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Biomedical subjects

William R Freeman

Publications and source records attributed to William R Freeman.

51 records · Page 3Linked to original sources
PubMed2002

Efficacy of Prinomastat) (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization.

PURPOSE: To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization. METHODS: C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research. RESULTS: AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg. CONCLUSIONS: AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.

Animals↗
PubMed2002

The effect of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinases, on uveal melanoma rabbit model.

PURPOSE: We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma model. METHODS: Uveal melanoma xenograft was implanted to suprachoroidal space in each eye of 24 pigmented rabbits which were immunosuppressed with cyclosporine. One week after surgery, the eyes were randomized to receive prinomastat or the vehicle of the prinomastat intravitreally every week for 4 weeks. The take rate of the xenograft, tumor height, apoptosis, and necrosis in the eyes which developed tumors from the treatment and control groups were compared. RESULTS: A tumor mass was identified in 8 of 24 (33%) prinomastat-treated eyes and 20 of 24 (83%) of the vehicle-treated eyes. Echographic measurements revealed a mean tumor height of 2.2 mm in the prinomastat-treated group and 3.8 mm in the control group in those eyes with take of tumor (p < 0.001). Stereomicroscopic measurements showed a mean tumor height of 1.9 mm in the treatment group and 3.9 mm in the control group (p < 0.001). The mean number of apoptotic nuclei detected per mm(2) of the histologic section in the non-necrotic tumor was 8.12 in the prinomastat-treated group and 0.57 in the control group (p < 0.001). Evaluation of the digital images in microscopic sections of the tumors on histologic slides revealed 29.6% necrosis in prinomastat-treated eyes as compared to 10.9% in vehicle-treated eyes (p = 0.003). CONCLUSIONS: These results suggest that prinomastat treatment significantly reduces the take rate and the growth rate of xenograft in uveal melanoma rabbit model.

Animals↗
PubMed2002

Human immunodeficiency virus type 2 (HIV-2) vector-mediated in vivo gene transfer into adult rabbit retina.

PURPOSE: To evaluate the potential usefulness of HIV-2 viral vector in in vivo retinal gene therapy. METHODS: An HIV-2 virus based viral vector was constructed and administered subretinally and intravitreally into rabbit eyes. After viral vector administration, the eyes were closely monitored for any adverse effects by slit lamp, indirect ophthalmoscopy, and fundus photography. Eyes were enucleated at specified times after injection, and reporter gene expression was identified within cell types and graded by the pattern and distribution of staining cells using fluorescent microscopy. RESULTS: The HIV-2 viral vector demonstrated efficient gene transfer into many types of retinal cells without apparent cytotoxicity. Notably with subretinal injection, the HIV-2 vector resulted in higher efficiency of transduction of photoreceptor cells than of the other cell types (p < 0.05). With the intravitreal administration of HIV-2 viral vectors, cellular transduction and transgene expression in the ganglion cell layer was the dominant finding. CONCLUSIONS: HIV-2 viral vector may be a useful gene delivery vehicle for retinal photoreceptor cells and ganglion cells. It deserves further exploration to investigate its potential merit in long term gene therapy protocols and in other animal species.

Animals↗
PubMed2002

Paradoxical activity of CMV retinitis in patients receiving highly active antiretroviral therapy.

PURPOSE: To report two types of atypical behaviors of cytomegalovirus (CMV) retinitis in the highly active antiretroviral therapy (HAART) era, including active CMV retinitis in the presence of persistently high CD4 cell counts during HAART and CMV retinitis that has not reactivated despite persistently low CD4 cell counts. METHODS: Prospective, longitudinal, observational study of a cohort of 116 patients with acquired immunodeficiency syndrome who had a history of CMV retinitis during the HAART era. RESULTS: Sixty (52%) of the 116 patients with acquired immunodeficiency syndrome and CMV retinitis were HAART responders. Subsequently, HAART failed for 9 of the 60 patients with low CD4 cell counts. Of these 9 patients, 5 developed reactivation of CMV retinitis, and 4 remained free of CMV retinitis despite CD4 cell counts of <50/microL and lack of anti-CMV therapy. Paradoxically, there was a patient with a documented median CD4 cell count of 204/microL for 19 months who had newly diagnosed active CMV retinitis. CONCLUSION: In the HAART era, CMV retinitis may remain quiescent despite extremely low CD4 cell counts, and rarely, CMV retinitis may become active in the setting of persistently high CD4 cell counts in a subset of HAART responders.

AIDS-Related Opportunistic Infections↗
PubMed2002

Retinal imaging with a low-cost micromachined membrane deformable mirror.

