Therapies for ulcers associated with nonsteroidal antiinflammatory drugs.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
S Schulman
Publications and source records attributed to S Schulman.
Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group.
PURPOSE: To compare the risk of recurrent venous thromboembolism in patients with and without antiphospholipid antibodies. PATIENTS AND METHODS: Anticardiolipin antibodies were tested 6 months after a first or second episode of venous thromboembolism. Of the patients with a first episode of venous thromboembolism only the 412 who received 6 months of anticoagulation were studied. Two hundred and eleven patients with a second episode received oral anticoagulation for 6 months or indefinitely. The therapy was targeted at an international normalized ratio (INR) of 2.0 to 2.85. All patients were followed up for 4 years after enrollment. RESULTS: Among the 412 patients with a first episode of venous thromboembolism the risk of recurrence was 29% in patients with anticardiolipin antibodies and 14% in those without antibodies (P = 0.0013). In those with antibodies, there was an increased risk during the first 6 months after cessation of anticoagulation. The risk of recurrence increased with the titer of the antibodies. Four-year mortality rate was 15% in those with antibodies and 6% in those without (P = 0.01). Among 34 patients with a second event of venous thromboembolism and anticardiolipin antibodies, there were no recurrences during anticoagulant therapy versus 20% in those who received only 6 months of treatment (P = 0.08). CONCLUSIONS: The presence of elevated titers of anticardiolipin antibodies 6 months after an episode of venous thromboembolism is a predictor for an increased risk of recurrence and of death. Patients with anticardiolipin antibodies and venous thromboembolism seem to benefit from prolonged oral anticoagulation.
Aged↗
Major surgery seems not to influence HIV disease progression in haemophilia patients.
The influence of major surgery on HIV disease progression and decline in CD4+ cell count was evaluated in 23 seropositive haemophilia patients. 24 HIV-infected patients served as non-operated controls. In addition, 32 age-matched seronegative subjects were included. The follow-up time was up to 5 years. During the course of the study, eight of the operated (35%) and 11 of the non-operated (48%) subjects developed HIV-related symptoms (P=0.267). The relative risk for developing HIV-related symptoms after surgery was 0.60 (95% CI 0.25; 1.48). A significant decline in CD4+ cell counts was observed in both the surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.001) and the non-surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.004) seropositive subgroup, but no difference between the two subgroups was seen (P=0.793). HIV (6.0 x 10(6)/l/month, 95% CI 2.1; 9.9 x 10(6), P=0.0005) but not surgery (-1.0 x 10(6)/l/ month, 95% CI -3.0; 0.96 x 10(6), P=0.647) was an independent predictor for the decline in CD34+ cell count. No interaction effect was observed between HIV infection and surgery (P=0.361). The annual amount of factor concentrate used for regular replacement therapy did not influence the decline in CD4+ cell count (P=0.492). We conclude that major surgery may be considered in symptom-free HIV-seropositive haemophilia patients, with CD4+ cell counts > or = 0.20 x 10(9)/l under similar premises as for seronegative subjects.
Adolescent↗
Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.
PURPOSE: Prior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas. PATIENTS AND METHODS: We correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival. RESULTS: Of 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overall median survival for patients with high versus low MGMT levels was 8 and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6 months, respectively (P=.008). Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months (n=40). The overall hazards ratio (risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19; age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60 years (1.11). Multivariate analysis showed that MGMT was independent of other known prognostic factors (age, performance status, histology). CONCLUSION: The MGMT level in tumor tissue specimens may be a predictive marker of survival in patients with malignant astrocytoma that is independent of other previously described prognostic variables.
Adult↗
The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group.
