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Biomedical subjects

C J Destache

Publications and source records attributed to C J Destache.

At least 19 recordsLinked to original sources
PubMed2001

Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model.

This study was designed to investigate the penetration across the blood-brain barrier of three doses of levofloxacin using a microdialysis probe implanted into the cerebrospinal fluid (CSF) of a rabbit pneumococcal meningitis model. The microdialysis guide cannula was implanted into rabbit subarachnoid space using a stereotaxic frame. After 3 days, 10(4) cfu Streptococcus pneumoniae serotype 3 in 0.3 mL saline was injected via intracisternal puncture and animals were allowed to incubate the organisms for 16-18 h. Groups of animals (n = 5) then received 7, 10.5 or 14 mg/kg iv of the drug over 10 min. Plasma samples were obtained via an ear vein 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h after the antibiotic infusion. CSF microdialysis effluent samples were collected every 0.5 h for the entire experiment. Plasma and microdialysis effluent samples were analysed by HPLC. AUC(0-8) in plasma and CSF were computed using the trapezoid rule. The elimination half-life in plasma and CSF was calculated using non-linear regression analysis. The unbound peak plasma concentrations for the three doses studied were 3.9, 6.4 and 10.3 mg/L, respectively. There was a significant increase in the plasma AUC(0-8) [29.7 +/- 6.3, 49.1 +/- 19.1 and 67.6 +/- 8.9 mg x h/L (P < 0.005)]. The unbound peak CSF concentrations were 3.8, 5.7 and 8.6 mg/L and occurred at 0-0.5 h after the administration of the dose. The AUC(CSF(0-8)) was significantly higher as the dose was increased (7 mg/kg, 15.8 +/- 6.6; 10.5 mg/kg, 37.3 +/- 7.8; and 14 mg/kg, 46.4 +/- 20.9 mg x h/L; P < 0.03). The penetration of levofloxacin averaged 53% for the 7 mg/kg dosage group, 76% for the 10.5 mg/kg group and 68% for the 14 mg/kg group. Our results demonstrate that levofloxacin penetration into the CSF averages 66% for the doses that would be used in clinical practice.

Animals↗
PubMed2001

Potential influence of timing of low-density lipoprotein cholesterol evaluation in patients with acute coronary syndrome.

OBJECTIVE: To determine the significance of timing of low-density lipoprotein (LDL) cholesterol evaluation in patients with chest pain as it relates to subsequent National Cholesterol Education Program (NCEP) treatment decisions. DESIGN: Prospective, observational study. SETTING: A university-affiliated tertiary care hospital. PATIENTS: Sixty-two patients with coronary heart disease who were not receiving lipid-lowering therapy and whose LDL levels were obtained 25-48 hours after onset of chest pain. INTERVENTION: We evaluated laboratory test results of patients with chest pain admitted to the cardiac care unit to determine risk to patients when LDL levels obtained inappropriately are used to make decisions regarding antihyperlipidemic therapy. MEASUREMENTS AND MAIN RESULTS: Inpatient and outpatient LDL levels were compared, and changes in NCEP treatment decisions analyzed. Differences between inpatient and outpatient LDL levels were significant (p<0.05), which frequently resulted in changes in therapy using the NCEP guidelines. The LDL levels of most inpatients were consistent with NCEP goals for patients with coronary heart disease, whereas the outpatient levels showed a need for drug therapy. CONCLUSION: Lipid values obtained 25-48 hours after hospital admission in patients with acute coronary syndromes do not represent baseline values and may significantly alter the treatment approach; thus, they should not be used to direct drug therapy.

Acute Disease↗
PubMed2001

Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs.

STUDY OBJECTIVE: To examine the impact of individualized pharmacokinetic monitoring (IPM) on the development of aminoglycoside-associated nephrotoxicity (AAN). DESIGN: Retrospective case-control study. SETTING: Two teaching hospitals. SUBJECTS: Two thousand four hundred five patients who received aminoglycosides. INTERVENTION: Aminoglycoside therapy dosed by either IPM or physicians' directions. MEASUREMENTS AND MAIN RESULTS: Patients receiving IPM were significantly less likely to develop AAN by both univariate (7.9% vs 13.2%, p=0.02) and multivariate methods (odds ratio 0.42, p=0.002). Female sex was protective against AAN. Age 50 years and above, high initial aminoglycoside trough, long duration of therapy, and concurrent piperacillin, clindamycin, or vancomycin increased risk of AAN. We estimated that IPM decreased AAN costs by $90,995/100 patients. CONCLUSION: Individualized pharmacokinetic monitoring significantly decreased the frequency of AAN and its associated economic costs.

