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Biomedical subjects

D Mungall

Publications and source records attributed to D Mungall.

At least 19 recordsLinked to original sources
PubMed1999

Desmin 370 (Opocrin SpA/Alfa Wassermann).

Alfa Wassermann, in collaboration with Opocrin, is developing Desmin 370, an antithrombotic agent which is in phase III clinical trials for the treatment of deep vein thrombosis, and may have potential in the treatment of pulmonary embolism. The antithrombotic effect is attributed to the inhibition of thrombin generation, potentiation of heparin cofactor II activity, and local fibrinolytic effects. Opocrin is the product patent holder (EP-00221977 and US-04973580), while Alfa Wassermann is the developer and responsible for the clinical research.

Journal Article↗
PubMed1998

Developing and testing a system to improve the quality of heparin anticoagulation in patients with acute cardiac syndromes.

We have taken a stepwise approach to improving the dosing of continuous intravenous heparin in patients with acute coronary syndromes. Our primary objective was to use computer modeling to develop a nomogram for managing heparin therapy and to put in place a continuous quality monitoring system to evaluate the nomogram's effectiveness. We prospectively collected data on 41 patients with unstable angina or myocardial infarction who were treated with heparin. Their response to heparin was computer modeled and the dose to achieve an activated partial thromboplastin time (aPTT) ratio of 2.0 was established. This dose was regressed against all demographic characteristics to establish predictors of heparin dose (phase I). The regression formula was used prospectively in 110 patients to initiate the infusion rate of heparin and a bolus dose to achieve an aPTT ratio of 2.5. Subsequent dosage adjustments were achieved by computer modeling the patient's aPTT response (phase II). A nomogram was developed that simulated the decisions achieved using computer-assisted methods. This was retrospectively tested and then prospectively tested in 50 patients using nursing staff (phase IV). The nomogram was then made generally available (phase IV) and has been tested in an additional 310 patients. Phase I: Of the original 41 patients, 32% of the aPTT ratios were in the therapeutic range, 36% were supratherapeutic, and 32% were subtherapeutic after the first 24 hours. Phases II and III resulted in 85% of the aPTT ratios between 1.5 and 2.5 at 24 hours. Phase 4 had similar results in 310 patients. The use of computer-assisted or a computer-generated nomogram to adjust heparin therapy results in better control of heparin therapy than using standard methods.

Adult↗
PubMed1997

Effect of weight, sex, age, clinical diagnosis, and thromboplastin reagent on steady-state intravenous heparin requirements.

BACKGROUND: There is a significant direct relationship between steady-state intravenous heparin dose requirements and total body weight. Less is known about whether sex, age, clinical diagnosis, and the thromboplastin used to measure the activated partial thromboplastin time (aPTT) affect heparin dose requirements. METHODS: Four cohorts of patients treated with intravenous heparin were gathered from 3 hospitals: 2 cohorts with deep vein thrombosis (DVT) and 2 cohorts with coronary artery disease (CAD). For each clinical diagnosis, half the patients were monitored using one aPTT reagent and the remainder were monitored using a second reagent. Heparin doses and aPTT measurements were recorded, and the dose necessary to achieve an aPTT ratio of 2.0 was calculated using a computer software program. RESULTS: We analyzed the records of 340 patients: 165 with DVT and 175 with CAD. Using analysis of variance, there was a significant difference in the steady-state heparin requirements among patients with DVT compared with patients with CAD (P < .001). For each clinical diagnosis, the use of a different thromboplastin reagent did not affect heparin dose requirements (P > .42). Linear regression modeling disclosed that the steady-state heparin dose for patients with DVT was a function of weight plus an effect modifier involving weight and age, whereas for patients with CAD there was only a weak relationship with weight. CONCLUSIONS: Steady-state heparin dose requirements were significantly different in patients with DVT compared with patients with CAD, suggesting that different dosing nomograms are needed for each condition. For patients with DVT, the accuracy of the initial heparin dose estimate may be improved by considering the patient's age and weight.

Aged↗
PubMed1995

Changes in plasma warfarin levels and variations in steady-state prothrombin times.

OBJECTIVE: To determine the relative contribution of changes in the plasma warfarin level to variation in the serial steady-state prothrombin times. METHODS: This was a prospective observational cohort study performed at two outpatient anticoagulation clinics. Serial prothrombin times and paired plasma total warfarin levels were determined in a convenience sample of otherwise healthy patients who required long-term oral anticoagulation therapy with warfarin. RESULTS: Serial measurements were obtained from 129 patients, 60 of whom provided three or more serial samples. Analysis of covariance showed a highly significant (p = 0.0001) relationship between the anticoagulant effect and the logarithm of the warfarin concentration (R2 = 0.75), with 15.3% of the total variance attributable to the effect of warfarin and 31.1% attributable to individual variation in sensitivity to warfarin. In an analysis of the subjects who had three or more serial measurements, the mean weighted correlation coefficient for the relationship between the logarithm of the warfarin concentration and the anticoagulant response varied widely, from strongly negative to strongly positive, and as the range of observed prothrombin times increased, stronger positive correlation was observed. CONCLUSIONS: In this cohort, the plasma warfarin level was a strong predictor of observed changes in serial prothrombin time measurements. However, the correlation between clotting times and warfarin levels varied widely among subjects, particularly when the range of observed prothrombin times was moderate. This suggests that in these subjects, other factors, such as measurement error or pharmacodynamic changes, played a major role.

