Pharmacokinetics of midazolam in sevoflurane-anesthetized cats.

OBJECTIVE: To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats. STUDY DESIGN: Prospective pharmacokinetic study. ANIMALS: A group of six healthy adult, female domestic cats. METHODS: Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg-1) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (fR), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO2) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling. RESULTS: The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg-1, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute-1 kg-1, respectively. No significant changes in HR, MAP, fR or Pe'CO2 were observed following midazolam administration. CONCLUSION AND CLINICAL RELEVANCE: In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.

Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone.

OBJECTIVE: To compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. STUDY DESIGN: Prospective, randomized, crossover controlled trial. ANIMALS: A group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation). METHODS: Dogs were allocated to two treatments: LHR (HR: 45-75 beats minute-1) and HHR (HR: 100-130 beats minute-1). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg-1 followed by 0.02-0.10 mg kg-1 hour-1) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 µg kg-1) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05. RESULTS: A three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute-1 kg-1) was 33.2 (24.0-48.0) and 61.3 (44.5-72.7), maximum concentration (ng mL-1) 33.6 (23.4-36.6) and 20.0 (16.7-28.0), apparent volume of the rapid peripheral compartment (mL kg-1) 436 (352-723) and 925 (499-1887), apparent volume at steady state (mL kg-1) 4064 (3453-6546) and 7195 (5077-8601), cardiac index (CI; mL minute-1 m-2) 2.83 (1.98-3.67) and 4.91 (3.22-6.09) and HR (beats minute-1) 68 (49-72) and 120 (102-129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs.

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice.

PURPOSE: To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. METHODS: Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. RESULTS: The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. CONCLUSION: The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs.

Evaluating Clinical Effectiveness and Pharmacokinetic Profile of Atomized Intranasal Midazolam in Children Undergoing Laceration Repair.

BACKGROUND: Atomized intranasal midazolam is a common adjunct in pediatrics for procedural anxiolysis. There are no previous studies of validated anxiety scores with pharmacokinetic data to support optimal procedure timing. OBJECTIVES: We describe the clinical and pharmacokinetic profile of atomized intranasal midazolam in children presenting for laceration repair. METHODS: Children 11 months to 7 years of age and weighing <26 kg received 0.4 mg/kg of atomized intranasal midazolam for simple laceration repair. Blood samples were obtained at 3 time points in each patient, and the data were fit with a 1-compartment model. Patient anxiety was rated with the Observational Scale of Behavioral Distress. Secondary outcomes included use of adjunctive medications, successful completion of procedure, and adverse events. RESULTS: Sixty-two subjects were enrolled, with a mean age of 3.3 years. The median time to peak midazolam concentration was 10.1 min (interquartile range 9.7-10.8 min), and the median time to the procedure was 26 min (interquartile range 21-34 min). There was a trend in higher Observational Scale of Behavioral Distress scores during the procedure. We observed a total of 2 adverse events, 1 episode of vomiting (1.6%) and 1 paradoxical reaction (1.6%). Procedural completion was successful in 97% of patients. CONCLUSIONS: Atomized intranasal midazolam is a safe and effective anxiolytic to facilitate laceration repair. The plasma concentration was >90% of the maximum from 5 to 17 min, suggesting this as an ideal procedural timeframe after intranasal midazolam administration.

Quantification of serum fentanyl concentrations from umbilical cord blood during ex utero intrapartum therapy.

Fetal IM injection of fentanyl is frequently performed during ex utero intrapartum therapy (EXIT procedure). We quantified the concentration of fentanyl in umbilical vein blood. Thirteen samples from 13 subjects were analyzed. Medians and ranges are reported as follows. Weight of the newborn at delivery was 3000 g (2020-3715 g). The dose of fentanyl was 60 µg (45-65 µg). The time between IM administration of fentanyl and collection of the sample was 37 minutes (5-86 minutes). Fentanyl was detected in all of the samples, with a median serum concentration of 14.0 ng/mL (4.3-64.0 ng/mL).

Increase in specific density of levobupivacaine and fentanyl solution ensures lower incidence of inadequate block.

