Liquid chromatography-tandem mass spectrometry and confirmation by liquid chromatography-high-resolution mass spectrometry hair tests to evidence use of tizanidine by racing cyclists.

Tizanidine, an imidazoline derivative close to clonidine, is a central alpha-2 adrenergic receptor agonist. Therapeutically, the drug is used as a muscle relaxant under the trade names Sirdalud™ or Zanaflex™. The drug is not prohibited by the World Anti-Doping Agency but, for therapeutic purposes, can only be obtained via a nominative temporary use authorization. The French public health police requested the laboratory to test for tizanidine in head hair specimens collected from international racing cyclists. Using Liquid chromatography-tandem mass spectrometry (LC/MS-MS) and confirmation by liquid chromatography-high-resolution mass spectrometry (LC/HRMS), after pH 9.5 borate buffer overnight incubation of 20 mg and subsequent solvents extraction, tizanidine was identified in the hair of three athletes at 1.1, 3.7, and 11.1 pg/mg. This is the first evidence that tizanidine is incorporated in human hair. However, it was not possible to interpret the data in terms of doses and frequency of use due to a lack of controlled study.

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.

Phase Transition Microemulsion of Brimonidine Tartrate for Glaucoma Therapy: Preparation, Characterization and Pharmacodynamic Study.

Purpose: The aim of this study was to formulate brimonidine tartrate loaded phase transition microemulsions (PMEs), which undergo phase transition from water in oil (W/O) microemulsions to liquid crystalline (LC) and then oil in water (O/W) microemulsions after instilled into the eye and prolong the precorneal residence time and ocular bioavailability for the effective treatment of glaucoma.Methods: The pseudo-ternary phase diagram was developed and various PMEs were prepared using Tween 80 and Span 80 with isopropyl myristate and water. Globule size and shape, physicochemical parameters, in vitro and ex vivo drug release of PMEs were studied. The in vivo anti-glaucoma efficacy of optimized PMEs was studied in an experimental rabbit eyes model and compared with marketed formulation (MF).Results: Globule size of PMEs was found less than 200 nm, which was confirmed by both dynamic light scattering technique and Transmission Electron Microscopy. Physicochemical properties such as pH, refractive index, percentage transparency, viscosity and conductivity were also found in the acceptable ranges. In vitro release studies of PMEs exhibited sustained release property. Ex vivo permeation study also supported the enhanced drug flux through cornea from PMEs as compared with MF. In pharmacodynamic study, a greater reduction in intraocular pressure was seen in PMEs as compared to MF.Conclusion: PMEs as ocular drug delivery system offer a promising approach to enhance the corneal contact, higher permeation and prolonged precorneal retention time in the eye leading to sustained drug release, enhanced bioavailability and patient compliance.

Optimization and Characterization of Brimonidine Tartrate Nanoparticles-loaded In Situ Gel for the Treatment of Glaucoma.

Purposes: The present study aimed to develop brimonidine tartrate loaded poly(lactic-co-glycolic acid) acid vitamin E-tocopheryl polyethylene glycol 1000 succinate (BRT-PLGA-TPGS) nanoparticles in thermosensitivein situ gel to improve mucoadhensive properties and drug holding capacity for the better management of glaucoma.Methods: Nanoparticles was optimized by means of Box-Behnken Design (BBD). The formulations were prepared using various concentration of PLGA (0.1-0.4% w/v) and TPGS (0.3-0.5% w/v). The analytical data of fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) depicted the drug excipients compatibility and confirmed the nanoparticles. Nanoparticles incorporated gel was evaluated for transcorneal permeability, gelation time, gelling temperature, and rheological studies. In addition, in vitro, transcorneal permeation drug release studies and intraocular pressure (IOP) for optimized gel was also performed. Biocompatibility of formulations was investigated in rabbit model.Results: The drug loaded nanoparticles exhibited 115.72 ± 4.18 nm, 0.190 ± 0.02, -11.80 ± 2.24 mV and 74.85 ± 6.54% of mean size, polydispersity index (PDI), zeta potential and entrapment efficiency (% EE), respectively. As compared to marketed eye drop, the sustained and continuous release BRT release from Poloxamer-based in situ gel was 85.31 ± 3.51% till 24 h. The transcorneal steady-state flux (136.32 µg cm-2 h-1) of optimized in situ gel was approximately 3.5 times higher than marketed formulation (38.60 µg cm-2 h-1) flux at 4 h. The optimized formulation produces 3 fold greater influences on percentage reduction of IOP (34.46 ± 4.21%) than the marketed formulation (12.24 ± 2.90%) till 8 h.Conclusion: The incorporation of optimized BRT-PLGA-TPGS nanoparticles into a thermosensitivein situ gel matrix to improve precorneal residence time without causing eye irritation and also serve the sustained release of BRT through cornea for effective management of glaucoma.

