Effect of sedative agent selection on morbidity, mortality and length of stay in patients with increase in intracranial pressure / 世界急诊医学杂志（英文）

BACKGROUND: To identify the effects of sedative agent selection on morbidity, mortality, and length of stay in patients with suspected increase in intracranial pressure. Recent trends and developments have resulted in changes to medications that were previously utilized as pharmacological adjuncts in the sedation and intubation of patients with suspected increases in intracranial pressure. Medications that were previously considered contraindicated are now being used with increasing regularity without demonstrated safety and effectiveness. The primary objective of this study is to evaluate and compare the use of Ketamine as an induction agent for patients with increased intracranial pressure. The secondary objective was to evaluate and compare the use of Etomidate, Midazolam, and Ketamine in patients with increased intracranial pressure. METHODS: We conducted a retrospective chart review of patients transported to our facility with evidence of intracranial hypertension that were intubated before trauma center arrival. Patients were identified during a 22-month period from January 2014 to October 2015. Goals were to evaluate the impact of sedative agent selection on morbidity, mortality, and length of stay. RESULTS: During the review 148 patients were identified as meeting inclusion criteria, 52 were excluded due to incomplete data. Of those the patients primarily received; Etomidate, Ketamine, and Midazolam. Patients in the Ketamine group were found to have a lower mortality rate after injury stratification. CONCLUSION: Patients with intracranial hypertension should not be excluded from receiving Ketamine during intubation out of concern for worsening outcomes.

Exploration of a new model of care in a psychiatry unit.

The model established at Orillia Soldiers Memorial Hospital involves family physicians as the most responsible physician. They act as "admission gatekeeper" for all unattached patients who are admitted to the psychiatry in-patient unit. A PubMed, EBSCO, OVID Medline, Embase, CINAHL, and Web of Science database review of the last 10 years (2006-2016) was undertaken. A satisfaction survey was undertaken. An intensive literature review found this model to be unique. The model has proved to be extremely efficient and cost-effective.

p38 pathway kinases as anti-inflammatory drug targets.

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38alpha is a key MAPK involved in tumor necrosis factor alpha and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases (e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38alpha has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.

The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist.

The in vitro activity of leridistim was characterized for cell proliferation, generation of colony-forming units (CFU) and differentiation of CD34+ cells. In AML-193.1.3 cells, leridistim exhibited a significant increase in potency compared to rhG-CSF, SC-65303 (an IL-3 receptor agonist) or an equimolar combination of rhG-CSF and SC-65303. CFU-GM assays demonstrated that at 50% of the maximum response, the relative potency of leridistim was 12-fold greater than the combination of rhG-CSF and rhIL-3 and 44-fold more potent than rhG-CSF alone. In multi-lineage CFU assays, a combination of erythropoietin (rhEPO) and leridistim resulted in greater numbers of BFU-E, CFU-GEMM and CFU-Mk than rhEPO alone. Ex vivo culture of peripheral blood or bone marrow CD34+ cells with leridistim substantially increased total viable cells over cultures stimulated with rhG-CSF, SC-65303, or a combination of rhG-CSF and SC-65303. Culture with leridistim, resulted in a greater increase in myeloid (CD15+/CD11b+), monocytic (CD41-/CD14+) and megakaryocytic (CD41+/CD14-) precursor cells without depleting the progenitor pool (CD34+/CD15-/CD11b-). These results demonstrate that leridistim is a more potent stimulator of hematopoietic proliferation and differentiation than the single receptor agonists (rhG-CSF and SC-65303) either alone or combined. These unique attributes suggest that leridistim may enhance hematopoietic reconstitution following myelosuppressive chemotherapy.

A single dose of pegylated leridistim significantly improves neutrophil recovery in sublethally irradiated rhesus macaques.

Leridistim, a member of the myelopoietin family of dual receptor agonists that binds interleukin-3 and G-CSF receptors, has been shown to enhance hematopoietic activity in rhesus monkeys above that observed with either cytokine alone or in combination. This study demonstrated the ability of a pegylated form of leridistim (peg-leridistim), administered s.c., as a single- or two-dose regimen separated by 4 or 7 days, to significantly improve neutrophil recovery following radiation-induced myelosuppression. Rhesus macaques were total body x-irradiated (250 kVp, TBI) to 600 cGy. Following TBI, two groups received peg-leridistim (n = 5) or leridistim (n = 4) at a dose of 600 microg/kg on day 1, while two other groups (both n = 4) received peg-leridistim at 200 microg/kg on day 1 and day 4, or day 1 and day 7. The irradiation controls (n = 7) received 0.1% autologous serum for 18 days. All peg-leridistim treatment schedules significantly improved all neutrophil-related parameters following TBI as compared with nontreated controls and were equivalent in effect when compared among themselves. Administration of a single high dose or two separate lower doses of peg-leridistim significantly improved neutrophil regeneration, in a manner equal to that of conventional daily or abbreviated every-other-day administration of leridistim in this nonhuman primate model of severe myelosuppression.

Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: effect of schedule, dose, and route of administration.

Leridistim is from the myelopoietin family of proteins, which are dual receptor agonists of the human interleukin-3 and G-CSF receptor complexes. This study investigated the effect of dosage, administration route, and schedule of leridistim to stimulate multilineage hematopoietic recovery in total body irradiated rhesus monkeys. Animals were x-irradiated on day 0 (600 cGy, 250 kVp) and then received, on day 1, leridistim s.c. in an abbreviated, every-other-day schedule at 200 microg/kg, or daily at 50 microg/kg, or i.v. daily or every-other-day schedules at 200 microg/kg dose. Other cohorts received G-CSF (Neupogen((R)) [Filgrastim]) in an every-other-day schedule at 100 microg/kg/day, or autologous serum (0.1%) s.c. daily. Hematopoietic recovery was assessed by bone marrow clonogenic activity, peripheral blood cell nadirs, duration of cytopenias, time to recovery to cellular thresholds, and requirements for clinical support. Leridistim, administered s.c. every other day, or i.v. daily, significantly improved neutrophil, platelet, and lymphocyte nadirs, shortened the respective durations of cytopenia, hastened trilineage hematopoietic recovery, and reduced antibiotic and transfusion requirements. A lower dose of leridistim administered daily s.c. enhanced recovery of neutrophil and platelet parameters but did not affect lymphocyte recovery relative to controls. Leridistim, a novel engineered hematopoietic growth factor administered at the appropriate dose, route and schedule, stimulates multilineage hematopoietic reconstitution in radiation-myelosuppressed nonhuman primates.

Promegapoietin, a family of chimeric growth factors, supports megakaryocyte development through activation of IL-3 and c-Mpl ligand signaling pathways.

OBJECTIVE: The signaling pathways induced by promegapoietin (PMP), a family of chimeric growth factors that activate the human IL-3 and c-Mpl receptors, were investigated. METHODS: The biological activity of PMP was examined by receptor binding, cell proliferation, ex vivo expansion of hematopoietic progenitor cells, and in vivo production of platelets. The activation of signaling pathways was examined by Western blot and Northern blot analyses. RESULTS: Two PMP molecules, PMP-1 and PMP-1a, induced proliferation of cells expressing the IL-3 receptor, c-Mpl, or both receptors and bound to the IL-3 receptor and c-Mpl with high affinity. Ex vivo expansion assays using human bone marrow CD34(+) cells suggested that PMP-1 induced greater total cellular expansion as well as expansion of CD41(+) megakaryocytic precursor cells than IL-3 or c-Mpl ligand alone. Subcutaneous administration of 50 microg/kg of PMP-1 for 10 days to rhesus monkeys resulted in increased platelet production in vivo from a baseline of 357 +/- 45 x 10(3) cells/mL to 1376 +/- 151 x 10(3) cell/mL. PMP-1 induced phosphorylation of the beta(c) subunit of IL-3 receptor and c-Mpl, JAK2, and STAT5b, but not STAT3. PMP-1 induced greater expression of Pim-1, c-Myc, and cyclin D2 than did either an IL-3 receptor agonist or c-Mpl receptor agonist alone. The magnitude of induction of early response genes was similar for PMP and the coaddition of IL-3 receptor agonist and c-Mpl receptor agonist. CONCLUSION: PMP combines the biological activities of IL-3 and c-Mpl ligand in a single molecule that can simultaneously activate signaling pathways induced by both these ligands.

Promegapoietin-1a, an engineered chimeric IL-3 and Mpl-L receptor agonist, stimulates hematopoietic recovery in conventional and abbreviated schedules following radiation-induced myelosuppression in nonhuman primates.

