RESUMEN
PURPOSE: To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis. METHODS: HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes. The antiviral activity was assessed by DNA reduction in vitro, and intraocular safety was assessed by ophthalmoscopy, electrophysiology, and histology after intravitreal injections, with resultant intravitreal concentrations of 0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by simultaneous intravitreal injection of HDP-P-GCV and herpes simplex virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at various times before HSV-1 intravitreal inoculation. Retinitis was scored with ophthalmoscopy and compared with controls. RESULTS: In vitro, the IC50 of HDP-P-GCV against HSV-1 and human cytomegalovirus (HCMV) infected cells was 0.02 and 0.6 microM, respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and maintained a good vitreous clarity at all doses except 2 mM final intravitreal concentration. Although cataracts were observed in some eyes at the higher doses, they were not observed in eyes with 0.2 mM final intravitreal concentration. No other indications of ocular toxicity were observed. Intravitreal injection of HDP-P-GCV with resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis rabbit model demonstrated a complete protection of the retina with the simultaneous treatment strategy and a 4 (P = 0.03) to 6-(P = 0.058) week significant protection of retina with the pretreatment strategies when compared with ganciclovir or blank liposome controls. CONCLUSIONS: In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting intravitreal injectable anti-CMV or anti-HSV compound. This self-assembling liposome system could be applicable for many compounds available for intraocular diseases.
Asunto(s)
Antivirales/administración & dosificación , Infecciones Virales del Ojo/prevención & control , Ganciclovir/análogos & derivados , Herpes Simple/prevención & control , Herpesvirus Humano 1/efectos de los fármacos , Profármacos/administración & dosificación , Retinitis/prevención & control , Cuerpo Vítreo/efectos de los fármacos , Animales , Antígenos Virales/análisis , Antivirales/síntesis química , Antivirales/toxicidad , Células Cultivadas , Citomegalovirus/efectos de los fármacos , Citomegalovirus/fisiología , Portadores de Fármacos , Evaluación Preclínica de Medicamentos , Electrorretinografía , Infecciones Virales del Ojo/patología , Infecciones Virales del Ojo/virología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/virología , Ganciclovir/administración & dosificación , Ganciclovir/síntesis química , Ganciclovir/toxicidad , Herpes Simple/patología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Inyecciones , Liposomas , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/virología , Oftalmoscopía , Profármacos/síntesis química , Profármacos/toxicidad , Conejos , Retinitis/patología , Retinitis/virologíaRESUMEN
PURPOSE: To evaluate the clinical treatment efficacy of a long-lasting intravitreous injectable anti-cytomegalovirus (CMV) liposomal drug, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA). METHODS: Sixty-four pigmented rabbits were used for evaluation of the potency and duration of action of ODG-PFA after intravitreal injection using a herpes simplex virus (HSV)-1 retinitis model. For the potency evaluation, liposomal ODG-PFA was injected into rabbit vitreous at the same time that HSV-1 virus was inoculated onto the retina (simultaneous treatment). For the duration evaluation, ODG-PFA was injected days or weeks before inoculation (pretreatment). Retinitis was clinically graded by indirect ophthalmoscopy, and the retinitis scores were compared across the treatment and control groups. RESULTS: Simultaneous treatment study revealed that ODG-PFA was much more potent than its parent compound, foscarnet (P = 0.0027). Pretreatment study indicated that ODG-PFA possesses a much longer antiviral effect (at least 2 weeks) than foscarnet after a single intravitreal injection. CONCLUSION: Liposomal ODG-PFA is a potent long-lasting intravitreal injectable antiviral compound that may be an ideal alternative for treatment of CMV retinitis in patients with acquired immunodeficiency syndrome.
Asunto(s)
Antivirales/administración & dosificación , Infecciones Virales del Ojo , Foscarnet/análogos & derivados , Herpes Simple/tratamiento farmacológico , Éteres Fosfolípidos/administración & dosificación , Retinitis/tratamiento farmacológico , Animales , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Portadores de Fármacos , Infecciones Virales del Ojo/tratamiento farmacológico , Infecciones Virales del Ojo/patología , Infecciones Virales del Ojo/virología , Estudios de Seguimiento , Foscarnet/administración & dosificación , Herpes Simple/patología , Herpes Simple/virología , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 1/patogenicidad , Liposomas , Conejos , Retina/patología , Retina/virología , Retinitis/patología , Retinitis/virología , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the intraocular distribution and metabolism of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA), following intravitreal administration. METHODS: Twenty rabbits received ODG-[14C]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal concentration. Two animals per group were sacrificed at different intervals post-injection. The drug levels in ocular tissues were determined with counting the radioactivity by Tracor Mark III Liquid Scintillation Counter. Four rabbits were used for analysis of the drug metabolism in vitreous by lipid extraction technique. RESULTS: The drug level in vitreous was 526 microM at day one and 227 microM at the fifth week. The vitreous half life was approximately four to five weeks. The retinal level of the drug was 292 microM at day one, 75 microM at the fifth week and 32 microM at the tenth week, which was still more than ten times higher than the IC90 against HCMV. Lipid extraction analysis showed that, in vivo, both ODG-PFA and PFA were present in vitreous, but in in vitro incubations with vitreous, ODG-PFA conversion to PFA was negligible. CONCLUSION: ODG-PFA possesses a long vitreous half life and sustained high drug level in retina. The vitreous did not metabolize drug but acted as a drug reservoir. Intravitreal liposomal ODG-PFA may be expected to be a long acting potent local therapy for CMV retinitis.