Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.

HPLC analysis of reduced and oxidized coenzyme Q(10) in human plasma.

BACKGROUND: The percentage of reduced coenzyme Q(10) (CoQ(10)H(2)) in total coenzyme Q(10) (TQ(10)) is decreased in plasma of patients with prematurity, hyperlipidemia, and liver disease. CoQ(10)H(2) is, however, easily oxidized and difficult to measure, and therefore reliable quantification of plasma CoQ(10)H(2) is of clinical importance. METHODS: Venous blood was collected into evacuated tubes containing heparin, which were immediately placed on ice and promptly centrifuged at 4 degrees C. The plasma was harvested and stored in screw-top polypropylene tubes at -80 degrees C until analysis. After extraction with 1-propanol and centrifugation, the supernatant was injected directly into an HPLC system with coulometric detection. RESULTS: The in-line reduction procedure permitted transformation of CoQ(10) into CoQ(10)H(2) and avoided artifactual oxidation of CoQ(10)H(2). The electrochemical reduction yielded 99% CoQ(10)H(2). Only 100 microL of plasma was required to simultaneously measure CoQ(10)H(2) and CoQ(10) over an analytical range of 10 microg/L to 4 mg/L. Intra- and interassay CVs for CoQ(10) in human plasma were 1.2-4.9% across this range. Analytical recoveries were 95.8-101.0%. The percentage of CoQ(10)H(2) in TQ(10) was approximately 96% in apparently healthy individuals. The method allowed analysis of up to 40 samples within an 8-h period. CONCLUSIONS: This optimized method for CoQ(10)H(2) analysis provides rapid and precise results with the potential for high throughput. This method is specific and sufficiently sensitive for use in both clinical and research laboratories.

An improved gas chromatography assay for topiramate monitoring in pediatric patients.

An improved micromethod involving capillary gas chromatographic assay with liquid-liquid extraction and nitrogen phosphorus detection (GC/NPD) was developed and validated for the determination of topiramate (TPM) in human body fluids. The galactopyranose analog of TPM was used as the internal standard. Capillary gas chromatographic conditions yielded typical retention times of 6.8 min for TPM and 7.2 min for the internal standard. Calibrations were linear between 1.0 and 32 microg/mL. Between-day precision (n = 17) for three serum controls (3.0, 10, and 24.5 microg/mL) resulted in coefficients of variation of 6.9%, 7.3%, and 4.9%, respectively. The limit of detection was 0.42 microg/mL. There was an excellent linear correlation between the fluorescence-polarization immunoassay (FPIA) and GC/NPD determinations of 56 patient specimens (r2 = 0.981). Chromatograms showed no interfering peaks with the respective blank human samples or from many commonly prescribed drugs. Because of improved specificity and decreased sample volume requirements, this micromethod should be particularly useful for monitoring TPM therapy in pediatric patients, for patients with impaired renal function, and for research studies.

Automated microanalysis of gabapentin in human serum by high-performance liquid chromatography with fluorometric detection.

An automated high-performance liquid chromatographic method for the determination of gabapentin, 1-(amino-methyl)cyclohexaneacetic acid, in serum is described. The procedure involves protein precipitation with methanol followed by using a robotized derivatization with o-phthaldialdehyde reagent and automated high-performance liquid chromatography. The analog of gabapentin, 1-(aminomethyl)cycloheptaneacetic acid, was used as the internal standard. Blank serum was fortified with gabapentin (0.1-10.0 microg/ml) and internal standard. Separation was achieved on a Waters 5-microm reversed-phase column (10 cmx4.6 mm) with mobile phase consisting of 0.02 M phosphate buffer (pH 4.5)-acetonitrile (50:50, v/v). Eluents were monitored by fluorescence spectroscopy with excitation and emission wavelengths of 230 and 420 nm, respectively. The calibration curve for gabapentin in serum was linear (r=0.999) over the concentration range 0.1-10.0 microg/ml. The inter- and intraassay variations for three different gabapentin concentrations were < or =10% throughout. The lower limit of quantitation was found to be 0.1 microg/ml. Chromatography was unaffected by a range of commonly employed antiepileptic drugs or selected amino acids.

Topiramate pharmacokinetics in infants.

