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.

Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).

INTRODUCTION: Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics. METHODS: Jacketed external telemetry with an implanted miniature blood pressure transmitter (JET-BP) was used to characterize the tolerability, functionality, and sensitivity of this study design in dogs. Thirty-six male or female beagles (n=6 dogs/sex/group) were administered vehicle control (reverse osmosis water) or etilefrine (1, 10mg/kg), sotalol (3, 30mg/kg), and hydralazine (1, 10mg/kg) on separate days. Telemetry data were evaluated for positive control article-related changes and retrospective power analysis was also completed. Animals were evaluated for instrumentation-related changes in clinical and anatomic pathology endpoints. RESULTS: All three positive controls elicited the expected pharmacologic responses that were statistically different at high and low doses. Retrospective power analysis confirmed this study design was able to statistically differentiate minor (approximately 5 to 15%) changes in electrocardiography and blood pressure values. This study also demonstrated the potential advantages of combining cardiovascular data across sex when the test article exposure and pharmacodynamics were consistent. Data collection using miniature telemetry blood pressure transmitters did not result in anatomic or clinical pathology findings that would prevent their use in general toxicology studies. DISCUSSION: This characterization study indicates that JET-BP in dogs offers a scientifically-robust method to evaluate novel therapeutics for potential cardiovascular liabilities.

The indirect sympathomimetic activity of etilefrine--a comparison with tyramine and ephedrine using [3H] noradrenaline.

The indirect sympathomimetic activity of etilefrine has been examined using the ventral caudal artery of the rat. This vessel has a rich sympathetic innervation and lends itself to studies on [3H]noradrenaline efflux from these sites. Etilefrine possessed significant indirect activity on the artery and this action, although less than that of tyramine, was equivalent to that caused by ephedrine. Pretreatment of the vessels with a mixture of iproniazid, doca, cocaine and UO521 (3',4'-dihydroxy-2-methyl propiophenone) significantly enhanced[3H]-noradrenaline efflux from the artery.

The effects of etilefrine on blood vessels in the rat tail.

Etilefrine was found to constrict blood vessels in the rat tail through a mechanism which was partly dependent on the sympathetic nerves present in these vessels. The response to the drug was enhanced by pretreagment with noradrenaline and cocaine, and totally abolished by the alpha-receptor antagonist phentolamine. When compared with several other sympathomimetic agents which were tested on the vessel, etilefrine appeared to have a low order of vasoconstrictor activity. These findings would seem to have considerable relevance to the clinical situation where an attempt has been made to use etilefrine in the treatment of patients with orthostatic hypotension.

Etilefrine and amezinium reduce uterine blood flow of pregnant guinea pigs.

Etilefrine and Amezinium are used during pregnancy to prevent hypotension and fetal growth retardation. The effect of these drugs on uterine blood flow (UBF), uterine vascular resistance (UVR) and fetal growth are, however, unknown. 31 guinea pigs were injected daily with Etilefrine (3 X 0.14 mg/kg) and Amezinium (0.14 mg/kg) from day 30 to day 60. Uterine blood flow was measured with radioactive-labeled microspheres. Uterine vascular resistance was calculated from arterial blood pressure and uterine blood flow. 10 guinea pigs treated with 0.9% sodium chloride served as controls. As a response to Etilefrine and Amezinium, UBF fell by 68 and 48%, respectively, accompanied by an increase in UVR. The fetal weight decreased only slightly. It is concluded that long-term application of anti-hypotensive drugs may be hazardous to uterine blood flow and fetal growth.

[Use of etilefrin as local vasoconstrictor in lower gynecologic surgery ]. / Utilisation de l'étiléfrine comme vasoconstricteur local dans la chirurgie gynécologique par voie basse.

In this randomized prospective study the authors have compared the effectiveness and side-effects of two local vasoconstrictor agents, etilefrine (Effortil) and ornithine 8 vasopressin (Por 8) in vaginal gynaecological surgery. Thirty-three patients entered the trial and were divided into two groups: G1 (15 patients) received Effortil, and G2 (18 patients) received Por 8. The products, administered at random, were diluted in saline 40 ml and injected into the cervix through 6 points. A 3-minute interval was allowed between injection and incision. The results were assessed on the basis of trans- and postoperative haemorrhage and haemodynamic variations. Palor of the cervix was achieved after 3 minutes in both groups; moderate bleeding was observed in only one of the G1 patients. Postoperative renewal of packing was necessary in 2 patients in G1 and 4 patients in G2. No electrocardiographic anomaly was recorded in any of the two groups. Diastolic BP was significantly higher in G2 than in G1 (P less than 0.002, Fisher test). Systolic BP was also elevated in that group (P less than 0.03, chi 2 test). Moderate reduction in heart rate was observed in both groups (P less than 0.3, Fischer test), but severe (48 beats/min) bradycardia was noted in one G2 patient.

