Hemodynamic and pharmacokinetic analysis of oxymetazoline use during nasal surgery in children.

OBJECTIVES/HYPOTHESIS: Oxymetazoline is an α-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures. STUDY DESIGN: Prospective trial. METHODS: Children ages 2 to 17 years undergoing functional endoscopic sinus surgery, turbinate resection, or adenoidectomy were enrolled. The surgeon placed oxymetazoline-soaked pledgets (1.5 mL of 0.05% solution) according to our usual clinical practice. Blood samples for oxymetazoline assay were drawn at 5, 10, 20, 45, 90, and 150 minutes, and hemodynamic data were recorded at 5-minute intervals. Data analysis included mixed-effects regression and population pharmacokinetic/pharmacodynamic modeling. RESULTS: The analysis included 27 patients, age 7 ± 4 years, who received between 2 and 12 pledgets (3-18 mL) of oxymetazoline. Relative bioavailability compared to the spray formulation was 2.3 (95% confidence interval [CI]: 1.6-3.2), with slow absorption from the mucosal surface (absorption half-life 64 minutes; 95% CI: 44-90). Mean arterial pressure did not increase with oxymetazoline instillation at the observed oxymetazoline serum concentrations (0.04-7.6 µg/L). CONCLUSIONS: Despite concerns regarding oxymetazoline administration to mucosal membranes, we found that hemodynamic changes were clinically negligible with our usual clinical use of pledgets soaked in oxymetazoline. Compared to data on oxymetazoline in spray formulation, bioavailability was increased twofold with pledgets, but systemic absorption was very slow, contributing to low serum concentrations and limited hemodynamic effects. LEVEL OF EVIDENCE: 1b. Laryngoscope, 129:2775-2781, 2019.

Vasoplegia treatments: the past, the present, and the future.

Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

Clinical Pharmacokinetics of Oxymetazoline Cream Following Topical Facial Administration for the Treatment of Erythema Associated With Rosacea.

BACKGROUND: Oxymetazoline cream 1.0% is FDA-approved for the topical treatment of persistent facial erythema associated with rosacea in adults. This phase 2, multicenter, randomized, double-blind, parallel-group study assessed the pharmacokinetics, safety, and tolerability of oxymetazoline in patients with moderate to severe erythema associated with rosacea. METHODS: Eligible patients were randomized to 1 of 8 treatment groups (oxymetazoline cream 0.5%, 1.0%, or 1.5% or vehicle applied topically either once or twice daily for 28 days). Pharmacokinetic analyses were conducted in patients receiving oxymetazoline. Plasma samples for pharmacokinetic assessments were collected prior to dosing and 6 times postdose on days 1 and 28. RESULTS: A total of 356 patients were included in the safety population (oxymetazoline, n=268; vehicle, n=88). Thirty patients (11.2%) in the oxymetazoline group reported treatment-related treatment-emergent adverse events, most of which were mild to moderate application-site reactions. Oxymetazoline, at all concentrations, was generally safe and well tolerated. Mean maximum observed plasma concentrations were ≤115 pg/mL across all groups; the highest mean values for area under the plasma concentration-time curve from time 0 to 24 hours following once- and twice-daily administration of oxymetazoline 1.5% were 1680 pg•h/mL and 2660 pg•h/mL, respectively. Systemic exposure to oxymetazoline increased dose proportionally with once- and twice-daily administration. CONCLUSION: These findings support the use of oxymetazoline for the treatment of persistent facial erythema associated with rosacea. J Drugs Dermatol. 2018;17(2):213-220.

Role of Topical Oxymetazoline for Management of Erythematotelangiectatic Rosacea.

OBJECTIVE: To review and summarize topical oxymetazoline's pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with erythematotelangiectatic rosacea. DATA SOURCES: Literature searches of MEDLINE (1975 to September 2017), International Pharmaceutical Abstracts (1975 to September 2017), and Cochrane Database (publications through September 2017) using the terms rosacea, persistent redness, α -agonist, and oxymetazoline. STUDY SELECTION AND DATA EXTRACTION: Results were limited to studies of human subjects, English-language publications, and topical use of oxymetazoline. Relevant materials from government sources, industry, and reviews were also included. DATA SYNTHESIS: Data support the efficacy of oxymetazoline for persistent facial redness. Little study beyond clinical trials cited in the drug approval process has been conducted. Current data suggest that oxymetazoline is similar in safety and efficacy to brimonidine. Head-to-head comparisons of topical α-agonists for erythema caused by rosacea are needed. CONCLUSION: The topical α-agonist, oxymetazoline, is safe and effective for reducing persistent facial redness associated with erythematotelangiectatic subtype of rosacea. Health care practitioners selecting among treatments should consider not only the subtype of rosacea but also individual patient response, preference, and cost.