The clinical presentation of a subarachnoid block (SAB) is dependent upon the intrathecal spread of local anesthetic (LA). Intrathecal distribution depends on the chemical and physical characteristics of LA, puncture site, technique used, patient anatomical characteristics and hydrodynamic properties of cerebrospinal fluid. We tried to determine whether a combined glucose/LA solution can render a clinically significant difference in sensory block distribution and motor block intensity.This was a controlled, randomized and double blinded study. The surgical procedures were stripping of the great or small saphenous vein and extirpation of remaining varicose veins. The study included 110 patients distributed into two groups: Hyperbaric (7.5 mg levobupivacaine (1.5 ml 0.5% Chirocaine) + 50 microg Fentanyl (0.5 ml Fentanil) and 1 ml 10% glucose (Pliva)) vs. Hypobaric (7.5 mg levobupivacaine (1.5 ml 0.5% Chirocaine) + 50 microg Fentanyl (0.5 ml Fentanil) and 1 ml 0.9% NaCl (Pliva, Zagreb)) adding to a total volume of 3.5 ml per solution. Spinal puncture was at L3-L4 level. Spinal block distribution was assessed in five minute intervals and intensity of motor block was assessed according to the modified Bromage scale. Pain was assessed with the Visual Analogue Scale. A statistically significant difference in sensory block distribution, motor block intensity and recovery time was established between hyperbaric and hypobaric solutions. By increasing the specific density of anesthetic solution, a higher sensory block, with lesser variability, a diminished influence of Body Mass Index, decreased motor block intensity and faster recovery time may be achieved.

Effects of fadolmidine, an α2 -adrenoceptor agonist, as an adjuvant to spinal bupivacaine on antinociception and motor function in rats and dogs.

α2 -Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2 -adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail-flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co-administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory-motor block and enables a reduction of the doses of both drugs. The results indicate that co-administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

Rate of elimination of γ-hydroxybutyrate from blood determined by analysis of two consecutive samples from apprehended drivers in Norway.

AIM: Gamma-hydroxybutyrate (GHB) is a common drug of abuse with an elimination half-life of 20-45 min. However, there is some evidence that GHB might exhibit saturation kinetics after ingesting high recreational doses. The aim of this study was to investigate the elimination kinetics of GHB from blood in people apprehended by the police for impaired driving and secondary to describe concentrations in all GHB-positive drivers. METHODS: Two consecutive blood samples were taken about 30-40 min apart from N = 16 apprehended drivers in Norway. GHB was determined in blood by an Ultra High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) method. The changes in GHB between the two consecutive blood samples allowed estimating GHB's elimination half-life, assuming first-order and zero-order elimination kinetics. GHB concentrations are also reported for N = 1276 apprehended drivers with GHB in blood. RESULTS: The median time interval between collecting the two blood samples was 36 min (range 20-56 min). The median concentration of GHB in the first blood sample was 56.5 mg/L (range 14.1-142 mg/L) compared with 47.8 mg/L in the second sample (range 9.75-113 mg/L). The median elimination half-life was 103 min (range 21-187 min), and GHB's median zero-order elimination rate constant was 21.0 mg/L/h (range 6.71-45.4 mg/L/h). Back-calculation to the time of driving resulted in GHB concentrations up to 820 mg/L assuming first-order kinetics and up to 242 mg/L assuming zero-order kinetics. In all drivers (N = 1276), the median GHB concentration was 73.7 mg/L and highest was 484 mg/L. CONCLUSION: The elimination half-life of GHB in blood samples from apprehended drivers was longer than expected compared with results of controlled dosing studies. Zero-order kinetics seems a more appropriate model for GHB when concentrations are back-calculated, and the median elimination rate was 21 mg/L/h.

Reservoir based fentanyl transdermal drug delivery systems: effect of patch age on drug release and skin permeation.

PURPOSE: To understand and evaluate the stability and skin permeation profiles of fentanyl reservoir systems as a function of patch age. METHODS: Drug release and skin permeation studies were performed using a modified USP apparatus 5 with a novel sample preparation technique. RESULTS: The amount of fentanyl present in the EVA/adhesive layer (EAL) increased from about 17% of label claim (LC) at 5 months to 25% LC at 22 months. The increase in the drug concentration was mainly observed in the peripheral EAL. Simultaneously, the alcohol content of the patch decreased as a function of patch age. A significant effect of patch age on the drug content in the EAL and the drug release from the system was observed; however, skin permeation studies did not indicate an increase in drug delivery rate. CONCLUSIONS: Novel sample preparation technique with USP Apparatus 5 allowed determination of in vitro skin permeation rates for fentanyl transdermal patches with different designs. Permeation rates with cadaver skin as substrate were found not to change with patch age despite changing drug concentration in the EAL.

