Gauchers disease

Of the surgical options available prior to enzyme therapy, splenectomy was most often recommended to combat thrombocytopenia and anemia, mechanical complications, and growth retardation. 

It is hoped that, in the future, Gaucher s disease, currently a model of enzyme replacement therapy, will prove to be a model of a curative form of gene transfer therapy for inherited metabolic disorders. In this case CD34 cells from the patient s blood will be genetically corrected in vitro and transplanted back into the patient. 

Similar to that of cytarabine, conversion of gemcitabine to dFdCMP by deoxycytidine kinase is saturated at infusion rates of approximately 10 mg/m per minute, which produce plasma drug concentrations in the range of 15 to 20 pM. In an attempt to increase dFdCTP formation, the duration of infusion at this maximum concentration has been extended to 150 minutes. In contrast to a fixed infusion duration of 30 minutes, the 150-minute infusion produces a higher level of dFdCTP within peripheral blood mononuclear cells and increases the degree of myelosuppression, but has uncertain effects on antitumor activity. 

Gemfibrozil is a fibric-acid derivative that decreases blood levels of triglycerides and VLDL by decreasing their production. It also decreases cholesterol and increases HDL. 

Gemfibrozil is indicated in the treatment of hypertriglyceridemia in adult patients with type IV or V hyperlipidemia that presents risk of pancreatitis and does not respond to diet and reduction of coronary heart disease risk in type Ilb patients who have low HDL levels (in addition to elevated LDL and triglycerides) and have not responded to other measures. 

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Hollak, C.E.M., van Weely, S., van Oers, M.H.J. and Aerts, J.M.F.G. (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. Journal of Clinical Investigation 93, 1288-1292. 

B. Friedman, K. Vaddi, C. Preston, E. Mahon, J. R. Cataldo, and J. M. A. McPherson, Comparison of the pharmacological properties of carbohydrate remodeled recombinant and placental-derived /i-Glucocerebrosidase Implications for clinical efficacy in treatment of Gaucher disease, Blood, 93 (1999) 2807-2816. 

Grabowski, G. 2005. Recent clinical progress in Gaucher disease. Current Opinion in Pediatrics 17(4), 519-524. 

Zhao, H. and Grabowski. G. 2002. Gaucher disease perspectives on a prototype lysosomal disease. Cellular and Molecular Life Sciences 59(4), 694-707. 

Krivit, W., Peters, C. and Shapiro, E. G. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachro-matic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12 167-176,1999. 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

Several gene therapies have received orphan drug designation these are treatments for cystic fibrosis, Gaucher disease, and metastatic brain tumor. 

Miglustat (60 Zavesca ) 1 -Deoxynoj irimycin (DNJ) Iminosugar Semi-synthetic NP Microbial Type 1 Gaucher disease (GDI) Inhibits glucosylceramide synthase activity 215-217, 525-531... 

Pastores GM, Barnett NL, Kolodny EH. (2005) An open-label, noncomparative study of miglustat in type I Gaucher disease Efficacy and tolerability over 24 months of treatment. Clin Ther 27 1215-1227. 

Weinreb NJ, Barranger JA, Charrow J, Grabowski GA, Mankin HJ, Mistry P. (2005) Giudance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol 80 223-229. 

Elstein D, Hollak C, Aerts JMEG Weely SV, Maas M, Cox TM, Lachmann RH, Hrebicek M, Platt EM, Butters TD, Dwek RA, Zimran A. (2004) Sustained therapeutic effects of oral miglustat (Zavesca, A-butyldeoxynojir-imycin, OGT 918) in type 1 gaucher disease. J Inherit Metab Dis 27 757-766. 

RL, Wustman BA, Huertas P, Powe AC, Pine CW, Khanna R, Schlossmacher MG Ringe D, Petsko GA. (2007) Stracture of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat Chem Biol 3 101-107. 

K. M. Osiecki-Newman, D. Fabbro, T. Dinur, S. Boas, S. Gatt, G. Legler, R. J. Desnick, and G. A. Grabowski, Human acid p-glucosidase Affinity purification of the normal placental and Gaucher disease splenic enzymes on N-alkyl-deoxynojirimycin-sepharose, Enzyme, 35 (1986) 147-153. 

B. Brumshtein, H. M. Greenblatt, T. D. Butters, Y. Shaaltiel, D. Aviezer, I. Sihnan, A. H. Futerman, and J. L. Sussman, Crystal structures of complexes of iV-butyl- and iV-nonyl-deoxynojirimycin bound to acid P-glucosidase. Insights into the mechanism of chemical chaperone action in Gaucher disease,... 

R. L. Lieberman, B. A. Wustman, P. Huertas, A. C. Powe, Jr., C. W. Pine, R. Khanna, M. G. Schlossmacher, D. Ringe, and G. A. Petsko, Structure of acid p-glucosidase with pharmacological chaperone provides insight into Gaucher disease, Nat. Chem. Biol., 3 (2007) 101-107. 

A. R. Sawkar, S. L. Adamski-Wemer, W.-C. Cheng, C.-H. Wong, E. Beutler, K.-P. Zimmer, and J. W. Kelly, Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles, Chem. Biol., 12 (2005) 1235-1244. 

L. Yu, K. Ikeda, A. Kato, I. Adachi, G. Godin, P. Compain, O. Martin, and N. Asano, a-l-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease, Bioorg. Med. Chem., 14 (2006) 7736-7744. 

O. R. Martin, Second-generation iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease, ChemMedChem, 6 (2011) 353-361. 

One example is an enzyme replacement drug used to treat a form of Gaucher disease, which is caused by an inherited error in the gene coding for the enzyme that breaks down the fatty substance cerebroside. In Gaucher disease, certain immune system cells... 

Like many recombinant treatments for chronic diseases, the recombinant replacement enzyme for Gaucher disease is very expensive A year s treatment can cost over 150,000, though most private insurance companies will reimburse patients for its use. 

Cerebroside—Fatty substance that fills up blood cells in Gaucher disease. 

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