Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular thioguanine nucleotides (6-TGN) are the major cytotoxic metabolites of mercaptopurine (6-MP). Red blood cell (RBC) 6-TGN concentrations were measured in a group of 120 consecutive children with lymphoblastic leukemia (ALL) to assess interpatient variability and its clinical importance. Assays were performed after at least 2 months 6-MP maintanance chemotherapy and a minimum 7 days unattenuated protocol dose of 75 mg/m2. Observed 6-TGN concentrations ranged from 126 to 832 pmol/8 x 10(8) RBCs (median, 275). There was a correlation between 6-TGN and neutropenia 14 days postassay (rs = .51; P less than .0005), and an inverse correlation between 6-TGN and the length of time uninterrupted full protocol dose was tolerated without neutropenia (rs = -.3; P less than .01). After a median follow-up of 49 months, 19 children had relapsed, of whom 17 (89%) had 6-TGN concentrations below the group median (log-rank chi 2 = 11.9; P less than .001). Multivariate analysis using Cox's proportional hazards regression showed the 6-TGN effect on disease control to be independent of diagnostic WBC count, sex, age, immunological cell type, French-American-British (FAB) type, variation in other antineoplastic therapy, and duration of remission at the time of 6-TGN assay. Children with ALL taking the same dose of 6-MP show great variability in its measurable cytotoxic effect, and this variability is apparently important in predicting treatment outcome.
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PMID:Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. 258 22

The commonly used immunosuppressive regimen after orthotopic heart transplantation consists of cyclosporine (CsA), azathioprine (AZA), and steroids. Although AZA therapy is generally regarded as unproblematic, its use can be associated with severe side effects, particularly myelosuppression. Since AZA is a prodrug, which must first be metabolized to its active metabolites, AZA therapy, in contrast to CsA therapy, cannot be controlled by measuring blood levels of this drug. Because of the myelosuppressive properties of the AZA metabolites, the 6-thioguanine nucleotides (6-TGN), the white blood cell count is usually monitored in patients on AZA therapy, and AZA is discontinued if neutropenia appears. In a group of 20 consecutive heart recipients, 6-TGN concentrations ranged from < 30 to 2,211 pmol/8 x 10(8) red blood cells (RBCs); levels < or = 450 pmol/8 x 10(8) RBCs were not associated with AZA-induced myelosuppression. Three cases of neutropenia were experienced, two of them with a fatal outcome. One patient died in septicemia owing to total myelosuppression. In this case an excessively high erythrocyte 6-TGN concentration (2,211 pmol/8 x 10(8) RBCs) was associated with a complete deficiency of thiopurine methyltransferase (TPMT), one of the main AZA detoxifying enzymes. The second patient, who had high RBC TPMT activity, developed neutropenia during rehabilitation, and AZA was withdrawn. Coincidentally, in this case the CsA blood level was only 132 g/L, and the RBC 6-TGN level was very low (maximum 46 pmol/8 x 10(8) RBCs). This patient rapidly developed cardiogenic shock with clinical signs of acute rejection and was given a second transplant on an emergency basis, but finally died from rejection of the second graft. Retrospectively, it was determined that neutropenia in this patient was not related to AZA toxicity. A high 6-TGN level (698 pmol/8 x 10(8) RBCs) was also seen in a third patient with mild neutropenia, who required allopurinol, an inhibitor of xanthine oxidase, the other major detoxifying enzyme for AZA. In this patient AZA therapy could be individually adapted by RBC 6-TGN monitoring. Based on our experience, we suggest that RBC 6-TGN monitoring allows for better individualization of treatment with AZA and may help avoid fatal complications.
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PMID:Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine? 873 60

Hermansky-Pudlak syndrome (HPS) has evolved into a group of genetically distinct disorders characterized by oculocutaneous albinism, a storage pool deficiency, and impaired formation or trafficking of intracellular vesicles. HPS-1 results from mutations in the HPS1 gene and affects approximately 400 individuals in northwest Puerto Rico due to a 16-bp duplication in exon 15. Another 13 mutations have been reported in non-Puerto Ricans. HPS1 codes for a 79.3 kDa cytoplasmic protein of unknown function. HPS-1 patients typically develop fatal pulmonary fibrosis in their fourth decade. HPS-2 is caused by mutations in ADTB3A, which codes for the beta3A subunit of the adaptor protein-3 complex, AP3. This coat protein complex has been localized to the TGN as well as to a peripheral endosomal compartment. Evidence indicates that AP3 plays a role in the stepwise process of vesicular trafficking which leads to formation of the melanosomal, platelet dense body and lysosomal compartments. All three known HPS-2 patients had childhood neutropenia and infections. HPS-3 results from mutations in HPS3 and affects central Puerto Ricans homozygous for a 3904-bp deletion removing exon 1. At least 8 non-Puerto Rican patients have other HPS3 mutations, including an IVS5+1G->A splicing mutation in five Ashkenazi Jewish patients. HPS3 codes for a 113.7 kDa protein of unknown function. HPS-3 manifests with mild hypopigmentation and bleeding. All types of HPS are diagnosed by whole mount electron microscopic demonstration of absent platelet dense bodies, and molecular diagnoses are available for the Puerto Rican HPS1 and HPS3 founder mutations. Mouse and Drosophila models provide candidates for new genes causing HPS in humans. These genes will reveal the pathways by which specialized vesicles of lysosomal lineage arise within cells.
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PMID:Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. 1212 11