Anti-Bacterial Agents↗
PubMed1999

Simple liquid chromatographic method for the analysis of the blood brain barrier permeability characteristics of ceftriaxone in an experimental rabbit meningitis model.

A simple LC method was developed and validated for the analysis of ceftriaxone in aqueous and biological samples. Chromatographic separation was achieved on a reversed-phase C18 microbore column (Hypersil 5 microm, 200x2.1 mm) with UV detection at 270 nm. This isocratic system was operated at ambient temperature and required less than 10 min of chromatographic time. The flow-rate was maintained at 0.5 ml min(-1). Cetyltrimethylammonium bromide (0.01 M) was utilized as the ion-pairing agent. For the analysis of the drug in the aqueous system, the mobile phase consisted of methanol-acetonitrile-phosphate buffer, pH 7.4 (20:20:60, v/v/v). The plasma and CSF systems used the same mobile phase constituents in a slightly different ratio (30:40:30, v/v/v). Lidocaine was used as an internal standard and the peak height ratios of the drug to that of the internal standard were linear over the concentration range of 0.0 to 16 microg ml(-1) only in the case of aqueous systems. Within-day and day-to-day relative standard deviations ranged from 0.3 to 2.2% and 1.1 to 5.9%, respectively. This method was used to: (1) quantify ceftriaxone in an aqueous system, in rabbit plasma using a simple protein precipitation procedure, and in the CSF; (2) evaluate the permeability characteristics of ceftriaxone across the blood-brain barrier through quantification of ceftriaxone in the CSF using a microdialysis sampling technique; and (3) analyze the effects of dexamethasone (a synthetic fluorinated corticosteroid used for the relief of cerebral edema) on the permeability of ceftriaxone across the blood brain barrier through quantification of ceftriaxone in the dexamethasone-treated animals with meningitis.

Animals↗
PubMed1999

Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis.

Limited data exist to guide physicians in the cost-effective treatment of acute exacerbation of chronic bronchitis (AECB). Therefore, the main objective of this study was to determine the antimicrobial efficacy and related costs for patients with AECB. A retrospective review of 60 outpatient medical records with a diagnosis of chronic obstructive pulmonary disease (COPD) and chronic bronchitis episodes from a pulmonary clinic of a teaching institution was undertaken. The participating patients had a total of 224 episodes of AECB requiring antibiotic treatment. Before review, empirical antibiotic choices were divided into first-line (amoxycillin, co-trimoxazole, tetracyclines, erythromycin), second-line (cephradine, cefuroxime, cefaclor, cefprozil) and third-line (co-amoxiclav, azithromycin, ciprofloxacin) agents. Patients receiving first-line agents failed significantly more frequently than third-line agents (19% vs 7%, P < 0.05). Additionally, patients prescribed first-line agents were hospitalized significantly more often for AECB within 2 weeks of outpatient treatment as compared with patients prescribed third-line agents (18.0% vs 5.3% third-line agents; P < 0.02). Time between subsequent AECB episodes requiring treatment was significantly longer for patients receiving third-line agents compared with first-line and second-line agents (P < 0.005). Pharmacy costs were lowest with first-line agents (first-line US$10.30 +/- 8.76; second-line US$24.45 +/- 25.65; third-line US$45.40 +/- 11.11; P < 0.0001), but third-line agents showed a trend towards lower mean total costs of AECB treatment (first-line US$942 +/- 2173; second-line, US$563 +/- 2296; third-line, US$542 +/- 1946). The use of third-line antimicrobials, co-amoxiclav, ciprofloxacin or azithromycin, significantly reduced the failure rate and need for hospitalization, prolonged the time between AECB episodes, and showed a lower total cost for the management of AECB. Prospective studies are needed to confirm these findings.

Acute Disease↗
PubMed1999

Diagnosis and treatment of complicated tubercular meningitis.

A 41-year-old woman was seen in no acute distress with an infected ventriculoperitoneal shunt. She underwent several revisions of the shunt but was readmitted to the hospital with nausea, vomiting, and neurologic sequelae. Results of spinal fluid analysis were white blood cells 68/mm3 (25% neutrophils), glucose less than 20 mg/dl, and protein 513 mg/dl. Cerebrospinal fluid, aerobic and anaerobic, and blood cultures were negative. Three weeks later the patient suffered a seizure and was prescribed antitubercular agents for a presumed diagnosis of tubercular meningitis. One week later, chest wound culture from her first visit suggested Mycobacterium tuberculosis, which was confirmed by DNA probe; cerebrospinal fluid culture eventually grew the organism. The patient fared well once she received antituberculosis agents. The time between first contact and treatment in the hospital delayed therapy.

