in preclinical studies

Gross, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:244–247, 2011

LAMA Or LAACAbbreviate as you can

A title for a Tibetan teacher of the DharmaLos Angeles Modern Auctions Los Angeles Music Academy

An animal Local Authority Members Association

Why Comivent and Atrovent MDI are not available?According to USA recommendation, CFC use should be prohibited by 31-12-2013.Manufacturers of these inhalers could stop selling them prior to these deadlinesBoehringer-Ingelheim is working with the FDA to ensure that the CFC-propellant version of Combivent will only be discontinued when a formulation of a similar albuterol-ipratropium combination to be delivered via Respimat inhalation device becomes available

Aclidinium bromide (LAMA) (Eklira Genuair, 400mcg, once)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

CORTICOSTEROIDSThey treat All Untreatable,

When You Can't add any More, Add Steroids

CORTICOSTEROIDSThe maximum benefit from these agents is obtained during the first two weeks of therapy and a longer duration of therapy or the use of doses larger than 40–60 mg of prednisone per day do not confer any additional benefitsThe maintenance use of inhaled corticosteroids has been shown in several trials to decrease the incidence of acute COPD exacerbations by 12–25%This effect is more pronounced in patients with more severe disease and those with a history of recurrent exacerbations Hanania and Sharafkhaneh, 2009

PDE4 InhibitorsWhich Isozyme

PDE-4 INHIBITORSPDE-4 is highly selective for cyclic AMP and represents the major cyclic AMP metabolising enzyme in all immunocompetent cells. Inactivation of cAMP by PDE-4 results in a pro-inflammatory cascadeTrials 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 exacerbationThe use of PDE-4 inhibitors during an acute exacerbation of COPD has not been evaluatedThe anti-inflammatory effect of PDE4 inhibitors raises the possibility that they could alter the natural history of COPD

Hanania and Sharafkhaneh, 2009

The major adverse effect of PDE4 inhibitors is nausea, which may be associated with vomiting. This appears to be due to a direct effect on PDE4 in the central nervous system emesis center.The sub-type PDE4D appears to be particularly important in mediating this responseCilomilast 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)Roflumilast, which is not selective among the PDE4 species, may be slightly more effective clinically in contrast to theophylline Rennard, 2011

Roflumilast, 500mg (Daxas®, Nycomed, Zurich, Switzerland) has recently been approved in Europe as an add on to bronchodilator treatment for the treatment of severe COPD (FEV1% predicted , 50%) associated with chronic bronchitis in adult patients with a history of frequent exacerbationsBased 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.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

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 inpatients with severe-to-very-severe COPD receiving concomitant LABAs.

Bateman et al , ERJ, doi: 10.1183/09031936.00178710, 2011

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

The most commonly reported adverse events were: diarrhea (5.9%), weight loss (3.4%), nausea (2.9%), abdominal pain (1.9%), and headache (1.7%).Other rare side effects include; insomnia, anxiety, nervousness, and depression, suicidal ideationIn doses > 100mg/kg, it has a pro-inflammatory properties.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

Theophylline is not used by inhalation.While active orally, theophylline derivatives have been found to be locally irritating, although modestly effective as inhaled bronchodilators .PDE4 inhibitors may be effective by the inhaled route

Rennard, 2011

Tetomilast, Otsuka’s PDE4 inhibitor It is in 2 phase II trials. Both trials have several dosage arms (12.5 mg to 50 mg, once daily. Both trials will last 2 years, completing in mid 2012

COMBINED THERAPIES

ALL IN ONE BOTTLE

Treatment with fluticasone/salmeterol combination therapy for three years resulted in a 25% reduction in the annual rate of moderate to severe exacerbation of COPD compared with placebo 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-up


Randomised 2-year clinical trial compared fluticasone/salmeterol (500/50 μg bid) to tiotropium

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

However, the fluticasone/salmeterol arm had a lower rate of systemic steroid-requiring exacerbation episodes while subjects on tiotropium had fewer antibiotic-requiring exacerbations


Dulera (fixed combination of formoterol and mometasone furoate, MDI)

Dulera that was developed by Schering-Plough and Novartis was approved for asthma in June 2010. It has now completed a Phase III study in patients with COPD. Presumably it will be coming to the FDA shortly for a COPD indication.


