Inhaled ciclosporin

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Ciclosporin is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. [1] It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, [2] rheumatoid arthritis, [3] dry eye [4] and other auto-immune related conditions. A variety of pre-clinical and clinical studies have been and are investigating its use to treat lung-related disorders via inhalation.

Contents

Formulation

Formulation of the drug for inhalation purposes has proved challenging because of ciclosporin's poor aqueous solubility. [5] Consequently, aerosol studies have often employed compatible solvents such as propylene glycol [6] or ethanol [7] as the vehicle for administration by nebulizer or have used more complicated aqueous-based formulations involving liposomes [8] [9] or other dispersions. [10] Dry powder inhaler [11] [12] as well as propellant metered dose inhaler (pMDI) formulations [13] [14] have also been created and evaluated in the laboratory and in early clinical studies.

Investigational uses

Ciclosporin was brought to market in 1983 but the first non human aerosol studies were not published until the late 1980s. These efforts probed the anti-inflammatory and immunosuppressive properties of ciclosporin after regional deposition of drug in the lungs.

Asthma

Ciclosporin has been touted as a therapeutic option in moderate to severe asthmatic patients [15] as a corticosteroid sparing agent. [16] Preclinical studies bear evidence to the fact that ciclosporin when administered orally or via inhalation is capable of blocking T-cell induced inflammation (e.g. via interleukin-2 and 13 formation), [17] [18] eosinophil [19] [20] and macrophage recruitment in the lungs. Its use to treat asthma via the oral route may be constrained by systemic side-effects [21] but this limitation may be avoided by targeting the lungs with therapeutic doses via inhalation. Pharmacokinetic evidence suggests that peak and trough levels of drug in the circulation are likely to be below the threshold of systemic toxicity. [22] In addition to biomarkers inhaled ciclosporin has been shown to inhibit airway hyperresponsiveness in rodent models [23] [24] and appears to have been well tolerated in volunteers and mild asthmatic patients receiving the drug in single and multiple doses via pMDI. [25] However, as of early 2009 there are no ongoing clinical trials further exploring ciclosporin's utility in asthma; in part, this may be a consequence of sporadic efficacy and side-effects (from oral use) in a condition that is historically managed by steroids. [26] [27]

Acute rejection

In light of the observations in relation to its use in asthma, the extension of ciclosporin's use to treat early rejection in the lungs was an obvious one, especially considering the increase in lung transplants performed in the USA and Europe since the mid-1980s. Numbers have increased from 33 in 1988 to 1468 in 2007. Furthermore, acute cellular rejection is common after transplantation and will occur in up to 90% of patients [28] and episodes are most likely to occur in the first post-operative year. [29] Consequently, the application of ciclosporin by oral and IV administration has led to efforts to treat acute and acute refractory rejection by direct aerosol administration first in animal models [30] [31] [32] and soon thereafter in transplant patients. [6] [33] Most of these early efforts were carried out by or associated with the University of Pittsburgh Medical Center. [34] A randomized, placebo-controlled trial of aerosolized ciclosporin that was published in the New England Journal of Medicine demonstrated a marked improvement in survival and reduction of chronic rejection incidence, but not in the primary endpoint of acute rejection. [35] This has warranted more detailed investigations of aerosolized drug to treat or prevent the varied conditions of rejection.

Chronic rejection

Chronic rejection of the lungs differs significantly from acute rejection. The condition is aptly known as bronchiolitis obliterans and clinically is diagnosed as bronchiolitis obliterans syndrome (BOS). Whereas acute rejection exhibits perivascular infiltration of mononuclear cells and attendant inflammation of the surrounding tissue [36] chronic rejection appears to have significant epithelial involvement and is essentially a fibro-proliferative disorder of the small airways. [37] The median survival after a confirmed diagnosis of BOS is just over 2 years. In fact, despite improvements in outcome associated with acute rejection, virtually no improvement in survival has been noted in chronic rejection over the last 20 years. [38] The surprising finding that aerosolized ciclosporin may prevent or delay development of this insidious condition has led to renewed interest with aerosolized ciclosporin formulations and one early stage trial involving a dry powder inhaler is recruiting while another phase III trial involving nebulized ciclosporin in propylene glycol is underway. [39] Early studies have also been conducted with liposome formulations in volunteers and patients.

Other

Inhaled ciclosporin has also shown promise in several other lung conditions. Early stage studies in mice have shown some benefit of ciclosporin as an adjuvant therapy in lung cancer when administered as a liposome aerosol in conjunction with paclitaxel. [40]

Related Research Articles

A bronchodilator or broncholytic is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be originating naturally within the body, or they may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions. Although this remains somewhat controversial, they might be useful in bronchiolitis and bronchiectasis. They are often prescribed but of unproven significance in restrictive lung diseases.

