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.

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 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.

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.

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.

Treatment of Narcolepsy with Sodium Oxybate While Breastfeeding: A Case Report.

BACKGROUND: Sodium oxybate is used in the treatment of narcolepsy. Currently no published literature supports its safety during breastfeeding, although it has a favorable pharmacokinetic profile for minimizing exposure. MATERIALS AND METHODS: We report a case of a 27-year-old primigravida with narcolepsy who was taking sodium oxybate for symptom control and contacted our Lactation Study Center for advice. Based on our current pharmacokinetic knowledge, she was advised to avoid breastfeeding 4 hours after a dose. RESULTS: Follow-up phone interviews were done and the patient reported that the feeding schedule was manageable, and she was able to exclusively breastfeed for 6 months of her infant's life. Based on pediatric records, her infant's growth and development were excellent. There were no noted side effects of the medication for the infant. CONCLUSIONS: This is the first report to our knowledge of breastfeeding during maternal therapy with sodium oxybate, which appears to be compatible with safe, exclusive breastfeeding when managed appropriately.

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.

Eficacia analgésica y seguridad del citrato de fentanilo oral transmucosa en pacientes intervenidos de miringotomía con drenaje transtimpánico / Analgesic efficacy and safety of oral transmucosal fentanyl citrate in patients undergoing myringotomy with tympanostomy drainage

Objetivo: Evaluar la eficacia y seguridad del citrato de fentanilo oral transmucosa como analgésico, sedante y ansiolítico en pacientes sometidos a miringotomía con drenaje transtimpánico. Material y métodos: Se estudiaron 80 pacientes. Los criterios de inclusión fueron: pacientes > 18 años, con estado funcional ASA I-II, programados para cirugía electiva de miringotomía con drenaje transtimpánico. Los criterios de exclusión fueron: estado físco ASA ≥ III, alergia al citrato de fentanilo oral transmucosa, consumo de inhibidores de la monoaminoxidasa, enfermerdad pulmonar severa y el embarazo. Se dividieron en dos grupos: Grupo A (n = 40) recibió 200 μg citrato de fentanilo oral transmucosa 20 minutos antes del procedimiento. Grupo B (n = 40) recibió placebo 20 minutos antes del procedimiento. Se estudió la presión arterial, la frecuencia cardiaca y la saturación de oxígeno cada 5 minutos. La escala visual analógica fue utilizada para evaluar el dolor. Para evaluar el nivel de sedación se utilizó la escala de Ramsay. Para medir la ansiedad se aplicó Spielberger State-Trait Anxiety Inventory Short Form. También fueron estudiados los efectos secundarios y la satisfacción del paciente. Resultados: La presión arterial y la frecuencia cardiaca tuvo valores más altos en el grupo placebo que en el grupo concitrato de fentanilo oral transmucosa (p < 0,05). El nivel promedio de la analgesia y los niveles de ansiedad eran más bajos en el grupo citrato de fentanilo oral transmucosa que en el grupo placebo (p < 0,05). El grado de sedación fue similar en ambos grupos. La satisfacción fue buena en el 100 % de los pacientes del grupocitrato de fentanilo oral transmucosa frente al 84,62 % en el grupo placebo debido a una mejor analgesia sin diferencia en los efectos secundarios asociados. Conclusiones: El citrato de fentanilo oral transmucosa es un buen analgésico, ansiolítico y sedante en miringotomías con drenaje transtimpánico con un perfil de seguridad excelente (AU)

Objective: To evaluate the efficacy and safety of oral transmucosal fentayl citrate as an analgesic, sedative and anxiolytic in patients undergoing myringotomy with tympanostomy drainage. Materials and methods: 80 patients were studied. Inclusion criteria were: patients > 18 years, ASA I and II undergoing elective myringotomy with tympanostomy drainage. Exclusion criteria were: ASA ≥ III, allergy oral transmucosal fentayl citrate, monoamine oxidase inhibitors consumption, severe lung disease and pregnancy. They were divided into two groups: Group A (n = 40) received 200 μg oral transmucosal fentayl citrate 20 minutes before proceeding. Group B (n = 40) received placebo 20 minutes before the procedure. Blood pressure, heart rate and oxygen saturation every 5 min was studied. The visual analog scale was used to assess pain. For the level of sedation Ramsay scale was used. To measure anxiety Trait Anxiety Inventory Spielberger State-Short Form was applied. They were also studied the side effects and the patient satisfaction. Results: Blood pressure and heart rate had highest values in the placebo group than the group with oral transmucosal fentayl citrate (p < 0,05). The average level of analgesia, anxiety levels were lower in the oral transmucosal fentayl citrate group than in the placebo group (p < 0,05). Sedation was similar in both groups. Satisfaction was good in 100 % of patients in group oral transmucosal fentayl citrate against 84,62 % in the placebo group due to better analgesia with no difference in side effects associated. Conclusions: Oral transmucosal fentayl citrate is a good analgesic, anxiolytic and sedative myringotomy with tympanostomy drain with an excellent safety profile (AU)

Effect of multiple intravenous doses of lanicemine (AZD6765) on the pharmacokinetics of midazolam in healthy subjects.

The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of 46 healthy volunteers were enrolled in the open-label, fixed-sequence, nonrandomized study. All volunteers received an oral dose of 5 mg of midazolam alone or after 6 days of 150 mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma Cmax of 1.51 µg/mL after 150 mg daily dosing to steady state. The geometric mean CL, Vss, and t1/2 of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least-squares mean ratios and 90% confidence intervals for midazolam AUC0- ∞ , and Cmax were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150 mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated.

