5-HT2A ( Ki = 0.17 nM ); α2c-adrenergic receptor ( Ki = 1.3 nM ); α2c-adrenergic receptor ( Ki = 1.3 nM ); D2 receptor ( Ki = 3.57 nM ); D3 receptor ( Ki = 3.6 nM ); D2L Receptor ( Ki = 4.16 nM )

In vitro activity: Risperidone binds to serotonin (5HT) and dopamine (DA) receptors, especially those found in the neurons of the limbic and striatal regions. Risperidone dramatically alters the amount of brain nerve growth factor (NGF), indicating that it has an impact on endogenous growth factor turnover. Risperidone either increases or decreases TrkB receptors in specific brain structures and significantly reduces BDNF concentrations in the hippocampus, occipital cortex, and frontal cortex.[1] In rat forebrain regions, risperidone dramatically increases D(2) binding by 34% in the medial prefrontal cortex. In rat forebrain regions, risperidone causes an even higher up-regulation of D(4) receptors in CPu (37%), NAc (32%), and HIP (37%).[2] Risperidone dramatically reduces activated microglia's ability to produce proinflammatory cytokines and NO.[3] Risperidone (1-50 mM) increases the intracellular accumulation of Rh123 in Caco-2 cells by IC(50) = 5.87 mM, which is the inhibitory effect of P-gp activity. [4]

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Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-γ and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α by IFN-γ-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.[3]

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 μM, respectively, whereas the IC50 values of PALI were >100 μM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood–brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1–50 μM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC50 value of 5.87 μM. Following exposure to 10 μM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB [4].

Risperidone does not significantly impact leptin levels, glucose tolerance, bodyweight gain (BWG), or food intake (FI), despite the fact that prolactin and corticosterone are markedly increased in male rats. In female rats, risperidone dramatically raises BWG and FI.[5] In white adipose tissue (WAT), risperidone (0.05 mg/kg) increases food intake and leptin gene expression; however, it has no effect on the rate of bodyweight gain in rats. In rats, risperidone (0.5 mg/kg) reduces bodyweight gain and increases serum prolactin concentrations and Ucp1 gene expression in BAT.[6]

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The antipsychotics haloperidol and Risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. [1]

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Changes in members of the dopamine (DA) D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) receptor families in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after prolonged treatment (28 days) with the atypical antipsychotics olanzapine, Risperidone, and quetiapine. Olanzapine and risperidone, but not quetiapine, significantly increased D(2) binding in medial prefrontal cortex (MPC; 67% and 34%), caudate-putamen (CPu; average 42%, 25%), nucleus accumbens (NAc; 37%, 28%), and hippocampus (HIP; 53%, 30%). Olanzapine and risperidone, but not quetiapine, produced even greater up-regulation of D(4) receptors in CPu (61%, 37%), NAc (65%, 32%), and HIP (61%, 37%). D(1)-like and D(3) receptors in all regions were unaltered by any treatment, suggesting their minimal role in mediating actions of these antipsychotics. The findings support the hypothesis that antipsychotic effects of olanzapine and risperidone are partly mediated by D(2) receptors in MPC, NAc, or HIP, and perhaps D(4) receptors in CPu, NAc, or HIP, but not in cerebral cortex. Selective up-regulation of D(2) receptors by olanzapine and risperidone in CPu may reflect their ability to induce some extrapyramidal effects. Inability of quetiapine to alter DA receptors suggests that nondopaminergic mechanisms contribute to its antipsychotic effects. [2]

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Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of Risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet. [5]

