An UPLC-MS/MS Method for Simultaneous Determination of Tropicamide and Phenylephrine in Rabbit Ocular Tissues and Plasma.

Purpose: Mixed eye drops containing 0.5% tropicamide and 0.5% phenylephrine are commercially available for cycloplegic refraction. Determining the pharmacokinetics (PK) and distribution of tropicamide and phenylephrine simultaneously in ocular tissues is an important but challenging issue. Herein, we developed a sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of tropicamide and phenylephrine concentrations in rabbit ocular tissues and plasma. Methods: The two analytes were extracted with ethyl acetate using etofesalamide as an internal standard and separated using a chromatographic C8 column with isocratic elution. Mass spectrometry analysis was performed with positive electrospray ionization and data were acquired in a multiple reaction monitoring mode. Results: We validated this method over a concentration range of 5-1,600 ng/mL for tropicamide and 1-320 ng/mL for phenylephrine in ocular tissues, as well as 0.5-64 ng/mL for both compounds in plasma. Inter- and intraday precisions in all samples were both <12.9% and the accuracy was within 92.1%-108.4%. The highest concentration of tropicamide was found in aqueous humor (Cmax: 29430 ng/g), while was in cornea for phenylephrine (Cmax: 3465 ng/g). All the ocular tissues concentrations were much higher than those of blood. Conclusion: This UPLC-MS/MS method allowed us to determine the PK and distribution of tropicamide and phenylephrine in rabbit ocular tissue, which may be helpful in the future development and application of mydriatic agents.

Pre-column derivatization method for determining phenylephrine in human plasma and its application in a pharmacokinetic study.

In the present study, a rapid derivatization liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to evaluate phenylephrine in human plasma. The plasma samples were processed to precipitate the proteins, followed by derivatization of the phenylephrine in the plasma with dansyl-chloride solution and extraction with methyl tert-butyl ether-n-hexane (2:1, v/v). The treated samples were analyzed on a Gemini C18 column with 3 min gradient elution, and sensitive detection was achieved with a Waters TQ-s. The method gave linear results over a concentration range from 0.020 to 10.0 ng/ml. The lower limit of quantification was 0.020 ng/ml. Intra- and inter-day precision was <15%, and accuracy was 95.0-105.3%. The validated LC-MS/MS method was successfully applied in the pharmacokinetic analysis of phenylephrine in Chinese subjects with common cold after a single-dose administration of 5, 10 or 20 mg phenylephrine. This pre-column derivatization method may also be applied for the analysis of endogenous hormones such as norepinephrine and adrenaline in a biological matrix.

Development of a Novel Simple Gel Formulation Containing an Ion-Pair Complex of Diclofenac and Phenylephrine.

BACKGROUND AND AIM: Since the pharmacological effects of diclofenac (DF) are short-lived because of its short half-life, prolongation of the pharmacological effect in a topical formulation is needed for more appropriate clinical use. For the enhancement of dermal accumulation and prolongation of the pharmacological effect of drugs, the aim of this study was to develop a simple gel formulation containing an ion-pair complex of DF and phenylephrine (PHE), which induce constriction of the vascular smooth muscles. MATERIALS AND METHODS: The ion-pair complex was prepared by mixing sodium DF and an ethanolic solution of PHE. The formed complex was characterized by powder X-ray diffraction (PXRD) and Fourier-transform infrared (FT-IR) spectroscopy. The ion-pair complex for the gel formulation was prepared by mixing an equimolar concentration of 50% 1,3-butylene glycol and distilled aqueous solution of 2% xanthan gum, which was characterized by proton nuclear magnetic resonance (1H-NMR). Skin permeation and accumulation of DF and PHE were evaluated by in vitro and in vivo studies. RESULTS: From the results of PXRD and FT-IR, it was suggested that new crystalline peaks formed by the ion-pair complex and their complex interacted with the carboxyl group in DF and the amino group in PHE. In the gel formulation, the ion-pair complexes were detected by 1H-NMR. The ion-pair complex enhanced the accumulation of DF in the skin in the in vitro study. On the other hand, PHE accumulation in the dermis increased with the ion-pair complex, as exhibited by the in vivo study. CONCLUSION: A new gel formulation containing the ion-pair complex of DF and PHE was developed, which improved the accumulation of DF in skin.

Sustained Release Bilayer Tablet of Ibuprofen and Phenylephrine Hydrochloride: Preparation and Pharmacokinetics in Beagle Dogs.

