Carolyn M. Myers

Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

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Publications (40)143.23 Total impact

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    ABSTRACT: The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation.
    Journal of Child and Adolescent Psychopharmacology 08/2007; 17(4):433-45. DOI:10.1089/cap.2007.0119 · 3.07 Impact Factor
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    ABSTRACT: To group patients receiving treatment for acute lymphoblastic leukemia (ALL) according to their oral mercaptopurine (6-MP) metabolite levels and to establish cut-off points to screen for potential poor clinical outcome. Methodological study using 6-MP metabolite levels from 48 adolescent ALL patients enrolled in a multicenter adherence study. Cluster analysis was the primary analytical technique. We used two validation methods (a split-sampling and a simulation technique) for validating the results. Four clusters were retained in our initial analysis using our first group of patients (n = 27). Three clusters (labeled 1, 2, and 4) exhibited the expected negative correlation between the two metabolites, that is, "high" values of one were associated with "low" values of the other. One cluster (labeled 3) had "low" levels for both TGN and MMP. Five of the 27 adolescents had their 6-MP "held" during the study. Post-hoc examination of the results revealed that all five grouped in Cluster 3 during the time that their medications were stopped, but grouped in other clusters at other times. The median ANC was highest in Cluster 3, consistent with low therapeutic drug levels. Parameters were reproducible with both validation methods. Values below the respective 75th centile for both TGN and MMP in Cluster 3 for the complete sample (n = 48) are suggested as representing a potentially higher risk for relapse. This study provides an objective method for identifying patients at risk for treatment failure due to suboptimal 6-MP therapy; the clinical significance of this approach should be examined in future studies.
    Pediatric Blood & Cancer 02/2006; 46(2):187-92. DOI:10.1002/pbc.20518 · 2.56 Impact Factor
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    ABSTRACT: Background: Depression is a common disorder in children and adolescents. It is often associated with psychologic distress, academic dysfunction, intrafamilial conflict, and the risk for suicide. For these reasons, safe and effective treatments are needed for depression in pediatric patients.Objective: This study considered the effectiveness of initiating the antidepressant paroxetine at a low dose and explored clinical and biochemical factors associated with response in juvenile depression.Methods: In this 8-week, single-center, open-label trial, children and adolescents with major depression were assessed weekly. Patients were initially treated with paroxetine at a dosage of 10 mg/d for 4 weeks. If a priori criteria for improvement were not met, the dosage of paroxetine was increased to 20 mg/d. Standard psychometric outcome measures were used. Prior to treatment, patients' phenotypes for cytochrome P450 2D6 and catechol O-methyltransferase activity were determined. Platelet-rich plasma serotonin was measured before and after 4 weeks of therapy. Plasma paroxetine concentration was measured after 4 weeks of treatment.Results: Thirty children and adolescents (15 boys, 15 girls) aged 6 to 17 years were enrolled and 29 were treated. Of the 27 patients who received at least 4 weeks of paroxetine treatment, 18 (66.7%) met improvement criteria at week 4. Open-label paroxetine was generally well tolerated and was associated with significant symptom amelioration by week 8 for most patients. Age, other demographic characteristics, and biochemical variables did not differ between the patients who had their dose of paroxetine increased and those who did not.Conclusions: The results of this study suggest that paroxetine 10 mg/d is effective in the open-label treatment of most depressed children and adolescents. For those who do not respond to this dosage, an increase to 20 mg/d appears to be an empirically supported treatment strategy.
    Current Therapeutic Research 09/2002; 63(9):588-601. DOI:10.1016/S0011-393X(02)80063-7 · 0.45 Impact Factor
  • Michael D. Reed, Carolyn M. Myers, Jeffrey L. Blumer
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    ABSTRACT: Background: An important aspect of a drug's biodisposition profile is the extent to which it binds to plasma proteins.Objective: The purpose of this laboratory investigation was to assess the potential for an in vitro drug-drug protein displacement interaction between ketorolac and midazolam.Methods: The protein binding of ketorolac and midazolam, individually and in combination, were determined in (1) human serum, (2) human albumin solution, and (3) human alpha1-acid glycoprotein solution using ultrafiltration technology. Total and free concentrations of ketorolac were quantitated by liquid chromatography, whereas those of midazolam were quantitated by gas chromatography. Drug concentrations used in this in vitro study were selected from published data reflecting realistic plasma drug concentrations observed after aggressive clinical drug dosing.Results: Both ketorolac and midazolam are extensively bound to serum protein. Over the concentration range studied, ketorolac bound primarily to albumin whereas midazolam bound extensively to albumin and alpha1-acid glycoprotein. Under the conditions of the present in vitro study, neither ketorolac nor midazolam demonstrated any effect on the extent to which either drug was bound in the 3 systems studied.Conclusions: The in vitro data derived in this study suggest that when present together, neither midazolam nor ketorolac influences the overall extent of protein binding of the other. Drug protein binding data derived in vitro should be cautiously extrapolated to in vivo conditions.
