A novel oral medicated jelly for enhancement of etilefrine hydrochloride bioavailability: In vitro characterization and pharmacokinetic evaluation in healthy human volunteers.

Etilefrine hydrochloride (ET) is a water-soluble drug that is used to treat hypotension, but it has a bitter taste and low bioavailability due to undergoing the first-pass effect. Thus, this study aimed to develop and evaluate oral medicated jelly (OMJ) containing ET that could offer an easily taken palatable dosage form with higher bioavailability. OMJ is a novel palatable drug delivery system that can easily be taken by pediatric and geriatric patients, as well as those with dysphagia. Moreover, OMJs offer rapid disintegration in saliva and rapid drug absorption through the buccal mucosa, avoiding the first-pass effect and increasing the drug bioavailability. Natural polymers such as pectin, guar gum, xanthan gum, tragacanth gum, and sodium alginate were used as jellifying agents, with the addition of calcium chloride as a crosslinking agent, to prepare OMJs using the heat and congealing method. The prepared OMJs were investigated by testing their viscosity, in vitro release, and texture analysis of firmness, consistency, stickiness, cohesiveness, springiness, gumminess, and chewiness using a texture analyzer. A full factorial design (21 × 51) was utilized to select the optimized OMJ. The optimized OMJ (J2), containing 4 % pectin, had a 7563 ± 55 cps viscosity, 8.32 ± 0.21 N firmness, 5.72 ± 0.18 µJ consistency, 1.30 ± 0.04 mJ stickiness, and 96.02 ± 3.74 % ET dissolved after 10 min. ET release was significantly increased (greater than4-fold) from the optimized OMJ compared with the market tablet. Moreover, the obtained results clarified the stability and the acceptable palatability of the optimized OMJ. The clinical investigation on healthy human volunteers revealed that the optimized OMJ (J2) had significantly higher Cmax (1.7 folds) when compared with the market tablet with a relative bioavailability of 154.55 %. Therefore, OMJs can be considered as promising, palatable, and easily swallowed dosage form that could enhance the bioavailability of drugs undergoing the first-pass effect.

Preparation and evaluation of fast-dissolving films of etilefrine hydrochloride for practical buccal dosing.

Etilefrine hydrochloride (ET) is an important drug in the treatment of hypotension, and parenteral injections and oral tablets are the conventional dosage forms. However, parenteral injections may cause abnormally high plasma levels as well as pain and necrosis, and oral tablets undergo first-pass metabolism. Although fast-dissolving buccal tablets were previously reported, the initial absorption rate was a little slow and the plasma levels were varied extensively. Recently, many films have been developed as novel dosage forms. Therefore, in the present study, film dosage forms containing ET were produced using water-soluble polymers and glycerin (GLY) as excipients to obtain a practical buccal dosage form. Films composed of ET, GLY, and sodium alginate (AL) exhibited good physical characteristics and rapid release in vitro (more than 70% at 2 min). The compacted AL film containing 2 mg ET (1 × 1 cm) exhibited rapid absorption (>19 ng/mL at 0.5 h), maintained an effective plasma level (>7 ng/mL) for a long time period (0.5-4 h), and had an adequate plasma concentration-time profile with a smaller standard error (<15.3 ng/mL). These results suggest that the present compacted buccal film is a superior dosage form of ET for practical use.

Refractory lymphorrhoea of the neck treated with etilefrine.

BACKGROUND: Intraoperative injury of the thoracic duct is an uncommon complication of head and neck surgery, which is difficult to manage and associated with serious consequences. We report a case of lymphorrhoea of the neck refractory to all the usual treatments that resolved in response to a treatment strategy described in thoracic and visceral surgery: use of a sympathomimetic drug, etilefrine. To our knowledge and after review of the literature, this is the first reported case of lymphorrhoea of the neck treated by etilefrine. CASE REPORT: Our patient presented massive lymphatic fluid leakage following left neck dissection as part of the management of oropharyngeal cancer with lymph node metastases. The treatments usually proposed, such as intraoperative repair and appropriate dietary and drug management, were not effective, resulting in multiple, severe complications. After evaluation of the benefit-risk balance, treatment with etilefrine was introduced at the dosages proposed in the literature for the management of chylothorax. This treatment allowed complete resolution of the lymphatic fluid leak after one week. DISCUSSION: Etilefrine can therefore be added to the treatment options for the management of lymphatic fluid leaks refractory to the usual treatments.

