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Lancet (London, England) Mar 1969
Topics: Daunorubicin; Heart; Humans; Leukemia, Myeloid, Acute
PubMed: 4179532
DOI: 10.1016/s0140-6736(69)91516-5 -
Cancer Treatment Reports Jan 1986
Review
Topics: Aclarubicin; Anthraquinones; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Cell Survival; Daunorubicin; Doxorubicin; Drug Evaluation; Epirubicin; Heart; Humans; Idarubicin; Leukemia; Menogaril; Mitoxantrone; Naphthacenes; Nogalamycin; Sarcoma; Structure-Activity Relationship
PubMed: 2935251
DOI: No ID Found -
Journal of Controlled Release :... Mar 2014Daunorubicin (DNR) is an effective inhibitor of an array of proteins involved in neovascularization, including VEGF and PDGF. These growth factors are directly related...
Daunorubicin (DNR) is an effective inhibitor of an array of proteins involved in neovascularization, including VEGF and PDGF. These growth factors are directly related to retina scar formation in many devastating retinal diseases. Due to the short vitreous half-life and narrow therapeutic window, ocular application of DNR is limited. It has been shown that a porous silicon (pSi) based delivery system can extend DNR vitreous residence from a few days to 3months. In this study we investigated the feasibility of altering the pore size of the silicon particles to regulate the payload release. Modulation of the etching parameters allowed control of the nano-pore size from 15nm to 95nm. In vitro studies showed that degradation of pSiO2 increased with increasing pore size and the degradation of pSiO2 was approximately constant for a given particle type. The degradation of pSiO2 with 43nm pores was significantly greater than the other two particles with smaller pores, judged by observed and normalized mean Si concentration of the dissolution samples (44.2±8.9 vs 25.7±5.6 or 21.2±4.2μg/mL, p<0.0001). In vitro dynamic DNR release revealed that pSiO2-CO2H:DNR (porous silicon dioxide with covalent loading of daunorubicin) with large pores (43nm) yielded a significantly higher DNR level than particles with 15 or 26nm pores (13.5±6.9ng/mL vs. 2.3±1.6ng/mL and 1.1±0.9ng/mL, p<0.0001). After two months of in vitro dynamic release, 54% of the pSiO2-CO2H:DNR particles still remained in the dissolution chamber by weight. In vivo drug release study demonstrated that free DNR in the vitreous at post-injection day 14 was 66.52ng/mL for 95nm pore size pSiO2-CO2H:DNR, 10.76ng/mL for 43nm pSiO2-CO2H:DNR, and only 1.05ng/mL for 15nm pSiO2-CO2H:DNR. Pore expansion from 15nm to 95nm led to a 63 fold increase of DNR release (p<0.0001) and a direct correlation between the pore size and the drug levels in the living eye vitreous was confirmed. The present study demonstrates the feasibility of regulating DNR release from pSiO2 covalently loaded with DNR by engineering the nano-pore size of pSi.
Topics: Animals; Antibiotics, Antineoplastic; Cell Line; Cell Proliferation; Daunorubicin; Delayed-Action Preparations; Drug Delivery Systems; Humans; Intravitreal Injections; Oxidation-Reduction; Porosity; Rabbits; Silicon; Vitreous Body
PubMed: 24424270
DOI: 10.1016/j.jconrel.2014.01.003 -
Journal de Pharmacologie 1986The pharmacokinetics, metabolism and disposition of doxorubicin and daunorubicin were studied for periods up to 100 hr in rabbits with (group II) or without a biliary...
