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Biomedical subjects

M D Reed

Publications and source records attributed to M D Reed.

At least 37 records · Page 2Linked to original sources
PubMed1999

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: 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. RESULTS: 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/mL.hr. 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. CONCLUSIONS: 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.

Adolescent↗
PubMed1998

Pharmacokinetics of metoclopramide in neonates.

Despite its wide use as a prokinetic agent in neonates and infants with gastroesophageal reflux (GER), the pharmacokinetics of metoclopramide have not been characterized in this pediatric subpopulation. A single-dose pharmacokinetic study of oral metoclopramide (0.1 to 0.15 mg/kg) was performed in 10 fasted premature infants (weight 1.1 to 3.2 kg) ranging from 31 to 40 weeks postconceptional age. Metoclopramide was quantitated from repeated blood samples (n = 9 over 24 hours) by high-performance liquid chromatography. A one-compartment open model with first-order absorption best described the plasma concentration-time data. No correlations were observed between gestational, postnatal, or postconceptional age and any of the pharmacokinetic parameters studied. Comparison of the pharmacokinetic parameters from the study cohort and those reported previously from a similar study of older infants revealed no statistically significant differences. However, a prolonged apparent plasma clearance (Cl/F) of metoclopramide was observed in 30% of the infants studied, and the mean Cl/F and apparent steady-state volume of distribution (Vdss/F) were approximately 1.4- and 2.1-fold higher, respectively, than values reported in previous studies of metoclopramide disposition in adults. These data suggest that metoclopramide pharmacokinetics may exhibit a developmental dependency. Thus, a metoclopramide dose of 0.15 mg/kg given orally every 6 hours is recommended for the initiation of prokinetic therapy with this agent in infants who are < or = 31 weeks postconceptional age.

Administration, Oral↗
PubMed1998

The antipsychotics. A pediatric perspective.

As can be discerned from this article, antipsychotics are commonly prescribed, and they are not used to treat only psychosis. Although some data support the use of typical antipsychotics in pediatric patients with a variety of psychiatric syndromes, concerns about the safety and tolerability of these agents often complicated their use and probably even interfered with case identification. A fundamentally new group of medications, the atypicals, have now become available and may not only have improved tolerability but also may have greater ability to reduce some target symptoms. Because of their superior side-effect profile in adults, some of these atypical treatments probably will be commonly prescribed despite a relative paucity of data about their use in the young. Moreover, although frequently prescribed in this age group, the overall prescription rate for antipsychotics will probably increase because of the putative improved safety profile of the newer agents. However, it is possible that serious side effects, such as tardive dyskinesia or neuroleptic malignant syndrome, may occur with these atypical agents. For this reason, the enthusiasm for prescribing these newer treatments should be tempered with the understanding that these agents, although they may in some ways be superior to their predecessors, still possess the potential for significant adverse events. Four atypical antipsychotics are currently marketed in the United States (see Table 2). One additional agent, ziprasodone, is undergoing clinical investigation. Ziprasodone has been shown to be superior to placebo in adults suffering from schizophrenia. Ziprasodone will probably be marketed in the United States in the near future. Whether all of these atypical drugs will have a place in the clinical armamentarium of the pediatric psychopharmacologist remains to be determined. Because the receptor binding profile of the atypical agents differ, it is not possible to assume that what is true for one of these agents is true for the others. Although results from most preliminary studies with atypical antipsychotics indicate that these are promising agents for pediatric patients, further research is needed to define just how these medications may be most judiciously used.

Adolescent↗
PubMed1998

Drug-drug interactions in pediatric psychopharmacology.

Serious consequences caused by drug-drug interactions continue to plague contemporary pharmacotherapy. The possibility of a drug-drug interaction should be suspected anytime a new or unexpected effect occurs that complicates the clinical management of a patient in the setting where the patient is receiving more than one drug. In this article, the authors address the mechanisms of pharmacokinetic-based drug-drug interactions focusing on important interactions that may occur with the common medications a pediatrician may prescribe to the child receiving psychoactive medication(s) prescribed by a child psychiatrist.

Adolescent↗
PubMed1998

Rational prescribing of extended-spectrum penicillin beta-lactamase inhibitor combinations: focus on ticarcillin/clavulanic acid.