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1. Risperidone is an atypical antipsychotic drug that possesses 5-hydroxytryptamine 5-HT2 receptor antagonism combined with milder dopamine D2 receptor antagonism. 2. Excessive bodyweight gain is one of the side-effects of antipsychotics. Risperidone treatment causes a greater increase in the body mass of patients than treatment with conventional antipsychotics, such as haloperidol. Therefore, the present study was undertaken in order to address the aetiology of the risperidone-induced bodyweight change in rats by examining the expression of leptin, an appetite-regulating hormone produced in white adipose tissue (WAT), and uncoupling protein (UCP)-1, a substance promoting energy expenditure in the brown adipose tissues (BAT). 3. Eight-week-old male rats were injected subcutaneously with risperidone (0.005, 0.05 or 0.5 mg/kg) twice daily for 21 days. Both bodyweight and food intake were monitored daily. On day 21, rats were decapitated and their serum leptin and prolactin concentrations were measured. Expression levels of leptin, Ucp1 and beta3-adrenoceptor (beta3-AR) genes in WAT and BAT were quantified using real-time polymerase chain reaction amplification. 4. Injection of 0.005 mg/kg risperidone into rats increased food intake and the rate of bodyweight gain, as well as the augmentation of leptin gene expression in WAT. Injection of 0.05 mg/kg risperidone increased food intake and leptin gene expression in WAT, but the rate of bodyweight gain was not affected. Injection of 0.5 mg/kg risperidone caused a reduction in bodyweight gain, as well as enhanced Ucp1 gene expression in BAT and serum prolactin concentrations. The serum leptin concentration and beta3-AR gene expression in WAT and BAT were not affected by injection of 0.5 mg/kg risperidone. 5. Although the changes in food intake observed in risperidone-injected rats were rationalized neither by serum leptin nor prolactin concentrations, the reduction in the rate of bodyweight gain following injection of 0.5 mg/kg can be explained, in part, by increased energy expenditure, as revealed by the remarkable increase in the UCP-1 mRNA expression level in BAT. The role of leptin in risperidone-induced alterations in bodyweight gain remain to be clarified [6].

Cell viability [3]
Cell viability was determined by colorimetric measurements of the reduction product of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetra-zolium bromide (MTT). After treatment with or without haloperidol and Risperidone, the original medium was removed from the 96-well plates, and the cells were incubated for 2 h at 37 °C in the presence of phenol red free minimum essential medium containing 0.5 mg/mL MTT. A 100 mL aliquot of acid–isopropanol (0.04 mol/L hydrochloric acid) was then added to each well, and the plates were incubated at 37 °C overnight to dissolve the formazan that had formed in the wells. MTT is reduced to formazan in the mitochondria of living cells. Reduced MTT was measured by means of a plate reader at a wavelength of 570 nm.

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Nitrite production assessment [3]
The accumulation of NO2−, a stable end-product, extensively used as an indicator of NO production by cultured cells, was assayed using the Griess reaction. The 6–3 cells were plated on 96-well tissue culture plates at 1 × 105 per 200 μl per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C. After 48 h, the cell-free supernatants were mixed with equal amounts of Griess reagent. Samples were incubated at room temperature for 15 min and subsequently absorbance was read at 540 nm using a plate reader.

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Western blotting for the detection of inducible NO synthase (iNOS) [3]
The 6–3 microglial cells were plated on 35 mm tissue culture dishes at a density of 1.8 × 106 cells per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C for 12 h. Afterwards, the cells were washed with PBS (pH 7.4) and lysed with sodium dodecylsulfate (SDS)-containing sample buffer. Proteins were separated in a 7.5% SDS–polyacrylamide gel and transferred onto a nitrocellulose membrane. The membrane was incubated with 5% non-fat dry milk to block non-specific binding. Subsequently, the membrane was incubated with iNOS antibodies and β-actin antibodies. The expression of iNOS and β-actin were detected using enhanced chemiluminescence system. The band intensity was quantified with a densitometric scanner. The experiments were performed three times independently.

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Cytokine release assessment [3]
The 6–3 cells were plated on 96-well tissue culture plates at 1 × 105 per 200 μl per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C. After 48 h, the collected media were assayed for cytokine (IL-1β, IL-6 and TNF-α) accumulation. Cytokines released into the culture medium were measured using mouse IL-1β, IL-6 and TNF-α enzyme-linked immunosorbent assay (ELISA) kits based on the quantitative “sandwich” enzyme immunosorbent technique. The assays were carried out according to the manufacturer's protocol. The sensitivity of this assay was 4 pg/ml.

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Intracellular Rh123 and DOX Accumulation Studies [4]
Intracellular accumulation of P-gp substrates Rh123 and DOX were measured to evaluate the P-gp activity in LLC-PK1/MDR1 and Caco-2 cells whereas LLC-PK1 was included as a negative control (van der Sandt et al, 2000). After reaching confluence, cells were preincubated at 37°C for 30 min with transport buffer (serum-free DMEM containing 25 mM N-2-hydroxyl piperazine-N′-2-ehane sulfonic acid, pH 7.4). Vehicle control (0.5% dimethylsulfoxide (DMSO)), specific concentrations of RSP/Risperidone, PALI, or PSC833 were added, then 5 μM of Rh123 or 10 μM of DOX were added for an additional 60 min incubation. After incubation, the solutions were discarded, and the cells were washed three times with ice-cold DPBS and solubilized with 1% Triton X-100. The fluorescence of Rh123 and DOX were measured by high-performance liquid chromatography (HPLC) assay. The concentrations were determined from the fluorescence value through the construction of Rh123 and DOX standard curves. The amount of Rh123 or DOX in each sample was standardized with the protein content as determined by the Lowry assay.

