bluuebunny/crossref_metadata_2025 huggingface dataset:
aPTT in Heparinized Patients: Influence of the Interval Between Sampling and Testing
Authors: Rachakonda Vikrant , Rachakonda Leelanand , Belliveau Robert R.
Published: November 2007

Activated partial thromboplastin times (aPTTs) from 29 whole blood samples were drawn from patients receiv ing unfractionated heparin through a constant intravenous drip. Three aPTTs were determined for each whole blood sample. The first aPTT was performed on a separated portion of the original sample at approximately 30 min from the time of sam pling. A second was performed on the same separated sample at approximately 90 min from the time of sampling, and the third was performed on the original sample at 90 min. The mean aPTT of the set of 30-minute separated samples was 79.7 seconds. The mean aPTT of the 90-minute separated samples was 72.8 seconds. The mean aPTT of the 90-minute original sample was 60.8 seconds. These results demonstrate that an aPTT performed 30 min after sampling yields a value signifi cantly greater than an aPTT performed at 90 min. The lower aPTT values may lead to an unnecessary increase in heparin dosage. This situation underscores the need to further investi gate the aPTT as a foundation for the standardization of the protocol for the use of heparin.
Pharmacokinetics and Pharmacodynamics of Argatroban as Studied by HPLC and Functional Methods: Implications in the Monitoring and Dosage-Optimizations in Cardiovascular Patients
Authors: Ahmad Sarfraz , Ahsan Ahmad , Iqbal Omer , Hoppensteadt Debra A. , Lewis Bruce E. , Walenga Jeanine M. , Fareed Jawed
Published: November 2007

Argatroban is a peptidomimetic reversible throm bin inhibitor that has been used as an anticoagulant in clinical trials related to heparin-induced thrombocytopenia (HIT). To monitor the absolute concentrations of argatroban and to relate the safety and efficacy of this drug with the circulating levels and corresponding prolongation of the activated clotting time (ACT), a specific method for the absolute measurement of this drug was developed. Initial studies for the validation of method included the quantitation of argatroban in normal volunteers administered with escalating doses of argatroban (15-40 μg/ kg/min) on four consecutive days for 4 h (ARG 102 Study). Pre- and postinfusion samples were analyzed by using the high performance liquid chromatography (HPLC) method. Argatro ban levels ranged from 0.5-4.5 μg/mL, postinfusion (0.84 ± 0.23 [day 1], 1.55 ± 0.34 [day 2], 2.92 ± 0.15 [day 3], 3.04 ± 0.49 [day 4]). A proportionate increase in the activated partial thromboplastin time (APTT) and ACT was observed. Simi larly, ecarin clotting time (ECT) also provided comparable re sults. Argatroban levels were also measured in a PTCA trial where this agent was used as an anticoagulant at 350 μg/kg bolus followed by 25 μg/kg/min to regulate the ACT between 400-450 sec (ARG 310 Study). In this angioplasty study, the levels of argatroban correlated well with the ACT (r2 > 0.8). In another clinical study, argatroban was used in conjunction with streptokinase for the management of acute myocardial infarc tion (AMI), the levels of this agent were quantitated at baseline and 2-8 h postthrombolysis (AMI Study). In the AMI study, mean argatroban levels at 2-8 h were between 1.5-2.0 μg/mL. Upon completion of the infusion, a time dependence in circu lating argatroban levels was noted. Since heparinization, he modilution, hypofibrinogenimia due to thrombolysis influence the ACT levels, absolute quantitation of argatroban in these patients provides a reliable means of monitoring and dosage optimization of this anticoagulant. Based on these observations and additional pharmacokinetics data, it is proposed that the currently used dosage of 350 μg/kg bolus followed by 25 μg/ kg/min infusion is optimal to achieve anticoagulation for inter ventional cardiovascular procedures. This translates into 3-5 μg/mL circulating concentration. For therapeutic anticoagula tion to mimic responses observed at an APTT of 70-100 sec, a bolus of 50 μg/kg followed by 10 μg/kg/min resulting in a circulating levels of approximately 1.0 μg/mL concentration is recommended.
Insulin Treatment Inhibits PAI-1 Production in NIDDM Patients with Endothelial Dysfunction
Authors: Galajda Peter , Baláž Dušan , Martinka Emil , Mokán Marian , Kubisz Peter
Published: November 2007

We examined 34 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with sulfonylurea regimens, 24 NIDDM patients with 2-3 months long-acting insulin treat ment and 19 age-matched normoinsulinemic healthy controls. NIDDM patients were divided into two subgroups, with and without endothelial dysfunction according to von Willebrand factor level 0.14 IU/mL. There were significant differences in PAI-1 levels among patients without endothelial dysfunction treated by sulfonylurea agents (median 48.1, range 14-108 ng/ mL) or insulin (27.9, 2-53 ng/mL) and patients with endothe lial dysfunction treated by sulfonylurea regimens (80.7, 43-217 ng/mL) or insulin, respectively, (16.7, 7-34 ng/mL) (analysis of variance p < .001). NIDDM subgroups were not different in metabolic parameters (C-peptide and triglyceride levels, body mass index) and platelet activation marker (platelet factor 4 values). von Willebrand Factor and thrombomodulin levels were elevated in groups with endothelial dysfunction (analysis of variance p < .001, p = .025, respectively). Insulin treatment was accompanied by decreased PAI-1 levels especially in pa tients with endothelial dysfunction. Insulin is the inhibitor of endothelial PAI-1 production induced by cytokines. Therefore, we suggest that long-term insulin application may decrease PAI-1 levels by direct inhibitive action on the endothelial PAI-1 compartment. This hypothesis requires further research.
Initiation of Warfarin Treatment in Outpatients with Nonrheumatic Atrial Fibrillation: A Scheme for Early Indication of Maintenance Dose
Authors: Pengo Vittorio , Zasso Antonella , Barbero Fabio , Biasiolo Allesandre , Rampazzo Patrizia , Brocco Tania
Published: November 2007

