Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

1992 ◽  
Vol 10 (11) ◽  
pp. 1666-1673 ◽  
Author(s):  
M A Smith ◽  
P C Adamson ◽  
F M Balis ◽  
J Feusner ◽  
L Aronson ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Pediatric Patients ◽  
Day Treatment ◽  
Pseudotumor Cerebri ◽  
Pharmacokinetic Studies ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pediatric Cancer Patients

PURPOSE Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. PATIENTS AND METHODS A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. RESULTS The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. CONCLUSIONS The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

Enhanced Oral Absorption of All-trans Retinoic Acid upon Encapsulation in Solid Lipid Nanoparticles

2020 ◽  
Vol 8 (6) ◽  
pp. 495-510
Author(s):  
Manoj Kumar ◽  
Garima Sharma ◽  
Dinesh Singla ◽  
Sukhjeet Singh ◽  
Vandita Kakkar ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Side Effects ◽  
Solid Lipid Nanoparticles ◽  
In Vitro Release ◽  
Lipid Nanoparticles ◽  
Solid Lipid ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Vitro Release

Background:: All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs). Methods:: ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done. Results:: Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs. Conclusion:: Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components. Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

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

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1202
Author(s):  
Bojjibabu Chidipi ◽  
Syed Islamuddin Shah ◽  
Michelle Reiser ◽  
Manasa Kanithi ◽  
Amanda Garces ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mitochondrial Fission ◽  
Normal Function ◽  
Mitochondrial Network ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Area And Perimeter

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.

Differential regulation of GPI‐linked molecules on leukaemic promyelocytes treated in vitro with all‐ trans retinoic acid

1996 ◽  
Vol 93 (2) ◽  
pp. 392-393 ◽  
Author(s):  
R. DI NOTO ◽  
E. M. SCHIAVONE ◽  
C. LO PARDO ◽  
F. FERRARA ◽  
C. MANZO ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Differential Regulation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 46028-46041 ◽  
Author(s):  
Farzaneh Atashrazm ◽  
Ray M. Lowenthal ◽  
Joanne L. Dickinson ◽  
Adele F. Holloway ◽  
Gregory M. Woods
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Therapeutic Potential ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Outcome of Childhood Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid and Chemotherapy

2004 ◽  
Vol 22 (8) ◽  
pp. 1404-1412 ◽  
Author(s):  
S. de Botton ◽  
V. Coiteux ◽  
S. Chevret ◽  
C. Rayon ◽  
E. Vilmer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Survival Rates ◽  
Age Groups ◽  
Pseudotumor Cerebri ◽  
Promyelocytic Leukemia ◽  
Results Of Treatment ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Purpose To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). Patients and Methods Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. Results Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P = .02) and incidence of microgranular M3 variant (P = .04). Conclusion ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy

2015 ◽  
Vol 26 (7) ◽  
pp. 763-773
Author(s):  
Muhammad N. Aslam ◽  
Shannon McClintock ◽  
Shazli P. Khan ◽  
Patricia Perone ◽  
Ronald Allen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Growth ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Acid Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Myeloid Leukemia Cell

Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 835-845 ◽  
Author(s):  
K. Kawamura ◽  
K. Hara ◽  
S. Fujiwara
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Ectopic Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Proximal Extremity ◽  
Developmental Role

We have extracted retinoids from the budding tunicate Polyandrocarpa misakiensis and, using HPLC, identified some major peaks as cis-retinal, all-trans-retinal and all-trans-retinoic acid, of which cis-retinal was most abundant (~2 micromolar). In developing buds, the amount of cis-retinal was about one-fifth that of the adult animals. In those buds, aldehyde dehydrogenase, which could metabolize retinal in vitro, was expressed in epithelial cells and then in mesenchymal cells at the proximal extremity, that is, the future developmental field of the bud. Exogenous retinoic acid comparable to the endogenous level could induce an additional field at the distal end of the bud, resulting in a double monster. The induction always accompanied an ectopic expression of aldehyde dehydrogenase. The results of this work suggest that retinoic acid or related molecule(s) act as an endogenous trigger of morphallactic development of Polyandrocarpa buds.

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