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Rh123 Transport Studies [4]
When RBMECs or Caco-2 cells reached confluence, the integrity of monolayers was checked by both TEER value and the transport rate of fluorescein, a recognized paracellular transport marker (van Bree et al, 1988). The qualified monolayers were rinsed two times with DPBS and preincubated with transport buffer at 37°C for 30 min. In all, 0.5% DMSO, RSP/Risperidone, or PSC833 was loaded at both sides of the monolayers, then Rh123 (5 μM) was added into the basolateral side for the basolateral to apical (B–A) transport study or apical side for the apical to basolateral (A–B) transport study. At designated times, 150 μl samples were taken from the receiver compartment, and the same volume of receiver compartment solution was replaced immediately after each sampling. Concentrations of Rh123 were determined by HPLC. Apparent permeability coefficients, Papp (cm/s) were calculated according to the following equation:

A total of 211 Long-Evans rats are utilized, comprising 56 females and 155 males. Three groups of approximately equal numbers of rats are injected with either 1.0 mg/kg of risperidone, 3.0 mg/kg of risperidone, or the vehicle used to administer the Risperidone solution as a control within each study. Twenty-six male rats (n = 9 in the vehicle and 3.0 mg/kg Risperidone groups; n = 8 in the 1.0 mg/kg Risperidone group) are used in the first experiment. They are tested for locomotor activity for 20 minutes every day starting on postnatal day 49 and continuing every day until postnatal day 53. The long-term effects of early-life Risperidone treatment on locomotion were examined in a follow-up study. In a third experiment, the effects of sex on early-life Risperidone's locomotor effects in young adult rats are investigated. Sixty male (n = 20 per treatment group) and fifty-six female (n = 19 rats in the vehicle and 3.0 mg/kg dose group, n = 18 in the 1.0 mg/kg dose group) rats are treated in this experiment. In a fourth experiment, rats given risperidone early in life were evaluated for reversal learning during adulthood. Treatment is given to 42 male rats (n=14 per treatment group).

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Drug treatment [5]
Racemic SUL and RisperidoneRIS were dissolved in 0.1 N HCl and tartaric acid respectively, and pH was adjusted to 7.0. Drugs were administered subcutaneously in a volume of 0.1 cc/100 g.
Blood sampling and oral glucose tolerance test [5]
General anesthesia was achieved by intramuscular administration of a solution made of Ketamine HCl (50 mg/ml), Xylazine HCl (5 mg/kg) and Acepromazine (1 mg/kg). The total volume was 1 ml/kg of BW. A catheter was placed in the tail dorsal artery and was filled with heparinized (2 U/ml) physiological saline at 12:00. The oral glucose tolerance test (glucose, 1 g/kg per gavage) was conducted in a counterbalanced order 36 h after surgery. Blood samples (0.1 cc) were removed before and after the glucose administration (at 0, 30, 60, 90 and 120 min; total 0.6 cc of blood) while the animal was gently placed in a plastic rodent restrainer. The catheter was immediately withdrawn at the end of the glucose tolerance test, and 2 days later the rats were decapitated after 6 hours of fasting. Trunk blood was collected for hormonal determination. For this purpose all animals were decapitated in a counterbalanced sequence between 17:00 and 19:00 h. In order to minimize the effects of stress on hormone levels, less than 1 minute elapsed between handling the animals and decapitation. Bodies were processed for body composition analysis (see below).

Experiment 1: Effects of Risperidone on BW and FI in female or male rats [5]
For each gender, 32 animals were randomly assigned to 4 groups of 8 subjects each, which received one of the following treatments: vehicle (0.1 cc/kg), Risperidone/RIS 0.125, 0.25 or 0.5 mg/kg for 16 days. These doses of RIS are known to induce little impairment in motor behavior in rats. Measurement of BWG and FI was conducted as stated above. Since no additional studies were carried out in males, an oral glucose tolerance test was conducted in the rats treated with VEH and RIS 0.5 mg/kg at day 14. Serum glucose and insulin levels were assessed in all blood samples. Leptin, corticosterone and prolactin levels were measured in blood samples collected immediately after decapitation of the animals at the end of the experiment.