BACKGROUND: A consensus has not been reached about the optimal duration of oral anticoagulant therapy after a second episode of venous thromboembolism. METHODS: In a multicenter trial, we compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had had a second episode of venous thromboembolism. Of 227 patients enrolled, 111 were randomly assigned to six months of anticoagulation and 116 were assigned to receive anticoagulant therapy indefinitely; for both groups, the target international normalized ratio was 2.0 to 2.85. The initial episodes of deep-vein thrombosis (n = 193) and pulmonary embolism (n = 34), as well as recurrent episodes, were all objectively confirmed. RESULTS: After four years of follow-up, there were 26 recurrences of venous thromboembolism that fulfilled the diagnostic criteria, 23 in the group assigned to six months of therapy (20.7 percent) and 3 in the group assigned to continuing therapy (2.6 percent). The relative risk of recurrence in the group assigned to six months of therapy, as compared with the group assigned to therapy of indefinite duration, was 8.0 (95 percent confidence interval, 2.5 to 25.9). There were 13 major hemorrhages, 3 in the six-month group, (2.7 percent) and 10 in the infinite-treatment group (8.6 percent). The relative risk of major hemorrhage in the six-month group, as compared with the infinite-treatment group was 0.3 (95 percent confidence interval, 0.1 to 1.1). There was no difference in mortality between the two groups. CONCLUSIONS: Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of venous thromboembolism was associated with a much lower rate of recurrence during four years of follow-up than treatment for six months. However, there was a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely.
Administration, Oral↗
Coagulation factor concentrates by continuous infusion.
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Blood Coagulation Factors↗
Tissue magnesium levels and the arrhythmic substrate in humans.
INTRODUCTION: Magnesium deficiency has been implicated in the pathogenesis of sudden death, but the investigation of arrhythmic mechanisms has been hindered by difficulties in measuring cellular tissue magnesium stores. METHODS AND RESULTS: To see if magnesium deficiency is associated with a propensity toward triggered arrhythmias, we measured tissue magnesium levels and QT interval dispersion (as an index of repolarization dispersion) in 40 patients with arrhythmic complaints. Magnesium was measured in sublingual epithelium using X-ray dispersive analysis. QT interval dispersion was assessed on 12-lead surface ECGs in all patients, and programmed stimulation was performed in 28. The sublingual epithelial magnesium level ([Mg]1), but the not the serum level, correlated inversely with QT interval dispersion in 40 patients (r = 0.58, P < 0.005); in 12 patients undergoing repeat testing on therapy, the change in magnesium also correlated inversely with the change in QT dispersion (r = 0.61, P < 0.05). Patients with left ventricular ejection fractions > 40% had significantly higher tissue magnesium and lower QT dispersion (34.5 +/- 0.5 mEq/L, 81 +/- 8 msec) than those with left ventricular ejection fractions < 40% (32.7 +/- 0.5 mEq/L, P < 0.01, and 114 +/- 9 msec, P < 0.05). There was no difference in either [Mg]1 or QT dispersion in the 16 patients with inducible monomorphic ventricular tachycardia versus the 12 noninducible patients. CONCLUSION: Reduced tissue magnesium stores may represent a significant risk factor for arrhythmias associated with abnormal repolarization, particularly in patients with poor left ventricular systolic function, but may not represent a risk for excitable gap arrhythmias associated with a fixed anatomic substrate (e.g., monomorphic ventricular tachycardia).
Adult↗
Optimal duration of oral anticoagulant therapy in venous thromboembolism.
Recent trials with sufficient statistical power have demonstrated that the duration of oral anticoagulation in many cases need to be extended well beyond 4-6 weeks. Since many individual factors, as risk of hemorrhage and of recurrence, compliance and cost have to be weighed into a decision, it is difficult to issue general recommendations. Several of these factors, especially those influencing the risk of recurrent event are reviewed here. The ideal solutions will perhaps only be achieved when we have learned how to combine the optimal duration with a time-adjusted decrease in oral anticoagulation.
Administration, Oral↗
Increased fetal loss in women with heritable thrombophilia.
BACKGROUND: A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately. FINDINGS: The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups. INTERPRETATION: Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.
Abortion, Spontaneous↗
Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.
We tested the hypothesis that the level of the DNA repair protein O6-alkylguanine-DNA alkyltransferase in brain tumors was correlated with resistance to carmustine (BCNU) chemotherapy. Alkyltransferase levels in individual cells in sections from 167 primary brain tumors treated with BCNU were quantitated with an immunofluorescence assay using monoclonal antibodies against human alkyltransferase. Patients with high levels of alkyltransferase had shorter time to treatment failure (P = 0.05) and death (P = 0.004) and a death rate 1.7 times greater than patients with low alkyltransferase levels. Furthermore, the size of the subpopulation of cells with high levels of alkyltransferase was correlated directly with drug resistance. For all tumors the variables most closely correlated with survival, in order of importance, were age, tumor grade, and alkyltransferase levels. For glioblastoma multiforme, survival was more strongly correlated with alkyltransferase levels than with age. These results should encourage prospective studies to evaluate alkyltransferase levels as a method, for identifying brain tumor patients with the best likelihood of response to BCNU chemotherapy.