Estudio comparativo de la efectividad del bloqueo ilioinguinal con dexketoprofeno como coadyuvante anestésico versus administración intramuscular de dexketoprofeno en los pacientes sometidos a hernioplastia inguinal elective / Effectiveness of ilioinguinal blockade with dexketoprofen in comparison to parenteral administration in patients undergoing elective open inguinal hernia repair

Objetivo: Análisis del resultado de la utilización de dexketoprofeno en la solución anestésica del bloqueo ilioinguinal (DKT INC) en comparación con la administración intramuscular (DKT im) en la hernioplastia inguinal electiva. Material y métodos: Estudio prospectivo, aleatorizado con análisis retrospectivo de los resultados de 120 pacientes consecutivos sometidos a hernioplastia inguinal convencional ambulatoria mediante anestesia local y sedación controlada por anestesista. Principales medidas de resultados: Tolerancia al procedimiento, necesidad de dosis suplementarias de propofol, intervalo libre de dolor tras la intervención, consumo diario de analgésicos en la primera semana postoperatoria, puntuación diaria de dolor percibido y recuperación de las actividades de la vida diaria. Resultados: Ambos grupos fueron comparables en relación a edad, sexo y tipo de hernia. El intervalo libre de dolor fue mayor de 12 horas en el 91,6 % del grupo DKT INC. El porcentaje de pacientes que no requirieron analgesia postoperatoria fue de 43,3, 40, 65,0 y 70 % en el grupo de DKT INC en los días 1 a 4 postoperatorio. El análisis de la varianza de medidas repetidas demostró un menor consumo de analgésicos (p = 0,004) y un menor dolor postoperatorio (p = 0,054) sin mostrar influencia en el grado de recuperación de las AVD. Conclusiones: La administración de DKT en la solución anestésica durante el bloqueo ilioinguinal en la hernioplastia inguinal mejora considerablemente el postoperatorio en términos de dolor percibido y consumo de analgésicos en comparación con la administración intramuscular, por lo que debería considerase su inclusión en los protocolos de bloqueo ilioinguinal en la reparación protésica de la hernia inguinal (AU)

Objective: Analysis of dexketorpofen action in anesthetic solution during ilioinguinal blockade in comparison with intramuscular administration in patients undergoing elective inguinal hernia repair. Patients and methods: Prospective, aleatorized with retrospective analysis of 120 consecutive patients undergoing elective open prosthetic inguinal hernia repair in the ambulatory setting with local anaesthesia and anaesthetic monitored sedation. Main results measures: Procedure tolerance, propofol administration requierements, free pain interval after operation, analgesic comsumption , daily pain score and recovery for daily activities where considered. Results: Both groups were similar in terms of age, sex and hernia classification. The pain free interval was grater than 12 hours in 91.6 % on INC DKT. The percentage of patients which didn’t required analgesia was 43.4, 40, 65.0 and 70 % in INC DKT group within postoperative days 1 and 4. ANOVA repeated measures showed a lower comsumption of analgesics (p = 0.004) and less postoperative pai (p = 0.054) but not influence in postoperative recovery. Conclusion: DKT administration in the anaesthetic solution at the time of ilioinguinal blockade increases postoperative recovery in terms of analgesic compsuntion and pain score in comparison with parenteral administration, therefor it should be considered in patients undergoing elective inguinal hernia repair with local anaesthesia (AU)

Prednisone has no effect on the pharmacokinetics of CYP3A4 metabolized drugs - midazolam and odanacatib.

We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2 mg was administered (Day -1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2 mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC(0- ∞) GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC(0-∞) GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day -1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg.

Azone® decreases the buccal mucosal permeation of diazepam in a concentration-dependent manner via a reservoir effect.

The purpose of this study was to examine concentration-dependent effects of Azone® (AZ) on the buccal absorption of diazepam (DIAZ). Porcine buccal mucosa was placed in modified Ussing chambers and pretreated with 10 µL of 0%, 5%, 20%, and 50% (w/v) AZ in ethanol. DIAZ was administered to the donor chamber either in solution or a chitosan-based gel. The donor chamber disappearance, receptor chamber appearance, and tissue retention of DIAZ were monitored over 2 h by HPLC, with AZ tissue disposition also measured by liquid chromatography-mass spectrometry profiling of tissue cryosections. DIAZ steady-state flux values significantly (p < 0.05) decreased 1.4- and 2.4-fold in 20% and 50% AZ-pretreated tissues, respectively. Only 20% and 50% AZ-pretreated tissues were also accompanied by an increased loss of DIAZ from the donor chamber, suggesting DIAZ was forming a reservoir in the buccal mucosa with higher AZ concentrations. Indeed, the percentage of the initial DIAZ dose remaining in the mucosa following a 2 h experiment was increased 3.0-fold with a 50% AZ pretreatment compared with control. AZ provided a concentration-dependent reservoir for DIAZ in buccal mucosa, resulting in retarded release into the receptor chamber, an approach that may be exploited for controlled release of DIAZ.

γ-Hydroxybutyric acid (GHB) is not an agonist of extrasynaptic GABAA receptors.

γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4ß1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4ß1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.

Experimental design in formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances.

With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1 M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195 -220 nm with polydispersity index below 0.15 and zeta potential between -30 and - 60 mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent.

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.