Monitoring rFVIII prophylaxis dosing using global haemostasis assays.

Secondary factor VIII (FVIII) prophylaxis converts severe haemophiliacs (FVIII:C < 1 IU dL(-1)) to a moderate phenotype (FVIII:C ≥ 1 IU dL(-1)), however, plasma FVIII:C is a poor predictor of bleeding risk. This study used thromboelastography (TEG) and thrombin generation assay (TGA) to quantify coagulation across a 48 h rFVIII prophylaxis period. 10 severe haemophiliacs with varying clinical bleeding phenotypes received their standard rFVIII prophylaxis dose and blood samples were obtained over 48 h. Measured parameters included FVIII:C, TEG and TGA at each time point. FVIII:C pharmacokinetics (PK) and correlation between global assay parameters was performed. The FVIII:C PK parameters were consistent with previous literature. There was significant correlation between FVIII:C and TEG R-time and aPTT (both P < 0.001). Significant correlations existed between FVIII:C and TGA peak, ETP and velocity parameters (all P < 0.001). At 24 h the TEG parameters were sub-therapeutic despite median FVIII:C of 13.0 IU dL(-1). TGA was sensitive to FVIII:C below 1 IU dL(-1). Those with the severest bleeding phenotype had the lowest TGA parameters. There was significant correlation between FVIII:C and TEG and TGA. TEG lost sensitivity at 48 h, but not TGA. Prospective studies are needed to determine whether these data can be used to design individualized rFVIII prophylaxis regimens.

Using exposure-response and biomarkers to streamline early drug development.

Biomarkers (BMs) are biological measures of PD drug effects or disease markers that may represent clinically significant patient outcomes, either efficacy or toxicity. Their use in drug development, especially as an integral part of PK/PD modeling, has become a popular strategy for optimizing development time and resources. This approach supports quantitative integration of information across different species and throughout the clinical phases I-III. If the BM is based on the mechanism of action (MOA) of the drug, it is expected to follow an exposure-response relationship (E-R). If it is also involved in causal pathways in the pathophysiology of the disease (POD), it may become a surrogate marker (SM). SMs allow prediction of clinical outcomes for different dosing regimens of drug candidates and patient individualization of treatment in clinical practice. Appropriate evaluation of BMs by mechanistic, epidemiological, and clinical pharmacology studies as part of the drug development process allow scientists to establish clinically relevant ER. In early drug development, known ERs for BMs facilitate translation of in vitro findings to in vivo consequences, interspecies PK/PD comparisons, and streamlining of dose-finding phase I and II studies, as well as assessment of new dosing regimen candidates for their likely clinical efficacy and safety, extrapolation of clinical study results to special populations (e.g., pediatrics), and interpretation of exposure differences found in food, drug interaction and special populations studies. Recently, two novel BMs, namely, P50, a measure of ex vivo/in vitro whole blood oxygen affinity and S(pO2), i.e., in vivo pulse oximetry, were used in the development of an allosteric synthetic hemoglobin modifier (SAM), efaproxiral, as PD endpoints; these BMs are based on the MOA of SAMs. Early use of these BMs established excellent in vitro/in vivo PK/PD correlations, appropriate interspecies PK and PD scaling as well as PD-guided phase I and II dose-finding studies. This approach allowed appropriate translation of in vitro and preclinical information along with early identification of sources of PK/PD variability. Frontloading drug development with the identification and use of mechanism-based (MOA/POD) BMs constitutes a rational strategy to quantitatively integrate PK/PD information and optimize dose finding.

Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.

Potential kinetic and dynamic interactions between the new class III antiarrhythmic dofetilide (D) and the calcium channel blocker verapamil (V) were determined in 12 young healthy male volunteers. A fixed sequence of V80 mg tid, placebo, D 0.5 mg bid, and D + V was given as matching active and placebo capsules. In steady-state conditions during combination treatment, a modest increase in mean (+/- SD) peak plasma concentration of dofetilide from 2.40 +/- 0.42 to 3.43 +/- 0.71 ng x ml(-1) (43% increase, p < 0.1) was noted. During the combination period, for the first 4 hours, mean AUC values for D increased from 7.4 +/- 1.0 (D alone) to 9.2 +/- 1.4 ng x h x ml(-1) (26% increase, p <0.1). No other significant pharmacokinetic interaction was seen. These transient changes were concurrent with trends for a dynamic interaction. The maximal mean increase in QT, over steady-state baseline values was 20 msec for D alone versus 26 msec during combination therapy. This relatively small interactive effect occurred only while peak plasma drug concentrations were developing at 1 to 3 hours after dosing and is probably caused by the known effect of verapamil to increase hepatic and portal bloodflow. In view of this interaction and the relationship between dofetilide plasma concentration and torsade, verapamil is contraindicated in patients receiving dofetilide.

