bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unique Pharmacokinetic Self-Potentiation of Idarubicin through Induction of Carbonyl Reducing Enzymes in Contrast to Other Anthracyclines, Pharmacologic and Clinical Study
Authors: Kishi Shinji , Yamashita Taro , Fukushima Toshihiro , Urasaki Yoshimasa , Seo Tamami , Nakamura Toru , Haba Toshihiro , Kamiya Ken-ichi , Murakami Jun , Ueda Mikio , Nakao Shinji , Ueda Takanori 
Published: April 2020

Abstract
Idarubicin (IDA) is one of the key drugs for treating hematological malignancies. Severe myelosuppression is one of the major adverse events of IDA. Interestingly, when IDA is administered in 2 consecutive courses of therapy, IDA tends to exert a stronger bone marrow suppressive effect in the second course compared with the first course while other anthracyclines such as daunorubicin tend to milder suppressive effect in the second course compared with the first course (Wiernik PH et al, Blood, 1992). In order to clarify this unique characteristics, in vivo and in vitro studies regarding the pharmacokinetic behavior were performed. When RLN-B2 (a rat liver cell line) was precultured in the presence of IDA, higher carbonyl reducing enzymes (CREs) activity was observed compared with non-precultured cells, suggesting the anthracycline-reducing enzymes was induced in the cells incubated in the presence of IDA. We examined the in vivo effects of IDA administration on the induction of CREs and subsequent enhanced formation of the 13-OH metabolite, idarubicinol (IDAol) which is more active compared with IDA and has a remarkably long half-life in the blood. The rats (F344) preadministered IDA showed higher enzymatic activity than that from non-preadministered rats (p &lt; 0.05). At 4 hours after IDA administration, the production of IDAol was facilitated in the preadministered group compared with the non preadministered group (p &lt; 0.05). Clinically, the duration of leucopenia was compared between IDA and mitoxantrone, an CREs independent anthraquinone, in combination with enocytabine, 6-mercaptopurine and etoposide. In 2 consecutive therapy, namely remission-induction and first consolidation therapy, in 30 cases of acute myelogenous leukemias, the duration of leucopenia was substantially equal in IDA group while it was substantially shorter in consolidation therapy compared with induction therapy in mitoxantrone group. These results suggest that CREs was induced by IDA pretreatment in vitro and in vivo, resulting in increased IDAol, which could potentiate the myelosuppressive and probably antitumor effects of IDA in contrast to other anthracyclines. This unique PK/PD characteristics of pharmacokinetic self-potentiation could be important in the safe and effective use of IDA in the therapy for hematological malignancies.
Acute Pulmonary Hemorrhage in Patients with Acute Myeloid Leukemia (AML) during Remission Induction Chemotherapy
Authors: Alameri Ali M , Koller Charles Asa , Pierce Sherry , Mattiuzzi Gloria 
Published: April 2020

Abstract
Background: Acute pulmonary hemorrhage is an established complication during remission induction in patients with AML. Its pathogenesis is not well known. Injury to the alveolar capillary endothelium and release of inflammatory cytokines may play a role. The standard management is usually not effective.
Aim: To analyze the course of patients with newly diagnosed AML who develop pulmonary hemorrhage during induction chemotherapy.
Study Group: 1765 patient with AML received frontline therapy from 1998–2005. We analyzed 53 patients (3%) who were admitted to medical intensive care unit due to acute pulmonary hemorrhage.
Results: The incidence of pulmonary hemorrhage was 3%. Outcome by patients characteristic was:
parameters category Total No. Pulmonary Hemorrhage (%) P value Age (years) &gt;60&#x2028; ≤60 998&#x2028; 767 32&#x2028; 21 3%&#x2028; 3% 0.569 Diagnosis M3&#x2028; M4-M5&#x2028; others 109&#x2028; 319&#x2028; 1337 812&#x2028; 33 7%&#x2028; 4%&#x2028; 2% 0.011 Platelet (×109/L) ≥20&#x2028; &lt;20 1475&#x2028; 290 43&#x2028; 10 3%&#x2028; 3% 0.624 WBC (×109/L) &gt;10&#x2028; ≤10 653&#x2028; 1112 32&#x2028; 21 5%&#x2028; 2% 0.000 Performance status 0–2&#x2028; 3–4 1662&#x2028; 103 44&#x2028; 9 3%&#x2028; 9% 0.000 Serum CR (mg/dl) &lt;1.5&#x2028; &gt;1.5 1622&#x2028; 140 46&#x2028; 7 3%&#x2028; 5% 0.150 HGB (g/dl) &lt;8.0&#x2028; &gt;8.0 872&#x2028; 893 32&#x2028; 21 4%&#x2028; 2% 0.105 Infection No&#x2028; Yes 1218&#x2028; 494 32&#x2028; 21 3%&#x2028; 3% 0.089
The predictive factors for pulmonary hemorrhage were: leukemia morphology (M3, M4–5), performance status and WBC count. The 8week survival of patients who develop pulmonary hemorrhage was 32%, (median survival days from pulmonary hemorrhage to death is 16 days).
Conclusion: pulmonary hemorrhage is a serious complication of induction therapy in AML. Modalities that reduce its incidence are needed.
Experience with the Combination of a Hypomethylating Agent and Valproic Acid in Pediatric Acute Myelogenous Leukemia
Authors: Rytting Michael , Zweidler-McKay Patrick , Hui Yang , Kantarjian Hagop , Garcia-Manero Guillermo 
Published: April 2020

