bluuebunny/crossref_metadata_2025 huggingface dataset:
State-of-the-Art Review : Nitric Oxide and Restenosis
Authors: Loscalzo Joseph
Published: November 2007

Restenosis after balloon angioplasty of vascu lar lesions in patients with atherothrombotic disease re mains an important complication of the procedure. At tempts to limit restenosis have been generally unsuccess ful. The endothelial cell normally produces several factors that limit the molecular and cellular events under lying the restenotic response. Chief among these is en dothelium-derived relaxing factor/nitric oxide. This sim ple molecule inhibits platelet activation, secretion, adhe sion, and aggregation; relaxes the underlying vascular smooth muscle cell; impairs leukocyte adhesion to the vessel wall; and limits vascular smooth muscle cell pro liferation. The mechanistic bases for these observations are presented in this overview, and experimental in vivo data that support the benefits of nitric oxide and nitric oxide donors in the prevention of restenosis are also re viewed.
Unique Case of Brothers with Moderate Factor XI Deficiency and One with Severe Bleeding After Surgery
Authors: Steel Barbara L. , Hassell Kathryn L. , Rajagopalan Chitra , Merritt Audrey A. , Parsons Thomas , Braun Thomas , Marlar Richard A.
Published: November 2007

Factor XI is the only contact factor whose de ficiency may result in a bleeding diathesis. This case re port describes two brothers with similar moderate factor XI deficiency (41% and 45%), but one brother had severe bleeding during invasive procedures whereas the other brother undergoing the same surgical procedure had no excessive bleeding. The bleeding in the first brother con tinued despite adequate factor XI levels; however, it was stopped only after EACA therapy. Also discussed is the importance of a sensitive aPTT reagent to the various factors and the role of the aPTT in predicting potential bleeding, since a normal aPTT was obtained prior to the first surgery. This case demonstrates that major bleeding can occur in heterozygous factor XI deficiency and the patient must be considered 'at risk' for potential bleeding and should be treated accordingly.
Clopidogrel: An Antithrombotic Drug Acting on the ADP-dependent Activation Pathway of Human Platelets
Authors: Savi Pierre , Heilmann Eric , Nurden Paquita , Laplace Marie-Claude , Bihour Claude , Kieffer Gilles , Nurden Alan T. , Herbert Jean-Marc
Published: November 2007

The aim of the study was to determine the effect of clopidogrel on adenosine diphosphate (ADP)- induced platelet activation in human volunteers. Platelets from human volunteers before and after a 7-day treatment with clopidogrel (75 mg/kg), were tested for their sensi tivity to ADP by measuring ADP-induced aggregation, adenylyl cyclase downregulation, and [3H]-2-MeS-ADP binding. Platelet membrane glycoprotein (GP IIb-IIIa; GP Ib, GMP-140) expression was measured by flow cy tometry using fluorescent-labeled antibodies or fibrino gen. After oral administration to human volunteers (75 mg/day for 7 days), clopidogrel, a novel ADP-selective antiplatelet agent, inhibited ADP-induced aggregation of platelets ex vivo. This effect was irreversible in nature, and no activity could be detected in the plasma of treated subjects. Although clopidogrel did not modify ADP- induced shape change, it prevented the inhibitory effect of ADP (but not that of epinephrine) on the prostoglandin- E 1 (PGE1)-induced increase in platelet cAMP. The num ber of binding sites for [ 3H]-2-MeS-ADP, a stable ana logue of ADP that labels ADP binding sites linked to the inhibition of stimulated adenylyl cyclase, was reduced from 525 ± 62 sites/cell in the controls to 32 ± 5 sites/cell after treatment with clopidogrel (p < 0.001). This effect occurred with no consistent change in the binding affinity of [3H]-2-MeS-ADP, indicating that inhibition of platelet functions by clopidogrel was mainly due to a selective and irreversible reduction of ADP binding sites on plate lets. Flow cytometry experiments showed that clopi dogrel selectively inhibited ADP-inducing binding of fi brinogen to platelets. This effect occurred through a ma jor reduction of the ADP-induced activation of the GP IIb-IIIa complex. These findings therefore indicate that clopidogrel downregulates platelet responses via a selec tive and direct interaction with the ADP receptors, me diating the inhibition of stimulated adenylyl cyclase ac tivity in human platelets.
Vascular Localization of the Heparin-binding Serpins Antithrombin, Heparin Cofactor II, and Protein C Inhibitor
Authors: Cooper Scott T. , Neese Laura L. , DiCuccio Michael N. , Liles Darla K. , Hoffman Maureane , Church Frank C.
Published: November 2007

Heparin is one of the most widely used drugs in the world, acting as an anticoagulant by stimulating the reaction between heparin-binding serpins and the serine proteases of the coagulation cascade. To determine whether the heparin-binding serpins antithrombin (AT), heparin cofactor II (HCII), and protein C inhibitor (PCI) were bound to glycosaminoglycans on the endothelial wall, a bolus of heparin (100 U/kg body weight) was in jected into human volunteers, and serpin concentrations and activities were measured in both pre- and postheparin plasma. No increase in circulating concentrations of AT, HCII, or PCI were observed in postheparin plasma. Sim ilarly, AT and HCII activities did not increase in posthe parin plasma. In contrast, the concentration of another heparin-binding protein, lactoferrin (LF), increased six- fold after heparin injection. Immunohistochemistry of hu man artery was performed using polyclonal antisera to AT, HCII, PCI, LF, and tissue factor pathway inhibitor (TFPI), another heparin-binding protein released by hep arin injection. AT, HCII, and PCI were present in the intima, whereas LF, TFPI, and traces of AT were found on the surface of the vessel wall. The distribution of the proteins in the vessel wall supports the results of the hep arin-injection studies and may give valuable clues to the role of each protein in vascular homeostasis.
Outcome of Infrainguinal Arterial Bypass Grafting in Limbs with Postthrombotic Syndrome
Authors: Karacagil Sadettin , Almgren Bo , Bergqvist David
Published: November 2007

