medications which may have anticholinergic effects or make patients more susceptible to anticholinergic effects , include , for example , a . drugs for nausea or dizziness , especially anticholinergic agents , e . g ., promethazine ( phenergan ), prochlorperazine ( compazine ), trimethobenzamide ( tigan ), meclizine ( antivert ), cyclizine ( marezine ), scopalamine b . drugs for parkinson &# 39 ; s disease , especially anticholinergic agents , e . g ., benztropine ; biperiden ; procyclidine ; trihxyphenidyl ; ethoproprazine c . antidepressants , especially tricyclics , e . g ., amitriptyline ( elavil ), doxepin ( sinequan ), imipramine ( tofranil ), trimipramine ( surmontil ), nortriptyline ( pamelor ), protriptyline ( vivactil ), amoxapine ( asendin ), maprotiline ( ludiomil ), clomipramine ( anafranil ); desipramine ( norpramin ) d . antihistamines , especially first - generation sedating antihistamines , e . g ., diphenhydramine ( benadryl ) chlorpheniramine ( chlor - trimeton ), hydroxyzine ( atarax / vistaril ), cyproheptadine ( periactin ) h . urinary and gt antispasmodics , e . g ., oxybutynin ( ditropan ), flavoxate ( urispas ), dicyclomine ( bentyl ), hyoscyamine ; belladonna alkaloids ; tolterodine ( detrol ), trospium , clindinium ; propantheline , pirenzepine , telenzepine , j . antipsychotics , e . g ., chloroprmazine ( thorazine ), thioridazine ( mellaril ), clozapine ( clozaril ), fluphenazine ( stelazine ), thiothixene ( navane ) a . reversible cholinesterase inhibitors , e . g ., edrophonium , tacrine donepizl , physostigmine , pyridostigmine , rivastigmine , galantamine , neostigamine , beta - adrenergic agonists that can be combined with aclidinium in the present invention particularly include β2 adrenergic agonists useful for treatment of respiratory diseases or conditions , for example , selected from the group consisting of arformoterol , bambuterol , bitolterol , broxaterol , carbuterol , clenbuterol , dopexamine , fenoterol , formoterol , hexoprenaline , ibuterol , isoprenaline , mabuterol , meluadrine , nolomirole , orciprenaline , pirbuterol , procaterol , reproterol , ritodrine , rimoterol , salbutamol , salmeterol , sibenadet , sulfonterol , terbutaline , tulobuterol , gsk - 597901 , gsk - 159797 , kul - 1248 , ta - 2005 and qab - 1491 , in free or pharmaceuticaly acceptable salt form . preferably , the β2 adrenergic agonist is a long - acting β2 adrenergic agonist , e . g ., selected from the group consisting of formoterol , salmeterol and qab - 149 in free or pharmaceutically acceptable salt form . corticosteroids that can be combined with aclidinium in the present invention particularly include those suitable for administration by inhalation in the treatment of respiratory diseases or conditions , e . g ., prednisolone , methylprednisolone , dexamethasone , naflocort , deflazacort , halopredone acetate , budesonide , beclomethasone dipropionate , hydrocortisone , triamcinolone acetonide , fluocinolone acetonide , fluocinonide , clocortolone pivalate , methylprednisolone aceponate , dexamethasone palmitoate , tipredane , hydrocortisone aceponate , prednicarbate , alclometasone dipropionate , halometasone , methylprednisolone suleptanate , mometasone furoate , rimexolone , prednisolone famesylate , ciclesonide , deprodone propionate , fluticasone propionate , halobetasol propionate , loteprednol etabonate , betamethasone butyrate propionate , flunisolide , prednisone , dexamethasone sodium phosphate , triamcinolone , betamethasone 17 - valerate , betamethasone , betamethasone dipropionate , hydrocortisone acetate , hydrocortisone sodium succinate , prednisolone sodium phosphate and hydrocortisone probutate . budesonide and mometasone are especially preferred pde4 inhibitors that can be combined with aclidinium in the present invention include denbufylline , rolipram , cipamfylline , arofylline , filaminast , piclamilast , mesopram , drotaverine hydrochloride , lirimilast , roflumilast , cilomilast , 6 -[ 2 -( 3 , 4 - diethoxyphenyl ) thiazol - 4yl ] pyridine - 2 - carboxylic acid , ( r )-(+)- 4 -[ 2 -( 3 - cyclopentyloxy - 4 - methoxyphenyl )- 2 - phenylethyl ] pyridine , n -( 3 , 5 - dichloro - 4 - pyridinyl )- 2 -[ 1 -( 4 - fluorobenzyl )- 5 - hydroxy - 1h - indol - 3 - yl ]- 2 - oxoacetamide , 9 -( 2 - fluorobenzyl )- n6 - methyl - 2 -( trifluoromethyl ) adenine , n - 3 , 5 - dichloro - 4 - pyridinyl )- 8 - methoxyquinoline - 5 - carboxamine , n -[ 9 - methyl - 4 - oxo - 1 - phenyl - 3 , 4 , 6 , 7 - tetrahydropyrrol [ 3 , 2 , 1 - jk ][ 1 , 4 ] benzodiazepin - 3 ( r )- yl ] pyridine - 4 - carboxamide , 3 -[ 3 -( cyclopentyloxy )- 4 - methoxybenzyl ]- 6 -( ethylamino )- 8 - isopropyl - 3h - purine hydrochloride , 4 -[ 6 , 7 - diethoxy - 2 , 3 - bis ( hydroxymethyl ) naphthalen - 1 - yl ]- 1 -( 2 - methoxyethyl ) pyridin - 2 ( 1h )- one , 2 - carbomethoxy - 4 - cyano - 4 -( 3 - cyclopropylmethoxy - 4 - difluroromethoxyphenyl ) cyclohexan1 - one , cis [ 4 - cyano - 4 -( 3 - cyclopropylmethoxy - 4 - difluoromethoxyphenyl ) cyclohexan - 1 - ol , ono - 6126 ( eur respir j 2003 , 22 ( suppl . 45 ): abst 2557 ) and the compounds claimed in the pct patent applications number wo03 / 097613 and pct / ep03 / 14722 and in the spanish patent application number p200302613 . ltd4 antagonists that can be combined with aclidinium in the present invention include tomelukast , ibudilast , pobilukast , pranlukast hydrate , zafirlukast , nitolukast , verlukast , sulukast , cinalukast iralukast sodium , montelukast sodium 4 -[ 4 -[ 3 -( 4 - acetyl - 3 - hydroxy - 2 - propylphenoxy ) propylsulfonyl ]- 4 - oxobutyric acid , [[ 5 -[[ 3 -( 4 - acetyl - 3 - hydroxy - 2 - propylphenoxy ) propyl ] thio ]- 1 , 3 , 4 - thiadiazol - 2 - yl ] thio ] acetic acid , 9 -[( 4 - acetyl - 3 - hydroxy - 2 - n - propylphenoxy ) methyl ]- 3 -( 1h - tetrazol - 5 - yl )- 4h - pyrido [ 1 , 2 - a ] pyrimidin - 4 - one , 5 -[ 3 - 2 -( 7 - chloroquinolin - 2yl ) vinyl ] phenyl ]- 8 -( n , n - dimethylcarbamoyl )- 4 , 6 - dithiaoctanoic acid sodium salt ; 3 -[ 1 -[ 3 -[ 2 -( 7 - chloroquinolin - 2 - yl ) vinyl ] phenyl ]- 1 -[ 3 -( dimethylamino )- 3 - oxopropylsulfanyl ] methylsulfanyl ] propionic acid sodium salt , 6 -( 2 - cyclohexylethyl )-[ 1 , 3 , 4 ] thiadiazolo [ 3 , 2 - a ]- 1 , 2 , 3 - triazolo [ 4 , 5 - d ] pyrimidin - 9 ( 1h )- one , 4 -[ 6 - acetyl - 3 -[ 3 -( 4 - acetyl - 3 - hydroxy - 2 - propylphenylthio ) propoxy ]- 2 - propylphenoxy ] butyric acid , ( r )- 3 - methoxy - 4 -[ 1 - methyl - 5 -[ n -( 2 - methyl - 4 , 4 , 4 - trifluorobutyl ) carbamoyl ] indol - 3 - ylmethyl ]- n -( 2 - methylphenysulfonyl ) benzamide , ( r )- 3 -[ 2 - methoxy - 4 -[ n -( 2 - methylphenylsulfonyl ) carbamoyl ] benzyl ]- 1 - methyl - n -( 4 , 4 , 4 - trifluoro - 2 - methylbutyl ) indole - 5 - carboxamide , (+)- 4 ( s )-( 4 - carboxyphenylthio )- 7 [ 4 ( 4 - phenoxybutoxy ) phenyl ]- 5 ( z )- heptenoic acid and the compounds claimed in pct patent application number pct / ep03 / 12581 . the words “ treatment ” amd “ treating ” are to be understood as embracing treatment and / or amelioration of symptoms of a disease or condition as well as treatment of the cause of the disease or condition . reference to “ prevention ” of a disease embraces prophylaxis and / or inhibition of the disease , aclidinium for use in the methods of the invention may be administered by any suitable route to provide local antimuscarinic action . it is preferably administered by inhalation , e . g ., as a powder , spray , or aerosol , preferably as a dry powder . pharmaceutical compositions comprising aclidinium may be prepared using conventional diluents or excipients and techniques known in the galenic art . for example , dry powder formulations may contain a powder mix for inhalation comprising the aclidinium and a suitable powder base ( carrier substance ) such as lactose or starch . use of lactose is preferred . suitable inhaler devices are known in the art . dosages will vary depending on , e . g ., the individual , the mode and frequency of administration , and the nature and severity of the condition to be treated . daily dosages for a 40 kg adult human may typically for example be on the order of 100 - 1000 micrograms of active agent in the form of dry powder for inhalation . in vitro stability of aclidinium compared with tiotropium and ipratropium and glycolpyrrolate stability in human plasma . the in vitro experiments are carried out at 36 ° c . and at a concentration of 5 μg / ml ( 6 μl of a 1 mg / ml dimethyl sulfoxide solution of each substance is added to a final volume of 1 . 