PURPOSE: This study's goal was to provide preliminary data on the pharmacokinetics of topiramate (TPM) in a cohort of infants (younger than 4 years) participating in an open-label trial of TPM in refractory infantile spasms. METHODS: The pharmacokinetics of TPM were assessed in infants receiving a stable TPM dose for >7 days during the extension phase of this trial. Blood samples were drawn just before and 0.5. 1, 1.5, 2, 4, 6, 8, and 12 h after the morning TPM dose. TPM plasma concentrations were determined by fluorescence polarization immunoassay. The noncompartmental analysis module of WinNonlin was used to calculate individual patient pharmacokinetics profiles. RESULTS: Five infants (ages, 23.5-29.5 months) formed the study cohort. These infants had been given TPM for a median of 9 months (range, 6-11 months) and were currently receiving between 11 and 38.5 mg/kg/day TPM. One was receiving TPM monotherapy, whereas four were taking concomitant antiepileptic medications (AEDs; n = 2, enzyme-inducing agents; n = 2, non-enzyme-inducing drugs). TPM pharmacokinetics in infants appears to be linear. In this cohort, mean TPM plasma clearance (CL/F, 66.6+/-27.4 ml/h/kg) was slightly higher than that reported for children and adolescents and therefore substantially higher than that reported for adults. TPM CL/F was higher and the calculated half-life shorter in the infants receiving concomitant enzyme-inducing AEDs. CONCLUSIONS: Based on this small cohort of patients, it appears that infants may require significantly larger TPM doses, based on weight, than children, adolescents, or adults. Titration to effect and not absolute TPM dose should guide therapy in this age group.

Special considerations for monitoring vancomycin concentrations in pediatric patients.

The objectives of this study were to estimate the prevalence of low or excessive vancomycin dosing after initiation of treatment in pediatric patients and to determine the factors that are most predictive of optimized vancomycin dosage in this group. Among 74 patients who underwent vancomycin concentration monitoring, low trough (< 4.0 micrograms/ml) and/or peak (< 15.0 micrograms/ml) concentrations were noted in 28 (38%) patients after the initiation of therapy but in only four of the 28 (14%) patients (p = 0.29) after optimization of the initial dosage. There were not toxic peak concentrations (> 60 micrograms/ml) reported during the study. In patients older than 1 month old, 11 low peaks were associated with troughs less than 7.5 micrograms/ml, whereas no low peaks were associated with troughs more than 7.5 micrograms/ml. The significant predictive variables of optimized vancomycin dosage in the reduced regression model (p < 0.00001; adjusted r2 =0.85; n = 36) were (log) initial dose (p < 0.0001), initial trough (p < 0.0001), and age (p = 0.009). Initial peak concentrations were not associated with the optimized dosage (p = 0.50). The results of this study indicate that approximately 40% of all pediatric patients will be at risk of significant underdosing if standard vancomycin dosing guidelines are followed and that patients older than 1 month old with initial trough concentrations less than 7.5 micrograms/ml are at a greater risk of low peak concentrations than individuals with trough concentrations more than 7.5 micrograms/ml. Monitoring vancomycin concentrations appears to be essential to prevent the underdosing of many pediatric patients; however, only initial trough vancomycin concentrations may be needed to optimize dosages.

Pharmacokinetic disposition of sequential intravenous/oral ciprofloxacin in pediatric cystic fibrosis patients with acute pulmonary exacerbation.

