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Biomedical subjects

P Ashton

Publications and source records attributed to P Ashton.

At least 19 recordsLinked to original sources
PubMed1996

Evaluation of a delivery system providing long-term release of cyclosporine.

OBJECTIVES: To examine the clearance of cyclosporine after intravitreal injection and to assess the kinetics and toxic effects of an intravitreal device that provides sustained delivery of cyclosporine. METHODS: Rabbits were divided into two groups to evaluate (1) the elimination kinetics after 1-microgram and 10-microgram intravitreal injections of cyclosporine and (2) the levels produced after implantation of a device that contained cyclosporine over 6 months. The toxic effects of the intravitreal device over 6 months were assessed in rabbits and cynomolgus monkeys. RESULTS: After the 10-microgram injection, the half-life was longer (10.8 hours vs. 4.2 hours) and the distribution volume was smaller (1.7 mL vs 3.2 mL) than after the 1-microgram injection. This difference can be attributed to saturable partitioning of the drug. The device resulted in a vitreous concentration of approximately 500 ng/mL throughout the study period. In the rabbit it resulted in reversible lens opacification and decreased b-wave amplitude. This toxic effect was not detected in the monkey. CONCLUSIONS: The device produces sustained intravitreal levels of cyclosporine. Although it was associated with reversible toxic effects in the rabbit, it was well tolerated in primates. Sustained-release implants are a promising new treatment for chronic uveitis.

Animals↗
PubMed1996

Intravitreal delivery of ciprofloxacin.

The objective of this work was to evaluate various methods of sustained delivery to achieve therapeutic intravitreal levels of ciprofloxacin as a potential therapy for endophthalmitis. Two types of intravitreal bioerodible sustained release devices of ciprofloxacin were evaluated in vitro. The most promising device was evaluated in rabbits and results compared with subconjunctival injections of a ciprofloxacin suspension. Subconjunctival injections failed to deliver therapeutic concentrations of ciprofloxacin into either the aqueous or vitreous. In vivo evaluation of the intravitreal device consistently delivered ciprofloxacin at levels above 1 ug/ml for up to four weeks. No retinal activity was noted by clinical examination or by electroretinogram. Intravitreal implantation of bioerodible ciprofloxacin devices can maintain vitreous concentrations above 1 ug/ml, more than the MIC90 of most organisms associated with endophthalmitis. Implantation of these devices appears to be well tolerated and may represent a viable treatment for this disease. Further studies in endophthalmitis models are needed to evaluate device efficacy.

Animals↗
PubMed1996

An intravitreal device providing sustained release of cyclosporine and dexamethasone.

PURPOSE: A device that releases cyclosporine and dexamethasone into the eye for extended periods of time might be beneficial in diseases such as proliferative vitreoretinopathy and uveitis. In this study we examine the pharmacokinetics and toxicity of cyclosporine and dexamethasone combined in an intravitreal sustained-release device and the toxicity of a similar device containing only dexamethasone in rabbits. METHODS: Rabbits were divided into three groups for (1) evaluation of the drug tissue levels and device release kinetics following implantation of a device containing 100 micrograms of cyclosporine labeled with 2 microCi of 3H-cyclosporine and 2 mg of dexamethasone; (2) evaluation of the toxicity of this intravitreal device; and (3) evaluation of the toxicity of a similar device containing 2 mg of dexamethasone only. Cyclosporine was measured using a scintillation counter and dexamethasone was measured by high pressure liquid chromatography (HPLC). Toxicity was evaluated by electroretinography, clinical examination, and light microscopy. RESULTS: Vitreous concentrations of cyclosporine (+/- standard deviation) averaged 0.06 (+/- 0.02) microgram/ml over 10 weeks. The average dexamethasone concentration over the 10 week period was 2.9 (+/- 0.9) micrograms/ml. Devices containing cyclosporine and dexamethasone released each drug at rates similar to devices containing cyclosporine or dexamethasone alone. Devices containing both cyclosporine and dexamethasone caused reversible depressions in the b-wave amplitude of photopic and scotopic electroretinograms (ERG's). There was no evidence of toxicity associated with the devices containing dexamethasone only. There was no drug-related toxicity evident on clinical or histopathologic examination of eyes with devices containing the combination of cyclosporine and dexamethasone or dexamethasone alone. CONCLUSIONS: We conclude that the device maintains potentially therapeutic levels of both cyclosporine and dexamethasone in the vitreous. Reversible electroretinographic abnormalities are attributable to cyclosporine. A sustained-release device containing cyclosporine and dexamethasone may be useful for reducing inflammation in diseases such as proliferative vitreoretinopathy and uveitis.

