Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The toxicity and marginal effectiveness of cytotoxic chemotherapy in metastatic non-small cell lung cancer (NSCLC) necessitates the search for new agents. Preliminary data in lung cancer and other malignant and premalignant disorders have identified retinoid compounds as potentially useful antitumor agents. Twenty-eight patients with metastatic NSCLC were treated with oral all-trans retinoic acid in a phase II trial. The study population consisted of patients with excellent performance status and minimal weight loss. Toxicities were generally mild and included cutaneous effects, headache, and myalgia. A significant number of patients developed elevations of hepatic transaminases or hyperlipidemia and 3 patients had treatment-related leukocytosis. Two patients (8%) achieved a partial response, and 1 had a mixed response. The duration of remission in the 2 responders was 7 and 13 months and the median survival of all patients 7 months. Therefore, all-trans retinoic acid has minimal activity as a single agent in NSCLC but warrants further study in combination with biological agents and chemotherapy.
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PMID:Phase II trial of all-trans retinoic acid in metastatic non-small cell lung cancer. 881 56

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, 4,258 +/- 1,006 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.
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PMID:Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery. 1105 29

Emphysema results from progressive destruction of alveolar septae and was considered irreversible until all-trans-retinoic acid (ATRA) was shown to reverse anatomic and physiologic signs of emphysema in a rat model. To evaluate the feasibility of ATRA as a clinical therapy, 20 patients with severe emphysema were enrolled into a randomized, double-blind, placebo-controlled pilot study. Participants included 16 male and 4 female former smokers, two with alpha(1)-antitrypsin deficiency. Patients were treated with either 3 mo of ATRA (50 mg/m(2)/d) or 3 mo of placebo, followed by a 3-mo crossover phase. Plasma drug levels were followed and outcome measures included serial pulmonary function tests, blood gases, lung compliance, computed tomography (CT) imaging, and quality of life questionnaires. In general, treatment was well tolerated and associated with only mild side effects including skin changes, transient headache, hyperlipidemia, transaminites, and musculoskeletal pains. Plasma drug levels varied considerably between subjects and decreased significantly over time in 35% of the participants. Physiologic and CT measurements did not change appreciably in response to therapy. We conclude that ATRA is well tolerated in patients with emphysema, and trials evaluating higher doses, longer treatment, or different dosing schedules are feasible.
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PMID:A pilot study of all-trans-retinoic acid for the treatment of human emphysema. 1187 21

Seven patients experiencing first (n = 5) or second (n = 2) relapse of acute promyelocytic leukemia (APL) were treated with a new synthetic retinoid, Am-80. All 7 patients were previously treated with all-trans retinoic acid (ATRA). Am-80 was orally administered at a dose of 6 mg/m2 daily. Chemotherapy was combined in 3 patients because of leukocytosis. All 7 patients achieved a complete remission (CR) during periods ranging from 36-56 days (median 52 days). Adverse effects such as hyperlipidemia and skin lesions, were tolerable. After achieving CR, 3 patients underwent allogeneic bone marrow transplantation and 4 patients received only consolidation chemotherapy. In 2 of 3 patients who received allogeneic transplantation, relapse free survival has lasted for 9.7 and 28.3 months. Furthermore, in 2 of 4 patients who received only chemotherapy, relapse free survival has lasted for 84.7 and 90.1 months. Am-80 is an active agent for APL patients who have relapsed from ATRA-induced remission.
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PMID:[Long-term follow up of re-induction with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukemia previously treated with all-trans retinoic acid: results of 7 cases from a single institute]. 1468 69

A new synthetic retinoid, Am-80 is expected to overcome all-trans retinoic acid (ATRA) resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein. In a preliminary study in Japan, 14 (58%) of 24 acute promyelocytic leukemia (APL) patients who had relapsed from ATRA induced complete remission (CR) achieved a second CR. Of these 14 CR patients, 4 of 6 who underwent allogeneic stem cell transplantation (SCT) are alive, and 4 of 8 patients who received only chemotherapy are alive without relapse for >4 years. Adverse events include xerosis, cheilitis, hyperlipidemia and so on, but these were generally milder than ATRA. In a phase 2 clinical trial, 25 (61%) of 41 patients entered CR. Among 23 first relapsed patients, 18 (78.3%) patients entered CR, indicating excellent salvage effects for ATRA-relapsed patients. Am-80 may improve disease free survival when used as remission induction and/or maintenance therapy, and it may be effective for relapse from ATRA-induced remission and be curative for patients who receive SCT or intensive post remission chemotherapy.
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PMID:[Clinical experience with a new synthetic retinoid, tamibarotene (Am-80) for relapsed or refractory acute promyelocytic leukemia]. 1653 27