Adult↗
PubMed1996

Pharmacodynamics and pharmacokinetics of A-80556 using microdialysis in a Streptococcus pneumoniae meningitis model.

Using microdialysis in a rabbit model of Streptococcus pneumoniae meningitis, the pharmacokinetics and pharmacodynamics of a new fluoroquinolone, A-80556, were determined. A-80556 (10 mg/kg iv) was administered to four rabbits. Saline was given to four separate control animals. A microdialysis probe perfused the CSF (2 microL/min) and effluent was collected at 0-0.25, 0.25-1, 1-2, 2-4, and 4-6 h after injection of A-80556. Seven blood samples were collected and analyzed by HPLC. At 0, 2, 4 and 6 h 300 microL of CSF was withdrawn for pharmacodynamic measurements. Plasma A-80556 concentrations demonstrated AUC0-infinity 2.40 +/- 0.272 micrograms.h/mL; T1/2 beta 1.07 +/- 0.011 h; Vd 6.35 +/- 0.50 L/kg; and Cl1 4.23 +/- 0.48 L/h.kg. Penetration into the CSF was 18.21%. Pharmacodynamics using time-kill curves showed a 3-log reduction in bacterial counts in CSF at 2 h after administration continuing for the remaining four hours of the experiment. These results demonstrate that microdialysis can be used for determination of drug penetration and efficacy in experimental S. pneumoniae meningitis.

Animals↗
PubMed1994

Cost considerations in therapeutic drug monitoring of aminoglycosides.

Aminoglycoside antibiotics are very important in the treatment of Gram-negative infections and as synergistic agents for the treatment of staphylococcal and streptococcal (group B streptococci and enterococci) infections. However, these agents have a narrow therapeutic index. Thus, a number of new antibiotics have been introduced in an attempt to reduce the number of patients treated with aminoglycosides. Unfortunately, these new antibiotics tend to be costly, and are often associated with development of resistance and treatment failure. Data suggest that a pharmacokinetic/pharmacodynamic relationship exists for some aspects of efficacy and toxicity of aminoglycosides. Serum drug concentrations and/or tissue accumulation are related to the development of nephrotoxicity, and individualised pharmacokinetic monitoring may decrease rates of nephrotoxicity. Peak serum drug concentrations and the ratio of peak serum drug concentration to minimum inhibitory concentration appear to correlate with clinical efficacy in the treatment of patients with bacteraemia or pneumonia. Therapeutic drug monitoring (TDM) has been used to optimise aminoglycoside therapy and reduce toxicity. Cost-effective approaches to drug selection and TDM are important considerations in the proper use of aminoglycosides.

Aminoglycosides↗
PubMed1993

Use of therapeutic drug monitoring in pharmacoeconomics.

The use of therapeutic drug monitoring (TDM) for drugs with a narrow therapeutic range has contributed substantially to the literature. The pharmacoeconomics of this service for hospitalized patients has demonstrated significant hospital savings. Appropriate use of this pharmacy-based service has demonstrated savings, reduction in total length of hospitalization, and cost avoidance with aminoglycoside-induced nephrotoxicity. Use of a Clinical Pharmacokinetic Service (CPS) for inpatient theophylline therapy and outpatient anticonvulsant therapy documents the pharmacoeconomic benefits provided by this service to both in- and outpatients. This report will discuss current literature with regard to pharmacoeconomics and cost-benefit analysis of TDM.

Cost-Benefit Analysis↗
PubMed1993

Effect of seven fluoroquinolones on the determination of serum creatinine by the picric acid and enzymatic methods.

