Constant infusion case of one compartment pharmacokinetic model with simultaneous first-order and Michaelis-Menten elimination: analytical solution and drug exposure formula.

The main objective of this article is to propose the closed-form solution of one-compartment pharmacokinetic model with simultaneous first-order and Michaelis-Menten elimination for the case of constant infusion. For the case of bolus administration, we have previously established a closed-form solution of the model through introducing a transcendent X function. In the same vein, we found here a closed-form solution of constant infusion could be realized through introducing another transcendent Y function. For the general case of constant infusion of limited duration, the closed-form solution is then fully expressed using both X and Y functions. As direct results, several important pharmacokinetic surrogates, such as peak concentration [Formula: see text] and total drug exposure AUC[Formula: see text], are found the closed-form expressions and ready to be analyzed. The new pharmacokinetic knowledge we have gained on these parameters, which largely exhibits in a nonlinear feature, is in clear contrast to that of the linear case. Finally, with a pharmacokinetic model adapted from that formerly reported on phenytoin, we numerically analyzed and illustrated the roles of different model parameters and discussed their influence on drug exposure. To conclude, the present findings elucidate the intrinsic quantitative structural properties of such pharmacokinetic model and provide a new avenue for future modelling and rational drug designs.

Simple and rapid quantification of serotonin transporter binding using [11C]DASB bolus plus constant infusion.

INTRODUCTION: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data. METHODS: [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol 160-179min and one scan after [11C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT-70 for 60-70min after start of tracer infusion, VT-90 for 75-90min, VT-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects. RESULTS: A Kbol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. VT-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for VT-90 and 0.77-0.93 for VT-120 in these regions. BPND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BPND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at VT-90. Cortical BPND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BPND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at VT-90 with ICC 0.70 and 0.63, respectively. CONCLUSIONS: We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both VT and BPND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT VT and BPND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.

Functional PET Neuroimaging in Consciousness Evaluation: Study Protocol.

Ensuring a robust and reliable evaluation of coma deepness and prognostication of neurological outcome is challenging. We propose to develop PET neuroimaging as a new diagnostic and prognosis tool for comatose patients using a recently published methodology to perform functional PET (fPET). This exam permits the quantification of task-specific changes in neuronal metabolism in a single session. The aim of this protocol is to determine whether task-specific changes in glucose metabolism during the acute phase of coma are able to predict recovery at 18 months. Participation will be proposed for all patients coming for a standard PET-CT in our center in order to evaluate global cerebral metabolism during the comatose state. Legally appointed representative consent will be obtained to slightly modify the exam protocol: (1) 18F-fluorodeoxyglucose (18F-FDG) bolus plus continuous infusion instead of a simple bolus and (2) more time under camera to perform dynamic acquisition. Participants will undergo a 55-min fPET session with a 20% bolus + 80% infusion protocol. Two occurrences of three block (5-min rest, 10-min auditory stimulation and 10-min emotional auditory stimulation) will be performed after reaching equilibrium of FDG arterial concentration. We will compare the regional brain metabolism at rest and during the sessions of auditory and emotional auditory stimulation to search for a determinant of coma recovery (18 months of follow-up after the exam). Emotional auditory stimulation should induce an activation of: the auditory cortex, the consciousness areas and the neural circuitry for emotion (function to coma deepness). An activation analysis will be carried out to highlight regional brain activation using dedicated custom-made software based on Python statistical and image processing toolboxes. The association between activation levels and the Coma Recovery Scale-Revisited (CRS-R) will be assessed using multivariate analysis. If successful, the results from this study will help improve coma prognosis evaluation based on the pattern of neuronal metabolism at the onset of the pathology. The study protocol, rationale and methods are described in this paper.

Continuous oral stable isotope ingestion to measure whole-body protein turnover.

