Regional distribution and in vivo binding of the atypical antipsychotic drug remoxipride. A biochemical and autoradiographic analysis in the rat brain

Køhler, Christer; Radesäter, Ann-Cathrin; Karlsson-Boethius, G.; Bryske, B.; Widman, M

doi:10.1007/bf01253110

Cited by 19 publications

(9 citation statements)

References 25 publications

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“…There is limited evidence for regional differences in 0 2 receptor occupancies after acute administration of a few compounds, e.g., remoxipride (Kohler et al 1992), but no studies have shown this to be the case after repeated administrations leading to a steady state level of drug in brain. Further, receptor inactivation studies in vivo using EEDQ have suggested that remoxipride (acute treatment) binds to a subpopulation (unspecified) of 0 2 receptors .…”

Section: Effects In Models For Antipsychotic and Eps Activity Limbic mentioning

confidence: 99%

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Arnt

Skarsfeldt

1998

Neuropsychopharmacology

683

443

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The pharmacological properties of the novel antipsychotic drugs (APDs) risperidone, sertindole, olanzapine, quetiapine, ziprasidone, remoxipride, and amperozide are reviewed and compared with haloperidol and clozapine. Focus is made on their receptor profiles, their effects in animal models used for evaluation of antipsychotic activity, and extrapyramidal side effects (EPS). In addition, the contrasting actions of these compounds on animal modelsDuring the last decade there has been a dramatic increase in the efforts to develop novel antipsychotic drugs (APDs) with improved clinical efficacy and fewer or no extrapyramidal side effects (EPS) than the classical APDs such as haloperidol and fluphenazine. These efforts were undoubtedly inspired by the previous development of clozapine, which fulfilled these criteria to a large extent, although having other troublesome side From the Pharmacological Research, H. Lundbeck A/S, Ohiliavej 9, DK-2500, Copenhagen-Valby, Denmark.Address correspondence to: J0rn Arnt, Pharmacological Research, H. Lundbeck A/5, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark.Received January 6, 1997; revised June 26, 1997; accepted July 7, 1997. effects (Baldessarini and Frankenburg 1991; Coward 1992;Wagstaff and Bryson 1995;Buchanan 1995; Ashby and Wang 1996).The novel APDs were assigned the popular term "atypical antipsychotic" drugs to differentiate them from the classic or "typical" APDs or neuroleptics. The most widely accepted definition of a neuroleptic is a compound that has antipsychotic activity and induces EPS with high frequency. The definition of "a typicality" was equivocal, however, because the term was often used for drugs before any clinical results were available. For example, the term was applied to a compound that induced little or no catalepsy in rats, and that was effective in another model believed to reflect antipsychotic activity, e.g., inhibition of O-amphetamine (AMPH)-induced hypermotility. A more precise definition is to base it solely on clinical evidence as a wide differentiation between the dosages used to control psychosis and those inducing EPS-or on other aspects of clinical superior-0893-133X/98/$19.00 PI! 50893-133X(97)00112-7 64 J. Arnt and T. Skarsfeldt ity over classic APDs, e.g., efficacy on negative symptoms of schizophrenia or in drug-resistant patients (for recent review, see Kinan and Lieberman 1996). However, because these very different characteristics are difficult to incorporate in a common definition, we suggest that the terminology "atypical" is best avoided. Indeed, as will be discussed, novel APDs show many individual differences.The suggested alternative terminology "novel APO" is also not precise, but it can be defined as a compound that has been shown to inhibit positive symptoms of schizophrenia and has either been recently launched or is in phase II/III clinical development. Their specific profiles can be described more precisely, e.g., EPS-free APO, etc. It is not anticipated that novel APDs will be marketed in the future, unless hav...

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Section: Effects In Models For Antipsychotic and Eps Activity Limbic mentioning

confidence: 99%

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Arnt

Skarsfeldt

1998

Neuropsychopharmacology

683

443

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“…In the pre-injection design FLA 797(-) was more effective than remoxipride, FLA908(-) and NCQ436(-) in preventing quinpirole-induced hypothermia. NCQ 436(-), which is the major metabolite in plasma and urine following remoxipride administration to the rat (Widman et al, 1992), was the least effective and also had a shorter action than remoxipride, probably due to rapid metabolic inactivation (Widman etal., 1992). When the antagonists were given after the agonists, remoxipride was as effective as NCQ436(-) (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Remoxipride binds to dopamine (DA) D 2 and sigma recepetors in vitro, while its affinity towards other neurotransmitter receptors is very low (K6hler etal., 1990;Malmberg etal., 1993). Most of the effects of remoxipride relevant for its antipsychotic properties are observed in rodent studies in the same dose-range as the compound inhibits in vivo binding in the brain of the DAD 2 receptor antagonist [3H]spiperone or [3H]raclopride (K6hler et al, 1992;Ogren et al, 1984). This indicates that the pharmacological effects of remoxipride in the rat most likely are mediated by blocking DAD 2 receptors.…”