2 ml ). after 3 minutes of pre - incubation , reaction is started by addition of the test substances . at pre - defined times of 0 , 5 , 15 , 30 and 60 min ., aliquots of 100 μl of the plasma are separated and the reaction stopped by the addition of 1 ml of a 20 mm , ph 4 . 0 sodium acetate buffer solution . the test substances are replaced with buffer for the control reactions . human plasma is obtained from volunteers by written informed consent . the blood is collected in tubes containing lithium heparin as anticoagulant , immediately centrifuged at 4 ° c . and the resultant plasma stored at − 20 ° c . when not in use . the determination of aclidinium , tiotropium , ipratropium and glyeolpyrrolate in human plasma ( 100 μl ) is carried out by high - performance liquid chromatography ( hplc ) using uv detection , at 238 nm for aclidinium and tiotropium , and 203 nm for ipratropium , and an automated online solid - phase extraction and injection procedure . a suitable chromatographic system consists of a high - pressure pump ( model 322 kontron for aclidinium and tiotropium and model 515 waters for ipratropium ), a prospekt system ( spark holland ) assisted by a 233xl sampling injector ( gilson medical electronics ), a tunable absorbance detector ( model 2487 , waters ass . ), and a digital alpha server 1000 4 / 266 computer with acces * chrom software ( perkin elmer nelson systems , inc .). chromatography for aclidinium and tiotropium determination is carried out on a spherisorb ods2 , 5 μm , 150 × 4 . 6 mm column ( waters ass .) with a guardapack μbondapak cn precolumn ( waters ass .) and a mobile phase ( 50 : 50 v / v for aclidinium and 22 : 78 v / v for tiotropium ) of acetonitrile : 20 mm , ph 3 . 0 sodium phosphate buffer solution containing 0 . 2 % triethylamine at a flow rate of 1 ml / min . the approximate retention times for aclidinium and tiotropium are 9 . 8 and 9 . 5 minutes respectively . chromatography for ipratropium determination is canned out on a symmetry c18 , 5 μm , 150 × 4 . 6 mm column ( waters ass .) and a mobile phase ( 12 : 88 , v / v ) of acetonitrile : 20 mm , ph 3 . 0 sodium phosphate buffer solution containing 0 . 2 % triethylamine at a flow rate of 1 ml / min . the approximate retention time of tiotropium is 9 . 5 minutes . the extraction of aclidinium , tiotropium and ipratropium from plasma is performed on c2 cartridges ( baker ) activated with 1 . 5 ml of acetonitrile and conditioned with 1 . 5 ml of water . plasma samples , previously diluted with 1 ml of a 20 mm , ph 4 . 0 sodium acetate buffer solution , were loaded into the c2 cartridges . after washing out the cartridges with 1 ml of water and 1 ml of acetonitrile : water ( 40 : 60 , v / v ) for aclidinium , or 3 ml of water for tiotropium or 1 of water and 1 ml of acatonitrile : water ( 10 : 90 , v / v ) for ipratropium , the remaining components are eluted with the mobile phase over 1 minute . there are no significant endogenous peaks at retention times of the analytes that would interfere with their quantitation . the recovery of aclidinium is about 95 % from human plasma . the recovery of tiotropium and ipratropium from plasma is between 80 - 100 %. glycopyrrolate stability in human plasma is using essentially the same procedures as for the other three drugs . the lower limit of quantitation is established at 5 ng / ml for all analytes . aclidinium is rapidly hydrolyzed in human plasma in its alcohol and acid metabolites . both metabolites of aclidinium are assayed on binding for m1 , m2 , m3 , and m4 human muscarinic receptors and are devoid of significant affinity for these receptors . the plasma half life of aclidinium in plasma is