A quick approach for medetomidine enantiomer determination in dog plasma by chiral liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study.

In the present study, a rapid, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of medetomidine enantiomers in dog plasma was developed and validated. The separation and individual quantification of chiral compounds can be a tricky task in LC. This is particularly true when target analytes have a relatively small mass, as is the case with medetomidine, a potent and highly specific α2-adrenoceptor agonist widely used in both human and veterinary medicine. The proposed approach is based on a quick liquid-liquid extraction with ethyl acetate and filtration prior to injection. The optimized mobile phase composition allowed to perfectly separate the two enantiomers of medetomidine in a short chromatographic run time, using a cellulose tris(4-methylbenzoate)-based chiral column. A lower limit of quantification of 0.1 ng/mL was reached for both analytes thanks to the high sensitivity and selectivity of MS/MS and the use of racemic medetomidine-d3 as internal standard prevented potential matrix effect. Linearity was satisfying (R2  > 0.99) over the range 0.1-25 ng/mL, as well as within- and between-session accuracy and precision, both always <15%. This method was also applied with success to a series of samples from a pharmacokinetic (PK) study aimed at comparing dex- and levomedetomidine behaviour after administration of the racemic mixture in dogs. The simple extraction procedure, which allows reduced solvent and time consumption without compromising analytical performances, makes this technique a useful tool for this kind of applications even when small animals are involved, due to the small amount of sample required.

Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database.

PURPOSE: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue. METHODS: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication. RESULTS: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported. CONCLUSION: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Ocular and systemic pharmacokinetics of brimonidine and brinzolamide after topical administration in rabbits: comparison between fixed-combination and single-drug formulations.

AIM: The aim of this study was to compare the ocular and systemic absorption of brimonidine (BMD) and brinzolamide (BZM) in rabbits after the topical administration of a fixed-combination ophthalmic suspension of 0.1% BMD tartrate and 1% BZM (FCBB) with that after the administration of the respective single-drug formulations. MATERIALS AND METHODS: Ocular and systemic drug absorption was estimated by determining BMD and BZM concentrations in the aqueous humor, retina/choroid, vitreous body, and blood/plasma by liquid chromatography/tandem mass spectrometry after the administration of FCBB, 0.1% BMD tartrate ophthalmic solution (0.1% BMD), or 1% BZM ophthalmic suspension (1% BZM) to rabbits. RESULTS: In concomitant administration, instilling 0.1% BMD and 1% BZM successively without interval lowered aqueous humor concentrations of both drugs compared to those observed with a 5-min interval. After FCBB administration, BMD and BZM concentrations in the aqueous humor were comparable with those observed after the administration of 0.1% BMD and 1% BZM, whereas BMD concentrations in posterior ocular tissues were equal to or higher than those observed after 0.1% BMD. Plasma BMD concentrations following the administration of FCBB were 0.8-fold lower than those after 0.1% BMD; no remarkable differences were observed in blood BZM concentrations for both formulations. CONCLUSIONS: FCBB achieved drug distribution in the aqueous humor and systemic exposure that were comparable to those for the single-drug formulations. The viscosity of FCBB may increase BMD distribution in the retina/choroid. The administration interval affects ocular drug absorption with the concomitant administration of 0.1% BMD and 1% BZM, which can be overcome by using the fixed-combination of both drugs.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

Effects of serum from breast cancer surgery patients receiving perioperative dexmedetomidine on breast cancer cell malignancy: A prospective randomized controlled trial.

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2 -AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 µg kg-1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937.

A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

Metabolite profiling of guanfacine in plasma and urine of healthy Japanese subjects after oral administration of guanfacine extended-release tablets.

Guanfacine is used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), metabolite profiling of guanfacine was performed in plasma and urine collected from healthy Japanese adults following repeated oral administration of guanfacine extended-release formulation. Unchanged guanfacine was the most abundant component in both plasma and urine (from the MS signal intensity). In plasma, the M3 metabolite (a sulfate of hydroxy-guanfacine) was the prominent metabolite; the M2 metabolite (a glucuronide of a metabolite formed by monooxidation of guanfacine), 3-hydroxyguanfacine and several types of glucuronide at different positions on guanfacine were also detected. In urine, the M2 metabolite and 3-hydroxyguanfacine were the principal metabolites. From metabolite analysis, the proposed main metabolic pathway of guanfacine is monooxidation on the dichlorobenzyl moiety, followed by glucuronidation or sulfation. A minor pathway is glucuronidation at different positions on guanfacine. As the prominent metabolites in plasma were glucuronide and sulfate of hydroxyguanfacine, which have no associated toxicity concerns, further toxicity studies of the metabolites, for example in animals, were not deemed necessary.