<span class="mw-page-title-main">Ciclosporin</span> Chemical compound

Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca.

<span class="mw-page-title-main">Tacrolimus</span> Immunosuppressive drug

Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogenic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a topical medication in the treatment of T-cell-mediated diseases such as eczema and psoriasis. For example, it is prescribed for severe refractory uveitis after a bone marrow transplant, exacerbations of minimal change disease, Kimura's disease, and vitiligo. It can be used to treat dry eye syndrome in cats and dogs.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Inhaler spacer</span>

A spacer is a device used to increase the ease of administering aerosolized medication from a metered-dose inhaler (MDI). It adds space in the form of a tube or "chamber" between the mouth and canister of medication. Most spacers have a one-way valve that allows the person to inhale the medication while inhaling and exhaling normally; these are often referred to as valved holding chambers (VHC).

<span class="mw-page-title-main">Salbutamol</span> Medication

Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks and exercise-induced bronchoconstriction, as well as chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution. Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.

<span class="mw-page-title-main">Transplant rejection</span> Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

<span class="mw-page-title-main">Nebulizer</span> Drug delivery device

In medicine, a nebulizer or nebuliser is a drug delivery device used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of asthma, cystic fibrosis, COPD and other respiratory diseases or disorders. They use oxygen, compressed air or ultrasonic power to break up solutions and suspensions into small aerosol droplets that are inhaled from the mouthpiece of the device. An aerosol is a mixture of gas and solid or liquid particles.

<span class="mw-page-title-main">Ipratropium bromide</span> Type of anticholinergic

Ipratropium bromide, sold under the trade name Atrovent among others, is a type of anticholinergic medication which opens up the medium and large airways in the lungs. It is used to treat the symptoms of chronic obstructive pulmonary disease and asthma. It is used by inhaler or nebulizer. Onset of action is typically within 15 to 30 minutes and lasts for three to five hours.

<span class="mw-page-title-main">Inhaler</span> Medical device

An inhaler is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with asthma and chronic obstructive pulmonary disease (COPD) being among the most notable.

<span class="mw-page-title-main">Bronchoconstriction</span> Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

<span class="mw-page-title-main">Metered-dose inhaler</span> Device that helps deliver a specific amount of medication to the lungs

A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil.

<span class="mw-page-title-main">Levosalbutamol</span> Chemical compound

Levosalbutamol, also known as levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Evidence is inconclusive regarding the efficacy of levosalbutamol versus salbutamol or salbutamol-levosalbutamol combinations, though levosalbutamol is believed to have a better safety profile due to its more selective binding to β2 receptors versus β1.

Tolypocladium inflatum is an ascomycete fungus originally isolated from a Norwegian soil sample that, under certain conditions, produces the immunosuppressant drug ciclosporin. In its sexual stage (teleomorph) it is a parasite on scarab beetles. It forms a small, compound ascocarp that arises from the cadaver of its host beetle. In its asexual stage (anamorph) it is a white mold that grows on soil. It is much more commonly found in its asexual stage and this is the stage that was originally given the name Tolypocladium inflatum.

<span class="mw-page-title-main">FKBP</span>

The FKBPs, or FK506 binding proteins, constitute a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes, ranging from yeast to humans, and function as protein folding chaperones for proteins containing proline residues. Along with cyclophilin, FKBPs belong to the immunophilin family.

<span class="mw-page-title-main">Dry-powder inhaler</span> Device that delivers medication to the lungs in the form of a dry powder

A dry-powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. DPIs are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema and COPD although DPIs have also been used in the treatment of diabetes mellitus.

<span class="mw-page-title-main">Pirbuterol</span> Chemical compound

Pirbuterol is a short-acting β2 adrenoreceptor agonist with bronchodilating action used in the treatment of asthma, available as a breath-activated metered-dose inhaler.

<span class="mw-page-title-main">Indacaterol</span> Chemical compound

Indacaterol is an ultra-long-acting beta-adrenoceptor agonist developed by Novartis. It needs to be taken only once a day, unlike the related drugs formoterol and salmeterol. It is licensed only for the treatment of chronic obstructive pulmonary disease (COPD). It is delivered as an aerosol formulation through a dry powder inhaler.

β2-adrenoceptor agonists are a group of drugs that act selectively on β2-receptors in the lungs causing bronchodilation. β2-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the non-selective beta-agonist isoprenaline was used. The aim of the drug development through the years has been to minimise side effects, achieve selectivity and longer duration of action. The mechanism of action is well understood and has facilitated the development. The structure of the binding site and the nature of the binding is also well known, as is the structure activity relationship.