Combined formoterol and tiotropium (Tiomate or Duova)

Relovair (fluticasone furoate + vilanterol trifenatate,GSK)

Long-acting beta agonist (LABA) in combination with the once-a-day inhaled corticosteroid (ICS), fluticasone furoate (FF) Developmental Status UK: Phase III Clinical Trials EU: Phase III Clinical Trials US: Phase III Clinical Trials

Recent studies indicate that triple therapy (MABA,ICS) have clinical benefits, nevertheless, larger long-term studies are clearly needed. Also, significant controversy regarding ICS still exists

Agusti and Vestbo, AJRCCM: doi:10.1164/rccm.201103-0405PP, 2011

Triple therapy does decrease the number of hospitalizations for severe/acute COPD exacerbations compared with LAAC monotherapy. There is insufficient evidence to determine if triple therapy is superior to the LAAC + LABA treatment regimen

Gaebel et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:206–243, 2011

In patients with progressive COPD, combinations of inhaled long-acting β2-agonists, long-acting anticholinergic agents, glucocorticoids, and new antiinflammatory agents such as oral PDEI4 may be indicated

Wedzicha, NEJM,364;12 march 24, 2011

PDE5 INHIBITORSBE CAREFUL ALERT, IT IS NOT TRUE ASSASSIN

Pulmonary VasculatureFor patients with COPD who have secondary pulmonary hypertension as a result of hypoxemia, oxygen is the therapy of choicePulmonary vasoconstriction serves to maintain ventilation-perfusion balance, and preserve oxygenation, pulmonary vasodilators also have the potential to worsen oxygenation. Whether pulmonary vasodilator drugs will prove useful to treat patients with COPD remains to be determined

Rennard, 2011

PDEI5Inhibitors 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

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

To date, there is still no effective anti-inflammatory treatment for COPD. While there are some modest effects of ICS and to a lesser extent of PDE4 inhibitors on clinical endpoints such as exacerbations, it remains to be proven whether the observed effects are due to changes of the underlying inflammation. 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 surgery

Beeh and Glaab, COPD: Journal of Chronic Obstructive Pulmonary Disease,2009, 6:395–403

TNF-a INHIBITORSThe use of humanised monoclonal antibodies (infliximab) and soluble TNF- receptors (etanercept) is currently being investigatedA recently published prospective study using infliximab in stable COPD patients failed to reveal any beneficial effects for this agent when used over six monthsthe long-term safety of this agent was questioned in this study, as the incidence of malignancy was higher in the treated patients compared with placebo


Infliximab (Remicade) 5-10mg/kg infusion. 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 Etanercept(Enbrel) 25 and 50 mg vials twice a week for 3 months then weekly. Used intramuscular. 50 mg in >63kg or 1 mg/kg

Currently Available Drugs That May Have Anti-inflammatory Actions in COPD

Macrolides: Anti-inflammatory effects of macrolides in COPD, both during acute exacerbations and during stable disease, are now being exploredTheophylline: 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 glucocorticoids

Rennard, 2011

Bimosiamose (Revotar Biopharmaceuticals)Bimosiamose (BIMO) is a pan-selectin antagonist, targeted against the selectin family of cell adhesion molecules which is comprised of three structurally related calcium-dependent carbohydrate binding proteins, E-, P- and L-selectin.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.