Experiment 2: Comparison between the effects of Risperidone and sulpiride on BW, FI, glucose tolerance, vaginal cycle, hormones and glucose tolerance in female rats [5]
Twenty-nine female rats were divided into 3 groups that received one of the following treatments for 12 days: 0.9% NaCl, 0.1 cc/kg (n=9), RIS 0.5 mg/kg (n=11) or SUL 20 mg/kg (n=9). This SUL dose has been shown to induce the maximal BWG after prolonged treatment.The intra-arterial catheter was placed on day 9 after onset of drug treatment, and was withdrawn when the glucose test was completed. On day 10 the animals were fasted for 6 hours and then the oral glucose tolerance test was conducted as described in the blood sampling section. Insulin and glucose were assessed in all blood samples. Leptin, corticosterone, prolactin, progesterone and estradiol concentrations were assessed in the basal samples obtained by decapitation on day 12.

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Risperidone was used. Eight-week-old male Sprague-Dawley rats, weighing 285–305 g, were housed individually, maintained on a 12 h light/dark cycle (lights on at 06.00 h) and allowed free access to standard rodent food (CE-2; 14.4 kJ/g, consisting of 12% fat, 29% protein and 59% carbohydrate) and water. Room temperature was maintained at 23 ± 1°C. After habituation for 3 days, rats were divided into four experimental groups. Three groups were injected twice daily (09.00 and 18.00 h) for 21 days by subcutaneous (s.c.) injection into the neck region with Risperidone at concentrations of 0.005, 0.05 or 0.5 mg/kg (n = 5, 6 and 5, respectively), with rats in their home chambers. Another 10 rats received s.c. injection into the neck region of vehicle (0.3% tartaric acid) twice daily at 09.00 and 18.00 h for 21 days. Bodyweight and food intake were recorded daily to the nearest 1.0 g just before the injection at 09.00 h. On day 21, 1 h after the 18.00 h injection, rats were decapitated. Blood samples were obtained from the trunk vessels and the sera were kept at −80°C until hormone assays could be performed. The epididymal WAT and interscapular BAT were rapidly removed and stored at −80°C prior to RNA extraction [6].

