Perspektiven in der Inhalationstherapie[1]

Zusammenfassung

Die inhalative Applikation von Medikamenten wird neue Anwendungsgebiete sowohl bei Lungenerkrankungen als auch in der systemischen Therapie gewinnen. Die Inhalation von Antibiotika ist bereits Standard in der Therapie der zystischen Fibrose. Bei Bronchiektasen, der schweren COPD mit bakterieller Kolonisation und bei invasiv beatmeten Patienten gibt es Hinweise auf die Wirksamkeit der Inhalation von Aminoglykosiden. Die Inhalation zur Substitution von alpha 1-Antitrypsin ist der i. v. Gabe beim Lungenemphysem bezüglich der intrapulmonalen Dosis überlegen. Auch wenn das inhalative Insulin wieder vom deutschen Markt genommen wurde, besteht weiter eine intensive Forschungstätigkeit auf dem Gebiet der Inhalation von Insulin und Heparin zur systemischen Therapie des Diabetes mellitus bzw. der Antikoagulation.

Abstract

Administration of drugs via the inhalation route will find new indications in the therapy for lung diseases. Furthermore, aerosolised drugs are of increasing interest for systemic treatment. The inhalation of antibiotics is already a well established therapy in cystic fibrosis. In bronchiectasis, severe COPD with bacterial airway colonisation and in mechanically ventilated patients, aerosolised aminoglycosides may provide benefit. Substitution of alpha1-antitrypsin in lung emphysema via inhalation seems to be superior to the intravenous administration. Inhaled insulin has currently been withdrawn from the market in spite of being approved by FDA and EMEA. However, intensive scientific research is still ongoing and many clinical studies are underway in the field of the inhalation of insulin, heparins and other systemic treatments.