The pharmacokinetics, metabolism and disposition of doxorubicin and daunorubicin were studied for periods up to 100 hr in rabbits with (group II) or without a biliary fistula (groups I and III) and with (group I) or without (groups II and III) ligatured ureters using high-performance liquid chromatography to separate parent drug and metabolites. The plasma decay of doxorubicin and daunorubicin was triexponential. Metabolites appearing in the plasma after doxorubicin and daunorubicin bolus i.v. injection were respectively doxorubicinol and daunorubicinol, the latter being the major compound after daunorubicin injection. The elimination of daunorubicin was faster than that of doxorubicin. No differences in the elimination were observed between the 3 groups. In bile, 21% of the injected dose of doxorubicin were excreted mainly as the parent drug and 60% of the injected dose of daunorubicin were excreted, mainly as daunorubicinol. Enterohepatic circulation did not affect the biliary excretion of both doxorubicin and daunorubicin. Ligature of ureters increased slightly the biliary excretion of doxorubicin. The hepatic clearance of daunorubicin was greater than that of doxorubicin. The total urinary excretion was not different between the II and III groups and amounted to 11.6 and 12.8% of the injected dose of doxorubicin and daunorubicin, respectively. Metabolic ratios of doxorubicinol/doxorubicin and daunorubicinol/daunorubicin were similar in bile and urine.
Topics: Animals; Bile; Daunorubicin; Doxorubicin; Enterohepatic Circulation; Female; Kidney; Kinetics; Liver; Models, Biological; Rabbits; Time Factors
PubMed: 3713196
DOI: No ID Found -
Journal of Clinical Pharmacology 1986Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy... (Clinical Trial)
Clinical Trial Review
Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.
Topics: Aclarubicin; Amsacrine; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Drug Evaluation, Preclinical; Epirubicin; Humans; Idarubicin; Kinetics; Menogaril; Mitoxantrone; Naphthacenes; Neoplasms; Nogalamycin; Rabbits
PubMed: 2944917
DOI: 10.1002/j.1552-4604.1986.tb02942.x -
Leukemia Apr 1988
Comparative Study
Topics: Daunorubicin; Doxorubicin; Humans; Leukemia, Myeloid, Acute
PubMed: 3163077
DOI: No ID Found -
Investigational New Drugs 19864-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is... (Review)
Review
4-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is superior to that of daunorubicin (DNR) or doxorubicin (DX). The drug is more potent than DNR and DX and is active by both the intravenous and the oral routes of administration. After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug. Idarubicinol has been shown to be an active metabolite in experimental models, being as potent and as active as the parent compound. Phase II clinical trials of Idarubicin have indicated that: By I.V. route Idarubicin is a potent antileukemic agent active in relapsed or refractory, ANLL, ALL (adult and pediatric) either as single agent or in combination with Ara-C at doses of 8-12 mg/m2 by i.v. day 1, 2 and 3 or 7-8 mg/m2 i.v. daily X 5 days (adults). There is evidence of lack of cross-resistance with parent drugs and other antileukemic agents. Phase III studies in previously untreated acute leukemias have been initiated. By oral route Idarubicin has antitumor activity in breast cancer at the doses of 35-45 mg/m2 q 3-4 weeks or 15 mg/m2 daily X 3 days q 3-4 weeks. Idarubicin has activity as a single agent in adult leukemias at the doses of 20-30 mg/m2/day X 3 days. The safety of administration (no risk of extravasation), the good tolerability and the reduced potential for cardiac toxicity, make oral Idarubicin particular attractive for further clinical development. Whether Idarubicin proves to be more effective and/or less cardiotoxic in clinical therapy than DNR or DX remains to be seen through prospective randomized studies which have been already initiated both in leukemias and solid tumors.
Topics: Administration, Oral; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Idarubicin; Infusions, Parenteral; Kinetics; Leukemia
PubMed: 3516918
DOI: 10.1007/BF00172021 -
Archives of Internal Medicine Nov 1978Seven adults with acute promyelocytic leukemia (APL) and disseminated intravascular coagulation were treated for remission induction with daunorubicin hydrochloride and...
Seven adults with acute promyelocytic leukemia (APL) and disseminated intravascular coagulation were treated for remission induction with daunorubicin hydrochloride and prednisone. In all patients the coagulopathy was managed with continuous-infusion heparin sodium and vigorous transfusion with platelets, cryoprecipitate, and fresh frozen plasma. Five patients survived induction; they all achieved complete remission (CR). Median duration of CR was 27 + months; two patients presently survive in their initial CR at 28 and 48 months. Recognition of APL as a distinct type of acute leukemia and prompt initiation of treatment aimed at rapid cytoreduction and control of the coagulopathy has resulted in a prolonged disease-free survival for the majority of patients.
