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Biomedical subjects

M H Chandler

Publications and source records attributed to M H Chandler.

At least 19 recordsLinked to original sources
PubMed1997

General versus subpopulation values in Bayesian prediction of aminoglycoside pharmacokinetics in hematology-oncology patients.

The predictive performance of Bayesian estimates incorporating pharmacokinetic values for hematology-oncology patients was compared with that of Bayesian estimates incorporating general population values. In study phase 1, medical records were reviewed for 50 adult patients with a hematologic or oncologic diagnosis who had received i.v. gentamicin or tobramycin. Aminoglycoside pharmacokinetic values were calculated for the patients by using a modified two-point Sawchuk-Zaske method, and the subpopulation mean for each variable was determined. In phase 2, data for 10 other hematology-oncology patients receiving aminoglycosides were entered into the Abbottbase Bayesian pharmacokinetics program. Aminoglycoside pharmacokinetic values and serum concentrations for each of these 10 patients were estimated, first using the program's general population values and then repeating the analysis using the subpopulation means for volume of distribution and renal clearance slope obtained in phase 1. The serum aminoglycoside concentrations predicted by each Bayesian method were compared with the actual peaks and troughs. Both the peak and trough predictions of the Abbottbase program using the subpopulation values for volume of distribution and renal clearance slope were significantly less biased than those predicted by the Abbottbase program incorporating the general population values. The methods did not differ significantly in precision. Use of subpopulation pharmacokinetic values in Bayesian predictions of serum aminoglycoside concentrations in hematology-oncology patients reduced bias significantly but had no significant effect on precision.

Adult↗
PubMed1996

Comparison of creatinine clearance estimation methods in patients with trauma.

The abilities of a modified Cockcroft-Gault equation and the standard equation to estimate creatinine clearance (CLcr) in trauma patients were compared. The medical records of patients with stable renal function who had been treated for trauma and had had a 24-hour urine collection for creatinine measurement were reviewed. Creatinine concentrations in urine and serum were used to calculate the actual CLcr, which was normalized to 1.73 sq m. CLcr was estimated by the modified equation (which normalized body weight to 72 kg) and by the standard equation using ABW, IBW, and dosing body weight (DBW). Values derived with the standard equation were normalized to 1.73 sq m. The predictive performances of the modified and standard equations in estimating the actual CLcr were then compared. Fifty patients were enrolled. The standard equation using IBW or DBW produced estimates that differed significantly from the actual CLcr. The modified equation and the standard equation using ABW did not differ significantly in bias or precision, but both were significantly less biased than the standard equation using IBW or DBW. The only significant difference among equations in precision was between the modified equation (the more precise) and the standard equation using IBW. There were no clinically significant differences among methods in gentamicin dosing simulations. The modified Cockcroft-Gault equation can be used to estimate CLcr in trauma patients with stable renal function.

Adult↗
PubMed1996

Integrating pharmacokinetics into point-of-care information systems.

Computer-based patient care information systems (PCIS) have emerged as an integral component of healthcare organisations. Currently, 4 models of PCIS exist: the centralised model, the hub-and-spoke model, the network model, and the distributed model. The centralised model has the advantage of a central patient database; however, a major disadvantage of this model is the inability to easily interface with other software packages. The hub-and-spoke model links satellite or feeder systems into a mainframe computer; thus, each satellite has the ability to work independently. This system is limited by the ability to interface satellite systems with the mainframe computer. The network model works via a local area network (LAN) using client server technology which allows for high speed data access and transfer. The network model does not provide an integrated view of patient information and can access only 1 host system at a time. The distributed model is similar to the network model in design but provides for data and system integration via relational databases. This allows for the creation of a central data repository and support for decision-support tools. Computer-assisted decision support has the potential to significantly improve clinical decision-making. Six types of computer-assisted decision-support have been defined: alerting, interpreting, assisting, critiquing, diagnosing and managing. Software representing each type of decision-support software has been incorporated into clinical practice; however, with the exception of drug interaction programs, widespread incorporation of decision-support software into PCIS is uncommon. Clinical pharmacokinetic programs are a category of pharmacy-related decision-support software, and current clinical pharmacokinetic software systems can be categorised as interpreting, assisting or critiquing decision-support. Despite the potential for significant clinical contributions, the integration of clinical pharmacokinetic software into PCIS is uncommon. Most packages are available only as stand alone programs or as a module of a pharmacy information system. These packages usually maintain their own centralised database and require special file transfer protocols for integration. Although PCIS are becoming more commonplace, the integration of commercial clinical pharmacokinetic packages into PCIS is limited. New technology using standardised and relational databases should allow for easier integration in the future.

