Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Asparaginase from Escherichia coli was immobilized by entrapment in a gel based on poly(2-hydroxyethyl methacrylate) with an activity as high as 730 I.U./g of dry gel. The apparent Michaelis constant for these gels was similar to that of the free enzyme. At 37 degrees C the immobilized enzyme had a half-life of more than 40 days, in vitro. The gel was freeze-dried, crushed and sieved to pass a 38 mum screen, giving a median particle size of 12 mum. C3H mice were injected intraperitoneally with 40 I.U. of L-asparaginase; the peak plasma activity after 4 hours was only 0.9 I.U. for the gel entrapped enzyme compared to a peak activity of 5.0 I.U. after 2 hours for the native L-asparaginase. Ninety percent of the plasma enzyme activity for the gel entrapped case was sedimentable at 21,000 X g, indicating a small leakage of the enzyme from the gel; the clearance for the enzyme activity in plasma had an initial half-life of 13 hours in contrast to a half-life of 2 hours for the native preparation. After intraperitineal injection of 5.0 I.U. into C3H mice, plasma L-asparagine fell to undetectable levels for 4 days and reappeared by day 8 for both the native and immobilized enzymes. Subcutaneously transplanted 6C3HED murine lymphoma was inhibited by 35, 78 and 100% after single intraperitoneal injections of immobilized L-asparaginase of 2, 4 and 8 I.U., respectively, as compared to 36, 53 and 86% for the native enzyme by the 14th day. Body weight changes after receiving immobilized L-asparaginase were essentially similar to those of animals receiving a comparable dose of native enzyme. These results indicate that while most of the immobilized L-asparaginase remains at the injection site, it produces a significant plasma L-asparagine depression and antitumor acitivity comparable to that of the native preparation without major toxicity.
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PMID:Gel entrapped L-asparaginase: kinetic behavior and antitumor activity. 24 45

Current therapy has resulted in improved prognosis in previously untreated children with acute lymphocytic leukemia less than 16 years of age. The induction phase of chemotherapy should include the use of at least prednisone and vincristine. This combination should result in a hematologic remission in about 90 per cent of the patients. The efficacy of the addition of either L-asparaginase or daunomycin, the consolidation phase or the periodic readministration of induction drugs has not been established. Specific central nervous system treatment, early in the course of therapy, is an integral component of recently reported effective protocols. Several modalities of prophalytic central nervous system therapy have been utilized. These include cranial irradiation plus intrathecal methotrexate, craniospinal irradiation and intrathecal methotrexate alone. An encephalopathy syndrome has been reported as a complication in 10 to 66 per cent of these patients. The most effective form of central nervous system therapy, associated with the least toxicity, has not been established. Maintenance chemotherapy should include a combination of two or more drugs. Complications are numerous, and include hematopoietic depression, immunosuppression, overwhelming infections, and, possibly, the development of secondary primary cancers. In the most successful protocols maintenance chemotherapy has been administered for 3 years. Because of the potential significant toxicity there is a need to define the optimal duration of maintenance therapy. Psychological complications developing in a patient with a disease now considered a potential long term chronic illness, rather than a disease once considered universally fatal, are also discussed. The possibility of an immunologic deficiency allowing for the initial development of acute lymphocytic leukemia and the role of immunotherapy are presented. While the use of intensive combination chemotherapy and specific central nervous system prophylactic therapy have resulted in an improved prognosis in childhood acute lymphocytic leukemia, because of a significant incidence of failures, a standardized single form of therapy has not been established.
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PMID:The definitive treatment of children with acute leukemia. 78 18

The immunosuppression first introduced in the 1950s acted indiscriminately, blocking or damaging all the cells that happened to be in mytosis. The toxic side effects were usually so severe that the overall results were not considered satisfactory. The major drawback to the commonly used combination of steroids and cytotoxic drugs is the high risk of overwhelming infections. The next step was the development of lymphocytotoxic drugs or procedures which were restricted to the elimination of the immunocompetent cells. This was achieved by the use of total lymphoid irradiation, thoracic duct cannulation, antilymphocyte globulin, L-asparaginase and steroids. Steroids not only intervene at many points of the immune response, but they also possess a remarkable anti-inflammatory potency. The current or third stage is that of immunopharmacology, which is characterized by selective immunoregulation using compounds or methods that specifically modulate defined subpopulations of immunocompetent cells. Ciclosporin is the first drug that fulfilled these requirements to some extent and that has proved of permanent clinical value. The new technology of monoclonals has allowed the production of highly specific antibodies directed toward lymphocyte subsets. The modulation of lymphokines is another potential approach for both immunosuppression and immunostimulation. The final phase of immunosuppression will be the induction of antigen-specific depression of allograft reactivity. Classical transplantation tolerance has been induced in a developing immune system, but it is virtually impossible to achieve in a fully developed immune system.
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PMID:The mode of action of immunosuppressive drugs. 350 52

