A mathematical model to describe drug release from thin topical applications

Release of a thin topical application of a drug is modeled by transient diffusion between the application, the underlying stratum corneum, and a receptor. Cases treated include sudden contact of the application with drug-free stratum corneum, and initially equilibrated application and stratum corneum. The method of solution is the numerical inversion of the analytic Laplace Transform of the exact solution, which has speed, accuracy and convenience advantages over classical analytical or numerical methods for coupled linear partial differential equations. The algorithm for long-time solutions in the time domain is also found, although this has no computational advantage over the direct numerical transform inversion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27653/1/0000034.pd

Bioavailability assessment of topical delivery systems: in vitro delivery of minoxidil from prototypical semi-solid formulations

An in vitro technique has been developed for evaluating the delivery performance of topical semi-solid formulations. A thin and uniform layer of formulation was applied in facsimile to actual usage conditions by troweling the vehicle across a thin. circular copper template (200 [mu]m in thickness). Approximately 30-45 mg of an oil-in-water cream, a water-in-oil cream or an ointment, each containing a range of concentrations of minoxidil, were applied over human cadaver skin within a defined circular area of 1.54 cm2. The rates of permeation of minoxidil from these formulations were determined by finite dose diffusion experiments. For formulations containing 2% minoxidil, the flux from the w/o cream tested was about 4 times higher than fluxes from the o/w cream and the ointment. Even though all w/o formulations were initially saturated with drug, the flux of minoxidil from these creams increased as the concentration of minoxidil was increased from 0.5% to 2%. In contrast, the delivery rates from the o/w cream and the ointment did not appear to be dependent on the minoxidil concentration applied (0.5-2%). Under the operative experimental conditions, the percent coefficients of variation of flux of minoxidil from these formulations were less than 20%. To achieve this low level of variability, the skin samples were all obtained from the same cadaver abdomen. If one assumes that the efficacy of a particular formulation is dependent on the ability of the drug to be released from the vehicle and diffuse through the skin, the studies show that the nature of the vehicle can profoundly affect delivery even when excess solid drug is present. They also indicate that reliable in vitro comparisons of drug delivery are possible as long as one performs the studies on skin samples taken from the same section of skin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28086/1/0000532.pd

Is post-trabeculectomy hypotony a risk factor for subsequent failure? A case control study

BACKGROUND: Ocular hypotony results in an increased break down of the blood-aqueous barrier and an increase in inflammatory mediator release. We postulate that this release may lead to an increased risk of trabeculectomy failure through increased bleb scarring. This study was designed to try to address the question if hypotony within one month of trabeculectomy for Primary Open Angle Glaucoma (POAG), is a risk factor for future failure of the filter. METHODS: We performed a retrospective, case notes review, of patients who underwent trabeculectomy for POAG between Jan 1995 and Jan 1996 at our hospital. We identified those with postoperative hypotony within 1 month of surgery. Hypotony was defined as an intraocular pressure (IOP) < 8 mmHg or an IOP of less than 10 mmHg with choroidal detachment or a shallow anterior chamber. We compared the survival times of the surgery in this group with a control group (who did not suffer hypotony as described above), over a 5 year period. Failure of trabeculectomy was defined as IOP > 21 mmHg, or commencement of topical antihypertensives or repeat surgery. RESULTS: 97 cases matched our inclusion criteria, of these 38 (39%) experienced hypotony within 1 month of surgery. We compared the survival times in those patients who developed hypotony with those who did not using the log-rank test. This data provided evidence of a difference (P = 0.0492) with patients in the hypotony group failing more rapidly than the control group. CONCLUSION: Early post-trabeculectomy hypotony (within 1 month) is associated with reduced survival time of blebs

Genome-wide RNA-Sequencing analysis reveals a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery

Fibrosis-related events play a part in most blinding diseases worldwide. However, little is known about the mechanisms driving this complex multifactorial disease. Here we have carried out the first genome-wide RNA-Sequencing study in human conjunctival fibrosis. We isolated 10 primary fibrotic and 7 non-fibrotic conjunctival fibroblast cell lines from patients with and without previous glaucoma surgery, respectively. The patients were matched for ethnicity and age. We identified 246 genes that were differentially expressed by over two-fold and p < 0.05, of which 46 genes were upregulated and 200 genes were downregulated in the fibrotic cell lines compared to the non-fibrotic cell lines. We also carried out detailed gene ontology, KEGG, disease association, pathway commons, WikiPathways and protein network analyses, and identified distinct pathways linked to smooth muscle contraction, inflammatory cytokines, immune mediators, extracellular matrix proteins and oncogene expression. We further validated 11 genes that were highly upregulated or downregulated using real-time quantitative PCR and found a strong correlation between the RNA-Seq and qPCR results. Our study demonstrates that there is a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery and provides new insights into the mechanistic pathways driving the complex fibrotic process in the eye and other tissues

