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.

Additive Proarrhythmic Effect of Combined Treatment with QT-Prolonging Agents.

Drug combinations may elevate the risk of proarrhythmia. The aim of the present study was to investigate whether combinations of non-cardiovascular agents induce an additive increase in the proarrhythmic risk. In 12 female rabbit hearts, a drug combination of cotrimoxazole (300 µM), ondansetron (5 µM) and domperidone (1 µM) was infused after obtaining baseline data. In another 13 hearts, a combination of cotrimoxazole (300 µM), ondansetron (5 µM) and erythromycin (300 µM) was infused. Monophasic action potentials and ECG displayed a significant QT prolongation in all groups. This was accompanied by a significant increase in action potential duration. Of note, addition of each drug resulted in a further increase in the QT interval. Furthermore, a significant elevation of spatial dispersion of repolarization was observed. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations and torsade de pointes (TDP) in both study groups. Under baseline conditions, no episodes of TDP recorded. After administration of the first agent, TDP occurred in 5 of 12 hearts (37 episodes) and 5 of 13 hearts (26 episodes), respectively. After additional infusion of the second drug, TDP were recorded in 7 of 12 hearts (55 episodes) and 8 of 13 hearts (111 episodes). After additional infusion of the third drug, TDP occurred in 11 of 12 hearts (118 episodes) and 9 of 13 hearts (88 episodes). Combined treatment with several non-cardiovascular QT-prolonging agents resulted in a remarkable occurrence of proarrhythmia. An additive and significant prolongation of cardiac repolarization combined with an increased spatial dispersion of repolarization represents the underlying electrophysiological mechanism.

Severe Proarrhythmic Potential of the Antiemetic Agents Ondansetron and Domperidone.

The potential of ondansetron and domperidone, both clinically established antiemetic agents, to increase the QT-interval has been described in several case reports. Therefore, the aim of the present study was to investigate whether these drugs may provoke polymorphic ventricular tachycardia in a sensitive experimental model of drug-induced proarrhythmia. In 10 female rabbits, ondansetron (1, 5 and 10 µM, n = 10) or domperidone (0.5, 1 and 2 µM, n = 8) was infused after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG reproduced the clinically observed QT-prolongation (ondansetron: 1 µM:+17 ms, 5 µM:+41 ms, 10 µM:+78 ms, p < 0.01; domperidone: 0.5 µM:+57 ms, 1 µM:+79 ms, 2 µM:+99 ms, p < 0.01). This was accompanied by a significant increase in action potential duration at 90% of repolarization. Administration of both agents also increased dispersion of repolarization (ondansetron: 1 µM:+12 ms, 5 µM:+17 ms; 10 µM:+18 ms, p < 0.05; domperidone: 0.5 µM:+19 ms, 1 µM:+27 ms; 2 µM:+23 ms p < 0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 9 of 10 ondansetron-treated hearts and induced polymorphic ventricular tachycardia (VT) resembling torsade de pointes in 7 of 10 ondansetron-treated hearts (86 episodes). Under the influence of domperidone, EAD and polymorphic VT occurred in 7 of 8 hearts (131 episodes). In the present study, both ondansetron and domperidone demonstrated a severe proarrhythmic potential. A significant prolongation of cardiac repolarization as well as a marked increase in spatial dispersion of repolarization represents the underlying electrophysiologic mechanisms. These results imply that application of ondansetron should be handled carefully. For regular administration, ECG monitoring should be mandatory.

Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels.

BACKGROUND: Metoclopramide and domperidone are prokinetic and antiemetic substances often used in clinical practice. Although domperidone has a more favorable side effect profile and is considered the first-line agent, severe cardiac side effects were reported during the administration of both substances. Cardiac Na channels are common targets of therapeutics inducing cardiotoxicity. Therefore, the aim of this study was to investigate whether the differential cardiotoxicities of metoclopramide and domperidone correlate with the block of Na channels. METHODS: Effects of metoclopramide and domperidone on the human α-subunit Nav1.5 expressed in human embryonic kidney 293 cells and on Na currents in neonatal rat cardiomyocytes were investigated by means of whole-cell patch clamp recordings. RESULTS: Tonic block of resting Nav1.5 channels was more potent for domperidone (IC50 85 ± 25 µM; 95% confidence interval [CI], 36-134) compared with metoclopramide (IC50 458 ± 28 µM; 95% CI, 403-513). Both agents induced use-dependent block at 10 and 1 Hz, stabilized fast and slow inactivation, and delayed recovery from inactivation. However, metoclopramide induced considerably smaller effects compared with domperidone. Na currents in rat cardiomyocytes displayed tonic and use-dependent block by both substances, and in this system, domperidone (IC50 312 ± 15 µM; 95% CI, 22-602) and metoclopramide (IC50 250 ± 30 µM; 95% CI, 191-309) induced a similar degree of tonic block. CONCLUSIONS: Our data demonstrate that the clinically relevant cardiotoxicity of domperidone and metoclopramide corresponds to a rather potent and local anesthetic-like inhibition of cardiac Na channels including Nav1.5. These data suggest that Nav1.5 might be a hitherto unrecognized molecular mechanism of some cardiovascular side effects, for example, malignant arrhythmias of prokinetic and antiemetic agents.

P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.

Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.