Adult↗
PubMed1994

Computer-assisted dosing of heparin. Management with a pharmacy-based anticoagulation service.

BACKGROUND: Expert consultation by means of established practice guidelines has been shown to lead to improved accuracy of inpatient anticoagulation therapy, with a reduction in the frequency of hemorrhagic complications. We evaluated a different strategy to improve the accuracy of in-hospital anticoagulation: pharmacy-based, computer-assisted dosing of intravenous heparin therapy. METHODS: Patients treated with computer-assisted dosing of heparin (N = 131) were compared with a randomly selected historical cohort (N = 57) in whom heparin therapy was managed by the primary physician. All patients treated by the pharmacy team received a bolus of heparin, 70 U/kg of ideal body weight, except for patients with pulmonary embolism, who received 100 U/kg of ideal body weight. A computer-generated infusion dose was selected (generally 13 to 16 U/kg per hour). The target was an activated partial thromboplastin time (APTT) ratio of 1.8 times the patient's baseline APTT, with a therapeutic range of 1.5 to 2.5 times baseline. Computer-assisted dosage recommendations were generated after each APTT measurement. RESULTS: In the historical control group, 62% of the patients achieved a therapeutic APTT during the first 24 hours; 17% failed to reach a therapeutic level by 48 hours. The median time to reach a therapeutic APTT was 15 hours. Of all 696 APTTs in this group, 42% were below, 43% in, and 15% above the therapeutic range. In the computer-assisted group, 90% achieved a therapeutic APTT within 24 hours (P < .001); 97% had a therapeutic APTT by 48 hours (P < .01). The median time to achieve a therapeutic APTT was 7 hours (P < .001). Of all 880 APTTs in this group, 17% were below, 75% in, and 8% above the therapeutic range (P < .001). CONCLUSIONS: Pharmacy-based, computer-assisted dosing of heparin is feasible and results in faster and more accurate anticoagulant dosing.

Aged↗
PubMed1992

Treatment of proximal deep-vein thrombosis using subcutaneously administered calcium heparin: comparison with intravenous sodium heparin.

In a prospective, randomized clinical trial we compared the efficacy of subcutaneously (SC) administered (every 8 h) calcium heparin to intravenous (IV) sodium heparin in the treatment of proximal deep-vein thrombosis (DVT). A secondary objective was to give enough heparin to achieve a therapeutic anticoagulant effect by the end of the first 24 h. Five of 36 patients (14%) in the SC heparin group failed to achieve a therapeutic anticoagulant effect by the end of the first 24 h compared to 2 of 23 patients (9%) in the IV group (p = NS; 95% CI for true difference = -11.7% to 22.1%). Two of 31 patients (6.5%) in the SC group had venographic evidence of clot propagation compared to 1 of 19 patients (5.3%) in the IV group (p = NS; 95% CI for true difference = -12.4% to 14.8%). The rate of major hemorrhagic complications was similar in each group (approximately 15%). We conclude: (1) using a large initial dose of SC heparin, a therapeutic anticoagulant effect can be readily achieved within 24 h, and (2) combining the results of this trial with previous studies, the efficacy of SC administered calcium appears to be comparable to IV sodium heparin.

Adult↗
PubMed1991

Predicting pharmacodynamic response to tissue plasminogen activator: a preliminary report.

All thrombolytic agents have produced significant variation in clinical response (patency, reocclusion, bleeding) when administered in recommended doses in patients with myocardial infarction. We have evaluated the in vitro clot lysis response in 19 normal subjects and the pharmacodynamic response to tissue plasminogen activator (TPA) in 9 patients with myocardial infarction using a new, fresh, whole blood clot lysis system. Further, we have developed a Bayesian forecasting system for predicting response to TPA. Sensitivity to TPA (slope of the concentration/log response curve) varied significantly in patients with myocardial infarction (mean, 1.05 +/- 1.1). The mean clearance, volume of distribution, and half life were 55 +/- 13 L/h, 41 +/- 47 L, and 0.41 +/- 0.46 h. Using from zero to three clot lysis feedback times, the mean percentage mean absolute error varied from 65 to 16.4%. A relationship between mean clot lysis time and clinical reperfusion was established. Thus, a system for quantitating and predicting response to TPA was developed and successfully tested. Future extensive clinical trials will be necessary to evaluate fully the use of this system in clinical practice.

Bayes Theorem↗
PubMed1991

Outpatient management of warfarin therapy: comparison of computer-predicted dosage adjustment to skilled professional care.