Revotars anti-inflammatory compound Bimosiamose is currently under clinical evaluation of its therapeutic potential in COPD. In a pilot trial, inhaled Bimosiamose was safe and well tolerated in patients with COPD. Moreover, although applied just for 9 days, it showed encouraging anti-inflammatory effects on sputum parameters.In an accepted clinical model of ozone challenge, inhalation of Bimosiamose led to a broad and favorable significant anti-inflammatory effect. 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

http://www.revotar.de/copd.htm

MATRIX METALLOPROTEASE-12 INHIBITORSMice that are deficient in MMP-12 seem to be totally protected from experimental emphysema, and just recently a large human genetic survey found that a single nucleotide substitution in the promoter region of MMP-12 (presumably down-regulating its expression) was associated with protection of smokers against loss of lung function and, intriguingly, in also protecting children with asthma.

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”.

Hunninghake GM, et al. NEJM 2009;361:2599–608

Gross, COPD: Journal of Chronic Obstructive Pulmonary Disease,2010, 7:307–309

NF-kB INHIBITORSThe nuclear factor (NF)- kB family plays a major role in control of both innate and adaptive immunity.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.NF- kB proteins are present in the cytoplasm in association with inhibitory proteins that are known as inhibitors of NF- kB (IκBs)


Inhibition of the enzymes that degrade IkBs (such as IkB kinase or IKK) may have some effect in COPD exacerbationsHowever, IKK inhibitor did not reduced the inflammatory cell burden in COPD model


CURCUMINCurcumin, a derivative of turmeric, is commonly used as a spice, flavouring agent, food preservative, colouring agent or for decoration.

It has a significant anti-inflammatory effect by suppressing NF-kB. The role of curcumin in COPD is not clear but is currently being evaluated


RESVERATROLResveratrol (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 wineIt has antioxidant, antineoplastic and anti-inflammatory propertiesResveratrol inhibited both basal and stimulated cytokine release by bronchoalveolar lavage (BAL) fluid macrophages from cigarette smokers and patients with COPDThe identification of its mechanisms of action and its role in COPD requires further study


StatinsThe statins inhibit cholesterol synthesis at a relatively early step in the pathway: the conversion of acetyl-CoA to mevalonate.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.This was true for both cardiac events and for COPD-related eventsThe same benefits, with lesser significance were found with ACEIs and ARBs

Rennard, 2011

In a retrospective study in patients with severe COPD, statin use is associated with significantly lower mPAP and PAWP despite older age and a higher prevalence of medical comorbidities such as HTN and coronary disease.Improvements in pulmonary hemodynamics may represent an addition to the growing list of potential benefits of statin use in COPD.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 PAWP

Reed et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:96–102, 2011

ANTI LEUKOTRIENSYES

MAY BENO

5-lipoxygenase inhibitorsThey have also been considered as possible treatments for COPDMK-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 treatments

Bernstein JA, et al. Respir Med. 2011;105:392-401

5-lipoxygenase inhibition, using zileuton reduces cysteinyl leukotriene levels in hospitalized patients with AECOPD. Whether this pharmacologic effect leads to improvements in clinically relevant outcomes (hospital LOS and treatment failure) is uncertainUsing 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 group

Woodruff et al, COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:21–29, 2011

ANTI-OXIDANTSIN THE LUNGS, WHAT IS OXIDIZED HAS GONE WITH THE WIND

In a relatively large study of 523 subjects, the anti-oxidant N-acetylcysteine (NAC) was assessed . No effect was observed on the rate of FEV1 decline over a 3-year interval. 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 glucocorticoids

N-acetylcysteine (NAC)

Rennard, 2011

Hydrogen as antioxidantH2 may be a unique, effective, and specific treatment for COPD. Given the fact that H2 can eliminate RNS and ROS is an important factor in the pathogenic process in COPDThe author hypothesized that H2 may be potentially effective for COPD by preventing its occurrence, exacerbation, and slowing its process.