Cold is a global common infectious disease accompanied by symptoms such as headache and stuffy nose. Ibuprofen (IBU) and phenylephrine hydrochloride (PE) were commonly used for common cold due to their different effects in relieving fever and the main symptoms such as nasal congestion and high sinus pressure. However, the commercial tablets of IBU and PE have to be administered 2 to 3 times per day due to their short half-life, with inconvenience for patient and fluctuations of plasma concentration. Bilayer tablet technology was utilized to design the IBU-PE sustained release tablets because of the significantly different solubility of IBU and PE in release media. The formulations of IBU layer and PE layer contain different viscosity grades of hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, hydrophilic diluent, and traditional glidant and lubricant. The sustained release bilayer tablet exhibited satisfying sustained release performance with the mechanisms of diffusion and matrix erosion. Compared with the conventional tablets, the IBU-PE sustained release bilayer tablet expressed significantly sustained-release behavior with decreased Cmax and prolonged Tmax in fasted conditions for IBU and PE. Though IBU of IBU-PE sustained release bilayer tablet was bioequivalent to the commercial IBU tablet, the relative bioavailability of PE from the bilayer tablets was 87.49 ± 20.00% (90% confidence interval was 72.3 to 102.5%), indicating bioinequivalence probably due to the "first pass" effect.

Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

INTRODUCTION: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites. METHODS: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis. RESULTS: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. DISCUSSION: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation.

Effects of generally recognized as safe (GRAS) and dietary compounds on phenylephrine metabolism in LS180 human intestinal cells.

Phenylephrine (PE) has low and variable oral bioavailability in humans, due in part to presystemic metabolism by sulfation. LS180 cells were used as a model of the human intestinal epithelium to examine phenylephrine metabolism and its inhibition by generally recognized as safe (GRAS) and dietary compounds. Curcumin, zingerone, resveratrol, guaiacol, pterostilbene and isoeugenol significantly inhibited phenylephrine disappearance, while vanillin, propylparaben and eugenol did not. However, when propylparaben was combined with either vanillin or eugenol, the phenylephrine disappearance was significantly inhibited. These data suggest that these compounds or combinations thereof may have potential to improve phenylephrine oral bioavailability.

An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.

Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.

The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children.

BACKGROUND: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. METHODS: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg-1 , 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. RESULTS: A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2 keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h-1 , central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h-1 , peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX ) of 25 mm Hg, and an EC50 of 10.3 µg L-1 . The effect on vasculature was immediate and T1/2 keo was not estimable. CONCLUSION: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX ) in children was half that in adults (EMAX 50 mm Hg).

Efficacy of an eye drop mixture for pupillary dilatation: A randomized comparative study / Eficacia de la mezcla de gotas oculares para la dilatación de la pupila: estudio aleatorizado y comparativo

Purpose: Pupillary dilatation with three types of eye drops is used regularly in the clinic; however, a mixture of these drops in a single bottle may be more beneficial in reducing workloads and resources. This study compared the efficacy in pupillary dilatation between two protocols of dilating drop instillation. Methods: This prospective, randomized, comparative study included 30 eligible Thai patients. The patients randomly received preoperative pupillary dilatations by either the conventional protocol (1% tropicamide (T), 10% phenylephrine (P) and 0.1% diclofenac (D) in three separate bottles) or the fixed combination (TPD) protocol which had the three types of eye drops mixed in a single bottle in a ratio of 4:3:3. The chi-square test and independent t-test were used to analyze the data. Results: The conventional protocol group and TPD protocol group each had 15 patients. Sixty minutes after the initial instillation, all patients in the TPD protocol and 13 patients (86.7%) in conventional protocol achieved at least 6mm in the shortest diameter. The mydriatic rate between protocols showed no difference. In patients who received the TPD protocol, the systemic effects on the mean arterial blood pressure and pulse rate decreased over time. Conclusion: The mixture of tropicamide, phenylephrine and diclofenac had a comparable efficacy for a pupillary dilatation to the conventional dilating drops in separate bottles. The systemic complications on blood pressure and arterial pulse of the TPD mixture were less than the conventional protocol (AU)