From among 336 infrainguinal bypass proce dures performed for treatment of atherosclerotic occlu sive disease, 27 patients with histories of deep venous thrombosis (DVT) were retrospectively analyzed with re gard to patency and limb salvage rates. In 25 patients, venous diagnosis was verified by antegrade phlebogra phy, which demonstrated postthrombotic changes in the deep venous system. Indications for infrainguinal bypass surgery were severe claudication (six patients), rest pain (nine patients), and nonhealing ulcer or gangrene (12 pa tients). Sixteen autologous saphenous vein grafts, six composite (PTFE-vein), and five prosthetic grafts were used. All 11 femorodistal bypass grafts occluded within 6 months compared to an 82% patency rate of femo ropopliteal bypasses. Among 16 femoropopliteal by passes, only one patient with poor runoff underwent lower leg amputation after bypass failure. On the other hand, all 11 patients with distal bypass underwent major amputation during the first 7 months. The dismal outcome of patients with previous DVT undergoing femorodistal bypass procedures in this small population might be due to the deleterious effect of venous outflow impairment on already limited distal runoff status due to severe athero sclerotic changes.
Chronic Platelet Activation and Acute Coronary Syndromes in 13 Middle-Aged Patients
Authors: Ozner Michael D. , Ahn Yeon S. , Horstman Lawrence L. , Jy Wenche , Kolodny Luciano , Myerberg Robert J.
Published: November 2007

We report on clinical, laboratory, and angiographic findings that appear to characterize a group of 13 middle-aged patients who suffered acute coronary syndromes (ACS) despite little angiographic evidence of atherosclerotic heart disease (ASHD) or other risk factors. Nine of the 13 were ≤46 years of age and the rest ranged to 59 years. All had evidence of platelet disorders (PD): seven had chronic immune thrombocytopenia (ITP), one had familial thrombocytopenia, and five had other disorders affecting platelets. Evidence of long-standing chronic platelet activation was the common feature of the group, as found by (i) elevated platelet microparticles (PMP), (ii) thrombocytopenia, and (iii) enhanced procoagulant activity of plasma. Data on the 7 with ITP were compared to 20 ITP without ACS: the former had higher PMP (p < 0.01) and platelet-associated IgM (p < 0.05) relative to the ITP patient controls. Another set of patient controls consisted of 20 ACS with documented ASHD: although activation indicators were abnormal also in this group relative to normal controls (p < 0.01), the PD group of 13 had more marked abnormalities in all tests (p < 0.03), particularly in PMP and thrombocytopenia (p < 0.01). The seven youngest in the PD group appeared to respond to antiplatelet therapy since no recurrence of coronary ischemia was seen in up to 3 years of observation. It is suggested that chronic platelet activation by antibodies or immune complex may predispose those in the PD group to ACS (e.g., when under stress) despite the absence of ASHD and few other known risk factors. The true incidence of this syndrome is unknown but may be substantial. Key Words: Chronic platelet activation-Platelet microparticles-Platelet.associated IgM-Immune thrombocytopenia-Acute coronary syndromes-Middle age.
Evans's Syndrome with Positive Lupus Anticoagulant and Antiphospholipid-Protein Antibodies
Authors: Musial Jacek , Frolow Marzena , Skotnicki Aleksander B. , Jankowski Milosz , Swadzba Jakub
Published: November 2007

We report a case of a 34-year-old Caucasian man with Evans's syndrome, first manifested in childhood as autoimmune thrombocytopenia. Besides anti-erythrocyte antibodies and platelet-associated immunoglobulins, this patient's serum showed also the presence of antiphospholipid-protein antibodies detected by coagulometric (lupus anticoagulant) as well as immunoenzymatic methods (anticardiolipin, antiprothrombin, and anti-β2-glycoprotein I antibodies). Over 25 years of clinical observation the patient never experienced any thromboembolic events. We suggest that in the pathogenesis of Evans's syndrome and related disorders a major role is played by an autoimmune reaction with a predilection to various cell phospholipid-containing membrane structures, possibly damaged by a yet unknown primary insult. The significance of these various antiphospholipid-protein antibodies as predictors of thromboembolic complications in such patients remains, however, to be established. Key Words: Evans's syndrome-Lupus anticoagulant-Antiphospholipid-protein antibodies.
Use of Aprotinin in the Control of Bleeding During Cardiopulmonary Bypass Surgery: Current Status
Authors: Pifarrè Roque
Published: November 2007

Excessive bleeding is one of the major complica tions of cardiac surgery with cardiopulmonary bypass (CPB). This complication is related to the operation and the defects in hemostasis induced by extracorporeal circulation. The system atic effects of CPB are called whole body inflammatory reac tion. Heparin, platelet dysfunctions, and fibrinolysis are the major causes of bleeding problems associated with CPB. Dif ferent pharmacological approaches have been used to reduce bleeding and the need for blood transfusions in patients under going cardiac surgery. The most effective is aprotinin, a serum protease inhibitor that is an antifibrinolytic with a platelet- preserving action. It inhibits the activation of the intrinsic co agulation system. Aprotinin therapy effectively reduces blood loss and donor blood requirements. According to most reports, it does not increase the risk of acute myocardial infarction, renal dysfunction, and mortality.
A Comparison of Heparin and New Anticoagulants for Cardiopulmonary Bypass Surgery
Authors: Belougne-Malfattie Emmanuelle , Aguejouf Omar , Labrousse Louis , Doutremepuich Christian
Published: November 2007