Abstract
Combination epigenetic therapy consists of the combination of a hypomethylating agent (5-aza-2′-deoxycitidine [decitabine] or 5-azacitidine) with a histone deacetylase (HDAC) inhibitor. We have performed two studies combining either decitabine (n=55) or 5-azacitidine (n=54) with valproic acid (VPA). VPA is a neurotropic agent with weak HDAC inhibitory capacity in the mM range. Both studies were open to children with relapsed or refractory AML age 2 or older. Of the 109 patients, 10 (9%) were considered pediatric patients (pts). Seven patients were treated with a fixed dose of intravenous decitabine (DAC) and escalating doses of VPA, and three patients were treated with 5-azacytidine, VPA and all-trans retinoic acid (ATRA). All of the pediatric pts were refractory to a minimum of two chemotherapy regimens for AML or had multiple relapses of AML. The median age was 17 (range 5–21), 5 (50%) were diploid, and the median WBC at presentation was 3.4 (range 0.9 to 16.3). Five of the 10 pts derived benefit from the combination. In the DAC plus VPA trial, three pts achieved a complete marrow response, defined as a hypocellular marrow with less than 5% blasts without recovery of peripheral counts. An additional pt had a partial response with 6% marrow blasts after therapy and improvement in transfusion requirements. In the 5AZA/VPA/ATRA trial, 1 complete marrow response was observed. No complete remission (CR) was observed. No differences were observed in terms of LINE methylation (measured using a bisulfite pyrosequencing assay) pretreatment in pediatric versus adult patients (44.7% [40–65] pediatric versus 46.3 [37–65] adult, p=0.3) or after therapy with the combination treatment. There was a trend towards higher bound VPA levels in the adult group on days 5 or 7 (median 72 [0–202] in adult versus 32 [2–114], p=0.49). Pediatric pts treated with DAC/VPA had less acetylation compared to adult pts (14% vs 35%) and showed no evidence of mRNA activation of p21. Overall, administration of DAC/VPA or 5AZA/VPA/ATRA was safe with no grade 3 or 4 toxicity and no induction mortality in the pediatric group. Combination epigenetic therapy has potential clinical activity in pediatric pts with highly pre-treated relapsed or refractory AML and should be studied in pediatric specific clinical trials.
A Phase II Trial of Bexarotene, a Retinoid X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Authors: Tsai Donald E. , Potuzak Melissa , Mato Anthony , Loren Alison Wakoff , Porter David , Stadtmauer Edward A. , Goldstein Steven , Perl Alexander , Swider Cezary , Bagg Adam , Youssef Emile , Luger Selina 
Published: April 2020

