Administration of all-trans retinoic acid through enteral tubes in acute promyelocytic leukemia: the handling of cytotoxic agents and clinical benefits

Okumura, Lucas Miyake; Okumura, Patricia Carvalho Baruel; Veroneze, Cleni

doi:10.1016/j.bjhh.2016.11.001

Cited by 7 publications

(5 citation statements)

References 7 publications

(18 reference statements)

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“…ATRA is thought to be important for neurogenesis, carcinogenesis, craniofacial morphogenesis, the formation of body axis and limbs, and the development of the lung, kidney, and eyes [ 33 , 34 , 35 , 36 , 37 ]. ATRA has been therapeutically used to treat acute promyelocytic leukemia [ 38 ], acne [ 39 ], and aging skin [ 40 ]. Additionally, studies are beginning to show that ATRA can modulate mitochondria.…”

Section: Introductionmentioning

confidence: 99%

All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Chidipi

Shah

Reiser

et al. 2021

Cells

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In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

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Section: Introductionmentioning

confidence: 99%

All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Chidipi

Shah

Reiser

et al. 2021

Cells

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“…Our tretinoin slurry preparation was based on a previously reported suspension from Okumura et al. 15 Key differences between the two preparations include our specific ratio of sterile water and mineral oil per capsule and a lower warming temperature. Our rationale for the smaller ratio of tretinoin capsules to sterile water and mineral oil compared to Okumura et al was to create a volume that could be easily administered by our nursing staff.…”

Section: Discussionmentioning

confidence: 99%

Extemporaneous compounding and administration of tretinoin slurry for acute promyelocytic leukemia

Przybylski

Jared

Fallon

2021

J Oncol Pharm Pract

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Introduction Acute promyelocytic leukemia (APL) is a potentially curable malignancy with 4-year overall survival rates >90%. Early complications from the disease or its treatment may result in a loss of oral access and require alternative administration of medications. Tretinoin has been the backbone of APL therapy since the late 1990s and is only available as a liquid filled capsule. Case report Two patients with high-risk APL were unable to safely swallow tretinoin capsules due to complications of their disease. Management & outcome We prepared a tretinoin slurry using tretinoin 10 mg capsules, sterile water, and mineral oil at a ratio of 1 capsule to 2.75 mL sterile water to 1.25 mL mineral oil. This was successfully administered to both patients and no doses of tretinoin slurry were missed by either patient. In the patient who has long-term follow up available, a complete remission was achieved. Discussion Due to tretinoin’s known teratogenicity, this capsule should not be crushed, cut, or open, which limits its use in patients without oral access. Alternative routes of administration, such as via a nasogastric tube or sublingually, have not been safe and effective. By preparing a tretinoin slurry in our hazardous extemporaneous compounding area, we were able to safely and effectively prepare a tretinoin slurry that was successfully administered to two patients. This alternative preparation did not alter long-term outcomes and represents a viable option for patients who do not have oral access.

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“…The preparation method for the liquid oral suspension used in this study is in accordance with that described by Okumura et al 10 . This form of preparation minimizes contact with the medication, aiming for occupational protection and optimizing the migration of the active ingredient to the oil phase, as well as being easily manipulated using low-cost and easily accessible materials.…”

Section: Rbfhssmentioning

confidence: 99%

“…Handling is recommended in a controlled environment to avoid occupational exposure, since the medication has teratogenic potential 8 . There are several preparation methods published in the literature, using the following vehicles: distilled water, milk, medium-chain triglycerides (MCT), water/mineral oil and oil, as well as the recommendation to aspirate the contents of the capsule [9][10][11] . Of particular interest is the preparation with water/mineral oil, since the water is added to break up the soft gel capsules and the mineral oil acts as a lipophilic vehicle for the ATRA, according to the method described by Okumura et al 10 .…”

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confidence: 99%

“…There are several preparation methods published in the literature, using the following vehicles: distilled water, milk, medium-chain triglycerides (MCT), water/mineral oil and oil, as well as the recommendation to aspirate the contents of the capsule [9][10][11] . Of particular interest is the preparation with water/mineral oil, since the water is added to break up the soft gel capsules and the mineral oil acts as a lipophilic vehicle for the ATRA, according to the method described by Okumura et al 10 . However, there are no studies on the stability of the adapted pharmaceutical form, which is extremely important since ATRA is sensitive to light, heat, and oxygen, especially when it is in solution 12 .…”

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confidence: 99%

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Estudo de estabilidade físico-química de preparação extemporânea líquida à base de tretinoína para administração via sonda

COELHO,

VEIGA,

DE SOUZA

et al. 2024

Rev Bras Farm Hosp Serv Saude

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Objetivo: O estudo visou investigar o teor e a estabilidade físico-química da formulação oral líquida obtida a partir de cápsulas gelatinosas moles de tretinoína (ATRA) no veículo óleo/água, visto a demanda desta formulação para pacientes entubados em tratamento de leucemia promielocítica aguda. Métodos: As análises foram realizadas por Cromatografia Líquida de Alta Eficiência (CLAE) acoplada a detector UV, utilizando coluna C-18. A corrida foi executada com fase móvel composta por água ultrapura com ácido acético glacial 0,5% (v/v) como solvente A e acetonitrila como solvente B, em corrida isocrática (25:75) (A/B), com fluxo de 1 mL/min, temperatura de 30°C e detecção em 355 nm. A injeção da amostra foi de 10 μL e o tempo de corrida foi de 12 min. As formulações orais foram preparadas a partir de ATRA (Vesanoid, FQM) em óleo mineral/água ultrapura (3:7) (v/v), por processo de dissolução e aquecimento a 40ºC, em dosadores orais protegidos da luz e conservadas sob refrigeração (2 - 8°C). As análises foram realizadas nos dias 1, 2, 3, 7, 9 e 14. Resultados: A preparação extemporânea apresentou estabilidade física visual aceitável, com alteração de aspecto pelo enrijecimento da fase aquosa corrigida com aquecimento da formulação em banho-maria a 40°C. O teor de ATRA foi considerado adequado até o D3, conforme a Farmacopeia Brasileira (FB) 6ª edição, apresentando 103,3%, 94,8% e 95,6%, nos dias 1, 2 e 3, respectivamente. A concentração de isotretinoína, produto de degradação, variou de 0,16% a 1,44%, entre os dias 1 e 14, respectivamente. Conclusão: Os resultados sugeriram que a preparação oral líquida apresentou teor satisfatório e estabilidade físico-química por até 48 horas após o preparo, quando conservada protegida da luz e sob refrigeração, conforme preconizado pela RDC 67/2007.

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Administration of all-trans retinoic acid through enteral tubes in acute promyelocytic leukemia: the handling of cytotoxic agents and clinical benefits

Cited by 7 publications

References 7 publications

All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Extemporaneous compounding and administration of tretinoin slurry for acute promyelocytic leukemia

Estudo de estabilidade físico-química de preparação extemporânea líquida à base de tretinoína para administração via sonda

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