Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.
 ...
PMID:A Phase I study of LGD1069 in adults with advanced cancer. 1043 65

Bexarotene is a selective retinoid X receptor (RXR) agonist. It binds to, and activates RXRs which function as ligand-activated transcription factors that control gene expression. This leads to modulation of cell growth, apoptosis, and differentiation. In patients with refractory or persistent early stage cutaneous T cell lymphoma (CTCL), the overall response rate was 54% after oral bexarotene 300 mg/m2/day. The overall response rate in patients with refractory or persistent advanced stage CTCL was 45% at the same dosage. An overall response rate of 63% was reported after topical bexarotene 0.1 to 1% twice daily in patients with early stage CTCL. Another trial reported an overall response rate of 44% after topical bexarotene 1% once daily escalated up to 4 times daily. Plaque elevation was significantly reduced, and the severity of moderate to severe psoriasis was substantially improved in patients receiving oral bexarotene 0.5 to 2 mg/kg/day. At clinically relevant oral dosages, bexarotene significantly decreases levels of serum thyrotropin and free thyroxine. The most common adverse events associated with oral bexarotene are hypertriglyceridemia, hypercholesterolemia, central hypothyroidism and headache. Reversible acute pancreatitis has occurred during oral bexarotene therapy. Adverse events associated with the topical formulation are limited to rash, pruritus, and pain.
 ...
PMID:Bexarotene. 1170 69

This study was designed as a multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized by center to placebo (16 patients, 31%), oral bexarotene 300 mg/m2/day (21 patients, 40%), or oral bexarotene 600 mg/m2/day (15 patients, 29%) following demonstration of stable or responsive disease after first-line chemotherapy. The study was prematurely terminated because of slow accrual after 54 patients enrolled. Median time to progression (TTP) from the beginning of study drug treatment was 56 days for placebo, 82 days for moderate-dose bexarotene (300 mg/m2/day), and 128 days for high-dose bexarotene (600 mg/m2/day) (P = 0.56, log-rank test). For prior chemotherapy responders only, median TTP from the beginning of study drug treatment was 56 days for placebo, 146 days for moderate-dose bexarotene, and 177 days for high-dose bexarotene. Of note, there were more chemotherapy responders randomized to the placebo group (63%) than the bexarotene treatment arms (48% and 47%), further supporting a bexarotene-related improvement in TTP. Bexarotene-related toxicity was manageable and consisted primarily of elevated serum triglycerides and asthenia, skin toxicity (dryness, peeling, flaking), thyroid dysfunction, and headache. Because this study was closed prematurely, it does not have the statistical power to detect differences among the treatment groups. This study shows that patients can tolerate bexarotene at initial doses up to 600 mg/m2/day after platinum-based chemotherapy and that bexarotene may have the potential to delay disease progression in patients with advanced non-small-cell lung cancer with previously stable or responsive disease following platinum-based chemotherapy.
 ...
PMID:Placebo-controlled trial of bexarotene, a retinoid x receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer. 1470 Apr 80

Although the introduction of third-generation antineoplastic agents in the treatment of non-small cell lung cancer has led to modest improvements in overall patient survival, lung cancer continues to be the leading cause of cancer-related death worldwide, and improved therapies are needed. Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and they represent an exciting new avenue for targeted therapy. Several synthetic retinoids that bind to retinoic acid receptors are currently being investigated in a variety of tumor types. However, many of these agents have been associated with cheilitis, skin reactions, severe headache, and hypertriglyceridemia. Synthetic agents that bind specifically to retinoid X receptors are called rexinoids. Bexarotene (Targretin; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is a novel, multitargeted synthetic rexinoid that is currently being investigated in the treatment of non-small cell lung cancer. Phase I and II studies have demonstrated that bexarotene is safe and well tolerated in this patient population either alone or in combination with chemotherapeutic agents. Patients treated with bexarotene experience manageable adverse events at reduced levels compared with retinoic acid receptor-specific retinoids. Bexarotene in combination with chemotherapeutic agents has demonstrated an encouraging median survival for patients with advanced non-small cell lung cancer compared with historical results with combination chemotherapy alone. Two phase III trials are currently under way to fully characterize the role of bexarotene in the treatment of this disease. The purpose of this review is to explore the rationale for rexinoids in the treatment of malignancies and to discuss the clinical profile of bexarotene in the treatment of non-small cell lung cancer.
 ...
PMID:Emerging role of rexinoids in non-small cell lung cancer: focus on bexarotene. 1563 50