[Intracavernous injections of etilefrin: its efficacy in the treatment of priapism in sickle cell patients]. / Injections intracaverneuses d'étiléfrine: efficacité dans le traitement curatif des épisodes de priapisme chez le drépanocytaire.

OBJECTIVE: To date, the treatment of priapism in sickle-cell patients has relied on measures aimed at lowering blood viscosity and acidosis and reducing the level of circulating hemoglobin S (hyperhydration, alkalinization, or exsanguinotransfusion...) Surgical cavernous-venous shunt may be proposed if conservative treatment fails. We examined the efficacy of intracavernous etilefrin injections. PATIENTS AND METHODS: From January 1996 through October 1997 (20 months) we performed 35 consecutive intracavernous injections of an alphastimulant, etilefrin in 7 sickle-cell patients (6 SS, 1 AS) who had experienced one or several episodes of low-flow priapism lasting 2 to 28 hours. RESULTS: Involution of the tumefaction was rapidly achieved in all cases. Tolerance was satisfactory, although some post-injection undesirable effects were reported by certain patients: moderate transient pain (2-5 min) in the retrosternal area, or intense pain in the penis (more intense than the priapism) which lasted 10 to 30 minutes. This work confirmed the earlier reported efficacy of intracavernous injections of etilefrin and suggests that the autonomous nervous system plays an important role in the genesis of this condition in sickle-cell patients. Patients should be informed about the observed undesirable effects which have not been reported previously in the literature. CONCLUSION: Etilefrin can be proposed as first line treatment for priapism in sickle-cell patients (at least in cases lasting less than 24 h). The pathogenic mechanism could involve neuromuscular dysfunction.

[Intracavernous injection of etilefrine hydrochloride in iatrogenic priapism].

Intracavernous injection of etilefrine hydrochloride (1 or 2 mg) was performed on four patients with fully erected penis after intracavernous injection of 40 mg of papaverine hydrochloride. One case needed three injections of etilefrine hydrochloride (1 mg), but the erection disappeared in the other three cases within 10 minutes after a single injection of 2 mg of etilefrine hydrochloride. The injection resulted in complete detumescence and relief of the erection in all cases. These observations strongly suggest that the intracavernous injection of etilefrine hydrochloride is effective in treating not only iatrogenic priapism but also priapism due to other etiologies. Also, it might be useful to control erection time after intracavernous injection therapy for impotence.

Effect of systemic blood pressure on microcollateral circulation evaluated by real-time contrast echocardiography.

BACKGROUND: In acute myocardial infarction, residual collateral-derived myocardial blood flow (CBF) within the ischemic area is one of the major determinants of infarct size. Management of systemic blood pressure (sBP) related to maintain collateral circulation is still difficult. The aim of this study was to reveal the influence of sBP on the rescue of area at risk by collateral circulation. METHODS: Real-time myocardial contrast echocardiography just after the onset of complete occlusion of the left circumflex coronary artery was performed in collateral-rich open-chest dogs. The video intensity of the ischemic area was evaluated during the occlusion and the CBF (A x beta) was calculated from a replenishment curve: y = A (1 - e(-beta t)). To analyze the effect of sBP on the collateral circulation, sBP was altered by infusion of nitroglycerin or etilefrine hydrochloride. To evaluate the defect size (%DS), every end-systolic myocardial contrast echocardiography image after left circumflex coronary artery occlusion was converted into binary images using custom offline software. RESULTS: The %DS increased and CBF slightly decreased at low sBP. The %DS decreased and CBF increased at high sBP. At excessively high sBP, %DS increased and CBF decreased again. CONCLUSION: Real-time myocardial contrast echocardiography, which is a useful noninvasive method to evaluate the collateral perfusion quantitatively, has a crucial role in the decision of patient treatment and management strategy of acute myocardial infarction.