Eighty-four outpatients with nonrheumatic atrial fibrillation starting oral anticoagulant treatment were adminis tered warfarin (10 mg/day) for the first 2 days of treatment. Prothrombin time, expressed as International Normalized Ratio (INR), was measured on day 3 and plotted against the weekly warfarin maintenance dose, defined as the dose able to maintain INR between 2.0 and 3.0 (therapeutic range) on three consecu tive occasions, 1 week apart. The data fit a regression line (r = 0.74, p < .0001) that we use to estimate the weekly maintenance dose of other patients.
Sticky Platelet Syndrome: A Case Report and Review of the Literature
Authors: Chittoor Sreeni R. , Elsehety Ahmed E. , Roberts Gary F. , Laughlin W. Robert
Published: November 2007

Thrombosis has been attributed to platelet function abnormalities in a variety of vascular diseases. A patient with superior sagittal sinus thrombosis noted to have a normal work- up for hypercoagulable state but who had hyperaggregability of platelets after stimulation with epinephrine is described. A di agnosis of sticky platelet syndrome, type II was eventually made.
Regional Thrombolysis with Urokinase for Central Venous Catheter-related Thrombosis in Patients Undergoing High-dose Chemotherapy with Autologous Blood Stem Cell Rescue
Authors: Schindler Joanne , Bona Robert D. , Chen Harry H. , Feingold Jay M. , Edwards Richard L. , Tutschka Peter J. , Bilgrami Syed
Published: November 2007

Fifty-one of 300 patients undergoing high-dose chemotherapy with (n = 245) or without (n = 55) autologous stem cell rescue developed central venous catheter-related thrombosis diagnosed by Doppler sonography or contrast ve nography. Eighteen of these individuals underwent regional thrombolysis defined as the infusion of urokinase into a super ficial vein of the ipsilateral upper extremity in a dose not suf ficient to produce systemic fibrinolysis by laboratory criteria. Urokinase was administered at a dose of 75,000-150,000 U/hour for 24 to 96 hours and contrast venography was per formed to assess response. All individuals had a partial or complete resolution of clinical signs and symptoms. Fifty per cent of patients also achieved a partial radiographic response defined as clot lysis with irregular canalization of the vein. Therapeutic doses of heparin for 5 to 7 days and warfarin for at least 3 months were commenced at the conclusion of urokinase therapy. Twelve catheters were salvaged and utilized subse quently until no longer required. Six catheters were removed because of poor catheter function or rethrombosis. The median interval from diagnosis of the thrombus until extraction of the 12 salvaged catheters was 3 months (range 1-8 months). Only a single patient who developed gastrointestinal bleeding re quired discontinuation of urokinase. Regional thrombolysis is safe, easy to administer, effective in many instances, less costly than the doses of antifibrinolytic agents required to induce sys temic fibrinolysis, and should be considered in patients receiv ing high-dose chemotherapy with autologous stem cell rescue who develop central venous catheter-related thrombosis. Key Words: Regional thrombolysis—Urokinase—Catheter—related thrombosis.
Normal Life Expectancy and Thrombosis-Free Survival in Aspirin Treated Essential Thrombocythemia
Authors: Michiels Jan Jacques
Published: November 2007

Focusing on platelet-mediated erythromelalgia as a specific, presenting, and single sign of essential thrombocy themia (ET) we were able to define the characteristic peripheral blood and bone marrow findings in ET patients. From 1974 to 1986 we treated 20 symptomatic ET patients with microvascu lar circulation disturbances including erythromelalgia (N = 18), atypical or typical transient ischemic attacks (N = 6), or acute coronary ischemic syndrome (N = 3) with aspirin and one course of busulfan. The mean platelet counts before and after busulfan treatment were 1,009 (range 545-1,525) and 241 (range 159-315) x 109/L, respectively. After induction of a complete remission, treatment with busulfan and aspirin was discontinued until symptoms returned. All 20 patients remained asymptomatic as long as ET was in maintained remission (platelet <350 x 109/L) for 4 to 61 (mean 36) months. Eight patients became symptomatic and 4 patients remained asymp tomatic at relapse of ET after a follow-up period of 19 to 61 and 31 to 46 months, respectively. Platelet counts at time of symp tomatic relapse in the 8 patients were 410, 450, 490, 500, 515, 545, 548, and 635 x 109/L and at time of asymptomatic relapse in 4 ET patients 577, 600, 648, and 725 x 109/L. Based on these observations, since 1986 we followed the strategy to treat ET patients with aspirin as long as the platelet count was between 400 and 1,000 up to 1,250 x 109/L. Clear indications to reduce the platelet count were bleeding, aspirin side effects, and plate lets counts above 1500 x 109/L. This nonleukemogenic or least toxic approach in ET is the rationale behind the normal life expectancy and subsequent thrombosis-free survival in 68 ET patients after a mean follow-up period of 6.2 years. Key Words: Essential thrombocythemia—Platelets—Erythro— melalgia—Transient ischemic attacks—Thrombosis—Life ex pectancy—Aspirin—Busulfan.
Effects on Hemostasis After Two-Year Use of Low Dose Combined Oral Contraceptives with Gestodene or Levonorgestrel
Authors: Prasad Rama N. V. , Koh Stephen C. L. , Viegas Osborn A. C. , Shan Ratnam S.
Published: November 2007