OBJECTIVE: Information about the pharmacokinetics of fluoroquinolone antibiotics in high risk children is scant. This study examined the disposition of sequentially administered intravenous and oral ciprofloxacin, as well as provided dosing recommendations, for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients. METHODS: After enrollment in a Food and Drug Administration approved protocol, the pharmacokinetic profiles of ciprofloxacin (CIP) administered to 18 children with cystic fibrosis (ages 5 to 17 years) were studied at steady state after sequentially administered intravenous (10 mg/kg every 8 h) and oral (20 mg/kg every 12 h) doses. All children enrolled met published criteria for exacerbation of Pseudomonas aeruginosa lung infection and received CIP intravenously (given as a 1-h infusion) followed by oral administration, each for a minimum of 3 days. All patients were at a mild to moderate stage in their disease with National Institutes of Health scores between 37 and 83. Blood samples were drawn at 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 (after both i.v. and oral dosing) and 12 h (oral only) after CIP administration. CIP serum concentrations were determined by high performance liquid chromatography. RESULTS: After oral CIP mean +/- SD peak serum concentrations and peak times were 3.7 +/- 1.4 mg/l and 2.5 +/- 1.8 h, respectively, compared with 5.0 +/- 1.5 mg/l and 1.0 +/- 0.3 h after completion of the i.v. infusion. Maximum concentrations, when normalized for dose, were 0.52 +/- 0.12 and 0.19 +/- 0.07 mg/l/kg after i.v. and oral dosing, respectively. The mean bioavailability of oral CIP for all patients was 76%; younger patients appeared to absorb oral CIP less than older subjects, 68% vs. 95%, respectively. For all patients elimination half-lives were 2.6 +/- 0.6 and 3.4 +/- 0.7 h after i.v. and oral administration, respectively, and did not differ by age. Total clearance after i.v. administration was 19.5 +/- 10.9 liters/h. No significant CIP-related adverse effects were noted. CONCLUSIONS: CIP doses of 30 mg/kg/day i.v. and 40 mg/kg/day orally must be administered to children with cystic fibrosis to achieve optimal therapeutic concentrations.

Vancomycin-binding characteristics in patients with serious infections.

STUDY OBJECTIVE: To examine the extent, variability, and factors affecting vancomycin protein binding. DESIGN: Prospective, open-label, cohort study. SETTING: A general hospital. PATIENTS: Forty-four adults [mean (+/- SD) age 50.9 +/- 17.1 yrs, range 16.8-92.0 yrs] with serious infections. INTERVENTIONS: Unbound (Vu) and total (Vtot) vancomycin concentrations were determined by fluorescence polarization immunoassay. A statistical analysis model used the maximum likelihood method to evaluate the association between several important variables and log Vu while controlling for log Vtot effects. MEASUREMENTS AND MAIN RESULTS: The mean fraction percentage of unbound vancomycin was 79.5 +/- 6.0% (range 53.0-96.3%). While controlling for Vtot the total variability of Vu was 8.3%, suggesting that vancomycin binding is relatively constant in sick adults. We were able to demonstrate a significant statistical interaction effect between gender and globulin protein concentration on Vu (p = 0.022). Globulin protein concentration in men was negatively associated with Vu (p = 0.0009), but there was no association in women (p = 0.645). Age, race, peak-trough association, serum creatinine, serum albumin, serum prealbumin, and hemodialysis were not significantly associated with log Vu in the statistical model. CONCLUSION: Compared with earlier studies in healthy adults, vancomycin binding appears to be decreased during acute illness, and intrapatient and interpatient variability are relatively small. Unbound vancomycin concentration appears to be gender dependent.

Development of a fluorescence polarization immunoassay for lorazepam quantification.

Lorazepam concentrations have been quantified in biological fluids using gas chromatography and high-performance liquid chromatography (HPLC). However, these methods are too time consuming and labor intensive for most nonresearch laboratories to offer. A fluorescence polarization immunoassay (FPIA) method for quantification of lorazepam was developed and validated using a reverse-phase HPLC method as the reference method. The FPIA method involves a single liquid-liquid extraction of 100 microliters of either serum or plasma, then direct analysis using the TDxFLx (Abbott Diagnostics, North Chicago, IL). FPIA calibrations were linear between 50 and 800 ng/ml using five calibrators prepared in human serum. Within-run precision (n = 10) for three serum controls (75, 300, and 600 ng/ml) resulted in coefficients of variation (CVs) of 5.7%, 5.4%, and 4.2%, respectively. Between-day precision studies for the three serum controls were 7.0%, 8.9% and 4.9%, respectively (n = 5). The analytical recovery of the three serum controls was 104.9%, 97.3% and 98.3%, respectively. There was an excellent linear correlation between the FPIA and HPLC determinations of 43 patient specimens (r = 0.990, slope = 0.961, intercept = 16.3). No interferences were found from many commonly prescribed nonbenzodiazepine drugs; however, other benzodiazepines that were tested will cross-react with this procedure and give inaccurate results. Therefore, this method should not be used in patients who are receiving other benzodiazepines in addition to lorazepam. The FPIA method described herein can be adapted to reliably measure lorazepam concentrations in serum or plasma.

