Administration Of L-asparaginase Research Articles

L-Asparaginase diabetes mellitus in rabbits: differing effects of two different schedules of L-asparaginase administration.

The diabetogenic effect of daily injections of 1000 i.u./kg body wt. E coli L-asparaginase was studied in male New Zealand white rabbits and compared with the diabetogenic effect of a single bolus of 10,000 I.U. E coli L-asparaginase/kg body wt. to determine whether the schedule of administration of the drug altered the diabetic syndrome produced. A daily injection of 1000 i.u. L-asparaginase/kg. body wt. was continued for 30 days. During this time glucose levels in rabbits allowed free access to food rose steadily, reaching levels of 717 +/- 63 mg/dl the day after the last injection. Levels of immunoreactive insulin fell, reaching their nadir, 53 +/- 4 pg/ml (approximately 50% of baseline) at 25 days. Glucose levels declined when therapy was discontinued, but remained significantly above control levels 46 days after insulin injections were stopped. (Glucose levels in L-asparaginase-treated groups vs. those in controls on day 46 after discontinuation: 116 +/- 3 vs. 104 +/- 1 mg/dl; P less than 0.0025.) Levels of immunoreactive insulin rose when therapy ended, reaching control levels 17 days after discontinuation. In contrast, a single bolus injection of 10,000 I.U. L-asparaginase/kg resulted in hyperglycemia with hyperinsulinemia. These data suggest that L-asparaginase can induce either a hypoinsulinemic or a hyperinsulinemic diabetic syndrome depending on the schedule of administration of the L-asparaginase and that a mild abnormality in glucose homeostasis persists after discontinuation of L-asparaginase therapy.

All Dex’ed Out With Nowhere to Go?

All Dex’ed Out With Nowhere to Go?

Cerebral thrombotic complications in adolescent leukemia/lymphoma patients treated with L-asparaginase-containing chemotherapy

We described the cerebral thrombotic complications developed in 2 adolescent patients treated with L-asparaginase-containing regimens. For determining risk factors, we retrospectively analysed hemostatic markers in 19 pediatric patients with leukemia or lymphoma who were treated with either 1 of the 2 L-asparaginase-containing regimens; 11 were treated with VLP1 and the remaining 8 were treated with the VLAD protocol. The data indicated that low coagulation factors in association with increased plasma D-dimer levels during or post-L-asparaginase administration combined with fresh frozen plasma infusion might have activated coagulation processes in these patients. Careful management is required to prevent such episodes in patients with markedly decreased coagulation factors and increased D-dimer levels following L-asparaginase administration.

Development of anti-asparaginase antibodies in childhood acute lymphoblastic leukemia.

L-asparaginase is a basic agent of antileukemic therapy, but allergic reactions against the drug and the development of anti-asparaginase antibodies are significant side-effects. The aim of our study was to estimate the presence of anti-asparaginase antibodies and to correlate the results with clinically apparent allergic reactions and with L-asparaginase activity during the treatment. We examined 13 children with newly diagnosed acute lymphoblastic leukemia (ALL), treated according to the Polish Pediatric Leukemia/Lymphoma Group protocol, based on ALL-BFM 95. Enzyme activity was estimated in serum samples, collected before each L-asparaginase administration, using the photometrical method. Anti-asparaginase antibody concentration was measured by enzyme-linked immunosorbent assay (ELISA) at the two time points: at the last day of L-asparaginase treatment in the induction and the reinduction phase. The mean L-asparaginase activity was 273 IU/L in the induction phase; no anti-asparaginase antibodies in this phase of treatment were found. The mean L-asparaginase activity was 425 IU/L in the reinduction phase of treatment; in five children anti-asparaginase antibodies were detected. In four of these five children low L-asparaginase activity and/or allergic reactions against L-asparaginase were noted. Our observations suggest a correlation between the presence of anti-asparaginase antibodies and L-asparaginase activity in childhood ALL.

Histopathological features of L-asparaginase-induced liver disease.

We studied the histopathological changes of liver in four patients who developed hepatomegaly and abnormal liver chemistry tests 2 to 20 days following administration of L-asparaginase as a part of a combination chemotherapy regimen for treatment of acute lymphoblastic leukemia. The severity of the liver disease due to L-asparaginase was unpredictable. One patient developed acute fulminant hepatic failure and required liver transplantation. The most consistent pathological change, observed in all four cases, was diffuse steatosis. Other changes included patchy hepatocyte necrosis, mixed inflammatory cell infiltrates in the portal tracts, and variable degrees of hepatocellular, or canalicular cholestasis, or a combination of these.