Topics: Adolescent; Adult; Blood Coagulation Factors; Blood Coagulation Tests; Chemical Precipitation; Daunorubicin; Disseminated Intravascular Coagulation; Drug Therapy, Combination; Female; Heparin; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Plasma; Prednisone; Remission, Spontaneous
PubMed: 281191
DOI: 10.1001/archinte.138.11.1677 -
Biochimica Et Biophysica Acta.... Feb 2020The interactions of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA), with phospholipid monolayers used as simple models of cell membranes, were...
The influence of charge and lipophilicity of daunorubicin and idarubicin on their penetration of model biological membranes - Langmuir monolayer and electrochemical studies.
The interactions of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA), with phospholipid monolayers used as simple models of cell membranes, were investigated. The results of Langmuir experiments together with Brewster angle microscopy showed that both drugs strongly affect cancer cell membranes composed of 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS). Electrostatic interactions allow positively charged DNR and IDA to interact with negatively charged DMPS polar heads but increased lipophilicity of IDA allows it to penetrate the layer more effectively than DNR and prevents from its expulsion at higher surface pressures. The analysis of the thermodynamical functions of hysteresis proves the presence of the enthalpically favorable interactions within the monolayer during its compression in the presence of idarubicin, which may form aggregates with DMPS molecules. The influence of the drugs was significantly less pronounced for a healthy cell model composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) due to the lack of strong electrostatic attractions. The interactions of drugs with pre-compressed phospholipid monolayers were also examined. The physical state of the monolayer and its packing determined only to some extent the penetration of anthracyclines. Since drug molecules first approach the polar region of the monolayer, the increase in surface pressure in time was more pronounced for negatively charged DMPS monolayers than for zwitterionic DMPC. Additionally, idarubicin was able to penetrate the precompressed DMPS monolayers more effectively than daunorubicin due to increased lipophilicity. This property of the drug was also responsible for IDA better penetration of hydrocarbon chains of supported DMPS monolayers compared to DNR, as shown by electrochemical studies.
Topics: Antineoplastic Agents; Cell Membrane; Daunorubicin; Dimyristoylphosphatidylcholine; Hydrophobic and Hydrophilic Interactions; Idarubicin; Static Electricity; Unilamellar Liposomes
PubMed: 31672546
DOI: 10.1016/j.bbamem.2019.183104 -
Proceedings of the National Academy of... Oct 2000The binding interactions of (-)-daunorubicin (WP900), a newly synthesized enantiomer of the anticancer drug (+)-daunorubicin, with right- and left-handed DNA, have been...
The binding interactions of (-)-daunorubicin (WP900), a newly synthesized enantiomer of the anticancer drug (+)-daunorubicin, with right- and left-handed DNA, have been studied quantitatively by equilibrium dialysis, fluorescence spectroscopy, and circular dichroism. (+)-Daunorubicin binds selectively to right-handed DNA, whereas the enantiomeric WP900 ligand binds selectively to left-handed DNA. Further, binding of the enantiomeric pair to DNA is clearly chirally selective, and each of the enantiomers was found to act as an allosteric effector of DNA conformation. Under solution conditions that initially favored the left-handed conformation of [poly(dGdC)](2), (+)-daunorubicin allosterically converted the polynucleotide to a right-handed intercalated form. In contrast, under solution conditions that initially favored the right-handed conformation of [poly(dGdC)](2), WP900 converted the polynucleotide to a left-handed form. Molecular dynamics studies by using the amber force field resulted in a stereochemically feasible model for the intercalation of WP900 into left-handed DNA. The chiral selectivity observed for the DNA binding of the daunorubicin/WP900 enantiomeric pair is far greater than the selectivity previously reported for a variety of chiral metal complexes. These results open a new avenue for the rational design of potential anticancer agents that target left-handed DNA.
Topics: Allosteric Regulation; Base Sequence; DNA; Daunorubicin; Models, Molecular; Stereoisomerism
PubMed: 11027298
DOI: 10.1073/pnas.200221397