Prediction of lidocaine tissue concentrations following different dose regimes during cardiac arrest using a physiologically based pharmacokinetic model.

BACKGROUND: The purpose of our study was to develop a physiologically based pharmacokinetic (PBPK) model describing the behavior of lidocaine in humans by scaling up physiological variables from animal models of cardiac arrest. We attempted to identify the optimal dose regime for lidocaine during cardiac arrest using this model. METHODS AND RESULTS: We designed a flow-dependent PBPK model representing nine body tissues for lidocaine. Physiological organ flow rates, tissue volumes, and plasma-tissue partition parameters for lidocaine in humans were taken from the literature. Data from published animal studies were used to estimate loss of organ blood flow during cardiac arrest and lidocaine tissue partition coefficients. The model assumed a 70 kg cardiac arrest patient. The following five lidocaine dose regimes were simulated: (1) 4 mg/kg i.v. push (IVP) (2) 1.5 mg/kg IVP then 1.5 mg/kg IVP in 4 min, (3) 3 mg/kg IVP, (4) 2 mg/kg IVP, and (5) 1.5 mg/kg IVP. A simulation of Regimen 2, which is the current American Heart Association (AHA) recommendation, suggests that the concentration of lidocaine is suboptimal at the decision point (3-5 min) to administer another dose. Regimen 4 offers a slightly more rapid progress towards optimal cardiac concentrations and more acceptable brain concentrations compared to regimes 1-3. CONCLUSION: Simulations from our PBPK model suggest that the current AHA lidocaine dose regime for cardiac arrest may not result in optimal lidocaine concentrations in the heart and brain. Simulations suggest that 2 mg/kg IVP may be the most acceptable lidocaine dose regime during cardiac arrest.

A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.

PURPOSE: Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT). METHODS AND MATERIALS: Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central vein over 60 min immediately before RT. Patients received supplemental O(2) via nasal cannula at 4 L/min during RSR13 infusion and RT. Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed. The pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint tonometry and expressed as an increase in p50, defined as the partial pressure of O(2) that results in 50% SaO(2). The RSR13 dose in the first cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT. RESULTS: Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiologic effect, and then diminished with a half-life of approximately 5 h. CONCLUSIONS: RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.

Allosteric modification of oxygen delivery by hemoglobin.

UNLABELLED: Hemoglobin affinity for oxygen is altered by pH, temperature, and high altitude, making oxygen more readily available to the tissues. RSR13 (Allos Therapeutics, Denver, CO), an analog of the drugs clofibrate and bezofibrate, causes a dose-dependent, rightward shift of the oxygen dissociation curve in animals and humans. We tested the safety, pharmacodynamic, and pharmacokinetics of RSR13, an allosteric modifier of hemoglobin, in patients having general surgery in a prospective, randomized, double-blinded, placebo-controlled, dose-escalation clinical trial. After the induction of general anesthesia with endotracheal intubation, 26 patients who consented were randomly assigned to receive an infusion of RSR13 or placebo (2:1) in an ascending dose scheme. Doses studied were 10, 20, 30, 40, 50, 60, 75, and 100 mg/kg infused for 30--60 minutes. Samples were taken for determination of RSR13 concentration in plasma, red blood cells, and urine, as well as for determination of the p50 in blood by using three-point tonometry at frequent intervals after the infusion of the study drug. The RSR13 administration resulted in a dose-dependent rightward shift of the oxygen dissociation curve, with the target p50 shift of 10 mm Hg achieved at the 75- and 100-mg/kg doses. No differences were seen between RSR13 and placebo groups in laboratory or hemodynamic findings, with the exception of a transient, limited increase in serum creatinine in 3 patients who received RSR13. These increases peaked at 48 h (2.2, 3.5, and 4.5 mg/dL respectively), were not associated with oliguria, did not require treatment, and did not prolong hospitalization in any patient. The reasons for the unexplained increases in serum creatinine were not evident, but potentially included surgery itself (nephrectomy), patient condition, or the concomitant administration of renally cleared medications or drugs that affect renal blood flow. IMPLICATIONS: We studied the safety and tolerance of an investigational drug, RSR13 (Allos Therapeutics, Denver, CO), in general surgery patients. This drug, which increases the amount of oxygen available to the body, was well tolerated by the 17 patients who received it. There were clinically relevant increases in serum creatinine in 3 patients, indicating a decrease in renal function, but these increases were short-lived and resolved without treatment.