Preparation of orally fast-dissolving tablets of etilefrine hydrochloride to achieve efficient absorption.

Etilefrine hydrochloride (ET) is commonly used in the treatment of hypotension in dosage forms of oral tablets and parenteral injections. However, oral tablets only temporarily achieve high plasma levels and have low bioavailability (BA), while intravenous injections may cause pain and necrosis around administration sites. In an attempt to overcome these limitations, the buccal delivery of ET using oral droplets has been investigated. In this study, a buccal tablet as an alternative dosage form was developed for practical use. Buccal tablets were prepared by the direct compression method with sodium alginate (AL) and mannitol (MA) as excipients. Their disintegration and in vitro drug release were rapid (more than 50% being released after 3 min). Furthermore, effective plasma levels (> 5-7 ng/mL) were reached within 0.5 h of buccal administration in rats. The systemic absorption of these tablets was similar to that of buccal droplets. Therefore, the ET buccal tablets developed herein have potential as an alternative dosage form for hypotension therapy.

Combination Therapy with Etilefrine and Pleurodesis for Refractory Congenital Chylothorax.

Etilefrine, a sympathomimetic agent, is reportedly effective against postoperative chylothorax. However, its effectiveness in treating congenital chylothorax was unknown. We report herein a case of refractory congenital chylothorax treated with etilefrine in a late preterm neonate with massive fetal chylous pleural effusion. The chylothorax was unresponsive to previous treatments, including dietary and pharmacological treatment and thoracic duct ligation. The pleural effusion decreased after intravenous etilefrine was begun on day of life (DOL) 84 and resolved after the addition of chemical pleurodesis with OK-432 on DOL 90. This combination therapy may be a viable treatment option for cases of congenital chylothorax that are unresponsive to other treatments.

Norepinefrina o etilefrina en tratamiento de hipotensión arterial intraoperatoria para artroplastia total de cadera / Norepinephrine or etilephrine in the tratamient of intraoperative arterial hypotension for total hip arthroplasty

La complicación frecuente, posterior a anestesia raquídea en artroplastia de cadera es Hipotensión Arterial Intraoperatoria, por eso la necesidad de evaluar un vasopresor que es útil para este propósito. Objetivos: Evaluar uso de norepinefrina y etilefrina para prevención de la hipotensión intraoperatoria inducida por la anestesia espinal en pacientes sometidos a artroplastia total de cadera. Materiales y Métodos: Ensayo clínico, simple ciego, transversal y prospectivo. 38 pacientes ambos sexos, edad 60 a 85 años, ASA II-III, anestesia espinal y acepten participar del estudio. Exclusión a edad 85 años, ASA IV-V, anestesia general, HTA y cardiopatía descontrolada. Grupo de estudio: grupo E (Etilefrina 2 mg bolo IV) y grupo N (Norepinefrina infusión 0.03 a 0.05 mcg/kg/min IV). El análisis estadístico se realizó prueba T student. Resultados: Edad media grupo E: 68 años y el grupo N 69,94 años. Presión arterial media basal (grupo E): 74,3 mmHg y (Grupo N): 72,4 mmHg, se encontró significancia estadística valor p <0,05 posterior a administración de anestésicos locales. Por su parte, la frecuencia cardiaca basal es de 73 latidos (grupo E), posterior a administración de etilefrina: 95 latidos; Grupo N: 70 basal y descenso de 10 latidos posterior a infusión de norepinefrina. Con una significancia estadística (valor p <0,05) en los tres momentos de medición (frecuencia cardiaca modificada con vasopresor, frecuencia cardiaca durante la cirugía y al finalizar la cirugía). Conclusiones: Uso de norepinefrina en infusión mantiene estabilidad hemodinámica dentro rangos normales. No hubo incidentes del uso de vasopresores por vía periférica.

