Mechanism-based PK-PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans.

The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16 mg/kg and (2) following double dosing of 3.8 mg/kg with different time intervals. The mechanistic PK-PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK-PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16 mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK-PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms.

Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration.

Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (nose-to-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.

Comparison of the agonist-antagonist interaction model and the pool model for the effect of remoxipride on prolactin.

AIMS: The tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built. METHODS: The remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM. RESULTS: According to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well. CONCLUSIONS: According to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time.

Evaluation of osmotic effects on coated pellets using a mechanistic model.

The aim of this study was to develop a simple experimental methodology and to develop a mechanistic model to characterize the release mechanism from pellets developing cracks during the release process with special focus on osmotic effects. The release of remoxipride from pellets coated with an ethyl cellulose film was chosen as a case study. Dose release experiments at different bulk osmotic pressures revealed that the release process was mainly osmotically driven. The model was used to calculate the solvent permeability of the coating, 1.1 x 10(-10)m(2)h(-1)MPa(-1). The model was validated by release experiments using similar pellets having different coating thicknesses. The effective diffusion coefficient of remoxipride in the coating was also calculated and found to be 1.7 x 10(-10)m(2)h(-1). A series of experiments was performed in which the osmotic pressure of the receiving solution was changed during the experiment. From the results of these experiments, the area of the cracks in the film, formed by the hydrostatic pressure built up inside the pellets, was estimated to be 3.5 x 10(-5)m(2)/m(2) coating. It could also be deduced that the solvent permeability of the coating film was affected by swelling in the same way at different osmotic pressures.

Modeling of prolactin response following dopamine D2 receptor antagonists in rats: can it be translated to clinical dosing?

Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2 receptor occupancy and plasma prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist-antagonist interaction model. Using interspecies scaling approaches, human D2 receptor occupancy and plasma prolactin concentrations were predicted for a range of clinical paliperidone and remoxipride doses. The predictions were compared with corresponding observations described in literature as well as with predictions from published models developed on human data. The pool model could predict D2 receptor occupancy and prolactin response in humans following single doses of paliperidone and remoxipride. Tolerance of prolactin release was predicted following multiple doses. The interaction model underpredicted both D2 receptor occupancy and prolactin response. Prolactin elevation may be deployed as a suitable biomarker for interspecies translation and can inform the clinical safe and effective dose range of antipsychotic drugs. While the pool model was more predictive than the interaction model, it overpredicted tolerance on multiple dosing. Shortcomings of the translations reflect the need for better mechanistic models.

New perspective therapy of breast cancer based on selective dopamine receptor D2 agonist and antagonist effects on MCF-7 cell line.

Different studies have shown the role of neurotransmitters (e.g., dopamine) in the progression of cancers via their various types of receptors. The aim of this study was to determine the pattern of dopamine receptors gene expression on MCF-7 cells and to evaluate the selective dopamine receptors agonist and antagonist effects on them. In addition, some other discoveries which are patented for the treatment of breast cancer are reviewed in this article. To determine the pattern of dopamine receptors gene expression in human breast cancer cells (MCF-7), RT-PCR was performed. Then, MCF-7 cells were treated by different doses of bromocriptine and remoxipride for 48 hours. Cell viability was evaluated by MTT assay. Thus, nuclear morphology of cells was analyzed by mixed dye florescent staining. Real time PCR technique was performed to determine the decreasing rate of proliferating cell nuclear antigen (PCNA) gene expression in treated MCF-7 cells. Finally, quantification of apoptosis and its difference with necrosis at the single cell level were assessed by Flowcytometery technique. This study revealed that, unlike remoxipride, bromocriptine suppressed proliferation of the MCF-7 cells (54.3% at 12.5µM bromocriptine concentration), but remoxipride could suppress the effect of bromocriptine. Bromocriptine has inhibitory effects on MCF- 7 cells by induction of apoptosis via D2-like receptors. Therefore, in future studies, bromocriptine can be used as a new choice for the treatment of tumoral breast cancer cells.

Newer antipsychotic drugs. A review of their pharmacology and therapeutic potential.

Despite the enormous benefits provided by antipsychotic medication in the management of schizophrenia, available compounds have serious limitations. Firstly, they are not always effective. Secondly, positive psychopathological symptoms may benefit more than negative or deficit symptoms. Thirdly, antipsychotics are generally associated with a variety of neurological adverse effects. Three drugs have recently been or are close to being introduced into widespread clinical use: clozapine, risperidone and remoxipride. Each of these compounds appears to have some advantages over traditional antipsychotic agents, particularly in terms of reduced propensity to induce adverse neurological effects. All three drugs have been shown to be clinically effective in large scale trials. Future clinical trials are required to establish their relative merits in comparison with one another.

