Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.
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PMID:Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices. 128 69

Two monoclonal antibodies (MAbs) against p27 and one against p17 of simian immunodeficiency virus (SIV) from rhesus macaques were produced and characterized by reacting with disrupted, viral antigens on immunoblots. Human immunodeficiency virus type 1 (HIV-1), HIV-2 and SIV isolates from sooty mangabey, stump-tailed macaque, rhesus macaque and African green monkey (SIVSM, SIVStM, SIVMAC and SIVAGM) were used for comparative analysis. The p27 monoclonal antibodies HE3 and FA2 reacted with SIVMAC and SIVSM, but not with HIV-1, HIV-2, SIVStM and SIVAGM. The p17 monoclonal antibodies reacted with SIVMAC and SIVStM, but not HIV-1, HIV-2, SIVSM and SIVAGM. The differential reactivity of these monoclonal antibodies indicated that common conserved antigenic epitopes are shared between SIVMAC and SIVSM with respect to p27 MAbs and between SIVMAC and SIVStM with respect to p17. Since these MAbs reacted differently with the SIV isolates, they are useful reagents for comparative pathogenesis studies for differentiating SIV isolates.
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PMID:Characterization of monoclonal antibodies that distinguish simian immunodeficiency virus isolates from each other and from human immunodeficiency virus types 1 and 2. 168 69

A small number of patients positive for the human immunodeficiency virus (HIV) have been reported as developing acute non-lymphoblastic leukaemia (ANLL) and none has achieved remission despite attempts at treatment. We report on a 34-year-old HIV positive heterosexual intravenous drug user who presented with ANLL (FAB classification M5, Monoblastic) and entered remission following one cycle of cytosine arabinoside and daunorubicin according to the 7-3 protocol of the Australian Leukaemia Study Group (ALSG). This was followed by consolidation of 5-2 as per ALSG and one cycle of maintenance with low dose cytosine arabinoside. Ten months after remission, he relapsed but achieved a second remission with the ALSG 7-3-7 protocol (7-3 plus etoposide) followed by consolidation with 5-2-5. He remained HIV positive but showed little progression towards the acquired immunodeficiency syndrome despite the intense immunosuppression. The duration of his second remission was five months. The patient died of septicaemia during the third attempt at remission induction 18 months after diagnosis. We conclude that HIV seropositivity is not an absolute contraindication to aggressive chemotherapy in those patients who develop ANLL.
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PMID:First and second complete remissions in a HIV positive patient following remission induction therapy for acute non-lymphoblastic leukaemia. 203 79

Immunoblastic lymphoma developed in a patient diagnosed as having angioimmunoblastic lymphadenopathy 5 years earlier. Chemotherapy schedules including alkylating agents were administered for 1 year, resulting in subsequent remission of the lymphoma. Thirty months after the start of chemotherapy, preleukemic changes were observed in peripheral blood and bone marrow, and acute nonlymphocytic leukaemia (M5 of the FAB classification) was diagnosed shortly afterwards. The possible role of both chemotherapy and the immunodeficiency associated to angioimmunoblastic lymphadenopathy in the pathogenesis of the leukemia is discussed.
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PMID:Sequential appearance of immunoblastic lymphoma and acute nonlymphocytic leukemia in a patient with angioimmunoblastic lymphadenopathy. 393 63

The metabolic fate of SK&F 107461 [Cbz-Ala-Ala-Phe psi [CHOHCH2] Gly-Val-Val-OMe], a potent and specific inhibitor of the protease encoded by human immunodeficiency virus type 1, in male Sprague-Dawley rats is described. SK&F 107461 is a hexapeptide analog containing a hydroxyethylene linkage in place of one of the peptide bonds, and in which the amino terminus is blocked with a carbobenzyloxy group and the carboxy terminus is modified to a methyl ester. The major metabolites of SK&F 107461 found in bile and urine after intravenous administration of 3H-labeled compound were characterized by LC/MS using either thermospray or continuous flow/FAB models of ionization. Approximately 80% of the administered radioactivity was recovered in the bile of bile duct-exteriorized rats following an intravenous dose. Radiochromatographic profiling indicated that SK&F 107461 was subject to extensive biotransformation. Structures were determined for three major biliary and five major urinary metabolites. Two of the major circulating plasma metabolites observed after intravenous bolus administration had similar retention times to metabolites that were observed in both bile and urine. A pathway for the biotransformation of SK&F 107461 in the rat is proposed. The parent molecule underwent two primary modes of metabolism. Hydrolysis of the carboxy-terminal ester or hydrolysis of the Ala-Ala peptide bond near the amino terminus were the primary metabolic events. All of the other metabolites characterized can be accounted for by exopeptidase activity subsequent to one or both of these primary events. There were no major metabolites observed resulting from anything other than hydrolysis of the ester or peptide bonds in the parent molecule.
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PMID:Characterization of the metabolites of the peptidomimetic human immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats using liquid chromatography/mass spectrometry. 749 45

A small number of patients seropositive for the human immunodeficiency virus (HIV) have been reported as developing acute non-lymphoblastic leukemia (ANLL). In the cases previously published, the authors never reported a study of the link joining HIV infection and leukemia. We describe here the case of a 41-year-old HIV positive patient who developed ANLL (FAB classification M5). Using molecular techniques, we looked for a direct link between these two co-existing diseases. We showed the absence of HIV expression in the malignant clone, suggesting that the association of ANLL and Acquired Immune Deficiency Syndrome is not a direct consequence of the myeloid precursors infection. Nevertheless a relationship may exist through a disorganization of the bone marrow micro-environment.
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PMID:Monoblastic leukemia in an HIV-infected patient: absence of viral expression in RNA blasts. 863 11

