Current Drug Delivery (v.9, #4)

Mesenteric fat hypertrophy is a common feature of inflammatory bowel diseases (IBD), especially Crohn's disease. Although this “creeping fat” has been observed in the early days of this disease, its biological relevance is not understood. This adipose tissue has been recognized to release large amounts of various cytokines such as TNFa and adipocytokines such as adiponectin or leptin. Whereas leptin is definitely a pro-inflammatory adipocytokine, the role of the prototypic anti-inflammatory adipocytokine, namely adiponectin, in intestinal inflammation is less clear. Some experimental studies suggest that it could exert also pro-inflammatory activities in the gut. An important role for metabolic aspects and potentially adipocytokines has also come from recent studies demonstrating that ATG16L1- deficient mice show a strikingly enhanced expression of both adiponectin and leptin in epithelial cells. Autophagy not only plays a key role in intestinal inflammation, but is also involved in the regulation of lipid metabolism. Another recently identified pathway in IBD, namely endoplasmic stress/XBP1, regulates fatty acid synthesis and facilitates adipogenesis and adipocyte differentiataion. Therefore, XBP1 could possibly link intestinal inflammation with the development of “creeping fat” in Crohn’s disease. Metabolic aspects have evolved as of key importance in experimental colitis and human IBD, and certain adipocytokines, autophagy, and ER stress might reflect the central players.

Inflammatory bowel diseases (IBD) are chronic relapsing and remitting disorders that have varying degrees of severity. However multiple studies have confirmed that a large proportion of patients on maintenance treatment lose response to anti-TNF therapy. This has led to increasing interest in the concept of ‘switching therapy out-of-class’ i.e. a nonanti- TNF antibody when patients either fail to respond (primary non-response, develop secondary non-response) or do not tolerate anti-TNF therapies. The most widely known and studied alternative class of antibodies therapies at present are the selective adhesion molecule inhibitors. Several antibodies exist which constitute selection adhesion molecule inhibitors, including Natalizumab, MLN-0002 (Vedolizumab) and ISIS 2302 (Alicaforsen) will be discussed in this review.

Patients with ulcerative colitis uniformly have disease involving the distal colon. When patients have disease limited to the left colon or symptoms suggestive of active rectal inflammation, guidelines recommend topical rectal therapies as first-line agents either as monotherapy or in conjunction with oral products. Rectal delivery modalities offer the advantage of delivering high local concentrations of active medication to the site of maximal inflammation with minimization of systemic side effects. Methods of rectal administration include suppositories, liquid enemas and foams. Suppositories are limited to the treatment of rectal disease, and patients often have difficulty retaining the liquid enema secondary to its high volume and consistency. Rectal foams reliability extend to the descending and sigmoid colon with application. Foams are further characterized by increased viscosity, lower volumes, finer dispersion on the colonic mucosa, and increased adhesiveness to the colonic mucosa compared with liquid enemas. Additionally, rectal foam agents demonstrate equal efficacy to their liquid enema counterparts yet consistently yield better patient tolerance, lower incidence of side effects, and increased patient acceptability. Currently available agents include 5-aminosalicylic acid and corticosteroids, both first and newer generation. This review focuses on clinical trials assessing efficacy, tolerability, and patient preferences for these agents as well as describing the currently available rectal foam products.

Crohn’s disease (CD) and ulcerative colitis (UC) represent two similar but probably not uniform entities of inflammatory bowel disease (IBD). Since up to now no curative treatment is available the therapeutic goal in active IBD is elimination or at least alleviation of symptoms and maintenance of remission. Glucocorticoids have been successfully used in the treatment of symptoms and inflammation. Due to the minor systemic side effects a topical drug delivery targeting the active substances directly to the inflamed sites would be the favorable administration. In this review the use of topical corticosteroids is discussed, based on a short description of their pharmacological properties.