Objetivo: La dilatación de la pupila con tres tipos de gotas oculares se utiliza normalmente en la práctica clínica; sin embargo, la mezcla de dichas gotas en un único envase puede resultar más beneficiosa a la hora de reducir las cargas de trabajo y los recursos. Este estudio comparó la eficacia entre dos protocolos de dilatación de pupilas. Métodos: Este estudio prospectivo, aleatorizado y comparativo incluyó a 30 pacientes tailandeses elegibles. A dichos pacientes se les dilató aleatoria y preoperatoriamente la pupila utilizando el protocolo convencional (1% tropicamida (T), 10% fenilefrina (P) y 0,1% diclofenaco (D) en tres envases separados), o el protocolo de combinación fija (TPD), que contenía los tres tipos de gotas oculares mezclados en un único envase, a un ratio de 4:3:3. Se utilizaron las pruebas de χ2 y la prueba independiente t para analizar los datos. Resultados: Tanto el grupo de protocolo convencional como el grupo TPD incluyeron a 15 pacientes. A los sesenta minutos de la instilación inicial, todos los pacientes del protocolo TPD y 13 pacientes (86,7%) del protocolo convencional lograron un mínimo de 6mm en el diámetro menor. La tasa midriática entre ambos protocolos no reflejó diferencia alguna. En los pacientes del protocolo TPD, los efectos sistémicos sobre la presión sanguínea media y el índice de pulso disminuyeron con el tiempo. Conclusión: La mezcla de tropicamida, fenilefrina y diclofenaco mostró una eficacia comparable a la de las gotas para dilatación de pupilas suministradas en envases separados. Las complicaciones sistémicas sobre la presión sanguínea y la presión arterial de la mezcla de TPD fueron menores a las del protocolo convencional (AU)

Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro methods.

The aim of the present paper was the development of semi-solid (hydrogels) and solid (film) ophthalmic formulations for the controlled release of two mydriatics: phenylephrine and tropicamide. The formulations - based on polyvinylalcohol and hyaluronic acid - were characterized, and release studies were performed with three different in vitro set-ups, i.e. Franz-type diffusion cell, vial method and inclined plane; for comparison, a solution and a commercial insert, both clinically used to induce mydriasis, were evaluated. Both gels and film allowed for a controlled release of drugs, appearing a useful alternative for mydriatics administration. However, the release kinetic was significantly influenced by the method used, highlighting the need for optimization and standardization of in vitro models for the evaluation of drug release from ophthalmic dosage forms.

Direct detection of phenylephrine 3-O-sulfate in LS180 human intestinal cells using a novel hydrophilic interaction liquid chromatography (HILIC) assay.

The efficacy of phenylephrine (PE) is controversial due to its extensive pre-systemic metabolism through sulfation to form phenylephrine-3-O-sulfate (PES). Hence quantitation of PES is important in order to study the metabolism of PE. There are no published methods available for direction detection of PES. We have developed and validated a hydrophilic interaction liquid chromatography (HILIC) method for the direct detection of PES and simultaneous detection of PE to study the enzyme kinetics and metabolism of PE to enable approaches to reduce the presystemic metabolism of PE. This is the first method which facilitates direct detection of PES and simultaneous detection of PE using a zwitterionic HILIC column with improved sensitivity in a single short run. The observed quantitative ranges of our method for PE and PES were 0.39-200µM and 0.0625-32µM (respectively) with a run time of 6.0min. The method was applied to the determination of PE and PES in LS180 human intestinal cell line, recombinant enzymes and human intestinal cytosol (HIC).

Pharmacokinetics, safety, and cardiovascular tolerability of phenylephrine HCl 10, 20, and 30 mg after a single oral administration in healthy volunteers.

BACKGROUND AND OBJECTIVES: Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers. METHODS: Twenty-eight adults were enrolled in this randomized, double-blind, placebo-controlled, single-dose, four-treatment crossover study. Subjects remained housed for 6 days to permit time-matched, serial measurements of pulse, blood pressure, and electrocardiograms (ECGs) for baseline and complete treatments on consecutive days. After fasting overnight, subjects were dosed with oral phenylephrine HCl 10, 20, or 30 mg or placebo. Pharmacokinetic blood samples were collected over 7 h, whereas pulse, blood pressure, and ECGs were measured over 12 h. Urine was collected over each 24-h period to quantify phenylephrine and metabolites. RESULTS: After oral administration, phenylephrine was rapidly absorbed with median times to maximum plasma concentrations (t max) from 0.33 to 0.5 h. For phenylephrine HCl 10, 20, and 30 mg, the mean (standard deviation) maximum concentration (C max) was 1354 (954), 2959 (2122), and 4492 (1978) pg/mL, and total systemic exposure [area under the plasma concentration-time curve from time zero to infinity (AUC∞)] was 955.8 (278.5), 2346 (983.8), and 3900 (1764) pg·h/mL, respectively. Both parameters increased disproportionally with increasing dose, as ß >1 in the power model. Negligible amounts of phenylephrine and phenylephrine glucuronide were excreted in urine. With increasing dose, percentages by dose of phenylephrine sulfate decreased, whereas percentages of 3-hydroxymandelic acid increased. Eight subjects reported nine mild adverse events; one (somnolence) was deemed to be treatment related. Means of time-matched differences in pulse and blood pressure from baseline showed similar fluctuations over 12 h among phenylephrine HCl doses and placebo, although small differences in systolic pressure were observed during the initial 2 h. No apparent dose-related effects were observed for Fridericia-corrected QT interval (QTcF) values, and individual changes from time-matched baseline (DQTcF). CONCLUSIONS: Maximum and total systemic exposures following singe doses of phenylephrine HCl 10, 20, and 30 mg increased disproportionally with increasing dose. Safety and cardiovascular tolerability were comparable among doses and placebo.

Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review.

BACKGROUND: Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects. METHODS: MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol. RESULTS: There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg). CONCLUSIONS: Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.

Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence.

A hollow microneedle (HM) was prepared to deliver a phenylephrine (PE) solution into the anal sphincter muscle as a method for treating fecal incontinence. The goal of this study was the local targeted delivery of PE into the sphincter muscle through the perianal skin with minimal pain using hollow microneedles, resulting in the increase of resting anal sphincter pressure. PE was administered on the left and the right sides of the anus of a rat through the perianal skin using 1.5mm long HM. An in vivo imaging system study was conducted after injection of Rhodamine B, and a histological study was performed after injection of gentian violet. The resting anal sphincter pressure in response to various drug doses was measured by using an air-charged catheter. Anal pressure change produced by HM administration was compared with change produced by intravenous injection (IV), subcutaneous (SC) injection and intramuscular (IM) injection. The change in mean blood pressure produced by HM administration as a function of PE dose was compared with change produced by PBS injection. A pharmacokinetic study of the new HM administration method was performed. A model drug solution was localized in the muscle layer under the perianal skin at the injection site and then diffused out over time. HM administration of PE induced significant contraction of internal anal sphincter pressure over 12h after injection, and the maximum anal pressure was obtained between 5 and 6h. Compared to IV, SC and IM treatments, HM treatment produced greater anal pressure. There was no increase in blood pressure after HM administration of PE within the range of predetermined concentration. Administration of 800µg/kg of PE using HM produced 0.81±0.38h of tmax. Our study suggests that HM administration enables local delivery of a therapeutic dose of PE to the anal sphincter muscle layer with less pain. This new treatment has great potential as a clinical application because of the ease of the procedure, minimal pain, and dose-dependent response.

An in-vivo evaluation of a MEMS drug delivery device using Kunming mice model.

The use of MEMS implantable drug delivery pump device enables one to program the desired drug delivery profile in the device for individualized medicine treatment to patients. In this study, a MEMS drug delivery device is prepared and employed for in vivo applications. 12 devices are implanted subcutaneously into Kunming mice for evaluating their long term biocompatibility and drug-delivery efficiency in vivo. All the mice survived after device implantation surgery procedures. Histological analysis result reveals a normal wound healing progression within the tissues-to-device contact areas. Serum analysis shows that all measured factors are within normal ranges and do not indicate any adverse responses associated with the implanted device. Phenylephrine formulation is chosen and delivered to the abdominal cavity of the mice by using either the implanted MEMS device (experimental group) or the syringe injection method (control group). Both groups show that they are able to precisely control and manipulate the increment rate of blood pressure in the small animals. Our result strongly suggests that the developed refillable implantable MEMS devices will serve as a viable option for future individualized medicine applications such as glaucoma, HIV-dementia and diabetes therapy.

Increased bioavailability of phenylephrine by co-administration of acetaminophen: results of four open-label, crossover pharmacokinetic trials in healthy volunteers.

PURPOSE: Over-the-counter combinations containing acetaminophen and phenylephrine for treatment of the common cold and influenza are widespread, but there are few data about pharmacokinetics of these two drugs used in combination. We aimed to investigate pharmacokinetic interactions between acetaminophen and phenylephrine. METHODS: A series of four randomised, open-label, crossover studies investigating phenylephrine and acetaminophen combination pharmacokinetics were undertaken (n = 28, 30, 6 and 26) using standard non-compartmental analyses. Time-concentration observations from these four studies were pooled to examine the interaction between these two compounds. Data were analysed using non-linear mixed effects models. RESULTS: Non-compartmental analyses showed an approximate doubling of phenylephrine plasma concentration when the standard 10-mg dose was administered in combination with acetaminophen. Population analysis was based on data from 90 subjects with 2050 observations. The relative bioavailability of phenylephrine 10 mg was doubled (Fbio 2.11, 95%CI 1.89, 2.31) when combined with acetaminophen 1000 mg, while the absorption half-time was reduced by 50 %. When combined with 500 mg of acetaminophen, bioavailability increased by 64 % (Fbio 1.64). Phenylephrine 5 mg in combination with acetaminophen 1000 mg produced a phenylephrine plasma time-concentration profile similar to that seen with phenylephrine 10 mg administered alone. CONCLUSIONS: The relative bioavailability of phenylephrine was increased when co-administered with acetaminophen.

Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product.

OBJECTIVES: The primary objective of this study was to compare the bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a new oral syrup with an established oral reference product. The secondary objective was to compare the safety of the new syrup and the reference product. METHODS: This was a single-centre, open-label, randomized, reference-replicated, crossover study. Healthy adult volunteers received one dose of syrup and two separate doses of a reference oral liquid formulation in a randomized sequence over three study periods, with a washout interval of ≥ 7 days between study periods. Blood samples were taken regularly postdose and analysed for paracetamol, phenylephrine hydrochloride and guaifenesin concentrations; adverse events were recorded. RESULTS: This study enrolled 45 subjects. For paracetamol and guaifenesin, the syrup and reference product were considered to be bioequivalent. Bioequivalence was not shown for phenylephrine hydrochloride. All adverse events were mild or moderate, most of which were considered formulation related. CONCLUSIONS: The syrup did not reach bioequivalence with the reference product, as bioequivalence could not be shown for phenylephrine hydrochloride. This may be due to differences in the excipients between the two products. Both the syrup and the reference product had a good safety profile and were well tolerated.

Determination of phenylephrine in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry.

This paper described a sensitive and rapid method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for the determination of phenylephrine in human plasma. Plasma samples were pre-purified by solid-phase extraction (SPE). The chromatographic separation was achieved with BEH HILIC column using a mixture of 10mM pH 3.5 ammonium formate and acetonitrile (10:90, v/v) under isocratic conditions at a flow rate of 0.4 mL/min. The mass spectrometry was carried out using positive electrospray ionization (ESI) and data acquisition was carried out in the multiple reaction monitoring (MRM) mode. The method was fully validated over the concentration range of 10.0-5000 pg/mL. The lower limit of quantification (LLOQ) was 10.0 pg/mL. Inter- and intra-batch precision was less than 15% and the accuracy was within 85-115%. Extraction recovery was 78.5%. Selectivity, matrix effects and stability were also validated. The method was applied to the pharmacokinetic study of phenylephrine hydrochloride in Chinese subjects.

Estado actual del uso de la fenilefrina en la paciente gestante sometida a cesárea con anestesia espinal / No disponible

La placenta es el órgano a través del cual el feto recibe oxígeno y nutrientes y elimina productos de desecho mientras está en el útero. Este órgano tiene diversas funciones: transferencia de sustancias, respiración, función endocrina y función barrera. El flujo uterino es el principal determinante del transporte de oxigeno entre el feto y la madre. Los objetivos a cumplir cuando se utiliza un fármaco con el fin de prevenir o tratar la hipotensión arterial son: la reducción de las náuseas y vómitos maternos, el efecto sobre el gasto cardiaco y la frecuencia cardiaca materna durante el intraoperatorio y los resultados neonatales, en cuanto a evaluación precoz del recién nacido. La efedrina se asocia con un pH más ácido y un menor exceso de base en el neonato. Hay un riesgo significativamente mayor de acidosis fetal con efedrina que con fenilefrina. Comparando los efectos maternos, la fenilefrina tiene mayor riesgo de bradicardia y los hallazgos hasta ahora apuntan a un perfil más favorable en el abordaje de la hipotensión arterial materna en las cesáreas electivas con anestesia espinal con la fenilefrina. Si la paciente tiene hipotensión y bradicardia, lo cual es menos frecuente, entonces debe ser tratada con efedrina y /o anticolinérgicos(AU)

The placenta is the organ through which the fetus receives oxygen and nutrients and removes waste products while in the uterus. This body has various functions: transfer of substances, respiration, endocrine function and barrier function. Uterine blood flow is the main determinant of oxygen transport between fetus and mother. The objectives to be met when using a drug to prevent or treat low blood pressure are: reducing maternal nausea and vomiting, the effect on cardiac output and heart rate during surgery, maternal and neonatal outcomes, measured as early assessment of the newborn. Ephedrine is associated with amore acidic pH and lower base excess in the neonate. There is a significantly increased risk of fetal acidosis with ephedrine than with phenylephrine. Comparing maternal effects, phenylephrine at higher risk of bradycardia and the findings so far point to a more favorable approach to maternal hypotension during elective cesarean section under spinal anesthesia with phenylephrine. If the patient has hypotension and bradycardia, which is less frequent, then it must be treated with ephedrine and/or anticholinergic drugs(AU)