Abstract
In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. Our previous phase I study in non-M3 AML showed evidence of leukemic response as manifested by reduction in bone marrow blast counts (15% response rate), improved platelet counts (41%) and improved neutrophil counts (26%). Based on these results, a phase II trial in non-M3 AML was initiated at the phase I MTD. In the current phase II trial, bexarotene (300mg/m2) was administered daily as monotherapy until disease progression or unacceptable side effects occurred. Fourteen patients have been enrolled: 8M/6F, median age 74 (range 20–83), 9 secondary AML (MDS or prior chemotherapy), 9 primary refractory or relapsed &lt; 1 year after induction, 5 no prior induction chemotherapy, 5 requiring hydroxyurea at the time of enrollment for leukemic blast control, 4 prior allogeneic stem cell transplant, 12 blood transfusion dependent, 11 platelet transfusion dependent, and 8 neutropenic. Overall, no significant adverse events were noted. All patients received prophylactic antihyperlipidemic agents and achieved good lipid control. Two patients developed mild hypothyroidism related to bexarotene. Five patients were evaluable with bone marrow biopsy at 2 months: 1 50% reduction in absolute blasts, 1 SD and 3 PD. Similar to data from our prior phase I study, evidence of clinical activity was manifested as platelet count response in 1 patient and neutrophil increases attributable to bexarotene in 2 patients. When combining the results of our phase I experience (27 patients) with our phase II data (14 patients), there is a suggestion of increased activity in patients with 5q minus abnormalities with 4/7 (57%) benefiting (2 BM response, 4 neutrophil improvements and 1 platelet response). Conversely rates of clinical benefit were lower in patients with multiple (&gt;3) cytogenetic abnormalities (2/13), relapse after stem cell transplant (1/9) or requiring hydroxyurea for peripheral blast control at the time of study enrollment (0/10). Bexarotene is very well tolerated at the dose level studied. Early evidence for clinical activity has been seen as exemplified by improvement in platelet count, increased neutrophil counts and decreased bone marrow blasts. In summary, we conclude that bexarotene is an active agent in a subgroup of patients with AML. Study enrollment continues with amended inclusion criteria to focus on patients more likely to benefit from treatment.
AVE5026: A New Hemisynthetic Ultra Low Molecular Weight Heparin with Enriched Anti-Xa Activity and Enhanced Antithrombotic Activity for Management of Cancer Associated Thrombosis
Authors: Hoppensteadt Debra , Jeske Walter , Walenga Jeanine M. , Fareed Jawed 
Published: April 2020

Abstract
AVE5026 is an ULMWH with a high anti-Xa activity associated with residual anti-IIa activity (ratio anti-Xa/IIa&gt;30). This ratio may be favorable for use in cancer patients as it may have a higher therapeutic window. This agent is a polydisperse mixture of oligomeric heparin fragments (molecular weight 2000–3000 daltons) prepared by partial and controlled depolymerization of porcine mucosal heparin (UFH).. The anticoagulant profile of AVE5026 has been previously reported (Hoppensteadt, et al. Blood 2007). To validate the hypothesis that AVE5026 is an appropriate antithrombotic in cancer, studies were carried out to determine its antithrombotic, bleeding, tumor growth, angiogenesis and apoptosis effects in animal models. AVE5026 produced a dose-dependent antithrombotic response in the rat laser model of microvascular thrombosis (2.5 mg/kg IV, 9±1.7 laser shots; 5.0 mg/kg SC, 8±1.6 laser shots; control 3±0.8 laser shots). The relative bleeding effects of AVE5026 in a rat tail bleeding model were negligible in comparison to enoxaparin (E) and UFH (all 5 mg/kg IV; UFH &gt;1000 sec; E 360±57 sec; AVE5026 209±29 sec; Control 215±32 seconds). Repeated administration of AVE5026 in dose ranges of 1–5 mg/kg od, SC for 14 days did not result in accumulation of the anti-Xa activity. Furthermore, in contrast to E, there was no enhancement of the hemorrhagic profile. Both E and AVE5026 inhibited tumor growth by regulating angiogenesis and apoptosis in a Lewis Lung carcinoma (14% vs. 22% decrease) rat model and in a Walker 256 carcinosarcoma model (21% vs. 30% decrease) Although comparable results to E were demonstrated in animal models of arterial thrombosis, the bleeding effect of AVE5026 were disproportionately lower. This superior safety-efficacy ratio may translate into improved antithrombotic efficacy with decreased bleeding risk, suggesting that AVE5026 may provide the optimal treatment strategy for the management of cancer associated thrombosis.
Prevention of Venous Thromboembolism in Medically Ill Patients: Global and Individual Adherences Adjust to Risk Groups
Authors: Grand Beatriz , Orosco Jorge , Cacchione Roberto , Duarte Patricio , Riveros Dardo 
Published: April 2020