Animals↗
PubMed1996

Intravitreal sustained release corticosteroid-5-fluoruracil conjugate in the treatment of experimental proliferative vitreoretinopathy.

PURPOSE: Proliferative vitreoretinopathy (PVR) remains the most common cause of failed retinal detachment (RD) surgery. The authors compared the effectiveness of two intraocular sustained-release codrugs in suppressing PVR in a rabbit model a surgically implantable pellet releasing 5-fluorouracil (FU) and dexamethasone (DX) for 1 week and an injectable intravitreal sustained-release suspension releasing 5-FU and triamcinolone acetonide for 1 month. METHODS: Sustained-release devices and suspensions were prepared to deliver equimolar quantities of corticosteroid and 5-FU. In group 1, devices were implanted surgically into the vitreous of the right eye of 10 New Zealand White rabbits. Ten control rabbits received surgical implantation of the suture only. In group 2, drug suspension was injected into the vitreous of the right eye of 10 New Zealand White rabbits. Ten control rabbits received injection of the vehicle only. One day later, each rabbit was injected intravitreally with 250,000 homologous rabbit dermal fibroblasts. Severity of PVR was graded clinically by two masked observers on days 3, 7, 10, 14, 21, and 28. RESULTS: In group 1, clinical severity of PVR was less in the experimental group than in the control group at all time points, this was only statistically significant on day 10 (P = 0.04). Six eyes developed moderate to severe tractional RD or bullous RD in the control group by day 10 compared with none in the experimental group (P = 0.01). In group 2, the median clinical grading of eyes in the experimental group was significantly less than that in the control group at all time points through day 21 (P < or = 0.01). CONCLUSIONS: Both the intravitreal sustained-release dexamethasone-5-FU device and the triamcinolone-5-FU suspension effectively inhibit the progression of PVR in a rabbit model. Simultaneous delivery of 5-FU and corticosteroid may target different components of the wound-healing process in this disease.

Animals↗
PubMed1995

Replacing ganciclovir implants.

PURPOSE: The authors report their surgical experience replacing empty ganciclovir implants in patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis. METHODS: A chart review of all patients receiving two or more ganciclovir implants was performed. RESULTS: Nine eyes in eight patients received two or more implants. The average time before a second implant was needed was 6 months. Cytomegalovirus retinitis was controlled in all patients except one. Three patients required intermittent intravenous exogenous anti-CMV therapy, one for persistent CMV retinitis and two for systemic CMV. Visual acuity of 20/40 or better was maintained in five of eight patients, despite a longstanding history of CMV retinitis. CONCLUSION: In this small series, most patients retained good vision after ganciclovir implant replacement.

AIDS-Related Opportunistic Infections↗
PubMed1995

The use of cervicography in the follow-up of cervical intraepithelial neoplasia treated by CO2 laser.

After treatment for cervical intraepithelial neoplasia (CIN) the follow-up of patients would be simplified if colposcopy could be safely omitted. A study of 50 patients was performed to determine the feasibility of such an approach. Cervical cytology, cervicography and colposcopy, with or without biopsy, was performed in each patient. From the results the following criteria for colposcopy were adopted: (a) patients thought to have CIN on cytology or cervicography, (b) inadequate cervicography picture (vagina covering cervix or poor quality photography), (c) high-risk factors present (immunosuppression, after cone biopsy, postmenopausal). In this study the number of colposcopies would have been reduced from 50 to 11 if these criteria were adopted. Cervical cytology combined with cervicography is a reasonable alternative to colposcopy and we feel this is a technique worth pursuing for the follow-up of patients treated for CIN.

Carbon Dioxide↗
PubMed1995

Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis.