Use of biopartitioning micellar chromatography and RP-HPLC for the determination of blood-brain barrier penetration of α-adrenergic/imidazoline receptor ligands, and QSPR analysis.

For this study, 31 compounds, including 16 imidazoline/α-adrenergic receptor (IRs/α-ARs) ligands and 15 central nervous system (CNS) drugs, were characterized in terms of the retention factors (k) obtained using biopartitioning micellar and classical reversed phase chromatography (log kBMC and log kwRP, respectively). Based on the retention factor (log kwRP) and slope of the linear curve (S) the isocratic parameter (φ0) was calculated. Obtained retention factors were correlated with experimental log BB values for the group of examined compounds. High correlations were obtained between logarithm of biopartitioning micellar chromatography (BMC) retention factor and effective permeability (r(log kBMC/log BB): 0.77), while for RP-HPLC system the correlations were lower (r(log kwRP/log BB): 0.58; r(S/log BB): -0.50; r(φ0/Pe): 0.61). Based on the log kBMC retention data and calculated molecular parameters of the examined compounds, quantitative structure-permeability relationship (QSPR) models were developed using partial least squares, stepwise multiple linear regression, support vector machine and artificial neural network methodologies. A high degree of structural diversity of the analysed IRs/α-ARs ligands and CNS drugs provides wide applicability domain of the QSPR models for estimation of blood-brain barrier penetration of the related compounds.

Comparative Clinical Pharmacokinetics of Midodrine and Its Active Metabolite Desglymidodrine in Cirrhotic Patients with Tense Ascites Versus Healthy Volunteers.

OBJECTIVE: Midodrine is an α-agonist prodrug of desglymidodrine used for the management of hypotension, and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites. The objective of the present work was to study the clinical pharmacokinetic parameters of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites, which may help in dose selection and improve treatment outcome. METHOD: This was a prospective, open-label, single-dose, parallel-group study. At first, a pilot study was performed on one healthy volunteer by taking serial blood samples at scheduled time intervals to validate the method of analysis and sampling times. The full study was then conducted by selecting 12 cirrhotic patients with tense ascites in one group and taking nine blood samples. We also selected five healthy volunteers as the control group and took 11 blood samples. RESULTS: Statistically significant differences were observed between the healthy volunteer group and the patients group in the area under the concentration versus time curve (AUC0-t) and maximum plasma concentration (Cmax) values of midodrine and desglymidodrine. Based on the results of the pharmacokinetic analysis, the patient group was further subdivided into those receiving the interacting drug ranitidine (five patients) and those not receiving the interacting drug (seven patients). CONCLUSIONS: Pharmacokinetic parameters of midodrine can differ significantly in cirrhotic patients with tense ascites from those in healthy individuals. Drug monitoring, dose adjustments, and drug-drug interactions should all be considered during therapy in this vulnerable patient group.

Analgesic synergy between opioid and α2 -adrenoceptors.

UNLABELLED: Opioid and α2 -adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2 -adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2 -adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both µ and δ opioid receptors can produce synergy with α2 -adrenoceptor agonists and that α2 -adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid-adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Optimal treatment of anaphylaxis: antihistamines versus epinephrine.

Anaphylaxis is a rapid, systemic, often unanticipated, and potentially life-threatening immune reaction occurring after exposure to certain foreign substances. The main immunologic triggers include food, insect venom, and medications. Multiple immunologic pathways underlie anaphylaxis, but most involve immune activation and release of immunomodulators. Anaphylaxis can be difficult to recognize clinically, making differential diagnosis key. The incidence of anaphylaxis has at least doubled during the past few decades, and in the United States alone, an estimated 1500 fatalities are attributed to anaphylaxis annually. The increasing incidence and potentially life-threatening nature of anaphylaxis coupled with diagnostic challenges make appropriate and timely treatment critical. Epinephrine is universally recommended as the first-line therapy for anaphylaxis, and early treatment is critical to prevent a potentially fatal outcome. Despite the evidence and guideline recommendations supporting its use for anaphylaxis, epinephrine remains underused. Data indicate that antihistamines are more commonly used to treat patients with anaphylaxis. Although histamine is involved in anaphylaxis, treatment with antihistamines does not relieve or prevent all of the pathophysiological symptoms of anaphylaxis, including the more serious complications such as airway obstruction, hypotension, and shock. Additionally, antihistamines do not act as rapidly as epinephrine; maximal plasma concentrations are reached between 1 and 3 hours for antihistamines compared with < 10 minutes for intramuscular epinephrine injection. This demonstrates the need for improved approaches to educate physicians and patients regarding the appropriate treatment of anaphylaxis.