Promegapoietin-1a (PMP-1a), a multifunctional agonist for the human interleukin 3 and Mpl receptors, was evaluated for its ability to stimulate hematopoietic reconstitution in nonhuman primates following severe radiation-induced myelosuppression. Animals were total body x-irradiated (250 kVp) to 600 cGy total midline tissue dose. PMP-1a was administered s.c. in several protocols: A) daily (50 microg/kg) for 18 days; B) nine doses (5 microg/kg) every other day for 3 weeks; C) a single high dose (100 microg/kg) at 20 hours, or D) a single high dose (100 microg/kg) at 1 hour following TBI. The irradiation controls received 0.1% autologous serum for 18 consecutive days. Hematopoietic recovery was assessed by bone marrow clonogenic activity, peripheral blood cell nadirs, duration of cytopenias, time to recovery to cellular thresholds, and requirements for clinical support. PMP-1a, irrespective of administration schedule, significantly improved all platelet-related parameters: thrombocytopenia was eliminated, the severity of platelet nadirs was significantly improved, and recovery of platelet counts to > or =20,000/miccrol was significantly reduced in all PMP-1a-treated cohorts. As a consequence, all PMP-1a-treated cohorts were transfusion-independent. Neutrophil regeneration was augmented in all treatment schedules. Additionally, all PMP-1a-treated cohorts showed an improvement in red blood cell nadir and recovery. PMP-1a in conventional or abbreviated schedules induced significant thrombopoietic regeneration relative to the control cohort, whereas significant improvement in neutrophil recovery was schedule-dependent in radiation-myelosuppressed nonhuman primates.

Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression.

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50 microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet < 20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.

Prevalence and risk association for Trichinella infection in domestic pigs in the northeastern United States.

To determine Trichinella infection in a selected group of farm raised pigs, 4078 pigs from 156 farms in New England and New Jersey, employing various management styles, were selected based on feed type (grain, regulated waste, non-regulated waste). The number of pigs bled from each farm were based on detecting infection assuming a 0.05 prevalence rate. Serum was tested by enzyme-linked immunoassay for antibodies to Trichinella spiralis. Seropositive pigs were tested by digestion at slaughter (when possible) for the presence of Trichinella larvae. Questionnaires completed at the time of serum collection were used to develop descriptive statistics on farms tested and to determine measures of association for risk factors for the presence of Trichinella-seropositive pigs. A total of 15 seropositive pigs on 10 farms were identified, representing a prevalence rate of 0.37% and a herd prevalence rate of 6.4%. A total of nine seropositive pigs and one suspect pig from six farms were tested by digestion; four pigs (representing three farms) harbored Trichinella larvae at densities of 0.003-0.021 larvae per gram (LPG) of tissue; no larvae were found in six pigs. Risk factors which were significantly associated with seropositivity included access of pigs to live wildlife and wildlife carcasses on the farm; waste feeding had no statistically significant association with seropositivity for Trichinella infection in pigs. The presence of Trichinella infection in pigs in New England and New Jersey has declined during the past 12 years when compared with previous prevalence studies.

Laparoscopic management of adnexal masses in pregnant women.

OBJECTIVE: To report on 14 cases of adnexal masses in the second trimester of pregnancy that were managed with laparoscopic surgery. STUDY DESIGN: A retrospective study. During the period between January 1994 and January 1998, 14 women presented with adnexal masses in pregnancy and were surgically managed with laparoscopy. A retrospective chart review of these patients was used to determine factors, including gestational age, operating time, length of hospital stay, pathology results, pregnancy outcomes and complications. RESULTS: Fourteen patients had laparoscopic removal of adnexal masses in their second trimester of pregnancy. Average gestational age was 16 weeks (range, 11.5-21), average operating time was 84 minutes (range, 32-145), and average hospital stay was 2.0 days (range, 1-5). Pathology revealed 4 serous cystadenomas, 3 mucinous cystadenomas, 3 mature teratomas, 3 functional cysts and 1 bilateral endometrioma. There were no postoperative complications except for one case of mild peritonitis, which resolved with expectant management. There were no cases of preterm labor associated with the surgery. Ten pregnancies continued to term without complications and delivered average-sized infants. Three pregnancies were in the third trimester without complications at this writing. There was one intrauterine fetal death at 31 weeks; it was found to be secondary to an acute cord accident on autopsy remote from surgery. CONCLUSION: Significant ovarian masses are diagnosed relatively frequently in the pregnant woman. The risk of malignancy is low, but complications resulting from distention, rupture and/or torsion of the adnexa can be a significant concern. As laparoscopic procedures improve and our experience with laparoscopy in the pregnant woman increases, most of these patients can forego laparotomy and be managed safely by laparoscopic removal of the mass. This series outlines laparoscopic technique and outcomes after removal of significant adnexal masses in pregnancy.

