The effect of anti-emetic drugs on rat embryonic heart activity.

Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications (AEM) (droperidol, domperidone, granisetron, metoclopramide and trifluoperazine) used to treat NVP have the unwanted side effect of hERG blockade. The hERG potassium channel is essential for normal heart rhythm in both the adult human and the human and rat embryo. Animal studies show hERG blockade in the embryo causes bradycardia and arrhythmia leading to cardiovascular malformations and other birth defects. Whole rat embryo in vitro culture was used to determine the effect of the above listed AEM and meclizine on the heart rate of Gestational day 13 rat embryos. These embryos are similar in size and heart development to 5-6-week human embryo. The results showed that all of the AEMs caused a concentration-dependent bradycardia. Droperidol had the lowest margin of safety.

Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve.

INTRODUCTION: Drug-induced QT-prolongation, often based on hERG K+ current inhibition, has become a major safety concern during drug development. Hence, regulatory guidelines require combined in vitro and in vivo assays to assess the potential of new chemical entities to delay ventricular repolarization. Here, results of a pharmacological validation study with the torsadogenic compound sotalol are presented. METHODS: Alteration of ECG parameters was investigated in both conscious and anesthetized Beagle dogs (cumulative infusions of D,L-sotalol; n=6). The repolarization reserve of the latter was reduced by neurolept anesthesia using the hERG blocker droperidol (0.25 mg/kg/h yielding mean plasma concentrations of 0.5 microM). Furthermore, hERG K+ current and action potentials (AP; rabbit Purkinje fibers) were measured in vitro. RESULTS: The Fridericia corrected QT interval, QTcF, in conscious dogs (control: 254+/-15 ms), was dose-dependently prolonged by D,L-sotalol (+42 ms at plasma levels of 261 microM; dose 30 mg/kg). In anesthetized dogs, baseline QTcF (337+/-35 ms) was already prolonged compared to conscious dogs. In addition, QTcF-increase (+90 ms) was more pronounced at lower D,L-sotalol plasma levels (181 microM; dose 10 mg/kg), and proarrhythmic markers Tpeak-Tend and short term variability of QT were increased. These in vivo findings are supported by in vitro data. The hERG K+ current was blocked by D,L-sotalol (IC50 approximately 1.2 mM, IC20 approximately 250 microM) and droperidol (IC50 approximately 0.1 microM, IC20 approximately 0.02 microM). Purkinje fiber APs were concentration-dependently prolonged by D,L-sotalol (APD90:+60% at 30 microM) and droperidol (APD90:+55% at 1 microM). Low droperidol concentrations increased the sensitivity of Purkinje fibers towards D,L-sotalol-mediated AP prolongation. DISCUSSION: In conclusion, the higher sensitivity of anesthetized dogs towards sotalol-induced QT-prolongation is due to a reduced cardiac repolarization reserve caused by the hERG blocker droperidol. Hence, the droperidol-/fentanyl-/N2O-anesthetized dog is a particularly sensitive animal model for the detection of drug-induced QT-prolongation in safety pharmacology studies.

Effects of anesthesia on a model of uncontrolled hemorrhage in rats.

OBJECTIVES: Excessive blood loss in a rat model of uncontrolled hemorrhage has been attributed to the vasodilatory effects of a droperidol-ketamine mixture used for anesthesia. The present study compared responses to droperidol-ketamine and pentobarbital with those responses of a control group without anesthesia during uncontrolled hemorrhage. DESIGN: Prospective, randomized, controlled trial. SETTING: University surgical research laboratory. SUBJECTS: Forty-five female Sprague-Dawley rats (210 to 275 g). INTERVENTIONS: Rats were randomly divided into three groups of 15 each according to the type of anesthesia: unanesthetized; pentobarbital; and droperidol-ketamine. A 75% tail resection was used to initiate hemorrhage. Mortality, survival time, and blood loss were monitored, and the differences between all three groups were tested using chi 2 test (mortality) and one-way analysis of variance (ANOVA) (survival and blood loss) for statistical significance. MEASUREMENTS AND RESULTS: Mean blood loss amounts at 15 mins were 8.9, 13.6, and 22.4 mL/kg for the unanesthetized, pentobarbital, and droperidol-ketamine groups, respectively. Mortality rates for the three groups were 0%, 0%, and 53% at 30 mins and 60%, 33%, and 93% at 90 mins, respectively. Mean survival times for these groups were 94, 135, and 39 mins, respectively. CONCLUSIONS: An excessive rate of blood loss due to the use of droperidol-ketamine anesthesia renders this model inappropriate for investigation of uncontrolled hemorrhage. The response of rats under pentobarbital anesthesia more closely approximates that of unanesthetized rats. However, the higher mortality rate despite the lesser hemorrhage observed in the latter group seems to indicate the existence of other factors (in addition to blood loss) that may contribute to the early death of these animals.