Abstract
Introduction: Venous thromboembolism (VTE) is an important problem for medical patients. In spite of the existence of evidence-based guidelines for prevention of VTE, prophylaxis for venous thromboembolism is underutilized.
Objective: To assess the global and individual adherences (adjust to risk groups) to venous thromboembolism prophylaxis guidelines (VTEPG) in medical ill patients.
Desing: Prospective observational study.
Setting: The 50-bed medical floors of a university hospital.
Material and Methods: Patients: All consecutively medically ill patients (pt) admitted during a 6-month period (n: 452).
VTEPG: the guide divided medical patients in risk groups (G); G1: No need of VTEP (35 pt); G2: myocardial infarction (9 pt); G3: Stroke (21 pt); G4: high risk with thrombophilia, previous VTE, cancer (113pt); G5: respiratory and congestive heart failure, pulmonary infection (137 pt); G6: trauma (5 pt); G7: not included in previous groups, required an individual evaluation to asses VTE risk (112pt).
Prophylaxis methods included: low dose unfractionated heparin (UFH) or low molecular weight heparin (enoxaparin 40 mg/d) and mechanical methods.
Main outcome measurements: 1- Global: correct application of the guide (defined by a coincidence between the prophylaxis received and the recommendation); 2-Adjust to risk group.
Results: Global adherence: Correct application of the guide was noted in 252 pts (56%);
Adjust to risk group: GR1:71%; GR2:44%; GR3:62%; GR4:76%; GR5:55%; GR6:60% and GR7:26%.
Conclusion:
In our experience in medical patients global adherence to guides was 56%, the best adherence was observed in high risk groups 76% and the lowest 26% in those patients that need an individual risk assessment. This study and follow up permitted us to detect inaccurate prophylaxis uses and take corrective measures.
Warfarin-Induced Skin Necrosis in Vasculitis
Authors: Corinaldesi Giorgio , Corinaldesi Christian 
Published: April 2020

Abstract
Warfarin-induced skin necrosis (WISN) is a dangerous and rare complication 0.01–0.1% of patients, typically occurs in middle-age between the 3rd and 10th days after initiation of therapy, it is characterised by the lack of vascular or perivascular inflammation; early histology shows cutaneous infarcts, haemorrhages of precapillary arterioles, fibrin deposit in the postcapillary venules within the walls, absence of arterioral thrombosis which are distinctive features. We have studied two patients: a 48-years old women with AF, and a 59 years old women with deep vein thrombosis treated with warfarin (INR of 2.5–3.0 was achieved). Clinically the patients developed pain and paresthesia, erythematous flush and hemorrhagic bullae and full-thickness with skin necrosis, the patients developed ecchymoses and purpura 2 weeks later the beginning of therapy, There were multiple and symmetric lesions reported over lower abdomen and upper extremities, buttocks, thighs, breast and areas of increased subcutaneous fat, painful lesions occurred suddenly. The disorder occurs more commonly in individual who are overweight, and/or with an underlying thrombophilia. The laboratory screen demonstrated ATIII, antinuclear antibody, ANCA, absence of anticardiolipin antibodies, and C- and S-protein deficiency, one patients had factor V-Leiden mutation. The differential diagnosis is with necrotizing fascitis, venous gangrene, heparin induced thrombocytopenia, Fournier’s gangrene, purple toe syndrome, cryofibrinogenemia. The management was conservative, warfarin was discontinued, intravenous heparin was started (2mg/Kg/day), fresh frozen plasma was given with corticosteroids; as an alternative, long term therapy included fondaparinux. Surgical debridement of the necrotic tissue is needed usually, followed by secondary healing, split thickness skin autograft or flap.
Lack of Impact on Platelet Increments by Number of Apheresis Platelet Units Transfused
Authors: Patel Anush , Bernstein Zale P. , Kepner James , Patel Anil , Ahluwalia Manmeet S , Becker Joanne L 
Published: April 2020

Abstract
Introduction: Prophylactic platelet transfusions are often given when a predetermined platelet count is reached and the amount given is that necessary to achieve a desired post count. This method of transfusion ignores the question of whether the patient receives increased benefit from transfusion when more than one unit is given. To determine what effect this practice has had on transfusion outcome and platelet utilization, we have reviewed 5 years of platelet transfusion data to look specifically at transfusion events when more than one single donor platelet was given during a 24 hour period.
Methods: Transfusion data was obtained from that used for utilization review 2002 –2006. The data was sorted to identify records indicating that 2 or more units of apheresis platelets were received in a 24 hour period. This information was further selected to include only those with hematologic diseases. The platelet counts identified for inclusion were the counts prior to the release of the first unit given during the day and the first count after the release of the last unit. The change in the platelet count for the number of units was recorded and averaged for each unit increment for each record. Statistical analysis was performed and was not statistically significant.
Results For the 5 year period, 86% of all platelet transfusions at our institution were given to patients with hematologic diseases and 27% of these were given as 2, 3, or 4 units within a 24 hour period. 716 records had 2377 days with multiple transfusions; 1802, 428, and 147 episodes of 2, 3, and 4 units respectively. The increase in platelet count for a single unit transfusion at our institution averages 32.3 ×109/L. The platelet increments for 2, 3, and 4 units showed no statistical increase from this number or each other. There is no trend for the final platelet count to be greater when more units are given. These results do not take patient condition or the use of specialized products into consideration.
Discussion: Our experience suggests that transfusions of multiple platelet units may not have a greater impact on platelet increments than that when fewer units are transfused. To fully understand this data and its potential impact on patient care, further subgroup analysis within the platelet increments and correlation with patient condition and the prescribed transfusion parameters is needed.
Figure Figure
Stability of Activated Recombinant Human Factor VII (rFVIIa) after 28 Days Storage at 24° C and 43° C
Authors: Dubick Michael A , Dorfman Ryan , Klemcke Harold G , Kheirabadi Bijan S , Holcomb John B 
Published: April 2020