Computers, Mainframe↗
PubMed1995

Dirithromycin increases ethinyl estradiol clearance without allowing ovulation.

OBJECTIVE: To use a novel, sensitive study design to detect a potential oral contraceptive (OC) and dirithromycin drug interaction by assessing the pharmacokinetics of the ethinyl estradiol (E2) component of a common OC and the potential failure of OC effectiveness. METHODS: In this nonblinded study, 20 healthy women using Ortho Novum 7/7/7-28 were selected for a three-OC-cycle study. Baseline measures included E2 and progesterone serum levels on days 21, 23, 25, and 27 of cycle one and days 1, 3, 5, and 7 of cycle two. During cycle two, 24-hour blood sampling and radioimmunoassay analysis for ethinyl E2 pharmacokinetics were performed on day 8 and pelvic ultrasound on day 13. Oral dirithromycin 500 mg/day for 14 days began on day 21 of cycle 2. After starting dirithromycin, cycle two and three serum E2, progesterone, and serial ethinyl E2 levels and pelvic ultrasound replicated the baseline schedule. Ovulation was assumed if E2 concentration was greater than 50 pg/mL, progesterone concentration was greater than 3 ng/mL, or if an ovarian cyst greater than 10 mm was present on ultrasound. RESULTS: Pharmacokinetic analysis demonstrated a small (7.6%) but statistically significant decrease (P = .03) in the mean ethinyl E2 24-hour area under the curve and an increase in apparent oral clearance. No woman ovulated, based on E2 levels and progesterone concentrations or ultrasound. CONCLUSION: Dirithromycin increased the apparent oral clearance of ethinyl E2. The clinical importance of the interaction may be negligible because no woman ovulated or had compromised OC effectiveness in this small series.

Adolescent↗
PubMed1995

Pharmacokinetic optimisation of vancomycin therapy.

Renewed interest in vancomycin over the past decade has led to an abundance of data concerning the pharmacokinetics of vancomycin, and its dosage selection and concentration-response relationships. No definitive data exist that correlate vancomycin serum concentrations with clinical outcomes. However, inconsistencies in sampling times for peak serum concentrations and differences in infusion times make interpreting vancomycin serum concentrations difficult. Furthermore, the evidence implicating vancomycin as a cause of oto- or nephrotoxicity is circumstantial, and these adverse effects may occur only in high-risk populations. Owing to the variability in its dose-serum concentration relationship and multicompartmental pharmacokinetics, several methodologies have been developed for instituting and adjusting vancomycin dosages. Nomograms rely on a fixed volume of distribution and the relationship between vancomycin clearance and creatinine clearance. Since both of these factors may be altered in certain populations, dosage methodologies (both traditional and Bayesian) that use population- or patient-specific pharmacokinetic data perform better than standard nomograms for initiating vancomycin therapy. Controversy still exists as to whether a 1- or a 2-compartment model is more appropriate for making dosage adjustments; however, steady-state rather than non-steady-state vancomycin serum concentrations should be used for dosage adjustments. Certain pathophysiological states such as age, bodyweight and renal function contribute to altered pharmacokinetics and may alter the design of the dosage regimen. Since no definitive relationship exists between vancomycin serum concentrations and either clinical outcome or adverse effects, considerable controversy surrounds the utility of monitoring serum vancomycin concentrations. Therefore, routine vancomycin serum concentration monitoring may be warranted only in specific populations, such as patients receiving concurrent aminoglycoside therapy or those receiving higher than usual dosages of vancomycin, patients undergoing haemodialysis and patients with rapidly changing renal function.