The frequent complication, after spinal anesthesia in hip arthroplasty is Intraoperative Arterial Hypotension, so the need to evaluate a vasopressor that is useful for this purpose. Objectives: To evaluate the use of norepinephrine and etilefrine for the prevention for intraoperative hypotension induced by spinal anesthesia in patients undergoing total hip arthroplasty. Methods: Clinical trial, simple blind, transverse and prospective. 38 patients of both sex, age 60 to 85 years, ASA II-III, spinal anesthesia and accept to participate in the study. Exclusion criteria: age 85 years, ASA IV-V, general anesthesia, hypertension and uncontrolled heart disease. Assigned in 2 groups:group E (Etilefrine 2 mg bolus IV) and group N (Norepinephrine infusion 0.03 to 0.05 mcg/ kg/ min IV). The statistical analysis was performed student T. Results: Age in group E: 68 years and group N 69.94 years. Mean arterial pressure baseline (group E): 74.3 mmHg, y (group N): 72.4 mmHg, Statistical significance p value <0.05 after administration of local anesthestics. In group E, the baseline heart rate is 73 beats when using ethylephrine up to 95 beats. Group N: baseline of 70 and descent of 10 beats when the norepinephrine infusion is started. The Statistical significance (p value <0.05) in three moment (heart rate with vassopresor, durant surgery and end surgery). Conclusions: Use of norepinephrine in infusion maintains hemodynamic stability within normal ranges. There were no incidents of peripheral vasopressor use.

Absorption behavior of etilefrine after buccal administration in rats.

Etilefrine hydrochloride (ET-HCl) is used in the treatment of hypotension. Dosage forms of orally administered tablets and parenteral injections are clinically available, but exhibit unfavorable characteristics, including cardiac toxicity, headaches, and damage at the injection site for the parenteral dosage form, and initially high plasma levels, fast elimination, and first-pass effects for its oral administration. Therefore, the buccal application of ET-HCl was herein investigated as an alternative to conventional administration routes. I.v., intragastric, and buccal administration were performed using rats, and absorption features were compared. Buccal application at open conditions for 1 h exhibited absolute bioavailability of more than 20%, while the intragastric administration gave much lower bioavailability (<10%). The drug residue and drug distribution in the oral mucosa were investigated in order to clarify drug transfer behaviors. In the application of ET-HCl solution using a cotton ball, higher plasma concentrations and their maintenance at higher levels were achieved at 10 mg/kg than at 2.5 mg/kg. In addition, absorption was greater with a longer application (4 h) than with a shorter application (1 h). Etilefrine (ET) was rapidly absorbed using aqueous buffer of pH 9.5 as the solvent. Open application was appropriate for achieving and maintaining higher plasma levels. Thus, in the buccal application of ET-HCl aqueous droplets, a wide distribution throughout the mucosal surface is important for achieving rapid absorption and the maintenance of plasma levels. These findings suggested that the buccal application should be feasible administration of ET-HCl.

Bolus administration of ephedrine and etilefrine induces transient vasodilation just after injection in combined epidural and general anesthesia patients: A randomized clinical study.

Hypotension commonly accompanies combined epidural and general anesthesia, and intravenous bolus ephedrine and etilefrine are widely used to correct hypotension. We have noticed that systemic vascular resistance (SVR) transiently decreases just after intravenous bolus administration of these drugs. The goal of the present study was to investigate whether bolus administration of these drugs decrease SVR just after intravenous administration in combined epidural and general anesthesia patients. We investigated 40 patients who were scheduled for elective abdominal surgery. Patients were chosen as subjects if their systolic arterial pressure decreased by 20% or to <100 mmHg at 30 min after the induction of general anesthesia. Baseline hemodynamic values were recorded, and after ephedrine 10 mg injection or etilefrine 2 mg injection (equipotent), the parameters were recorded again at 0.5 min and once each min for the next 5 min thereafter. The 40 patients were enrolled into the ephedrine (n = 20) or etilefrine (n = 20) treatment groups. Patient characteristics were comparable in both groups. After ephedrine injection, SVR decreased significantly at the 1-min time point, whereas after etilefrine injection, SVR decreased significantly at the 0.5- to 2-min time points compared with baseline values. SVR at the 0.5- to 1-min time points was lower in the etilefrine versus the ephedrine group. Both drugs transiently decreased SVR after intravenous injection, but etilefrine decreased SVR much more than ephedrine, indicating that more vasodilation occurred after the injection of etilefrine than after ephedrine. It is thus important to recognize the different characteristics of these drugs.