Literatur

• 1 Buhl R, Berdel D, Criee C P. et al . Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma bronchiale.  Pneumologie. 2006;  60 139-177
• 2 Vogelmeier C, Buhl R, Criee C P. et al . Leitlinie der Deutschen Atemwegsliga und der Deutschen Gesellschaft zur Diagnostik und Therapie von Patienten mit chronisch obstruktiver Bronchitis und Lungenemphysem.  Pneumologie. 2007;  61 323-340
• 3 Ratjen F, Doering G, Nikolaizik W H. Effect of inhaled tobramycin on early pseudomonas aeruginosa colonisation in patients with cystic fibrosis.  Lancet. 2001;  358 983-984
• 4 Ramsey B W, Pepe M S, Quan J M. et al . Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.  N Engl J Med. 1999;  340 23-30
• 5 Ratjen F, Rietschel E, Kasel D. et al . Pharmakokinetics of inhaled colistin in patients with cystic fibrosis.  J Antimicrob Chemother. 2006;  57 306-311
• 6 Mendelman P M, Smith A L, Kenny A M. et al . Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis or bronchiectasis: comparison with activity in serum.  Am Rev Respir Dis. 1985;  132 761-765
• 7 Burns J L, Van-Dalfsen J M, Shawar R M. et al . Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis.  J Infect Dis. 1999;  179 1190-1196
• 8 Barclay M L, Begg E J, Chambers S T. et al . Adaptive resistance to tobramycin in pseudomonas aeruginosa lung infection in cystic fibrosis.  J Antimicrobial Chemotherapy. 1996;  37 1155-1164
• 9 Doering G, Conway S P, Heijerman H GM. et al . Antibiotic therapy against pseudomonas aeruginosa in cystic fibrosis: a European consensus.  Eur Respir J. 2000;  16 749-767
• 10 Smith A L, Fiel S B, Mayer-Hamblett N. et al . Susceptibility testing of pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis.  Chest. 2003;  123 1495-1502
• 11 Westerman E M, De Boer A H, Le Brun P P. et al . Dry powder inhalation of colistin in cystic fibrosis patients: a single dose pilot study.  J Cyst Fibros. 2007;  6 284-292
• 12 Geller D E, Konstan M W, Smith J. et al . Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety.  Pediatr Pulmonol. 2007;  42 307-313
• 13 Gibson R L, Retsch-Bogart G Z, Oermann C. et al . Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.  Pediatr Pulmonol. 2006;  41 656-665
• 14 Barker A F. Bronchiectasis.  N Engl J Med. 2002;  346 1383-1393
• 15 Murphy T F, Sethi S. Bacterial infection in chronic obstructive pulmonary disease.  Am Rev Respir Dis. 1992;  146 1067-1083
• 16 Kohlhäufl M, Scheuch G, Häußinger K. Antimikrobielle Aerosoltherapie bei Bronchiektasen?.  Pneumologie. 2004;  58 499-504
• 17 Scheinberg P, Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis.  Chest. 2005;  127 1420-1426
• 18 Drobnic M E, Sune P, Montoro J B. et al . Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with pseudomonas aeruginosa.  Ann Pharmacother. 2005;  39 39-44
• 19 Bilton D, Henig N, Morrissey B. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of pseudomonas aeruginosa infection in adult bronchiectasis.  Chest. 2006;  130 1503-1510
• 20 Soler-Cataluna J J, Martinez-Garcia M A, Roman S anchez . et al . Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.  Thorax. 2005;  60 925-931
• 21 Calverley P, Anderson J A, Celli B. et al . Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.  N Engl J Med. 2007;  356 775-789
• 22 Patel I S, Seemungal T AR, Wilks M. et al . Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations.  Thorax. 2002;  57 759-764
• 23 Wilkinson T M, Patel I S, Wilks M. et al . Airway bacterial load and FEV₁ decline in patients with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2003;  167 090-1095
• 24 Calverley P M, Spencer S, Willits L. et al . Withdrawal from treatment as an outcome in the ISOLDE study of COPD.  Chest. 2003;  124 1350-1356
• 25 Aaron S D, Vandemheen K L, Fergusson D. et al . Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone-Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease.  Ann Intern Med. 2007;  146 545-555
• 26 Szafranski W, Cukier A, Ramirez A. et al . Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.  Eur Respir J. 2003;  21 74-81
• 27 Patel I S, Vlahos I, Wilkinson T M. et al . Bronchiectasis, Exacerbation Indices, and Inflammation in Chronic Obstructive Pulmonary Disease.  Am J Respir Crit Care Med. 2004;  170 400-407
• 28 Tsang K W, Chan K, Ho P. et al . Sputum elastase in steady-state bronchiectasis.  Chest. 2000;  117 420-426
• 29 Stockley R A, Bayley D, Hill S L. et al . Assessment of airway neutrophils by sputum colour: correlation with airways inflammation.  Thorax. 2001;  56 366-372
• 30 Sethi S. Infection etiology of acute exacerbations of chronic bronchitis.  Chest. 2000;  117 (Suppl. 2) 380S-385S
• 31 Rohde G, Wiethege A, Borg I. et al . Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation - a case control study.  Thorax. 2003;  58 37-42
• 32 Rohde G, Schlosser B, Arinir U. et al . Die Rolle von Atemwegsinfektionen bei der chronisch-obstruktiven Lungenerkrankung.  Med Klinik. 2007;  102 893-898
• 33 Langer M, Mosconi P, Cigada M. et al . Long-term respiratory support and risk of pneumonia in critically ill patients. Intensive care unit group of infection control.  Am Rev Respir Dis. 1989;  140 302-305
• 34 MacIntyre N R, Rubin B. Should aerosolized antibiotics be administered to prevent or treat ventilator-associated pneumonia in patients who do not have cystic fibrosis?.  Respiratory care. 2007;  52 416-421
• 35 Palmer L B, Smaldone G C, Simon S R. et al . Aerosolized antibiotics in mechanically ventilated patients: delivery and response.  Crit Care Med. 1998;  26 31-39
