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  • 1
    Electronic Resource
    Electronic Resource
    All-trans retinoic acid significantly increases 5-year survival in patients with acute promyelocytic leukemia: long-term follow-up of the New York study (1997)
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. S25 
    Details
    ISSN: 1432-0843
    Keywords: Key words All-trans retinoic acid ; Promyelocytic ; leukeumia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  All-trans retinoic acid (ATRA) induces a high incidence of complete remission (CR) in patients with acute promyelocytic leukemia (APL); however, the magnitude of this agent’s contribution to increased rates of cure of this disease has not yet been established. From 1990 to 1995 we used RA as remission induction therapy in 103 APL patients (73 newly diagnosed and 30 previously treated) who were retinoid-naive and were treated on the basis of initial morphology. Patients whose diagnosis was changed on the basis of the results of molecular testing (n = 13) were withdrawn from RA treatment and given chemotherapy alone. After achieving a CR, previously untreated patients received several cycles of consolidation chemotherapy, usually with idarubicin and cytosine arabinoside. Among individuals whose diagnosis was molecularly confirmed, 54 of 65 new patients (83%) and 25 of 30 previously treated patients (83%) achieved a CR. All induction failures in molecularly diagnosed cases were due either to early death or to premature withdrawal. Median disease-free and overall survival rates recorded for all newly diagnosed patients are currently 〉40+ and 〉43+ months, respectively. We subsequently examined a subset of 27 newly diagnosed patients treated during the first 2 years of this program whose actual median follow-up period is now 〉5 years. Median disease-free and overall survival rates recorded for this group are 〉57+ and 〉58+ months, respectively; 56% of these patients are alive in first remission. These results significantly exceed those achieved using chemotherapy alone in a historical control group of 80 patients consecutively treated at this center from 1975 to 1990, whose median disease-free and overall survival rates were 11 and 19 months, respectively; only 22% of these patients were alive in first remission at 5 years. Although a high proportion of previously treated patients also achieved a CR after RA treatment, median disease-free and overall survival rates noted for that group were markedly lower (i.e., 7.5 and 10.9 months, respectively). Thus, data from patients whose median follow-up period is now 〉5 years have confirmed earlier projections and indicate that the use of RA for remission induction yields an approximately 2.5-fold increase in the proportion of patients who have presumably been cured of this disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051057
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  • 2
    Electronic Resource
    Electronic Resource
    Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 313-318 
    Details
    ISSN: 1432-0843
    Keywords: Key words All-trans-retinoic acid ; Chemoprevention ; Inhalers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5–17 h), lower peak serum concentrations (aerosol 71 ± 31 ng/ml, IT 68 ± 50 ng/ml), and lower liver levels (aerosol 111 ± 28 ng/g, IT 753 ± 350 ng/g) than the same dose administered IV (2 h, 838 ± 56 ng/ml, 4258 ± 1006 ng/g, respectively; P 〈 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800000148
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  • 3
    Electronic Resource
    Electronic Resource
    Clinical study of an organic arsenical, melarsoprol, in patients with advanced leukemia (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 417-421 
    Details
    ISSN: 1432-0843
    Keywords: Key words Organic arsenical ; Melarsoprol ; Advanced leukemia ; As2O3 ; Inorganic arsenic trioxide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Inorganic arsenic trioxide (As2O3) induces a high proportion of complete remissions in relapsed patients with acute promyelocytic leukemia (APL). Previously, we have shown that both As2O3 and melarsoprol, an organic arsenical used for the treatment of trypanosomiasis, exhibit broad antileukemic activity against both chronic and acute myeloid and lymphoid leukemia cell lines. Given the breadth of this activity, we initiated a clinical study to evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in patients with refractory or resistant leukemia. Using the antitrypanosomal dose and schedule, patients received escalating intravenous doses daily for 3 days, repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and 3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200 mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean peak plasma concentrations of the parent drug were obtained immediately after injection, ranged from 1.2 μg/ml on day 1 to 2.4 μg/ml on day 3, were dose proportional, and decayed with a t1/2≅ 15 min. A minor clinical response (regression of splenomegaly and lymphadenopathy) was observed in a patient with chronic lymphocytic leukemia. Central nervous system (CNS) toxicity proved limiting on this dose and schedule. Three patients experienced generalized grand mal seizures during the second week of therapy. We concluded that this dose and schedule of melarsoprol is associated with excessive CNS toxicity and that verification of the striking preclinical activity in patients with leukemia will require developing an alternative dose and schedule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050998
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    Paper (German National Licenses)
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