PURPOSE: Uveitis often runs a chronic course requiring long-term therapy. Topical treatment results in poor intravitreal penetration, and systemic therapy is associated with significant side effects. The authors investigated whether an intravitreal sustained-release dexamethasone device was effective in the treatment of severe panuveitis in a rabbit model. METHODS: Twenty New Zealand white rabbits were immunized twice subcutaneously with 10 mg of Mycobacterium tuberculosis H37Ra antigen. Twelve days later, sustained-release dexamethasone devices were implanted into the vitreous of the right eye of 10 rabbits. Ten control rabbits received a sham device. One day later, rabbits were challenged with an intravitreal injection of 33 micrograms of antigen. Three animals in each group were sacrificed on post-challenge days 7 and 13 for aqueous white blood cell (WBC) count, protein determination, and histologic examination. To simulate chronic inflammation with exacerbations, the eight remaining eyes were rechallenged with intravitreal antigen on day 15 and were observed for 3 1/2 months. Inflammation was graded clinically by two masked observers. Retinal function was evaluated by electroretinography (ERG). Light microscopy was used to evaluate the eyes histopathologically. The amount of residual drug in the devices was measured on day 13 and at the end of the experiment. RESULTS: By all clinical criteria measured--anterior chamber cells, flare, and vitreous opacity--treated eyes had significantly less inflammation than untreated eyes (P < 0.05). Clinical examination correlated well with objective data. Both protein concentration (P < 0.05) and aqueous WBCs (P < 0.02) were approximately 10-fold higher, and ERGs were significantly depressed (P < 0.05) in untreated eyes compared to treated eyes. Histopathologic examination showed marked inflammation and tissue disorganization in the untreated compared to the treated eyes. After antigen rechallenge, inflammation in experimental eyes was still less than in control eyes. Late complications such as corneal neovascularization, cataract, and hypotony were also less in the treated eyes than in the untreated eyes. At the end of the experiment (99 days after device implantation), approximately 30% of drug remained in the devices. CONCLUSIONS: The intravitreal sustained-release dexamethasone device is highly effective in suppressing inflammation and preventing complications after two episodes of experimental uveitis in a rabbit model for at least 3 1/2 months. This device may be useful in the management of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy.

Animals↗
PubMed1994

Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. A randomized controlled clinical trial.

BACKGROUND AND METHODS: We performed a randomized controlled clinical trial to assess the safety and efficacy of a 1 microgram/h ganciclovir implant for the treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Patients with previously untreated peripheral CMV retinitis were randomly assigned either to immediate treatment with the ganciclovir implant or to deferred treatment. Standardized fundus photographs were taken at 2-week intervals and analyzed in a masked fashion. The study end point was progression of retinitis based on the photographic assessment. RESULTS: Twenty-six patients (30 eyes) were enrolled. The median time to progression of retinitis was 15 days in the deferred treatment group (n = 16) vs 226 days in the immediate treatment group (n = 14) (P < .00001, log-rank test). During the study, 39 primary implants and 12 exchange implants were placed in immediate-treatment eyes, deferred-treatment eyes that progressed, or contralateral eyes that developed CMV retinitis. Postoperative complications in the total series included seven late retinal detachments and one retinal tear without detachment. Final visual acuity was 20/25 or better in 34 of 39 eyes. The estimated risk of developing CMV retinitis in the fellow eye was 50% at 6 months. Biopsy-proven visceral CMV disease developed in eight (31%) of 26 patients. The median survival was 295 days. CONCLUSION: The ganciclovir implant is effective for the treatment of CMV retinitis. Patients with unilateral CMV retinitis treated with the implant are likely to develop CMV retinitis in the fellow eye, and some patients will develop visceral CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed1994

Review: implants.

An implantable sustained release device has been developed to treat chronic disorders of the eye. The device, consisting of a central core of drug encased in layers of permeable and impermeable polymers, can be implanted subconjunctivally or intravitreally. This technique was used to develop a ganciclovir device which, when implanted into the vitreous, maintains therapeutic vitreous levels of drug for 8 months. Initial studies in patients with cytomegalovirus (CMV) retinitis indicate that this treatment may offer better control of the disease and fewer side effects than existing therapies. Cyclosporine A devices were prepared for the treatment of uveitis. Early data suggests that these devices maintain therapeutic levels in the vitreous for approximately 3 years. Work on efficacy and toxicity is continuing. Although clinical applications of these devices are likely to be restricted to diseases requiring chronic drug therapy, they can be used to investigate optimal delivery rates. Subconjunctivally implanted devices releasing 5-FU for 12 days maintained filters in cynomolgus monkeys for 3 months. Similar devices maintained low intraocular pressure in 75% of high risk filter patients.

Animals↗
PubMed1994

Treatment of cytomegalovirus retinitis with intravitreal injection of liposome encapsulated ganciclovir in a patient with AIDS.

To study its safety and efficacy in treating cytomegalovirus (CMV) retinitis, an AIDS patient received an intravitreal injection of liposome encapsulated ganciclovir in the right eye. The left eye served as a control, receiving intravitreal free ganciclovir. The right eye showed no retinal haemorrhages or detachment; however, vision declined initially, stabilising later. Weekly examination showed neither progression of the CMV retinitis nor new lesions in the right eye. The left eye showed reactivation of old CMV retinitis. Liposome encapsulated ganciclovir reduced the number of intravitreal injections, stabilising CMV retinitis, and warrants further study.

AIDS-Related Opportunistic Infections↗
PubMed1993

Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir.

