Interactions of bexarotene (LGD1069, Targretin) with the coagulation system (original) (raw)
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An evidence-based review on bexarotene
Tumor Discovery
Bexarotene is a selective retinoid X receptor agonist of utmost clinical importance. The United States Food and Drug Administration has approved this drug for its effects on cutaneous T-cell lymphoma. Bexarotene has shown great potential, demonstrating enhanced therapeutic activity against a plethora of tumor types, both as a single agent and as an adjuvant with other targeted agents. Despite its potential, bexarotene has turned out to be a nostrum, and formulation-related studies that explore its use have not received much emphasis. Poor aqueous solubility and low bioavailability are challenges in developing an appropriate formulation of this drug. In this review, we aim to provide insights into recent research conducted on formulation development, recent pharmacological findings, patents, and future research requisites of bexarotene, based on the literature gathered from authentic web resources and research articles. Bexarotene is a diamond in the rough, as many researchers have n...
A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Clinical Cancer Research, 2008
Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines.We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m 2 until evidence of disease progression or unacceptable adverse events occurred. Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m 2 ), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m 2 . Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to V5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m 2 /d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
Bexarotene is the first synthetic rexinoid approved for the treatment of all stages of cutaneous T-cell lymphoma (CTCL) however the mechanism of bexarotene action is unknown. We examined the effects of bexarotene on induction of apoptosis and expression of its cognate receptors in well-established CTCL cell lines (MJ, Hut78, and HH). CTCL cells were treated with 0.1, 1, and 10 microM bexarotene for 24, 48, 72, and 96 h. Apoptosis was determined by flow-cytometry analysis of sub-G(1) hypodiploid nuclei and annexin V binding populations. Apoptosis-associated proteins and retinoid receptors were detected by Western blots. Bexarotene treatment at 1 and 10 microM for 96 h increased the number of cells with sub-G1 populations and annexin V binding in a dose-dependent manner compared with vehicle controls (DMSO) in all three cell lines, respectively. Bexarotene treatment suppressed the expression of retinoid X receptor alpha and retinoic acid receptor alpha proteins in all three lines comp...
INDIAN DRUGS, 2018
A simple precise and rapid Reverse Phase High Performance Liquid Chromatographic method has been developed for quantitative determination of antineoplastic drug bexarotene and its capsule formulation. In this method Synchronis (C18, 25cm×4.6mm id , 5μ) column with mobile phase consisting of buffer (25mM ammonium acetate w/v solution adjusted to pH 4.0 with diluted acetic acid) and acetonitrile in the ratio of (20: 80 v/v) in an isocratic mode was used. The detection was carried out at 262 nm and 20.0 μL injection volume was selected, with the flow rate of 1.0 mL/min being used. The linearity range of bexarotene shows concentration between 5-200 μg/mL. Retention time of bexarotene was found to be 12.58 minutes. Mobile phase itself was used as a diluent. The method was validated as per ICH guidelines and is simple, fast, accurate, precise and can be applied for routine quality control analysis of bexarotene in its formulation.
Journal of Clinical Oncology, 2006
Purpose To evaluate the effect of bexarotene on survival in patients with relapsed non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB NSCLC with pleural effusion or stage IV NSCLC, who had Eastern Cooperative Oncology Group performance status 0 to 2, and were previously treated with ≥ two different regimens that must have included a platinum and a taxane, received oral bexarotene 400 mg/m2/d plus concomitant levothyroxine and a lipid-lowering agent. Primary efficacy end point was survival. Results For the 146 assessable patients treated with bexarotene, median age was 66 years (range, 34 to 87 years), 51% were men, and the median number of prior regimens was three (range, one to seven). The overall median survival was 5 months (95% CI, 4 to 7 months) and the 1-year survival was 23% (95% CI, 16% to 31%). Survival was significantly longer in patients with bexarotene-induced hypertriglyceridemia and/or skin rash. In 26 patients who had both adverse effect...