Dose-Response Relationship, Drug↗
PubMed1994

Creatinine-clearance estimates for predicting gentamicin pharmacokinetic values in obese patients.

The Cockcroft-Gault and Salazar-Corcoran equations were compared with respect to prediction of gentamicin pharmacokinetic values in obese and nonobese patients, and the results were used to formulate guidelines for calculating initial gentamicin dosages in obese patients. Creatinine clearance (CLcr) was estimated by applying the Cockcroft-Gault equation using total body weight (TBW), ideal body weight (IBW), and dosage weight (DW) and with Salazar-Corcoran equations using fat-free body mass (FBM) in 100 obese and 100 nonobese patients. Gentamicin pharmacokinetic values (k, CL, and t1/2) were estimated by using CLcr estimated by each method and standardized to a body surface area of 1.73 sq m. Actual pharmacokinetic values were determined by using steady-state gentamicin concentrations and a modified Sawchuk-Zaske equation; these values were compared with the predicted values. In the obese patients, pharmacokinetic values predicted from standardized CLcr by the Cockcroft-Gault equation using estimated DW were not significantly biased, compared with actual values; most predictions produced by the other methods were significantly biased. Predictions produced by the DW method were generally more precise than those resulting from the other methods. In nonobese patients, k values estimated by the Cockcroft-Gault equation using IBW were not significantly biased, while values obtained with all other methods were biased. All methods were biased when predicting CL and t1/2 in nonobese patients. Significant correlations existed between standardized estimates of CLcr (by all methods) and pharmacokinetic values in both groups. Predictions of gentamicin k, CL, and t1/2 were best overall when CLcr was estimated by the Cockcroft-Gault equation using DW, rather than by other methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A simplified high-performance liquid chromatographic method for direct determination of warfarin enantiomers and their protein binding in stroke patients.

A simplified method for direct determination of warfarin enantiomers by high-pressure liquid chromatography with fluorescence detection has been developed. This method involves solid phase extraction of warfarin in plasma, precolumn derivatization to form diastereoisomeric esters, and post-column reaction to discriminate each enantiomer separately. Ultrafiltration was employed in the separation of unbound warfarin enantiomers. Twelve plasma samples from six stroke patients taking warfarin regularly were analyzed. The average concentration of total warfarin was 0.47 +/- 0.17 mg/L for the S-isomer and 0.69 +/- 0.18 mg/L for the R-isomer. The average protein binding was 99.67 +/- 0.33% for S-warfarin and 99.44 +/- 0.33% for R-warfarin. This methodology provides a quick and reliable technique for determining enantiomeric protein binding of warfarin in clinical settings.

Aged↗
PubMed1994

Pharmacokinetics of anti-infective agents in paediatric patients.

Various differences in drug disposition exist between children and adults. For example, the volume of distribution (Vd) for many drugs is larger in children than in adults. Other parameters, including excretion and elimination may be altered in children compared with adults. The penicillins and cephalosporins are used commonly for the treatment of infection in paediatric patients. The increased Vd in children contributes to the increased elimination half-life of these agents. Clearance of the acylureido-penicillins is increased in children with cystic fibrosis, a disease that decreases the elimination half-life for these drugs. Aminoglycosides distribute into extracellular fluid and their pharmacokinetic profile is affected by changes in Vd. The Vd for aminoglycosides is slightly higher in children than in adults. Children with cystic fibrosis, burns, or cancer have higher clearance rates and larger Vd values for aminoglycosides. Few data in the literature address the pharmacokinetics of other anti-infective agents, including vancomycin, teicoplanin, erythromycin, metronidazole, chloramphenicol, and cotrimoxazole (trimethoprim-sulfamethoxazole), in children. Similarly, there is little information regarding the pharmacokinetic profile of antivirals and antifungals in children. Dosage guidelines are available to enable the clinician to initiate anti-infective therapy in children. Subsequent dosage requirements may change based on the patient's current clinical condition. Although several studies have investigated the pharmacokinetics of anti-infectives in neonates and adults, data for children are limited. Therefore, further studies are required so that the ever growing arsenal of anti-infectives can be administered appropriately to children.