The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of enoxaparin in end-stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight nonthrombosed patients with ESRD requiring hemodialysis. INTERVENTION: All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple-dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2-fold prolongation in antifactor Xa activity half-life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single-dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady-state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady-state concentrations within the therapeutic range. CONCLUSIONS: Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.

Effect of chronic renal failure on the disposition of highly hepatically metabolized drugs.

OBJECTIVE: The objective of this study was to investigate the effect of renal impairment on the disposition of an extensively metabolized drug, i.e., drug X. Drug X has a hepatic extraction ratio of less than 0.1 and free fraction in plasma of less than 1% in healthy volunteers. METHODS: Pharmacokinetic (PK) parameters of drug X were obtained from subjects with normal renal function (I, n = 6), as well as in subjects with mild (II, n = 5), moderate (III, n = 7) and severe renal impairment (IV, n = 5). Disease-PK models were developed to describe the changes of PK parameters with respect to renal function measured by creatinine clearance. While experimentally observed data are presented for drug X, additional simulations were performed for other drugs that are extensively metabolized (extensive metabolism is defined as metabolism that accounts for more than 90% of total drug elimination). The simulated scenarios included drugs that have a low extraction ratio (ER) and with high plasma protein binding (PPB), low ER and with low PPB, high ER and with high PPB, or high ER and with low PPB. RESULTS: Systemic clearance of drug X, a low ER and high PPB drug, in renal patients depended on the simultaneous effects of renal disease on protein binding and intrinsic metabolic clearance. Protein binding of drug X was related to creatinine clearance in an inverse hyperbolic relationship, while the unbound intrinsic metabolic clearance declined linearly with creatinine clearance. Because the disease effects on these two factors offset each other in terms of total systemic clearance, the lowest total systemic clearance was not observed in the severely renal impairment patients, but rather in the moderately impaired group. Additional simulations showed that for low ER drugs that are highly metabolized, the pattern and magnitude of systemic clearance change in renal patients depended on how the disease affected PPB and/or intrinsic metabolic clearance. But the systemic clearance of high ER drugs would not be as susceptible to the effect of renal disease as that of low ER drug. CONCLUSIONS: Chronic renal disease should not be considered as an isolated event that affects only renally excreted drugs. Uremia may also modify the disposition of a highly metabolized drug by changes in plasma protein binding and/or hepatic metabolism.

Pharmacokinetic/pharmacodynamic modeling in drug research and development.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.

Evaluation of truncated areas in the assessment of bioequivalence of immediate release formulations of drugs with long half-lives and of Cmax with different dissolution rates.

PURPOSE: To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for drugs with long half-lives and to study the relationship between Cmax and in vitro dissolution rates. METHODS: Monte-Carlo simulations were conducted using actual mean plasma concentrations of five long half-life drug products. The simulations were based on a catenary pharmacokinetic system in which the drug disposition in the body was represented by a one-or two-compartment model, characterizing the observed mean profiles. The influence of dramatic changes in the in vitro dissolution rate constant 'kd', was simulated in scenarios consisting of 20 crossover trials with 24 subjects per trial, comparing a fast dissolving reference and a hypothetical, slow dissolving test formulation. RESULTS: The AUC's truncated after the completion of distribution phase were found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the Cmax measure was insensitive to the changes in the in vitro dissolution rate. The Cmax measure was found to be useful in the bioequivalence assessment since it reflected both the rate and extent of absorption. (Cmax/AUCt) measure was specific to absorption rate. CONCLUSIONS: For the bioequivalence determination of long half-life drug products, (1) the use of truncated AUC's after completion of the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may be insensitive to input rate changes, if the absorption rate is not constrained by the input rate in relation to the distribution or elimination rate. (3) (Cmax/AUCt) may be more specific to 'ka' differences, but Cmax reflects differences in both rate and extent of absorption.