We studied 67 healthy women who were randomly allocated to receive third generation gestodene (Gynera®) or second generation levonorgestrel (Microgynon 30®) combina tion of low-dose estrogen oral contraceptives (OCs) for their hemostatic effects over 2 years. Hemostatic changes were ap parent within 3 months of OC use. Hematocrit (Hct) was not affected, but hemoglobin (Hb) concentration decreased by 18 months. Shortened prothrombin time (PT) and activated plasma thromboplastin time (APTT) were associated with elevated fi brinogen within the 12-month use of both OCs. Factor VII was reduced only in Micro 30 during the 18 months of use. En hanced thrombin-antithrombin (TAT)-complex level was seen at 18 months of Gynera use. Prothrombin fragment 1+2 (F1+2) rise was seen at 3 months with Micro 30. Reduced antithrombin III (ATIII) activity was seen at 18 months with Gynera and at 24 months with Micro 30. Increased protein C activity was seen at 3 months and reduced protein S occurred at 18 months of Gynera use. Tissue plasminogen activator (t-PA) activity was enhanced for 6 months in both OCs with raised D-dimer levels for 12 months with Gynera and 6 months with Micro 30. De creased t-PA antigen was seen at 18 months and decreased urokinaselike plasminogen activator (u-PA) antigen occurred throughout the 24 months of both OCs use. Enhanced u-PA activity was only seen in Gynera users. Elevated plasminogen levels were apparent throughout both OCs use. PAI-1 levels were significantly decreased with Micro 30. With Gynera, the decreased PAI-1 activity was seen only at 18 months and PAI-1 antigen at 12 months. No change in platelets and von Wil lebrand factor (vWF) were seen in long-term OC use except that β-thromboglobulin (β-TG) showed decreased trends reaching statistical significance by 18 and 24 months of Micro 30 use and by 24 months of Gynera use. A further significant decrease in β-TG, u-PA antigen, ATIII, and protein S levels were seen 3 months after pill stoppage compared with pretreat ment levels. Activated protein C resistance (APCR) was nega tive in all subjects before and during OC use. The study indi cated dynamic balance between coagulation and fibrinolysis with no endothelial activation. However, because some hemo static markers showed wide fluctuations during OC use, a longer term study is warranted to investigate any adverse he mostatic changes that might enhance the risks of venous thromboembolism in Asian subjects known to be less prone to thrombosis. Key Words: Oral contraceptives—Hemostasis.
State-of-the-Art Review : Outcome of Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in Japan
Authors: Mori Yoshitaka , Wada Hideo , Tamaki Shigehisa , Minami Nobuyuki , Shiku Hiroshi , Ihara Toshiaki , Omine Mituhiro , Kakisita Eizo
Published: November 2007

We examined 159 patients with thrombotic throm bocytopenic purpura and hemolytic uremic syndrome in Japan. The subjects were divided in three groups; 90 patients with thrombotic thrombocytopenic purpura, 51 patients with vero toxin-induced hemolytic uremic syndrome, and 18 patients with drug-induced hemolytic uremic syndrome. Eighty-two percent of the patients with thrombotic thrombocytopenic pur pura had associated neurological disorders and 78% of drug- induced hemolytic uremic syndrome associated with pulmo nary edema. Renal insufficiency was noted in the 69% cases with both hemolytic uremic syndrome groups. Seventeen pa tients with thrombotic thrombocytopenic purpura had systemic lupus erythematosus and 6 were pregnant. Autoantibody were positive in 53% of thrombotic thrombocytopenic purpura. Sev enty-seven percent of patients with thrombotic thrombocytope nic purpura received plasma exchange at 4,000 mL/day three times a week, 71 % antithrombotic agents, and 78% steroid administration, respectively. However, 27% of the patients with hemolytic uremic syndrome were treated by hemodialysis in addition to antithrombotic agents. When drug-induced hemo lytic uremic syndrome was diagnosed, the drug was immedi ately discontinued and the patients were treated with antiplate let agents. Seventy-four percent of the patients with thrombotic thrombocytopenic purpura were alive at 26 weeks compared with 95% of those with hemolytic uremic syndrome. As throm botic thrombocytopenic purpura had a high mortality rate in Japan, we should carry out early diagnosis and early treatment.
State-of-the-Art Review : The Effect of Antiplatelet Drugs, Heparin, and Preanalytical Variables on Platelet Function Detected by the Platelet Function Analyzer (PFA-100®)
Authors: Kottke-Marchant Kandice , Powers James B. , Brooks Linda , Kundu Sourav , Christie Douglas J.
Published: November 2007