Heparin is still the major anticoagulant of choice during CPB, but it may cause thrombocytopenia and severe bleeding in patients. In light of these complications, the devel opment of new anticoagulant drugs seemed to be necessary for these patients. Many experimental studies focused on r-hirudin, which presented a less hemorrhagic effect than heparin. How ever, neither antagonist has been shown to reverse this effect.
Transaminase Elevation in Patients Treated with Unfractionated Heparin or Low Molecular Weight Heparin for Venous Thromboembolism
Authors: Girolami Bruno , Prandoni Paolo , Rossi Laura , Girolami Antonio
Published: November 2007

The purpose of this study was to evaluate the in cidence of transaminase elevation in patients treated with un fractionated (UFH) or low molecular weight heparin (LMWH). Patients receiving UFH, nadroparin, or reviparin for venous thromboembolism and with normal baseline transaminase val ues were evaluated for serum transaminase levels 10-14 days after the start of heparin therapy or at the end of treatment. The incidence of high transaminase was 4.7% overall (95% CI, 2.2 to 7.3), while it was 2.9% (95% CI, 0.1 to 5.6) and 6.7% (95% CI, 2.5 to 11.0) with UFH and LMWH treated patients, respec tively. The difference was equal to -3.8% (95% CI, -8.9 to 1.2) and the common odds ratio was equal to 0.38 (95% CI, 0.12 to 1.16, p = .09). Nadroparin treated patients showed a 5.7% (95% CI, 1.3 to 10.2) incidence of high transaminase levels, while reviparin treated patients presented a 10.3% incidence (95% CI, -0.7 to 21.4). The comparison with UFH showed a mild trend in favor of UFH when compared with nadroparin, but not with reviparin. In conclusion, the incidence of trans aminase increase during heparin treatment for a venous throm boembolic event is equal to 3%, 6%, and 10% in UFH-, na droparin-, and reviparin-treated patients, respectively. LMWHs showed a slightly higher average incidences of hypertransami nasemia as compared with UFH. Differences did not reach statistical significance. Key Words: Unfractionated heparin— Low molecular weight heparin—Hypertransaminasemia.
Plasminogen Activator Inhibitor Type-1 (PAI-1) Levels Are Decreased in NIDDM Patients treated with Insulin
Authors: Galajda Peter , Martinka Emil , Staško Ján , Mokáň Marian , Kubisz Peter
Published: November 2007

We examined 25 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with sulfonylurea (SU) regi mens, 14 NIDDM patients with 8-12 weeks long-acting insulin (INS) treatment and 15 age-matched normoinsulinemic healthy controls. Plasminogen activator inhibitor-1 (PAI-1) levels were significantly increased in NIDDM patients treated by SU agents (median 58.9, range 14-217 ng/ml) compared to patients with insulin therapy (median 20.7, 4-53 ng/ml) and normal controls (median 10.8, 4-52 ng/ml) (p < 0.001). Non-insulin- dependent diabetes mellitus subgroups were not different in other hemostatic (von Willebrand factor, thrombomodulin, tis sue factor pathway inhibitor, platelet factor-4 levels) and meta bolic (C-peptide, triglycerides) parameters and PAI-1 levels did not correlate with these hemostatic and metabolic parameters. This finding suggests that insulin application itself may cause decreased PAI-1 levels, probably by influence on intracellular calcium. This hypothesis requires further research. Key Words: PAI-1—Insulin treatment—Non—insulin—dependent diabetes mellitus.
Heparin-tissue Factor Pathway Inhibitor Complexes: Anticoagulant and Pharmacokinetic Properties
Authors: Wun Tze-Chein , Palmier Mark O.
Published: November 2007

Exogenous addition of full-length tissue factor pathway inhibitor (FL-TFPI) to plasma caused a greater pro longation of prothrombin time (PT) than activated partial thromboplastin time (APTT). In contrast, heparin elicited a greater prolongation of APTT than PT. These results suggest that FL-TFPI and heparin exert their anticoagulant activity pri marily through inhibition of the extrinsic and intrinsic path ways, respectively. Using a dilute thromboplastin-induced clot ting assay, it was found that FL-TFPI was ~37-fold more potent than the carboxyl terminus truncated form (CT-TFPI) in pro longing the clotting time, which indicated that the positively charged carboxyl terminus of FL-TFPI was crucial for its an ticoagulant activity. Both FL-TFPI and CT-TFPI could exert synergistic anticoagulant action with heparin when TFPIs and heparin were added sequentially to plasma. However, when FL-TFPI was complexed with heparin before addition to the plasma, the effect on anticoagulant activity was dependent on the weight ratio of heparin:FL-TFPI. Addition of the hepa rin:FL-TFPI complex at weight ratios <1.25:1 gave a dPT clot ting time shorter than that of addition of FL-TFPI alone sug gesting that neutralization of the positively charged carboxyl terminus of FL-TFPI by heparin could also decrease its anti coagulant activity. Addition of heparin:FL-TFPI complex at weight ratios ≥1.25:1 gave an additive or synergistic antico agulant effect compared to the individual anticoagulant effects of heparin and FL-TFPI. In contrast, addition of preformed N-acetyl heparin:FL-TFPI and low molecular weight hepa rin :FL-TFPI complexes in above weight ratios to plasma caused only inhibition of the anticoagulant activity of FL-TFPI. Pharmacokinetic studies of FL-TFPI and heparin:FL-TFPI complex were carried out in rabbits. Both pharmacokinetic data could be fitted into a biexponential clearance model. Full- length TFPI had a very short t1/2α (1.4 min) and a relatively long t1/2β (92 min) with AUCβ (92%) dominant. Heparin :FL- TFPI, in contrast, had a prolonged t1/2α (15 min) and a similar t1/2β (116 min) with AUCα (88%) dominant. The overall clear ance was ∼2.6-fold faster for FL-TFPI than heparin:FL-TFPI complex. Constant infusion studies confirmed that it was pos sible to achieve the same steady state level of TFPI in the circulating plasma by infusing 2.6-fold less complex than in fusion of the FL-TFPI alone.
Factor V Leiden (Activated Protein C Resistance) Versus Factor V Deficiency in Padua, Italy
Authors: Girolami Antonio , Simioni Paolo , Zanon Ezio , Girolami Bruno , Marchiori Antonio
Published: November 2007