An improved micromethod for vancomycin determination by high-performance liquid chromatography.

A micromethod using reversed-phase high-performance liquid chromatography for the analysis of vancomycin in human serum or plasma was developed. Ristocetin was used as the internal standard. Chromatographic conditions included an amino propyl column, a mobile phase with 62% acetonitrile and 38% sodium phosphate buffer (pH 7.0), a total run time of 10 min, and ultraviolet absorbance detection at 225 nm. Multilevel calibration was found to be linear between 1.0 and 100 micrograms/ml with correlation coefficients of the calibration line slope consistently > 0.999. Recovery of vancomycin from serum was nearly complete, and no interference from commonly used drugs was observed. This procedure is simple, sensitive, rapid, precise, selective, and requires only 50 microliters of serum or plasma for completion.

Salivary theophylline monitoring: reassessment and clinical considerations.

To assess the reliability of salivary theophylline concentrations for patient monitoring, concentrations of theophylline in sera and saliva of 50 patients (ages 6-81 years) receiving oral or parenteral theophylline were determined by two methods: a rapid dry-phase apoenzyme reactivation system (ARIS) and fluorescence polarization immunoassay (FPIA). Saliva production was stimulated by both citric acid (CA) and parafilm (PF). With both analytical methods, there were excellent correlations between salivary theophylline concentration, CS, and unbound serum theophylline concentration CU (r2 > 0.95), and between CS and total serum theophylline concentration, CT (r2 > 0.85). CA- and PF-stimulated CS by FPIA resulted in concentrations within 2.0 micrograms/ml of the actual CU for 100% of the samples measured (n = 47). By ARIS, 100% of the PF-stimulated CS and 93.6% of the CA-stimulated CS determinations were within 2.0 micrograms/ml of the CU (n = 47). To evaluate the predictive capabilities of PF- and CA-stimulated saliva, one-half (n = 24) of the patients were randomly selected and their data used to predict the CT for the remaining patients. FPIA PF-CS predicted 83.3% (20/24) of CT within +/- 2 micrograms/ml, while ARIS CA-CS predicted 75.0% within +/- 2 micrograms/ml. There was no difference between FPIA CS and ARIS CS results by multivariate analysis of variance (MANOVA), but there was a difference between PF-CS and CA-CS (p < 0.05). However, when CU was used as a covariant, there was no significant difference. Using appropriate saliva collection procedures and the FPIA system, we conclude that CS provides adequate reliability for therapeutic drug monitoring of theophylline.

Determination of the pharmacokinetic profiles of insulin-like growth factor binding proteins-1 and -2 in rats.

The insulin-like growth factor binding proteins (IGFBPs) are present in serum and alter the half-life of IGF-I and II in the vascular compartment. Because both IGFBP-1 and 2 have been proposed as regulators of IGF transport, we directly determined their distribution and elimination characteristics in rats. 125I-IGFBP-1 and 2 were injected into anesthetized normal rats. Multiple blood samples were drawn over time and the trichloroacetic acid precipitable radioactivity used to determine their pharmacokinetic profiles. The mean residence time for IGFBP-1 was 129 +/- 31 min and for IGFBP-2 116 +/- 24 min. The volume of distribution at steady state was 300 +/- 87 ml/kg for IGFBP-1 and 242 +/- 32 ml/kg for IGFBP-2. The elimination half-life was 120 +/- 26 min for IGFBP-1 and 144 +/- 32 for IGFBP-2. The results show that two separate methods of analysis give equivalent results for estimation of half-lives of these forms of IGFBPs and that their half-lives are substantially greater than that reported for free IGF-I, but less than that reported for the 150-kilodalton IGF complex. The findings suggest that these proteins equilibrate with extravascular compartments and may have a role in modulating transvascular transport of IGF-I and II.

Determination of salivary digoxin with a dry strip immunometric assay.