Neutropenia Associated with Vincristine and L‐Asparaginase Induction Chemotherapy for Canine Lymphoma

Vincristine (VCR) and L‐asparaginase (L‐ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L‐ASP cause severe neutropenia in some dogs. It has been recommended that L‐ASP be administered 12–24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/l‐ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosup‐pression, especially the interval between VCR and L‐ASP administration. Medical records of 147 dogs were reviewed. L‐ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L‐ASP, and 18% had neutrophil counts of <l,000 cells/μL. The median neutrophil count was 3,712 cells/μL (range 0— 30,968 cells/μL). No correlation was found between administration interval and day 7 neutrophil count (P= .84) or development of gastrointestinal signs, including vomiting (P= .80), diarrhea (P= .52), and decreased appetite (P= .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P= .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L‐ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L‐ASP administration may not be necessary to avoid toxicity.

Low plasma levels of hemostatic proteins during the induction phase in children with acute lymphoblastic leukemia: A retrospective study by the JACLS. Japan Association of Childhood Leukemia Study.

Thromboembolic and bleeding events are serious complications associated with the administration of L-asparaginase (ASP) during the induction phase in children with acute lymphoblastic leukemia (ALL). Prophylactic supplementation of plasma-derived coagulation products remains controversial. The purposes of this study were to examine the plasma levels of hemostatic proteins during the induction phase and the efficacy of prophylactic replacement of plasma-derived products. A multicenter retrospective survey on the incidence of hemostatic complications and the frequency of prophylactic replacement of plasma-derived products among children with ALL who under went ASP therapy was conducted. All patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-97 protocol. Thirty-six (67%) of the 54 JACLS-treatment centers responded and provided information on 127 patients. Clinically relevant hemostatic complications occurred in two patients (1.6%;2/127); one patient suffered intracranial bleeding 5 days after beginning the protocol, and the second patient suffered an ischemic attack during an ASP treatment. The administration of ASP(10 000 u/m2 x six doses) led to significant reductions in the plasma fibrinogen (180 +/- 74 to 105 +/- 57 mg/dL),antithrombin III (AT III) (126 +/- 21 to 73 +/- 18%),and plasminogen levels (97 +/- 17 to 52 +/- 18%). These laboratory parameters returned to normal levels 2 weeks after completion of the ASP treatment. Forty-eight patients (38%)received AT III concentrate (AT III-supplement group). The AT III level of the AT III-supplement group was significantly lower than that of the AT III non-supplement group, not only during the ASP therapy, but also prior to the ASP therapy. A greater percentage of patients in the AT III-supplement group received fresh-frozen plasma and in greater amounts than those in the AT III non-supplement group. Severe hemorrhage and thrombosis were uncommon in the ALL patients who underwent ASP therapy in comparison with the degree of coagulation changes. Prophylactic administration of AT III concentrate or fresh-frozen plasma did not demonstrate clear beneficial effects in the treatment of ALL in preventing thromboembolic events.

ANTITHROMBIN III SUPPLEMENTATION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH L-ASPARAGINASE

The change of plasma antithrombin III (AT) levels after supplementation of AT concentrates was examined in ALL children with acquired AT deficiency following L-asparaginase (ASP) administration. The patients received AT concentrates of 34.5 - 7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 - 0.62% and 0.70 - 0.16 mg/dL per unit AT infused per kilogram of body weight, respectively. The activity decreased to 62.0 - 7.7% of the peak values by 48 hours after supplementation. The administration of AT concentrates constantly increased the plasma AT activity in ALL children treated with ASP, which may minimize the acquired prothrombotic state.

Increased serum trypsin and elastase-1 levels in patients undergoing L-asparaginase therapy.

Although there is abundant literature on the association of L-asparaginase and acute pancreatitis in patients undergoing chemotherapy, few studies have investigated the usefulness of pancreatic enzyme measurement in the early diagnosis of L-asparaginase-induced acute pancreatitis. We measured levels of serum pancreatic enzymes before, during, and after L-asparaginase therapy in nine children with acute lymphocytic leukaemia or non-Hodgkin lymphoma. Serum levels of amylase, pancreatic isoamylase, and lipase did not change between the 1st and 30th day of L-asparaginase administration. However, the serum trypsin and elastase- levels, 10 and 20 days after beginning L-asparaginase therapy, were significantly higher than those prior to therapy. L-asparaginase may induce subclinical pancreatitis and the estimation of serum trypsin and elastase-1 may be useful in the early diagnosis of L-asparaginase-induced acute pancreatitis.