<span class="mw-page-title-main">Pulmonary drug delivery</span>

Pulmonary drug delivery is a route of administration in which patients use an inhaler to inhale their medications and drugs are absorbed into the bloodstream via the lung mucous membrane. This technique is most commonly used in the treatment of lung diseases, for example, asthma and chronic obstructive pulmonary disease (COPD). Different types of inhalers include metered-dose inhalers (MDI), dry powder inhalers (DPI), soft mist inhalers (SMI) and nebulizers. The rate and efficacy of pulmonary drug delivery are affected by drug particle properties, breathing patterns and respiratory tract geometry.

References

  1. ↑ Calne, R (Mar 2004). "Cyclosporine as a milestone in immunosuppression". Transplant. Proc. 36 (2 Suppl): 13S–15S. doi:10.1016/j.transproceed.2004.01.042. PMID   15041300.
  2. ↑ Madan V, Griffiths CE. "Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):239-50.
  3. ↑ Kitahara K, Kawai S. "Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2007 May;19(3):238-45. Review.
  4. ↑ Ridder, WH 3rd (Dec 2008). "Ciclosporin use in dry eye disease patients". Expert Opin Pharmacother. 9 (17): 3121–8. doi:10.1517/14656560802500613. PMID   19006483. S2CID   72181779.
  5. ↑ Czogalla, A (2009). "Oral cyclosporine A--the current picture of its liposomal and other delivery systems". Cell Mol Biol Lett. 14 (1): 139–52. doi:10.2478/s11658-008-0041-6. PMC   6275704 . PMID   19005620.
  6. 1 2 Iacono, AT; Smaldone, GC; Keenan, RJ; Diot, P; Dauber, JH; Zeevi, A; Burckart, GJ; Griffith, BP (May 1997). "Dose-related reversal of acute lung rejection by aerosolized cyclosporine". Am J Respir Crit Care Med. 155 (5): 1690–8. doi:10.1164/ajrccm.155.5.9154878. PMID   9154878.
  7. ↑ O'Riordan TG, Iacono A, Keenan RJ, Duncan SR, Burckart GJ, Griffith BP, Smaldone GC. "Delivery and distribution of aerosolized cyclosporine in lung allograft recipients. Am J Respir Crit Care Med. 1995 Feb;151 (2 Pt 1):516-21.
  8. ↑ Gilbert, BE; Wilson, SZ; Garcon, NM; Wyde, PR; Knight, V (Oct 1993). "Characterization and administration of cyclosporine liposomes as a small-particle aerosol". Transplantation. 56 (4): 974–7. doi: 10.1097/00007890-199310000-00037 . PMID   8212222. S2CID   39895268.
  9. ↑ Trammer, B; Amann, A; Haltner-Ukomadu, E; Tillmanns, S; Keller, M; Högger, P (Nov 2008). "Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo". Eur J Pharm Biopharm. 70 (3): 758–64. doi:10.1016/j.ejpb.2008.07.001. PMID   18656538.
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  12. ↑ Zijlstra, GS; Rijkeboer, M; Jan; van Drooge, D; Sutter, M; Jiskoot, W; de Weert, M; Hinrichs, WL; Frijlink, HW (Jun 2007). "Characterization of a cyclosporine solid dispersion for inhalation". AAPS J. 9 (2): E190–9. doi:10.1208/aapsj0902021. PMC   2751408 . PMID   17614361.
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  20. ↑ Khan LN, Kon OM, Macfarlane AJ, Meng Q, Ying S, Barnes NC, Kay AB. "Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor, and eotaxin.
  21. ↑ Kay, AB (May 1994). "Immunosuppressive agents in chronic severe asthma". Allergy Proc. 15 (3): 147–50. doi:10.2500/108854194778702838. PMID   7523242.
  22. ↑ Katz, A; Coran, AG; Oldham, KT; Guice, KS (Jun 1993). "Decreased oxidized glutathione with aerosolized cyclosporine delivery" (PDF). J Surg Res. 54 (6): 597–602. doi:10.1006/jsre.1993.1091. hdl:2027.42/30777. PMID   8412070.
  23. ↑ Xie, QM; Chen, JQ; Shen, WH; Yang, QH; Bian, RL (Mar 2002). "Effects of cyclosporin A by aerosol on airway hyperresponsiveness and inflammation in guinea pigs". Acta Pharmacol. Sin. 23 (3): 243–7. PMID   11918849.