    Current Therapeutic Research 08/2001; 62(8):558-565. DOI:10.1016/S0011-393X(01)80061-8 · 0.45 Impact Factor
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    ABSTRACT: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/ Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.
    Journal of the American Academy of Child & Adolescent Psychiatry 09/1999; 38(8):952-9. DOI:10.1097/00004583-199908000-00010 · 6.35 Impact Factor
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    ABSTRACT: Objective: We compared bolus-infusion with continuous-infusion administration of granisetron antiemetic therapy in patients undergoing haematopoietic stem-cell transplantation.Methods: We evaluated in a double-blind fashion the efficacy and pharmacokinetics of intravenous bolus-dose granisetron (10 µg/kg bodyweight/day) versus continuous-infusion granisetron (10 µg/kg bodyweight infused over 24 hours) in patients undergoing haematopoietic stem-cell transplantation. Antiemetic therapy was begun within 30 minutes of starting chemotherapy and was continued for 2 days after cytotoxic treatment was completed. All patients also received intravenous dexamethasone 10mg every 12 hours during cytotoxic therapy. Haloperidol 2mg intravenously was permitted as rescue therapy in patients who experienced two or more episodes of vomiting within a 24-hour period.Results: Forty-three patients (median age 42 years, range 19 to 65 years) were studied: 24 received bolus-dose and 19 continuous-infusion granisetron. Complete success (no vomiting) was observed in nine patients in the bolus-dose group compared with seven in the continuous-infusion group. Success with rescue antiemetic treatment (haloperidol) was observed in 10 patients in the bolus-dose group compared with three patients in the continuous-infusion group. Failures were noted in five bolus-dose and nine continuous-infusion-treated patients. Granisetron pharmacokinetics were determined in five patients receiving the drug by continuous-infusion and in seven patients after bolus-dose administration. Pharmacokinetic parameter values ranged widely but were similar between the two groups. No relationship between granisetron success or failure and granisetron plasma concentration or pharmacokinetic characteristics was observed.Conclusion: Continuous-infusion granisetron does not appear to possess any antiemetic superiority to bolus-dose administration in the transplant setting.
    Clinical Drug Investigation 01/1999; 17(2):155-165. · 1.70 Impact Factor
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    ABSTRACT: The pharmacokinetics of teicoplanin were assessed after a single dose and under multidose conditions in 12 infants and children. Study patients ranged in age from 2.4 to 11 years. Each patient received teicoplanin 6 mg/kg body weight given intravenously over 20-30 min, once daily for five consecutive days. Multiple timed blood and urine samples were obtained over the 6 day sampling period and were analysed for teicoplanin by both microbiological assay and HPLC. Three-compartment pharmacokinetic analysis was used to describe the drug's disposition characteristics. Peak and 24 h trough serum teicoplanin concentrations averaged 39.3 and 1.8 mg/L after the first dose with little accumulation observed after 5 days of therapy. Teicoplanin disposition was variable; V(d)ss ranged from 0.31 to 0.68 L/kg, t(1/2)gamma from 6.5 to 18.1 h and CI from 29 to 51 mL/h/kg. A substantial amount of the administered drug distributed rapidly to the largest, third compartment, with egress approximately four-fold slower than ingress. The majority of the drug was excreted unchanged in the urine. Teicoplanin administration was well tolerated by all study subjects. Using the teicoplanin pharmacokinetic data derived in our study, a dose of teicoplanin 8 mg/kg body weight administered every 12 h should achieve target serum trough concentrations averaging 11 mg/L in children. Higher doses, e.g. 15 mg teicoplanin/kg administered every 12 h, may be needed for the treatment of deep-seated staphylococcal infections and/or endocarditis.