B lineage-derived malignant proliferation is a well recognized complication of HIV infection. Acute myeloid leukemias have been reported but no complete review of these cases has been performed. The Medline database was reviewed for the years 1980-1997. Eighteen cases of AML have been reported. When previously known, HIV infection was present for 40 months. In 7 patients HIV infection and AML were diagnosed simultaneously. According to the FAB classification, 5 cases were M2, 8 M4, 5 M5. Extramedullary localizations (skin, testis, spleen) were noticed in 10 patients. Non-treated patients had a survival of 2.7 weeks versus 9.8 months in patients treated with chemotherapy. Pathophysiologic studies were performed in 3 cases: reverse transcriptase activity and p24 antigen were noted in tumoral cultured cells in 1 case; absence of viral particules in culture in another one; absence of cloned DNA provirus integration in blasts cells in a third patient. Based on the observed high rate of M4/M5 (72%) versus 19-36% expected in a non HIV-infected population, we postulate that the association of AML and HIV is not coincidental. The monocytotropism of HIV, the chronic cytokines-mediated activation of monocyte/macrophages, the immunodeficiency may explain this association.
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PMID:[Acute myelocytic leukemia in immunodeficiency virus infection]. 1002 98

Burkitt's lymphoma is a highly aggressive lymphoma identified and described in the last century by Denis Burkitt in Africa, in areas endemic for malaria. Since its description in African children, it has been recognized outside areas with endemic malaria, frequently also in children as well as among individuals with an underlying immunodeficiency. Since its initial designation as Burkitt's lymphoma, this type of lymphoma and lymphomas closely resembling it have received a variety of names in different classifications of lymphomas and leukemias: undifferentiated lymphoma, Burkitt's and non-Burkitt's type in the modified Rappaport Classification, malignant lymphoma, small non-cleaved cell, Burkitt's type in the Working Formulation, Burkitt's lymphoma and high-grade B-cell lymphoma, Burkitt-like in the REAL Classification, and acute lymphoblastic leukemia, L3 type in the FAB Classification. With the publication of the WHO Classification of Haematopoietic and Lymphoid Tumors, the nomenclature of this lymphoma has come full circle, and it is once again known simply as Burkitt's lymphoma. In recent years, efforts have focused on improving therapy for this rapidly proliferating neoplasm while minimizing, to the extent possible, treatment-associated toxicity. These efforts have led to the development of high-intensity, short-duration combination chemotherapy that has proven extremely effective for a high proportion of Burkitt's lymphoma patients. The differential diagnosis of Burkitt's lymphoma is broad, and precise diagnosis based on histologic, immunophenotypic, and genetic features remains the critical first step in planning appropriate therapy.
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PMID:Burkitt's lymphoma: clinicopathologic features and differential diagnosis. 1661 33

Human serum albumin (HSA) has an extraordinary ligand-binding capacity, and transports Fe(III)heme and medium- and long-chain fatty acids. In human immunodeficiency virus-infected patients the administered drugs bind to HSA and act as allosteric effectors. Here, the binding of Fe(III)heme to HSA in the presence of three representative anti-HIV drugs and myristate is investigated. Values of the dissociation equilibrium constant K(d) for Fe(III)heme binding to HSA were determined at different myristate concentrations, in the absence and presence of anti-HIV drugs. Nuclear magnetic relaxation dispersion profiles of HSA-Fe(III)heme were measured, at different myristate concentrations, in the absence and presence of anti-HIV drugs. Structural bases for anti-HIV drug binding to HSA are provided by automatic docking simulation. Abacavir and nevirapine bind to HSA with K(d) values of 1 x 10(-6) and 2 x 10(-6) M, respectively. Therefore, at concentrations used in therapy (in the 1-5 x 10(-6) M range) abacavir and nevirapine bind to HSA and increase the affinity of heme for HSA. In the presence of abacavir or nevirapine, the affinity is not lowered by myristate. FA7 should therefore be intended as a secondary binding site for abacavir and nevirapine. Binding of atazanavir is limited by the large size of the drug, although preferential binding may be envisaged to a site positively coupled with FA1 and FA2, and negatively coupled to FA7. As a whole, these results provide a foundation for the comprehension of the complex network of links modulating HSA-binding properties.
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PMID:Modulation of heme and myristate binding to human serum albumin by anti-HIV drugs. An optical and NMR spectroscopic study. 1772 15

Ataxia telangiectasia (AT) is a rare autosomal recessive multisystem disorder characterised by cerebellar degeneration, immunodeficiency and cancer predisposition. Around 10% of AT patients develop lymphoid malignancies, but the development of myeloid leukaemia with AT (AT-AML) is extremely rare, and there have been no previous publications regarding suitable therapies. Here, we first describe a successful therapeutic experience in a patient with AT-AML (FAB-M1) who attained remission after induction therapy and maintained stable disease for a year. To minimise therapy-induced toxicity, low-dose induction was applied first, though this was obviously insufficient and the patient subsequently responded well to dose-intensified short-term chemotherapy. In this report, we suggest a curative therapeutic approach for AT-AML, though the issue of how best to manage patients with cancer complicated by immunodeficiency remains undecided.
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PMID:Successful treatment of acute myeloid leukaemia in a patient with ataxia telangiectasia. 2395 78


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