Stability of Melphalan Solution for Intravitreal Injection for Retinoblastoma

Buitrago, Emiliano; Lagomarsino, Eduardo; Mato, Gabriel; Schaiquevich, Paula

doi:10.1001/jamaophthalmol.2014.2324

Cited by 18 publications

(11 citation statements)

References 4 publications

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“…Its quick degradation corresponds to the spontaneous hydrolysis to monohydroximelphalan and dihydroximelphalan. 28…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, melphalan (0.3 mg/ml) in a 0.9% sodium chloride solution was stable for up to 3 h at 4°C and for 2 h at room temperature without light protection. 28 Even so, there was a possible degradation of 10%, in addition the cold precipitation of melphalan is not mentioned. 29 The stability increased with a 3% sodium chloride solution.…”

Section: Resultsmentioning

confidence: 99%

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Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol

Solana-Altabella¹,

Valero²,

Balaguer³

et al. 2020

J Oncol Pharm Pract

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Retinoblastoma is the most common paediatric ocular tumour, which appears in the retina. Without treatment, retinoblastoma grows and destroys the internal ocular globe architecture, even leading to metastasis. When treated, overall survival is close to 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localised treatment. The aim of this study is to describe the implementation of a new intravitreal chemotherapy retinoblastoma treatment protocol for children implanting vitreous seeds through intravitreal melphalan injections and to evaluate the patients' health outcomes treated with it. Between December 2014 and July 2018, seven patients were treated with this protocol. They received a mean of 3.3 cycles of intravitreal melphalan with standard doses of 30 mcg per cycle. In the seven eyes treated in our hospital, the response was as expected; three eyes with vitreous seedings (43%) were successfully treated. The main adverse effects presented by all patients were scars at cryogenisation points. In two patients, the appearance of 'salt and pepper' retinopathy was reported. Oncology pharmacists, as part of the treatment team, can provide information about recommended doses, expected adverse effects, stability of preparations, most appropriate method of processing, packaging, and methods of drug administration, to ensure efficacy and especially safety in the administration of these drugs.

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“…Its quick degradation corresponds to the spontaneous hydrolysis to monohydroximelphalan and dihydroximelphalan. 28…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol

Solana-Altabella¹,

Valero²,

Balaguer³

et al. 2020

J Oncol Pharm Pract

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“…Due to melphalan's relative insolubility, it is known that melphalan begins to come out of solution after an hour. 36 The ease and speed with which intra-arterial microcatheters could be positioned, vascular anatomy explored, and the dominant ophthalmic artery selectively catheterized in our model in our hands allowed multiple rabbits to be treated within this 1-hour window (up to four rabbits within the hour). Another difference is that rabbits are merangiotic, with the retinal vessels lying immediately above the surface of the retina, rather than under the internal limiting membrane as is the case in humans.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma

Daniels

Froehler

Pierce

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeCurrent intra-arterial chemotherapy (IAC) drug regimens for retinoblastoma have ocular and vascular toxicities. No small-animal model of IAC exists to test drug efficacy and toxicity in vivo for IAC drug discovery. The purpose of this study was to develop a small-animal model of IAC and to analyze the ocular tissue penetration, distribution, pharmacokinetics, and treatment efficacy.MethodsFollowing selective ophthalmic artery (OA) catheterization, melphalan (0.4 to 1.2 mg/kg) was injected. For pharmacokinetic studies, rabbits were euthanized at 0.5, 1, 2, 4, or 6 hours following intra-OA infusion. Drug levels were determined in vitreous, retina, and blood by liquid chromatography tandem mass spectrometry. To assess toxicity, angiograms, photography, fluorescein angiography, and histopathology were performed. For in situ tissue drug distribution, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was performed. The tumor model was created by combined subretinal/intravitreal injection of human WERI-Rb1 retinoblastoma cells; the tumor was treated in vivo with intra-arterial melphalan or saline; and induction of tumor death was measured by cleaved caspase-3 activity.ResultsOA was selectively catheterized for 79 of 79 (100%) eyes in 47 of 47 (100%) rabbits, and melphalan was delivered successfully in 31 of 31 (100%) eyes, without evidence of vascular occlusion or retinal damage. For treated eyes, maximum concentration (Cmax) in the retina was 4.95 μM and area under the curve (AUC0→∞) was 5.26 μM·h. Treated eye vitreous Cmax was 2.24 μM and AUC0→∞ was 4.19 μM·h. Vitreous Cmax for the treated eye was >100-fold higher than for the untreated eye (P = 0.01), and AUC0→∞ was ∼50-fold higher (P = 0.01). Histology-directed MALDI-IMS revealed highest drug localization within the retina. Peripheral blood Cmax was 1.04 μM and AUC0→∞ was 2.07 μM·h. Combined subretinal/intravitreal injection of human retinoblastoma cells led to intra-retinal tumors and subretinal/vitreous seeds, which could be effectively killed in vivo with intra-arterial melphalan.ConclusionsThis first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.

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“…[7][8][9][10][11] Sterile saline is used to prepare melphalan, and it is unlikely that this vehicle agent provides retinal toxicity. 12 Dose-dependent retinal toxicity has been described in animal models using electroretinograms (ERGs) and histological evaluation.…”

Section: F I G U R Ementioning

confidence: 99%

Cystoid macular edema following intravitreal chemotherapy treatment for retinoblastoma

Panthagani

Montecinos

López

et al. 2020

Pediatric Blood & Cancer

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Stability of Melphalan Solution for Intravitreal Injection for Retinoblastoma

Cited by 18 publications

References 4 publications

Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol

Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol

Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma

Cystoid macular edema following intravitreal chemotherapy treatment for retinoblastoma

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