The combined administration of daniplestim and Mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression.

This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl-L) administration in nonhuman primates following severe, radiation-induced myelosuppression. Rhesus monkeys were total body x-irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post-TBI, animals were s.c. administered daniplestim (100 microg/kg bid; n = 4), Mpl-L (10 microg/kg qd; n = 3), daniplestim (100 microg/kg bid) plus Mpl-L (10 microg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/microl) was significantly decreased by the administration of daniplestim (6.5 d, p = .01), Mpl-L (3.0 d, p = .003) and the coadministered daniplestim/Mpl-L (1.3 d, p = .001) compared to controls (10.4 d). As monotherapy Mpl-L but not daniplestim significantly improved the PLT nadir (21,000/microl, p = .023 and 5,000/microl, p = .266, respectively) compared to the control (3,000/microl). The combined administration of daniplestim and Mpl-L significantly improved the PLT nadir (28,000/microl, p = .007) compared to both the control cohort (3,000/microl) and the daniplestim only cohort (5,000/microl, p = .043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl-L cohorts (d 18) than in the Mpl-L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl-L alone neither shortened the duration of neutropenia (ANC<500/microl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl-L administration (76/microl, p = .001 and 50/microl, p = .093, respectively) compared to the controls (8/microl). Coadministration of daniplestim and Mpl-L significantly improved the ANC nadir (196/microl, p = .001) compared to either the AS- or the monotherapy-treated cohorts. Also the duration of neutropenia observed in the AS-controls (16.2 d) was significantly reduced in the daniplestim/Mpl-L cohort (10.8 d, p = .002). The combined administration of daniplestim and Mpl-L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation-induced bone marrow myelosuppression.

Isolation and structure of leukotriene-A4 hydrolase inhibitor: 8(S)-amino-2(R)-methyl-7-oxononanoic acid produced by Streptomyces diastaticus.

The novel amino acid 8(S)-amino-2(R)-methyl-7-oxononanoic acid (1) was isolated from the soil-borne microorganism Streptomyces diastaticus during our screening for inhibitors of leukotriene-A4 hydrolase (LTA4H), a requisite enzyme in the biosynthesis of the potent inflammatory mediator leukotriene-B4 (LTB4). The structure of 1 was determined by detailed spectroscopic analyses and is related to 7-keto-8-aminopelargonic acid (2), a biosynthetic precursor of biotin. The relative potency of 1 (LTA4H IC50 = 0.6 microM) warranted further biological studies.

Inhaled misoprostol blocks guinea pig antigen-induced bronchoconstriction and airway inflammation.

Inhaled E-type prostaglandins (PGE) have been shown to modulate responses to both allergic and nonallergic provocation. Misoprostol, a PGE1 analog, was developed as an antiulcer agent because it prevents gastrointestinal ulceration. Little is known about the effect inhaled misoprostol has on the airway and whether its potential antiasthmatic activity would be similar to other PGEs. Nebulizied solutions of misoprostol and PGE2 effectively blocked the acute bronchospasm caused by a subsequent inhaled antigen challenge in actively sensitized guinea pigs. The minimal concentration to result in a significant reduction in specific airway resistance was 3 and 30 micrograms/ml for misoprostol and PGE2, respectively. Exposure to a 300 micrograms/ml nebulized misoprostol solution provided significant protection for 2 h. Eosinophil recovery in bronchoalveolar lavage performed 24 h after antigen challenge was significantly reduced by 72%. In a chronic model of antigen-induced airway inflammation in which guinea pigs are given multiple antigen exposures over a 3-wk period, both misoprostol and its free acid-active metabolite 5C-30695 significantly reduced bronchoalveolar lavage eosinophils by 50 to 55%. Treatment with TRFK5, a monoclonal antibody to interleukin-5, resulted in a 76% decrease in eosinophil recovery. The combination of antibronchoconstrictive and anti-inflammatory effects suggests that inhaled misoprostol may be an effective treatment for the acute and chronic symptoms of asthma.

Characterization of 5-lipoxygenase inhibitors in biochemical and functional in vivo assays.

