Intravitreal pharmacokinetics and retinal concentrations of ganciclovir and foscarnet after intravitreal administration in rabbits

PURPOSE: To perform a detailed pharmacokinetic study and to evaluate the drug levels reached in the retina after the intravitreal administration of ganciclovir and foscarnet to rabbits. METHODS: Retinal and vitreal levels of both drugs were measured by high-performance liquid chromatography at 1, 6, 12, 24, 36, 48, 60, and 72 hours after a single intravitreal injection of 196 microg and 800 microg of ganciclovir and 960 microg of foscarnet to three groups of 24 pigmented rabbits. A noncompartmental pharmacokinetic analysis was used. RESULTS: Both drugs incorporated rapidly into the retina, but no equilibrium was observed between the drug levels in the vitreous humor and retina. Mean ganciclovir levels in vitreous and retina were 179.6 microg/g and 131.3 microg/g (dose of 196 microg), 755.7 microg/g and 381.6 microg/g (dose of 800 microg) at 1 hour after administration, decreasing to 0.1 microg/g, 0.6 microg/g, 0.8 microg/g, and 0.7 microg/g, respectively, by 72 hours. Mean foscarnet levels in vitreous and retina were 944 microg/g and 217.1 microg/g at 1 hour after administration, decreasing to 74 microg/g and 17.1 microg/g, respectively, by 72 hours. Whereas both doses of ganciclovir yielded retinal levels above the mean inhibitory concentration (IC50) of most human cytomegalovirus (CMV) isolates for more than 60 hours, foscarnet retinal levels were lower than the CMV IC50 before 36 hours had elapsed after administration. CONCLUSIONS: The results suggest that the intravitreal administration of ganciclovir has a better pharmacokinetic profile than foscarnet for the treatment of retinitis caused by CMV and other herpes viruses and support the administration of intravitreal ganciclovir twice a week as a treatment for CMV retinitis.     

Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.

PURPOSE: To determine intraocular toxicity and efficacy of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long-acting, nontoxic intravitreous injectable drug delivery system for cytomegalovirus (CMV) retinitis. METHODS: ODG-PFA was synthesized by coupling the phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and formulated as micelles and liposomes at concentrations so that, after injection into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM, 0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63 mM for liposomal formulation. The compounds were injected, and toxicology evaluations were performed. RESULTS: Intravitreal injections of micellar ODG-PFA resulted in aggregation of the material in vitreous and variable local retinal damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion of the compounds and a clear vitreous, using final concentration in the vitreous of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was 0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal injection was estimated to be 1470:1. CONCLUSIONS: Lipid-derivatized foscarnet liposome formulations may be a useful long-acting delivery system for the therapy of CMV retinitis.     

Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits

The ocular toxicity of liposome-intercalated amphotericin B and commercial amphotericin B were compared after intravitreal injection in healthy pigmented rabbits. Ophthalmoscopic observations over 5 weeks following a single intravitreal injection showed vitreal band formation and focal retinal damage after doses of commercial amphotericin B as low as 5 micrograms. Such lesions were not seen in animals given liposomal amphotericin B in doses up to 20 micrograms. Histopathologic examination showed areas of retinal atrophy or necrosis in five of 16 rabbits given commercial amphotericin B in doses of 5-20 micrograms but in none of 16 rabbits given the same doses of liposomal amphotericin B (P = 0.02). Small white vitreal bodies were seen clinically in virtually all animals given liposomal amphotericin B or "empty" (drug-free) liposomes but in only a few animals given commercial amphotericin B; these deposits may represent residual lipid. Concentrations of amphotericin B ranged from 0.4 to 1.0 micrograms per ml of vitreous humor 5 weeks after injection of 5-20 micrograms of either formulation. These studies indicate that liposome association markedly reduces the ocular toxicity of amphotericin B.     

Intravitreal delivery of oligonucleotides by sterically stabilized liposomes.