Mutagenesis and Chemical Rescue Indicate Residues Involved in β-Aspartyl-AMP Formation by Escherichia coli Asparagine Synthetase B

Site-directed mutagenesis and kinetic studies have been employed to identify amino acid residues involved in aspartate binding and transition state stabilization during the formation of beta-aspartyl-AMP in the reaction mechanism of Escherichia coli asparagine synthetase B (AS-B). Three conserved amino acids in the segment defined by residues 317-330 appear particularly crucial for enzymatic activity. For example, when Arg-325 is replaced by alanine or lysine, the resulting mutant enzymes possess no detectable asparagine synthetase activity. The catalytic activity of the R325A AS-B mutant can, however, be restored to about 1/6 of that of wild-type AS-B by the addition of guanidinium HCl (GdmHCl). Detailed kinetic analysis of the rescued activity suggests that Arg-325 is involved in stabilization of a pentacovalent intermediate leading to the formation beta-aspartyl-AMP. This rescue experiment is the second example in which the function of a critical arginine residue that has been substituted by mutagenesis is restored by GdmHCl. Mutation of Thr-322 and Thr-323 also produces enzymes with altered kinetic properties, suggesting that these threonines are involved in aspartate binding and/or stabilization of intermediates en route to beta-aspartyl-AMP. These experiments are the first to identify residues outside of the N-terminal glutamine amide transfer domain that have any functional role in asparagine synthesis.

Coexistence of Life Threatening Chemotherapy Related Leukoencephalopathy, Saggital Sinus Thrombosis and Multiple Organ Failure in a Child with Acute Lymphoblastic Leukemia: An Unusual Case with Clinical Recovery

A nine-year old girl with T cell acute lymphoblastic leukemia (ALL) had acute severe neurologic complications at the end of the remission-induction chemotherapy course. Thirty-six hours following triple intrathecal (IT) therapy and intravenous (IV) administration of L-asparaginase (L-asp), tetraplegia developed and she became unconscious. She had bouts of hypertension and persistent tachycardia unresponsive to digitalis therapy. Magnetic resonance imaging (MRI) showed multiple brain white matter hyperintensities and filling defects in the saggital sinus, suggesting thrombosis. Over the 40 days, in addition to her neurologic compromise she also had transient diabetes mellitus, severe hyperlipidemia, hypoproteinemia and edema, liver and heart failure and staphylococcus aureus sepsis with prolonged bone marrow depression. Despite, coexistence of all these chemotherapy related complications, her neurologic functions and multiple organ failure improved gradually. After a 70 days’ period of interruption, chemotherapy was resumed and continued without any further complications. Although, the etiology of her extensive sensitivity to some drugs remains unclear, we believe that it is important to document these unusual events in this child.

L-Asparagine depletion in plasma and cerebro-spinal fluid of children with acute lymphoblastic leukemia during subsequent exposures to ErwiniaL-asparaginase

Monitoring L-asparagine (L-ASN) plasma levels could provide information useful for determining whether the dosage or schedule of L-asparaginase (L-ASE) administration is adequate. Very few data are available on depletion caused by the Erwinia chrysanthemi (E. chrysanthemi) product. Since it has been suggested that L-ASN depletion may have been overestimated in the past due to residual L-ASE activity, samples in this study have been analyzed after deproteinization with sulphosalicylic acid. Patients undergoing subsequent exposures to L-ASE derived from E. chrysanthemi have been investigated. Fifty-four children with newly diagnosed acute lymphoblastic leukemia (ALL) at our institution entered this study. L-ASE was given at conventional doses (10,000 IU/sqm) every three days during the induction phase (8 doses, first exposure) or twice a week (4 doses, second exposure) during the reinduction phase. High-dose L-ASE (i.e., HD-L-ASE 25,000 IU/sqm) was given weekly, for a total of 20 doses, as a second or third exposure during the reinduction and/or maintenance phases. To determine the plasma levels of L-ASN, samples were deproteinized with sulphosalicylic acid, stored at -80 degrees C and then analyzed by HPLC after precolumn derivatization with o-phthaldialdehyde. The CSF samples were analyzed by the same procedure. An experiment was carried out to detect in vitro L-ASE deactivation in patients' plasma. L-ASN plasma depletion was observed in 80% of the cases during the first exposure to conventional doses of L-ASE and only in 25% of the cases during the second or third exposures to either conventional or high doses of L-ASE. A correlation was found between plasma and CSF L-ASN levels. Activity inhibitory to L-ASE was found in the plasma of patients not depleted during L-ASE treatment and was not found in the plasma of those in whom L-ASN plasma depletion was obtained. L-ASN plasma depletion is regularly obtained in the majority of patients during the first exposure to conventional doses of E. chrysanthemi L-ASE. Conversely, in most cases depletion does not occur during subsequent exposures. Studies should be performed to evaluate whether L-ASE derived from different species or conjugated with polyethylene-glycole are effective in obtaining L-ASN plasma depletion in patients previously treated with Erwinia C. L-ASE. The clinical impact of L-ASN depletion should also be investigated in large cohorts of patients.