    Journal of Antimicrobial Chemotherapy 07/1997; 39(6):789-96. DOI:10.1093/jac/39.6.789 · 5.44 Impact Factor
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    ABSTRACT: To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine. The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function. A 16-bed pediatric intensive care unit serving both medical and surgical patients. The study was performed using 14 dopamine-treated and five untreated control patients. Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female. All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease. Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score. All treated patients received dopamine as a continuous intravenous infusion. Infusion rates were determined by caregivers and ranged from 3.0 to 20 micrograms/kg/min. Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity. Measured rates of dopamine infusion (3.0 to 18.3 micrograms/kg/min) were consistently less than the nominal rates (3.0 to 20.0 micrograms/kg/min) of infusion (p < .0001) due in part to calculations based on the hydrochloride salt rather than dopamine base. At similar steady-state infusion rates, plasma dopamine concentrations varied over a four-fold range, with steady-state concentrations at even the lowest infusion rate exceeding endogenous concentrations by at least ten-fold. Variations in steady-state plasma dopamine concentration reflected large age-associated variations in dopamine clearance, which was found to be saturable at concentrations of > 200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age. COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of > 100 ng/mL. These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates. While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine.
    Critical Care Medicine 01/1997; 25(1):181-9. DOI:10.1097/00003246-199701000-00032 · 6.15 Impact Factor
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    ABSTRACT: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants. A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques. Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose. Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.
    Clinical Pharmacology &#38 Therapeutics 11/1996; 60(4):405-13. DOI:10.1016/S0009-9236(96)90197-6 · 7.39 Impact Factor
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    ABSTRACT: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants. A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug. Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses. Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.
    Clinical Pharmacology &#38 Therapeutics 11/1996; 60(4):424-34. DOI:10.1016/S0009-9236(96)90199-X · 7.39 Impact Factor
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    ABSTRACT: To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children. A prospective clinical study. A pediatric intensive care unit (ICU) in a university hospital. Clinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation. A stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patient's level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography. Twenty-nine patients were enrolled into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propofol loading dose; 28 patients completed the study. All patients were sedated immediately after the first 2.5-mg/kg propofol loading dose. Eight patients were adequately sedated with the starting propofol dose regimen, whereas five patients required downward dose adjustment and 11 patients required dosage increases to achieve optimal sedation. Four patients failed to achieve adequate sedation after five dose escalations and the drug was stopped. Recovery from sedation (COMFORT score of > or = 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but < or = 1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2 and V3, which are two-and 20-fold greater in volume, respectively, than V1. Redistribution from V2 and V3 into V1 was much slower than ingress, underscoring the importance of the propofol concentration in V1 as reflective of the drug's sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment. We conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2 and V3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.
    Critical Care Medicine 10/1996; 24(9):1473-81. DOI:10.1097/00003246-199609000-00008 · 6.15 Impact Factor
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    ABSTRACT: Objectives Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants.Methods This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide.ResultsTotal clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect.Conclusions The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.Clinical Pharmacology & Therapeutics (1996) 60, 414-423; doi:
    Clinical Pharmacology &#38 Therapeutics 09/1996; 60(4):414-423. DOI:10.1016/S0009-9236(96)90198-8 · 7.39 Impact Factor
  • Intensive Care Medicine 06/1996; 22(2). DOI:10.1007/BF03216402 · 5.54 Impact Factor
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    ABSTRACT: We report here a method for measuring mononuclear cell catechol-O-methyltransferase (COMT) activity which is ideally adapted to clinical studies. The method measures the O-methylation of dopamine to 3-methoxytyramine and 4-methoxy-3-hydroxyphenethylamine. Whole mononuclear cell sonicate is incubated with saturating concentrations of dopamine, S-adenosyl-L-methionine and magnesium chloride in sodium-potassium phosphate buffer at pH 7.3. An organic solvent extraction using ethyl acetate is then used for product separation, followed by high-performance liquid chromatography with electrochemical detection for product separation and quantification. This method allows both O-methylated products, 3-methoxytyramine and 4-methoxy-3-hydroxyphenethylamine, to be isolated and quantified separately. The apparent Michaelis constants for dopamine and S-adenosyl-L-methionine using this method are similar to values reported previously (0.51 and 14 microM, respectively). The optimal concentration of magnesium chloride is eight to ten times higher than previously reported. No endogenous inhibitors were apparent using this assay. The within-day coefficient of variation using this method is 7% when measuring 3-methoxytyramine and 5% when measuring 4-methoxy-3-hydroxyphenethylamine. The between-day coefficient of variation is 11%. Mononuclear cell COMT activity can be detected using protein concentrations as low as 0.75 mg/ml, corresponding to 2-3 ml of whole blood. The small amount of blood required per sample allows multiple sample analysis from a single patient, including infants.