The pregnant patient with inflammatory bowel disease presents a number of challenges to the clinician. In addition to the management of the patient’s disease activity and the potential effects of disease on pregnancy, the clinician must also take into consideration any iatrogenic complications that may arise from the medical management of these conditions. Furthermore, should the patient elect to breastfeed her infant, the effect of drugs that may be passed through the breast milk must also be considered. This article focuses specifically on the issues of drug transfer to the fetus and to the breastfeeding infant. Meperidine is the sedative of choice for endoscopic procedures on pregnant patients, while benzodiazepines and propofol may be used with certain caveats. Amoxicillin/clavulanic acid and metronidazole are preferred if antibiotics are indicated for perianal Crohn’s disease or pouchitis. The majority of medications used in the treatment of luminal IBD in pregnancy are not associated with significant adverse effects, and thus can generally be used safely. Certain medications, such as aminosalicylates, corticosteroids, and cyclosporine, appear low risk, while others such as methotrexate and thalidomide are clearly contraindicated. The role of other immunomodulators and biologics remains to be clearly defined, although early experience with infliximab and similar agents appear to be low risk. Safety in breastfeeding varies considerably among medications. There are many issues to address when considering pharmaceutical intervention in the pregnant patient, and patients should be carefully counseled regarding potential teratogenicity or adverse outcomes of medication used during pregnancy and breastfeeding.

Anemia is common in inflammatory bowel disease (IBD), with a prevalence ranging from 8.8% to 73.7%. This wide range reflects the definitions used and the populations studied. Although many patients are reported to be asymptomatic, systematic studies have shown anemia to have a significant impact on quality of life. Consequently treatment should be instituted early. The commonest cause of anemia in IBD is iron deficiency, predominantly related to gastrointestinal blood loss. Anemia of chronic disease often occurs concomitantly, due to cytokine-mediated impaired erythropoiesis and dysregulated iron metabolism. Oral iron is a simple and effective method for treating iron deficiency, but requires long courses of treatment. It is also theoretically implicated with worsening intestinal inflammation, via the production of toxic reactive oxygen species. Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly. In patients failing to respond to intravenous iron, the anemia of chronic disease is most likely to be causative. In this setting evidence suggests that additional erythropoietin therapy can be effective. Blood transfusions should be avoided as part of routine management and reserved for patients with substantial acute gastro-intestinal bleeding, where there is a risk of hemodynamic compromise. This article discusses the underlying physiology of anemia in IBD, and presents the current evidence supporting treatment options available.

Polymers and Drug Delivery Systems by Gemma Vilar (367-394).
In the treatment of health related dysfunctions, it is desirable that the drug reaches its site of action at a particular concentration and that this therapeutic dose range remains constant over a sufficiently long period of time to alter the process. However, the action of pharmaceutical agents is limited by various factors, including their degradation, their interaction with other cells, and their incapacity to penetrate tissues as a result of their chemical nature. For these reasons, new formulations are being studied to achieve a greater pharmacological response; among these, polymeric systems of drug carriers are of high interest. These systems are an appropriate tool for time- and distribution-controlled drug delivery. The mechanisms involved in controlled release require polymers with a variety of physicochemical properties. Thus, several types of polymers have been tested as potential drug delivery systems, including nano- and micro-particles, dendrimers, nano- and micro-spheres, capsosomes, and micelles. In all these systems, drugs can be encapsulated or conjugated in polymer matrices. These polymeric systems have been used for a range of treatments for antineoplastic activity, bacterial infections and inflammatory processes, in addition to vaccines.

The present study was carried out with a view to enhance dissolution rate of poorly water-soluble drug glipizide (GZ) (BCS class II) using polyethylene glycol (PEG) 6000, PEG 8000 and poloxamer (PXM) 188 as carriers. Solid dispersions (SDs) were prepared by melting method using different ratios of glipizide to carriers. Phase solubility study was conducted to evaluate the effect of carrier on aqueous solubility of glipizide. SD was optimized by drug content estimation and in vitro dissolution study and optimised SD was subjected to bulk characterization, Scanning electron microscopy (SEM), Fourier transformation infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction study (XRD). Preclinical study was performed in mice to study the decrease in blood glucose level from prepared SD compared with pure drug. Due to high solubility and drug release, PXM 188 in weight ratio of 1:2 was optimized. Decrease in blood glucose level in mice from SD was significantly higher (p < 0.05) compared to pure glipizide. Thus, solid dispersion technique can be successfully used for the improvement of the dissolution profile of GZ.

In patients with diabetes, hyperglycemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to the production of vascular endothelial growth factor (VEGF) in the retina. PKC activation and increased concentration of VEGF are likely to play a key role in diabetic microvascular complications, particularly change in vascular permeability, inflammation, fluid leakage and ischemia in the retina. PKC comprises a super family of isoenzymes that is activated in response to various stimuli. The PKC family consists of 12 isomers that possess distinct differences in structure, substrate requirement, expression and localization. PKC isomer selective inhibitors and VEGF trap are likely to be new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease. A new promising therapy for diabetic retinopathy is undergoing Phase III trials, in which they proposed to target PKC βII isomer using Ruboxistaurin by oral administration. Besides retina, PKC βII isomer is found in higher concentration in brain, spleen, etc. So, oral targeting may be a questionable approach since generalized inhibitors may prove toxic in the treatment of diabetic retinopathy and ocular delivery may be a better alternative approach.