Effectiveness of etilefrine regimen for chylothorax after esophagectomy with thoracic duct resection.

BACKGROUND: Management of postoperative chylothorax generally involves nutritional regimens as well as pharmacological and surgical therapies, but a clear consensus has yet to be reached. METHODS: Retrospective review of 371 patients who underwent esophagectomy for esophageal cancer was performed. They were patients with squamous cell carcinoma or adenocarcinoma of the esophagus including Siewert type I/II tumor of the esophagogastric junction who underwent subtotal esophagectomy. Of these patients, 19 patients who were diagnosed with chylothorax as a postoperative complication were enrolled in this study. RESULTS: Conservative treatment achieved cure in 16 patients among 19 patients. The duration of chylothorax tended to be longer in the no-etilefrine group (n = 5) than in the etilefrine group (n = 11) (27.8 vs. 11.6 days; p = 0.078). The 14 patients among 19 patients resected the thoracic duct. Etilefrine was used in 12 of these 14 patients. Among these 12 patients, 3 required surgical treatment and the remaining 9 patients were cured with conservative treatment. The duration of chylothorax was shorter in the conservative treatment group than in the surgical treatment group (11.9 vs. 36.3 days; p = 0.052). In addition, with the use of etilefrine as adjuvant therapy, cure was achieved in 9 patients (75%) without surgical intervention. CONCLUSIONS: The findings of this study suggest that when used concurrently with conventional treatments, etilefrine facilitates early chest tube removal. In addition, post-thoracic duct resection chylothorax, which frequently requires surgical treatment because of the general less effectiveness of conservative treatments, showed high successful rate (75%) to etilefrine treatment.

Spectrofluorimetric determination of certain adrenergic agonist drugs in their pure forms and pharmaceutical formulations: Content uniformity test application.

A new, simple, sensitive and rapid spectrofluorimetric method has been developed for determination of certain adrenergic agonists such as isoxsuprine hydrochloride, ritodrine hydrochloride and etilefrine hydrochloride in their pure forms and pharmaceutical dosage forms. The method depends on micellar enhancement of the native fluorescence of investigated drugs by using 2% w/v sodium dodecyl sulfate (SDS) as an anionic surfactant. The enhanced fluorescence intensity of investigated drugs was measured at 305 nm after excitation at 278 nm. The interaction of studied drugs with SDS was studied, and the enhanced fluorescence intensity was exploited to develop an assay method for the determination of investigated drugs. The relative fluorescence intensity-concentration plots were rectilinear over the range 0.15-3.00 µg ml-1 , with low quantification limits of 0.132, 0.123 and 0.118 µg mL-1 for isoxsuprine, ritodrine and etilefrine, respectively. The proposed method was successfully applied for determination of studied drugs in their pharmaceutical formulations. Moreover, the high sensitivity of the proposed method allows performing the content uniformity testing of the studied drugs in their tablets by using the official United States Pharmacopeia (USP) guidelines. Statistical comparisons of the results with those of the reported methods revealed excellent agreement and indicated no significant difference in accuracy and precision.