The platelet function analyzer (PFA)-100® is a newly developed instrument that provides a rapid, in vitro, quantitative measurement of platelet adhesion and aggregation in whole blood flowing through a small aperture under high shear conditions. Thirty patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and ten normal in dividuals were included in this study. In vitro and in vivo studies were conducted to discern the effect of combinations of antiplatelet drugs (aspirin, ticlopidine, abciximab) and heparin on the performance of the device as well as the effects of preanalytical variables, such as method of sample collection and ex vivo anticoagulants. Studies were also conducted ex amining the effect of aperture size (standard 150 μm vs. smaller 120 μm) on the ability of the device to detect the effect of antiplatelet drugs. There was no difference in mean PFA- 100® closure time with citrate versus PPACK anticoagulants or with venipuncture vs. sheath sampling. Closure times did not vary with heparin administration. Closure times were slightly longer for patients taking aspirin plus ticlopidine compared to aspirin alone (p = NS). In contrast adenosine disphosphate (ADP) induced platelet aggregation was significantly less in patients that took aspirin plus ticlopidine vs. aspirin alone (p = .0005). In vitro, there was a dose-dependent increase in closure time for both aperture sizes with increasing abciximab concen tration. Although both cartridges showed infinite closure times at an abciximab concentration of 2.25 μg/mL, there was a slight benefit to using the 120 μm aperture cartridges at abcix imab concentrations of 1.75 to 2.0 μg/mL. In ten patients who were followed during abciximab therapy to assess the effect of aperture size, the PFA-100® was able to detect in vivo platelet inhibition by abciximab, but detection of recovery from abcix imab-induced platelet dysfunction was slightly better for the PFA-100® with the 120 μm aperture compared to the standard 150 μm aperture collagen/ADP cartridge.
Acquired von Willebrand Disease in Monoclonal Gammapathies: Effectiveness of High-dose Intravenous Gamma Globulin
Authors: Michiels Jan Jacques , van Vliet Huub H. D. M.
Published: November 2007

The reported underlying lymphoproliferative dis orders associated with acquired von Willebrand disease (AvWD) include benign monoclonal gammapathy, multiple myeloma, Waldenström disease, chronic lymphocytic leuke mia, non-Hodgkin lymphoma, and hairy cell leukemia. The AvWD in patients with a monoclonal gammapathy and/or a lymphoproliferative disorder is featured by a prolonged bleed ing time, normal platelet count, and a decreased or absent ris tocetine-induced platelet aggregation in combination with a prolonged aPTT and normal PT due to low levels of factor VIII/von Willebrand factor (vWF) parameters in the absence of a factor VIII inhibitor in the Bethesda assay. In vitro and vivo experiments consistently showed that the anti-vWF autoanti bodies in monoclonal gammapathies cause a rapid clearance of the factor VIII/vWF complex from the circulation after DDAVP and factor VIII/vWF concentrate infusion. Multimeric analysis of the vWF usually show a type 11-like AvWD due to the absence of large vWF multimers as the consequence of the rapid clearance of the anti-vWF-factor VIII/vWF complex from the circulation. There is a poor response to intravenous DDAVP and factor VIII/vWF concentrate infusion, but high dose intravenous gamma globulin (1 g/kg for 2 days) usually induces a transient correction of the factor VIII/vWF param eters for 1 to a few weeks.
Exclusion and Diagnosis of Deep Vein Thrombosis by a Rapid ELISA D-dimer Test, Compression Ultrasonography, and a Simple Clinical Model
Authors: Michiels Jan Jacques , Oortwijn Wija J. , Naaborg Ronald
Published: November 2007

The classical clinical signs of deep vein thrombo sis (DVT) are unspecific and may be found in several other conditions besides DVT. Therefore, patients suspicious of DVT are subjected to elaborate invasive or noninvasive evidence- based procedures that actually confirm DVT in only 20% to 30% of patients in this setting. However, simple laboratory tests and noninvasive strategies to exclude and diagnose DVT are becoming available in the clinical emergency setting of outpatients. In the presented literature, a sound basis is pro vided for quantifying clinical judgment for the diagnosis of acute proximal DVT. The number of positive clinical findings at time of first suspicion of DVT appears to correlate directly with the probability of acute proximal DVT. The modified clinical model of Landefeld and Wells for DVT allows reason able accurate classification of patients into low, moderate, and high probability for suffering DVT. The rapid automated en zyme-linked immunoabsorbant assay (ELISA) VIDAS D- dimer presently available can be rapidly performed in daily practive and emergency situations and is accurate to a high degree, especially in ruling out ongoing venous thromboem bolic processes. The sequential use of the rapid ELISA VIDAS D-dimer test and compression ultrasonography in a well- designed clinical setting using a simple clinical model predicts a significant improvement due to a high sensitivity near 100% for the exclusion and diagnosis of DVT in the majority of outpatients with suspect DVT. A prospective decision analysis management study is proposed to exclude and diagnose DVT based on the rapid ELISA VIDAS D-dimer test and compres sion ultrasonography within the context of a ready-to-use simple clinical model. The proposed simple model of a rational diagnosis of deep vein thrombosis (RADIA DVT) has to be tested in a large multicenter study of more than 1,000 outpa tients with suspected DVT. This model would be less expen sive, easy to perform, and likely yield a significant simplifica tion and improvement of highly accurate evidence-based ex clusion or diagnosis of DVT on the basis of which clear-cut indications of anticoagulation could be appropriately initiated or safely withheld.
Serum Cardiolipin Antibodies in Cancer Patients with Thromboembolic Events
Authors: Ozgüroğlu Mustafa , Arun Banu , Erzin Yusuf , Demir Gökhan , Demirelli Fuat , Molinas Mandel Nil , Büyükünal Evin , Serdengeçti Süheyla , Berkarda Bülent
Published: November 2007