Limited sampling strategy in rats to predict the inhibited activities of hepatic CYP3A.

The present study was undertaken in order to evaluate feasibility of a limited sampling strategy (LSS) to predict the systemic clearance of midazolam (MDZ), which is a hepatic CYP3A activity phenotyping probe. Groups of rats pretreated with or without serial doses of ketoconazole, which is a selective inhibitor on CYP3A, were used as training set. Linear regression analysis and a Jack-knife validation procedure were performed based on plasma MDZ concentrations at specific time points after sublingual vein injection of MDZ to establish the most informative LSS equations for accurately estimating the clearance of MDZ. Another group of rats in the same setting was used as the validation set to confirm the individual values of estimated clearance (Clest) that were derived from the predictive equations developed in the training set. LSS that were derived from one, two or three sampling times, namely 90 min, 60-90 min, 30-60-90 min and 30-60-120 min, gave the best correlation and acceptable errors between the values of observed clearance (Clobs) and Clest and were chosen to evaluate hepatic CYP3A activity. Our results supported the hypothesis that using limited plasma sampling is simpler than the usual method of estimating CYP3A phenotyping by predicting the systemic clearance of MDZ when the hepatic activity of CYP3A is reduced in the rat. This experimental design offers opportunities to reduce animal use in the study of drug metabolism.

Modern neuraxial labor analgesia: options for initiation, maintenance and drug selection.

In the present review we outline the state-of-the-art of neuraxial analgesia. As neuraxial analgesia remains the gold standar of analgesia during labor, we review the most recent literature on this topic. The neuraxial analgesia techniques, types of administration, drugs, adjuvants, and adverse effects are investigated from the references. Most authors would agree that central neuraxial analgesia is the best form to manage labor pain. When neuraxial analgesia is administered to the parturient in labor, different management choices must be made by the anesthetist: how will we initiate analgesia, how will analgesia be maintained, which local anesthetic will we use for neuraxial analgesia and which adjuvant drugs will we combine? The present manuscript tries to review the literature to answer these questions.

The effect of intranasal administration of remifentanil on intubating conditions and airway response after sevoflurane induction of anesthesia in children.

BACKGROUND: Intubation without the use of muscle relaxants in children is frequently done before IV access is secured. In this randomized controlled trial, we compared intubating conditions and airway response to intubation (coughing and/or movement) after sevoflurane induction in children at 2 and 3 min after the administration of intranasal remifentanil (4 mcg/kg) or saline. METHODS: One hundred eighty-eight children, 1-7-yr old, were studied. Nasal remifentanil (4 mcg/kg) or saline was administered 1 min after an 8% sevoflurane N2O induction. The sevoflurane concentration was then reduced to 5% in oxygen, and ventilation assisted/controlled. An anesthesiologist blinded to treatment assignment used a validated score to evaluate the conditions for laryngoscopy and response to intubation. Blood samples for determination of remifentanil blood concentrations were collected from 17 children at baseline, 2, 3, 4, and 10 min after nasal administration of remifentanil. RESULTS: Good or excellent intubating conditions were achieved at 2 min (after the remifentanil bolus) in 68.2% and at 3 min in 91.7% of the children who received intranasal remifentanil versus 37% and 23% in children who received placebo (P<0.01). The mean remifentanil plasma concentrations (+/-sd) at 2, 3, 4, and 10 min were 1.0 (0.60), 1.47 (0.52), 1.70 (0.46), and 1.16 (0.36) ng/mL, respectively. Peak plasma concentration was observed at 3.47 min. There were no complications associated with the use of nasal remifentanil. CONCLUSIONS: Nasal administration of remifentanil produces good-to-excellent intubating conditions in 2-3 min after sevoflurane induction of anesthesia.

Midazolam with bupivacaine for improving analgesia quality in brachial plexus block for upper limb surgeries.

