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)

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

Lung transplantation has become an accepted treatment modality for end stage lung disease including emphysema, fibrosing alveolitis, cystic fibrosis, pulmonary hypertension and bronchiectasis. Despite the use of potent immunosuppressive drugs, acute rejection occurs frequently, especially in the first few weeks and months after transplantation. Bacterial, viral and fungal infections frequently occur in lung transplant recipients. Rapid diagnosis and adequate treatment of infections is needed. The side effects with the use of long term immunosuppressive agents includes renal toxicity, hypertension, neurotoxicity, hyperlipidemia, leucopoenia, hyperglycaemia, weight gain, osteoporosis and malignancy. However, obliterative bronchiolitis (OB) which is regarded as a chronic rejection process remains the dominant cause of morbidity and mortality in the long-term survivors of lung transplantation. This article focuses on the postoperative and long term management of lung transplant recipients.
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PMID:Lung transplantation: management and complications. 1184 31

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

A 60-year-old man presented to the Emergency Department (ED) with large, painful, indurated plaques on the right thigh, left abdomen, left chest, and right chest, which began without any preceding trauma on the right thigh 3 weeks prior to presentation in the ED. He was initially treated with cefazolin 1 g three times daily as home infusions. When the lesions continued to progress, he was admitted to the hospital and placed on amoxicillin/clavulanate and vancomycin. He had a single episode of fever of 102 degrees F, but his white blood cell count and differential remained normal. An initial biopsy showed a dermal inflammatory infiltrate composed primarily of neutrophils and eosinophils with rare flame figures in the dermis. There was minimal fat seen in this biopsy. A differential diagnosis of Wells or Sweet's syndrome was entertained, and he was placed on 60 mg/day prednisone with no resolution of his symptoms. The patient's past medical history included hypertension, hyperlipidemia, peripheral neuropathy, and hiatal hernia. His family history was significant for emphysema in both parents and coronary artery disease in his father. Both of his parents smoked cigarettes. His grandfather, who was a coal miner, also had emphysema. Whilst on antibiotics and prednisone, the plaques on the patient's right thigh, right abdomen, and left chest expanded and ulcerated, draining an oily liquid (Figs 1 and 2). An incisional biopsy was obtained from his thigh. Histopathology showed a septal and lobular panniculitis with fat necrosis, neutrophils, and histiocytes (Fig. 3). Special stains for organisms were negative. Tissue sent for bacterial and fungal culture had no growth. Amylase and lipase levels were normal. Rheumatoid factor, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), cryoglobulins, and antiphospholipid antibodies were all normal. The alpha1-antitrypsin level was low at 25 mg/dL (ref. 75-135). The alpha1-antitrypsin phenotype was PiZZ. The patient had a normal glucose-6-phosphate dehydrogenase level and was placed on dapsone 200 mg/day. The inflammation resolved and, over the course of several months, the involved areas healed with scarring. The patient denied any pulmonary complaints but, during his hospitalization, was found incidentally to have an oxygen saturation of 88% on room air. He was sent for evaluation by a pulmonologist, and pulmonary function tests revealed a mixed restrictive and obstructive pattern with a forced expiratory volume in 1 to forced vital capacity (FEV(1)/FVC) ratio of 63% of predicted. He had never smoked. He was placed on supplemental oxygen but, as his pulmonary disease has been stable, he has not been treated with intravenous antitrypsin inhibitor.
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PMID:alpha1-Antitrypsin deficiency presenting with panniculitis and incidental discovery of chronic obstructive pulmonary disease. 1791 Jul 20

Chronic obstructive pulmonary disease (COPD) is often associated with co-morbidities. Metabolic disorders like hyperlipidemia and diabetes occur also in underweight COPD patients, although the mechanism is uncertain. Subcutaneous adipose tissue (SAT) plays an important role in energy homeostasis, since restricted capacity to increase fat cell number with increase in fat cell size occurring instead, is associated with lipotoxicity and metabolic disorders. The aim of this study is to show the protective role of SAT for the metabolic disorders in pulmonary emphysema of a murine model. We found ectopic fat accumulation and impaired glucose homeostasis with wasting of SAT in a murine model of elastase-induced pulmonary emphysema (EIE mice) reared on a high-fat diet. ONO-AE1-259, a selective E-prostanoid (EP) 2 receptor agonist, improved angiogenesis and subsequently adipogenesis, and finally improved ectopic fat accumulation and glucose homeostasis with restoration of the capacity for storage of surplus energy in SAT. These results suggest that metabolic disorders like hyperlipidemia and diabetes occured in underweight COPD is partially due to the less capacity for storage of surplus energy in SAT, though the precise mechanism is uncertained. Our data pave the way for the development of therapeutic interventions for metabolic disorders in emphysema patients, e.g., use of pro-angiogenic agents targeting the capacity for storage of surplus energy in the subcutaneous adipose tissue.
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PMID:Improvement of metabolic disorders by an EP2 receptor agonist via restoration of the subcutaneous adipose tissue in pulmonary emphysema. 2826 59

Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.
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PMID:Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist. 3125 45