Analysis of salivary digoxin using a rapid dry chemistry, enzyme-labeled immunometric assay (ELIA) was compared with fluorescence polarization immunoassay (FPIA). Saliva and serum samples were obtained from 40 hospitalized patients who were taking digoxin chronically and from 8 patients just prior to treatment with digoxin. Unstimulated saliva samples were collected from 20 patients; however, saliva volumes from 10 pediatric patients were inadequate to permit analysis by FPIA, and 1 other had unmeasurable concentrations by both methods. Stimulated saliva was collected by having patients chew a small piece of Parafilm for 1-2 min. Salivary digoxin was analyzed using the same procedure recommended for serum digoxin by each manufacturer. There were no significant differences found between ELIA and FPIA determinations of unstimulated or stimulated salivary digoxin, serum digoxin, or saliva/serum concentration ratios. The saliva/serum ratio of the unstimulated group was approximately twice that of the stimulated group (p less than 0.01) by both methods, suggesting that salivary digoxin concentration decreases with increased saliva production rate. Excellent correlations were found between ELIA and FPIA salivary digoxin concentrations and between stimulated saliva and serum concentrations by both assays. Weaker correlations were observed between unstimulated saliva and serum concentrations. There was no evidence of assay interference with either method in eight nondigitalized patients, each taking an average of 6.5 medications. The ELIA appears to provide equivalent results compared with the FPIA for the determination of salivary digoxin concentration. Further investigations are needed before salivary digoxin concentration monitoring can be recommended as an acceptable alternative to serum monitoring.

Increased serum clearance and degradation of 125I-labeled IGF-I in protein-restricted rats.

Dietary protein restriction in young rats stunts growth and decreases serum insulin-like growth factor I (IGF-I) concentrations. To investigate the possibility of a diet-induced accelerated clearance of IGF-I, the clearance of 125I-labeled IGF-I was determined by measuring the radioactivity in serum obtained at different intervals after bolus injection in 5-wk-old rats that had received either a normal 15% protein diet (P15; n = 6) or a 5% protein isocaloric diet (P5; n = 7) for 1 wk. The clearance and volume of distribution of 125I-IGF-I were increased in P5 rats by 58 and 75%, respectively, whereas the terminal elimination half-life was not changed. The calculated IGF-I production rate was decreased by 40% in P5 rats. The intermediate distribution phase (alpha) was twofold faster in P5 than in P15 animals, and 125I-IGF-I was preferentially bound to IGF binding proteins in the 40-kDa complex in P5 rats. These observations might explain the increased clearance and degradation of IGF-I in the P5 rats. Dietary protein restriction appears to lower serum IGF-I concentrations by both decreasing its production rate and increasing its clearance.

Intraindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.

The intraindividual variability of salivary carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations was studied in six healthy male volunteers. During three consecutive 1-week phases, subjects took one of the antiepileptic drugs (AED) for 5 days. Nine saliva and nine blood samples were collected simultaneously over the last 4 days of each phase. Salivary, unbound serum, and total serum CBZ, PB, and PHT concentrations were determined by fluorescence polarization immunoassay. Individual mean saliva (Cs)/total serum (Ct), unbound serum (Cu)/Ct, and Cs/Cu concentration ratios for CBZ, PB, and PHT were similar to those reported previously. The intraindividual mean (+/- SD) coefficients of variation (%) of the Cs/Ct, Cu/Ct, and Cs/Cu ratios for CBZ were 4.8 +/- 2.2%, 4.4 +/- 1.8%, and 5.0 +/- 1.9%, respectively; for PB they were 5.1 +/- 0.8%, 3.6 +/- 0.9%, and 6.4 +/- 1.0%, respectively; and for PHT they were 7.4 +/- 3.1%, 5.5 +/- 1.2%, and 8.3 +/- 3.2%, respectively. The mean Cs/Ct and Cu/Ct ratios for CBZ and PHT were not significantly different, but they were different for PB (p = 0.01). However, the range of individual coefficients of variation of the Cs/Ct ratio for PB was 4.0-6.2%, which is acceptable for clinical monitoring. We conclude that the intraindividual variability of CBZ, PB, and PHT concentrations in saliva, based upon the saliva/serum concentration ratios of each AED, is not a factor that should dissuade clinicians from using saliva for the therapeutic monitoring of these agents.

Methsuximide for intractable childhood seizures.

Methsuximide was added to the therapeutic regimens of 25 children with intractable epilepsy. In 15 patients the drug was well tolerated and resulted in a 50% or greater reduction in seizure frequency. No serious or irreversible adverse effects were seen. Methsuximide is frequently overlooked and may be an effective adjunctive antiepileptic for children with intractable seizures.