Abstract
The stability of rFVIIa (Novo Seven) was evaluated over a 28 day period. Lyophilized recombinant factor VIIa (1.2 mg/vial configuration) powder was tested at recommended storage conditions of 4°C or accelerated stability testing conditions of 24°C and 65% ± 5% relative humidity (RH) and 43°C plus 65% ± 5% RH. No significant change was noted in the appearance of any of the rFVIIa samples based on turbidity and visual appearance of the lyophilized cake and reconstituted liquid product. rFVIIa activity was determined by bioassay using a modified prothrombin time (PT). Chemical integrity of the rFVIIa product was determined by reverse-phase HPLC and by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). No significant changes were observed in the activity of any of the 28 day-stored samples based on the modified PT as compared to the initial baseline 4°C samples. Reverse Phase-HPLC detected a single primary peak that accounted for 97% of the material. No significant degradation of this peak was observed in any of the 28 day-stored samples compared to the initial baseline 4°C samples. Non-reduced SDS-PAGE revealed a 50,000 molecular weight band and reduced SDS-PAGE showed 30,000 and 20,000 molecular weight bands. No significant changes were observed in the protein bands in any of the 28 day-stored samples analyzed by reduced and non-reduced SDSPAGE as compared to the initial baseline 4°C samples. Taken together, these data suggest that in vitro rFVIIa activity and chemical integrity of the lyophilized powder remain intact for at least 28 days even at 43°C with 65% relative humidity.
Increased Levels of Anaphylatoxin (C5a) and Bradykinin in End-Stage Renal Disease Patients on Maintenance Hemodialysis. Potential Relevance to Heparin Mediated Hemodynamic Responses
Authors: Adiguzel Cafer , Bansal Vinod , Cunanan Josephine , Litinas Evangelos , Hoppensteadt Debra , Fareed Jawed 
Published: April 2020

Abstract
Besides the upregulation of inflammatory mediators, end stage renal disease (ESRD) patients maintained on hemodialysis are subjected to periodic exposure to heparin and contact activation due to procedural settings. Recently the presence of a heparin contaminant, namely hypersulfated chondroitin sulfate was linked with the adverse reactions and deaths observed in these patients (Kishmoto, et al. N J Med 2008). To validate this report we measured both the C5a anaphlatoxin and bradykinin levels in ESRD patients prior to and after maintenance hemodialysis. The control group comprised of 40 normal healthy individuals were included to establish the normal level of these mediators. A sandwich ELISA method utilizing a monoclonal antibody which is specific for human C5a and bradykinin were used in these studies. Both the C5a and bradykinin were elevated in pre-dialysis samples from ESRD patients (C5a: 3.2±0.6 ng/ml vs 14.2± 4.6 ng/ml, bradykinin: 6.4±1.8 ng/ml vs 9.3±2.4 ng/ml). Moreover, dialysis itself produced an increase in both the C5a and bradykinin levels. Moreover, the postdialysis samples were further increased, suggesting that dialysis and heparinization itself result in the up-regulation of these mediators. Supplementation of heparin to the plasma also resulted in the generation of both C5a and bradykinin. The plasma samples included in these studies represents patients who were not treateded with the contaminant heparin. Additional studies on in-vitro generation of these markers with contaminated heparin and the isolated contaminant showed that both of these triggered the generation of C5a and bradyknin. These results suggest that both C5a and bradykinin are up-regulated in ESRD patients and this level can be further augmented by dialysis and heparinization. Therefore, additional factors may have contributed to the complex adverse reaction profiles and deaths in patients administrated with contaminated heparin.