Objective: To investigate the effect of LBP on differentiation and maturation of healthy human peripheral blood-derived dendritic cells cultured in different tumor microenvironment in vitro, and discuss the molecular and immunological mechanisms of LBP in treatment of tumor. Methods: In this study, we procured the peripheral blood-derived dendritic cells precursor cell by the Density gradient centrifugation method, and used the tumor-cell supernatant to prepare conditioned medium. The GM-CSF and IL-4 induced DCs precursor cell differentiation to DCs, the TNF-α promoted the immature DCs developed to mature DCs. In this way, we detected the influence of LBP on the expressions of surface molecules of DCs cultured in different environments, and especially on the role of related-immunity and NF-&#x3BA;B activity. Results: In LBP-treated group, the molecular phenotype of DCs, its capacity to stimulate allogeneic lymphocyte proliferation, and the levels of IL-12p70 and IFN-&#x3B3; secretion were higher than the untreated group (p < 0.05), with statistical significance. Meanwhile the expression of NF-&#x3BA;B of the DCs in the medium treated by the LBP was higher than the untreated group (p < 0.05), also with statistical significance. Between the two different tumor microenvironment groups, the cell nucleus protein NF-&#x3BA;B expression is obviously different, the hepG2.2.15 group higher than the hepG2 group. Conclusion: LBP could increase the expression of the phenotype of DCs, the secretion of IL-12p70 and IFN-&#x3B3; in MLR, and enhance the NF-&#x3BA;B expression, especially in the virus-related group, suggesting LBP plays the anti-tumor role stronger in the virus-related environment and this phenomenon correlates with the NF-&#x3BA;B signaling pathway.

Topical ocular drug administration is the most preferred route for treating conditions affecting the surface of the eye as well as anterior segment diseases; this is mainly due to the rapid and localised drug action and patient acceptability. However, the ocular bioavailability is typically less than 5% from conventional ophthalmic dosage forms such as eye drops. This is mainly due to the unique anatomical and physiological features of the eye. One of the effective pharmaceutical approaches is to provide a controlled and continuous drug release to the surface of the eye to compensate drug loss by nasolacrimal drainage and non-productive absorption of the topically applied drug. This review provides a critical appraisal (advantages and drawbacks) of the different drug delivery strategies that provides controlled and continuous drug supply to the surface of the eye; it covers research conducted over the past three decades.

A three-component nanoparticle consisting of biotinylated Trastuzumab antiHer2 antibody, tat transferring peptide and radiolabeled antisense oligomer, linked together through streptavidin, have shown promise in the delivery to Her2+ tumor in mice following intravenous administration and with evidence of radiotherapeutic efficacy. These results have encouraged us to consider the nanoparticle as a delivery vehicle for RNA interference therapy in which the radiolabeled antisense oligomer is replaced with an unlabeled siRNA duplex. The siRNA stability within the nanoparticle was first confirmed by incubation with RNase A. The interferon responses, that indicate off-target cytotoxicity, were evaluated by quantitative real-time RT-PCR in BT-474 (Her2+) human breast cancer cells by measuring the mRNA expression of 2’, 5’-oligoadenylate synthetase (OAS1) and Stat-1, two key interferon-responsive genes. Thereafter the cytotoxicity induced by the siRNA nanoparticle was evaluated by a clonogenic survival assay in BT-474 cells while the Her2 expression of these target cells was evaluated for evidence of specific gene silencing. The siRNA within the three-component anti- Her2/neu siRNA nanoparticle was largely protected from RNase-dependent degradation and did not activate an interferon response. The nanoparticle effectively and significantly inhibited colony formation of the target cells and silenced the Her2 gene expression at 5 nM compared with the identical nanoparticle with a scrambled siRNA. Our delivery nanoparticle, with tumor targeting provided by the antibody and its accumulation without entrapment, possibly due to the transfecting peptide, delivered an siRNA duplex to the proper subcellular localization for specific and effective gene silencing in culture by what appears to be an siRNA mechanism.