PURPOSE: The efficacy of sterically stabilized liposomes for delivering a model phosphodiester oligonucleotide intravitreally was investigated in the rabbit. METHODS: Ocular distribution and clearance from the vitreous humor of a model 16-mer oligothymidylate (pdT16) were evaluated in the rabbit by radioactivity measurements after intravitreal injection of either a solution or liposomes containing the [33P]pdT16 oligonucleotide. The integrity of pdT16 was investigated using a competitive hybridization assay. RESULTS: The residual concentration of the [33P]pdT16 oligonucleotide within the ocular tissues was significantly increased after intravitreal administration of the liposomal suspension compared with a simple solution. Administration of liposome-encapsulated pdT16 oligonucleotide resulted in sustained release into the vitreous and the retina-choroid compared with release from the solution and in a reduced distribution to nontarget tissues (sclera, lens). In addition, liposomes protected the phosphodiester oligonucleotide against degradation. This was not observed after administration of the free oligonucleotide. CONCLUSIONS: The intravitreal injection of a phosphodiester oligonucleotide encapsulated within liposomes is a new way of delivering intact oligonucleotide to the eye in a controlled manner. This offers interesting prospects for the treatment of retinal diseases.     

Treatment of herpes retinitis in an animal model with a sustained delivery antiviral drug, liposomal 1-O-octadecyl-SN-glycerol-3-phosphonoformate.

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.     

Intravitreal pharmacokinetics in rabbits of the foscarnet lipid prodrug: 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA).

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.     

Intravitreal toxicology and therapeutic efficacy of the carboxymethyl ester of the 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a novel lipid antiviral prodrug for intraocular drug delivery.

This study was conducted to evaluate the vitreous clarity and intraocular therapeutic index of three preparations ofthe carboxymethyl ester of 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zealand white rabbits were intravitreally injected with one of three preparations of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intraocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injection of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitreal compound aggregates in eyes with the middle and high doses. The intraocular therapeutic index was lower than 465:1. Intravitreal injection of liposomal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final intravitreal concentrations. No retinal toxicity was confirmed for the 1.12 mM final intravitreal concentration at the eight week observation following injection. The intraocular therapeutic index was between 585-1037:1. ODG-PFA-O-Me possesses better vitreous compatibility than ODG-PFA. Liposomal ODG-PFA-O-Me can be intravitreally injected with a resulting clear vitreous and high intraocular therapeutic index. Liposomal ODG-PFA-O-Me could be a long acting nontoxic intravitreous injectable drug for CMV retinitis.     

Effect of size and lipid composition on the pharmacokinetics of intravitreal liposomes

We investigated the influence of size and lipid composition on the pharmacokinetic behavior of liposomes and their contents in the rabbit eye. Small and large unilamellar vesicles (SUV and LUV), prepared with and without cholesterol in the membrane, were injected intravitreally in rabbits. The vesicles were labelled with 125I and contained 51Cr-EDTA in the aqueous compartment. The mode of elimination of the vesicles from the vitreous humor is uncertain but may be via the anterior route; 51Cr-EDTA, like gentamicin, probably is eliminated by the anterior route. The rate of clearance of the lipid label appeared to be related to the size but not to the cholesterol content of the liposomes. Liposome-encapsulation prolonged the half-life of 51Cr-EDTA by up to 11-fold in the vitreous humor of normal eyes. The prolongation was greatest with cholesterol-containing vesicles, presumably because these are most stable, and was somewhat greater with large than with small vesicles. For SUV and LUV, the rate of elimination of 51Cr-EDTA from the normal eye was determined mainly by the rate of leakage from the liposomes, whereas for SUV-cholesterol and LUV-cholesterol, it was determined mainly by the rate of clearance of the liposomes themselves. Both 51Cr-EDTA and liposomes (125I label) had a shorter half-life in infected than in normal eyes. Encapsulation of 51Cr-EDTA prolonged its half-life by up to sevenfold in infected eyes; the effect was greatest with cholesterol-containing vesicles. These results suggest that both the structure of the liposome and the state of the eye may markedly affect the pharmacokinetic behavior of intravitreal liposomes.     