• 36 Liberati A, D’Amico R, Pifferi S. et al . Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care.  Cochrane Database Syst Rev. 2004;  1 CD000022
• 37 Nieuwenhoven C A Van, Buskens E, Bergmans D C. et al . Oral decontamination is cost-saving in the prevention of ventilator-associated pneumonia in intensive care units.  Crit Care Med. 2004;  32 126-130
• 38 Badia J R, Soy D, Adrover M. et al . Disposition of instilled versus nebulized tobramycin and imipenem in ventilated intensive care unit (ICU) patients.  Journal of Antimicrobial Chemotherapy. 2004;  54 508-514
• 39 Crystal R G, Brantly M L, Hubbard R C. The alpha1- antitrysin Gene and its mutations.  Chest. 1989;  95 196
• 40 Perlmutter D H, Pierce J A. The alpha1-antitrypsin gene and emphysema.  J Appl Physiol. 1989;  257 L 147
• 41 Pierce J A. Antitrypsin and emphysema.  JAMA. 1988;  259 2890
• 42 Wewers M D, Casolaro M A, Sellers S E. et al . Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema.  N Engl J Med. 1987;  316 1055-1062
• 43 Hubbard R C, Crystal R G. Augmentation therapy of alpha 1-antitrypsin deficiency.  Eur Respir J. 1990;  9 44s-52s
• 44 Wencker M, Banik N, Buhl R. et al . Langzeittherapie des alpha1-Antitrypsin-mangelassoziierten Lungenemphysems mit humanen alpha1-Antitrypsin.  Pneumologie. 1998;  52 545-552
• 45 Kropp J, Wencker M, Hotze A. et al . Inhalation of [123I]alpha1-protease inhibitor: toward a new therapeutic concept of alpha1-protease inhibitor deficiency?.  J Nucl Med. 2001;  42 744-751
• 46 Hubbard R C, Crystal R G. Strategies for aerosol therapy of alpha1-antitrypsin deficiency by the aerosol route.  Lung. 1990;  Suppl 565-578
• 47 Cantin A M, Woods D E. Aerosolized prolastin supresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection.  Am J Respir Crit Care Med. 1999;  160 1130-1135
• 48 Vogelmeier C, Kirlath I, Warrington S. et al . The intrapulmonary half-life and safety of aerosolized a1-protease inhibitor in normal volunteers.  Am J Respir Crit Care Med. 1997;  155 536-541
• 49 Hubbard R C, McElvaney N G, Sellers S E. et al . DNA-produced alpha 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with alpha 1-antitrypsin deficiency.  J Clin Invest. 1989;  84 1349-1354
• 50 Hubbard R C, Brantly M L, Sellers S E. et al . Anti-neutrophil-elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin.  Ann Intern Med. 1989;  111 206-212
• 51 Itoh H, Ishii Y, Maeda H. et al . Clinical observations of aerosol deposition in patients with airway obstruction.  Chest. 1981;  80 837-840
• 52 Sweeney T D, Brain J D, Leavitt S A. et al . Emphysema alters the deposition pattern of inhaled particles in hamsters.  Am J Pathol. 1987;  128 19
• 53 Schulz H, Brand P, Heyder J. Particle deposition in the respiratory tract. In: Gehr P, Heyder J, editor. Particle-lung interactions. New York, Basel: Dekker 2000: 229-290
• 54 Brand P, Friemel I, Meyer T. et al . Total deposition of therapeutic particles during spontaneous and controlled inhalations.  J Pharmaceut Sci. 2000;  89 724-731
• 55 Brand P, Maas Enriquez M, Meyer T. et al . Neue Strategien zur kontrollierten Inhalation von alpha 1-Antitrypsin.  Pneumologie. 2003;  57 153-158
• 56 Brand P, Häußinger K, Meyer T. et al . Intrapulmonary distribution of deposited particles.  J Aerosol Med. 1999;  12 275-284
• 57 Brand P, Meyer T, Sommerer K. et al . Alveolar deposition of monodisperse aerosol particles in the lung of patients with COPD.  Exp Lung Res. 2002;  28 (1) 39-54
• 58 Sommerer K, Meyer T, Brand P. et al . Evaluation of an optimal device for peripheral deposition in patients with lung emphysema.  Drug delivery to the lungs. 2001;  12 171-174
• 59 Müllinger B, Meyer T, Sommerer K. et al . Patient individualized inhalation optimizes peripheral lung deposition.  Drug delivery to the lungs. 2001;  12 23-26
• 60 Griese M, Ramakers J, Krasselt A. et al . Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis.  Am J Respir Crit Care Med. 2004;  169 822-888
• 61 Griese M, Latzin P, Kappler M. et al . Alpha1 Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients.  Eur Respir J. 2007;  29 240-250
• 62 Köhler D, Fleischer W. Medikamente. In: Theorie und Praxis der Inhalationstherapie. Köhler D, W. Fleischer (Eds.). Arcis Verlag 2000: 71-99
• 63 Gonda I. Systemic delivery of drugs to humans via inhalation.  J Aerosol Med. 2006;  19 47-53
• 64 Siekmeier R, Scheuch G. Systemische Therapie mit Aerosolen: Beispiele zur pulmonalen Verabreichung von Makromolekülen zur systemischen Therapie.  Atemw.-Lungenkrkh. 2006;  31 391-410
• 65 Heubner W, deJongh S E, Laquer E. et al . Ueber Inhalation von Insulin.  Klin Wochenschr. 1924;  3 2343
• 66 Gaenslein M. Über Inhalation von Insulin.  Klin Wochenschr. 1925;  4 71
• 67 Brain J D. Inhalation, Deposition and Fate of Insulin and other Therapeutic Proteins.  Diabetes Technologies and Therapeutics. 2007;  9 S4-S15
• 68 Rosner S W. Heparin administered as an aerosol.  Vasc Dis. 1965;  125 131-134
• 69 Köhler D. Aerosolized heparin.  J Aerosol Med. 1994;  7 307-314
• 70 Scheuch G, Müllinger B, Spannagl M. et al . Antikoagulation durch kontrollierte Inhalation von Certoparin.  Atemw.-Lungenkrkh. 2005;  31 420-430
• 71 Haeussermann S, Brand P, Herpich C. et al .The inhalation of low molecular weight heparin for systemic anti-coagulative action. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ. (Eds.), Respiratory Drug Delivery VIII. Davis Healthcare Int. Publ.: River Grove, IL 633-637

1 Prof. Dr. Dieter Köhler zum 60. Geburtstag gewidmet.