Peptidoleukotriene (PLT) release and absorption from the airways of the isolated perfused guinea pig lung following chemical and antigenic challenge.

PURPOSE: To study the release and absorption of peptidoleukotrienes (PLTs) from the airways of the guinea pig lung following calcium ionophore A23187 (CI), benzalkonium chloride (BAC), ethylene diamine tetra-acetic acid (EDTA) or ovalbumin (OA) challenge. METHODS: PLT C4/D4/E4 were quantified in the perfusate of the isolated perfused guinea pig lung (IPGPL) following intratracheal administration of CI, BAC, EDTA or OA in different doses. The formation and airway-to-perfusate transfer kinetics of PLTs were analyzed by fitting mean data for cumulative PLT in perfusate vs. time to an A-->B-->C first-order release and transfer model, with dose-dependent transfer rate constants. RESULTS: CI induced apparent first order release of PLTs with a t1/2 approximately equal to 1.2 minutes. The amount of PLT released was CI dose-dependent, as was the airway-to-perfusate transfer rate constant. These reached maxima of 0.254 microgram and 0.0557 min.-1, respectively, around a CI dose of 100 micrograms. In OA-sensitized IPGPL preparations, OA induced a similar dose-dependent release of PLTs, although the rates of PLT release were much greater and more variable than those seen with CI. In OA sensitized IPGPL preparations, at an OA dose of 1000 micrograms, the maximum amount of PLT released was 0.289 micrograms and the maximal airway-to-perfusate transfer rate constant was 0.0229 min-1. BAC and EDTA failed to induce quantifiable PLT release from the airways. CONCLUSIONS: Rapid release of the inflammatory mediators, PLT C4/D4/E4, could be induced in the unsensitized IPGPL by CI, and in the sensitized IPGPL by OA. Transfer into perfusate occurred in both cases with dose-dependent t1/2 ranging from 12.4 through 57.8 minutes.

Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin.

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Pharmacokinetics and CNS pharmacodynamics of the 5-HT1A agonist buspirone in humans following acute L-tryptophan depletion challenge.

This study was designed to evaluate the relationship between the pharmacokinetic(s) (PK) and CNS pharmacodynamic(s) (PD) of buspirone, an antidepressant/anxiolytic, in 6 healthy male volunteers placed on an acute L-tryptophan deficient (ATD) diet. The study was a randomized, double-blind, placebo-controlled, four-period, three-way crossover study. The first study period was a single-blind familiarization period in which all subjects received placebo. During the remaining three study periods, subjects received either placebo, 10 mg or 30 mg oral buspirone. Subjects were administered the ATD diets 5 h prior to buspirone/placebo administration during each study period. All subjects underwent serial measurements of resting electroencephalography (REEG) and vigilance electroence-phalography (VEEG), cognitive tests, subjective rating scales, and blood was sampled for determination of unbound plasma L-tryptophan, serum prolactin, serum cortisol and plasma buspirone and its active metabolite, 1-pyrimdylpiperazine (1-PP). The ATD diet reduced the unbound plasma L-tryptophan concentrations to 20% of their baseline values. The intraindividual and interindividual variability in the unbound L-tryptophan concentration drop was less than 10% and 15%, respectively. Peak L-tryptophan depletion occurred 5 h after ATD diet was administered; L-tryptophan depletion lasted for approximately 11 h, and L-tryptophan concentrations recovered to baseline values approximately 13 h after administration of the ATD diet. PK-PD analysis for buspirone showed that: 1) peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC infinity) for buspirone following the 10 mg dose in this study were higher than those reported previously in the literature; 2) there was a transient response in the neuroendocrine measures, subjective rating scales and the EEG, but no changes in the cognitive tests with increasing doses of buspirone; 3) the PD measures were correlated with the doses of buspirone, but not with plasma concentrations of buspirone and 1-PP; and 4) the subjective rating scales were the most sensitive indicators of buspirone's CNS effects. This study provides evidence that ATD diet is a simple, specific and non-toxic experimental method to lower plasma L-tryptophan concentrations and thereby (indirectly) deplete brain tryptophan and serotonin (5-HT) concentrations. The ATD challenge may serve as a model of depression in healthy volunteers because of its ability to induce transient symptoms of the disease. Comparison of the results from this study to those reported in the literature suggests that the use of the ATD diet decreases the buspirone-induced neuroendocrine response, increases the buspirone-induced changes in subjective rating scales and, at the same time, increases the systemic exposure to buspirone and 1-PP.