Cough and MucusAlthough the pathophysiology of cough and mucus secretion in COPD remains incompletely understood, it is likely that neural reflexes play an important role 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 studies

Rennard, 2011

Systemic Effects(respiratory vs systemic COPD paradigm)

Nutritional supplementation has been demonstrated to lead to weight gain in at least a subset of COPD patients Anabolic androgens have been shown to result in increased muscle mass. The clinical benefits of the two interventions remain controversial

Rennard, 2011

Tesamorelin(Egrift)Weight loss in COPD is associated with a poor prognosis. Attempts to reverse it by aggressive refeeding, weight training, or by administration of anabolic agents have been only questionably successful at either restoring fat free mass or improving survivalTesamorelin is an analogue of human GHRHTesamorelin is undergoing a trial as a treatment for weight loss in severe COPD

Gross, Journal of COPD, The COPD Pipeline XI (August 2011)

RivaroxbanRivaroxban is a once-daily oral direct factor Xa inhibitor that has been developed to avoid the need for regular INR measurements


OM-85 BV It is an immunomodulatory agent from detoxified

bacterial extract, has also been used in multiple studies for prevention of COPD exacerbations.

However, a recent meta-analysis concluded that consistent evidence across multiple important outcomes which clearly demonstrates clinical benefit does not exist


OMALIZUMABIf it works, it is not neither COPD nor Xolair

Omalizumab, the anti-IgE monoclonal (Xolair) It has entered a phase II study in COPD patients with elevated IgE levels. The study is sponsored primarily by National Jewish Hospital and the primary outcome is the frequency of acute exacerbations


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

endobronchial therapy

Hydrogel or AeriSeal It is an agent being studied for “biologic lung volume reduction”.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 months

Criner GR et al AJRCCM 2009; 179:791–8)

CELL THERAPY, STEM CELL AND NANOMEDICINE

EVERY BREAK-THROUGH IDEA STARTED LIKE THIS

THIS THE FUTURE MEDICINE

Lung RegenerationIn 1997, Massaro and Massaro demonstrated that, following the development of emphysema, administration of all-trans retinoic acid stimulates the formation of new alveolar wall in a rat modelThis experiment demonstrated that pulmonary emphysema was not, as was once believed, entirely irreversible. These original experiments have been repeated in the mouse, but not in other species

Rennard, 2011

Two limited trials with all-trans retinoic acid, which is approved for the treatment of leukemia, have been conducted in patients with COPD. Although no untoward adverse effects were observed, no therapeutic benefits were observed eitherRetinoic acid acts on three intracellular receptors: RAR-ɑ, RAR-β and RAR-γ.It appears that the RAR-γ receptor may be particularly important in stimulating new alveolar wall formation.RAR-γ receptor have been developed and are undergoing clinical trials both in patients with a-1PIdeficiency-associated emphysema and in smokers with normal levels of a-1 PI with emphysema

Rennard, 2011

Rodent growth, which can continue throughout life, differs in many respects from that of other mammalian species. 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. This raises the possibility that lung regeneration in the human may be facilitated by concurrent cell-based therapies

Rennard, 2011

Potential therapeutic strategiesthat could stimulate tissue repair in COPD

Hepatocyte growth factorGranulocyte colony stimulating factor

Rennard, 2011

Stem Cell TherapyThere is a trial of autologous ‘stem cells’ for severe COPD. The primary outcome is spirometry at 12 months and did not show a significant change in the 4 subjects studied.No adverse events were reported.

Ribeiro-Paes et al. Int J of COPD 2011;6:63–71 DOI 10.2147/COPD.S15292

TheranosticsTheranostics: the pairing of a diagnostic test with a therapyIt is considered the pathway to personalized medicineNano-based theranostics can offer many benefits for COPD patients including real-time diagnosis of lung inflammatory state and treatment, optimal therapy for individual patients and reduction in adverse drug effects

The good1. LABA2. MABA3. COMBINED THERAPY4. PDE4I5. MATRIX METALLOPROTEASE-12 INHIBITORS6. INHALED SELECTIN ANTAGONISTS

The bad1. Antileukotriens2. PDE5I3. Anti-IgE4. Smoking cessation methods5. Mucoactive drugs6. Weight gain interventions

The ugly1. Anti TNF drugs2. NF-kB antagonists3. Systemic anti selectins

The great promise1) Nano-based theranostics2) Anti-oxidants3) Cell therapy4) And to pray and say:

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future directions in copd management

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