Regulation of striatal aromatic L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors.

Previous experiments have shown that blockade of dopamine D1 or D2 receptors by SCH 23390 or pimozide increases aromatic L-amino acid decarboxylase (AADC) activity in the rat striatum and the mesolimbic system. This study examined whether other dopamine receptor antagonists affect AADC activity and if there is an interaction between dopamine D1 and D2 receptor blockade on AADC activity. The possible effect of dopamine receptor agonists on AADC activity has been investigated as well. Administration of cis-flupenthixol (0.5 and 1 mg/kg) increased striatal AADC activity (by 25 and 26% above controls) and similar effects were observed with remoxipride (0.5-4 mg/kg) (by 18-27% above controls). Pretreatment with cycloheximide (10 mg/kg) did not change the increases produced by cis-flupenthixol (0.5 mg/kg). The administration of non-neuroleptic trans-flupenthixol did not change AADC activity. Combined treatment with SCH 23390 (0.1 mg/kg) and remoxipride (0.5 mg/kg), but not combination of SCH 23390 (0.1 mg/kg) and pimozide (0.3 mg/kg), showed higher increases of AADC activity than by the individual treatments, suggesting an interaction between the effects of the two drugs. Bromocriptine, but not (-)-quinpirole and d-amphetamine, significantly reduced the striatal AADC activity by 23% at the dose of 10 mg/kg. The results further demonstrate that AADC is a regulated enzyme in the rat brain.

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 micrograms/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na+ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.

Locomotor inhibition, yawning and vacuous chewing induced by a novel dopamine D2 post-synaptic receptor agonist.

The N-n-propyl analog of dihydrexidine ((+/-)-trans-10, 11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine) is a dopamine receptor agonist with high affinity for dopamine D2 and D3 receptors (K0.5 = 26 and 5 nM, respectively). Members of the hexahydrobenzo[a]phenanthridine structural class are atypical because they display high intrinsic activity at post-synaptic dopamine D2 receptors, but low intrinsic activity at dopamine D2 autoreceptors. The present study examined the effects of (+/-)-N-n-propyl-dihydrexidine on unconditioned behaviors in rats. The most striking results observed were large, dose-dependent decreases in locomotor activity (e.g., locomotor inhibition), and increases in vacuous chewing; yawning was also increased at the highest dose of (+/-)-N-n-propyl-dihydrexidine. The locomotor inhibition and yawning induced by (+/-)-N-n-propyl-dihydrexidine were blocked by pre-treatment with (-)-remoxipride (S(-)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2, 6-dimethoxybenzamide), a dopamine D2 receptor antagonist, but not by the dopamine D1 receptor antagonist (+)-SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Vacuous chewing was decreased by both (-)-remoxipride and (+)-SCH23390. These data support the hypothesis that a subpopulation of post-synaptic dopamine D2 receptors has a critical role in decreases in locomotor activity and induction of vacuous chewing and yawning.

Neurochemical effects of prolonged treatment with remoxipride as assessed by intracerebral microdialysis in freely moving rats.

1. At three microdialysis sessions, dialysates were collected from the striatum of the same rats. 2. Microdialysis session 1. A single s.c. injection of remoxipride (40 mumol/kg), resulted in increased dialysate concentrations of dopamine, DOPAC and HVA. 3. Microdialysis session 2. Continuous administration of remoxipride (8.6 mumol/rat/day) for 14 days, using mini-osmotic pumps, produced maintained elevated levels of dopamine, DOPAC and HVA. 4. Microdialysis session 3. A challenge dose of remoxipride (40 mumol/kg s.c.), given to the rats after a 48-hour wash-out period following the continuous remoxipride treatment, increased the dialysate concentrations of dopamine, DOPAC and HVA to similar extent as at dialysis session 1. 5. It is concluded that after long-term treatment of remoxipride, an adaptation of the basal state of the DA system appears to take place, implying a lowering of basal DA release and DA metabolism. However, the capacity to respond with increased DA release and DA metabolism to renewed remoxipride treatment is retained, indicating little, if any, tolerance.

Investigation into the antinociceptive potential of remoxipride administered intrathecally in sheep.