BACKGROUND & AIMS: Protein kinetic responses to nutrition and exercise interventions are commonly evaluated using a primed-constant infusion of stable isotope tracers. While this methodology is state-of-the-art, the required preparation at a certified pharmacy makes the utilization of isotope infusion both expensive and logistically cumbersome. Oral tracer ingestion has been used to quantify 24-h whole-body protein status; however, this does not permit examination of acute interventional effects. Ingestion of a priming bolus, followed by continuous ingestion of stable isotope tracer in a 'sip feeding' fashion may provide a more feasible alternative for quantifying acute kinetic responses. Therefore, the purpose of this study was to evaluate the viability of a primed continuous oral sip-ingestion method of stable isotope tracers for the evaluation of whole-body protein kinetics. METHODS: In a randomized, crossover design, eight healthy adults (63% female; Age: 29.4 ± 5.8 yrs; BMI: 24.3 ± 2.7 kg/m2) completed two, two-period stable isotope oral ingestion studies, consisting of a 3 h basal fasted period, followed by a 4-h post-ingestion period. After the basal period, subjects ingested either 6.3 g (Low) or 12.6 g (High) of an essential amino acid (EAA) enriched whey protein supplement. The continuous oral sip-feed method was initiated with a primed oral bolus dose of L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine, and L-[ring-2H4]tyrosine, followed by oral sip doses of L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine every 10 min to approximate steady state tracer enrichment. Blood samples were taken throughout the basal and post-meal periods to determine tracer enrichment. Whole-body net protein balance (NB), synthesis (PS), breakdown (PB), and exogenous hydroxylation were calculated for each period. Repeated measure ANOVAs (treatment × time) were used to assess differences in protein kinetics. RESULTS: Using the sip feed method, NB, PS, and hydroxylation were significantly increased with ingestion of protein (p < 0.05) during the postprandial period, regardless of amount of protein ingested; ΔNB from the postabsorptive to postprandial period was significantly greater for high compared to low protein (p = 0.026; low = 6.2 ± 5.1 g protein·240 min-1; high = 11.8 ± 3.9 g protein·240 min-1). CONCLUSION: The current study provides preliminary evidence that continuous oral sip-feeding of stable isotope tracer is a feasible method that provides physiologically relevant measures of protein metabolism. Assessments of variance and individual responses revealed high measurement variability with the sip-feed method compared to previously published constant infusion responses, but ΔNB, ΔPS, and ΔPB were comparable. In situations where constant infusion is not feasible, oral sip-feeding could be used as an alternative method for measurement of acute, postprandial protein metabolism.

Effects of bolus injection of 5-fluorouracil on steady-state plasma concentrations of 5-fluorouracil in Japanese patients with advanced colorectal cancer.

OBJECTIVES: The irinotecan (CPT-11) + 5-fluorouracil (5-FU)/leucovorin (LV) + UFT/LV chemotherapy, in which repetitive oral administration of UFT/LV replaces the infusion of 5-FU/LV in the FOLFIRI regimen, has been proposed previously. In this study, five of 10 patients were injected with a bolus of 5-FU and the other were not injected with it in order to examine the effect of omitting it in terms of pharmacokinetics of 5-FU. METHODS: The treatment consisted of the intravenous infusions of CPT-11 at 100 mg/m(2 )and l-LV at 15 mg/m(2), and the injection of a bolus of 5-FU at 500 mg/m(2) on day 1, and the repetitive oral administration of UFT/LV (300 mg/m(2)/day as tegafur + 75 mg/day of LV) on days 1-5. A total of 13 measurements of the plasma concentrations of uracil, 5-FU and tegafur were made per patient within 48 hr after the start of chemotherapy and the value of area under the concentration-time curve (AUC(0-48)) was evaluated. The plasma concentration was also determined at 2 weeks to assess long-term exposure to 5-FU. RESULTS: The plasma concentrations of 5-FU at 24 hr after the start of treatment were 27.4 ng/mL and 9.4 ng/mL in the patients with and without the bolus injection, respectively. At 48 hr, they were 31.3 ng/mL and 10.4 ng/mL with the AUC(0-48) values of 22.16 mg h/L and 0.65 mg h/L, respectively. The 5-FU was detected in the plasma at 226 hr after the last administration of UFT/LV for the patients with the bolus injection, but not for those without. CONCLUSION: A bolus of 5-FU on day 1 provided long-term exposure to 5-FU.

