Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect. Following induction and DI treatment there was complete (</=1 microM) or moderate (1-10 microM) depletion of serum asparagine levels in the large majority of samples tested over the 4-week period in both O-treated and E-treated subjects. Similarly, depletion of cerebrospinal fluid asparagine levels during induction was similar between O-treated and E-treated subjects. The number of days asparaginase activity exceeded >0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant. Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years. The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). 1776 59

The cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion. The 2 native forms of L-asparaginase are derived from Escherichia coli and Erwinia chrysanthemi. The half-lives (t((1/2))) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t((1/2)), pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t((1/2)) of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t((1/2)). Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t((1/2)) of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase. So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.
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PMID:Acute lymphoblastic leukaemia: a guide to asparaginase and pegaspargase therapy. 1803 Oct 78

Little is known about octreotide therapy in asparaginase-associated pancreatitis (AAP) in children. Of the 59 children with acute lymphoblastic leukemia (ALL) receiving E. coli L-asparaginase, 5 patients (8.5%) developed AAP. Octreotide was administered to four patients. Clinical and laboratory improvement were evident after octreotide therapy. There were no deaths and no severe adverse side effects were noted. No pseudocysts were detected; however, two of the four patients developed diabetes. One child without octreotide treatment developed chronic pancreatitis and pseudocyst. We conclude that octreotide therapy appears to be safe and potentially beneficial in the management of AAP in children.
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PMID:Octreotide therapy in asparaginase-associated pancreatitis in childhood acute lymphoblastic leukemia. 1872 19

L-asparaginase (ASNase) is a common chemotherapy agent for the treatment of lymphoid malignancies. L-asparaginase has been reported to cause clinical pancreatitis in both humans and canines. Canine pancreatic lipase immunoreactivity (cPLI) is now a common diagnostic tool for evaluating pancreatitis in dogs. A total of 52 dogs were enrolled into this study. Canine pancreatic lipase immunoreactivity (cPLI) concentrations were evaluated before and after administration of ASNase, vincristine, or both. All dogs enrolled in the study were evaluated for signs compatible with clinical pancreatitis. No dogs receiving ASNase alone showed evidence of clinical pancreatitis after administration. Also, there was no statistically significant change in cPLI concentrations before or after treatment. Fourteen percent of dogs that received both vincristine and ASNase concurrently had elevated concentrations of cPLI after treatment. Of the 11 dogs with clinical signs compatible with pancreatitis after any chemotherapy treatment, no dog had a cPLI concentration > 400 microg/dL. In conclusion, ASNase did not cause clinical pancreatitis in this cohort of dogs but larger sample sizes are required to further validate this data.
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PMID:A pilot study evaluating changes in pancreatic lipase immunoreactivity concentrations in canines treated with L-asparaginase (ASNase), vincristine, or both for lymphoma. 1943 78

The incidence of pancreatitis in patients with haematopoetic neoplasms who are treated with L-asparaginase is fom 2 to 24%. In majority of cases the pancreatitis is oedematous and self-limiting. Acute haemorrhagic or necrotizing pancreatitis caused by L-asparaginase is rare but potentially life-threatening complication. We present 2 cases of acute pancreatitis in children aged 2 and 4 years. They were diagnosed to have acute lymphoblastic leukaemia and were treated according to the ALLLIC BFM 2002 protocol. Acute pancreatitis developed in these children after induction therapy and was followed by formation of a pseudocyst. In both cases the diagnosis of this complication was made directly after phase I of the protocol I (after eighth dose of L-Asparaginase). In the first case the course of acute pancreatitis was mild. Normalization of the amylase levels occurred after 7 days and the diagnosis of post inflammatory cyst was made 15 days after the first signs of the disease. But thereafter, during the additional complication (pneumonia with Pseudomonas aeruginosa bacteriemia) the pancreatic cyst became infected. In the second case acute pancreatitis had a severe course and the child required treatment in the Intensive Care Unit for 21 days. The cyst was diagnosed after 20 days from the beginning of symptoms. The surgical procedure, applied in both cases was internal drainage by anastomosis of the cyst with the back wall of the stomach. Antileukaemic treatment was recommenced after 6-8 weeks when complications resolved. Currently both children are well and remain in haematological remission and continue maintenance chemotherapy.
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PMID:[Acute pancreatitis during chemotherapy of acute lymphoblastic leukaemia complicated with pseudocyst]. 1953 25