Absorption↗
PubMed1993

Influence of serum separator tubes on total and free phenytoin concentrations and dosages.

The influence of serum separator tubes (SSTs) on total and free phenytoin concentrations and phenytoin dosages was evaluated in patients treated with phenytoin. Thirty blood samples were obtained from 18 patients. Equal volumes of blood were placed into SSTs and plain tubes. Samples were centrifuged, and serum analyzed for total and free phenytoin by fluorescence polarization immunoassay (FPIA) at 2, 24, and 48 h. Total phenytoin concentrations collected in SSTs were significantly lower than those collected in plain tubes at 2 (12.3 vs 12.8 mg/L, p < 0.01), 24 (11.4 vs 12.9 mg/L, p < 0.01), and 48 h (10.9 vs 12.9 mg/L, p < 0.01). These differences resulted in significantly higher calculated maximum rates of metabolism (Vmax) and daily phenytoin dosages (R0) for SSTs at 24 (Vmax: 10.4 vs 10.1 mg/kg/day; R0: 8.2 vs 8.0 mg/kg/day, p < 0.01) and 48 h (Vmax: 10.8 vs 10.3 mg/kg/day; R0: 8.5 vs 8.1 mg/kg/day, p < 0.01). Free phenytoin concentrations from SSTs were significantly lower at 48 h (1.56 vs 1.61 mg/L, p < 0.05). However, there were no significant differences in calculated dosages. Observed statistical differences in total phenytoin concentrations can be clinically important for making dosage adjustments, especially in patients undergoing nonlinear elimination. Thus, SSTs should not be used to collect blood for total serum phenytoin determination.

Adult↗
PubMed1993

Computers in pharmacokinetics. Choosing software for clinical decision making.

Over the past 20 years, pharmacokinetic programs have been developed for clinical decision making. These clinical pharmacokinetic software programs are designed to assist the clinician in the analysis, interpretation and reporting of serum drug concentration data for a variety of medications. The programs vary in the extent of features and range of medications supported and thus warrant careful review before selecting or purchasing such a program for routine use. A series of programs which are commercially available in the United States was reviewed for this article. The focus of the review is not to recommend a single program or to provide a ranked list of commercially available programs. Information is presented to clinicians to better their understanding of the features of these computer-based clinical resources. As an introduction to this topic, the information presented concentrates on the system and support features. Those programs that were reviewed demonstrate the ability to assist in the analysis of serum or plasma drug concentration data for most of the medications that warrant therapeutic drug monitoring. They provide both Bayesian and non-Bayesian methods for predicting serum drug concentrations. Standard personal computers were sufficient to run each of the programs reviewed. In addition, most programs offered technical and clinical support. However, the quality of the user manuals and training material varies among software programs. In-depth analytical comparisons are currently being conducted for future publication.

Computers↗
PubMed1992

Differential response of beta-adrenergic receptor-mediated heart rate and aortic blood flow acceleration to timolol.

The apparent affinity of beta-adrenergic receptors for timolol in the sinus node and ventricular myocardium was compared in 11 normal male subjects. Sinus nodal function was assessed by heart rate, and left ventricular systolic function was assessed by Doppler-derived aortic blood flow acceleration. The dose of isoproterenol required for a heart rate or acceleration increase of 35% (I35) was determined before and 2 hours after an oral 10 mg dose of timolol. The apparent affinity constant (ka) for timolol binding to the receptor was calculated from the serum timolol concentration and the ratio of the I35 after timolol/I35 before timolol. The I35 for sinus node and ventricular myocardium were not significantly different from one another. The ka for timolol binding to the sinus node (1.14 x 10(6) mol/L), however, was significantly greater (p less than 0.05) than ka for ventricular myocardium (7.85 x 10(5) mol/L). These findings suggest that beta-adrenergic receptors in the sinus node may have an overall greater affinity for beta-blocking agents than do receptors in the ventricular myocardium.

Adult↗