This study was undertaken to investigate a pos sible association of anticardiolipin antibodies (ACLAs) in can cer patients with thromboembolic events. Twenty-five patients with solid tumors complicated with acute thrombosis, 36 cancer patients without any thrombotic events, and a group of 20 healthy volunteers without thrombosis or malignancy were in cluded. The mean age of the cancer patients with and without thrombosis and healthy subjects were 50 years (range 20-75), 45 years (range 23-66), and 40 years (range 20-68), respec tively. Deep venous thrombosis (n = 16) and thrombosis of the central venous port-catheter systems (n = 9) were confirmed by Doppler sonography in all patients. IgG and IgM isotypes of ACLAs were quantitated by enzyme-linked immunosorbent as say with normal levels of <23 GPL and <11 MPL, respectively. Mean values of IgG ACLAs were found similar in cancer pa tients with acute thrombosis (13.8 ± 4.9 GPL), without throm bosis (12.8 ± 5.4 GPL) or in healthy subjects (14.8 ± 5.5 GPL). Although the mean values of IgM ACLAs were within normal limits in all groups, cancer patients with thrombotic events had higher levels of IgM ACLAs (mean = 10.5 ± 2.2 MPL) than cancer patients without thrombosis (mean = 4.6 ± 2.4 MPL) (p = .01). Healthy subjects also had lower levels of IgM ACLAs (mean = 7.1 ± 3.2 MPL) than cancer patients with thrombosis (p = .16). In addition, a higher percentage of cancer patients with or without thrombosis had IgM and IgG ACLA levels above normal limits compared with healthy controls. In con clusion, our study suggests an association between ACLAs or IgG and particularly IgM isotypes and venous thrombosis in malignancy. Identification of cancer patients who are at higher risk for developing thromboembolic events might lead to a better selection of patients for prophylactic anticoagulant therapy.
Effects of Aprosulate, a Novel Synthetic Glycosaminoglycan, on Coagulation and Platelet Function Parameters: A Prospective, Randomized Phase I Study
Authors: Schenk Joachim F. , Radziwon Piotr , Mörsdorf Stefan , Eckenberger Peter , Breddin Hans K.
Published: November 2007

In a phase I clinical trial the effect of the highly sulfated polyanion "Aprosulate" was studied in healthy volun teers using different coagulation and platelet function param eters. Eighteen healthy volunteers aged 21 to 30 years received two single subcutaneous doses of aprosulate (0.5 mg/kg body weight; 1.0 mg/kg body weight), or unfractionated heparin (Calciparin® 7,500 IU). The washout period between the dif ferent drugs/doses was at least 7 days. Coagulation and platelet function parameters (activated partial thromboplastin time, Heptest, fibrinogen, von Willebrand factor, ristocetin cofactor, platelet adhesion to siliconized glass, and platelet-induced thrombin generation time [a new method for measuring throm bin generation in platelet-rich plasma in the presence of plate lets]) were assessed during 24 hours after each injection. Aprosulate led to a significant and dose-dependent prolonga tion of activated partial thromboplastin time and Heptest. This effect lasted for 4 hours (activated partial thromboplastin time) to 8 hours (Heptest). Activated partial thromboplastin time was not prolonged after the injection of unfractionated heparin (7,500 IU). Fibrinogen, von Willebrand factor, and ristocetin cofactor remained unchanged with both drugs. Platelet induced thrombin generation time was slightly prolonged and platelet adhesion was slightly diminished up to 2 hours using 0.5 mg/kg aprosulate, and up to 4 hours using 1.0 mg/kg aprosulate while the platelet induced thrombin generation time system was not influenced by the subcutaneous injection (7,500 IU) of unfrac tionated heparin. Both drugs and doses were well tolerated. Plasma transaminase concentrations alanin aminotransferase and aspartate aminotransferase serum values were slightly in creased in some volunteers but returned to normal during or after the study (<4 weeks). Further clinical trials will have to establish whether aprosulate is an effective drug for the pro phylaxis of deep venous thrombosis.
Mild Myocardial Stunning Affects Platelet Aggregation and Certain Hemostatic Factors in Swine
Authors: Serebruany Victor L. , Yurovsky Vladimir V. , Gurbel Paul A.
Published: November 2007

Myocardial stunning is characterized by transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. Platelet activation and he mostatic abnormalities have been described in patients with unstable angina and acute myocardial infarction, however, their role in the pathogenesis of myocardial stunning is unknown. The purpose of this study was to determine if platelet aggre gation and certain hemostatic factors change during myocardial stunning following brief coronary arterial occlusion. Nine Yorkshire swine underwent left anterior descending coronary artery occlusion for 8 minutes followed by 90 minutes of reper fusion. Blood samples were obtained at baseline, at 4 and 8 minutes of occlusion, and at 60 and 90 minutes of reperfusion. Platelet aggregability and concentrations of antithrombin III, protein C, protein S, fibronectin, endothelin 1, and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto- PGF 1a) were measured in systemic circulation. The occlusion phase was associated with a decline of endothelin 1 (—13.6%), and TxB2 (—19.6%), and elevation of antithrombin III (+40.2%) and protein C (+22.9%). Mild myocardial stunning was associated with a significant increase in platelet aggrega tion (+33.7%), endothelin-1 (+24.7%), 6-keto-PGF1a (+41.5%), TxB2 (+11.9%), and protein C (+42.3%) during the reperfusion phase. There were no changes in plasma fibronectin and total protein S. Thus, mild myocardial stunning following brief coronary artery occlusion is associated with substantial dynamic changes in platelet aggregability and certain hemo static factors. These results may be relevant to understanding the mechanisms determining myocardial stunning and coronary arterial patency following reperfusion.
Conversion of etoposide phosphate to etoposide under ambulatory infusion conditions
Authors: Webster Lorraine K. , Crinis Nicholas A. , Davis Jillian R. , Millward Michael J.
Published: November 2007

Objective: To determine the extent of conversion of etoposide phosphate, a water-soluble prodrug for etoposide, to etoposide at concentrations and temper atures likely to occur during ambulatory infusion.