Ten homozygous patients with factor V deficiency and 19 homozygous patients with activated protein C (APC) resistance were seen in Padua during the last 30 or 3 years, respectively. The actual numbers of heterozygous patients seen during the same periods of time were 41 and 306, respectively. All patients came from the northeastern part of Italy with a population of 10,000,000 people. The probable prevalence of homozygous patients was obtained by multiplying the actual number by four. The theoretical prevalence of heterozygous patients was obtained using the formula 2 qp, where q is the frequency of the abnormal gene as calculated by the square root of frequency of the homozygotes and p is the frequency of the normal allele as calculated by the formula p = (1 - q). Using such calculations, the number of heterozygotes probably exist ing in northeastern Italy is 39,840 and 56,497, respectively for the factor V deficiency and for APC resistance. After correction for the different observation periods (3 years vs. 30 years), there are 56,497 per 10 million people (5.6% of the population) for factor V Leiden. The prevalence of factor V deficiency is 0.39% of the population. Therefore the factor V Leiden muta tion responsible for APC resistance appears to be more preva lent than factor V deficiency on the basis of actual figures and accepted theoretical calculations.
Elevated Plasma Vascular Endothelial Cell Growth Factor and Thrombomodulin in Juvenile Diabetic Patients
Authors: McLaren Margaret , Elhadd Tarik A. , Greene Stephen A. , Belch Jill J. J. F.
Published: November 2007

The major cause of morbidity and mortality in pa tients with type 1 diabetes mellitus is vascular disease and the death rate in this group of patients can be up to six times that of the general population. Elevated levels of blood glucose can cause endothelial cell damage, and markers of endothelial dam age such as von Willebrand factor (vWF) and thrombomodulin (TM) have been reported to increase in adult diabetic patients. Growth factors are strongly linked to smooth muscle cell pro liferation that contributes significantly to the vascular occlusive process and it has been shown that vascular endothelial cell growth factor (VEGF) stimulates release of vWF from endo thelial cells. Vascular endothelial cell growth factor levels have been shown to be increased in vitreous fluid from the eyes of diabetic patients with proliferative retinopathy compared to those without. In this study we have shown that plasma levels of both TM and VEGF were significantly increased in juvenile diabetic patients with no clinical evidence of vascular disease compared to normal age and sex-matched control subjects. Me dian TM levels were 45.5 ng/mL (I.Q.R. 34 to 56 ng/mL) and 61 ng/mL (I.Q.R. 41 to 72 ng/mL) in the control group and in the diabetic patients respectively ( p = .0005) and median lev els of VEGF were 19.6 pg/mL (I.Q.R, 15.9 to 28.1 pg/mL) in the control group and 37.1 pg/mL (I.Q.R. 22.1 to 50.3 pg/mL) in the diabetic patients (p = .027 Mann-Whitney U test). This suggests that microvascular disease begins in childhood and can be detected using laboratory tests before any clinical changes are apparent. Key Words: Diabetes mellitus— Thrombomodulin—Vascular endothelial cell growth factor.
R-Hirudin as Anticoagulant in Regular Hemodialysis Therapy: Finding of Therapeutic R-Hirudin Blood/Plasma Concentrations and Respective Dosages
Authors: Bucha Elke , Nowak Goetz , Czerwinski Rralf , Thieler Heinrich
Published: November 2007

Recently heparin-induced thrombocytopenia type II has been diagnosed more frequently and does not exclude hemodialysis patients. Up to now, recombinant hirudin is the only available anticoagulant showing no immunologic cross reactions with heparin. However, the use of r-hirudin in hemo dialysis patients with different degrees of residual renal func tions is impossible using standard dosages because elimination of r-hirudin varies depending on the degree of residual renal function. Therefore the first study was carried out using con secutive r-hirudin anticoagulated hemodialyses to determine the appropriate dose of r-hirudin. Ten hemodialysis patients with creatinine clearance values ranging between 0 and 13 mL/min/1.73m2 were anticoagulated with r-hirudin. An initial bolus of 0.1 mg/kg bwt before the first hemodialysis, resulted in an average r-hirudin blood concentration of 305 ng/mL at the end of treatment. The dose for each of the following four he modialyses was adjusted individually to reach the minimum therapeutic r-hirudin blood concentration. At the end of these treatments the mean blood r-hirudin concentration was 422 ng/mL. The necessary mean doses ranged between 0.008 and 0.125 mg/kg bwt correlating to the creatinine clearance values of the patients. All hemodialyses of the study were effective and safe. Bleeding times determined during r-hirudin antico agulation were significantly lower than control values mea sured 2 days after a heparin administration. The study proved that r-hirudin may be an efficient and safe heparin alternative as a hemodialysis anticoagulant when the individual's residual renal function is noted for dosage and dose adjustment and is controlled by drug monitoring using the ecarin clotting time.
Synthetic Pentasaccharides Do Not Cause Platelet Activation by Antiheparin-Platelet Factor 4 Antibodies
Authors: Ahmad Sarfraz , Jeske Walter P. , Walenga Jeanine M. , Hoppensteadt Debra A. , Wood Jennifer J. , Herbert Jean-Marc , Messmore Harry L. , Fareed Jawed
Published: November 2007