In a prospective, randomized clinical trial, we compared the accuracy of warfarin dosage-adjustments predictions using a computer program to the skill of an experienced anticoagulation nurse-specialist. The computer program predicts the steady state warfarin dose by applying Bayesian forecasting techniques to a mathematical model of the dynamic pharmacologic response to warfarin. Fifty patients who were receiving chronic warfarin therapy and who required a dosage adjustment because their prothrombin time was greater than or equal to 2 s away from their target prothrombin time were enrolled. The baseline characteristics of each group were similar, including the mean of the absolute value of the differences between initial prothrombin times and corresponding target prothrombin times. After a new a new warfarin dose was predicted, the prothrombin time was measured at least 7 days after dosage adjustment. Overall, the results in each group were comparable. There was no significant difference between groups and the mean of the absolute value of the differences between final prothrombin times and target prothrombin times, nor was there a difference in the proportion of patients who had a final prothrombin time within 2 s of the target prothrombin time. We conclude that the accuracy of warfarin dosage adjustments made using computer modeling is comparable to the skill of an anticoagulation nurse-specialist.

Administration, Oral↗
PubMed1990

Predicting the daily prothrombin time response to warfarin.

Our objective was to evaluate the effectiveness of a computer program to predict daily prothrombin time (PT) response to warfarin therapy using prospectively collected data. The program's predictive performance (precision) and accuracy (bias) were evaluated using fraction mean absolute error and fraction mean error, respectively. We analyzed data from 40 patients using from zero to nine PT feedbacks. The fraction mean absolute error varied from 0.058 to 0.13. The program utilized a pharmacokinetic/pharmacodynamic Bayesian forecasting system to predict prothrombin response.

Aged↗
PubMed1987

Pharmacodynamics of warfarin at steady state.

We studied the pharmacodynamics of warfarin in chronically treated patients. Two methods were used to estimate the pharmacodynamic parameters M/Kd and Cmax (mg/L). In Method 1 the prothrombin time response was modeled directly without use of warfarin concentrations and Method 2 used warfarin concentrations and prothrombin time response to estimate M/Kd and Cmax. The mean Cmax and M/Kd for Method 1 (n = 88) were 5.5 +/- 2.3 mg/L and 51 +/- 46 and for Method 2 (n = 27) 6.3 +/- 2.8 mg/L and 35.4 +/- 13. When Method 1 was applied to the same 27 patients in Method 2, the mean Cmax and M/Kd were 5.7 +/- 3.3 mg/L and 36.1 +/- 14.9. These differences were not significant. Multiple regression analysis revealed that the value of Cmax and M/Kd varied between medical centers. No other patient characteristics were found to be significant. We conclude that modeling steady-state prothrombin time response directly adequately describes pharmacodynamic response to warfarin.

Humans↗
PubMed1984

Plasma protein binding of warfarin: methodological considerations.

Recent theoretical work has suggested that radiochemical impurities can significantly alter the binding results for highly protein-bound drugs. We compared protein binding of warfarin by ultrafiltration and equilibrium dialysis with 98% radiochemically pure [14C]warfarin. Ultrafiltration and equilibrium dialysis were performed at 37 degrees C and pH 7.45 on the plasma of patients receiving chronic warfarin therapy. Binding to plasma from seven patients were measured in duplicate by both a nonspecific radioisotopic technique and a specific HPLC technique. The nonspecific technique gave percentage of free warfarin values of 1.84 +/- 0.11 (mean +/- SD) and 1.59 +/- 0.14 for ultrafiltration and equilibrium dialysis, respectively. The HPLC procedure yielded a percentage of free warfarin by ultrafiltration of 0.969 +/- 0.203 and a value of 0.690 +/- 0.095 by equilibrium dialysis (p less than 0.05). The HPLC procedure for protein binding was performed on plasma samples from 12 additional patients and yielded a percentage of free warfarin of 1.01 +/- 0.69 by ultrafiltration and 0.44 +/- 0.34 by equilibrium dialysis (p less than 0.05). It can be concluded that radiochemical impurities may lead to significant overestimation of the percentage of free warfarin. Ultrafiltration yielded a higher percentage of free warfarin than did equilibrium dialysis, but the ability to distinguish binding differences among patients was similar.

Blood Proteins↗
PubMed1983

Individualizing theophylline therapy: the impact of clinical pharmacokinetics on patient outcomes.

We have studied 19 male patients whose theophylline therapy was individualized by a clinical pharmacokinetics service and 34 male patients with empirically derived dosages. All patients were admitted to the medical intensive care unit. Patients in the pharmacokinetics group had fewer adverse reactions (15.7 vs. 50%), shorter intensive care unit stay (6.6 +/- 5.5 vs. 12.4 +/- 16.3 days), shorter hospital stay (15.4 +/- 10 vs. 22.3 +/- 14.1 days), and a shorter period of time to be placed on oral therapy (5.2 +/- 3.1 vs. 8.6 +/- 7.2 days) than the group with empirically derived regimens. The pharmacokinetic method used to individualize theophylline therapy offered an accurate and efficient method of achieving therapeutic concentrations. We conclude that the use of clinical pharmacokinetics to individualize theophylline therapy offers substantial benefits over empirical assessments.

Aged↗