PURPOSE: To study the retina in normal subjects with a high-resolution imaging system using adaptive optics for wave front aberration correction. METHODS: We used a low-cost 37-element micromachined membrane deformable mirror (MMDM) with a continuous membrane as the reflective surface. A Hartmann-Shack wave front sensor with cooled charge coupled device camera was used to measure the wave front aberration. Zernike polynomials were used to describe the wave front shape. We developed a mirror control system to compensate for wave aberrations. We tested this instrument in normal subjects. RESULTS: We were able to image the retina in monochromatic laser light and document the increase in resolution. While it is hard to estimate the exact size of the smallest structures in the image, we were able to subjectively grade the image quality. The system is able to compensate for higher order aberrations present in the human eye. CONCLUSION: The capabilities of correcting ocular aberrations are limited by the number of adjustable elements in the mirror and the deflection range of the surface. The advantage of the MMDM system is its low cost when compared with other adaptive optics solutions such as piezodriven mirrors and spatial light modulators. This technique may allow for improved resolution for clinical fundus photography.

Adult↗
PubMed2002

Treatment or prevention of herpes simplex virus retinitis with intravitreally injectable crystalline 1-O-hexadecylpropanediol-3-phospho-ganciclovir.

PURPOSE: To evaluate an intraocular drug delivery system consisting of the crystalline ammonium salt of 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV) as a slow-release form of the drug. METHODS: A dosage of 0.885, 1.57, 2.8, 4.486, or 8.85 micromol of ammonium salt HDP-P-GCV in 0.1 mL was intravitreally injected into rabbit vitreous. The toxicity and safety were evaluated with ophthalmoscopy, electroretinography, and pathology. Drug vitreous levels were determined at various time intervals by means of HPLC. The treatment efficacy and duration of efficacy were tested in a herpes simplex virus (HSV)-1 retinitis rabbit model. RESULTS: Intravitreal injections of the compound revealed clear vitreous of optic axis, a desirable drug depot in the inferior vitreous cavity, and no clinical toxicity, except for variable mild local posterior subcapsular cataract and local retinal toxicity with high doses. HPLC analysis showed free ammonium salt of HDP-P-GCV in the upper vitreous at a level of 0.2 microM 12 weeks after the 2.8-micromol initial intravitreal dose. Drug concentration was still 1.95 microM 20 weeks after the 8.85-micromol initial intravitreal dose. These concentrations (0.2 and 1.95 microM) were 10 and 100 times higher, respectively, than the median inhibitory concentration (IC(50)) of HSV-1 (0.023 microM). Treatment with the highest nontoxic dose (2.8 micromol) and the highest dose (8.85 micromol) showed significant protection from HSV-1 infection (P < 0.05) and provided sustained antiviral effect after a single intravitreal drug injection. CONCLUSIONS: The crystalline ammonium salt of HDP-P-GCV may be a very useful local therapy for herpes family viral retinitis.

Animals↗
PubMedDate not supplied

Efficient gene transfer to retinal pigment epithelium cells with long-term expression.

PURPOSE: To evaluate the safety and efficiency of feline immunodeficiency virus (FIV) vectors for gene delivery into the mammalian retina. METHODS: A first-generation FIV vector was constructed and administered into rabbit eyes at two different concentrations by intravitreal or subretinal routes. A second-generation FIV vector was also constructed and administered subretinally into both rabbit and rat eyes at the same concentration. After vector administration, eyes were monitored using slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, and electroretinogram. After the rabbits were killed, eye tissues were processed for light microscopy and immunohistochemical analysis. RESULTS: Administration of both first- and second-generation FIV vectors produced transient vitritis and/or papillitis in rabbits, without other pathologic abnormalities. Retinal pigment epithelium (RPE) cells were the predominant cell type transduced in rabbit eyes, but ganglion cells and Muller cells were also transduced. Transduction was confined to the retinal bleb area. The second-generation FIV vector transduced RPE cells much more efficiently than the first-generation vector (95% vs. 4.5%, respectively; P = 0.0015) in rabbit eyes. In contrast, no toxicity was evident over a 24- to 25-month follow-up period after injection of the second-generation FIV vector into rat eyes. Tropism in the rat eye was similar, including RPE and ganglion cells, and the RPE transduction rate was also high (50%). Transgene expression was persistent in both species over the duration of the experiment. CONCLUSION: Second-generation FIV vectors can efficiently transfer genes into RPE cells with resulting long-term expression, properties potentially valuable to gene therapy approaches to some retinal diseases.

Animals↗
PubMedDate not supplied

HIV-associated retinopathy in the HAART era.