A synthetic selective inhibitor of factor Xa, the pentasaccharide SR90107A/Org31540 is in clinical develop ment for the prophylaxis of postsurgical deep vein thrombosis. Another synthetic pentasaccharide with even more sustained inhibition of factor Xa, SanOrg34006, has also been developed. Both of these agents were tested in comparison to unfraction ated heparin and a low molecular weight heparin (enoxaparin) for their relative platelet activation potential in heparin-induced thrombocytopenia assays. Sera from patients (n = 30) with heparin-induced thrombocytopenia were pooled and validated for heparin-dependent aggregation responses. Using heparin- platelet factor 4 Sepharose columns, antibodies to heparin- platelet factor 4 were purified from the same pool. The effects of heparin, enoxaparin, SR90107A/Org31540, and San Org34006 were evaluated in a platelet aggregation assay using platelet donors (n = 10). At comparable concentrations, hep arin and enoxaparin consistently produced platelet activation, whereas both pentasaccharides failed to produce a response at a concentration up to 100 μg/mL (∼50 μM). Similarly, in the 14C-serotonin release and flow cytometric assays, heparin and enoxaparin produced positive responses (n = 30), whereas the two pentasaccharides consistently failed to produce any effect. These observations suggest that the two pentasaccharides with highly selective anti-Xa activity are devoid of generating anti heparin-platelet factor 4 antibody, do not produce heparin- induced thrombocytopenic responses and may inhibit active heparin-induced thrombocytopenia antibody platelet activation.
Cytogenetic monitoring of pharmaceutical staff working with cytostatic drug preparations: A 5-year follow-up
Authors: Peschke Michael , Nagel Sibylle , Haamann Frank , Melzer Simone , Meier Klaus
Published: November 2007

Introduction. Cytostatic drug preparation in hos pital pharmacies leads to a concentration of expo sure on a few people and requires considerable protective measures.

Methods. To prove the efficiency of those standards, 45 people who routinely prepare cyto static drugs were monitored with cytogenetic tests, Micronucleus-rate (MN), and Sister Chroma tid Exchange-rate (SCE), once a year over a period up to 5 years. All participants of the study received a physical examination before they began prepar ing cytostatic drugs. Baseline MN and SCE were performed at the time. Individual comparisons for the tests between pre- and post-exposure, and a comparison between an exposed and an unex posed group were then performed.

Results. During the 5-year follow-up there were no hints of genotoxic effects as a result of handling cytostatic drugs.

Conclusion. Thus, it appeared that the safety precautions employed at this Institute were ade quate.
Do topotecan concentrations in saliva reflect plasma concentrations?
Authors: van Warmerdam Ljc , Rosing H. , ten Bokkel Huinink WW , Maes Raa , Beijnen JH
Published: November 2007

Purpose. There is an increasing interest to use saliva as biological fluid for drug monitoring as it reflects adequately, in some cases, drug concentrations in plasma. A great advantage is that it can be obtained conveniently by a noninvasive method. We describe our experience with respect to the practical use of saliva for pharmacokinetic monitoring of the novel anticancer agent topotecan.

Patients and Methods. Eighty-one saliva sam ples and corresponding plasma samples were ob tained 2 hours after the end of infusion from 15 patients with either ovarian cancer or small cell lung cancer, receiving 1.5 mg/m 2 per day topotecan for 5 consecutive days every 3 weeks. Saliva was obtained by a citric-acid containing dental cotton roll which stimulated the saliva flow.

Results. The plasma topotecan concentrations varied between 3.67 and 24.4 ng/mL, with an intrapa tient (day-to-day) variation of only 9.8%, and an inter patient variation of 27.2%. The saliva concentrations varied between 5.34 and 74.2 ng/mL, with an intrapa tient variation of 25.3%, and an interpatient variation of 53.5%. The mean plasma/saliva topotecan ratio was 0.66 (range 0.21 to 1.58) and was both patient dependent and dependent on the sampling time. The day-to-day variation of the plasma/saliva concentra tion ratio in this daily times five schedule was 27.6%, and the interpatient variation was 45.5%. The saliva concentrations of topotecan were not related to the occurrence of mucositis, which was noted in some patients.

Conclusion. Based on the large variability in the plasma/saliva ratios, we conclude that in our investi gational setting saliva is not a reliable matrix for topotecan analysis and that plasma sampling is to be preferred.
The development of a national oncology pharmacy audit database in the United Kingdom of Great Britain and Northern Ireland
Authors: Stanley A.P. , Austin M.C.
Published: November 2007

Audit has become an important facet of service and patient management over the last 5 to 10 years. The importance of Audit has received particular emphasis in the UK through the endorsement of both its concepts and its practice from the government via the National Health Service Executive and professional bodies such as the Royal Pharmaceutical Society and the General Medical Council.