The extent of ultrastructural spinal cord pathology reflects disease severity in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) has been studied for decades as an animal model for human multiple sclerosis (MS). Here we performed ultrastructural analysis of corticospinal tract (CST) and motor neuron pathology in myelin oligodendrocyte glycoprotein (MOG) peptide 35-55- and MP4-induced EAE of C57BL/6 mice. Both models were clinically characterized by ascending paralysis. Our data show that CST and motor neuron pathology differentially contributed to the disease. In both MOG peptide- and MP4-induced EAE pathological changes in the CST were evident. While the MP4 model also encompassed severe motor neuron degeneration in terms of rough endoplasmic reticulum alterations, the presence of intracytoplasmic vacuoles and nuclear dissolution, both models showed motor neuron atrophy. Features of axonal damage covered mitochondrial swelling, a decrease in nearest neighbor neurofilament distance (NNND) and an increase of the oligodendroglial cytoplasm inner tongue. The extent of CST and motor neuron pathology was reflective of the severity of clinical EAE in MOG peptide- and MP4-elicited EAE. Differential targeting of CNS gray and white matter are typical features of MS pathology. The MOG peptide and MP4 model may thus be valuable tools for downstream studies of the mechanisms underlying these morphological disease correlate

Topical Drug Delivery from Thin Applications: Theoretical Predictions and Experimental Results

Stainless-steel templates of various thicknesses (75, 200, 800, and 1600 µm) were used to apply propylene glycol/water gels containing methyl or propyl p -aminobenzoates to silicone rubber membranes, and drug delivery was studied with the use of the Bronaugh diffusion cell under conditions in which the drug was initially in thermodynamic equilibrium with respect to the application and membrane. Theoretical diffusion profiles were generated with the use of a model which assumes that diffusional gradients exist within the application. To use the model equation, previously derived for the initial condition in which the drug is in thermodynamic equilibrium with respect to the application and membrane, drug diffusivity in both the application and the membrane and the drug's membrane/ vehicle partition coefficient were independently determined. In general, agreement between experimental and theoretical results was within 25%.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41540/1/11095_2004_Article_305860.pd

Drug Transport from Thin Applications of Topical Dosage Forms: Development of Methodology

There are presently no standards for in vitro research dealing with the release and delivery of drugs from semisolid dosage forms, largely because of inherent experimental difficulties. Among the problems, it has proven difficult to apply dosage forms to membranes mounted in in vitro diffusion cells in facsimile to the manner in which the dosage forms are applied clinically. In the present studies, methodology has been developed which allows films with thicknesses approaching clinical dimensions to be spread evenly over silicone rubber membranes. Using methyl p -aminobenzoate as a test permeant and gelled water and water/propylene glycol solvent systems as test vehicles, it has proven possible to spread films as thin as 75 µm, yielding highly reproducible delivery profiles. Using this application technique, it has been shown how the diffusive clearance of drug from films of fixed composition placed over a resistant membrane is dependent on the thickness of application. For a given medium and thickness of application, when the vehicle composition is enriched in propylene glycol, partitioning into the membrane is suppressed, resulting in a lessening of the absolute rate of delivery and, consequently, a prolongation of the period over which drug is released. Increasing the membrane's resistance, i.e., increasing the membrane's thickness, likewise slows down the absolute delivery rate, extending the effective period of total clearance of drug from the applied film.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41524/1/11095_2004_Article_306209.pd

Comparison of Krypton and Argon Laser Photocoagulation: Results of Simulated Clinical Treatment of Primate Retina

• We compared the clinical and histological effects of argon blue-green laser (ABGL), argon green laser (AGL), and krypton red laser (KRL) photocoagulation on the primate retina. Burns were produced in juxtafoveal and papillomacular bundle and in nonmacular areas in a manner simulating treatment of a choroidal neovascular membrane (NVM). In the juxtafoveal and papillomacular bundle areas, ABGL photocoagulation caused extensive inner retinal damage while KRL photocoagulation spared inner retinal structures. The effects of AGL photocoagulation in the fovea were intermediate in extent between KRL and ABGL photocoagulation. Axonal transport studies also showed differential effects of these wavelengths on retinal ganglion cell function. Nonmacular effects were similar for all three modalities. These results suggest that the krypton red wavelength may be more suitable than the argon green or argon blue-green wavelengths in treating choroidal NVMs near the fovea

Cell Proliferation After Laser Photocoagulation in Primate Retina: An Autoradiographic Study

• Argon blue-green laser and krypton red laser (KRL) photocoagulation were applied to primate retinas at intervals ranging from two to 23 days before the animals were killed. An injection of tritiated thymidine was given intravitreally three days before death. Argon bluegreen laser photocoagulation induced cell proliferation in the retina and retinal pigment epithelium seven days after treatment, with quiescence at 23 days. Krypton red laser photocoagulation induced similar cell proliferation not only in the retina and retinal pigment epithelium but also around choroidal vessels and in the stroma of the choroid. Peak thymidine uptake occurred seven days after KRL treatment. There was less uptake at two and 11 days and no uptake at 23 days. Thymidine uptake in the retina and choroid also was detected with low levels of KRL treatment. True cell hyperplasia (cell division) occurred after laser treatment; only KRL treatment induced cellular reaction in the choroid