Comparison of methods for the assessment of central nervous system stimulant response after dextroamphetamine administration to healthy male volunteers.

The objective of this investigation was to evaluate a series of potential pharmacodynamic measures of central nervous system stimulation, including quantitative electroencephalography (EEG) and neuroendocrine, mood, and psychomotor performance measures. The reproducibility and sensitivity of the measures were compared. The study was conducted in two parts. The first part investigated the interindividual and intraindividual variability associated with a series of potential pharmacologic response measures under baseline (i.e., drug-free) conditions. It was an open-label, three-period pilot study in which healthy male volunteers underwent a series of tests (EEG, a visual continuous performance task, a finger tapping task, and self-rated mood scales) repeatedly during each study period. The second part evaluated the sensitivity of a series of potential response measures to detect the effects of dextroamphetamine, and was a double-blind, placebo-controlled, four-period crossover study in nine healthy male volunteers. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine or placebo orally and underwent the same series of tests as in Part I in addition to blood collection for determination of serum prolactin and dextroamphetamine levels. Peripheral response to dextroamphetamine was assessed by heart rate and blood pressure measurement. The greatest variability among days, within days, and among participants was associated with the quantitative electroencephalographic parameters studied. First-session effects were apparent for several of the tests, including EEG. Consistent response on EEG (increased alpha power) to dextroamphetamine was observed only in the three subjects who had a baseline alpha activity greater than 35%. Serum prolactin levels were inversely associated with the amount of dextroamphetamine administered, with the largest decrease in serum prolactin levels observed after the 5-mg dose, and this finding was statistically significant. Mood scales showed that three of nine participants experienced dysphoria after at least one dose level of dextroamphetamine. The effect on mood was generally greater as the dose increased. Doses could not be distinguished based on the results of the performance tests. Serum prolactin concentration was the most sensitive measure of central nervous system stimulation on EEG produced by dextroamphetamine under these study conditions. Cardiovascular measures were more sensitive measures of dextroamphetamine effects than the central nervous system measures.

Determination of unbound L-tryptophan in human plasma using high-performance liquid chromatography with fluorescence detection.

An assay for the measurement of unbound L-tryptophan concentrations in plasma was developed using reverse-phase HPLC with fluorescence detection. Unbound L-tryptophan from plasma was obtained using the Amicon MPS-1 ultrafiltration device. L-tryptophan binding to the membrane in the ultrafiltration device was not significant. A linear relationship between the peak-area ratios (peak-area of L-tryptophan to internal standard) and concentrations of L-tryptophan was obtained in the range of 0.1 microgram/mL to 2.5 micrograms/mL. The intra-assay precision was less than 10% for each control (0.18 microgram/mL, 0.75 microgram/mL and 2.0 micrograms/mL). The inter-assay precision was less than 15% for each control; the accuracy for each control; the accuracy for each control, expressed as percent difference from nominal (%DFN), was less than 12%. This method was used to determine unbound L-tryptophan concentrations in plasma from nine male subjects who participated in a clinical study.

Flucytosine dosing in an obese patient with extrameningeal cryptococcal infection.

A 31-year-old, obese woman with extrameningeal cryptococcal disease was admitted to the Medical College of Virginia for antifungal therapy. Various physiologic variables influence flucytosine pharmacokinetics, and there are no guidelines for dosing the agent in obese patients. This patient received a dosage based on her ideal body weight, and serum drug concentrations were monitored. She recovered without sequelae.

[Effect of duration of infusion on elimination rate of alfentanil]. / Einfluss der Infusionsdauer auf das Eliminationsverhalten von Alfentanil.