Within specialities, such as pharmacy services to oncology departments, the relative scale of operation makes self or even local peer-reviewed audit inappro priate. There needs to be a more broad based and less isolated comparison of standards, ideally with exter nal peer review. Furthermore because oncology phar macy tends to be run from small, very busy units the audit process would require additional time, re sources, or data collection. An appropriate audit process should, therefore, be based around existing work practices and not require additional resources. Bearing in mind these principles, a collaboration between a group of oncology pharmacists and a specialized health care firm was developed and the JANUS project and the NOPAD (National Oncology Pharmacy Database) established. The scheme relies on computer extraction of core data from existing working records. While being completely anonymous of patients and reporting centre. Data are then pro cessed into the NOPAD database which can be used by a reporting centre to compare their internal audit data to a national core data set, and for academic research into pharmacy practices in oncology phar macy. Furthermore information from the database has to be sold in a "washed out" form to oncology firms to pay for the running costs of the service. Although not universally subscribed to throughout the UK, there has been around an 80% uptake of the concept and further project looking to extend the database to cover support therapies, and/or other therapeutic areas as well as linking this drug usage picture to the UKs cancer registries disease distri bution picture.

Some of the background to this unique UK initiative are presented, and the mechanism by whic the project works for UK centres is described.
Pharmaceutical care and the cancer patient
Authors: Ignoffo Robert J. , King Reginald
Published: November 2007

Purpose. The primary objective of this paper is to discuss pharmaceutical care of the oncology patient in the context of recent recommendations made by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and recent changes in Health Care Reform.

Data Sources. We reviewed the literature through a MEDLINE search from 1985 to 1995. We searched the following terms: pharmaceutical care, cancer, patient, and pharmacist. We restricted the search to the English language. We also have incor porated several of our practice guidelines as examples of tools that can be used in the implementation of pharmaceutical care. We also focused on areas that the JCAHO guidelines specify as important pharma ceutical care issues in the cancer patient.

Data Extraction. Within the framework of drug prescribing, drug administration, drug monitoring, and patient education, we have provided interven tions that may potentially improve outcomes in can cer patients.

Data Synthesis. The advent of managed care will require that the pharmacist be more involved in the care and management of the cancer patient. This activity will necessitate that the pharmacist document the impact of interventions on patient outcomes. Although tumor response and survival are classic outcomes that are assessed in the cancer patient, other outcome indicators may be used to evaluate interventions made by the pharmacist.

Conclusions. This review offers strategies for implementing pharmaceutical care in the cancer pa tient. Because we did not present study results on patient outcomes, it is unknown which of these proposed pharmacist interventions are important fac tors in the implementation of pharmaceutical care in this patient population. Although pharmaceutical care is the new paradigm in pharmacy practice, we must perform prospective studies to determine its value to the cancer community.
Chemical stability of cyclophosphamide, trofosfamide, and 2- and 3-dechloroethylifosfamide in aqueous solutions
Authors: Kaijser G.P. , Aalbers T. , Beijnen J.H. , Bult A. , Underberg W.J.M.
Published: November 2007

The degradation kinetics of various oxazaphospho rines : trofosfamide, cyclophosphamide, and 2- and 3-dechloroethylifosfamide was studied by means of a high-performance liquid chromatographic method. The results were compared with the kinetics of ifosfamide. It appeared that the pres ence and the site of the chloroethyl group influ enced the chemical stability of the compounds.
An evaluation of the stability of granulocyte colony stimulating factor on short-term storage and delivery from an elastomeric infusion system
Authors: Tivnann Helen Ann , Gaines-Gas Rose , Thorpe Robin , Mire-Sluis Anthony Richard
Published: November 2007

Aim. To evaluate the stability of granulocyte col ony stimulating factor (G-CSF) (lenograstim) on the 14-day storage and delivery from an elastomeric infusion system (infusion device).

Methods. Infusion devices were filled with two different concentrations of G-CSF and stored for various times at 4°C under sterile conditions. Samples of G-CSF solution were then released through the infusion device and bioassayed on the G-CSF dependent murine cell line G-NFS-60.

Results. There was no statistically significant loss of bioactivity of G-CSF throughout storage and delivery from the devices for the maximum 14-day period tested at either concentration of G-CSF.

Conclusion. The devices can be filled with G-CSF and stored at 4°C for up to 14 days under sterile conditions without loss of biological activ ity, suggesting that these devices are compatible with this biological material and suitable for its short-term storage.
Elimination of NQ01 gene expression by vitamin E
Authors: Kolesar Jill M. , Talbert Robert L. , Kuhn John G.
Published: November 2007

Objective. NQ01 codes for NAD(P)H:Quinone ox idoreductase (NQOR, DT-diaphorase) which cata lyzes the two electron reduction of quinones. NQOR may protect against quinone-mediated carci nogenicity and activate bioreductive alkylating agents. NQ01 gene expression is induced in re sponse to variety of stimuli, including oxidative stress. Gene expression of NQ01 in response to the antioxidant vitamin E was investigated in this case report.

Case Summary. Baseline NQ01 gene expression was 7.5 × 10-6 ng NQ01/mL cDNA in one healthy, male (age 46) adult nonsmoking volunteer. The sub ject subsequently began taking vitamin E (α-tocoph erol, Bronson) 400 IU/d. NQ01 gene expression after 30 days of vitamin E administration was undetect able. The volunteer discontinued vitamin E and NQ01 gene expression was 1.46 × 10-6 ng NQ01/mL cDNA after 30 days. Vitamin E was restarted and after 30 and 60 days, NQ01 gene expression was again undetectable.