Reducing chorioretinal viral counts with intravitreal foscarnet injections in a rabbit model of Herpes simplex virus type-1 retinitis.

The efficacy of intravitreal foscarnet injections was evaluated in a rabbit model of Herpes simplex virus type-1 (HSV-1) retinitis. In untreated infected animals, viral titration revealed that the optic chiasm, vitreous and chorioretina were positive for HSV-1. On the other hand, foscarnet treatment significantly decreased the viral count in the chorioretina when compared to the untreated group. Immunolocalization of HSV in untreated infected animals clearly showed infected cells in the outer and inner layers of the retina and also in the ciliary body of the eye. Clinical examination by indirect ophthalmoscopy indicated an absence of optic nerve congestion and a lower level of vitritis in foscarnet treated animals compared to the untreated group. It is concluded that intravitreal injections of foscarnet reduced the viral titer in the chorioretina in a rabbit model of HSV-1 retinitis. This route of administration might be valuable for the treatment of CMV retinitis in AIDS patients with sight threatening lesions or intolerance to intravenous anti-CMV drugs.     

万古霉素在正常兔眼和细菌性眼内炎兔眼内的药代动力学研究

背景万古霉素近年来常被作为金黄色葡萄球菌性眼内炎治疗的首选药物,万古霉素在眼内药代动力学的研究报道较少。目的观察万古霉素在正常兔眼和细菌性眼内炎兔眼房水、玻璃体及血清中质量浓度的变化,并进行药代动力学参数比较。方法选取健康成年兔72只,采用随机数字表法分为正常组和眼内炎组,每组36只。眼内炎组兔右眼玻璃体腔内接种2000CFU／ml金黄色葡萄球菌建立眼内炎模型,注射后72h待出现典型的眼内炎表现时,兔眼玻璃体腔内注射10g／L万古霉素注射液0．1ml,分别于注射后0．5、2、4、6、12、24、48、72、84h经兔耳缘静脉采血2ml,之后以空气栓塞法处死动物,摘除眼球,收集房水和玻璃体,利用高效液相色谱仪紫外（HPLC—UV）法检测万古霉素在血液、房水和玻璃体内的质量浓度。3p97药代动力学软件拟合药代动力学参数。结果HPLC法的准确度和精确度符合生物样品的检测要求。玻璃体腔内注射万古霉素后,其在正常兔眼内的代谢呈二室模型,拟合曲线的高峰质量浓度Cmax分别为50．16mg／L和751．42mg／L,t1/2为51．04h和53．21h;其在金黄色葡萄球菌性眼内炎兔眼中代谢呈一室模型,高峰质量浓度Cmax分别为24．94mg／L和687．66mg／L,t1/2分别为11．42h和12．91h,2组动物血药质量浓度均较低,差异无统计学意义（P〉0．05）。正常组和眼内炎组玻璃体腔内注射万古霉素后随时间延长,玻璃体中万古霉素的质量浓度逐渐下降,而房水中出现先升高后下降的趋势。与正常组相应时间点比较,眼内炎组玻璃体和房水中万古霉素的质量浓度均明显下降,差异均有统计学意义（P〈0．05,P〈0．01）。结论HPLC能满足万古霉素药代动力学分析的需要;万古霉素在正常兔眼内的质量浓度较高,清除缓慢,而在细菌性眼内炎兔眼中质量浓度较低、清除较快。     

Treatment of CMV retinitis with intravitreal foscarnet

PURPOSE: To assess the tolerability and efficacy of intravitreal injections of foscarnet in cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome (AIDS). METHODS: Patients with CMV retinitis resistant and/or intolerant to intravenous foscarnet and ganciclovir and resistant to intravitreal ganciclovir were included. The induction therapy consisted of intravitreal injections of 2,400 micrograms of foscarnet twice a week. The assessment was performed by clinical examination and photographies of the fundus. RESULTS: Three patients (four eyes) have been included. Three eyes were administered seven and one eye eight intravitreal injections. The tolerability was good, but the efficacy was mere: the retinal lesions became less edematous, but they still extended. CONCLUSION: In these four eyes with CMV retinitis resistant to intravitreal ganciclovir, intravitreal injections of foscarnet were well tolerated but did not stop the progression of the retinitis.     