Impact of reinduction regimens for relapsed and refractory acute lymphoblastic leukemia in adults.

The clinical outlook for adults with acute lymphoblastic leukemia (ALL) has improved with the use of intensive chemotherapy. Complete remissions (CR) are achieved in 80% of adults but the majority relapse on maintenance chemotherapy and a few exhibit primary resistance to induction therapy. This report compares the various salvage treatments and provides guidance in selecting a regimen with the optimum clinical outcome. Regimens using high-dose ara-C (HDAC) in combination with mitoxantrone, amsacrine, or idarubicin are superior to HDAC alone or with L-asparaginase. The sequential administration of methotrexate and L-asparaginase is equally effective. The duration of second CR is short for all chemotherapeutic regimens.

A Case of ALL with Transient Hyperlipemia due to L-Asparaginase Administration

A Case of ALL with Transient Hyperlipemia due to L-Asparaginase Administration

Effects of tizanidine on morphine physical dependence: Attenuation and intensification

It has previously been shown that subchronic and acute administration of L-asparaginase and glutaminase inhibitors D-Aspartic acid (D-ASP) and prolyl-leucyl-glycinamide (PLG) intensifies and attenuates morphine (M) physical dependence, respectively, by the inhibition of ASP and glutamic acid (GLU) production, and subsequently their normal releases. Tizanidine (TIZ) has long been known to be an α2-adrenoceptor agonist and inhibitor of ASP and GLU release. Therefore, in this study TIZ has been administered subchronically during the development of M physical dependence to rats in which M-containing pellets had been implanted or acurately 30 min before naloxone (NL)-induced abstinence syndrome. The subchronic administration of TIZ intensified NL-precipitated abstinence syndrome whereas its acute adminnistration attenuated it, as did D-ASP and PLG. On the other hand, TIZ added into the medium prevented the in vitro M-dependent-made guinea pig ileum from contracting following NL application. Furthermore, TIZ stopped the already started contraction by NL of the M-dependent ileum, which completely relaxed later. These effects of TIZ on M-dependent ileum were antagonized by the α2-adrenoceptor antagonist yohimbine. The intensification by subchronic TIZ administration of abstinence syndrome was attributed to the lesser release of ASP and GLU, which resulted in the larger blockade of M of ASPergic/GLUergic receptors due to the lesser release of their endogenous agonist ASP and GLU and consequently the higher upregulation of the receptors. The attenuation by acute TIZ administration of NL-precipitated abstinence syndrome was explained with lesser release of ASP and GLU and concomitantly the lesser stimulation of the receptors. The results of the in vitro experiments were considered supporting evidence for the fact that α2-adrenoceptor aginistic effect of causes the inhibition of ASP and GLU release and for this action TIZ has already been combined with dextromethorphan in the treatment of heroin addicts.

Incidence of thrombotic complications in adult patients with acute lymphoblastic leukaemia receiving L-asparaginase during induction therapy: a retrospective study. The GIMEMA Group.

The incidence of thrombotic complications chronologically related to L-asparaginase administration is retrospectively analyzed in 238 adult ALL patients treated according to the GIMEMA protocol ALL 0288. The patients (126 males and 112 females, aged 12-68 years, median 29) received E. coli L-asparaginase (L-ase) in the induction phase at a dosage of 6000 U/m2/day x 7 d starting on d 15, as well as vincristine, prednisone, daunorubicin and cyclophosphamide, the last-named by random 1:1. Ten patients (4.2%) developed thrombotic complications 5-15 d (median 11 d) after the start of L-ase treatment. The thrombotic events, which were lethal in 5 patients, involved the cerebral sinus (5 cases), the cerebral arteria (2 cases), the portal vein (1 case), the pulmonary district (1 case), and a deep vein in the lower extremity (1 case). The occurrence of these complications was not related to the general thrombotic risk factors, nor to the main clinical and laboratory data registered at diagnosis and immediately before the start of L-asparaginase treatment. The present study documents for the first time in a sufficiently large series of adult ALL patients that the incidence and the severity of thrombotic events related to L-ase administration are relevant and need further consideration.