Discussion: In this subject we have demon strated the ability of vitamin E to effectively eliminate NQ01 gene expression in vivo as measured by a quantitative RT-PCR CE-LIF assay. Vitamin E modu lates signal transduction pathways in response to oxidative stress possibly by downregulation of nu clear factor kappa B (NF-kB). NF-κB, in turn, increases the gene transcription of NQ01. We hypothesize that vitamin E decreases the gene expression of NQ01 by this signaling pathway; by decreasing NF-KB, which in turn downregulates NQ01 gene expression. This may be important for oncology patients because as dem onstrated in vitro, decreased NQOR activity results in resistance to mitomycin-C.

Conclusion. Treatment with pharmacological doses of vitamin E can result in NQ01 gene expres sion down regulation in vivo when analyzed by RT-PCR CE-LIF. This interaction, role in the signaling. cascade, and its potential influence on an individuals response to chemotherapy represents an important avenue of exploration.
Clinical pharmacokinetics in oncology: Outcome in vancomycin
Authors: Aldaz Pastor Azucena , de la Asunción Inmaculada Tejedor , Gonzalez-Criado Carolina , Idoate Garcia Antonio
Published: November 2007

The University Clinic of Navarra is a general teaching hospital with a total of 413 beds, 60 of which are oncology beds. Of the specimens analysed in 1994 by the clinical pharmacokinetics unit, 53.2% were per formed in cancer patients and 27.3% were performed in patients receiving vancomycin.

Methods. We established 10 criteria governing both the process and the result in assessing the quality of vancomycin pharmacokinetic monitoring in oncological patients. We performed a retrospective assessment of the data-monitoring follow-up sheets of 100 cancer patients treated with vancomycin and whose serum vancomycin levels were monitored by the clinical pharmacokinetics unit between April 1993 and March 1994.

Results. Overall, the degree of compliance with the 10 defined criteria was good, even though 100% compliance was achieved only in criterion 5 (use of the kinetic method) and criterion 8 (repetition of monitoring must be justified). The lowest compliance was obtained in criterion 1 (evaluation of the initial medical prescription) and criterion 6 (the serum creatinine and daily fluid balances, parameters en compassed within the clinical assessment of the pa tient).

Conclusions. The detailed analyses of the crite ria performance suggest that the process of serum sample extraction in the wards should be improved and the frequency of serum creatinine testing should be increased. Corrective measures have been pro posed, and once they are developed, accepted, and implemented, the criteria will be reevaluated and a further audit performed to determine the usefulness of the changes made.
Liposomal doxorubicin: Doxil®
Authors: Patel J.
Published: November 2007

Objective: Many cytotoxic chemotherapy agents have a narrow therapeutic index. In fact, in some patients, the onset of serious adverse effects may precede any therapeutic benefit. The use of lipo somes to target drug delivery to the site of action can improve a drug's therapeutic index by increasing its efficacy while minimizing toxicity. Liposomal doxo rubicin (Doxil®, Sequus Pharmaceuticals, Inc.)* is the first liposomal chemotherapy product to be approved in the United States. The purpose of this review is to provide a basic understanding of liposomal drug delivery, describe the unique pharmacokinetic prop erties of liposomal doxorubicin (Doxil®), and, finally, comment on this novel drug's place in therapy. Data Sources: Manual and on-line (Medline) literature searches were performed. Search terms included were the brand and generic names of the product, Kaposi's sarcoma, and liposomes. The med ical information department of Sequus Pharmaceuti cals was contacted.

Study Selection: If available, controlled clinical trials with scientific merit were reviewed. Nonran domized studies, case reports, review articles, and letters to editors were considered if appropriate.

Conclusions: Liposomal chemotherapy is one of many attempts to improve cytotoxic chemotherapy by maximizing tumor cell kill while minimizing pa tient adverse effects. Liposomal doxorubicin (Doxil®) is the first of such products approved for use in the United States and has a unique formulation and advantageous pharmacokinetic profile. Liposomal doxorubicin (Doxil®) is both a safe and effective agent in the treatment of advanced AIDS-related Ka posi's sarcoma. The efficacy of liposomal doxorubicin (Doxil®) in the treatment of refractory solid tumors such as breast cancer, lung cancer, colorectal cancer, renal cell cancer, ovarian cancer, and sarcoma has not been demonstrated uniformly. Limited data are avail able regarding the cardiotoxicity potential of this agent; currently no definitive conclusions can be made. Further investigation will be needed to find the ideal dose, dose schedule, and monitoring parameters for the use of liposomal doxorubicin (Doxil®) in patients with solid tumors.
Economic evaluation of 4% albumin solution, gelatine, and hydroxyethylamidon for plasma volume expansion in cancer patients
Authors: Pinguet Frédéric , Poujol Sylvain , Martel Pascal , Roch Isabelle , Bressolle Francoise
Published: November 2007

Purpose. Given the potential advantages of the use of hydroxyethylamidon, the purpose of this cost analysis was to examine the economic consequences of the use of such derivatives compared to albumin and gelatine for fluid resuscitation in patients with various types of cancer.

Methods. We report on the economic evalua tion conducted at the Montpellier Anticancer Center between July 1989 and December 1995. Patients with various types of cancer were included in the study. About 310 patients were treated each year. Since January 1991, an economic policy was undertaken to reduce the cost of treatment by volume expanders.

