the term “ same biological activity ” means the biological , physiological or therapeutic activity or functionality compared with the relevant properties of said peptides and polypeptides , preferably vip or pacap . the term “ derivative or analogue ” means a peptide compound which is derived more or less directly from the corresponding peptide , such as vip or pacap as such , and is altered by some additions , deletions , mutations or modifications without altering the biological properties of the parent peptide . suitable vip derivatives are , for example , disclosed in wo 8905857 , wo 9106565 , ep 0663406 and wo 9729126 ( fmoc protected vip ). the term includes also conjugates of peptides and polypeptides according to the invention that consist of the parent peptide or polypeptide coupled to lipophilic entities , such as liposomes . vip — liposome products are , for example , disclosed in wo 9527496 or wo 9735561 , and have improved properties with respect to bioavailability and proteolytic degradation . furthermore , the term includes also fragments , slightly modified fragments including truncated forms . the term “ stabilized form ” means a derivative or analogue of the peptides according to the invention , wherein the parent peptide was altered in order get more stability and increased half - life in blood and serum . such stabilized forms are preferred if the polypeptide is fragmented by enzyme activity . possible stabilized forms are cyclic peptides , fusion proteins , preferably fc - fusion proteins or pegylated peptides , for example pegylated vip or pegylated peptides according to the invention . the addition of polyethylene glycol increases stability of the peptides and polypeptides of this invention at physiological ph as compared to non - pegylated compounds . the pegylated polypeptide / protein is also stabilized with regard to salts . the term “ fusion protein ” means a compound , especially a stabilized form , consisting of a peptide according to the invention , which is fused to another peptide polypeptide or protein . such a protein is preferably an immunoglobulin molecule , more preferably a fragment thereof , most preferably a fc portion of an igg molecule , preferably an igg1 . a fc - vip fusion protein is described in wo 200024278 and shows an improved half - life in serum and blood . fc fusions according to invention are fc - peptide seq id no . 2 and fc - peptide seq id . no 3 , and fc - peptide seq id no . 4 , wherein preferably the peptide is fused to the c - terminal of the fc portion of the immunoglobulin . the term “ individual or patient ” preferably refers to mammals , especially is humans . the compound is used in a pharmaceutical composition and formulations , comprising , as a rule , a pharmaceutically acceptable carrier , excipient or diluents . techniques for the formulation and administration of the compounds of the present invention may be found in “ remington &# 39 ; s pharmaceutical sciences ” mack publishing co ., easton pa . the term “ synthetic peptide ” comprises according to the understanding of the invention peptides , which consist of natural amino acids and partially of chemically modified natural amino acid residues , and have been produced either completely by chemical synthesis , or by recombinant methods in combination with chemical modification of single amino acid residues . in case of the novel peptides according to the invention , which consist of 28 amino acid residues , a standard peptide synthesis is preferred . as used herein , the term “ pharmaceutically acceptable carrier ” means an inert , non toxic solid or liquid filler , diluent or encapsulating material , not reacting adversely with the active compound or with the patient , or any other formulation such as tablets , pills , dragees , capsules , gels , syrups , slurries , suspensions and the like . suitable , preferably liquid carriers are well known in the art such as sterile water , saline , aqueous dextrose , sugar solutions , ethanol , glycols and oils , including those of petroleum , animal , vegetable , or synthetic origin , for example , peanut oil , soybean oil and mineral oil . the formulations according to the invention may be administered as unit doses containing conventional non - toxic pharmaceutically acceptable carriers , diluents , adjuvants and vehicles that are typical for parenteral administration . unit doses according to the invention may contain daily required amounts of the compound according to the invention , or sub - multiples thereof to make up the desired dose . the optimum therapeutically acceptable dosage and dose rate for a given patient ( mammals , including humans ) depends on a variety of factors , such as the activity of the specific active material employed , the age , body weight , general health , sex , diet , time and route of administration , rate of clearance , enzyme activity , the object of the treatment , i . e ., therapy or prophylaxis and the nature of the disease to be treated . therefore , in compositions and combinations in a treated patient ( in vivo ) a pharmaceutical effective daily dose of the peptide of this invention is between about 5 ng and 200 μg / kg body weight , preferably between 20 ng and 20 μg / kg body weight . the preferred administration of the peptides according to this invention is the inhalation of aqueous solutions containing a peptide of the invention . the aqueous solution is preferably an isotonic saline solution ( nacl ) which can contain additional drugs or other suitable ingredients . preferably , the peptide compounds