Pharmacological effects and lung-binding characteristics of a novel VIP analogue, [R15, 20, 21, L17]-VIP-GRR (IK312532).
ABSTRACT A novel VIP derivative, [R15, 20, 21, L17]-VIP-GRR (IK312532), relaxed potently the carbachol-induced contraction of guinea-pig isolated trachea with longer duration than that induced by VIP. IK312532 competed with [125I]VIP for the binding sites in the rat lung in a concentration-dependent manner. There was considerable decrease in specific [125I]VIP binding in each lobe of right and left lung 0.5 h after the intratracheal administration of IK312532 (50 microg/rat) as dry powder inhaler (DPI). Rosenthal analysis revealed that the administration of IK312532 (50 and 100 microg/rat)-DPI brought about a significant decrease of maximal number of binding sites (Bmax) for specific [125I]VIP binding in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung VIP receptors. This effect by IK312532 in the posterior lobe of the right lung was dose-dependent and lasted until at least 2 h after the intratracheal administration. Furthermore, the antigen-evoked infiltration of granulocytes in the rat bronchiolar mucosa was markedly suppressed by the intratracheal administration of IK312532 (50 microg/rat)-DPI. In conclusion, the present study has shown that IK312532 exhibits long-lasting relaxation of tracheal smooth muscles and that the intratracheal administration of this peptide exerts a significant occupancy of lung VIP receptors as well as a suppression of the antigen-evoked infiltration of granulocytes in the bronchiolar mucosa. Thus, the formulation of IK312532 as DPI may be a pharmacologically useful drug delivery system for the therapy of pulmonary diseases such as asthma.
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ABSTRACT: Cigarette smoke (CS) has been identified as a predominant causative factor for chronic obstructive pulmonary disease (COPD), so CS-exposed rodent model of COPD has drawn considerable interest and attention for fundamental study and drug discovery. In the present study, using experimental COPD model rats, the therapeutic potential of a newly prepared respirable powder (RP) formulation of a long-acting VIP derivative, [Arg(15,20,21), Leu(17)]-VIP-GRR (IK312532), was assessed with a focus on pro-inflammatory biomarkers, morphological and histochemical changes, and infiltrated cells in the respiratory system. CS exposure of rats for 11 days led to the marked infiltration of inflammatory cells, except for eosinophils, in bronchiolar epithelium, followed by goblet cell metaplasia and hyperplasia. However, inhalation of IK312532-RP (50μg/rat) in the CS-exposed rats resulted in 74 and 71% reductions of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with 68% decrease of goblet cells. Biomarker study demonstrated that the inhaled IK312532-RP could suppress the CS-evoked increase of myeloperoxidase in both plasma and lung by 87 and 70%, respectively, possibly leading to potent suppression of neutrophilic inflammatory symptoms. The results from TUNEL staining were indicative of apoptotic damage in respiratory tissues of the CS-exposed rats, and there appeared to be marked decrease of TUNEL-positive cells in the CS-exposed rat with inhaled IK312532-RP. The present findings suggest that an inhalable formulation of IK312532 might be efficacious as a therapy for COPD or other airway inflammatory diseases because of its potent immunomodulating activities.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2010; 41(3-4):508-14. · 2.61 Impact Factor
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ABSTRACT: Due to recent developments in biochemical engineering and in the understanding of the physiopathology of many diseases, therapeutic biologics are expected to become of increasing importance. Pulmonary delivery of these proteins could constitute an attractive, non-invasive alternative to parenteral delivery. It can be considered for either topical use for treating lung diseases or for systemic use for treating a variety of other diseases. However, administration of proteins to the lungs presents several challenges such as the need for appropriate formulation strategies to overcome high inter-particle interactions and physico-chemical degradation that can lead to loss of biological activity and/or safety issues. In addition, various lung clearance mechanisms have to be avoided to provide a sufficient level of intact protein in the lungs. If systemic action is desired, it is also necessary for the molecule to cross the alveolar epithelium, which is particularly challenging for large proteins with many hydrophilic domains. The purpose of this article is to review the main challenges in the formulation of proteins for inhalation and the possible strategies that can be applied. Because of the particular success of dry formulations in stabilising proteins, there is a special focus on their development, along with the drying techniques and stabilising excipients used. Finally, an overview is given of the existing commercial preparations and of the main clinical developments in inhaled proteins for either topical or systemic applications.International journal of pharmaceutics 03/2013; · 2.96 Impact Factor
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ABSTRACT: Purpose of review: Vasoactive Intestinal Peptide (VIP) is a neuropeptide, expressed by lymphoid as well as neural cells, which has diverse effects on the cellular mediators of inflammation and immunity and is also a potent neurotransmitter. VIP seems to have a major role in the homeostasis of the respiratory system, while several studies, including clinical trials, suggest that VIP-inhaled agonists could be used in respiratory therapeutics. In this review, we provide an introduction to the field of VIP research geared to clinical and research pulmonologists. Recent Findings: As a neurotransmitter, VIP exerts a potent bronchodilatory and vasodilatory effect and also is supposed to induce the house-keeping mucus secretion by submucosal glands. On the other hand, it has immunomodulatory functions which include humoral immune response suppression, inhibition of vascular and bronchial remodeling and inflammation and attenuation of the cigarette smoke extract-induced apoptotic death of alveolar L2 cells. Recent research on a wide spectrum of lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, and sarcoidosis indicates a potential therapeutic role of a VIP agonist. Simultaneously, novel stabilized inhaled VIP agonists and drug delivery systems have been proposed as a promising candidate alternative drug with minimized side effects. These data are supported by the results of certain, limited clinical trials which have already been conducted. Conclusion: Ongoing research continues to clarify the immunomodulatory effects of VIP and to confirm animal findings with human studies. A major challenge for investigators will be to determine whether stabilized inhaled-VIP agonists could be used in respiratory therapeutics.Hippokratia 01/2012; 17(1):12-16. · 0.59 Impact Factor