Dexamethasone delivery

Tan DT, Chee S, Lim L, LimA. Randomized clinical trial of a new dexamethasone delivery system (Surodex) for treatment of post-cataract surgery inflammation. Ophthalmology 1999 106 223-231. 

Sustained intraocular dexamethasone delivery has been shown to effectively treat uveitis in a rabbit model (10). Masked observers graded intraocular inflammation and retinal function was evaluated by electroretinography (ERG). Eyes that received a sustained-release dexamethasone device had significantly reduced clinical signs of intraocular inflammation when compared with control eyes that received a sham device. Objectively, treated eyes had lower protein concentrations and leukocyte counts than control eyes. Furthermore, untreated eyes had significantly depressed ERGs and more histological evidence of tissue inflammation when compared with treated eyes (Fig. 5). 

Kodama M, Numaga J, Yoshida A, et al. Effects of a new dexamethasone-delivery system (Surodex) on experimental intraocular inflammation models. Graefes Arch Exp Ophthalmol 2003 241(11) 927-933. 

Allergic reactions to insulin include erythema, pruritus, and indurations,22 which usually are transient. For the more troublesome reactions, treatment options include dexamethasone, desensitization, or change in delivery system (i.e., insulin pump or inhaled insulin). 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Current recommendations are to administer betamethasone, 12 mg IM every 24 hours for two doses, or dexamethasone, 6 mg IM every 12 hours for four doses, to pregnant women between 26 and 34 weeks gestation who are at risk for preterm delivery within the next 7 days. Benefits from... 

The same strategy was applied in colon-specific delivery of two corticosteroids used to treat inflammatory bowel disease [20][21], Indeed, budeso-nide /3-D-glucuronide and dexamethasone /3-D-glucuronide underwent ready hydrolysis in the luminal contents of rat colon and caecum. Rat mucosal homogenates were less active, and hydrolysis in human fecal samples was quite low. Based on these and other studies, the prodrugs were found to be suitable candidates for delivery of corticosteroids to the large intestine. 

MRXSOl/lipid shell + dexamethasone prodrug Ultrasound-activated drug delivery [83]... 

In an analysis of 595 preterm infants born at 26-32 weeks gestation during a randomized controlled trial for the prevention of lung disease, glucocorticoids given to women at risk of preterm delivery promoted fetal lung maturation, reduced the incidence of respiratory distress syndrome, and reduced neonatal morbidity and mortality (370). Dexamethasone was given as either two doses of 12 mg 24 hours apart or four doses of 6 mg every 6 hours. Mortality was 9.2% after three or more courses, compared with 4.8% after one or two courses. This association was not explained by other factors (maternal or other common preterm morbidities). 

Diabetes mellitus in a 36-year-old man with acute pancreatitis could not be controlled with continuous subcutaneous insulin infusion, even with doses up to 1800 U/ day, because of insulin resistance (168). Intravenous insulin by pump had to be stopped because of a catheter infection. The continuous subcutaneous infusion of freeze-dried insulin and the addition of aprotinin, a protease inhibitor, soluble dexamethasone or prednisolone, and intravenous immunoglobulin was ineffective. An implantable pump for intraperitoneal delivery established good regulation at a dosage of 30 U/day. 

Liposomes have been used in the local delivery of drugs to the oral mucosa. Farshi et al. [96] studied the biodistribution of dexamethasone sodium phosphate (DSP) encapsulated in multilamellar vesicle (MLV) liposomes labeled with 99mTc in ulcerated and intact oral mucosae of rats. The liposomes were found to localize the drug in the ulcerated area and increase local drug concentration while decreasing systemic concentration. 

Hastings et al. [55] used this same in vitro technology to assess the enhancement delivery of dexamethasone using the Visulex iontophoretic system. The Visulex applicator and a freshly excised rabbit sclera were positioned between two halves of a side-by-side diffusion cell with the conjunctival side of the sclera facing the applicator (Figure 26.10). The donor drug solution (1 mg of dexamethasone phosphate) was present in the applicator, and diluted vitreous humor was modeled in the receptor cell. One milliampere direct current was applied for 60 min, and samples were collected during different treatment periods. It was demonstrated that the Visulex system produced a twofold increase in the amount of dexamethasone phosphate delivered after 60 min, compared with a standard iontophoretic administration (without the Visulex applicator). 

Steroids are poorly investigated for the transcorneal route despite the fact that dexametha-sone seems to have a much higher corneal penetration than the positively charged antibiotics after corneal iontophoresis. Eljarrat-Binstock et al. [56] used dexamethasone phosphate-loaded hydrogels for the iontophoretic delivery, applying only 5.1 mA/cm2 current for 1 and 4 min. Enormous amounts of dexamethasone (3077.5 and 1363.7 pg/g) were detected... 

Patil SD, Papadmitrakopoulos F, Burgess DJ. Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. Journal of Controlled Release 2007, 117, 68-79. 

Hickey T, Kreutzer D, Burgess DJ, Moussy F. Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices. Biomaterials 2002, 23, 1649-1656. 

C. Kenyon, R. Nardi, D. Wong, G. Hooper, I. Wilding, and D. Friend, Colonic delivery of dexamethasone A pharmacoscintigraphic clinical evaluation, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 25 553-554 (1996). 

Melgert et al. studied the delivery of the corticosteroid dexamethasone to fibrotic livers [240], Dexamethasone has more potent and broader anti-inflammatory effects compared with naproxen. It inhibits the release of inflammatory mediators like TNF-a, IFN-y, and IL-6 and acts as an NFkB inhibitor [241, 242], Dexamethasone coupled to albumin (Dexa-HSA) was specifically taken up by sinusoidal cells in fibrotic rat livers, whereas dexamethasone itself was mainly taken up by hepatocytes. In vivo, Dexa-HSA promoted survival in endotoxin-induced liver inflammation in rats [240], In vitro, anti-inflammatory effects of the conjugate were measured in endotoxin-challenged liver slices. Dexa-HSA inhibited the release of nitric oxide and TNF-a in a dose-dependent manner (Melgert et al. unpublished data). To further enhance the delivery to KC at present dexamethasone is coupled to manHSA, and this conjugate is studied with respect to the pharmacokinetic profile and pharmacotherapeutic effects in fibrotic rats. 

Lincoff A, FurstJ, Ellis S, Tuch R, Topol E, Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol 1997 29 808-816. 

In ophthalmology, both trans-scleral and transcomeal dmg delivery has been studied. Drags investigated include fluorescein, tobramycin, gentamicin, ticarcillin, cefazolin, dexamethasone and ketoconazole. Iontophoresis has been found to be both safe and effective in delivering the required doses locally, at the intended site of action. Excepting for lidocaine, which has been tested in human volunteers, all the other drags have been tested in rabbits. 

At present a few studies of nanofibers and nanombes are focused on CNS drug delivery. One study evaluated electrospun nanofibers of a degradable polymer, PLGA, loaded with antiinflammatory agent, dexamethasone, for neural prosthetic applications (Abidian and Martin, 2005). A conducting polymer, poly(3,4-ethylenedioxythiophene), was deposited to the nano-fiber surface and the coated nanofibers were then mounted on the microfabricated neural microelectrodes, which were implanted into brain. The drug was released by electrical stimulation that induced a local dilation of the coat and increased permeability. 

A typical example of this type of activation-controlled CrDDS is the development of an iontophore-tic drug delivery system, named Phoresor by Motion Control, to facilitate the percutaneous penetration of antiinflammatory drugs, such as dexamethasone sodium phosphate, to surface tissues. 

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