lower than 5 minutes for human . moreover , aclidinium is stable in acid aqueous solutions ( ph ≦ 4 ) and the hydrolytic cleavage of the ester bond takes place at neutral and basic phs . in contrast , the other three antimuscarinic esters are quite resistant to degradation by esterases in plasma . plasma degradation for tiotropium ( 16 %), ipratropium ( 0 %), glycolpyrrolate ( 9 %) is not biologically significant during the time of this study ( 60 mm ). clinical phase i study : aclidinium bromide is tested in a phase i , double - blind , partial cross - over , placebo controlled study to assess the activity , pharmacokinetics and tolerability of aclidinium . methods : 12 healthy male volunteers are randomly assigned to 1 of 4 treatment sequences comprising single doses of aclidinium ( 50 , 300 and 600 micrograms ) or placebo administered by dry powder inhaler . the washout period between administrations is at least 6 days . efficacy endpoints are specific airway conductance ( sgaw ), airway resistance ( raw ) and bronchial hyperresponsiveness ( pc35 sgaw methacholine ). results : aclidinium significantly increases sgaw at all time - points ( 1 - 24 h , p & lt ; 0 . 001 vs placebo ). correspondingly , raw is significantly decreased by aclidinium at all timepoints except 1 h and 24 h ( po . 001 vs placebo ). aclidinium 300 and 600 micrograms also significantly reduces pc35 sgaw methacholine at all post - administration timepoints ( p & lt ; 0 . 001 vs placebo ): the methacholine doses required to decrease sgaw by 235 % were 142 . 7 and 181 . 7 vs 27 . 1 mg / ml , for aclidinium 300 and 600 micrograms vs placebo , respectively , at 24 h , and 207 . 1 and 256 . 0 vs 35 . 5 mg / ml , respectively , at 2 h . neither aclidinium nor its metabolites are detected in plasma and no study - drug - related adverse events are reported . conclusion : aclidinium produces significant and long - lasting protection against methacholine - induced bronchoconstriction in healthy male volunteers , demonstrating its suitability for once - daily dosing , notwithstanding that plasma levels are not even detectable . clinical phase ii study : a double - blind , randomised , placebo - controlled , cross - over trial assesses the pharmacodynamics , pharmacokinetics and tolerability of aclidinium and its effects in copd patients methods : men with copd ( fevi & lt ; 65 % predicted ) with demonstrated airway reversibility to ipratropium are randomised to 1 of 4 treatment sequences comprising single doses of aclidinium ( 100 , 300 and 900 micrograms ) and placebo administered by dry powder inhaler with a washout period of 1 week between doses . lung function measurements include fevi and fvc . results : 17 males ( mean age 63 . 5 y , mean fev , 1 . 63 l ) participate in the study . aclidiniun ( 100 , 300 and 900 micrograms ) significantly increases mean fevi auc ( 0 - 24 )/ 24 compared with placebo ( 1 . 800 [ p = 0 . 002 ], 1 . 798 [ p & lt ; o . ooo1 ] and 1 . 827 [ po . ooo1 ] l vs 1 . 597 l , respectively ). the increase in fevi are statistically significant at 24 h for all doses . aclidinium 300 and 900 micrograms produces greater peak fevi effects and the time to maximal onset occurres earlier than with the 100 micrograms dose . similar trends are seen with fvc . no plasma levels of aclidinium or its alcohol metabolite are detected ; low levels of its acid metabolite can be detected following the 900 microgram dose . aclidinium is well tolerated : only 6 cases of mild or moderate headache ( vs 2 with placebo ) and 1 of mildly increased sweating appear possibly related to treatment . conclusion : single doses of aclidinium ( 100 , 300 and 900 micrograms ) produce a rapid and long - lasting bronchodilation in patients with copd , notwithstanding that plasma levels are not detectable .
the invention provides methods of inhalation treatment of a respiratory disease or condition in a patient in need to such treatment without producing in said patient systemic antimuscarinic effects , comprising administering to said patient an effective amount of aclidinium .