Systemic administration of remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p<0.05) increase in nociceptive thresholds as judged by a focused mechanical stimulus (blunt pin) applied to the forelimb of four sheep. However, this dose of remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system. Conversely, intrathecal xylazine (100 and 200 microg), an alpha-adrenergic agonist with antinociceptive properties, did not produce forelimb weakness although the higher dose (200 microg) produced significant sedation. In vitro autoradiography was performed on cervical spinal cord sections taken from sheep. Remoxipride displaced [3H] YM-09151-2, a selective D2 antagonist, from densely-labelled areas in the superficial layer of the dorsal horn, lamina X and ventral horn. Even though there are possible anatomical substrates within the spinal cord for both an antinociceptive and motor disturbance action of remoxipride, the behavioural data suggest that the spinal cord is unlikely to be the primary site of antinociceptive action for systemically-administered doses of remoxipride.

Single dose pharmacodynamics of thioridazine and remoxipride in healthy younger and older volunteers.

Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9 h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.

Disposition of remoxipride in Chinese schizophrenic patients.

The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride.

Accelerated dissolution rate analysis (ACDRA) for controlled release drugs. Application to Roxiam.

Accelerated dissolution rate analysis by elevated temperature has been applied to the release of remoxipride from a controlled release drug. Roxiam, and compared to the standard USP method. A PLS model has been used in evaluating the factors of importance of the release as well as for the comparison to the standard USP method. Accelerated Dissolution Rate Analysis (ACDRA) offers the possibility of substantial reduction of analysis time. The time needed for one analysis with ACDRA is less than 5% of the USP-method. The automated analytical procedure is well suited for use in process control as well as in the early stages of the formulation development.

Mechanistic model for drug release during the lag phase from pellets coated with a semi-permeable membrane.

A new mechanistic model of drug release during the lag phase from coated pellets undergoing cracking in the coating due to the hydrostatic pressure built up inside the pellet has been developed. The model describes dynamically all the main release processes occurring during the lag phase in pellets coated with a semi-permeable membrane, i.e. the influx of solvent driven by the difference in osmotic pressure across the coating, dissolution of the drug, swelling of the pellet due to solvent accumulation, build-up of hydrostatic pressure inside the pellet, tensile stress acting on the coating, and the efflux of the dissolved drug. The water uptake is described using irreversible thermodynamics theory, while the tensile stress is described using solid mechanics theory. Importantly, the model allows the prediction of the lag time prior to crack formation. The effect of the pellet size, the pellet shape and the coating thickness on the lag time and on the lag phase release profile has been investigated via computer simulations. The model was validated by comparison with dose release data obtained from pellets coated with an ethyl-cellulose-based film. The good agreement found between the predicted release and the experimental data confirmed the validity of the model.

A dose-finding study with remoxipride in the acute treatment of schizophrenic patients.

Two hundred and forty-two patients with acute schizophrenia were enrolled in a double-blind, comparative, dose-finding study of a novel antipsychotic, remoxipride. Remoxipride was evaluated in a low (30 to 90 mg), medium (120 to 240 mg) and a high (300 to 600 mg) dose range and compared with a haloperidol (15 to 45 mg), which was administered to a similar group of patients. The results support the antipsychotic effect of remoxipride, with maximum efficacy occurring at daily doses between 120 mg and 600 mg. Side-effects were more frequent at doses of remoxipride over 300 mg. In all groups, remoxipride caused consistently fewer extrapyramidal side-effects than haloperidol. The antipsychotic effect of remoxipride may be derived from specific blockade of dopamine D2 receptors in the mesolimbic tract. The findings also suggest that remoxipride may have a therapeutic effect on negative symptoms of schizophrenia.

In vivo validation of the release rate and palatability of remoxipride-modified release suspension.

Remoxipride, a D2-dopamine receptor antagonist, is well tolerated and completely absorbed after oral administration. Because of its extremely bitter taste, an oral palatable suspension was developed by using a taste-masking microencapsulation. The bioavailability of remoxipride was investigated in two studies in healthy volunteers after administration of a 100-mg dose in suspension. The first study used a capsule as reference, and the second study a plain solution. Taste assessment was carried out in the second study. The extent of bioavailability was the same when comparing the oral suspension to a capsule and to a plain solution. However, the rate of absorption is delayed, and Tmax was 3.0 hr after the suspension, 1.0 hr after the oral solution, and 1.6 hr after the capsule. The release rate in vitro from the suspension was determined by applying the USP-paddle method. By using numerical convolution and deconvolution, the release rates in vivo and in vitro were shown to be similar when using water with 0.5% sodium lauryl sulfate as dissolution liquid. The taste-masked oral suspension is suitable for full-scale production, with good control of the encapsulation process and of the preparation of a suspension.