Hyperglycemia has been described as a common event occurring during acute lymphocytic leukemia chemotherapy. It is associated with the synergistic effect of L-asparaginase and glucocorticoids, and related to poor outcome. Our goal was to compare clinical and laboratory findings between hyperglycemic episodes occurring during childhood acute lymphocytic leukemia induction chemotherapy. Here we describe 12 (3.8%) high-risk patients of 311 total patients, 9 (75%) of who are female. The 12 patients presented with 16 hyperglycemic episodes classified into adverse or satisfactory categories. There were no differences in clinical or laboratory variables among groups, although the majority of episodes occurred in pubescents, regardless of the type of glucocorticoid employed. Despite the fact that only 1 patient was overweight, pancreatitis was not diagnosed. Although we could not determine whether hyperglycemia predicts an adverse outcome, glucose evaluation played an important role during induction chemotherapy. To date, recognized risk factors for hyperglycemia no longer explain our findings, thus other mechanisms related to insulin secretion and action should be further studied.
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PMID:Transient hyperglycemia during childhood acute lymphocytic leukemia chemotherapy: an old event revisited. 1970 Nov 54

Over the past several decades, L-asparaginase, an important component of therapy for acute lymphoblastic leukemia (ALL), has typically been administered intramuscularly rather than intravenously in North America because of concerns regarding anaphylaxis. We evaluated the feasibility of giving polyethylene glycosylated (PEG)-asparaginase, the polyethylene glycol conjugate of Escherichia coli L-asparaginase, by intravenous infusion in children with ALL. Between 2005 and 2007, 197 patients (age, 1-17 years) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-01 and received a single dose of intravenous PEG-asparaginase (2500 IU/m(2)) over 1 hour during remission induction. Serum asparaginase activity more than 0.1 IU/mL was detected in 95%, 88%, and 7% of patients at 11, 18, and 25 days after dosing, respectively. Toxicities included allergy (1.5%), venous thrombosis (2%), and pancreatitis (4.6%). We conclude that intravenous administration of PEG-asparaginase is tolerable in children with ALL, and potentially therapeutic enzyme activity is maintained for at least 2 weeks after a single dose in most patients. This trial was registered at www.clinicaltrials.gov as #NCT00400946.
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PMID:Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. 2000 9

L-asparaginase (L-ASNase) has been an essential component of multiagent chemotherapy for acute lymphoblastic leukemia in childhood for over 3 decades. There are currently 2 Food and Drug Administration (FDA)-approved formulations of L-ASNase derived from Escherichia coli and 1 non-FDA approved formulation derived from Erwinia chrysanthemi. Modifications in L-ASNase have included pegylation, which decreases drug immunogenicity and increases the half-life, allowing less frequent administration. Although L-ASNase is well-tolerated in most patients and causes little myelosuppression, significant toxicities occur in up to 30% of patients. Hypersensitivity is the most common toxicity of L-ASNase therapy and limits the further use of the drug. Other significant toxicities relate to a reduction in protein synthesis and include pancreatitis, thrombosis, central nervous system complications, and liver dysfunction. The spectrum of common toxicities and the efficacy of different formulations of L-ASNase are presented in this review.
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PMID:Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. 2072 51

The study of enzyme immobilization using an extracorporeal shunt system is essential to eliminate the side effects of L-asparaginase (L-Asnase; including hepatic toxicity, allergic reaction, pancreatitis, central nervous system toxicity and decreased synthesis of blood clotting factors) when it was applied as an anticancer drug given directly to patients by injection. Thus, the novel monolith and coating enzymatic reactors of L-asparaginase were provided in this assay and a microchip electrophoresis-laser induced fluorescence (MCE-LIF) method was set up for the enzyme kinetics study. The enzymatic reactors would be a promising in vitro therapeutic method in an extracorporeal shunt system for acute lymphoblastic leukemia (ALL) treatment. For the first time, L-asparaginase was covalently bound to the polymer monolith and coating in the capillary and the activity characteristics of these enzymatic microreactors have been probed by Michaelis-Menten kinetic constants. Meanwhile, the D,L-amino acids were chirally separated using microchip electrophoresis with a laser induced detector and D,L-aspartic acid (D,L-Asp) were tested for the L-asparaginase enzymatic reactor kinetics study. Furthermore, human serum adding with L-asparagine (L-Asn) as the sample was hydrolyzed by the enzymatic microreactors. The results demonstrated that the developed enzymatic microreactor of L-asparaginase would be a potential therapeutic protocol for ALL treatment.
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PMID:Monolith and coating enzymatic microreactors of L-asparaginase: kinetics study by MCE-LIF for potential application in acute lymphoblastic leukemia (ALL) treatment. 2146 10

A dog with lymphosarcoma was evaluated for vomiting, lethargy, and abdominal pain 48 h after treatment with L-asparaginase. Based on drug administration, clinical signs, bloodwork, and elevated canine pancreatic lipase immunoreactivity, L-asparaginase-associated pancreatitis was diagnosed. This is an acknowledged toxicity; however, its pathophysiology and incidence rate in veterinary patients are unknown and sparsely documented.
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PMID:Asparaginase-associated pancreatitis in a dog. 2237 3


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