Several potent and selective inhibitors of 5-lipoxygenase (5-LO) have been recently developed with excellent activity in certain in vivo assays of leukotriene production. The efficacy of three such inhibitors that have been in clinical trials (zileuton, A-78773 and ZD2138) were evaluated in: 1) ex vivo whole blood assay, 2) dermal Arthus reaction, and 3) functional airway response. In addition, a model of eicosanoid production in rat lung was developed that provides a simple assay for evaluation of the biochemical efficacy of 5-LO inhibitors in the lung. Bronchoalveolar lavage of rat lung with calcium ionophore A23187 resulted in rapid and robust production of PGE2, 6-keto-PGF1 alpha, thromboxane (TxB2), and leukotriene B4 (LTB4). Supplementation of lavage fluid with archidonic acid markedly augmented production of all eicosanoids except LTB4. All three inhibitors were potent and selective blockers of LTB4 production in the ex vivo whole blood assay and in the dermal Arthus reaction. In contrast, higher doses of inhibitor were needed to block LTB4 production in the rat lung lavage model than were needed to block ex vivo whole blood LTB4 production when both end points were measured in the same animal. Similarly, zileuton and A-78733 were less effective in suppressing the functional airway response to antigen in sensitized guinea pigs, whereas both inhibitors were effective in suppressing LTB4 production in the ex vivo whole blood assay. These results demonstrate that different 5-LO inhibitors have markedly distinct efficacy for inhibition of leukotriene production, depending on the animal model.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid and selective induction of blood eosinophilia in guinea pigs by recombinant human interleukin 5.

Interleukin 5 (IL-5) has been implicated as a causal mediator in the development of pulmonary eosinophilia and airway hyperreactivity in human asthma. Supportive evidence for a pathogenic role of IL-5 in this disease has been provided by guinea pig models in which antigen-induced lung eosinophilia and bronchial hyperresponsiveness have been specifically attenuated with a neutralizing antibody to IL-5. In the present report, we describe a rapid mechanism-based model of IL-5-induced eosinophilia in the guinea pig. Our results show that intravenous injection of human IL-5 induced a 5-10-fold increase in the percentage and number of eosinophils in blood within 1 hour. In contrast, neutrophils and mononuclear cells were not recruited during this time. The increase in eosinophils was blocked by pretreatment of animals with an anti-IL5 monoclonal antibody (TRFK5) in doses similar to those which inhibit eosinophilia in guinea pig asthma models. Furthermore, dexamethasone, a potent inhibitor of eosinophilia in guinea pig asthma, profoundly suppressed the eosinophilia induced by human IL-5. This rapid model will be useful for elucidating the eosinophil activating properties of IL-5 in vivo and may potentially facilitate the development of IL-5 receptor antagonists for the specific blockade of the eosinophilic inflammation observed in human asthma.

Inactivation of an animal and a fungal catalase by hydrogen peroxide.

We have quantitatively compared the rates of peroxide-dependent inactivation of bovine liver catalase and Aspergillus niger catalase as class representatives of catalases that contain tightly bound NADPH and those that do not. Inactivation of these catalases in the presence of ethanol has also been quantitated in an effort to assess the importance of compound II, an inactive form of bovine liver catalase, in the inactivation reaction. The values of k2, the second-order rate constant for inactivation calculated for the bovine enzyme, in the absence and presence of ethanol, respectively, were 8.9 +/- 0.26 and 8.5 +/- 0.27 M-1 min-1. In contrast, the values for the A. niger enzyme were 0.51 +/- 0.069 and 10.5 +/- 0.32 M-1 min-1. The A. niger enzyme is more stable toward hydrogen peroxide-induced inactivation than the liver enzyme. The A. niger enzyme is markedly destabilized by 20 mM ethanol, whereas the inactivation of the liver enzyme is unaffected by ethanol. Reaction of bovine liver catalase with ethyl hydroperoxide produced the characteristic absorption spectrum of compound I and in the absence of ethanol the spectrum associated with compound II. In contrast, the fungal enzyme developed compound I spectrum but spectral changes that might be ascribed to compound II were barely detected in the Soret region. Spectral changes for A. niger catalase in the visible region were modified by the presence of ethanol but could not be clearly correlated with the bovine catalase compound II spectra either in the presence or absence of ethanol. The stability of the fungal and bovine catalases in the presence of hydrogen peroxide is quantitatively documented. The enzymes are also shown to be different in their response to ethanol and in the formation of compound II-like species with ethyl hydroperoxide. It appears unlikely that compound II is an intermediate in the hydrogen peroxide-mediated inactivation reaction of either catalase under catalatic assay conditions.