Antithrombin III concentrations associated with L-asparaginase administration.

Antithrombin III concentrations associated with L-asparaginase administration.

Effects of single-dose l-asparaginase on coagulation values in healthy dogs and dogs with lymphoma

Summary Ten healthy dogs and 10 dogs with multicentric lymphoma were given a single dose of l-asparaginase at a rate of 10,000 IU/m2 of body surface. Assessment of concentrations of contributors to the coagulation process and of the ability to coagulate including antithrombin III, one-stage prothrombin time, prothrombin-proconvertin time, activated partial thromboplastin time, plasminogen, fibrinogen, and platelet number were performed prior to drug administration (day 0). These tests were repeated 24 hours (day 1), 48 hours (day 2), and 7 days after treatment with l-asparaginase. Antithrombin-III concentrations were significantly lower in the dogs with lymphoma than in healthy dogs on days 0, 1, 2, and 7; however, with the exception of day 1, mean values remained within normal limits. There was also a difference between the 2 groups in prothrombin/proconvertin values on day 7 and in platelet number on day 2, with the lymphoma group having significantly shorter prothrombin/proconvertin time than healthy dogs, and the difference in platelet numbers being associated with increased counts in the healthy dogs. Data obtained from the healthy dogs and dogs with lymphoma for each coagulation test were pooled for each treatment day (0, 1, 2, and 7), and day-0 values for each coagulation test were compared with data obtained on days 1, 2, and 7. Antithrombin-III concentration on day 7 was significantly lower than on day 0, prothrombin/ proconvertin time on day 1 was significantly longer than on day 0, and fibrinogen concentrations on days 1 and 2 were significantly lower than on day 0. Evidence of clinical hemorrhage or thrombosis was not found in any dog subsequent to l-asparaginase administration. Results of this study suggest that although individual coagulation test results may be altered, a single dose of l-asparaginase does not clinically alter coagulation in either healthy dogs or dogs with multicentric lymphoma.

Changes in hemostatic and fibrinolytic proteins in patients receiving L-asparaginase therapy.

Hemostatic changes were evaluated in ten patients with acute lymphoblastic leukemia and lymphoma who received chemotherapy with L-asparaginase, vincristine, and prednisolone for 1 week. Following treatment, prothrombin time and activated partial thromboplastin time were significantly prolonged, while a marked decrease in fibrinogen levels was observed. The values for cross-linked fibrin degradation products, however, remained within normal limits during treatment, which excluded the possibility of disseminated intravascular coagulation. The concentrations of coagulation inhibitors (antithrombin III, protein C, and protein S), plasminogen, and alpha 2 antiplasmin also significantly decreased; however, levels of both tissue-type plasminogen activator and plasminogen activator inhibitor, which are synthesized in endothelial cells, increased during the treatment. Although a decrease was observed in concentrations of many coagulation factors, including subunits A and B of factor XIII, the activity and antigenicity of factor VII significantly increased following the treatment. From this study, we concluded that these hemostatic abnormalities caused by the administration of L-asparaginase produced a labile condition that easily inclines to bleeding or thrombosis.

The effect of L-asparaginase on lipid metabolism during induction chemotherapy of childhood lymphoblastic leukaemia.

L-asparaginase is an effective antileukaemic drug and a potent inhibitor of hepatic protein synthesis. Its effect on lipid metabolism was studied in two cohorts of children with ALL, one of whom received L-asparaginase concomitantly with three other drugs (protocol BFM 79). In the second protocol (BFM 83) administration of L-asparaginase was arranged to follow the other three drugs in time sequence. The two major findings of this study were elevated serum levels of total cholesterol and a strong increase in serum triglycerides. The former change was due to an increase in alpha-cholesterol and could not be attributed to L-asparaginase because it was also found following protocol BFM 83 before the administration of the drug. Elevations of total triglycerides were due to high levels of exogenous chylomicron bound triglycerides and were limited in occurrence almost exclusively to the period of L-asparaginase monotherapy. Hypothyroidism was excluded as a possible pathogenetic mechanism. These changes in lipid metabolism induced by L-asparaginase during intensive remission induction chemotherapy are fully reversible.