Antibodies, Monoclonal↗
Multiple joint procedures in a single operative session on hemophilic patients.
Hemophilia is a coagulation disorder wherein frequent hemarthroses result in premature joint degradation. This hemophilic osteoarthropathy is polyarticular, and despite modern coagulation possibilities, acute hemarthroses and chronic synovitis are common. Because repair of a single joint in polyarthritic conditions may not improve the patient's functional ability a policy has been adopted to create a functional limb. This therapeutic protocol succeeded in gaining the objectives of a functional limb, and it was noted that the complication rate was less than expected and that the rehabilitation period was relatively short.
Adult↗
Role of fibrin sealants in surgical procedures on patients with hemostatic disorders.
Fibrin sealants have until now been used to a very limited extent in patients with a bleeding diathesis. The authors have accumulated experience from 8 minor and 40 major surgical procedures, plus 10 circumcisions and 118 tooth extractions in 106 patients suffering from hemophilia A, B, or von Willebrand's disease. Most of the patients had the severe form of the disease. The authors were able to show a reduction of blood loss and of requirements for replacement therapy with factor concentrates. The literature on the application of fibrin sealants in this group of patients, which mainly deals with dental procedures, is reviewed and compared with data from the current study. The composition of the glue is of major significance and is discussed in detail.
Blood Coagulation Disorders↗
Anticoagulation in venous thrombosis.
Major studies addressing various aspects of the treatment of deep vein thrombosis are reviewed. It has lately been demonstrated that heparin should be dosed according to body weight and is preferably given as subcutaneous injections twice daily. Alternatively, low-molecular-weight heparins may be given in a fixed dose once daily, which does not require monitoring. Oral anticoagulation should be started concomitantly with heparin and targeted at an international normalized ratio of 2.0-3.0. This treatment should continue for a longer duration than previously accepted, in many cases for 6 months. For patients with contraindications to oral anticoagulation, secondary prophylaxis with a low-molecular-weight heparin is also effective and safe.
Administration, Oral↗
Feasibility of using recombinant factor VIIa in continuous infusion.
Recombinant factor VIIa (rFVIIa; NovoSeven) is a recent addition to the hemostatic alternatives for the treatment of hemophiliacs with inhibitors. A drawback in the use of rFVIIa has been its half-life of only about 2 h, which necessitates very frequent and punctual injections. We evaluated the stability of reconstituted, but not further diluted, rFVIIa in 3 infusion systems (WalkMed 350 and CADD-Plus minipumps and Meddex 2001 syringe pump). The factor VII (F VII) activity was maintained for at least 3 days at room temperature with only a minor and clinically insignificant increase in oxidized forms of rFVIIa and minimal leaching of the plastic softeners dibutylphthalate and di-octylphthalate after 24-48 h. Addition of heparin, 5-10 U/ml, to reconstituted rFVIIa caused a loss of about 50% of the activity within 4 h of storage in the infusion system, whereas low molecular weight heparin had no such effect. Repeated samples showed that the infusion systems maintained sterility. Reconstituted rFVIIa did not support bacterial growth when inoculated with Staphylococcus aureus or Escherichia coli to any greater extent than did reconstituted factor VIII, lidocaine in saline or heparin in saline. Two patients were treated with continuous infusion of rFVIIa on 4 occasions (total knee arthroplasty, wound revision, and twice straightening of a 90 degrees contracture of the knee under general anaesthesia). A preoperative pharmacokinetic evaluation was performed, and the clearance was used to calculate the maintenance dose, aiming at a FVII level of 10 U/ml, which proved to be a hemostatic level. The first patient had no change in the clearance during the two treatment episodes. He suffered from repeated thrombophlebitis at the infusion site. The second patient had a progressive decrease of the clearance from 86.4 to 24.7 ml/h/kg. He received during the first treatment a parallel infusion with heparin (approximately 250 U/24 h) to the same venous access and did not develop thrombophlebitis during 3.5 days of therapy. For the second episode low molecular weight heparin was added directly to the infusion bag, and no adverse effects were observed. Continuous infusion with rFVIIa is thus feasible with the minipumps used by us, eliminates the need for 2 h injections and reduces the total dose of rFVIIa by 50-75%, depending on the behaviour of the clearance.