Cholesterol 7alpha-hydroxylase (CYP7A1) plays a key role in maintaining lipid and bile salt homeostasis as it is the rate-limiting enzyme converting cholesterol to bile acids. Deficiency of CYP7A1 leads to hyperlipidemia in man and mouse. Hyperlipidemia is often seen in patients when treated with high-dose retinoic acid (RA), but the molecular mechanisms remain elusive. Our present study revealed that CYP7A1 mRNA expression is greatly repressed by RA in both human hepatocytes and HepG2 cells where increased fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) expressions were also observed, suggesting farnesoid X receptor (FXR) and retinoid X receptor (RXR) were activated. Promoter reporter assays demonstrate that all-trans RA (atRA) specifically activated FXR/RXR. However, detailed molecular analyses indicate that this activation is through RXR, whose ligand is 9-cis RA. Knocking down of FXR or RXRalpha by small interference RNA (siRNA) in human hepatocytes increased CYP7A1 basal expression, but the repressive effect of atRA persisted, suggesting there are also FXR/RXR-independent mechanisms mediating atRA repression of CYP7A1 expression. Chromatin immunoprecipitation (ChIP) assay and cell transfection results indicate that PGC-1alpha plays a role in the FXR/RXR-independent mechanism. Our findings may provide a potential explanation for hyperlipidemic side effects observed in some patients treated with high-dose RA.
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PMID:Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms. 2033 15

Therapy-related acute promyelocytic leukemia (t-APL) is a well-recognized form of APL for which the underlying etiology has been well characterized. The pathogenesis of de novo (dn-APL) remains unknown; but epidemiologic studies have consistently identified increased body mass index (BMI), younger age, and ethnicity as possible risk factors. We analyzed demographics, clinical features, and treatment responses in a contemporary series of 64 patients treated with all-trans-retinoic acid and anthracycline-based therapy to assess for differences in these two etiologically distinct patient groups. Compared with patients with t-APL (n = 11), those with dn-APL (n = 53) had a greater median BMI (31.33 vs. 28.48), incidence of obesity (60.4% vs. 27.3%) (P = 0.04), and history of hyperlipidemia (45.3% vs. 18.2%) (P = 0.01). Fewer t-APL than dn-APL patients achieved complete remission at 63.6% vs. 92.5% respectively (P = 0.008). This was the result of a higher induction mortality rate of 36.4% vs. 7.5% respectively (P = 0.008). No cases of leukemic resistance were seen in either group. Overall survival (OS) was inferior in t-APL compared with dn-APL at 51% vs. 84%, respectively (P < 0.005), primarily as a result of higher induction mortality. Relapse occurred in nine patients (16.1%) overall, but no relapses occurred in the t-APL cohort. Our observations provide further support for the hypothesis that abnormalities in lipid homeostasis may in some way be of pathogenic importance in dn-APL. Therapy-related APL is sensitive to standard therapy with no cases of resistance or relapse seen. The inferior OS of the t-APL was due to induction mortality, possibly reflecting prior therapy.
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PMID:Therapy-related acute promyelocytic leukemia: observations relating to APL pathogenesis and therapy. 2202 92

Even though the role of all-trans lycopene from tomato in controlling atherosclerosis was reported, but no report is available on the cis-isomer of lycopene obtained from an easily available source green algae Chlorella marina. So in this study, Sprague Dawley rats fed with high-cholesterol diet were given standard drug lovastatin; algal lycopene (AL) (cis/all-trans 40:60) and tomato all-trans lycopene (TL) and the following parameters were studied. Total cholesterol, low-density lipoprotein, triglycerides were decreased significantly and the high-density lipoprotein levels were increased on treatment with AL. The activities of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase were found to be increased, whereas thiobarbituric acid reactive substances levels were decreased in AL when compared to the drug and TL-treated rats. The activities of inflammatory marker enzymes like cyclooxygenase, 15-lipoxygenase in monocytes and myeloperoxidase, C-reactive protein and ceruloplasmin levels in serum were found to be decreased on treatment with AL. Histopathological studies revealed that lycopene from this alga could reduce fatty liver and aortic plaque when compared to the drug and TL. Algal lycopene showed very significant antioxidant and anti-inflammatory effect in high-cholesterol fed rats. Therefore, AL from C. marina would be recommended for the treatment of hyperlipidemia.
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PMID:Effect of lycopene from Chlorella marina on high cholesterol-induced oxidative damage and inflammation in rats. 2388 96