Regulation of serum insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat pregnancy.

Serum concentrations of insulin-like growth factor-I (IGF-I) in rats are reduced dramatically in the latter half of pregnancy, decreasing from 1758 +/- 356 ng/ml at 12 days of pregnancy (mean +/- SD) to 761 +/- 192 ng/ml at 15 days. After parturition, IGF-I increases to nonpregnant values in 4 days. Using ligand blotting, we have demonstrated that most of the serum IGF binding proteins (IGFBPs) are concurrently reduced during pregnancy. IGFBP-3, the predominant IGFBP in nonpregnant serum, is reduced to 1.3% of nonpregnant values by 21 days of pregnancy and begins to rise within 1 h postpartum (PP). The sera of 21-day pregnant (but not nonpregnant) rats degrade IGFBP-3 in vitro, and this degradation is prevented by the protease inhibitor antipain. Decreased serum IGF-I concentrations during pregnancy, therefore, may result from reduced IGFBP-3 concentrations causing increased IGF-I clearance. In addition, steady state IGF-I mRNA and peptide levels in liver are decreased in 21-day pregnant rats (37% and 42% of 4 day PP levels, respectively), suggesting that decreased synthesis of IGF-I may also lead to lower serum IGF-I concentrations. After bolus injection, [125I]IGF-I is cleared from the serum of pregnant rats nearly 5 times faster than that of 4 day PP rats (1.21 vs. 0.25 ml/min/kg, respectively). Urinary clearance is relatively insignificant (less than 4%), and [125I]IGF-I does not cross the placenta. The intermediate distribution phase of IGF-I is slower in pregnant rats than in PP rats (t1/2 alpha, 17.1 vs. 5.4 min), whereas the terminal elimination of IGF-I is twice as fast (t1/2 beta, 228.1 vs. 106.4 min). The prolonged IGF-I distribution phase in the pregnant rats may result from decreased concentrations of 34,000 and 30,000 mol wt IGFBPs, which may transport IGF-I to tissues. The faster serum elimination half-life may result from diminished IGFBP-3, leading to greater IGF-I availability to tissues in pregnancy.

Evaluation of the Ames Seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.

The performance of the dry-phase apoenzyme reactivation immunoassay system (ARIS) for the measurement of carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations in saliva was compared with fluorescence polarization immunoassay (FPIA). Blood and saliva samples were collected from 163 adult and pediatric epilepsy patients, then analyzed using both methods. Regressions between ARIS saliva CBZ, PB, and PHT concentrations, and FPIA unbound and total serum concentrations were highly correlated, but the ARIS technique was somewhat less precise than the FPIA. Valproic acid co-medication did not affect the relationships between ARIS and FPIA saliva concentrations and unbound serum concentrations of PHT, but did disrupt the relationship between ARIS and FPIA saliva PHT and total serum PHT. The sensitivity, specificity, predicted value positive (PV+) of a therapeutic concentration, and predicted value negative (PV-) of a concentration outside the therapeutic range for the ARIS saliva technique compared very well with FPIA for CBZ, PB, and PHT. The ARIS technique for CBZ, PB, and PHT saliva determination provides acceptable accuracy, precision, and sensitivity for therapeutic monitoring. In practice, the benefits of the ARIS saliva technique, including ease of collection, safety, patient/parent acceptance, and short analysis time, are striking.

Rapid loading of critically ill patients with carbamazepine suspension.

To determine the rate and factors that affect carbamazepine absorption, six patients being treated in the pediatric intensive care unit for frequent seizures received loading doses (7.4 to 10.4 mg/kg) of carbamazepine suspension by either nasogastric or nasoduodenal tube. Carbamazepine serum concentrations were determined 15, 30, 60, 120, and 480 minutes after administration by fluorescence polarization immunoassay. One patient who had an ileus did not attain therapeutic concentrations (greater than 4.0 mg/L). The other five patients with normal gastrointestinal function achieved mean serum concentrations at 1 hour and 2 hours of 4.3 mg/L and 7.3 mg/L, respectively. Delayed gastric emptying and concurrent enteral feedings appear to slow the absorption of carbamazepine. No adverse effects were observed. Rapid loading with carbamazepine suspension appears to be a useful alternative for the management of critically ill pediatric patients who are experienced frequent seizures.