are used in said solutions in a stabilized form as specified above . especially preferred solutions are isotonic nacl solutions containing the peptide in a pegylated form . the concentration of the peptide used in therapy in said solutions vary according to the invention between 10 mg and 300 mg / l solution , preferably between 30 mg and 100 mg / l . if stabilized forms , such as pegylated forms of the peptides of the invention as specified above , are used the concentration as well as the over - all dosage of the selected peptide of the invention can decreased , as a rule . the inhalation of the peptides according to the invention can be carried out , as a rule , 1 - 4 times a day for 5 - 45 minutes , preferably 10 - 20 minutes , according to the severity of the disease and the efficacy of the compounds used for the treatment . for inhalations the compound according to the invention is preferably brought in an aerosol form . aerosols and techniques to make them are well known in the art . aerosols applicable by inhalers containing a peptide of the invention are preferred especially in the case of copd . administration by nasal spray techniques are also suitable . administration of the synthetic peptides according to the invention , includes also nanoparticles or nanobeads to which the peptides according to the invention are linked or coupled chemically or by van - der waals forces , or in which said peptides are encapsulated . nanoparticles or - beads are naturally derived or synthetic mostly spherical particles with a diameter of & lt ; 1000 nm , preferably & lt ; 500 nm , more preferably & lt ; 200 nm . the peptide delivery to the target cells can be improved by release out of inhaled nanobeads comprising a peptide according to the invention : the peptide is less likely to become degraded after a bolus delivery while all cell receptors are fully loaded , and the peptide can be protected by nano - beads , produced out of other enzyme substrates which , as mentioned above , competitively inhibits the enzymatic degradation of the therapeutic peptide . according to the invention nanobeads as carrier to deliver peptides deep into the lung by inhalation by , for example , ultrasonic nebulising , which produce a drop size of about 1 - 5 , preferably 3 μm . hence , each microdroplet carries many nanobeads loaded with the therapeutic novel peptide according to the invention . suitable nanobeads are well known in the art , such as lipo - particles ( liposomes ), protamin ( already known from insulin depot therapy ), poly ( d , l - lactic - co - glycolic ) acid ( plga ), thiolate or other polymeric carrier substrates . a comprehensive overview presenting nanoparticles suitable for drug delivery systems , which can be applied to the current invention , can be taken , for example , from j pharm pharmaceut sci , 2000 , 3 ( 2 ), 234 - 258 . therapeutically effective doses of the peptides according to the invention or their pharmaceutical compositions may be administered alone or as adjunctive therapy in combination with other pharmaceutically effective compounds , such as compounds with other drugs , e . g . fast - acting beta2 - agonists ( such as albuterol ), anticholinergic bronchodilators ( such as ipratropium bromide ), long - acting bronchodilators , inhaled or oral corticosteroids , antibiotics , or antiproliferative compounds , e . g . d - 24851 , imatinib mesylate , or guanylhydrazone cni - 1493 . chronic obstructive pulmonary disease ( copd ) is characterised by progressive airflow limitation associated with chronic inflammation . vasoactive intestinal peptide ( vip ) is a potent bronchodilator , vasodilator and anti - inflammatory agent . the efficacy and safety of vip in patients was assessed with moderate to severe copd . the present double - blind , randomized , placebo - controlled study was undertaken in an outpatient setting . copd patients ( n = 34 ) were randomly assigned vip 50 μg ( n = 17 ), or placebo ( n = 17 ), given per inhalation , 4 times daily for 12 weeks . vip serum concentration was measured in all patients . primary outcomes were health - related quality of life and exercise capacity . secondary outcomes included the lung function parameters and copd exacerbations . in copd , vip serum concentrations were lower compared to controls ( fig1 ). thirty ( 88 %) patients completed the study ( table 1 ). post - bronchodilator forced expiratory volume in 1 second ( fev1 ) significantly improved with vip by 0 . 107 l and vital capacity ( ivc ) by 0 . 160 l compared with placebo ( p & lt ; 0 . 01 ) ( fig2 ). according to the short 36 - item questionnaire ( sf - 36 ) developed for medical outcomes studies , the improvement in quality of life was greater with vip ( 4 . 08 ) than with placebo ( 0 . 20 ) ( table 2 ). similarly , borg dyspnea scale result was greater with vip (− 0 . 20 units at rest and − 1 . 07 after exercise ) than with placebo ( 0 . 21 units at rest and 0 . 43 units after exercise ) ( fig3 ); exercise capacity increased by 32 . 7 m ( p & lt ; 0 . 01 ) in the vip group as compared to placebo group (− 8 . 