Design: Etoposide phosphate solutions were prepared at equivalent etoposide concentrations of 15 and 1.5 mg/mL in ambulatory infusion cassettes and stored protected from light at 18 to 20°C and 37°C. Daily samples were taken for 7 days.

Main Outcome Measure: Instability was as sessed as percentage conversion of etoposide phos phate to etoposide. Both drugs were measured using high-performance liquid chromatography.

Results: At room temperature, there was less than 2% conversion of etoposide phosphate to etopo side. At 37°C, there was a cumulative conversion to etoposide of 6.6% after 7 days at both the low and high concentrations.

Conclusion: Etoposide phosphate displays a temperature-dependent, concentration-independent conversion to etoposide over 7 days of less than 7%. Previous studies have confirmed the chemical stabil ity of etoposide up to 96 hours but have suggested that the maximum recommended etoposide concen tration to prevent crystal formation in infusion solu tions is 0.4 mg/mL. To be conservative, if the maxi mum conversion of etoposide phosphate to etoposide over 7 days is estimated to be 10%, and 0.3 mg/mL is selected as the maximum etoposide concentration, then the maximum concentration of etoposide phos phate should be the equivalent of 3.0 mg/mL etopo side. Therefore, prepared under aseptic conditions in a laminar flow cytotoxic safety cabinet, up to 3.0 mg/mL etoposide as etoposide phosphate in 0.9% sodium chloride can be delivered by ambulatory infusion, protected from light, over 96 hours. This will permit therapeutic doses of etoposide, as etopo side phosphate, to be delivered continuously by ambulatory infusion. Given that the extent of conver sion to etoposide was temperature dependent, it is recommended that the infusion cassette remain be low 37°C and preferably as close to room temperature as possible.
Prolonged response to flutamide withdrawal and initiation of aminoglutethimide in a patient with metastatic prostate cancer
Authors: Middleman Matthew N. , Lush Richard M. , Sartor Oliver , Reed Eddie , Figg William D.
Published: November 2007

Objective. To present a patient with metastatic pros tate cancer who has experienced an extended re sponse to the withdrawal of flutamide and the con comitant initiation of aminoglutethimide.

Case Summary. A 73-year-old male was diagnosed with advanced metastatic prostate cancer. He received treatment with suramin, leuprolide, and flutamide. After progressing on this regimen his flutamide was discon tinued and aminoglutethimide was initiated. His re sponse to this treatment has reached almost 3 years, with no evidence of progression.

Discussion. The response to the withdrawal of flutamide is thought to arise from a mutated androgen receptor that recognizes hydroxyflutamide, the active metabolites of flutamide, as an agonist. The receptor continues to recognize endogenous steroids as agonists. The addition of the adrenal steroid synthesis inhibitor, aminoglutethimide may play a role in enhancing this response phenomenon.

Conclusions. This patient is progression free for approximately 3 years following the withdrawal of flutamide. This maneuver has been found to have activity in a subset of patients who have been treated for metastatic prostate cancer with combined andro gen blockade.
Occupational health and staff monitoring: A genetic toxicologist's viewpoint
Authors: Ferguson Lynnette R.
Published: November 2007

This is a summary of some of the points raised in a round table discussion on occupational health and in two workshops on staff monitoring, held as part of ISOPP IV. It is not intended as a comprehensive review on these issues. It is, however, intended to focus discussion on some of the controversial areas from the perspective of a genetic toxicologist. Pharmacists who have points to add or disagree with, or who wish to discuss or debate these issues further might address such comments as "Letters to the editor" in this journal.
Does determination of tissue platinum levels by mass spectroscopy have potential for monitoring exposure of pharmacy personnel to platinum-based antineoplastic drugs? A pilot study
Authors: Webster Penelope Jane , Ng Kingsley , Snitch Peter , Jones Sandra L. , Amos Nicola , Hamett Paul R.
Published: November 2007

The mutagenic and carcinogenic properties of cyto toxic drugs have led to concern over potential haz ards to pharmacy personnel who are required to prepare cytotoxic drugs. The platinum compounds cisplatin and carboplatin are frequently used antican cer agents and are unique by virtue of their suitability for quantification by highly sensitive physical meth ods such as inductively coupled plasma mass spec troscopy (ICPMS). We have performed a pilot study of ICPMS determination of platinum levels in biological samples from pharmacists preparing chemotherapy, including platinum-based antineoplastic drugs. In pa tients treated with platinum compounds, elemental platinum was readily detected in plasma and whole leukocytes and bound to leukocyte DNA for at least 4 weeks after treatment. However, in 28 pharmacists from our institution (18 involved in preparation of platinum-based compounds, 10 controls), tissue plat inum levels were below the limit of detection (0.05 nmol/L) by ICPMS. ICPMS measurement of platinum levels has the potential to be used to monitor health care workers for exposure to platinum-based cytotox ics. Exposure may result from accidental exposure to a platinum-based compound or may be due to poor technique by personnel preparing chemotherapy doses. We are intending to institute a prospective monitoring policy to gather further data.
A phase I trial of recombinant gamma interferon administered intravenously on a daily × 5 schedule
Authors: Koeller Jim , Brown Thomas D. , Beougher Kenneth , Golando James , Bonnem Eric M. , VonHoff Daniel D.
Published: November 2007

Objective: To determine the maximally tolerated dose and associated toxicity of r-γ-IFN. In addition, to evaluate the development of serum IFN neutralizing factors. Design: This is an open-labeled, Phase I dose escalating trial.