BACKGROUND: The effectiveness of highly active antiretroviral therapy (HAART) in restoring immune function in patients with acquired immunodeficiency syndrome (AIDS) has led to changes in the incidence, natural history, management, and sequelae of human immunodeficiency virus (HIV)-associated retinopathies, especially cytomegalovirus (CMV) retinitis. METHODS: The medical literature pertaining to HIV-associated retinopathies was reviewed with special attention to the differences in incidence, management strategies, and complications of these conditions in the eras both before and after the widespread use of HAART. RESULTS: In the pre-HAART era, CMV retinitis was the most common HIV-associated retinopathy, occurring in 20%-40% of patients. Median time to progression was 47 to 104 days, mean survival after diagnosis was 6 to 10 months, and indefinite intravenous maintenance therapy was mandatory. Retinal detachment occurred in 24%-50% of patients annually. Herpetic retinopathy and toxoplasmosis retinochoroiditis occurred in 1%-3% of patients and Pneumocystis carinii choroiditis, syphilitic retinitis, tuberculous choroiditis, cryptococcal choroiditis, and intraocular lymphoma occurred infrequently. In the HAART era the incidence of CMV retinitis has declined 80% and survival after diagnosis has increased to over 1 year. Immune recovery in patients on HAART has allowed safe discontinuation of maintenance therapy in patients with regressed CMV retinitis and other HIV-associated retinopathies. Immune recovery uveitis (IRU) is a HAART dependent inflammatory response that may occur in up to 63% of patients with regressed CMV retinitis and elevated CD4 counts and is associated with vision loss from epiretinal membrane, cataract, and cystoid macular edema. CONCLUSIONS: The incidence, visual morbidity, and mortality of CMV retinitis and other HIV-associated retinopathies have decreased in the era of HAART and lifelong maintenance therapy may safely be discontinued in patients with restored immune function. Patients with regressed CMV retinitis, however, may still lose vision from epiretinal membrane, cystoid macular edema, and cataract secondary to IRU.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Prefilled syringe needles versus standard removable needles for intravitreous injection.

PURPOSE: To investigate differences in the scleral resistance between standard disposable 27 gauge (G) needle versus the Macugen prefilled syringe needle. METHODS: Observational study at one eye center. One injecting physician performed 46 intravitreous injections using standard Becton Dickinson 27 G needles and 71 intravitreous injections using Macugen needles during January to May 2005. The procedure in two patients was videotaped and analyzed frame by frame. Microphotographs of used needles were analyzed. RESULTS: There were no complications during the injection procedure in either group. Microphotographic analysis after injection revealed 3 and 5 facets on standard 27 G needle and Macugen needles, respectively. The bevel forming the tip of the 27 G needle was steeper and longer than that of the Macugen needle. The inside diameter in the standard 27 G needle was 220 microm versus 210 microm in the Macugen needle. CONCLUSION: There are differences in needle design between commonly used disposable 27 G needles and 27 G Macugen needles which result in higher resistance to penetration with Macugen needle. Careful needle design is an important concern in manufacturing prefilled syringes with needles attached to them.

Animals↗
PubMedDate not supplied

Uveitic angle closure glaucoma in a patient with inactive cytomegalovirus retinitis and immune recovery uveitis.

We report a case of uveitic acute angle closure glaucoma in a patient with acquired immunodeficiency syndrome (AIDS) associated with inactive cytomegalovirus retinitis and immune recovery vitritis. We conducted a long-term, follow-up examination of a 47-year-old male with AIDS and inactive cytomegalovirus retinitis caused by immune recovery on highly active antiretroviral therapy (HAART). We found vitritis and ultimate development of uveitic glaucoma in the postoperative periods following repair of retinal detachment and extracapsular cataract extraction with intraocular lens implant. An episode of acute angle closure secondary to posterior synechiae and iris bombé subsequently developed, requiring peripheral laser iridotomy. Immune recovery in the setting of inactive cytomegalovirus retinitis can result in intraocular inflammation severe enough to cause angle closure glaucoma and profound ocular morbidity.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Oral fluorescein angiography in patients with choroidal neovascularization and macular degeneration.

OBJECTIVE: To evaluate image quality of oral fluorescein angiography in patients with age-related macular degeneration and choroidal neovascularization. MATERIALS AND METHODS: Twenty four patients with proven choroidal neovascularization were examined in a prospective observational case series. Confocal oral and intravenous fluorescein angiography were performed using the Heidelberg Retina Angiograph. Oral and intravenous image quality were compared in a masked fashion. RESULTS: Choroidal neovascularization could be diagnosed in all patients using intravenous angiograms. Oral fluorescein angiography accurately detected the presence or absence of choroidal neovascularization in all patients and could determine the classification of choroidal neovascularization, location, and extent and borders in 20 (83.3%) of 24 patients. Early, mid, and late phases of oral angiograms occurred at 8, 15, and 26 minutes, respectively. CONCLUSION: Oral fluorescein angiography using the confocal Heidelberg Retina Angiograph allowed detection of choroidal neovascularization in all patients in this study. Visualization of extent and type of choroidal neovascularization was possible in most eyes with choroidal neovascularization. These findings suggest oral angiography is an excellent screening tool for choroidal neovascularization and allows guidance of treatment in the majority of cases.

Administration, Oral↗