Diffusion of [<sup>3</sup>H]Dexamethasone in Rat Subcutaneous Slices after Injection Measured by Digital Autoradiography

Moussy, Yvonne; Dungel, Paul; Hersh, Lawrence

doi:10.1002/bp060226r

Cited by 6 publications

(5 citation statements)

References 7 publications

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“…Moussy and coworkers have explored the effect of dexamethasone (DEX) on the foreign body response and found that DEX slowly released from microspheres had a beneficial effect on the foreign body response to subcutaneously‐implanted sutures in rats 24. In an attempt to understand the spatial effect of locally released steroids, they also found that the primary effect of DEX was confined to a very small area (several mm), as verified by direct in vivo measurement, mathematical modeling,6 and autoradiography in subcutaneous tissue slices 25. The Burgess laboratory has demonstrated the use of a PLGA microsphere‐based controlled release system to release DEX in concert with angiogenic growth factors 7, 26, 27.…”

Section: Discussionmentioning

confidence: 92%

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Ward

Hansen

Massoud

et al. 2010

J Biomedical Materials Res

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Chronically implanted biosensors typically lose sensitivity 1-2 months after implantation, due in large part to the development of a collagen-rich capsule that prevents analytes of interest from reaching the biosensor. Corticosteroids are likely candidates for reducing collagen deposition but these compounds have many serious side effects when given over a prolonged period. One method of assessing whether or not locally released corticosteroids have a systemic effect is to measure cortisol concentrations in venous serum. We hypothesized that a very low release rate of the potent corticosteroid, dexamethasone, would lead to a localized anti-inflammatory effect without systemic effects. We found that reduction in subcutaneous granulocytes (primarily eosinophils), and to a lesser extent, reduction of macrophages served as a good local indicator of the steroid effect. When released over a 28-day period, a total dexamethasone dose of < or =0.1 mg/kg led to a consistent reduction in the number of granulocytes and macrophages found in the local vicinity of the implant without a reduction of these cells at distant tissue locations. The lack of suppression of serum cortisol with these doses confirmed that low-release rates of dexamethasone can lead to consistent local anti-inflammatory effects without distant, systemic effects. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

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Section: Discussionmentioning

confidence: 92%

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Ward

Hansen

Massoud

et al. 2010

J Biomedical Materials Res

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“…An intravaginal environment on the other hand, while providing defined and homeostatically controlled temperature and internal pressure at the matrix surface, putatively entails additional mass transport of sublimed matrix vapors away from the eroding surface via a series of diffusion and convection steps typically observed for implanted devices (36,37). Adult ewes were chosen for an animal model due to their average intravaginal surface area being very similar to the average value measured in women (23,38,39).…”

Section: Resultsmentioning

confidence: 99%

Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices

et al. 2012

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PurposeUse of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.MethodsTenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.ResultsDrug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.ConclusionSubliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

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“…The diffusion coefficient was estimated from the known value for dexamethasone in the subcutaneous tissue. 14 Note that the molecular masses of dexamethasone and salubrinal are 392 Da and 480 Da, respectively.…”

Section: Methodsmentioning

confidence: 99%

Modelling the Molecular Transportation of Subcutaneously Injected Salubrinal

Chen

Zhang

Duan

et al. 2011

Biomed Eng Comput Biol

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For the subcutaneous administration of a chemical agent (salubrinal), we constructed a mathematical model of molecule transportation and subsequently evaluated the kinetics of diffusion, convection, and molecular turnover. Salubrinal is a potential therapeutic agent that can reduce cellular damage and death. The understanding of its temporal profiles in local tissue as well as in a whole body is important to develop a proper strategy for its administration. Here, the diffusion and convection kinetics was formulated using partial and ordinary differential equations in one-and three-dimensional (semi-spherical) coordinates. Several key parameters including an injection velocity, a diffusion coefficient, thickness of subcutaneous tissue, and a permeability factor at the tissue-blood boundary were estimated from experimental data in rats. With reference to analytical solutions in a simplified model without convection, numerical solutions revealed that the diffusion coefficient and thickness of subcutaneous tissue determined the timing of the peak concentration in the plasma, and its magnitude was dictated by the permeability factor. Furthermore, the initial velocity, induced by needle injection, elevated an immediate transport of salubrinal at t , 1 h. The described analysis with a combination of partial and ordinary differential equations contributes to the prediction of local and systemic effects and the understanding of the transportation mechanism of salubrinal and other agents.

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Diffusion of [³H]Dexamethasone in Rat Subcutaneous Slices after Injection Measured by Digital Autoradiography

Cited by 6 publications

References 7 publications

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices

Modelling the Molecular Transportation of Subcutaneously Injected Salubrinal

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Diffusion of [3H]Dexamethasone in Rat Subcutaneous Slices after Injection Measured by Digital Autoradiography

Cited by 6 publications

References 7 publications

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices

Modelling the Molecular Transportation of Subcutaneously Injected Salubrinal

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Diffusion of [³H]Dexamethasone in Rat Subcutaneous Slices after Injection Measured by Digital Autoradiography