The Experts below are selected from a list of 54 Experts worldwide ranked by ideXlab platform
Ronald A. Chalmers - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo studies with human carrier erythrocytes loaded with polyethylene glycol-conjugated and native adenosine deaminase.
British journal of haematology, 2000Co-Authors: Bridget E. Bax, Murray D. Bain, L. D. Fairbanks, Adb Webster, Ronald A. ChalmersAbstract:Polyethylene glycol-conjugated adenosine deaminase (Pegademase) is used for enzyme replacement therapy for patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. The entrapment of Pegademase within human energy-replete carrier erythrocytes using a hypo-osmotic dialysis procedure was investigated with the objective of prolonging the in vivo circulatory half-life of the enzyme and maintaining therapeutic blood levels. Native unmodified adenosine deaminase (ADA) was similarly studied. The efficiency of Pegademase entrapment was low (9%) whereas the entrapment of native unmodified ADA was substantial (50%), suggesting that the polyethylene glycol side-chains were impeding intracellular entrapment. The biochemical characteristics and the osmotic fragility of these carrier erythrocytes were not adversely affected by the entrapment of either Pegademase or native ADA. In vivo survival studies of Pegademase-loaded 51Cr-labelled carrier erythrocytes in an ADA-deficient adult patient showed a mean cell half-life of 16 d. Carrier erythrocyte-entrapped Pegademase and native ADA had in vivo half-lives of 20 and 12.5 d, respectively, demonstrating that entrapment prolongs the half-life over that of plasma Pegademase, which has a circulating half-life of 3-6 d. These results provide the basis for a more extensive clinical evaluation of carrier erythrocyte-entrapped native adenosine deaminase therapy.
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The Entrapment of Polyethylene Glycol-Conjugated Adenosine Deaminase (Pegademase) and Native Adenosine Deaminase in Human Carrier Erythrocytes
Erythrocytes as Drug Carriers in Medicine, 1997Co-Authors: Bridget E. Bax, Murray D. Bain, L. D. Fairbanks, H. Anne Simmonds, Ronald A. ChalmersAbstract:Severe combined immunodeficiency (SCID) is a rare disorder with an incidence of 1:66 000. It is characterised by a defective humoral (hypogammaglobulinaemia) and cellular (lymphopenia) immunity and if untreated is severe and often lethal. Some 20% to 25% of SCID cases are due to a deficiency of adenosine deaminase (EC 3.5.4.4). Adenosine deaminase (ADA) is normally present in all mammalian cells and catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and 2′-deoxyinosine respectively for either salvage and re-utilisation or metabolism to uric acid and excretion. The major route of adenosine metabolism at physiological substrate levels is phosphorylation rather than deamination, this is because the K m for adenosine kinase (EC 2.7.1.20) is lower than that of ADA. Adenosine in excess of physiological levels is degraded by ADA. The major source of 2′-deoxyadenosine is DNA turnover and the main route of its metabolism is deamination by ADA.
J. Milton Harris - One of the best experts on this subject based on the ideXlab platform.
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Effect of pegylation on pharmaceuticals
Nature Reviews Drug Discovery, 2003Co-Authors: J. Milton Harris, Robert B. ChessAbstract:Polypeptides that are being discovered by the biotechnology industry hold great promise as new drug candidates to target specific disease symptoms. However, polypeptide drugs are rapidly degraded by proteolytic enzymes and neutralized by antibodies, among other shortcomings. This reduces their half-life and circulation time, thereby limiting their therapeutic effectiveness. Pegylation of polypeptide drugs protects them and improves their pharmacodynamic and pharmacokinetic profiles. The pegylation process attaches repeating units of polyethylene glycol (PEG) to a polypeptide drug. For the past 30 years, scientists have improved various chemistries to build PEG polymers and attach them to a polypeptide drug of choice. Among the first pegylated drugs approved by the FDA in the early 1990s were pegaspargase for leukemia and Pegademase for severe combined immunodeficiency disorder. More recently, pegylated drugs for the treatment of hepatitis C, acromegaly, rheumatoid arthritis, neutropenia, various cancers, wound healing, and other disorders either have been approved or are undergoing clinical trials. Researchers will continue to perfect the chemistries employed in pegylation to develop more polypeptide therapeutic products. Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, pegylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance.
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Development of Pegylated Interferons for the Treatment of Chronic Hepatitis C
BioDrugs, 2001Co-Authors: Antoni Kozlowski, Stephen A. Charles, J. Milton HarrisAbstract:The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound. A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents. Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-α for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-αs, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.
Robert Whaley - One of the best experts on this subject based on the ideXlab platform.