  24. ↑ Arima, M; Yukawa, T; Terashi, Y; Makino, S (Dec 1994). "Effect of inhaled cyclosporin A on the allergen-induced late asthmatic response and increased in airway hyperresponsiveness in a guinea pig model of asthma". Arerugi. 43 (11): 1316–25. PMID   7887807.
  25. ↑ Rohatagi, S; Calic, F; Harding, N; Ozoux, ML; Bouriot, JP; Kirkesseli, S; DeLeij, L; Jensen, BK (Nov 2000). "Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients". J Clin Pharmacol. 40 (11): 1211–26. doi:10.1177/009127000004001106. PMID   11075307. S2CID   10004392.
  26. ↑ Gaga, M; Zervas, E; Grivas, S; Castro, M; Chanez, P (2007). "Evaluation and management of severe asthma". Curr. Med. Chem. 14 (9): 1049–59. doi:10.2174/092986707780362961. PMID   17439402.
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  29. ↑ Bando, K; Paradis, IL; Komatsu, K; Konishi, H; Matsushima, M; Keena, RJ; Hardesty, RL; Armitage, JM; Griffith, BP (Jan 1995). "Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation". J Thorac Cardiovasc Surg. 109 (1): 49–57. doi: 10.1016/s0022-5223(95)70419-1 . PMID   7815807.
  30. ↑ Dowling, RD; Zenati, M; Burckart, GJ; Yousem, SA; Schaper, M; Simmons, RL; Hardesty, RL; Griffith, BP (Aug 1990). "Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts". Surgery. 108 (2): 198–204. PMID   2382220.
  31. ↑ Keenan, RJ; Duncan, AJ; Yousem, SA; Zenati, M; Schaper, M; Dowling, RD; Alarie, Y; Burckart, GJ; Griffith, BP (Jan 1992). "Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation". Transplantation. 53 (1): 20–5. doi: 10.1097/00007890-199201000-00003 . PMID   1733067. S2CID   12010964.
  32. ↑ Blot F, Tavakoli R, Sellam S, Epardeau B, Faurisson F, Bernard N, Becquemin MH, Frachon I, Stern M, Pocidalo JJ, et al. "Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study. J Heart Lung Transplant. 1995 Nov-Dec;14 (6 Pt 1):1162-72.
  33. ↑ Keenan, RJ; Iacono, A; Dauber, JH; Zeevi, A; Yousem, SA; Ohori, NP; Burckart, GJ; Kawai, A; Smaldone, GC; Griffith, BP (Feb 1997). "Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients". J Thorac Cardiovasc Surg. 113 (2): 335–40. doi: 10.1016/s0022-5223(97)70331-3 . PMID   9040628.
  34. ↑ McCurry, KR; Iacono, AT; Dauber, JH; Grgurich, WF; Pham, SM; Hattler, BG; Keenan, RJ; Griffith, BP. "Lung and heart-lung transplantation at the University of Pittsburgh". Clin Transpl. 1997: 209–18.
  35. ↑ Iacono, AT; Johnson, BA; Grgurich, WF; Youssef, JG; Corcoran, TE; Seiler, DA; Dauber, JH; Smaldone, GC; Zeevi, A; Yousem, SA; Fung, JJ; Burckart, GJ; McCurry, KR; Griffith, BP (Jan 2006). "A randomized trial of inhaled cyclosporine in lung-transplant recipients". N Engl J Med. 354 (2): 141–50. doi: 10.1056/nejmoa043204 . PMID   16407509. S2CID   33787892.
  36. ↑ Martinu, T; Chen, DF; Palmer, SM (Jan 2009). "Acute rejection and humoral sensitization in lung transplant recipients". Proceedings of the American Thoracic Society. 6 (1): 54–65. doi:10.1513/pats.200808-080go. PMC   2626504 . PMID   19131531.
  37. ↑ Belperio, JA; Weigt, SS; Fishbein, MC; Lynch, JP (Jan 2009). "Chronic lung allograft rejection: mechanisms and therapy". Proceedings of the American Thoracic Society. 6 (1): 108–21. doi:10.1513/pats.200807-073go. PMID   19131536. S2CID   23071315.
  38. ↑ Orens, JB; Garrity, ER Jr (Jan 2009). "General overview of lung transplantation and review of organ allocation". Proceedings of the American Thoracic Society. 6 (1): 13–9. doi:10.1513/pats.200807-072go. PMID   19131526.
  39. ↑ "Ciclosporin clinical trials". Clinicaltrials.gov. Retrieved 3 June 2011.
  40. ↑ Knight, V; Koshkina, NV; Golunski, E; Roberts, LE; Gilbert, BE (2004). "Cyclosporin an aerosol improves the anticancer effect of Paclitaxel aerosol in mice". Trans Am Clin Climatol Assoc. 115: 395–404. PMC   2263789 . PMID   17060982.
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