OBJECTIVE: To investigate in vitro the interaction of seven fluoroquinolone antibiotics with the determination of serum creatinine by the picric acid and enzymatic methods. DESIGN: This blind, in vitro study assayed duplicate serum samples for creatinine by the picric acid and enzymatic methods with averaged spiked concentrations of 2.71, 13.56, 27.12, and 108.47 mumol/L of ciprofloxacin, fleroxacin, lomefloxacin, ofloxacin, 1-ofloxacin, sparfloxacin, and temafloxacin. Cefoxitin (in concentrations of 233.9, 1169.6, 1754.4, and 2339.2 mumol/L) was used as a positive control for the picric acid assay. SETTING: University-affiliated hospital, Department of Pharmaceutical Services and Clinical Chemistry section of the Department of Pathology. MAIN OUTCOME MEASURE: The serum creatinine samples spiked with the seven substituted fluoroquinolones and cefoxitin were assayed by both the picric acid and enzymatic assays. Statistical analysis compared the spiked samples with blank serum by Student's t-test and concentration ranges were compared by analysis of variance. A statistically significant interference with serum creatinine was p < 0.05. RESULTS: None of the substituted fluoroquinolones interfered significantly with the determination of serum creatinine by either method. Cefoxitin significantly interfered with the determination of serum creatinine by the picric acid method. CONCLUSIONS: Fluoroquinolones do not interfere with the determination of serum creatinine by either the picric acid or enzymatic method.

Anti-Infective Agents↗
PubMed1992

Impact of food on the bioavailability of encainide.

The bioavailability of drugs that undergo extensive presystemic hepatic metabolism may be increased by concomitant ingestion with food. The effect of food on the bioavailability of encainide, a class IC antiarrhythmic agent, was evaluated in 14 healthy subjects in this randomized crossover study. The subjects received encainide 35 mg every 8 hours for 7 days and were randomized to receive their test dose of encainide with food or after an overnight fast. Encainide area-under-the-concentration versus time curve (AUCs) were detectable in 3 of 14 subjects after fasting and in 7 of 14 after feeding. Although food increased the mean encainide AUC by more than threefold, this increase did not reach statistical significance because of the large number of subjects with indeterminate encainide AUCs. Food did significantly increase the AUC of O-demethyl-encainide (ODE), but not the AUC of methoxy-O-demethyl-encainide (MODE). Despite the increase in ODE AUC, no significant effect on the surface electrocardiogram 2 hours after dose administration could be detected. Food may increase the bioavailability of encainide and one of its active metabolites (ODE). The clinical relevance of this pharmacodynamic effect warrants further evaluation.

Adult↗
PubMed1992

Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism.

There is no universally accepted approach to the initiation of systemic anticoagulant therapy. In an open, randomized study, two anticoagulant regimens that differed only in the timing of warfarin therapy after the start of heparin were compared. We randomized 119 patients with acute thromboembolic events to receive warfarin either within 48 hours of the start of heparin (early group, n = 63) or 96 hours or later after the start of heparin (late group, n = 56). Heparin was given as a 5000 IU bolus as a constant infusion titrated to maintain the activated partial thromboplastin time at 1.5 to 2 times control values. Warfarin was started at 10 mg daily for 3 days and the dose was titrated to maintain the prothrombin time at 1.2 to 1.5 times control values. There were no significant differences between the early and late warfarin groups with regard to age, sex, indication for anticoagulation, heparin dose, mean activated partial thromboplastin time during heparin, warfarin dose at discharge, length of warfarin therapy before discharge, bleeding, recurrent thromboembolic events, or mortality rates. Time to the start of warfarin after heparin was 31 hours and 108 hours in the early and late groups, respectively. Length of hospitalization, hospital costs, and the incidence of heparin-induced infusion phlebitis and thrombocytopenia were significantly less in the early group compared with the late group. Early initiation of warfarin after heparin is safer, less expensive, and as effective as the late initiation of warfarin.

Aged↗
PubMed1992

Predictive performance of Bayesian and nonlinear least-squares regression programs for lidocaine.

The predictive performance of two computer programs for lidocaine dosing were evaluated. Two-compartment Bayesian and nonlinear least-squares regression programs were used in two groups of patients (15 acute arrhythmia patients and 14 chronic arrhythmia patients). Lidocaine was given as a 1.5 mg/kg bolus and a 2.8 mg/min infusion for 48 h. A second bolus (0.5 mg/kg) was given 10 min after the first bolus over 2 min. Serum samples of the patients receiving lidocaine were drawn at 2, 15, 30 min and 1, 2, and 4 h and were used in forecasting the serum concentrations at 6, 8, 12, and 48 h. Predictive performance was assessed by mean error and mean-squared error. The results (mean +/- 95% confidence intervals) demonstrated the Bayesian program predicted a significant (p less than 0.05) difference at 12 h between the two arrhythmia groups (acute 0.52 [-0.95; -0.09] and chronic 0.28 [0.12; 0.44]). The results also demonstrated the Bayesian method was significantly more precise compared to the nonlinear least-squares regression program at 8, 12, and 48 h for the acute group. While caution is warranted, this study demonstrated that the predictive performance by a two-compartment Bayesian model is more accurate in predicting future lidocaine serum concentrations than that by nonlinear least-squares regression.