Drug Stability↗
Design and assessment of clinical trials on continuous infusion.
Continuous infusion of coagulation factors is becoming increasingly popular, and is mirrored by the accelerating rate of publications on this topic. However, several questions remain, particularly regarding efficacy. For this purpose, well designed trials are required. Some guidelines for such trials are presented here.
Clinical Trials as Topic↗
Review of pumps for continuous infusion of coagulation factor concentrates: what are the options?
Continuous infusion of coagulation factor concentrates has become more popular in recent years because it can substantially reduce the cost of surgery for a patient with hemophilia. This technique has also been used successfully for treatment of severe bleeds, induction of immune tolerance and short-term prophylaxis. The large selection of devices complicates the choice of an infusion system for this delivery approach. However, choosing the best type of device for a particular situation may determine the success or failure of continuous infusion.
Factor VIII↗
The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Duration of Anticoagulation (DURAC) Trial Study Group.
An impaired fibrinolytic function has been described in several case-control studies of patients with venous thromboembolism (VTE). In the present study the correlations between some fibrinolytic compounds and future recurrent VTE were investigated. Blood samples for analysis of tissue-type plasminogen activator (t-PA) antigen before and after 10 min of venous occlusion (V.O.) and plasminogen activator inhibitor type 1 (PAI-1) activity were taken at 6 months after the first episode of VTE or the first recurrent VTE in 784 and 207 patients, respectively, who were anticoagulated for 1.5 or 6 months (first VTE) and 6 months or indefinitely (first recurrence). During a follow-up of 3-6 years from the event which qualified for inclusion there have been 177 recurrences. All initial and recurrent events were verified with objective diagnostic methods. Using cut off points of 10.0 ng/ml for t-PA antigen before V.O. and 30 AU/ml for PAI-1 in samples taken at rest, there were more patients above those levels in the groups with than without further recurrence (t-PA antigen, 50% versus 36%, p = 0.001; PAI-1, 18% versus 12%, p = 0.045). In the 495 patients, who received oral anticoagulation for 6 months, t-PA antigen at rest discriminated better, with 59% versus 34% of patients above 10 ng/ml in the groups with and without recurrence, respectively (p < 0.001). The t-PA antigen levels after V.O. and the fibrinolytic capacity (t-PA antigen after V.O. minus t-PA antigen before V.O.) were distributed similarly in patients with and without new recurrences. There was a statistically significant positive correlation between age and t-PA antigen (p < 0.001), and by analysis of covariance the difference between the groups with and without further recurrence regarding t-PA antigen disappeared. In conclusion, increased levels of PAI-1 and t-PA antigen in VTE-patients correlate with development of recurrent VTE within the next 3-6 years, but the value of these components in predicting future events for the individual patients is limited.
Anticoagulants↗
Cyclosporine therapy for acquired factor VIII inhibitor in a patient with systemic lupus erythematosus.
The case of a 27-year-old woman with systemic lupus erythematosus and development of an autoantibody against factor VIII during an exacerbation of her underlying disorder is described. Attempts to eliminate the antibody with high dose gammaglobulin and repeated courses of cyclophosphamide failed, whereafter she received cyclosporine in increasing doses. When therapeutic serum levels of cyclosporine were achieved (150-350 ng/ml) the inhibitor rapidly decreased and disappeared with a concomitant normalization of the factor VIII levels. Treatment with cyclosporine was subsequently reduced and discontinued after one year, and at present no inhibitor is detectable. In view of the successful results with cyclosporine treatment in 4 of 6 previous cases and in all 3 previous cases with autoimmune disorders, this regimen should be evaluated in a systematic manner as a potential first line drug in patients with acquired hemophilia and an underlying autoimmune disorder.
Adult↗