Inhibitors of propagation of coagulation: factors V and X
British Journal of Clinical Pharmacology, 2011
Cardiovascular diseases are still the most important cause of morbidity and mortality in western countries and antithrombotic treatment is nowadays widely used. Drugs able to reduce coagulation activation are the treatment of choice for a number of arterial and/or venous thromboembolic conditions. Some of the drugs currently used for this purpose, such as heparins (UFH or LMWH) and VKA, have limitations consisting of a narrow therapeutic window and an unpredictable response with the need of laboratory monitoring in order to assess their efficacy and safety. These drawbacks have stimulated an active research aimed to develop new drugs able to act on single factors involved in the coagulation network, with predictable response. Intense experimental and clinical work on new drugs has focused on synthetic agents, which could preferably be administered orally and at fixed doses. The most advanced clinical development with new anticoagulants has been achieved for those inhibiting FXa and some of them, like fondaparinux, are already currently used in clinical practice. Other agents, such as rivaroxaban, apixaban, otamixaban and edoxaban are under development and have already been studied or are currently under investigation in large scale phase III clinical trials for prevention and treatment of venous thromboembolism, atrial fibrillation and acute coronary syndromes. Some of them have proved to be more effective than conventional therapy. Data on some agents inhibiting FVa are still preliminary and some of these drugs have so far been considered only in patients with disseminated intravascular coagulation secondary to sepsis. Investigators. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST-and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008; 118: 2038-46. 23 Warkentin TE, Cook RJ, Marder VJ, Sheppard JA, Moore JC, Eriksson BI, Greinacher A, Kelton JG. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106: 3791-6. 24 Warkentin TE. Fondaparinux: does it cause HIT? Can it treat HIT? Expert Rev Hematol 2010; 3: 567-81. V. Toschi & M. Lettino 576 / 72:4 / Br J Clin Pharmacol 25 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Haemost 2008; 34: 39-57. 26 Harenberg J, Vukoievic Y, Milkus G, Joerg I, Weiss C. Long elimination half-life of idraparinux may explain major bleeding and recurrent events of patients from the van Gogh trials. J Thromb Haemost 2008; 6: 890-2. 27 Savi P, Herault JP, Duchaussoy P, Millet L, Schaeffer P, Petitou M, Bono F, Herbert JM. Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy.
Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion
British Journal of Dermatology, 2006
Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m )2 , which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed. Bexarotene (Targretin Ò ; Ligand Pharmaceuticals Inc., San Diego, CA, U.S.A) is a retinoid X receptor-selective retinoid (a rexinoid), which is approved in the U.S.A. for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients refractory to at least one prior systemic therapy and in Europe for the treatment of patients with skin manifestations of advanced-stage CTCL refractory to at least one systemic therapy. It is recommended as a second-line therapy for the treatment of mycosis fungoides and Sézary syndrome in a number of national and international guidelines. The evidence in support of bexarotene was provided by two phase II/III clinical studies, which have shown this agent to be effective as an oral treatment for refractory early and advancedstage CTCL. 5,6 Among 58 patients with refractory or persistent early-stage CTCL (stages I-IIA), 54% of those treated with the optimal bexarotene daily dose of 300 mg m )2 , and 67% of those taking higher doses of up to 650 mg m )2 , had a complete clinical response or partial response (at least a 50% improvement sustained for more than 4 weeks). 5 The median time to response was 8AE1 weeks with 300 mg m )2 dose and 13AE1 weeks at higher doses (where pauses in therapy occurred, which may explain the slower response), and the median time to disease progression during treatment was 30 and 73AE7 weeks, respectively. This study also included an arm in which patients received bexarotene at 6AE5 mg m )2 daily, with a response rate of 20%. Subsequently, 11 of the 15 patients in this low-dose group crossed over to the higher dose and 73% responded, indicating that the common practice of titrating from low to higher dose bexarotene in order to minimize adverse events is unlikely to have a negative impact on the clinical outcome.