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Pegademase BOVINE: REPLACEMENT THERAPY FORSEVERE COMBINED IMMUNODEFICIENCY DISEASE
2016Co-Authors: Connie R. Lee, Constance A. Mckenzie, Kathy D. Webster, Robert Whaley, Phann. DAbstract:ABSTRACf: Severe combined immunodeficiency (SCID) represents a syndrome characterized by abnormal function of cellular and humoral immunity. Of the various types of SCID, approximately one-fourth are associated with adenosine dearninase (ADA) deficiency. Treatment consists of bone marrow transplantation, red blood cell transfusions, enzyme replacement, and, more recently, gene therapy. Pegademase bovine is the sole agent available for enzyme replacement therapy of SCID associated with ADA deficiency. The drug is administered intramuscularly to infants from birth and to children of any age at time of diagnosis. At present, few adverse effects or drug interactions have been documented. Although it is expensive (approximately $60 000 annually), Pegademase bovine offers an alternative to standard means of therapy. DlCP Ann Pharmacother 1991;25:1092-5. SEVERE COMBINED IMMUNODEFICIENCY (SCID) represents
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Pegademase Bovine: Replacement Therapy for Severe Combined Immunodeficiency Disease:
DICP : the annals of pharmacotherapy, 1991Co-Authors: Connie R. Lee, Constance A. Mckenzie, Kathy D. Webster, Robert WhaleyAbstract:Severe combined immunodeficiency (SCID) represents a syndrome characterized by abnormal function of cellular and humoral immunity. Of the various types of SCID, approximately one-fourth are associated with adenosine deaminase (ADA) deficiency. Treatment consists of bone marrow transplantation, red blood cell transfusions, enzyme replacement, and, more recently, gene therapy. Pegademase bovine is the sole agent available for enzyme replacement therapy of SCID associated with ADA deficiency. The drug is administered intramuscularly to infants from birth and to children of any age at time of diagnosis. At present, few adverse effects or drug interactions have been documented. Although it is expensive (approximately $60 000 annually), Pegademase bovine offers an alternative to standard means of therapy.
H. Bobby Gaspar - One of the best experts on this subject based on the ideXlab platform.
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Pegademase bovine (PEG-ADA) for the treatment of infants and children with severe combined immunodeficiency (SCID).
Biologics : targets & therapy, 2009Co-Authors: Claire Booth, H. Bobby GasparAbstract:Adenosine deaminase deficiency (ADA) is a rare, inherited disorder of purine metabolism characterized by immunodeficiency, failure to thrive and metabolic abnormalities. A lack of the enzyme ADA allows accumulation of toxic metabolites causing defects of both cell mediated and humoral immunity leading to ADA severe combined immune deficiency (SCID), a condition that can be fatal in early infancy if left untreated. Hematopoietic stem cell transplant is curative but is dependent on a good donor match. Other therapeutic options include enzyme replacement therapy (ERT) with Pegademase bovine (PEG-ADA) and more recently gene therapy. PEG-ADA has been used in over 150 patients worldwide and has allowed stabilization of patients awaiting more definitive treatment with hematopoietic stem cell transplant. It affords both metabolic detoxification and protective immune function with patients remaining clinically well, but immune reconstitution is often suboptimal and may not be long lived. We discuss the pharmacokinetics, immune reconstitution, effects on systemic disease and side effects of treatment with PEG-ADA. We also review the long-term outcome of patients receiving ERT and discuss the role of PEG-ADA in the management of infants and children with ADA-SCID, alongside other therapeutic options.
Bridget E. Bax - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo studies with human carrier erythrocytes loaded with polyethylene glycol-conjugated and native adenosine deaminase.
British journal of haematology, 2000Co-Authors: Bridget E. Bax, Murray D. Bain, L. D. Fairbanks, Adb Webster, Ronald A. ChalmersAbstract:Polyethylene glycol-conjugated adenosine deaminase (Pegademase) is used for enzyme replacement therapy for patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. The entrapment of Pegademase within human energy-replete carrier erythrocytes using a hypo-osmotic dialysis procedure was investigated with the objective of prolonging the in vivo circulatory half-life of the enzyme and maintaining therapeutic blood levels. Native unmodified adenosine deaminase (ADA) was similarly studied. The efficiency of Pegademase entrapment was low (9%) whereas the entrapment of native unmodified ADA was substantial (50%), suggesting that the polyethylene glycol side-chains were impeding intracellular entrapment. The biochemical characteristics and the osmotic fragility of these carrier erythrocytes were not adversely affected by the entrapment of either Pegademase or native ADA. In vivo survival studies of Pegademase-loaded 51Cr-labelled carrier erythrocytes in an ADA-deficient adult patient showed a mean cell half-life of 16 d. Carrier erythrocyte-entrapped Pegademase and native ADA had in vivo half-lives of 20 and 12.5 d, respectively, demonstrating that entrapment prolongs the half-life over that of plasma Pegademase, which has a circulating half-life of 3-6 d. These results provide the basis for a more extensive clinical evaluation of carrier erythrocyte-entrapped native adenosine deaminase therapy.
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The Entrapment of Polyethylene Glycol-Conjugated Adenosine Deaminase (Pegademase) and Native Adenosine Deaminase in Human Carrier Erythrocytes
Erythrocytes as Drug Carriers in Medicine, 1997Co-Authors: Bridget E. Bax, Murray D. Bain, L. D. Fairbanks, H. Anne Simmonds, Ronald A. ChalmersAbstract:Severe combined immunodeficiency (SCID) is a rare disorder with an incidence of 1:66 000. It is characterised by a defective humoral (hypogammaglobulinaemia) and cellular (lymphopenia) immunity and if untreated is severe and often lethal. Some 20% to 25% of SCID cases are due to a deficiency of adenosine deaminase (EC 3.5.4.4). Adenosine deaminase (ADA) is normally present in all mammalian cells and catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and 2′-deoxyinosine respectively for either salvage and re-utilisation or metabolism to uric acid and excretion. The major route of adenosine metabolism at physiological substrate levels is phosphorylation rather than deamination, this is because the K m for adenosine kinase (EC 2.7.1.20) is lower than that of ADA. Adenosine in excess of physiological levels is degraded by ADA. The major source of 2′-deoxyadenosine is DNA turnover and the main route of its metabolism is deamination by ADA.