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.
- SourceAvailable from: Alexander G Mathioudakis[Show abstract] [Hide abstract]
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. · 0.36 Impact Factor
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ABSTRACT: Background: Dry powder inhaler (DPI) systems are widely accepted as an alternative to injection and oral administration of therapeutic peptides and proteins. In contrast to oral therapy, pulmonary administration eliminates the potential for poor absorption and high metabolism in the gastrointestinal tract and it also evades first-pass effects in the liver. Inhalation therapy does not cause pain, unlike injection therapy, and this reduces the strain on the patient, possibly leading to improved treatment outcomes. Objective: Alongside the expansion of the DPI market, the science and engineering of dry powder formulations and devices have also grown. In this review, we present information regarding some recent advances in this expanding field, with emphasis on pulmonary delivery of therapeutic peptides and proteins. Methods: The scope of this review was defined by patent information on DPI devices, formulations and pulmonary delivery of therapeutic peptides and proteins for topical and systemic administration. Patent and bibliographic searches were carried out using various databases and websites, including CAplus, United States Patent and Trademark Office patent full-text and image database, Industrial Property Digital Library, Esp@cenet, World Intellectual Property Organization patentscope, Freepatentsonline, and PubMed database. Results/conclusion: A number of research efforts have demonstrated the feasibility of pulmonary delivery systems for therapeutic peptides and proteins, employing novel inhaler devices, powder engineering technologies, functional drug carriers and absorption enhancers. Optimized drug delivery would be achieved not only by improving relatively simple inhaler devices but also by more sophisticated formulations that disperse easily in the air stream.Expert Opinion on Therapeutic Patents 04/2008; 18(4):429-442. · 3.44 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; · 3.99 Impact Factor