OBJECTIVE: To provide an overview of the clinical pharmacokinetics and pharmacodynamics of ticarcillin/clavulanic acid and to reassess traditional dosage recommendations based on contemporary pharmacokinetic and pharmacodynamic principles. DATA SOURCES: Published ticarcillin and clavulanic acid pharmacokinetic data derived from infants and children combined with data obtained from a rigorous, dose-escalation study performed in 12 healthy adults. Pharmacodynamic correlates were derived from published in vitro susceptibility data for the combination drug ticarcillin/clavulanic acid. DATA SYNTHESIS: Limited differences were observed in the pharmacokinetic disposition profiles between ticarcillin and clavulanic acid and relative to subject age. Integration of these data with defined pathogen minimum inhibitory concentrations underscores the appropriateness of an extended dosing interval (e.g., q8h to q12h) for many infections and demonstrates the probable therapeutic interchangeability of the following three intravenous dosing regimens: 3.1 g every 6 hours, 75 mg/kg every 8 hours, and 100 mg/kg every 12 hours of a 30:1 ticarcillin/clavulanic acid combination. CONCLUSIONS: Integration of pharmacokinetic and pharmacodynamic data is an appropriate means to assess/reassess dosing recommendations for antimicrobial agents. Initial ticarcillin/clavulanic acid dose recommendations did not account for known dynamic interactions for this combination antibiotic. Pharmacokinetic data in infants, children, and adults support a less frequent dosing interval (q8h to q12h) for the treatment of infections arising outside the central nervous system.

Age Factors↗
PubMed1998

Predicting grief symptomatology among the suddenly bereaved.

Social scientists have long been interested in the study of grief and bereavement, but only recently has research focused on the aftereffects of sudden loss. Theory and research alike suggest that grief is multidimensional and that specific grief reactions have a unique set of predictors. The purpose of this study is to examine the relative contribution of risk factors in explaining variations in specific grief reactions following a sudden death. Data for this study come from medical examiners' reports and mail-back surveys of survivors of sudden loss from suicide or accident. The results indicate that several characteristics of the survivor, mode of death, and social support are important determinants of grief symptomatology. This research concludes by directing future theoretical and empirical endeavors to examine more fully the role of relational factors in influencing grief experiences following bereavement.

Adaptation, Psychological↗
PubMed1997

The pharmacokinetics of teicoplanin in infants and children.

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.

Anti-Bacterial Agents↗
PubMed1997

Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children.

The pharmacokinetic characteristics of cefepime were determined after first dose (n = 35) and again under steady-state conditions (n = 31) with a group of 37 infants and children. In eight subjects, a cefepime dose given by intramuscular injection was substituted for an intravenous dose, and disposition characteristics were studied again. Study subjects ranged in age from 2.1 months to 16.4 years, and all had normal renal function. Each patient received 50 mg of cefepime/kg of body weight intravenously every 8 h, up to a total maximum individual dose of 2 g. With the exception of one study patient who received a single cefepime dose for surgical prophylaxis, the patients received cefepime for 2 to 13 days. Elimination half-life (t1/2), steady-state volume of distribution, total body clearance, and renal clearance after first dose administration averaged 1.7 h, 0.35 liter/kg, and 3.1 and 1.9 ml/min/kg, respectively. Although cefepime t1/2 and mean residence time (MRT) were slightly longer for subjects <6 months of age than for older subjects, no differences in cefepime disposition characteristics between first dose and steady-state evaluations were observed. t1/2 (1.8 versus 1.9 h) and MRT (2.3 versus 3.2 h) were slightly prolonged after intramuscular administration, reflecting the influence of absorption from the intramuscular injection site on cefepime elimination. Bioavailability after intramuscular administration averaged 82% (range, 61 to 124%). Fifty-seven percent of the first dose and 88.9% of the last dose were recovered as unchanged drug in urine over the 8- and 24-h sampling periods, respectively. These pharmacokinetic data support a single cefepime dosing strategy for patients > or =2 months of age. The integration of the cefepime pharmacokinetic data generated in our study with the MICs for important pathogens responsible for infections in infants and children supports the administration of a dose of 50 mg of cefepime/kg every 12 h for patients > or =2 months of age to treat infections caused by pathogens for which cefepime MICs are < or =8 mg/liter.

Adolescent↗
PubMed1996

A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children. DESIGN: A prospective clinical study. SETTING: A pediatric intensive care unit (ICU) in a university hospital. PATIENTS: 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. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Adolescent↗
PubMed1996

Continuous propofol infusion for the relief of treatment-resistant discomfort in a terminally ill pediatric patient with cancer.

PURPOSE: To determine the effectiveness of propofol as adjunctive therapy in the treatment of drug-resistant discomfort in a terminally ill pediatric patient. PATIENT AND METHODS: A 3-year-old child with advanced rhabdomyosarcoma and severe drug-resistant discomfort was studied. Propofol was administered as adjunctive therapy to provide relief from severe discomfort. RESULTS: Propofol was initiated with a loading dose of 1.2 mg/kg followed by a continuous intravenous infusion of 1.2 mg/kg/h. Over the next 10 days, additional loading doses were administered and the infusion rate was increased to a maximum of 32 mg/kg/h. After the addition of propofol, our patient's discomfort improved greatly without the occurrence of propofol-associated adverse events. CONCLUSIONS: Propofol appears to be an effective adjunct to opioids and a promising alternative to barbiturate therapy in the treatment of drug-resistant discomfort in terminally ill pediatric patients.

Abdominal Neoplasms↗
PubMed1995

Pharmacokinetic-based ticarcillin/clavulanic acid dose recommendations for infants and children.

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

Child↗