Effects of cafedrine/theodrenaline, etilefrine and ephedrine on uterine blood flow during epidural-induced hypotension in pregnant sheep.

INTRODUCTION: Maternal hypotension is a major concern in obstetric anesthesia, and concerns have been raised about standard vasopressor therapy with ephedrine. Therefore, we evaluated the maternal and fetal hemodynamic effects of two potential alternatives to ephedrine. METHODS: Hypotension was induced by epidural administration of lidocaine in 6 chronically instrumented pregnant ewes (at 118-122 days of gestation, term 145 days). Three treatments were studied: 25 mg ephedrine, 5 mg etilefrine and 100 mg cafedrine/5 mg theodrenaline (C/T) intravenously. Mean fetal and maternal blood pressure and heart rate, uterine blood flow, as well as fetal and maternal arterial blood gases were recorded for 60 min. RESULTS: All three vasopressors increased maternal blood pressure, accompanied by a significant increase in uterine blood flow. C/T caused marked maternal tachycardia, whereas ephedrine decreased maternal heart rate. Maternal and fetal blood gases did not change during any of the three treatment regimens. CONCLUSION: All three vasopressors restored maternal blood pressure and uterine blood flow after epidurally induced maternal hypotension. However, restoration of uterine perfusion was delayed and less pronounced with C/T.

[Proof of beta-2-adrenergic activity of etilefrin (effortil) via aimed recording of its tocolytic action (author's transl)]. / Nachweis der beta-2-adrenergen Wirkung von Etilefrin (Effortil) durch gezielte Registrierung seines tokolytischen Effektes.

In 21 normal deliveries the intrauterine pressure was measured continuously during the first stage of labor. Thus the tocolytic efficiency of Etilefrin was revealed. Intensity and duration of the tocolytic effect were related to the dose. Pressure and frequency of the contractions were diminished. Therefore these results are conclusive that Etilefrin, generally given for its alpha- and beta 1 mimetic effects, has an additional beta 2-mimetic and tocolytic component.

Sympathovagal effects of spinal anesthesia assessed by the spontaneous cardiac baroreflex.

BACKGROUND: The changes in sympathovagal balance induced by spinal anesthesia remain controversial. The spontaneous baroreflex method allows the continuous assessment of the spontaneous engagement of the cardiac baroreflex, giving an index of sympathovagal balance. The purpose of this study was to follow the effects of spinal anesthesia on spontaneous baroreflex sensitivity. METHODS: Continuous electrocardiogram and noninvasive blood pressure were recorded in 24 patients scheduled for elective inguinal hernia repair and randomly assigned to three groups: (1) no volume loading, (2) volume loading of 15 ml/kg lactated Ringer's solution, and (3) continuous infusion of etilefrine (an ephedrine-like drug). Each patient was studied before, during, and after bupivacaine-induced spinal anesthesia (mean sensory block: T4). Spontaneous baroreflex sensitivity and parameters of time-domain analysis of heart rate variability were calculated from 30 min of recording of each period. RESULTS: No significant change in spontaneous baroreflex slope or parameters of time-domain analysis were observed after regional anesthesia in any group. However, three patients experienced episodes of bradycardia and hypotension in the absence of a high block; these three patients showed an increase in spontaneous baroreflex sensitivity and time-domain parameters. CONCLUSIONS: Using a noninvasive, continuous technique to estimate cardiac sympathovagal balance, no significant variation in autonomic balance induced by spinal anesthesia was observed. However, untoward episodes of bradycardia and hypotension occurred in three patients, who could not be prospectively identified by the parameters studied.

The cardiovascular effects of etilefrine.

Intravenous etilefrine increases the pulse rate, cardiac output, stroke volume, central venous pressure and mean arterial pressure of healthy individuals. Peripheral vascular resistance falls during the infusion of 1-8 mg etilefrine but begins to rise at higher dosage. Marked falls in pulse rate, cardiac output, stroke volume and peripheral bloodflow, accompanied by rises in mean arterial pressure, occur when etilefrine is infused after administration of intravenous propranolol 2,5 mg. These findings indicate that etilefrine has both beta 1 and alpha adrenergic effects in man.

[Effect of fetanol on animal tolerance in ftorotan anesthesia]. / Vliianie fetanola na vynoslivost' zhivotnykh v usloviiakh ftorotanovogo narkoza.