Administration of either Escherichia coli asparaginase or guinea pig serum to C3H/HE mice with the 6C3HED lymphosarcoma is followed by depression of glycine in the tumor. This decrease in cellular glycine concentration does not occur in a tumor resistant to asparaginase. The inhibition of the lymphosarcoma by asparaginase can be reversed by intraperitoneal injection of asparagine or glycine. This reversal appears to be specific because lysine, threonine, serine, and aspartic acid were ineffective. Loss of cellular glycine may be more important than loss of asparagine because of the requirement for glycine in purine synthesis.
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PMID:Glycine inhibition of asparaginase. 490 4

L-Asparaginase was immobilized in microparticles of polyacrylamide. Such particles were then injected by intramuscular/subcutaneous, intraperitoneal, or intravenous routes into mice to investigate the immunological consequences of the immobilization. Entrapment of L-asparaginase in microparticles did not prevent the formation of antibodies in intensively treated animals. Intraperitoneal and intravenous injections of particles produced significantly higher antibody levels than soluble L-asparaginase. Antigen administered intramuscularly/subcutaneously in microparticles elicited, however, a weak immune response. Dependent on the route of administration, the particles may thus function as an adjuvant. A modified Arthus reaction in the foot pads of immunized mice indicated that antigenicity decreased when L-asparaginase was immobilized in microparticles. Injection of free L-asparaginase, intramuscularly/subcutaneously (2 x 20 IU) in the preimmunized mice produced no effects on the serum level of L-asparagine, whereas intramuscular/subcutaneous injection of L-asparaginase in microparticles produced a depression of the serum concentration. It is concluded that the intramuscular/subcutaneous injection of L-asparaginase in microparticles is the choice route of administration with respect to duration and the immunological reaction.
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PMID:Acrylic microspheres in vivo V: Immunological properties of immobilized asparaginase in microparticles. 621 69

Ten children with acute lymphocytic leukemia developed transient diabetes mellitus during treatment with L-asparaginase and prednisone. Serum glucose, plasma insulin, and plasma glucagon levels were measured when the patients were hyperglycemic. Six of the children were restudied several months later when there were no clinical or laboratory signs of glucose intolerance. Hyperglycemia induced by L-asparaginase and prednisone was associated with depression of plasma insulin and, despite the inhibiting action of L-asparaginase on protein synthesis, a corresponding elevation of plasma glucagon. Thus patients with diabetes mellitus induced by L-asparaginase and prednisone have relative hyperglucagonemia similar to other patients with diabetes mellitus.
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PMID:Relative hyperglucagonemia in L-asparaginase-and prednisone-induced glucose intolerance in management of acute lymphocytic leukemia. 634 Sep 6

In 4 adults with malignant lymphoma and in 3 cases of acute lymphoblastic leukemia the acid phosphatase activity in lymphocytes during the consecutive cycles of polychemotherapy was examined paralelly with the estimation of the receptors for sheep erythrocytes. Depression of the enzymatic reaction was observed immediately after the onset of the cytostatic treatment, its normalization between the cycles and after the full remission was reached. A remarkable and lasting decrease of the phosphatase positive lymphocytes and a change in the expression of the enzymatic reaction was noticed in the course of L-asparaginase administration. The presented investigations are the continuation of the authors' earlier studies on the positive correlation between the rosette test with neuraminidase treated sheep erythrocytes and the acid phosphatase activity in lymphoproliferative diseases.
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PMID:Acid phosphatase activity of the lymphocytes during polychemotherapy of lymphoproliferative diseases. 694 30

Eleven patients with leukemia and lymphoma were treated with 14 courses of E. coli L-asparaginase. Abnormalities of the coagulation screening tests and decreased fibrinogen levels were observed in all patients during treatment. Significant depressions of functional (mean 32%) and antigenic (mean 48%) antithrombin III were observed by day 14 of therapy. There was no laboratory evidence of intravascular coagulation during 11/14 courses of L-asparaginase. Crossed immunoelectrophoresis of plasma obtained at the antithrombin nadir did not demonstrate an abnormal pattern which can be associated with an abnormal antithrombin III or an increase in antithrombin III-coagulation factor complexes. The major underlying mechanism of this depression is believed to be decreased hepatic synthesis, and the low levels of antithrombin III may be associated with an increased risk of thrombosis.
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PMID:Depression of functional and antigenic plasma antithrombin III (AT-III) due to therapy with L-asparaginase. 704 2

The early hope that L-asparaginase would be a breakthrough in medical treatment, with selective toxic effects based on the qualitative presence or absence of a specific enzyme (asparagine synthetase), has not been realized. Despite its failure to live up to early hopes, L-asparaginase is now commercially available because of its usefulness in treating selected forms of acute leukemia and T-cell lymphoid neoplasms. By and large, hints of useful activity in other tumors have not been confirmed, and L-asparaginase remains experimental for all other indications. It is variably toxic in man, and severe toxic effects are not unusual. Toxic reactions are generally hypersensitivity reactions or depression of protein synthesis.
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PMID:L-Asparaginase: human toxicology and single agent activity in nonleukemic neoplasms. 704 81

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.
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PMID:Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults. 743 89


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