An experimental intravitreal sustained-release device containing ganciclovir was used to treat 22 patients with acquired immunodeficiency syndrome-associated cytomegalovirus retinitis. Fourteen eyes were excluded (five not involved and nine with macular scarring and/or severe debility). Thirty eyes received the ganciclovir intraocular device implant and were prospectively followed up from 16 to 419 days (median, 125 days). Twenty-seven (90%) of 30 eyes showed stabilization of the retinitis. Nine (33%) of 27 eyes showed reactivation of the retinitis once the device was empty of ganciclovir; seven received a replacement device, with subsequent stabilization of the retinitis. Postoperative complications included vitreous hemorrhage (n = 1), endophthalmitis (n = 1), and progressive retinitis (n = 2). Late retinal detachment was seen in three eyes (11%) at 35 to 140 days. Survival analysis of all 30 eyes revealed the mean time to progression of retinitis to be 19 weeks (133 days). The ganciclovir intraocular device offers a promising alternative for the treatment of cytomegalovirus retinitis associated with acquired immunodeficiency syndrome.

AIDS-Related Opportunistic Infections↗
PubMed1993

Clearance and distribution of ciprofloxacin after intravitreal injection.

This study was designed to determine the drug concentration and clearance after intravitreal injection of ciprofloxacin. Ciprofloxacin (100 micrograms/0.1 cc) was injected into the vitreous of normal eyes and into eyes that had undergone lensectomy and vitrectomy. Drug concentration was determined using high-pressure liquid chromatography analysis 0.5, 2, 4, and 12 hours after injection. In normal eyes, the elimination half life was 2.2 hours with a distribution volume of 1.2 ml. In aphakic vitrectomized eyes, the half life was 1 hour and the distribution volume was 1.4 ml. The majority of the drug appears to leave via a transretinal route, but clearance was not inhibited by probenecid. Because of the relatively short half life, intravitreal administration of ciprofloxacin for the treatment of endophthalmitis would provide only short-term therapy and would need to be supplemented by other forms of treatment.

Animals↗
PubMed1992

Sustained-release ganciclovir therapy for treatment of cytomegalovirus retinitis. Use of an intravitreal device.

A surgically implantable device for sustained intravitreal release of ganciclovir has been developed. The device delivers ganciclovir intraocularly over approximately 4 to 5 months. Eight patients with acquired immunodeficiency syndrome (AIDS) and associated cytomegalovirus (CMV) retinitis were recruited as part of a phase 1 study. Thirteen eyes with active CMV retinitis underwent surgical implantation of the ganciclovir device. All eyes showed resolution of the CMV retinitis; none showed progression. Visual acuity remained unchanged in three eyes, improved in six eyes, and decreased in four eyes. Surgical complications included mild vitreous hemorrhage, astigmatism, and suprachoroidal placement of the device. Retinal detachment occurred in three eyes as the retinitis resolved. This new intraocular drug delivery system offers many advantages compared with intravenous therapy or repeated intravitreal ganciclovir injections for the management of CMV retinitis in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Intravitreal sustained-release ganciclovir.

Current treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome involves frequent intravenous administration of sodium ganciclovir that often results in unacceptable side effects. We have developed devices that release ganciclovir at rates of 2 micrograms/h and 5 micrograms/h in vitro. When implanted into the vitreous of rabbit eyes, mean intravitreal ganciclovir levels of 9 mg/L and 16 mg/L were maintained for more than 80 and 42 days, respectively. Devices were well tolerated, with no toxic effects attributable to the polymers used in the devices. This investigation indicates that these devices can maintain therapeutic levels of drug for extended periods and are well tolerated in the rabbit eye. They may prove useful in the clinical management of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.

Animals↗
PubMed1992

Intravitreal ganciclovir pharmacokinetics in rabbits and man.

Cytomegalovirus (CMV) retinitis occurs in immunocompromised patients and can be treated by repeated intravenous or intravitreal injections of ganciclovir (GCV) or foscarnet. Due to toxicity and complications these modalities are not ideal. The development of alternative administration routes is hindered by a lack of pharmacokinetic data. Devices giving pseudo zero order release of GCV were implanted intravitreally first in rabbits and then in patients with AIDS associated CMV retinitis as part of a Phase I clinical trial. Steady state intravitreal GCV levels were obtained immediately after death and the elimination rate constants were calculated assuming first order pharmacokinetics. Normalizing for retinal surface area, distribution volume and anatomic volume, the retinal elimination rate constants were calculated. These were found to be 0.017 cm-2hr-1 in rabbits and 0.015 cm-2hr-1 in man. This indicates that the rabbit eye is a good model for studying intravitreal pharmacokinetics of ganciclovir and suggests a common elimination mechanism which may be trans-retinal.

Animals↗