Study of the in vitro metabolic profile of a new α2-adrenergic agonist in rat and human liver microsomes by using liquid chromatography-multiple-stage mass spectrometry and nuclear magnetic resonance.

A potent synthetic α2-adrenergic agonist called PT-31, (3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione), was recently detected as a potential drug to be used as an adjuvant drug to treat chronic pain. The excellent pharmacological property of PT-31 highlights the importance in elucidating its metabolism, which could provide valuable information about its metabolite profile for further pharmacokinetics studies and additionally to estimate the impact of its metabolites on the efficacy, safety and elimination of PT-31. In this work, the study of the in vitro metabolism of PT-31 was initially carried out by using a liquid chromatography coupled to ion trap multiple-stage mass spectrometer (LC-IT-MSn) and a hybrid triple quadrupole/linear ion trap mass spectrometer (LC-QTrap). The production of at least three unknown oxidative metabolites was observed. Structural identification of the unknown metabolites was carried out by combination of LC-MS experiments, including selected reaction monitoring (SRM) and multi-stage full scan experiments. Further analysis of 1H-NMR led to the structural confirmation of the major metabolite. The results indicated that PT-31 was metabolized by a hydroxylation reaction in the imidazolidine-2,4-dione ring in rat and human liver microsomes, producing the metabolite 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4-dione in rat liver microsomes. A carbon hydroxylation onto the benzyl ring, produced two other minor metabolites of the PT-31 in rat liver microsomes.

Effect of Ultra-Small Chitosan Nanoparticles Doped with Brimonidine on the Ultra-Structure of the Trabecular Meshwork of Glaucoma Patients.

Brimonidine, an anti-glaucoma medicine, acts as an adrenergic agonist which decreases the synthesis of aqueous humour and increases the amount of drainage through Schlemm's canal and trabecular meshwork, but shows dose-dependent (0.2% solution thrice daily) toxicity. To reduce the side effects and improve the efficacy, brimonidine was nanoencapsulated on ultra-small-sized chitosan nanoparticles (nanobrimonidine) (28 ± 4 nm) with 39% encapsulation efficiency, monodispersity, freeze-thawing capability, storage stability, and 2% drug loading capacity. This nanocomplex showed burst, half, and complete release at 0.5, 45, and 100 h, respectively. Nanobrimonidine did not show any in vitro toxicity and was taken up by caveolae-mediated endocytosis. The nanobrimonidine-treated trabeculectomy tissue of glaucoma patients showed better dilation of the trabecular meshwork under the electron microscope. This is direct evidence for better bioavailability of nanobrimonidine after topical administration. Thus, the developed nanobrimonidine has the potential to improve the efficacy, reduce dosage and frequency, and improve delivery to the anterior chamber of the eye.

Pharmacokinetics and Pharmacodynamics of Immediate-Release Versus Extended-Release Guanfacine in Adult Daily Smokers.

BACKGROUND: Guanfacine is Food and Drug Administration approved for hypertension and attention-deficit hyperactivity disorder and has been used off-label for migraine prophylaxis, heroin withdrawal, and more recently smoking cessation. Previous studies have shown positive effects of 3 mg/d of immediate-release (IR) guanfacine on smoking outcomes, but the dose equivalency of the IR and extended-release (ER) formulations is unknown. PROCEDURES: A within-subject design was used to compare the pharmacokinetics and pharmacodynamics of 3 mg/d of IR, 4 mg/d of ER, and 6 mg/d of ER guanfacine in adult daily smokers (n = 5). Plasma medication levels, vital signs, cigarettes per day, tobacco craving, and adverse events were assessed. Medication was titrated to stable dosing after each laboratory day (3 mg/d IR, then 4 mg/d ER, then 6 mg/d ER). RESULTS: Plasma medication levels did not differ between the 3 mg/d of IR and 4 mg/d of ER doses after 24 hours from last dose and were highest at the 6 mg/d of ER dose (3 mg/d IR: M = 3.40 ng/mL, SE = 0.34 vs 4 mg/d ER: M = 3.46 ng/mL, SE = 0.67 vs 6 mg/d ER: M = 5.92 ng/mL, SE = 1.02). All doses of guanfacine decreased heart rate and blood pressure from baseline. Absolute values of cigarettes per day (6 mg/d ER) and tobacco craving (4 and 6 mg/d ER) were lowest with the ER formulations. Treatment-emergent adverse events were subject rated as minimal to mild, except dry mouth. CONCLUSIONS: We demonstrated similar pharmacokinetic profiles between 3 mg/d of IR guanfacine and 4 mg/d of ER guanfacine, as hypothesized. All doses of guanfacine were well tolerated.