In the present study the disposition of alfentanil after cessation of a constant rate infusion was compared with intravenous bolus injections. In 11 patients undergoing intervertebral disk surgery general anaesthesia was induced with midazolam, alfentanil and vecuronium; anaesthesia was maintained with a constant rate infusion (1.5 to 2 micrograms/kg/min, 1.0 micrograms/kg/min at the end of the infusion period) of alfentanil. The parameters of bolus injections were obtained from 5 patients undergoing lithotripter therapy; an intravenous bolus of 15 micrograms/kg was given. After infusion times of 60 to 120 minutes the mean elimination half life of alfentanil was significantly increased (227 +/- 166 min) compared to the bolus injection (50.8 +/- 9.5 min). There were significant correlations of the elimination half life with the age (r = 0.53, p = 0.03) of the patients, the total dose (r = 0.607, p = 0.01) and the infusion time (r = 0.612, p = 0.01). The total clearance of alfentanil in the bolus group was 385 +/- 138 ml/min and in the infusion group 620 +/- 215 ml/min. There were no significant correlations between the total clearance of alfentanil and the total dose and between the duration of infusion and total clearance. The clinical implications of our study: After prolonged continuous infusions of alfentanil a significant reduction of the elimination rate has to be considered. The patients must be observed very carefully in the recovery room in order to prevent a possible respiratory depression.

Assessment of 24-hour gastric pH measurements in trauma patients receiving intravenous famotidine by intermittent bolus versus continuous infusion administration.

OBJECTIVE: To compare the effects of intermittent bolus versus continuous infusion intravenous famotidine on gastric pH in critically ill trauma patients. DESIGN: Twenty patients were randomized to receive famotidine by intermittent bolus or continuous infusion for 24 hours. Patients fasted during the study period. Hourly gastric pH measurements were made using an indwelling sensor/sump tube. SETTING: The study was conducted in a university teaching hospital. PARTICIPANTS: Adult patients admitted to the neurosurgical or surgical/trauma intensive care unit within 72 hours of traumatic injury were enrolled in the study if they had two consecutive hourly gastric pH readings of < 4 without receiving antacids, sucralfate, or histamine2-antagonists. MAIN OUTCOME MEASURES: Groups were compared with regard to (1) total dose of famotidine received/24 hours, and (2) number of dosage changes required to maintain a gastric pH value of > or = 4. RESULTS: The median dose of famotidine required to maintain a gastric pH > or = 4 was 50 mg/24 h (25th-75th percentiles = 40-55 mg) in the intermittent bolus group compared with 42 mg/24 h (25th-75th percentiles = 42-52 mg) in the continuous infusion group (p = 0.9577). A dosage increase was required by 5 of 8 patients (62 percent) receiving intermittent bolus therapy, whereas only 2 of 8 patients (25 percent) in the continuous infusion group required a dosage adjustment (p = 0.315, power = 0.318). CONCLUSIONS: Intravenous famotidine (40-50 mg/d) effectively controlled gastric pH in critically ill trauma patients. Patients treated with intermittent bolus therapy required slightly more drug and more frequent dosage adjustments to achieve a gastric pH > or = 4. These differences did not reach statistical significance.

Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin.

A double-blind, randomized, crossover study assessed the effects of a single 40-mg dose of fluvastatin on the steady-state pharmacokinetics of digoxin in chronically treated patients. After demonstrating consistent digoxin serum concentrations as part of the inclusion criteria, 18 patients received a single dose of either fluvastatin or placebo, with a 1-week washout period between crossover to the other treatment. For each patient, 14 serum samples were drawn and urine collected over 24 hours; all samples were assayed for digoxin using a fluorescence polarization immunoassay. The following pharmacokinetic parameters were determined using noncompartmental techniques: area under the curve for 24 hours (AUC24); time to maximum concentration after digoxin (tmax); maximum concentration after digoxin dosing (Cmax); concentration at 24 hours after fluvastatin or placebo (Cmin); total amount excreted in the urine over 24 hours (U24); and urinary clearance (Clren). The pharmacokinetic data were analyzed for sequence, patient nested with sequence, and period and treatment differences using ANOVA, Schuirmann's two one-sided testing approach, confidence intervals, and power analysis. The AUC24, Cmax, and tmax for digoxin were considered bioequivalent with the two treatments. The differences in Cmax, U24, and Clren were statistically significant but were not considered to be clinically relevant due to the low magnitude of the difference (< 20%). There were no clinically significant adverse reactions attributable to either digoxin or fluvastatin.