    Journal of Chromatography A 08/1992; 578(2):175-88. DOI:10.1016/0378-4347(92)80414-L · 4.26 Impact Factor
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    ABSTRACT: A procedure for determining human platelet monoamine oxidase (MAO) with dopamine (DA) as substrate is described. High-performance liquid chromatography (HPLC) with electrochemical detection (ED) was used to separate and detect components of the reaction mixture. The method for platelet preparation was also improved and only 2 ml of blood were required. Following a 10-min incubation of the platelet preparation with DA in 0.1 M Tris buffer (pH 9.0), excess DA substrate was removed by adsorption on a cation-exchange resin. The reaction product, 3,4-dihydroxyphenylacetaldehyde, was adsorbed on acid-washed alumina, eluted with 0.1 M perchloric acid and analyzed by HPLC. Simple, clean chromatograms were obtained with good reproducibility using 3,4-dihydroxybenzylamine as an internal standard. The within-sample, between-samples and between-day relative standard deviations were 0.9, 3.7 and 6.1%, respectively. The apparent Michaelis constant and maximum velocity were 0.10 mM and 0.37 nmol/ protein, respectively. This HPLC-ED method offers a good alternative to methods using radioactivity.
    Journal of Chromatography A 04/1992; 575(1):39-49. DOI:10.1016/0378-4347(92)80501-G · 4.26 Impact Factor
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    ABSTRACT: The first-dose and multidose pharmacokinetics of imipenem and cilastatin were evaluated in 41 premature infants during their first week of life. Premature infants (gestational age, less than or equal to 37 weeks) were assigned to receive 10-, 15-, 20-, or 25-mg/kg doses of imipenem-cilastatin (1:1) as a single- or multiple-dose regimen. A total of 39 infants received a single dose, whereas 18 infants received multiple doses. No differences were observed in pharmacokinetic parameter estimates for either agent relative to the dose administered or infant body weight; thus, the data were pooled. Elimination half-life, steady-state volume of distribution, and body clearance averaged 2.5 h, 0.5 liter/kg, and 2.5 ml/min per kg, respectively, for imipenem and 9.1 h, 0.4 liter/kg, and 0.5 ml/min per kg, respectively, for cilastatin. Similar values for these parameter estimates were observed after multidose administration, although substantial accumulation of cilastatin in serum was observed. A total of 21% of the imipenem and 43% of the cilastatin were excreted unchanged in the urine over a 12-h collection period. Corresponding renal clearances averaged 0.4 and 0.2 ml/min per kg for imipenem and cilastatin, respectively. Substantial differences were observed in the route by which imipenem was cleared from the body compared with data from adult volunteers. These data suggest that infants should receive an imipenem dose of 20 mg/kg administered every 12 h for the treatment of bacterial infections outside the central nervous system.
    Antimicrobial Agents and Chemotherapy 07/1990; 34(6):1172-7. DOI:10.1128/AAC.34.6.1172 · 4.45 Impact Factor
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    ABSTRACT: The single-dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight-matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VSSF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty-two percent of the ciprofloxacin dose was excreted in the urine (0-48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolities were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P less than .05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24-hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.
    The Journal of Clinical Pharmacology 08/1988; 28(8):691-9. DOI:10.1002/j.1552-4604.1988.tb03202.x · 2.47 Impact Factor
  • Carolyn M. Myers, Jeffrey L. Blumer
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    ABSTRACT: A versatile and sensitive method requiring no internal standard was developed for quantitating ciprofloxacin in serum, urine and sputum by high-performance liquid chromatography with fluorescence detection. Acetonitrile and chloroform were employed to remove protein and lipophilic substances from an aqueous, ciprofloxacin-containing sample layer. The proportions of acetonitrile and 0.1 M potassium phosphate, pH 2.5, in the mobile phase were varied to suit the purpose of the assay. For the routine determination of ciprofloxacin pharmacokinetics, isocratic 19% acetonitrile was used. A gradient from 15 to 35% acetonitrile was chosen to show the appearance of metabolites which formed during the biodisposition of ciprofloxacin. In the latter case urine samples were diluted for assay and protein was precipitated from serum samples with trichloroacetic acid. Four fluorescent metabolites were observed in all patient specimens, and with tandem ultraviolet detection two additional ultraviolet-absorbing metabolites were readily found in urine specimens.