Setting: This trial was carried out at a Veteran's Administration and Army hospital.

Patients: Patients with advanced malignancies for whom no known effective therapy is available were eligible. Patients must have adequate organ function, a performance status of 2 or lower and a minimal life expectancy of 2 months.

Intervention: Patients received escalating doses of r-γ-IFN (0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 X 106 IU/m2) daily for 5 days given intravenously over 2 hours every other week.

Main Outcome Measures: Tumor response was followed clinically, with radiographic support when appropriate. Toxicity was evaluated using the World Health Organization (WHO) standard toxicity grading guidelines. Serum samples were used to monitor and evaluate the IFN neutralizing factors.
Pancreatitis and fatal ARDS following high-dose cytarabine induction for acute myelogenous leukemia
Authors: Wittbrodt Eric T , Aviles Victor M
Published: November 2007

Objective. To describe a case of fatal acute respira tory distress syndrome (ARDS) and pancreatitis aris ing from high-dose cytarabine induction therapy.

Case Summary. A 50-year-old male without a history of hepatobiliary disease and with a diagnosis of acute myelogenous leukemia was treated with high-dose cytarabine therapy. Tumor lysis occurred promptly; the white cell count reached a nadir of 100/mm 3 3 days after initiation of therapy. Severe mid-epigastric pain, fever, hypotension, and increased lipase and amylase occurred on the 6th day of cytara bine therapy. Cytarabine was discontinued 6 days after initiation. Serum amylase and lipase were persis tently elevated; respiratory failure due to ARDS ensued, and the patient expired of refractory hypoxemia.

Discussion. Cytarabine-associated pancreatitis is a rare occurrence. Literature reports have described pancreatitis after high-dose cytarabine therapy for induction of remission of ALL and acute myelogenous leukemia. Pancreatitis resolved in all reported cases on discontinuation of cytarabine. In our patient, drug-induced pancreatitis likely provoked the onset of ARDS, which concluded with fatal respiratory failure. The absence of positive cultures decreased the likeli hood of sepsis-induced ARDS; the time course of cytarabine administration was temporally associated with the development of pancreatitis.

Conclusions. Acute pancreatitis is a rare but potentially fatal event associated with high-dose cy tarabine therapy.
Extravasation of topotecan, a report of two cases
Authors: Oostweegel Lonneke MM , van Warmerdam Laurence JC , Schot Margaret , Dubbelman Ria C , Ten Bokkel Huinink Wim W , Beijnen Jos H
Published: November 2007

Objective. Extravasations of anticancer agents may give serious complications and specific therapy might be needed. Topotecan is a new cytotoxic drug and is used in many clinical studies. In our clinic two extravasations of topotecan occurred, and the clinical consequences are discussed.

Clinical Features. The extravasations oc curred in two patients who were receiving topo tecan intravenously because of ovarian carcinoma stage III. The patients experienced some discom fort caused by the expansion of soft tissue. How ever, no serious complications were observed.

Case Progress and Outcome. Both patients received all further courses of topotecan without any negative effects.

Conclusion. In conclusion, besides stopping the injection, trying to aspirate the fluid, keeping the arm high, and cooling the swelling, we advise no specific measures to be taken after extravasa tion of topotecan.
Human resource issues in cytotoxic drug dispensing
Authors: Roos Ian , Makela Tuija
Published: November 2007

Introduction. The human resource issues for phar macists manipulating and dispensing cytotoxic drugs in safety cabinets and clean rooms, in accordance with Australian Standards, have been investigated. The technology is regulating, resulting in very formal procedures and work practices. Often staff work under conditions of restricted environmental stimula tion that can have effects on cognitive functioning and reduce efficiency for demanding tasks.

Methods. Discussions were held with senior staff of twenty hospitals treating patients with cancer, one manufacturing facility, and one research laboratory, regarding work in cytotoxic drug suites. A survey was administered to staff working in these facilities. Issues explored included: work practices; rosters; cleaning; work flow; ergonomics; quality of work environment; clothing; certification of facilities, and training.

Results and Discussion. The survey shows that the major stressors for people working in the facilities are the physical conditions, especially the tempera ture, and the lack of control over workflow. It confirms the importance of windows in the working environment and the need for communication facili ties. Design deficiencies in the technology that impact the quality of the work environment are identified. There are age differences with regard to perceptions of risk from cytotoxic drugs. The study identifies the need for further training, both in technique and understanding of the technology.

Conclusion. Whilst minimising risk to staff, the adoption of the technology has had an impact on environment. Identification of these issues should enable improved facilities and work environment.
Review : Topoisomerase I inhibitors: 2. Irinotecan
Authors: Skirvin J. Andrew , Relias Valerie
Published: November 2007

Purpose. The primary objective of this article is to discuss the pharmacology, pharmacokinetics, clinical use, and adverse effects of the approved topoisomer ase I inhibitors. This is the second in a series of two articles and will focus on irinotecan.

Data Sources. We reviewed the literature through a MEDLINE search of English language arti cles from 1985 through 1998. Relevant articles cited in the titles obtained from the MEDLINE search were also used. The following terms were used for purpose of conducting the MEDLINE search: topoisomerase inhibitors, irinotecan, topoisomerase I, camptosar, and CPT-11.

Data Extraction. We have reviewed the current literature to discuss the pharmacology, pharmacokinet ics, clinical use, toxicity, drug interactions, indications, formulation, dosage and administration, and pharmaceu tical issues surrounding the use of irinotecan.