Delay and stability of central venous administration of norepinephrine in children: a bench study.

UNLABELLED: In children, because of the dead volume of the central venous catheter (CVC) and the low flow rate of norepinephrine (NE) infusion, the delay between start-up and effective administration can be adversely long. A theoretical calculation enables to estimate the delay and variations of effective administration. However, numerous factors can hinder this theoretical approach. Herein, we measured via bench testing the actual delay and stability of NE administration kinetics. Using an assembly reproducing our currently-implemented catecholamine administration protocol, diluted NE (200 µg ml(-1)) was infused at an initial rate of 2 ml h(-1) (theoretically 6.67 µg min(-1)) for a period of 24 h. An assay measuring the amount of NE (µg) exiting the CVC was conducted by high-pressure liquid chromatography with colorimetric detection. The theoretical calculation of the delay in administered NE, taking into account a CVC dead volume of 0.3 ml, was 9 min. The measured percentage of the administered dose as a function of time in minutes (M) was M0-M3 (0 %), M3-M6 (0 %), M6-M9 (13 %), M9-M12 (28 %), M12-M15 (70 %), and M15-M18 (100 %) The amount of NE (µg) at fixed rate (2 ml h(-1)) was established at 6.9 ± 0.4 µg min(-1) during the 24 h. CONCLUSION: Continuous NE infusion via a CVC at low rate is stable. In children, because of CVC dead volume and low flow rate infusion, the delay in achieving intended dose delivery is significantly longer than that estimated by theoretical calculation. New modalities of initiation of catecholamine infusion adapted to the child are warranted.

A review of analgesic compounds used in food animals in the United States.

Extralabel drug use for pain relief in the United States is regulated under the Animal Medicinal Drug Use Clarification Act. Agents that may provide analgesia in livestock include local anesthetics, nonsteroidal antiinflammatory drugs, opioids, α2-agonists, and N-methyl-d-aspartate receptor antagonists. The challenges associated with providing pain relief in food animals and the salient pharmacokinetic and pharmacodynamic features of the analgesic compounds that could potentially be used in livestock are reviewed. The potential use of novel agents such as bicarbonate, magnesium, ethanol, and gabapentin to augment analgesia is also discussed.

Absorption characteristics of epidural levobupivacaine with adrenaline and clonidine in children.

AIM: To determine if the addition of adrenaline, clonidine, or their combination altered the pharmacokinetic profile of levobupivacaine administered via the caudal epidural route in children. METHODS: Children aged <18 years old scheduled to undergo sub-umbilical surgery were administered caudal levobupivacaine plain 2.5 mg · ml(-1) or with adjuvants adrenaline 5 mcg · ml(-1) or clonidine 2 mcg · ml(-1) or their combination. Covariate analysis included weight and postnatal age (PNA). Time-concentration profile analysis was undertaken using nonlinear mixed effects models. A one-compartment linear disposition model with first-order input and first-order elimination was used to describe the data. The effect of either clonidine or adrenaline on absorption was investigated using a scaling parameter (Fabs(CLON), Fabs(ADR)) applied to the absorption half-life (Tabs). RESULTS: There were 240 children (median weight 11.0, range 1.9-56.1 kg; median postnatal age 16.7, range 0.6-167.6 months). Absorption of levobupivacaine was faster when mixed with clonidine (Fabs(CLON) 0.60; 95%CI 0.44, 0.83) but slower when mixed with adrenaline (Fabs(ADR) 2.12; 95%CI 1.45, 3.08). The addition of adrenaline to levobupivacaine resulted in a bifid absorption pattern. While initial absorption was unchanged (Tabs 0.15 h 95%CI 0.12, 0.18 h), there was a late absorption peak characterized by a Tabs(LATE) 2.34 h (95%CI 1.44, 4.97 h). The additional use of clonidine with adrenaline had minimal effect on the bifid absorption profile observed with adrenaline alone. Neither clonidine nor adrenaline had any effect on clearance. The population parameter estimate for volume of distribution was 157 l 70 kg(-1). Clearance was 6.5 l · h(-1) 70 kg(-1) at 1-month PNA and increased with a maturation half-time of 1.6 months to reach 90% of the mature value (18.5 l · h(-1) 70 kg(-1)) by 5 months PNA. CONCLUSIONS: The addition of adrenaline decreases the rate of levobupivacaine systemic absorption, reducing peak concentration by half. Levobupivacaine concentrations with adrenaline adjuvant were reduced compared to plain levobupivacaine for up to 3.5 hours. Clonidine as an adjuvant results in faster systemic absorption of levobupivacaine and similar concentration time profile to levobupivacaine alone. Adding adrenaline with clonidine does not alter the concentration profile observed with adrenaline alone.