PET measurement of "GABA shift" in the rat brain: A preclinical application of bolus plus constant infusion paradigm of [18F]flumazenil.

INTRODUCTION: We measured the tiagabine-induced enhancement of the GABAA receptor's affinity for benzodiazepine ligands ("GABA shift") using [18F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [18F]FMZ binding were compared to that of [18F]FMZ PET with single bolus injection (SB). MATERIALS AND METHODS: Sprague-Dawley rats underwent [18F]FMZ PET scans with B/I, which consisted of baseline and "GABA shift" sessions in a scan, or scans with SB one week apart. Tiagabine (10mg/kg) was intravenously injected after the baseline session. [18F]FMZ binding potentials (BPND) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BPND changes (%) before and after the tiagabine treatment were also calculated. RESULTS: In PET studies with B/I (Kbol=20min), [18F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [18F]FMZ BPND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BPND change (B/I) and 6-14% BPND change (SB), respectively. In PET studies with SB, a statistically significant increase of [18F]FMZ BPND was found only in the striatum, due to the greater inter-individual variance compared to those with B/I. CONCLUSIONS: Data demonstrated that an [18F]FMZ PET study with B/I (Kbol=20min) is both reliable and sensitive for the assessment of altered GABAA receptor function induced by tiagabine treatment in the rat brain. These results may help to improve the efficiency of the development of new GABA-targeting drugs in the preclinical stage using [18F]FMZ PET.

Comparison of bolus injection and constant infusion methods for measuring muscle protein fractional synthesis rate in humans.

BACKGROUND: The use of stable isotope tracer techniques to measure muscle protein fractional synthesis rate (FSR) has been well established and widely used. The most common method that has been utilized so far is a primed constant infusion (CI) method, which requires 3-4 h of tracer infusion. However, recently our group has developed a bolus injection (BI) method, which requires an injection of bolus of tracer and can be completed within 1 h. In this study, we compared calf (gastrocnemius) muscle protein FSR measured using these two different methods--CI and BI. METHOD: FSRs were measured in eight people (5 men and 3 women; age: 62.3±6.9 years (mean±SD); body weight: 75.4±21.5 kg) at basal, postabsorptive state using L-[ring-2H5]-phenylalanine. In the CI protocol, a primed continuous infusion was given for 4 h, and muscle biopsies were taken at 120 and 240 min; in the BI, a bolus injection of the tracer was given at 0 min and biopsies were taken at 5 and 60 min. Tracer enrichments in blood and muscle tissue were determined by gas chromatography-mass spectrometry. Data are expressed as mean±SE; t-test, linear regression and Levene Median equal variance test analyses were performed. RESULTS: CI FSR was 0.066±0.006%/h, whereas BI FSR was 0.058±0.008%/h, p=NS. The linear regression analysis showed a significant relationship between BI and CI, p=0.038. The intra-class correlation coefficient was 0.83. The standard deviation of the differences in the measurements was 0.015%/h. The Levene Median equal variance test demonstrated no difference in variance between the CI and BI measurements (p=0.722). CONCLUSION: No difference could be detected in calf muscle protein FSR measured by CI and BI methods; the BI method can be used for the measurement of muscle protein FSR in humans.

Conscious sedation/local anesthesia in the office-based surgical and procedural facility.

The safety, efficacy, and rapid recovery of conscious sedation/local anesthesia make this anesthetic technique useful in the ambulatory setting. The care of the sedated patient requires a team effort. The individual role and responsibility of patient, surgeon, anesthesia provider, and nursing staff are discussed. Using data obtained from a series of 1400 consecutive cases, the authors' experience with conscious sedation/local anesthesia is presented. The current technique, using low-dose propofol, is described in detail. Using conscious sedation, the patient's level of consciousness is depressed, but respiratory drive and airway reflexes are maintained and anesthesia is provided by infiltration of local anesthetic.