Results. During the study period, the pharma ceutical price of these drugs, the number of patients, and the number of days of hospitalization remained relatively stable. From 1991 to 1995 of this economic evaluation, we observed a regular decrease in the utilization of fluid expanders. Indeed, 2370 vials were used in 1990 and only 868 in 1995. In 1991, a new plasma volume expander, hydroxyethylamidon, be

came commercially available. Consequently, from 1992, we observed a decrease in the use of 4% albumin; then, from 1993, there was a decrease in the use of gelatine. In 1989, the mean cost of each vial was $46; it was $16 in 1995. This decrease is attrib utable to a progressive substitution of 4% albumin, then of gelatine, by hydroxyethylamidon. During the 24 first months of the present study, the total cost of plasma volume expanders was approximately $180,000 (July 1989 to June 1991); it was $164,000 during the following 54 months (July 1991 to Decem ber 1995).

Conclusion. The pharmaceutical economic pol icy and the risk of using blood product have contrib uted to a decrease in the total cost of the different drugs used as plasma volume expanders. To date, the savings realized have been ∼$75,000 annually.
A comparison of the safety and efficacy of ondansetron versus granisetron as prophylaxis against chemo/ radiotherapy-induced nausea and vomiting in bone marrow transplantation patients. A double-blinded, randomized, prospective, pilot study
Authors: Or Reuven , Kupaluchnik Yosef , Drakos Pavlos , Nagler Arnon , Cass Yaakov
Published: November 2007

Introduction. Nausea and vomiting (N&V) are well known and distressing side effects of chemoradio therapy. Conditioning protocols for patients undergo ing bone marrow transplantation (BMT) consist of highly emetogenic high-dose chemotherapy with or without total body irradiation (TBI). The 5HT3 (sero tonin receptor) antagonists heralded a marked im provement in controlling chemotherapy-induced N&V. Ondansetron and granisetron have been avail able for some time with limited information available concerning their pharmacological and pharmacoeco nomic differences and patient acceptability.

Patients and Methods. This pilot study initiated comparison of the two drugs and evaluated the antiemetic efficacy and safety of a single daily dose of ondansetron, 16 mg, plus dexamethasone, 10 mg, compared to granisetron, 3 mg, plus dexamethasone, 10 mg, in patients receiving high dose chemotherapy (±TBI), prior to BMT. The 12-month pilot study was double-blinded, randomized, and prospective. A non- homogenous cohort of 23 patients (10 receiving ondansetron and 13 granisetron) were enrolled.

Results. No significant differences in the efficacy of the two protocols were observed. In each arm about 50% of the patients had a complete response, and a similar number had a major response.

Side Effects. The most common adverse events reported during the study included diarrhea and head ache. No patients were withdrawn due to side effects.

Conclusions. Our preliminary findings suggest that both of these two antiemetic protocols are safe and similarly effective in preventing chemotherapy-induced emesis in patients receiving BMT conditioning.

Discussion. Further evaluation in a multicenter study should now be made to compare efficacy, safety, cost-effectiveness, and quality of life parame ters of these two drugs.
Formulation of a flush solution of heparin, vancomycin, and colistin for implantable access systems in oncology
Authors: Vincentelli J. , Braguer D. , Guillet P. , Delorme J. , Carles G. , Perez R. , Duffaud F. , Nicoara A. , Drancourt M. , Favre R. , Crevat A.
Published: November 2007

Introduction: Because of the increased use of im plantable access systems, the incidence of blood stream and catheter infections associated with these systems has concomitantly increased. Classically, he parin-lock flush solutions were used to prevent thrombosis; more recently, vancomycin was added to the solution to prevent infections caused by Gram- positive bacteria, particularly coagulase-negative Staphylococci. Disorders due to Gram-negative organ isms have now appeared in oncologic patients. We therefore tested the addition of colistin to heparin- vancomycin solutions. Colistin was chosen for its good activity against Gram-negative bacteria (98% susceptibility in our hospital), its good tolerance due to low systemic passage, and its low cost.

Methods: We developed formulations contain ing heparin (100 IU/mL) and various concentrations of vancomycin (10-500 μg/mL) and colistin (10-100 μg/mL) in 0.9% NaCl. Each sterile solution was tested for physical and chemical compatibility (spectropho tometry, nuclear magnetic resonance, and pH mea surements) and its antibacterial activity (against ox acillin-resistant Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae exhibiting broad- spectrum betalactamase (BSBL), imipenem-resistant Pseudomonas aeruginosa) for 2 months at 4°C and at room temperature.

Results: The most suitable combination of drugs is heparin (100 IU/mL), vancomycin (100 μg/mL), and colistin (100 μg/mL). This flush solution main tains activity when stored at 4°C for up to 1 month.

Conclusions: We feel that the combination of heparin, vancomycin, and colistin can be used as a flush solution for indwelling catheters.
Coping with cancer and developing of cytotoxic reconstitution service at a private hospital in the UK
Authors: Sewell G.J.
Published: November 2007

Editorial Note. This commentary article was written by an eminent UK pharmacist, Dr Eddie Fullerton and his pharmacist wife Kath, who describe their experi ences during Eddie's treatment for bowel cancer. The positive, negative and practical aspects of ambulatory treatment are portrayed through the eyes of both pharmacist and cancer patient. The article goes on to describe Kath's unique role as "personal pharmacist" and caregiver.

To avoid any detraction from the personal and humanistic nature of this article, the manuscript has been published in its original form with minimal editorial intervention. Dr Fullerton died on 9 Novem ber 1996.