Revisiting clonidine: an innovative add-on option for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity and impulsivity. Although much evidence supports the use of psychostimulants as a first-line treatment in children and adolescents, up to 30% of patients may have an inadequate response to these medications. For these patients, addition of an α2-adrenoceptor agonist can further improve ADHD symptoms. The α2-adrenoceptor agonists may work in a synergistic fashion with stimulants through regulation of prefrontal cortex function. Early studies were completed with immediate-release clonidine (CLON-IR), which requires multiple daily doses and achieves a higher maximum concentration more rapidly than the more recently developed extended-release clonidine (CLON-XR). Pharmacokinetic properties of CLON-XR may be responsible for differences in efficacy and tolerability between the CLON-IR and CLON-XR formulations. Recent double-blind, placebo-controlled trials have shown that extended-release α2-adrenoceptor agonists are safe and effective, both as monotherapy and as adjunctive treatment with stimulants. This review will focus on clonidine used in conjunction with stimulants to optimize treatment of ADHD.

Review article: Dexmedetomidine in children: current knowledge and future applications.

More than 200 studies and reports have been published regarding the use of dexmedetomidine in infants and children. We reviewed the English literature to summarize the current state of knowledge of this drug in children for the practicing anesthesiologist. Dexmedetomidine is an effective sedative for infants and children that only minimally depresses the respiratory system while maintaining a patent airway. However, dexmedetomidine does depress the cardiovascular system. Specifically, bradycardia, hypotension, and hypertension occur to varying degrees depending on the age of the child. Hypertension is more prevalent when larger doses of dexmedetomidine are given to infants. Consistent with its 2-hour elimination half-life, recovery after dexmedetomidine may be protracted in comparison with other sedatives. Dexmedetomidine provides and augments analgesia and diminishes shivering as well as agitation postoperatively. The safety record of dexmedetomidine suggests that it can be used effectively and safely in children, with appropriate monitoring and interventions to manage cardiovascular sequelae.

Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes.

Synephrine is a natural compound, frequently added to ephedra-free dietary supplements for weight-loss, due to its effects as a nonspecific adrenergic agonist. Though only p-synephrine has been documented in plants, the presence of m-synephrine has also been reported in weight-loss products. The use of synephrine in dietary supplements was accompanied by reports of adverse effects, especially at the cardiovascular level. It is well known that the imbalance in cardiac glutathione levels can increase the risk of cardiomyopathy. The present work aimed to study the role of organic cation-mediated transport of m- and p-synephrine and the possibility that p- and m-synephrine induce intracellular changes in glutathione levels in calcium-tolerant freshly isolated cardiomyocytes from adult rat. After a 3 h incubation with 1 mM p- or m-synephrine, the intracellular content of synephrine was measured by gas chromatography/ion trap-mass spectrometry (GC/IT-MS); cell viability and intracellular glutathione levels were also determined. To evaluate the potential protective effects of antioxidants against the adverse effects elicited by m-synephrine, cells were pre-incubated for 30 min with Tiron (100 µM) or N-acetyl-cysteine (NAC) (1 mM). To assess the influence of α(1)-adrenoceptors activation in glutathione depletion, a study with prazosin (100 nM) was also performed. The results obtained provide evidence that organic cation transporters OCT3 and OCT1 play a major role in m- and p-synephrine-mediated transport into the cardiomyocytes. The importance of these transporters seems similar for both isomers, although p-synephrine enters more into the cardiomyocytes. Furthermore, only m-synephrine induced intracellular total glutathione (GSHt) and reduced glutathione (GSH) depletion. NAC and Tiron were able to counteract the m-synephrine-induced GSH and GSHt decrease. On the other hand, the incubation with prazosin was not able to change m-synephrine-induced glutathione depletion showing that this effect is independent of α(1)-adrenoceptor stimulation. In conclusion, both positional isomers require OCT3 and OCT1-mediated transport to enter into the cardiomyocytes; however, the hydroxyl group in the p-position favours the OCT-mediated transport into cardiomyocytes. Furthermore, the structural isomerization of synephrine influences its toxicological profile since only m-synephrine caused GSH depletion.