Etilefrina vs fenilefrina en hipotensión por anestesia espinal para cesárea: ensayo clínico multicéntrico, controlado, aleatorizado y doble ciego / Etilefrine vs. phenylephrine for hypotension during spinal anesthesia for cesarean section: Multicenter, randomized, double blind controlled clinical trial

Introduction: Hypotension after spinal anesthesia in cesarean section should be minimized. The use of vasopressors is an effective measure to treat hypotension. The objective of this paper is to compare the safety and effectiveness of etilefrine vs. phenylephrine in the management of this condition. Methods: This multicenter, double-blind trial between August 2009 and November 2010 included 196 patients with hypotension during spinal anesthesia for cesarean delivery; the patients were randomized to receive etilefrine or phenylephrine as vasopressor. The primary outcome was the fetal umbilical arterial pH. The secondary outcomes were: fetal acidosis (umbilical arterial pH < 7.20), Apgar score at 1 and 5 min, need for intubation and admission to the neonatal intensive care unit for newborns, and time of hypotension, total dose of vasopressor, atropine requirement, intravenous fluids volume and incidence of nausea and vomiting in mothers. Results: 98 patients received etilefrine and 98 phenylephrine. There were no differences in umbilical arterial pH (7.27 vs. 7.28, respectively, P = 0.493). The total dose of vasopressor (5.66 vs. 6.51ml, respectively, P = 0.024) and total time of hypotension (2.78 vs. 3.25 min, respectively, P = 0.021) were lower in the etilefrine group. Other outcomes studied showed no statistically significant differences. Conclusion: Etilefrine and phenylephrine are equally effective for the treatment of hypotension during spinal anesthesia for cesarean delivery. This study found no difference in the maternal or fetal outcomes.

Introducción: La hipotensión que ocurre luego de anestesia espinal para cesárea debe minimizarse. El uso de vasopresores es una medida eficaz para su tratamiento. El objetivo de este trabajo es comparar la seguridad y efectividad de etilefrina vs fenilefrina para manejo de esta condición. Métodos: En este estudio multicéntrico y doble ciego, entre agosto de 2009 y noviembre de 2010, 196 pacientes con hipotensión durante anestesia espinal para cesárea, fueron asignadas aleatoriamente para recibir etilefrina o fenilefrina como vasopresor. El resultado primario fue el pH arterial umbilical fetal. Los resultados secundarios fueron: acidosis fetal (pH arterial umbilical < 7,20), puntaje Apgar al 1 y 5 minutos, necesidad de intubación e ingreso a la unidad de cuidados intensivos neonatal para los recién nacidos; y tiempo de hipotensión, dosis total de vasopresor, necesidad de uso de atropina, líquidos endovenosos totales e incidencia de nausea y vómito para las madres. Resultados: 98 pacientes recibieron etilefrina y 98 fenilefrina. No se encontraron diferencias en el pH arterial umbilical (7,27 vs 7,28 respectivamente; p = 0,493). La dosis total de vasopresor (5,66 vs. 6,6 ml, respectivamente; P = 0,024) y el tiempo total de hipotensión (2,78 vs. 3,25 min, respectivamente; p = 0,021), fueron menores en el grupo de etilefrina. Los demás desenlaces estudiados no presentaron diferencia estadísticamente significativa. Conclusión: La etilefrina y la fenilefrina son igualmente efectivas para el tratamiento de la hipotensión por anestesia espinal para cesárea. Este estudio no encontró diferencia en los resultados fetales ni maternos.

Development and validation of a hydrophilic interaction liquid chromatography with tandem mass spectrometry method for the simultaneous detection and quantification of etilefrine and oxilofrine in equine blood plasma and urine.

A sensitive hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the simultaneous detection and quantification of etilefrine and oxilofrine in equine blood plasma and urine. The method is highly sensitive and specific with good precision and accuracy. In plasma the limit of detection and limit of quantification are 0.03 and 0.1 ng/mL, respectively, for both analytes. In urine the limit of detection and limit of quantification are 0.3 and 1 ng/mL, respectively, for both analytes. The suitability of the method for doping control analysis in equine species is demonstrated by analyzing postadministration samples collected after a single intravenous administration of 50 mg etilefrine to a standardbred mare. Etilefrine was detected up to 120 h in urine and up to 48 h in plasma. Etilefrine is highly conjugated in equine urine whereas it exists in the free form in equine plasma. Therefore, enzyme hydrolysis prior to sample preparation is recommended for the detection and quantification of etilefrine and oxilofrine in equine urine.