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)

A 35-year-old man with refractory cutaneous Ki-1 lymphoma was salvaged successfully with oral 13-cis-retinoic acid (1 mg/kg/day). He had a complete remission lasting for 20 months before a single nodule recurred on his skin. Excisional biopsy of the recurrent tumor revealed a distinct morphologic change, suggesting cellular differentiation toward a more benign phenotype. No significant side effects were noted except mild xerostomia, bone pain, and hyperlipidemia. The authors believe that 13-cis-retinoic acid should be considered in the treatment of cutaneous Ki-1 lymphoma.
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PMID:13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-1 lymphoma. 184 87

Alterations in lipid metabolism have been reported under treatment of various skin disorders with oral retinoids. In 36 patients, mostly psoriatics, under administration of aromatic retinoid (Ro 10-9359) in various dosages serum triglycerides and cholesterol were estimated; in 25 out of 36 patients lipid analysis of the lipoproteins and apoproteins A (HDL) and B (LDL) has been performed. To reveal possible similarities of lipid changes under the two main retinoids we determined the same parameter in 10 patients with conglobate acne treated orally with 13-cis-retinoic acid (isotretinoin/Ro 4-3780 1mg/kg b.w.). Under both drugs serum triglyceride and cholesterol levels were significantly increased. In contrast to the results under the aromatic derivate the HDL- and LDL-cholesterol fractions were changed under isotretinoin. The apoprotein A (HDL) was found significantly increased under aromatic retinoid. Elevated serum lipids mostly occurred in patients having risk factors such as preexisting lipid abnormalities, obesity, diabetes mellitus, heavy smoking, alcohol abuse and hyperlipemia-inducing drugs. Patients to be treated with these drugs should be carefully followed up in order to minimize the risk for atheromatosis.
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PMID:[Changes in serum lipid fractions as a side effect of oral retinoids]. 621 75

It has been widely accepted that the remnants of the intestinally-derived lipoprotein chylomicrons, i.e., chylomicron remnants (CMR), are cleared from the circulation by a receptor genetically distinct from the well-known LDL-receptor. This second receptor was initially considered as a receptor specific for apo E, in contrast to the LDL-receptor, which binds both apo B and apoE. This article critically examines the current dogma of the putative CMR receptor, as well as both supporting and conflicting evidence for the recently-proposed identity of this receptor with the LDL-receptor related protein (LRP). Next, we introduce the lipolysis-stimulated receptor, LSR, which bears all the biochemical characteristics of the CMR receptor. In addition, the apparent number of LSR expressed in the liver is inversely correlated with nonfasting levels of plasma triglycerides. A change in LSR expression and parallel inverse change in plasma triglycerides is observed in rats treated with hyperlipidemic (retinoic acid) or hypolipidemic (fish oil in MaxEPA) agents, indicating that LSR represents a definite target for pharmacological management of hyperlipidemia. In support of this notion is the observation that MaxEPA, which causes an increase in LSR expression, also reduces both plasma triglyceride and cholesterol levels in the thus far intractable homozygous Watanabe heritable hyperlipidemic rabbit.
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PMID:Lipolysis-stimulated receptor: a newcomer on the lipoprotein research scene. 762 72

Vitamin A and its analogues have been reported to increase the release of tissue plasminogen activator in vitro. The aim of the present study was to reevaluate these findings and to investigate whether retinoids in doses used in dermatological therapy could enhance the release of endothelial fibrinolytic factors. Our results showed that endothelial cells incubated in vitro with retinoic acid increased the release of tissue plasminogen activator to the supernatant without concomitant secretion of plasminogen activator inhibitor-1. In patients treated with isotretinoin or etretinate these findings were confirmed, showing enhanced baseline tissue plasminogen activator concentrations in plasma in association with unchanged levels of plasminogen activator inhibitor-1 and von Willebrand factor. These findings are consistent with chronically augmented tissue plasminogen activator secretion without evidence of endothelial cell damage and may be of importance for the interpretation of the safety of lon-term therapy with regard to retinoid-induced hyperlipemia and the development of cardiovascular disease.
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PMID:Retinoids and fibrinolysis. 857 51

Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma.
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PMID:Isotretinoin and recombinant interferon alfa-2a therapy of metastatic malignant melanoma. 868 22

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

As many as 20% of the survivors of acute myocardial infarction present with the heritable form of hyperlipidemia, termed familial combined hyperlipidemia (FCHL). Some of the genes reported to be involved in this disorder, such as those for lipoprotein lipase (LPL) and apolipoprotein (apo) C-III, are controlled by a peroxisome proliferator-activated receptor (PPAR)/retinoic acid receptor X (RXR) regulatory system, which is retinoic acid dependent. If, as we hypothesized, the availability of retinoic acid or its precursor retinol (vitamin A) could be altered in FCHL, this could help explain some aspects of the phenotypic expression of the disease. We therefore measured plasma retinol concentrations in 30 FCHL subjects and 56 controls. Plasma retinol concentrations in FCHL subjects were significantly lower than that of control subjects (1.96 +/- 0.83 mumol/L vs 2.91 +/- 1.23 mumol/L, respectively; P < 0.0001). This novel finding of significantly decreased concentrations of plasma retinol in FCHL relative to control subjects gives support to the hypothesis that vitamin A might be involved in the expression of this disorder.
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PMID:Low plasma vitamin A concentrations in familial combined hyperlipidemia. 943 57

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.
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PMID:Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. 965 87

Human immunodeficiency virus (HIV) protease inhibitor (PI) therapy is frequently associated with a syndrome increasingly referred to as lipodystrophy syndrome, which is characterized by peripheral lipoatrophy, fat accumulation within the abdomen, in the breasts of women, and over the cervical vertebrae ("buffalo hump"), hyperlipidemia, and insulin resistance. In the largest study to date, peripheral lipoatrophy (an estimated 0.35-kg fat loss per month overall from the face, limbs, and upper trunk) was observed in association with all licensed PIs after a median 10 months of PI therapy. Diabetes mellitus type II appears to be a related, but less common, adverse effect. The lipodystrophy syndrome may be a result of the inhibition of 2 proteins involved in lipid metabolism that have significant homology to the catalytic site of HIV protease-namely, cytoplasmic retinoic acid binding protein type 1 and low density lipoprotein-receptor-related protein.
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PMID:HIV protease inhibitor-related lipodystrophy syndrome. 1086 Aug 98

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


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