OBJECTIVE: To compare the onset, duration and postoperative pain scores of supraclavicular block with bupivacaine alone and bupivacaine-midazolam combination. STUDY DESIGN: Randomized controlled clinical trial. PLACE AND DURATION OF STUDY: The Postgraduate Medical Institute, Hayatabad Medical Complex, Peshawar, from April 2005 to June 2007. METHODOLOGY: A randomized controlled clinical trial was conducted on 50 ASA-I or II adult patients undergoing upper limb surgeries under supraclavicular brachial plexus block. Patients were randomly allocated into two groups of 25 each. Patients in group A were administered 30 ml of 0.5% bupivacaine and those in group B were given 30 ml of 0.5% bupivacaine with midazolam 50 microg x kg-1. Hemodynamic variables (heart rate, noninvasive blood pressure, oxygen saturation), pain scores, rescue analgesic requirements and sedation score were recorded for 24 hours postoperatively, and compared using ANOVA with significance at p <0.05. RESULTS: The onset and duration of sensory and motor block was significantly faster and longer in group B compared to group A (p < 0.001). Pain scores were significantly lower in group B for 24 hours postoperatively (p < 0.001). Demand for rescue analgesic were significantly less in group B. Hemodynamics and sedation scores did not differ between the groups in the studied period. CONCLUSION: Bupivacaine (0.5%) in combination with Midazolam (50 microg x kg-1) quickened the onset as well as prolonged the duration of sensory and motor blockade of the brachial plexus for upper limb surgery. It improved postoperative analgesia without producing any adverse events compared to plain bupivacaine (0.5%) in equal volume.

A preliminary study on plasma concentration achieved following intrapterygomandibular space injection of dexamethasone as a route of drug delivery with lignocaine inferior alveolar nerve block-correlation of clinical effects.

PURPOSE: To determine the quantity of dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone when co-administered with inferior alveolar nerve block correlating with the clinical effects in the postoperative phase. OBJECTIVE: A preliminary prospective study to evaluate the dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone with 2% lignocaine inferior alveolar nerve block to achieve hemi-mandibular anesthesia for minor oral surgical procedures and derive clinical correlations. BACKGROUND: Dexamethasone is a glucocorticoid, chiefly used for the management of postsurgical sequelae like trismus and swelling in maxillofacial surgical practice. Conventionally, parenteral dexamethasone is administered via intravenous or intramuscular route. Intrapterygomandibular space injection is a novel route of steroid delivery described in literature. For minor oral surgical procedures in maxillofacial surgical practice requiring inferior alveolar nerve block, dexamethasone can be administered along with local anesthetic through a single injection as a mixture (twin mix). METHODS: Prospective double-blind randomized clinical trial was designed to evaluative plasma concentration of dexamethasone achieved following injection of a freshly prepared mixture of 1.8 ml of 2% lignocaine with adrenaline (1:200000) and 1 ml (4 mg) dexamethasone [2.8 ml solution of twin mix] in the pterygomandibular space. The 30 candidates included for the trial were randomly split into three study groups (ten each)-(1) control group (C); (2) intramuscular group (IM); (3) intraspace group (IS). RESULTS: The mean plasma dexamethasone concentration at 30 min postinjection in group IM was 226.41 ± 48.67 ng/ml and for IS group it was 209.67 ± 88.13 ng/ml. Post hoc (Bonferroni-Holm test) intergroup comparison for plasma dexamethasone concentration (IM and IS) was found statistically insignificant (P = 0.605). CONCLUSION: Intraspace route of drug administration can be utilized to deliver dexamethasonized local anesthetics safely with predictable clinical effects in the patients requiring mandibular minor oral surgery under local anesthesia.

Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate.

This study assessed the absolute and relative bioavailabilities and transmucosal and gastrointestinal absorbency of fentanyl buccal tablet (FBT) and oral transmucosal fentanyl citrate (OTFC). In a randomized crossover design, 26 healthy subjects received FBT 400 microg (transmucosal), FBT 800 microg (oral), OTFC 800 microg (transmucosal), and fentanyl 400 microg (intravenous). The transmucosal FBT had the highest absolute bioavailability (0.65) compared with the oral FBT (0.31) or transmucosal OTFC (0.47). More fentanyl was absorbed transmucosally from FBT than OTFC (48% vs 22%). Median t(max) values were shorter following the transmucosal FBT (47 minutes) than the oral FBT (90 minutes) or the transmucosal OTFC (91 minutes). Transmucosal administration of FBT compared with dose-normalized OTFC resulted in higher total systemic fentanyl exposure, higher early systemic exposure, and higher C(max). The rate and extent of fentanyl absorption were greater following administration of FBT compared to OTFC. An approximately 30% smaller dose of FBT achieved systemic exposures comparable to OTFC.

Detection of gamma-hydroxybutyrate in striatal microdialysates following peripheral 1,4-butanediol administration in rats.