Data Synthesis. The topoisomerase I inhibitors are new antineoplastic agents with a unique mechanism of action. Promising areas of application include colo rectal cancer, non-small-cell lung cancer, small-cell lung cancer, cervical cancer, and lymphomas. Clinical trials detailing the activity of topoisomerase I inhibitors in these areas are presented.
Review : Statistical methods in clinical research: A review for pharmacists
Authors: Dranitsaris George
Published: November 2007

Objective. Pharmacists have been recognized as both clinicians and researchers. As clinicians, they have to be able to critically review the results of clinical trials and to determine whether the fmdings of these studies were justified based on the methodology. As investigators, pharmacists must select the appropriate research design to answer the main study hypothesis. This paper will review basic statistical concepts that the oncology pharmacist can use to evaluate clinical trials and to design research studies.

Data Sources. A variety of articles accessed from a MEDLINE search and statistical reference texts were used.

Data Extraction. The information was re viewed, and statistical concepts relevant to oncology pharmacy practice were included.

Data Synthesis. The concepts of descriptive and inferential statistics are presented. Detailed nu merical examples of how differences between two independent groups can be evaluated for statistical significance are provided. Similarities and differences between hypothesis testing and estimation are also highlighted.
Evaluating the nephrotoxicity of cytotoxic agents using a rat kidney perfusing model
Authors: Pagel Horst
Published: November 2007

The nephrotoxicity of a number of chemother apeutic drugs may be a great problem from the clinical point of view, especially under a high dose therapy. It has been shown that, under certain circumstances, the maximum dose of a cytotoxic agent is not administered by the tox icity in the bone marrow but by the renal toxic ity. The renal mechanisms of action of cytotoxic drugs are poorly understood. The kidney seems to be very sensitive to the actions of these substances. In addition, the kidney plays a spe cial role in comparison with other organs be cause of the existence of an osmotic gradient in the renal medulla that results in a higher local concentration of systemically given cytotoxic drugs than in the remaining organism. The exper imental model of the isolated perfused rat kidney is a powerful tool to investigate the nephrotoxicity of chemotherapeutic agents. In this preparation, functional parameters can be changed in a con trolled manner, and systemic influences on renal function are eliminated.
Classrooms as lexical environments
Authors: Meara Paul , Lightbown Patsy M. , Halter Randall H.
Published: November 2007

In many second/foreign-language classrooms, students are expected to learn much or even most of their vocabulary without explicit instruction, simply through exposure to a rich variety of words in meaningful contexts. In fact, however, there are few studies which would allow us to estimate the number of words learners are typically exposed to in second/foreign-language classrooms. In this study, the vocabulary available in the speech of ten teachers in intensive communicative ESL classes for children in Quebec was analysed using specially designed computer programs. The words which occurred in classroom transcripts were classified according to their status as high-frequency or 'unusual' words, according to lists developed by Nation (1986). The working assumption was that a large number of unusual words would be indicative of a rich lexical environment, whereas the absence or extreme rarity of such words would indicate that the classroom vocabulary was poor. The number of unusual words was found to be quite low in short periods of classroom interaction. However, an interpretation of the findings suggest that the actual richness of the vocabulary available may be greater than it appears in terms of this measure.
Childhood chronic pain and health care professional interactions: shaping the chronic pain experiences of children
Authors: Dell'Api Melissa , Rennick Janet E. , Rosmus Christina
Published: November 2007

Children with chronic pain meet numerous healthcare professionals during their search to understand their pain. Through semi-structured interviews, this qualitative study sought to understand the experiences of five children with chronic pain as they encountered healthcare professionals. In the majority of these interactions, children reported feeling misunderstood, disbelieved and abandoned. The findings of this study demonstrate that children's experiences with professionals influence their approach towards current and future healthcare encounters. All children discussed their guarded relationships with healthcare providers. Children also developed negative perceptions about their pain, in particular believing that their experience with chronic pain was life-threatening, and demanded major life adjustments. Interactions with healthcare professionals have a tremendous influence on children's perceptions and chronic pain experiences. In order to better understand and care for children with chronic pain, it is essential that healthcare professionals provide children with the opporunity to communicate their unique experiences with pain.
Here's an idea: ask the users! Young people's views on navigation, design and content of a health information website
Authors: Franck Linda S. , Noble Genevieve
Published: November 2007

Use of the internet to provide health information to young people is a relatively recent development. Few studies have explored young people's views on how they use internet health websites. This study investigated the navigation, design and content preferences of young people using the Children First for Health (CFfH) website. Young people from five secondary schools completed an internet site navigation exercise, website evaluation questionnaire and participated in informal discussions. Of the participants, 45 percent visited the website section aimed at older adolescents within their first two clicks, regardless of their age. There were conflicting preferences for design and strong preference for gender-specific information on topics such as appearance, relationships, fitness and sexual health. The findings indicate the importance of gaining young people's views to ensure that health information websites meet the needs of their intended audience. Cooperation from schools can facilitate the process of gaining young people's views on internet website navigation, design and content.
A review of chemical burns
Authors: Seth R. , Chester D. , Moiemen N.
Published: November 2007

Chemical Burns make up 3% of burns center admissions and have a mortality rate that varies from 4.1 to 13%. There are over 25,000 products capable of causing chemical burns. These injuries may cause significant tissue necrosis and have the potential for systemic toxicity. This article gives an overview of the various types of chemical burns along with their management. Chemical warfare agents and extravasation injuries will also be briefly discussed.