Experiments on 20 dogs with simultaneous recording of bioelectrical activity of the brain cortex, medial thalamus, heart, arterial pressure, respiration and oxygen tension in brain tissues have shown that purposive correction of arterial hypotension with the aid of pharmacological substances, particularly fetanol increases the resistance of the brain cortex and respiratory center, thereby raising the animals' tolerance of increasing ftorotan anesthesia.

The action of relaxin, fenoterol and etilefrine on uterine motility of the rat.

In uterine motility tests in virgin rats, the inhibitory action of the peptide hormone relaxin has been compared with the actions of fenoterol and etilefrine. At molecular levels, relaxin and fenoterol showed similar uterine inhibitory activity. Etilefrine was markedly less effective in inducing uterine relaxation. By pretreatment with propranolol, the inhibitory action of both fenoterol and etilefrine could be prevented but not the tocolytic effect of relaxin. Etilefrine, in higher doses, developed alpha-receptor activity as demonstrated by resumed uterine contractions. The doses required to induce beta 2- and alpha-activities differed by a factor of approximately 4,000.

Venoconstrictor agents mobilize blood from different sources and increase intrathoracic filling during epidural anesthesia in supine humans.

The authors studied the effects of dihydroergotamine (DHE) and etilefrine hydrochloride (E) on the regional distribution of 99mTc-marked erythrocytes during epidural anesthesia in eight supine men to determine if vasoactive agents with venoconstrictor action would enhance cardiac filling during epidural anesthesia. Radioactivity was recorded with a gamma camera, and its distribution determined in the thorax, abdomen, and limbs. Arterial and central venous pressure, heart rate, and calf volume by plethysmography were measured. During epidural anesthesia with a sensory block up to T4/5, DHE (7.5 micrograms/kg) reduced the radioactivity, i.e., blood volume, in both the innervated (-5.9 +/- 3.5%) and denervated muscle/skin (-16.9 +/- 7%) regions, and increased it in both the intrathoracic (+7.0 +/- 2.3%), and splanchnic vasculature (+4.2 +/- 3.2). In contrast, E (6 micrograms X kg-1 X min-1) decreased the blood volume most markedly in the splanchnic region (-5.4 +/- 0.7%) and increased it in the thorax (+2 +/- 0.6%). All these changes were statistically significant. The combined effects were estimated to be equivalent to a transfusion of nearly 1.01 of blood. Both drugs reversed the hypotensive action of epidural anesthesia. During epidural anesthesia, DHE preferentially constricted the capacitance vessels in skeletal muscle and skin irrespective of the state of innervation, whereas E preferentially constricted the splanchnic vasculature. In the doses used, the two agents replenished in an additive fashion the central circulation during epidural anesthesia.

[Influence of blood pressure control on delivery in pregnant rats in a warm environment].

The relation between blood pressure and delivery in pregnant rats was investigated when the blood pressure of pregnant rats was controlled by a pressor or antihypertensive drug in the middle or final stage of pregnancy. All of the pregnant rats studied delivered in a 23 degrees C environment in spite of blood pressure control by a pressor or antihypertensive drug. At 33 degrees C, the pregnant rats were divided into two groups whose blood pressure was increased severely (160-175 mm Hg) or moderately (145-155 mm Hg) at 10 days of pregnancy. Those in the former group delivered, but those in the latter died in the final stage of pregnancy. When the pregnant rats in the group with high blood pressure on day 10 were treated with a antihypertensive drug in the middle stage of pregnancy or with a pressor drug in the final stage, the mortality rate was 100 per cent in both cases. The delivery rate was 57 per cent when the pregnant rats were treated with a antihypertensive drug from the middle to the final stage of pregnancy. In the group with low blood pressure on day 10, all of the pregnant rats delivered when they were treated with a pressor drug in the middle stage of pregnancy. However, the delivery rate was 89 per cent when the pregnant rats were treated with antihypertensive drug in the final stage of pregnancy.

Changes in etilefrine-induced CNS effects when associated with theophylline.

A diverse set of techniques (curiosity, chimney test, changes in barbiturate-induced sleep time, spontaneous motor activity, swimming ability, body temperature) was used to study theophylline (T)-induced changes in CNS etilefrine (E). T antagonized the depressive effects produced by high doses of E. Nevertheless, the LD50 of E was not modified when both drugs were administered simultaneously.