    Journal of Chromatography A 12/1987; 422:153-64. DOI:10.1016/0378-4347(87)80448-6 · 4.26 Impact Factor
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    ABSTRACT: Ciprofloxacin has potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia strains isolated from cystic fibrosis patients. Our previous single-dose pharmacokinetic and pharmacodynamic studies identified important differences between cystic fibrosis patients and age- and sex-matched controls. Based on these data, 30 acutely ill cystic fibrosis patients (aged 18 to 44 years) received 750 mg of ciprofloxacin orally every eight hours for 21 days. Multiple timed serum, urine, and sputum samples for pharmacokinetic analysis were obtained on Days 3, 12, 14, and 21 of the study. Estimates of steady-state pharmacokinetic parameters averaged (+/- SD): t1/2 beta, 3.8 (1) hours; Vd/F, 4.4 (2) liters/kg; Cl/F, 772.9 (301) ml/minute/1.73 m2; Fe, 46 percent; peak, 5.4 (2) mg/liter; and trough, 1.8 (0.8) mg/liter. Serum ciprofloxacin concentrations and pharmacokinetic estimates remained unchanged throughout the study. Sputum ciprofloxacin concentrations exceeded those observed in serum. Sputum cultures revealed 43 P. aeruginosa (MIC90 = 2 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml) strains. Sputum ciprofloxacin concentrations exceeded the MIC90 for P. aeruginosa approximately fivefold, yet only eight isolates were fully suppressed. Posttreatment sputum cultures revealed 35 P. aeruginosa (MIC90 = 16 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml). All patients showed clinical improvement based upon the results of pulmonary function tests and an acute clinical efficacy score (median pre 49/post 60). No patients experienced drug-related toxicity. Ciprofloxacin monotherapy is effective for the acute treatment of cystic fibrosis patients. The development of pathogen resistance during oral therapy may limit its utility in ambulatory patients.
    The American Journal of Medicine 05/1987; 82(4A):174-9. · 5.30 Impact Factor
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    ABSTRACT: The efficacy and pharmacokinetics of piperacillin monotherapy were studied in 46 patients with cystic fibrosis. Two patients were dropped from the study within 24 hr of enrollment because of drug-associated nausea and vomiting. Initially fourteen older patients (greater than 12 years) receiving piperacillin 450 mg/kg/day underwent a preliminary evaluation. Based on the results, 30 younger patients (less than or equal to 12 years) randomized in a double-blind fashion received either 600 or 900 mg/kg/day of piperacillin in six divided doses. Pharmacokinetic parameter estimates for t1/2 Vdss, and Cl were similar for first dose and steady-state evaluations. In 27 patients, approximately 43% of the administered dose was recovered in the urine after 4 hr. Piperacillin CiR averaged 49% of the total Cl. No difference in overall clinical efficacy could be identified between 600 and 900 mg/kg/day of piperacillin using two different objective scoring systems. Although a reduction in sputum Pseudomonas colony counts was greater following the 900 mg/kg/day regimen, this appeared to be independent of clinical effect. In 14 patients (32%), a distinct adverse serum-sicknesslike reaction was observed. The incidence of this reaction appeared to increase as the dose of piperacillin increased. All signs and symptoms of this reaction resolved within 36 hr of discontinuing piperacillin administration but recurred immediately on rechallenge in four patients. All patients with the adverse reaction were subsequently treated with beta-lactam antibodies without ill effect. Overall, clinical improvement appeared to be independent of the piperacillin dose. Our data support the use of total daily piperacillin dosages not exceeding 600 mg/kg.
    Pediatric Pulmonology 03/1987; 3(2):101-9. DOI:10.1002/ppul.1950030212 · 2.30 Impact Factor

Publication Stats

541 Citations
143.23 Total Impact Points


  • 1986–2007
    • Case Western Reserve University School of Medicine
      • • Department of Pediatrics
      • • Department of Psychiatry
      Cleveland, Ohio, United States
  • 1981–2001
    • Case Western Reserve University
      • • School of Medicine
      • • Rainbow Babies and Children's Hospital
      Cleveland, OH, United States