6 m ) using the six minutes walking test ( fig4 ). ten exacerbations with placebo and only 8 with vip were observed ( table 3 ). vip is a safe and effective drug for treatment of copd , it reduces exacerbations , improves lung function , and health - related quality of life . long - term studies are needed , however , to fully assess its efficacy in copd . the airway inflammatory response in cf is persistently neutrophilic , marked by upregulation of neutrophil chemotactic mediators such as interleukin 8 ( il - 8 ) and leukotriene b4 ( ltb4 ); florid accumulation of neutrophils in the airways ; and neutrophil activation , with release of toxic products such as neutrophil elastase . the initial inflammatory response to most bacterial stimuli , in the lung and elsewhere , is “ acute ”, that is , neutrophil dominant such as the inflammation by copd . two cf patients were treated with 200 μg vip daily , per inhalation and measured their lung function for and after 3 months treatment by vip . post - bronchodilator forced expiratory volume in 1 second ( fev1 ) and vital capacity ( vc ) significantly improved with vip treatment after 3 months ( table 4 ). the combination of low serum vip levels in copd patients , the vip receptor up - regulation in chronic bronchitis patients , the pleiotrope anti - inflammatory effects of vip , the possibility for local administration and the lack of local and systemic side effects in our trial , makes vip a promising candidate for treatment of copd and cf . furthermore the inventors synthesized the synthetic peptides according to the invention , preferably peptide seq id no . : 2 ( a - 15 ), seq id no . : 3 ( a - 18 ) and seq id no . : 4 ( a - 20 ) with new structure and compared their anti - inflammatory and vasodilatory properties with vip in vitro by the methods described in the following examples . the synthesis of the peptides according to the invention was carried out by known standard methods . peripheral blood mononuclear cells were isolated from whole venous blood from 12 stable copd patients and 12 healthy probands by ficoll density gradient centrifugation . monocytes were differentiated in rpmi - 1640 medium supplemented with 5 % fcs , antibiotics and 10 − 8 m 1 , 25 - dihydroxycholecalciferol ( sigma ) in a humidified atmosphere with 5 % co2 at 37 ° c . for infection simulation , macrophage stimulation and experimental in vivo treatment the differentiated cells were incubated either with lps , with lps and seq id no . : 1 ( vip ) or seq id no . : 2 ( a - 15 ) or seq id no . : 3 ( a - 18 ), or with medium alone for control . to test the hypothesis whether or not the macrophages utilize the vip - signaling pathway to modulate and limit the immune response , the inflammation reaction in vitro was stimulated and no ( produced by inos ) production by the cells was measured under inflammation and under in vitro therapy with vip and the peptides according to the invention ( seq id nos 2 and 3 ). nos increased dramatically by lps after 24 hours . simultaneous incubation of lps with vip and the peptides according to the invention revealed a marked anti - inflammatory response found after 24 hours ( table 5 ). this anti - inflammatory response was better by both vip - analogues according to seq id nos . 2 and 3 . effects of vip and the peptides according to the invention are mediated by specific g - protein coupled receptors . three distinct receptor subtypes , with differing affinity for the peptides , have been cloned and characterized as receptors 1 and 2 ( vpac1 and vpac2 ) and pituitary adenylate cyclase activating polypeptide receptor ( pac1 ). the secondary messenger is cyclic adenosine mono phosphate ( camp ). the capacity of vip and the peptides according to the invention ( seq id no 2 and 3 ) on camp regulation were compared by following methods : cells derived from pulmonary artery ( pasmc ) were seeded in 24 well plates and cultured in dmem containing 10 % fetal calf serum ( gibco lifesciences , karlsruhe ), penicillin ( gibco lifesciences , karlsruhe , 100 u / ml ) streptomycin ( gibco lifesciences , karlsruhe , 100 u / ml ) to confluency . after serum starvation for 3 hours cells were incubated with vip or the peptides according to the invention with or without 3 - isobutyl 1 - methyl xanthine for 20 min which has been shown to be the optimal incubation time for analysis of cyclic amp production . the incubation is stopped by rinsing cells with pbs and immediate lysis of cells with hcl ( 0 . 1n ) containing 3 - isobutyl 1 - methyl xanthine ( 500 μm ) to block further hydrolysis of camp . lysed cells were centrifuged and the supernatants assayed for camp using an commercially available cyclic amp elisa ( assay designs , inc ., michigan , distribution by bio trend , köln ). vip increases the cyclic amp content of pasmc . higher increase were observed after stimulation with the novel peptides according to the invention ( seq id no . 2 and 3 ) ( table 6a , 6b and 6c ). elisa assays and il - 4 , il - 6 , il - 8 , il - 10 , il1 - b und tnf - a measurement in fibroblasts and bronchial smooth muscle cells after fcs stimulation in vitro elisa assays for il - 4 , il - 6 , il - 8 , il - 10 , il1 - b und tnf - a were performed according to the manufactures instructions ( bd - pharmingen ). the cytokine secretion under fcs stimulation in each experiment was set to 100 % for each cell donor and experiment . all other results were expressed relative to 100 %. for statistical analysis we used paired student &# 39 ; s t - test , or the wilcoxon signed rank test .
the present invention relates to novel peptides that are highly biologically and pharmacologically active as therapeutic agents for the treatment of numerous lung diseases or lung and / or bronchi related diseases , especially chronic obstructive pulmonary disease , cystic fibrosis , and bronchiolitis obliterans . the synthetic peptides according to the invention are derivatives of vasoactive intestinal peptide and show enhanced physical , pharmacological and biological / therapeutic properties compared to vip .