Oral bioavailability of clonidine in children.

BACKGROUND: Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75-100% but is unknown in children. METHODS: Children (3-10 years) undergoing adenotonsillectomy were administered oral clonidine 4 mcg·kg(-1) mixed with apple fruit drink as premedication. Intravenous plasma was assayed for clonidine concentration at 5, 15, 30, 45 min and 1, 2, 4, 6, 12, 18 h after administration. Clonidine plasma concentrations were determined by liquid chromatography-mass spectroscopy, and pharmacokinetic parameters were calculated using nonlinear effects mixed-effects models. Current data were pooled with published time-concentration profiles from children (n = 49) administered intravenous clonidine to determine oral bioavailability. RESULTS: There were eight children studied (age 3-10 years, weight 10.5-36 kg). A two-compartment model with first-order absorption and elimination was used to describe time-concentration profiles. Population parameter estimates (CV%; 95% CI), standardized to a 70-kg person, were absorption half-life (Tabs), 0.45 (85.1; 0.221-0.884) h, absorption lag time (Tlag), 0.148 (91.2; 0.002-0.316) h, Clearance (CL) 17.9 (30.3; 16-20.3) l·h(-1) per 70 kg, between compartment clearance (Q) 121 (44.3; 80.1-165) l·h(-1) per 70 kg, central volume (V1) 81.2 (71.5; 60.7-105) l·70 kg(-1), peripheral volume of distribution (V2) 113 (33.9; 91-131) l·70 kg(-1). The oral bioavailability was 55.4% (CV 6.4%; 95% CI 0.469, 0.654). CONCLUSIONS: Clonidine administered with an apple fruit drink displays a variable and relatively slow absorption after oral administration (T(max) 1.04 h, C(max) 0.77 mcg·l(-1)). The oral bioavailability was 55.4%, which is less than reported in adults. Consequently, higher oral doses of clonidine (per kg) are required when this formulation is used to achieve concentrations similar to those reported in adults.

Single dose bioequivalence study of alpha-methyldopa tablet formulations using a modified HPLC method.

BACKGROUND AND OBJECTIVE: The purpose of the present study was to compare the bioavailability of a new methyldopa (CAS 555-30-6) tablet formulation with that of a reference formulation in 12 healthy male subjects using a modified HPLC method. METHODS: The study was designed as an open label, single-dose, randomized study with a cross-over design. Under fasting conditions, each subject received one 250-mg tablet orally as a single dose of a test or reference formulation on two treatment days. The treatment periods were separated by a one-week washout period. The blood samples were collected at different time points after each administration and determined using a rapid and reliable modified HPLC method. The method used was validated for specificity, accuracy, precision and sensitivity. The pharmacokinetic parameters (Cmax, AUC0-t, AUC0-infinity) were statistically compared by analysis of variance (ANOVA) for test and reference formulations. RESULTS AND DISCUSSION: All validation criteria for the developed HPLC method were in acceptable range. The maximum plasma concentration (Cmax) of alpha-methyldopa was 270.3-1864.9 ng/ml for the test and 224.5-1585.6 ng/ml for the reference formulation. The mean AUC0-infinity of alpha-methyldopa was 2002.1-10614.8 and 2076.8- 9056.3 ng x h/ml for the test and reference formulation, respectively. The calculated 90% confidence intervals for the mean test/reference ratios of mentioned parameters were 92.48-115.94, and 88.82-101.13 which are in the bioequivalence range. The statistical tests did not show any statistical differences between formulations suggesting that methyldopa tablet of test and reference can be considered as bioequivalent preparations. CONCLUSION: A rapid and reliable HPLC method with fluorescence detector was developed to analyze alpha-methyldopa in human plasma. Based on the obtained results the test formulation of alpha-methyldopa is bioequivalent to the reference formulation.