Comparison of liposome-encapsulated acyclovir with acyclovir ointment: ocular pharmacokinetics in rabbits.

A positively charged liposomal formulation for topical administration of acyclovir (ACV) was investigated in comparison with a commercial ACV ointment, by determining the pharmacokinetic profile of the drug in the aqueous humor of rabbits after topical administration. The ointment was tested at two different strengths: undiluted (3.0%) and diluted to the same ACV concentration as the liposomal vehicle (0.12%). A liquid formulation containing ACV plus "empty" liposomes and an isotonic aqueous ACV solution were also tested. The applied ACV dose was 0.18 mg, except for the full-strength (3.0%) ointment, in which case it was 1.5 mg. The ACV liposomal dispersion (LIPO-ACV) produced a significantly higher drug concentration profile in the aqueous with respect the three reference formulations containing the same ACV concentration, and showed a 90-minute plateau. The aqueous humor ACV concentration maintained by LIPO-ACV during the plateau was in the upper range of the ID(50)s (0.01 to 0.7 microg/mL) reported for Herpes simplex type 1. In spite of the much higher dose (1.5 versus 0.18 mg), the area under curve (AUC) produced by the full-strength 3.0% ointment was only 1.6 times greater than that corresponding to the liposomal vehicle. In vitro release tests through a cellophane membrane substantiated the concept that positively charged liposomal formulations owe their efficacy to interactions with the positively charged corneal epithelium.     

Comparison of complications after Ahmed versus Baerveldt implant in glaucoma patients: one year follow-up

AIM: To compare surgical results of the Ahmed and Baerveldt implant procedures in glaucoma patients at 1y follow-up at Jakarta Eye Center (JEC) Eye Hospitals. METHODS: This cohort retrospective study was conducted on glaucoma patients aged ≥18y who had undergone Ahmed and Baerveldt implant surgery. Intraocular pressure (IOP), visual acuity, glaucoma medication, success rate, early and late postoperative complications, and the number of resurgeries were analyzed. RESULTS: A total of 351 eyes in the Ahmed group and 94 eyes in the Baerveldt group were included in this study. At 1y follow-up, the mean IOP was found to be significantly lower in the Baerveldt group (13±4.47 mm Hg) compared to the Ahmed group (15.02±5.73 mm Hg; P=0.025). Glaucoma medication was required in both the Ahmed and Baerveldt groups (58.92% vs 71.67%). Comparable success rate was found in both groups. The Ahmed group revealed a complete and qualified success of 86.82%, and failure of 13.17%. Similarly, the Baerveldt group showed complete and qualified success in 87.75% and failure in 12.25% cases. In the Ahmed group, 11.97% early complications, 26.06% late complications and 9.97% resurgeries were observed. In comparison, in the Baerveldt group, 23.40% early complications, 30.95% late complications and 11.70% resurgeries were observed. CONCLUSION: Both groups of glaucoma implants show significant IOP reduction, however, the Baerveldt implant group demonstrates greater IOP reduction with more failure rates and complications than the Ahmed implant group.     

Multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation

Background

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). Although much effort has been put into dealing with CMV retinitis secondary to acquired immunodeficiency syndrome (AIDS), the few reports which have been published have mainly focused on treatment of CMVR after HSCT.