An evaluation of three neuroleptanalgesic combinations in rabbits.

In this study, novel combinations of analgesics and neuroleptics were used in the rabbit in an attempt to produce a surgical level of anesthesia. A commercially available mixture of fentanyl (0.06 mg/kg) and droperidol (3.0 mg/kg; F/D) was evaluated alone and in combination with either the benzodiazepine derivative, diazepam (2 mg/kg) or the alpha-2 adrenoceptor agonist, detomidine (20 micrograms/kg). Rabbits were anesthetized on consecutive weeks with one of the three regimens. Heart rate, respiratory rate, blood pressure, and arterial blood gases (pH, PCO2, PO2) were measured throughout each trial. The times of loss and return of palpebral, righting, and pedal reflexes were recorded. The addition of diazepam to the F/D combination caused marked prolongation of the duration of reflex loss for all reflexes. If the duration of reflex loss for F/D is considered to be 100%, then F/D plus diazepam (F/D/diazepam) prolonged the duration of reflex loss to 547% and 204% for righting and pedal reflex, respectively. The combination of F/D/diazepam produced significantly different results from those for either of the other combinations for righting reflex and palpebral reflex. The results for F/D/diazepam were also markedly different from F/D for pedal reflex, but were not significantly different from those for F/D/detomidine. Prolongation of the duration of reflex loss was more moderate with the addition of detomidine (148% and 174% for righting and pedal reflexes, respectively). Reflexes persisted in some rabbits for each anesthetic regimen. Palpebral reflex was preserved in one of the rabbits given F/D/diazepam, four of five rabbits given F/D, and in two rabbits given F/D/detomidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Histopathology and evaluation of potentiation of morphine-induced antinociception by intrathecal droperidol in the rat.

Clinical studies have indicated that a low dose of the dopamine D2-receptor antagonist droperidol given epidurally potentiate the antinociceptive effect of epidural morphine. The present study was conducted in order to evaluate this drug interaction in a rat model. Rats were given morphine and droperidol intrathecally in several combinations of doses. It was found that droperidol had no antinociceptive effect by itself, nor in combination with morphine. It was also shown that droperidol and morphine exert no histopathological effects on the rat spinal cord. This discrepancy between clinical findings and experimental pain studies suggests different modes of action of droperidol in the two situations.

[Changes in the pharmacodynamic properties of promedol, droperidol and dimedrol in burn shock and combined radiation-thermal injury]. / Izmeneniia farmakodinamicheskikh svoistv promedola, droperidola i dimedrola pri ozhogovom shoke i kombinirovannom radiatsionno-termicheskom porazhenii.

Toxic and pharmacological properties of promedol, droperidol and dimedrol were studied during burn shock and combined radiation and thermal injury (CRTI). Acute toxicity and analgesic effect of promedol were shown to increase in the given period Droperidol analgesic effect enhanced in burn and CRTI, cataleptic action enhanced only in CRTI. A decrease of antihistaminic activity of dimedrol was more pronounced in CRTI.

[Effects of general anaesthesia with halothane and neuroleptic anaesthesia on free plasma amino acids (author's transl)]. / Auswirkung von Halothan und Neuroleptika auf die freien Plasmaaminosäuren.

Changes of plasma amino acids in animal studies were observed after administration of different narcotic drugs. In a randomised study the effects of neuroleptic anaesthesia and general anaesthesia with halothane on free plasma amino acids in respect to liver toxicity were investigated in patients during microsurgery of the middle ear. 24 hours postoperatively in both groups a significant increase of branched chain amino acids and of phenylalanine as metabolic sign of stress was found. Typical changes of amino acids as shown in hepatic failure could not be seen in both groups. The study showed that none of the narcotics used had a toxic effect on liver function as measured by the levels of free plasma amino acids and that for disagrees with the results of animal studies.

The influence of orphenadrine HCl in overdose alone and in combination with droperidol on respiration and circulation in the rat.

Orphenadrine HCL was intravenously administered to rats under urethane anesthesia to investigate whether the primary cause of death in orphenadrine intoxication is respiratory arrest or cardiac standstill. The spontaneously breathing animals died from apnoe after a mean dose of 63 + 11 mg/kg. The artificially ventilated animals died from cardiac arrest after a mean dose of 144 +/- 47 mg/kg. It was concluded that primary cause of death is respiratory insufficiency and that hypoventilation can mask the cardiotoxicity of orphenadrine. On the analogy of earlier experiments in dogs the ability of droperidol to counteract the influence of orphenadrine was investigated. Droperidol enhanced the influence of orphenadrine on respiration and had no influence on the cardiotoxic influence of orphenadrine in the rat.