Section: Introductionmentioning

confidence: 93%

Dopamine D2 blocking activity and plasma concentrations of remoxipride and its main metabolites in the rat

Ögren

Lundström

Nilsson

et al. 1993

J. Neural Transmission

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Remoxipride and its active metabolites, the phenolic compounds FLA797(-) and FLA908(-) and the catecholic NCQ436(-) and haloperidol, were examined for their ability to block hypothermia in the rat induced by dopamine (DA) D2 receptor stimulation. In addition, plasma levels of remoxipride and its active metabolites were measured using HPLC methods. Remoxipride (1 mumol/kg), given 30 or 15 min prior to, or 5 and 15 min after, the DA agonists, blocked the hypothermia induced by the DA D2 receptor agonists quinpirole (0.25 mg/kg s.c.) and pergolide (0.1 mg/kg s.c.). Administration of remoxipride by the i.v. or s.c. routes was more effective than by the i.p. route. FLA797(-), FLA908(-), and haloperidol were more effective than remoxipride in preventing the hypothermia caused by quinpirole, while NCQ436(-) was less effective than remoxipride. The variation in time of remoxipride's action and effectiveness in blocking the induced hypothermia followed the variations in plasma concentrations. The plasma concentrations of the active metabolites were below the limit of determination (< 2 nmol/l). Based on estimation of free brain concentrations at effective dose levels together with in vitro affinities for the DA D2 receptor it was concluded that the metabolites FLA797(-), FLA908(-), and NCQ436(-) do not appear to contribute to the antagonism of DA D2 mediated neurotransmission following a low remoxipride dose (1 mumol/kg).

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“…Remoxipride, an antipsychotic agent, is transported from the CP vascular bed to the CSF and thereafter to the interstitial fluid of the medial caudate nucleus, hippocampus, thalamus, and cerebellum. One hour after injection of 3 H-remoxipride, there is a gradient of radioactivity from the ventricles to deep regions of the cerebrum including the forebrain (83). This pattern of drug distribution from CP to CSF to brain is similar to that of vitamin C. Autoradiograms reveal that intravenous 14 C ascorbate rapidly penetrates the BCSFB (but not the BBB).…”

Section: Caudatey Yputamenmentioning

confidence: 92%

Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

et al. 2005

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The choroid plexus (CP), i.e., the blood-cerebrospinal fluid barrier (BCSFB) interface, is an epithelial boundary exploitable for drug delivery to brain. Agents transported from blood to lateral ventricles are convected by CSF volume transmission (bulk flow) to many periventricular targets. These include the caudate, hippocampus, specialized circumventricular organs, hypothalamus, and the downstream pia-glia and arachnoid membranes. The CSF circulatory system normally provides micronutrients, neurotrophins, hormones, neuropeptides, and growth factors extensively to neuronal networks. Therefore, drugs directed to CSF can modulate a variety of endocrine, immunologic, and behavioral phenomema; and can help to restore brain interstitial and cellular homeostasis disrupted by disease and trauma. This review integrates information from animal models that demonstrates marked physiologic effects of substances introduced into the ventricular system. It also recapitulates how pharmacologic agents administered into the CSF system prevent disease or enhance the brain's ability to recover from chemical and physical insults. In regard to drug distribution in the CNS, the BCSFB interaction with the blood-brain barrier is discussed. With a view toward translational CSF pharmacotherapy, there are several promising innovations in progress: bone marrow cell infusions, CP encapsulation and transplants, neural stem cell augmentation, phage display of peptide ligands for CP epithelium, CSF gene transfer, regulation of leukocyte and cytokine trafficking at the BCSFB, and the purification of neurotoxic CSF in degenerative states. The progressively increasing pharmacological significance of the CP-CSF nexus is analyzed in light of treating AIDS, multiple sclerosis, stroke, hydrocephalus, and Alzheimer's disease.

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Regional distribution and in vivo binding of the atypical antipsychotic drug remoxipride. A biochemical and autoradiographic analysis in the rat brain

Cited by 19 publications

References 25 publications

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Dopamine D2 blocking activity and plasma concentrations of remoxipride and its main metabolites in the rat

Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

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