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Biomedical subjects

P Ashton

Publications and source records attributed to P Ashton.

At least 19 recordsLinked to original sources
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

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↗
PubMed1992

A mechanistic study on the enhancement of corneal penetration of phenylephrine by flurbiprofen in the rabbit.

The effect of flurbiprofen on the corneal penetration of phenylephrine was investigated using isolated albino rabbit corneas mounted in the Ussing diffusion chamber. The corneal penetration of phenylephrine was increased 5-11 times by 4-16 mM flurbiprofen. Such an increase in the corneal penetration of phenylephrine by flurbiprofen appeared to correlate with the increase in the lipophilicity of phenylephrine by flurbiprofen due to ion pair formation. The magnitude of increase at 16 mM flurbiprofen was 2.4 times less than that afforded by 0.5% EDTA and 16.3 times less than that afforded by deepithelizing the cornea. Since flurbiprofen also increased the corneal penetration of benzoic acid and sorbitol with which it cannot form ion pairs, increased lipophilicity of phenylephrine due to ion pair formation with flurbiprofen was unlikely to be the only mechanism that enhanced corneal penetration. An additional mechanism under our experimental conditions of prolonged exposure of the cornea to the phenylephrine-flurbiprofen combination was lowering of the barrier function of the corneal epithelium by concentrations of flurbiprofen greater than that used therapeutically.

Animals↗
PubMed1992

Subconjunctival sustained release 5-fluorouracil.

The authors have developed a sustained release device for 5-fluorouracil (5-FU) made up of a 12 mg pellet of drug coated in a mixture of permeable and impermeable polymers. When implanted subconjunctivally in rabbits, these devices released 5-FU at approximately 1 mg/d for over 10 days. Devices were implanted into four cynomolgus monkey eyes after posterior lip sclerotomy. One eye (treatment) received a device that contained 12 mg 5-FU and the other eye (control) received a placebo device that contained no drug. In control eyes, intraocular pressures returned to normal within 1 wk. In treatment eyes, pressures remained significantly lower throughout the experimental period (3 mo). There was no indication of impaired wound healing, corneal toxicity, inflammation, or damage to the ciliary body in rabbits or monkeys.

Animals↗
PubMed1991

Formulation influence on conjunctival penetration of four beta blockers in the pigmented rabbit: a comparison with corneal penetration.

The objective of this study was to compare the influence of pH, tonicity, benzalkonium chloride, and EDTA on the conjunctival and corneal penetration of four beta blockers--atenolol, timolol, levobunolol, and betaxolol. Drug penetration was evaluated using the isolated pigmented rabbit conjunctiva and cornea in the modified Ussing chamber. The conjunctiva was more permeable than the cornea to all four beta blockers. Formulation changes caused larger changes in corneal than in conjunctival drug penetration, especially for the hydrophilic beta blockers, atenolol and timolol. Raising the solution pH to 8.4 caused the largest increase in corneal penetration for all drugs except atenolol. This increase was greater than that obtained by removing the corneal epithelium. The same formulation also increased conjunctival drug penetration, although to a lesser extent. In the case of timolol, the formulation changes evaluated brought about similar changes in its ocular and systemic absorption with good in vitro-in vivo correlations. The above findings indicate that in making formulation changes to maximize corneal drug penetration, it is necessary to evaluate possible changes in conjunctival drug penetration, hence systemic absorption. Moreover, because the conjunctiva plays an active role in the noncorneal route of ocular drug absorption, the relative contribution of the noncorneal to the corneal routes to ocular drug absorption may also be altered by formulation changes.

Animals↗
PubMed1991

Location of penetration and metabolic barriers to levobunolol in the corneal epithelium of the pigmented rabbit.

The objective of this study was to determine which of the five or six corneal epithelial layers was rate-limiting in the corneal penetration and metabolism of levobunolol in the pigmented rabbit. Corneal penetration and metabolism were evaluated using the isolated cornea in the modified Ussing chamber. Levobunolol and its metabolite, dihydrolevobunolol, were assayed by reversed phase high-performance liquid chromatography using spectrophotometric detection. EDTA (0.1 and 0.5%) and benzalkonium chloride (0.005-0.05%) were used to disrupt the integrity of the corneal epithelial layers. EDTA, which loosened the tight junctions between the superficial corneal epithelial cells, reduced both the transcorneal flux and metabolism of levobunolol. In contrast, benzalkonium chloride, which disrupted the integrity of the outermost corneal epithelial layers, enhanced the transcorneal levobunolol flux while reducing its extent of metabolism. The extent of enhancement in transcorneal flux afforded by 0.025% benzalkonium chloride was comparable to that seen in the deepithelized cornea. Within 5 min of contact by the corneal epithelium with this preservative, the ratio of dihydrolevobunolol concentration on the endothelial to the epithelial side was reduced by two-thirds. Although direct confirmation is required, the above findings are consistent with the hypothesis that the rate-limiting layer to corneal penetration of levobunolol resides in the outermost two to three layers of the corneal epithelium, whereas the metabolic barrier resides in deeper lying regions.

Animals↗
PubMed1990

Collagen shield delivery of trifluorothymidine.

Corneal and aqueous levels of topically applied trifluorothymidine (F3T) were compared with and without the collagen shield in normal and damaged rabbit eyes. Shields were presoaked in 1% F3T for 15 minutes prior to application. Rabbits received either a presoaked shield, 1% F3T drops every two hours, or both. Corneal and aqueous levels of F3T were measured at 30 minutes, two, four, and eight hours. If 5 mm epithelial defects were created, the collagen shield and topical F3T drops produced significantly higher levels of F3T than drops alone at all periods tested (P less than .05). A presoaked shield alone produced greater levels of F3T than drops alone at 30 minutes and two hours (P less than .05). Collagen shields did not enhance F3T levels in eyes with intact epithelium. Implications for treatment of herpetic keratouveitis are discussed.

Alcohols↗
PubMed1990

The effect of chlorhexidine acetate on the corneal penetration of sorbitol from an arnolol formulation in the albino rabbit.

The effect of chlorhexidine acetate on the corneal penetration of sorbitol was evaluated in vitro using the enucleated pigmented rabbit cornea mounted in a modified Ussing chamber. Sorbitol penetrated the cornea poorly when compared with arnolol, a beta blocker. Sorbitol penetration was improved 85% by 0.01% chlorhexidine acetate, 2.9 times by 0.1% EDTA, and 9.6 times by stripping the corneal epithelium prior to the start of the experiment. By comparison, 0.01% chlorhexidine acetate and stripping the corneal epithelium improved the corneal penetration of arnolol only 30% and 74%, respectively, whereas stripping the corneal epithelium did not affect the corneal penetration of chlorhexidine acetate. Collectively, the above findings indicate that changes in corneal integrity may dramatically affect the corneal penetration of some inert excipients in ophthalmic formulations. Such a possibility must be considered carefully in the selection of excipients.

Amino Alcohols↗
PubMed1989

A pilot study of three potential vaccines for leprosy in Bombay.

Three vaccines, BCG Glaxo alone (vaccine A), BCG Glaxo plus 10(7) killed Mycobacterium vaccae (vaccine B), and BCG Glaxo plus 10(7) killed M. leprae (vaccine C), were given to groups of selected children. The effects of these vaccines on subsequent quadruple skin testing 1-3 years after vaccination were compared. All three vaccines equally and significantly (p less than 0.00001) increased positivity to tuberculin, but only vaccine B was found to significantly enhance development of skin-test positivity to leprosin A (p less than 0.002). The data support the evidence previously obtained in rural Iran that the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone.

Adolescent↗