Acute Disease↗
PubMed1992

Comparative pharmacodynamics of intravenous lidocaine in patients with acute and chronic ventricular arrhythmias.

OBJECTIVE: To evaluate the pharmacodynamics of intravenous lidocaine in patients with acute-onset and chronic ventricular arrhythmias. DESIGN: Open-label, pharmacodynamic evaluation. SETTING: Private, university-affiliated, hospital coronary-care unit. PATIENTS: Twenty cardiac patients with acute-onset ventricular ectopy and 20 with chronic ventricular ectopy. INTERVENTIONS: Intravenous lidocaine was administered to all patients as a 1-mg/kg bolus, a 0.5-mg/kg bolus, and a 2.8-mg/min constant infusion for 48 hours. MAIN OUTCOME MEASURES: Changes in ventricular premature beat (VPB) frequency against total treatment period frequency and by an hour-to-hour assessment of changes in VPB frequency compared with total baseline frequencies. Response was defined as greater than or equal to 80 percent total VPB reduction, greater than or equal to 90 percent paired VPB reduction, and total abolition of nonsustained ventricular tachycardia events. RESULTS: A statistically significant difference in the pharmacodynamic effects of lidocaine were observed during the first eight hours of treatment in patients with acute-onset and chronic VPBs. The number of patients with acute-onset VPBs who responded to lidocaine in the first hour of treatment did not change significantly over the remaining hours of treatment. Response to lidocaine was less in patients with chronic VPBs than in patients with acute-onset VPBs. The response rate to lidocaine was significantly less during the first eight hours in patients with chronic VPBs than in patients with acute-onset VPBs. Following eight hours of treatment, the response rates between acute-onset and chronic VPB patients were not significantly different. Mean lidocaine plasma concentrations were not different between the groups. In addition, there were no significant differences in the incidence of adverse effects between the two groups. CONCLUSIONS: The onset of antiarrhythmic effect as measured by suppression of ventricular ectopy is delayed in patients with chronic VPBs compared with patients with acute-onset VPBs. Decisions about lidocaine response in patients with chronic VPBs cannot be made accurately in the first eight hours of therapy.

Acute Disease↗
PubMed1991

Influence of mexiletine on the pharmacokinetics of theophylline in healthy volunteers.

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two-way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained-release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2 beta, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline-mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0-24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine therapy.

Adult↗
PubMed1991

Pharmacokinetic and tolerance evaluation of actisomide, a new antiarrhythmic agent, in healthy volunteers.

The pharmacokinetics and tolerance of actisomide (SC-36602) were determined following intravenous doses of 2.1, 4.2, and 8.4 mg/kg infused over five hours. Plasma concentrations observed in the low-dose group (2.1 mg/kg) were below the assay's limit of detection and were not included in the pharmacokinetic analysis. The following pharmacokinetic parameters were obtained in the medium-dose (4.2 mg/kg) and high-dose (8.4 mg/kg) groups, respectively: peak plasma concentration 4.25 +/- 0.26 and 7.81 +/- 0.31 micrograms/mL; area under the plasma concentration versus time curve 19.79 +/- 2.96 and 39.81 +/- 7.05 h.micrograms/mL; elimination rate constant of the beta phase 0.105 +/- 0.77 and 0.093 +/- 0.009 h(-1), and half-life 8.85 +/- 4.61 and 7.51 +/- 0.69 h. Left ventricular ejection fraction decreased by 10, 11, and 16 percent in the low-, medium-, and high-dose groups, respectively. Heart rate was not altered during the low-dose infusion. At the medium- and high-dose levels, resting peak heart rate increased by 18 and 27 percent, respectively. Systolic and diastolic blood pressures were not significantly changed in any of the dose groups. Changes in electrocardiographic intervals for the three dose groups were not significant except at the highest dose where an average 20 percent increase in the QRS interval was seen. Mild subjective adverse effects (dizziness, taste perversion, and circumoral paresthesia) which did not necessitate discontinuing the infusion occurred in the highest dosage group. Further studies are warranted to more fully characterize the pharmacokinetic profile and therapeutic potential of actisomide.

Adult↗