Pharmacokinetics, Safety, and Efficacy of Intravitreal Digoxin in Preclinical Models for Retinoblastoma

Mandal

Drug Deliv. and Transl. Res.

et al. 2016

303

249

Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations.

Section: Pharmacokinetics Of Drugs Under Diseased Conditionsmentioning

confidence: 64%

A comprehensive insight on ocular pharmacokinetics

Mandal

Drug Deliv. and Transl. Res.

et al. 2016

303

249

Pharmacology Res & Perspec

“… 24 , 25 Moreover, a second chemotherapeutic agent is usually required to reduce the number of injections, and serve as an alternative in cases with intravitreal melphalan resistance. 19 Thiotepa , 26 Methotrexate , 27 Topotecan , 10 , 19 Etoposide , 2 Carboplatin , 18 , 28 and Digoxin 29 were evaluated as other intravitreal chemotherapeutics in retinoblastoma. Among these alternatives the in vivo safety studies on repeated intravitreal injection of Digoxin and Carboplatin, as available agents especially in developing countries, is limited.…”

Section: Introductionmentioning

confidence: 99%

“… 38 Only one study in the literature assessed the safety of a single intravitreal Digoxin injection in preclinical retinoblastoma models. 29 …”

Section: Introductionmentioning

confidence: 99%

“…In this experimental study, we intended to compare the ocular safety of repeated intravitreal injections of 1 µg Carboplatin and 10 µg Digoxin in healthy albino rabbits based on the previous studies. 29 , 31 We aimed to assess the possible toxicity of these drugs on the retina based on the electroretinography (ERG) findings as a functional test, as well as structural evaluations on histopathological specimens from enucleated eyes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Khodabande

Ghassemi

Amoli

et al. 2021

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.

“…However, chemotherapeutic drugs influence all cells in the body, not only cancer cells, inducing a series of detrimental complications such as appetite and hair loss, nausea, vomiting and sore mouth (8). Despite recent advances in local delivery strategies for chemotherapy, few agents have been incorporated into the chemotherapeutic armamentarium for RB treatment (9). Thus, the exploration of novel antitumor agents with reduced side-effects and enhanced therapeutic effects in RB patients are crucial and are urgently required.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the therapeutic effects of lobaplatin and carboplatin on retinoblastoma in vitro and in vivo

et al. 2020

Retinoblastoma (RB) is one of the most aggressive malignancies affecting infants and children. Platinum drugs are commonly used in the treatment of RB; however, their efficacy is often compromised by drug resistance and severe toxicity. The present study aimed to investigate and compare the toxicity and antitumor activity of the third-generation platinum drugs, carboplatin and lobaplatin, in vitro and in vivo. The Y79 RB cell line was treated with carboplatin or lobaplatin in vitro and then used to establish xenografts in immunodeficient nude mice in vivo; the effects of pharmacological doses of these drugs were then assessed. High concentrations of carboplatin and lobaplatin markedly inhibited Y79 RB cell proliferation in vitro. In addition, the lobaplatin group exhibited higher proportions of early-stage apoptotic cells than the carboplatin group, while no significant differences in the proportions of cells in the S phase were observed between the 2 groups, as shown by flow cytometry. Significant changes in the E2F1/Cdc25a/Cdk2 pathway in the RB cells were detected by RNA-seq following carboplatin or lobaplatin intervention. RT-qPCR, immunofluorescence and immunohistochemical analyses in vivo and in vitro demonstrated that the trends of drug-induced inhibition of tumor pathological changes may have been regulated through the E2F1/Cdc25a/Cdk2 pathway, and that lobaplatin was more effective than carboplatin in controlling tumors in vivo. On the whole, the findings of the present study demonstrate that lobaplatin is associated with lower cytotoxicity and exerts more prominent therapeutic effects than carboplatin on Y79 RB cells in vitro and in mice in vivo.