Methods

This clinical interventional retrospective study included 14 patients (eight men; mean age 23.89?±?12.09; 23 eyes) who suffered from CMV retinitis after stem-cell transplantation, in order to evaluate the efficacy and safety of multiple intravitreal injections of ganciclovir (IVG) for patients with CMV retinitis. All patients received 4 injections of IVG of 1 mg at 1 week intervals, and were followed up weekly for at least 2 months with measurement of best-corrected visual acuity (BCVA) and CMV levels in anterior aqueous humor with real-time polymerase chain reaction. Anterior aqueous humor was obtained before each injection.

Results

The levels of CMV in anterior aqueous humor showed significant decrease from (6.34?±?15.78)?×?10⁵ copies/ml at baseline to (5.22?±?12.15)?×?10³ copies/ml at 1 month (P?<?0.001, Mann–Whitney U test). CMV couldn’t be detected in 11 eyes (47.8 %) after two injections, and this rose to 18 eyes (78.3 %) at 1 month. The mean logMAR BCVA was 0.659?±?0.572 at baseline and 0.680?±?0.527 at 2 months, which suggested no significant improvement (P?=?0.736, Mann–Whitney U test) during the procedure. All patients experienced improved vitreous opacity and diminished area of the lesion under funduscopy after 4 injections of IVG. No severe complications developed.

Conclusions

Multiple IVG seemed to be beneficial for patients with CMV retinitis after stem-cell transplantation, in reducing CMV levels in aqueous humor. Further study to optimize the dose of ganciclovir is needed in order to achieve better treatment outcomes.     

Detection of CMV DNA in the aqueous humor of AIDS patients with CMV retinitis by AMPLICOR CMV test

The present study was performed to detect the cytomegalovirus (CMV) DNA in the aqueous humor from the eyes of acquired immunodeficiency syndrome (AIDS) patients with CMV retinitis. Detection of CMV DNA in the aqueous humor in the eyes with active CMV retinitis was compared with detection of CMV DNA in inactive retinitis. CMV DNA in the aqueous humor was evaluated before and after treatment with intravitreal injection of ganciclovir. CMV DNA in the aqueous humor was measured by AMPLICOR CMV test. Forty-two eyes of 35 AIDS patients were diagnosed ophthalmoscopically as having CMV retinitis that was subclassified as either active or inactive. The active and inactive CMV retinitis cases were distinguished based on clinical evaluations and fundus photographs. The results showed that 37 of the 42 eyes (88.1%) were positive for CMV DNA prior to treatment, while in 29 of these 37 eyes (78.4%), the aqueous humor became CMV DNA-negative after the treatment. Successful treatment with the intravitreal injection of ganciclovir was associated with a reduction in the detection of CMV DNA in the aqueous humor. CMV DNA was not detected in the aqueous humor of patients with quies cent CMV retinitis. In conclusion, the AMPLICOR CMV test was found to be a reliable tool for differentiating active and inactive CMV retinitis, and is useful for helping to select the optimal treatment regimen. The intravitreal injection of ganciclovir is highly effective in reducing detectable CMV DNA in the aqueous humor.     

Clearance of intravitreal voriconazole

Purpose To investigate the elimination rate of voriconazole after intravitreal injection in rabbits. METHODS: Intravitreal injections of 35 microg/0.1 mL voriconazole were administered to rabbits. Vitreous and aqueous humor levels of voriconazole were determined at selected time intervals (1, 2, 4, 8, 16, 24, and 48 hours), and the in vitreous half-life was calculated. Four to six eyes per time point after injection were enucleated and immediately stored at -80 degrees C. Aqueous humor samples were withdrawn before enucleation, and vitreous samples were obtained from ocular dissection and isolation at various time intervals. Voriconazole concentrations in vitreous and aqueous humor were assayed with high-performance liquid chromatography (HPLC). RESULTS: The concentration of intravitreal voriconazole at various time points exhibited exponential decay with a half-life of 2.5 hours. The mean vitreous concentration was 18.912 +/- 2.058 microg/mL 1 hour after intravitreal injection; this declined to 0.292 +/- 0.090 microg/mL at 16 hours. The mean aqueous concentration was much lower and showed a decline from 0.240 +/- 0.051 microg/mL at 1 hour to undetectable levels 8 hours after injection. CONCLUSIONS: Vitreous concentrations achieved during the first 8 hours were greater than the previously reported minimum inhibitory concentrations (MICs) of organisms most involved in fungal endophthalmitis. A rapid decline of intravitreal concentration suggests that supplementation of intraocular voriconazole to maintain therapeutic levels may therefore be required in clinical settings. Further studies are needed to determine the elimination rate of voriconazole after intravitreal injection in humans.     