The illicit use and abuse of 1,4-butanediol (1,4-BD) results from its presumed conversion to gamma-hydroxybutyrate (GHB) and subsequent pharmacological effects via action on GABA-B and GHB-specific receptors. Using in vivo microdialysis we measured the appearance of GHB in the striata of rats after peripheral 1,4-BD administration. We developed and utilized an HPLC-UV (215 nm) detection of GHB that yielded a limit of quantification (S/N=10) of 2.0 micro g/mL (40 ng/injection) and a limit of detection (S/N=3) of 0.75 micro g/mL (15 ng/injection). GHB appeared in the striatal microdialysates within 20 min after intraperitoneal (i.p.) administration of varying doses of 1,4-BD. GHB concentrations reached dose-dependent maxima 80-100 min post-1,4-BD administration, with peak values of 10.6+/-2.9, 25.3+/-3.4 and 48.1+/-7.1 micro g/mL (mean+/-S.E.M.), corresponding to 1,4-BD doses of 250, 500 and 750 mg/kg, respectively. The conversion of 1,4-BD to GHB was completely prevented by the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP), administered prior to 1,4-BD, as evidenced by the failure of GHB to appear in the striatal microdialysates. Sleep times in animals were similarly correlated with GHB concentrations in the microdialysates.

Potential surrogate markers for gamma-hydroxybutyrate administration may extend the detection window from 12 to 48 hours.

The exogenous administration of gamma-hydroxybutyrate (GHB) as a drug of abuse, and especially in date rape sexual assaults, has recently increased. Chromatographic techniques are used to detect GHB in blood or urine, with a window of detection limited to 12 h. This brief window makes the proof of administration problematic in most rape cases. This study is aimed to extend the window of detection through surrogate markers of GHB administration. Microarray technology is used in a DBA/2J mouse model to detect gene expression changes in peripheral blood after GHB exposure at times as long as 96 h post exposure. This study focuses on two of the most significantly altered transcripts, epiregulin and phosphoprotein enriched in astrocytes 15 (Pea-15). Both genes have increased the ribonucleic acid expression (8.5- and 4.6-fold upregulation at 96 h, respectively) in GHB-dosed mice (1 g/kg) as compared with the control. To confirm these results at the protein level, an intracellular flow cytometric assay is developed to detect protein level changes in the peripheral blood of both these potential biomarkers after GHB exposure. These results suggest that after further development, epiregulin and Pea-15 may prove to be significant surrogate markers in the indirect detection of GHB administration.

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CLiv) or in vitro hepatocyte intrinsic clearance (CLint) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed.

Experience with remifentanil in neonates and infants.

Remifentanil is a relatively new synthetic opioid, which is not licensed worldwide for neonates and infants. Because of its unique pharmacokinetic properties with a short recovery profile, it could be the ideal opioid for neonates and infants, who are especially sensitive to respiratory depression by opioids. Therefore, we conducted a MEDLINE search on all articles dealing with the use of remifentanil in this important subgroup of patients. Most experience with remifentanil in neonates and infants is as maintenance anaesthesia during surgery. In approximately 300 neonates and infants, remifentanil proved to be an effective and safely used opioid for this indication. However, very limited data exist on remifentanil for analgesia and sedation of mechanically ventilated paediatric intensive care patients. Further research with remifentanil in neonates and infants should focus on this group of patients because remifentanil, with its very short context-sensitive half-life, could result in shorter extubation times compared with commonly used opioids such as morphine or fentanyl.

Release and Skin Permeation of Scopolamine From Thin Polymer Films in Relation to Thermodynamic Activity.

The object was to demonstrate if the diffusional flux of the drug out of a drug-in-adhesive-type matrix and its subsequent permeation through an excised skin membrane is a linear function of the drug's thermodynamic activity in the thin polymer film. The thermodynamic activity, ap(*), is defined here as the degree of saturation of the drug in the polymer. Both release and release/permeation of scopolamine base from 3 different poylacrylate pressure-sensitive adhesives (PSAs) were measured. The values for ap(*) were calculated using previous published saturation solubilities, wp(s), of the drug in the PSAs. Different rates of release and release/permeation were determined between the 3 PSAs. These differences could be accounted for quantitatively by correlating with ap(*) rather than the concentration of the drug in the polymer films. At similar values for ap(*) the same release or release/permeation rates from the different polymers were measured. The differences could not be related to cross-linking or presence of ionizable groups of the polymers that should influence diffusivity.