Formulation and Evaluation of Matrix Diffusion Controlled Transdermal Patches of Domperidone hydrochloride

A matrix dispersion type transdermal drug delivery system of domperidone was developed using different ratios of rosin with Eudragit RL and Eudragit RS. The effect of the polymers on the technological properties, i.e., drug release, water vapor transmission rate, percentage moisture loss and thickness were investigated. The patch containing Eudragit RL: Eudragit RS (8:2) showed a release of 87.10% in 12 h. Formulation D1 emerged as the most satisfactory formulation as far as the technological properties were concerned. Further skin permeation and skin irritation studies were carried out on rat skin and rabbit respectively. Therefore it can be concluded that the patch containing Eudragit RL: Eudragit RS in the ratio 8:2 achieved the desired objectives of transdermal drug delivery systems, such as overcoming of first pass effect, extended release and reduced frequency of administration(AU)

Se ha desarrollado un sistema de administración de fármaco transdérmico de matriz de dispersión de domperidona utilizando diferentes coeficientes de resina con Eudragit RL y Eudragit RS. Se ha investigado el efecto de los polímeros en las propiedades tecnológicas, es decir, liberación del fármaco, coeficiente de la transmisión del vapor del agua, porcentaje de pérdida de humedad y espesor. El parche con Eudragit RL: Eudragit RS (8:2) ha mostrado una liberación de 87,10% en 12 h. La formulación D1 ha resultado ser la formulación más satisfactoria, en la medida que afecta a las propiedades tecnológicas. Se han llevado a cabo otros estudios sobre permeabilidad e irritación cutánea en piel de ratones y de conejos respectivamente. Por lo tanto, se puede determinar que el parche que contiene RL: Eudragit RS en un coeficiente de 8:2 ha alcanzado los objetivos fijados de los sistemas de administración de fármaco transdérmico como una superación del efecto del primer pase, liberación prolongada y frecuencia reducida de administración(AU)

Gender-related differences in drug-induced prolongation of cardiac repolarization in prepubertal guinea pigs.

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (I(Kr) ) or/and the slow (I(Ks)) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I(Ks) blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD( 90)) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD(90) prolongation induced by domperidone or dofetilide (I(Kr) blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD( 90) caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD(90) when exposed to indapamide, 2) no gender-related differences were observed for I( Kr) blockers, and 3) verapamil treatment did not uncover gender-related differences in I(Kr) or I(Ks) block, although it augmented prolongation of cardiac repolarization by I(Kr) blockers.

Comparison of the effects of metoclopramide and domperidone on HERG channels.

Torsades de pointes (TdP) is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT prolongation and TdP is blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by HERG (human ether-a-go-go-related gene). The gastroprokinetic agent cisapride is a potent blocker of HERG currents and serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation have been reported in patients taking cisapride. The aim of the present study was to compare the effects of the gastroprokinetic agents domperidone and metoclopramide on HERG channels transiently expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both domperidone and metoclopramide concentration-dependently blocked HERG currents, and the following values were calculated for IC(50) (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 micromol/l and 0.95 for metoclopramide. The observation that the extent of block of HERG currents by domperidone increased at more positive membrane potentials whereas block of HERG currents by metoclopramide displayed a smaller degree of voltage dependency seems to indicate that domperidone and metoclopramide have distinct binding sites on HERG channels. In conclusion, the potency for block of HERG currents is about 100-fold lower for metoclopramide when compared to domperidone.

Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A.

The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.

In vivo mutagenicity evaluation of domperidone in Drosophila germ cells and rat bone marrow cells.

Possible induction of chromosome aberrations and gene mutations by domperidone was studied in vivo respectively by a micronucleus test on female rats and a sex-linked recessive lethal test on Drosophila. In accordance with previous results all these studies revealed negative findings for domperidone so that it can be concluded that domperidone has no potential to induce chromosome aberrations and/or gene mutations.

Peripheral DA receptor blockade facilitates behavioural recovery from nigrostriatal damage.

Animals were injected via the intraperitoneal route with the peripheral dopamine receptor blocker domperidone for three days before receiving bilateral lesions of the lateral hypothalamus. Pretreatment with domperidone significantly facilitated recovery from lesion imposed deficits in consummatory behaviour and motor reflex control. The enhanced behavioural recovery achieved with domperidone pretreatment was similar to that which occurs with other dopamine receptor blockers but such recovery has been attributed to the central effects of these compounds. The results from this study demonstrate that recovery from catecholamine depleting lesions, attributed previously to the development of striatal receptor hypersensitivity, may also be due to changes in dopamine receptors outside the blood-brain barrier.

Changes in blood-brain barrier permeability to drugs in decompressed rats.

A study has been made of changes in permeability of the blood-brain barrier (BBB) to drugs following exposure to compression-decompression. Fifty-five rats were exposed to 6.1 b (abs) air for 90 min and subsequently linearly decompressed to the ambient pressure during a period of 3 min. Thirty-five rats serving as controls were kept at the ambient pressure. Catalepsy, which is mediated through the striatal dopamine receptors, was used as a behavioral indicator for the penetration of drugs into the brain. A comparison was made between drugs that normally pass the BBB (atropine, 10 mg/kg; haloperidol, 2 mg/kg) and drugs that do not readily pass the BBB as a rule (methylatropine, 10 mg/kg; domperidone, 10-20 mg/kg). Evans blue, injected intravenously, was used for the visualization of possible changes in the BBB permeability. It was found that methylatropine significantly prevented haloperidol-induced catalepsy in decompressed rats, in comparison with control rats. However, this prevention was not so intense as that found after injection of a similar dose of atropine. Domperidone induced a weak catalepsy in decompressed rats, but failed to induce any catalepsy in control rats. Gross and fluorescence-microscopic examination revealed an increased penetration of Evans blue into the brains of the decompressed rats. It is concluded that compression-decompression exposure can induce a limited but significant breakage of the BBB, leading to an increase in the central effects of the drugs that normally display poor penetration of the BBB. The measurement of behavioral changes provided a new and relevant technique for studying the changes of BBB permeability to drugs.