Intravitreal administration of antisense oligonucleotides: potential of liposomal delivery

Antisense oligonucleotides are short synthetic fragments of genes that are able to inhibit gene expression after being internalized by cells. They can therefore be used as antiviral compounds particularly, for the treatment of ocular viral infections (i.e. Herpes simplex virus or Cytomegalovirus, CMV). Antisense oligonucleotides are however poorly stable in biological fluids and their intracellular penetration is limited. Although oligonucleotides are now currently used in therapeutics for the treatment of CMV by intravitreal injection (Vitravene) their main drawbacks impose to repeat the number of administrations which can be very harmful and damaging. A system that is able to permit a protection of oligonucleotides against degradation and their slow delivery into the vitreous would be more favorable for improving patient compliance. The use of liposomes for intravitreal administration can be very promising since these lipid vesicles are able to protect oligonucleotides against degradation by nucleases and they allow to increase the retention time of many drugs in the vitreous. In this review, the potentialities of liposomes for the intravitreal delivery of oligonucleotides will be discussed.     

Pharmacokinetic behavior of intravitreal triamcinolone acetonide prepared by a hospital pharmacy

Purpose  We developed a new hospital pharmaceutical preparation of triamcinolone acetonide (TA) for intravitreal injections using sodium hyaluronate as the vehicle. The purpose of this study was to compare the pharmacokinetic behavior of this hospital pharmacy preparation of TA (HPP-TA) to that of a commercial preparation of TA (CP-TA) in rats. Methods  We injected the two preparations of TA into the vitreous humor of male Wistar rats. The rats were killed between days 1 and 21, and the concentration of TA in the vitreous was measured by high-performance liquid chromatography to determine the pharmacokinetic parameters. We also examined the microscopic appearance of the TA particles in these preparations. Results  The elimination half-life was 6.08 days for the CP-TA and 5.78 days for the HPP-TA. A two-compartment model was suitable to approximate the pharmacokinetic behavior of HPP-TA in the vitreous body, but this model was not suitable for CP-TA, because its pharmacokinetic behavior was not sufficiently stable. The particle size of CP-TA was largest, followed by TA powder and HPP-TA. Many particles were agglutinated in the CP-TA preparation, whereas the TA particles were fine and dispersed in the HPP-TA medium. Conclusions  The TA particle size and the suspension medium are likely important factors in the preparation of a safe and stable suspension of TA. HPP-TA satisfied these requirements and should be suitable for clinical use.     

Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits

AIM:To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form.METHODS:Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection.RESULTS:The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form.CONCLUSION: The result of this study shows the beneficial effects of PLGA in prolonging the residency of bevacizumab in the vitreous. And the drug delivery system may have potential as a treatment modality for related disease.     

2mg与3mg更昔洛韦玻璃体注射治疗AIDS患者巨细胞病毒性视网膜炎的效果比较

目的 比较玻璃体注射2 mg和3 mg更昔洛韦治疗获得性免疫缺陷综合征(AIDS)患者巨细胞病毒性视网膜炎(CMVR)的有效性和安全性.设计 前瞻性比较性病例系列.研究对象 2016-2020年北京地坛医院AIDS合并CMVR患者63例(86眼).方法 患者随机分为2 mg组(41眼)和3 mg组(45眼),在接受更昔...