Low-dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials.

BACKGROUND: The aim of this study was to provide an integrated analysis of safety and efficacy data for brimonidine tartrate ophthalmic solution 0.025 per cent (low-dose; Bausch & Lomb Incorporated), a topical vasoconstrictor for relief of ocular redness. METHODS: Integrated efficacy data from two randomised, double-masked, vehicle-controlled studies in subjects with ocular redness as well as safety data from the two efficacy studies, a vehicle-controlled safety study, and a pharmacokinetic study were analysed. Efficacy outcomes analysed included investigator-assessed ocular redness (scale, 0-4) before treatment instillation and at five to 240 minutes post-instillation on Day 1, at five minutes post-instillation on Days 15 and 29, and one week after treatment discontinuation (Day 36), and redness self-assessed by subjects recorded daily in diaries. Safety assessments included adverse events, ophthalmic examinations, and rebound redness upon treatment discontinuation. Drop comfort (scale, 0-10) was a tolerability measure. RESULTS: The efficacy population included 117 subjects (brimonidine, n = 78; vehicle, n = 39). The safety population included 635 subjects (brimonidine, n = 426; vehicle, n = 209). Investigator-assessed ocular redness was significantly lower with brimonidine versus vehicle at all post-instillation time points on Day 1 (mean change from pre-instillation of -1.4 units for brimonidine and -0.2 units for vehicle; p < 0.0001). Subject-assessed ocular redness was also significantly lower with brimonidine versus vehicle (mean treatment difference in average daily ratings of -0.9; p < 0.0001). There was no evidence of tachyphylaxis through Day 29 and rebound redness was rare. Incidence of ocular adverse events was low, the most common being reduced visual acuity (brimonidine, 4.0 per cent; vehicle, 4.3 per cent) and conjunctival hyperaemia (2.6 and 2.9 per cent, respectively). Both brimonidine and vehicle were rated as very comfortable (mean post-instillation scores, 0.4-0.5). CONCLUSION: In this integrated analysis, low-dose brimonidine significantly reduced ocular redness with no tachyphylaxis, and minimal rebound redness, and was generally safe and well tolerated.

The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: A clinical trial.

OBJECTIVES: Dexmedetomidine, a highly selective central α2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. METHODS: 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 µg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0. RESULTS: Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068±0.0017 vs. 0.0102±0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43±0.58 vs. 2.02±0.84 L/kg; P = 0.041). CONCLUSIONS: This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients.

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. METHODS: Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. RESULTS: A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. CONCLUSIONS: Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers.

AIMS: Alpha-2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer-controlled dexmedetomidine infusion in healthy volunteers. METHODS: After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibres were blocked with a brachial plexus block. Volunteers received a dexmedetomidine target-controlled infusion for 15 min, to a target concentration of 0.3 ng ml-1 . Arterial blood samples were collected during and for 60 min after dexmedetomidine infusion for PK analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was carried out using nonlinear mixed-effect models. RESULTS: We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3 ng ml-1 over the 15-min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. A three-compartment model provided a better fit to the data than a two-compartment model. CONCLUSIONS: We found that dexmedetomidine-induced vasoconstriction is concentration dependent over time. Dexmedetomidine PK were best estimated by a three-compartment model with allometric scaling. Our results may contribute to future modelling of dexmedetomidine-induced haemodynamic effects.

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine.

Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug's peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

Pharmacokinetics and selected pharmacodynamics of romifidine following low-dose intravenous administration in combination with exercise to quarter horses.

Romifidine is an alpha-2 adrenergic agonist used for sedation and analgesia in horses. As it is a prohibited substance, its purported use at low doses in performance horses necessitates further study. The primary goal of the study reported here was to describe the serum concentrations and pharmacokinetics of romifidine following low-dose administration immediately prior to exercise, utilizing a highly sensitive liquid chromatography-tandem mass spectrometry assay that is currently employed in many drug testing laboratories. An additional objective was to describe changes in heart rate and rhythm following intravenous administration of romifidine followed by exercise. Eight adult Quarter Horses received a single intravenous dose of 5 mg (0.01 mg/kg) romifidine followed by 1 h of exercise. Blood samples were collected and drug concentrations measured at time 0 and at various times up to 72 h. Mean ± SD systemic clearance, steady-state volume of distribution and terminal elimination half-life were 34.1 ± 6.06 mL/min/kg and 4.89 ± 1.31 L/kg and 3.09 ± 1.18 h, respectively. Romifidine serum concentrations fell below the LOQ (0.01 ng/mL) and the LOD (0.005 ng/mL) by 24 h postadministration. Heart rate and rhythm appeared unaffected when a low dose of romifidine was administered immediately prior to exercise.