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Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

ABSTRACT: To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups underwent three consecutive injections of the drugs with 1-week intervals. Baseline electroretinography (ERG) was recorded from both eyes of all the animals prior to injection and was repeated 1st day, 1st week, and 1st month after the last injection. All rabbits were sacrificed 1 month after the last injection, and histological studies were done. Mean a and b wave amplitudes decreased significantly at 1st day, 1st week, and 1st month after the last intravitreal injection of 10 µg Digoxin in comparison with other groups (p-value: .02). Contradictory, 1 µg Carboplatin injected eyes had minimal ERG changes. There were some nonspecific ERG changes with unclear clinical significance in non-injected contralateral control eyes of Digoxin and Carboplatin groups in comparison with the control eyes of the Saline group. Histological studies revealed considerable neural retinal atrophy in injected eyes of the Digoxin group. Intravitreal 10 µg Digoxin might have more local ocular toxicity in comparison with intravitreal Carboplatin in albino rabbit eyes. Future studies should assess the induced toxicity of intravitreal injection of these drugs on the non-injected contralateral eye.

SUBMITTER: Khodabande A

PROVIDER: S-EPMC8273607 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

Khodabande Alireza A Ghassemi Fariba F Asadi Amoli Fahimeh F Riazi-Esfahani Hamid H Mahmoudzadeh Raziyeh R Mehrpour Mohammad M Valipour Niloufar N

Pharmacology research & perspectives 20210801 4

To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups unde ...[more]

PMID: 34250764

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Project description:X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of intravitreal administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e(10) and 2e(11) vector genomes per eye (vg/eye), were tested and ocular inflammation was monitored over a 12-week period by serial ophthalmological and histopathological analysis. A mild ocular inflammatory reaction, consisting mainly of vitreous infiltrates, was observed within 4 weeks from injection, in both 2e(10) and 2e(11) vg/eye groups and was likely driven by the AAV8 capsid. At 12-week follow-up, ophthalmological examination revealed no clinical signs of vitreitis in either of the dose groups. However, while vitreous inflammatory infiltrate was significantly reduced in the 2e(10) vg/eye group at 12 weeks, some rabbits in the higher dose group still showed persistence of inflammatory cells, histologically. In conclusion, intravitreal administration of AAV8-scRS/IRBPhRS into the rabbit eye produces a mild and transient intraocular inflammation that resolves, at a 2e(10) vg/eye dose, within 3 months, and does not cause irreversible tissue damages. These data support the initiation of a clinical trial of intravitreal administration of AAV8-scRS/IRBPhRS in XLRS patients.

Project description:PurposeTo test the safety and preliminary efficacy of rapid, nonpharmacologic anesthesia via cooling for intravitreal injections.DesignSingle-center, randomized phase 1 dose-ranging safety study (ClinicalTrials.gov identifier, NCT02872012).ParticipantsAdults 18 years of age or older with a diagnosis of exudative macular degeneration or diabetic macular edema requiring bilateral anti-vascular endothelial growth factor therapy were included.MethodsA handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye before intravitreal treatment (IVT). In 22 patients undergoing bilateral IVT, 1 eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at 1 of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS; range, 1-10) at 2 time points: (1) immediately after IVT and (2) 4 hours after IVT. Treated eyes were assessed for ocular safety 24 hours after IVT.Main outcome measuresWe determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately after IVT and 4 hours after IVT in eyes receiving cooling anesthesia were compared with eyes receiving SOC.ResultsA total of 44 eyes were treated, 22 with cooling anesthesia and 22 with SOC. No dose-related toxicity was found with cooling anesthesia. Mild, transient adverse events were recorded in 32% of patients treated with cooling anesthesia versus 44% of patients receiving SOC. The mean±standard error of the mean (SEM) VAS pain scores immediately after intravitreal injection were 2.3 ± 0.4 for patients receiving SOC and 2.2 ± 0.6 in patients receiving -10° C cooling anesthesia (P = 0.8). Mean±SEM pain scores 4 hours after injection were 1.6 ± 0.4 for SOC and 1.2 ± 0.5 in the combined -10° C arms (P = 0.56). Total mean±SEM procedure time was 124 ± 5 seconds for patients treated with cooling anesthesia versus 395 ± 40 seconds for SOC (P < 0.0001).ConclusionsUltra-rapid cooling of the eye for anesthesia was well tolerated, with -10° C treatment resulting in comparable levels of anesthesia to SOC with a reduction in procedure time.

Dataset Information

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

Publications

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

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