Absorption, Distribution and Excretion
Risperidone is well absorbed. Its absolute oral bioavailability is 70% (CV = 25%). Compared to solution, the relative oral bioavailability of tablets is 94% (CV = 10%). Risperidone is extensively metabolized in the liver. Compared to young healthy subjects, renal clearance of risperidone and its metabolite 9-hydroxyrisperidone is decreased and the elimination half-life is prolonged in healthy elderly individuals. The volume of distribution of risperidone is approximately 1–2 L/kg. Risperidone is cleared by the kidneys. Clearance is decreased in elderly individuals and patients with creatinine clearance (ClCr) between 15 and 59 mL/min, with the latter showing a reduction of approximately 60%. Risperidone is well absorbed. Its absolute oral bioavailability is 70% (coefficient of variation CV = 25%). Compared to solution, the relative oral bioavailability of tablets is 94% (coefficient of variation CV = 10%). Risperidone is rapidly distributed, with a volume of distribution of 1–2 L/kg. In plasma, risperidone binds to albumin and α1-acid glycoprotein. The plasma protein binding rate of risperidone is 90%, while that of its major metabolite, 9-hydroxyrisperidone, is 77%. Risperidone and 9-hydroxyrisperidone do not interchange plasma protein binding sites. High concentrations of sulfadiazine (100 μg/mL), warfarin (10 μg/mL), and carbamazepine (10 μg/mL) only result in a slight increase in the free fractions of risperidone (10 ng/mL) and 9-hydroxyrisperidone (50 ng/mL), the clinical significance of which is unclear. Within a dose range of 1 to 16 mg daily (0.5 to 8 mg twice daily), the plasma concentrations of risperidone, its major metabolite 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose-dependent. After oral administration of solution or tablets, the mean peak plasma concentration of risperidone occurs approximately 1 hour later. In rapid metabolizers, peak concentrations of 9-hydroxyrisperidone occur at approximately 3 hours, while in slow metabolizers, they occur at approximately 17 hours. Steady-state concentrations of risperidone are reached within 1 day in rapid metabolizers; in slow metabolizers, it is expected to take approximately 5 days to reach steady state. Steady-state concentrations of 9-hydroxyrisperidone are reached within 5–6 days (measured in rapid metabolizers). Risperidone and 9-hydroxyrisperidone are present in human milk. For more complete data on the absorption, distribution, and excretion of risperidone (a total of 6 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Risperidone is primarily metabolized by the hepatic cytochrome P450 2D6 isoenzyme to 9-hydroxyrisperidone (i.e., paliperidone), which has approximately the same receptor affinity as risperidone. Hydroxylation depends on debromoquine 4-hydroxylase, and risperidone metabolism is influenced by debromoquine 4-hydroxylase gene polymorphism. Risperidone also undergoes minor N-dealkylation. Risperidone is primarily metabolized in the liver. Its main metabolic pathway involves hydroxylation of risperidone to 9-hydroxyrisperidone via the CYP2D6 enzyme. A secondary metabolic pathway involves N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity to risperidone. Therefore, the clinical efficacy of this drug depends on the combined concentration of risperidone and 9-hydroxyrisperidone. CYP2D6, also known as debromoquine hydroxylase, is an enzyme that metabolizes many antipsychotics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is influenced by genetic polymorphism (approximately 6%-8% of Caucasians and a very small number of Asians have very low or no CYP2D6 activity, classifying them as "weak metabolizers"), and is easily inhibited by various substrates and some non-substrate substances (especially quinidine). CYP 2D6 metabolizers rapidly convert risperidone to 9-hydroxyrisperidone, while CYP 2D6 poor metabolizers convert it much more slowly. Although risperidone concentrations are lower in fast metabolizers than in slow metabolizers, and 9-hydroxyrisperidone concentrations are higher, the pharmacokinetic characteristics of risperidone and 9-hydroxyrisperidone are similar in both fast and slow metabolizers after single and multiple administrations. Known metabolites of risperidone include 9-hydroxyrisperidone, paliperidone, 3-[2-[4-(6-fluoro-2-hydroxy-1,2-benzoxazol-2-onthiol-3-yl)piperidin-1-yl]ethyl]-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, 3-ethyl-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, etc. 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole. It is primarily metabolized by the hepatic cytochrome P450 2D6 isoenzyme to 9-hydroxyrisperidone, which has a roughly similar receptor binding affinity to risperidone. Hydroxylation depends on debromoquine 4-hydroxylase, and metabolism is influenced by debromoquine 4-hydroxylase gene polymorphisms. Risperidone also undergoes minor N-dealkylation. Elimination pathway: Risperidone is primarily metabolized in the liver. In healthy older adults, the renal clearance of both risperidone and its metabolite 9-hydroxyrisperidone is reduced, and the elimination half-life is prolonged compared to younger, healthy subjects.
Half-life: 20-24 hours

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Biological half-life
The half-life is 3 hours for vigorous metabolizers and up to 20 hours for weak metabolizers.
After administration of risperidone extended-release tablets (Risperdal Consta), the apparent half-life of risperidone and its metabolite 9-hydroxyrisperidone is 3 to 6 days, with plasma concentrations showing a single exponential decrease. The half-life of risperidone is 3-6 days, which is related to microsphere erosion and subsequent risperidone absorption.
In rapid metabolizers, the apparent half-life of risperidone is 3 hours (CV=30%), and in slow metabolizers it is 20 hours (CV=40%). In rapid metabolizers, the apparent half-life of 9-hydroxyrisperidone is approximately 21 hours (CV=20%), and in slow metabolizers it is approximately 30 hours (CV=25%). After single and multiple administrations, the pharmacokinetics of risperidone and 9-hydroxyrisperidone in combination were similar in fast metabolizers and slow metabolizers, with an overall mean elimination half-life of approximately 20 hours.

Toxicity Summary
Blocking dopamine D2 receptors in the limbic system can alleviate positive symptoms of schizophrenia, such as hallucinations, delusions, and behavioral and speech abnormalities. Blocking serotonin 2 (5-HT2) receptors in the mesocortical pathway leads to dopamine overdose and enhanced dopamine transmission, thereby enhancing dopamine delivery and eliminating core negative symptoms. Risperidone does not affect dopamine receptors in the nigrostriatal pathway, thus avoiding extrapyramidal side effects. Like other 5-HT2 receptor antagonists, risperidone binds to α1-adrenergic receptors and weakly to histamine H1 and α2-adrenergic receptors. Toxicity Data
LD50 = 82.1 mg/kg (oral administration to mice). Interactions
Given that risperidone primarily acts on the central nervous system, caution should be exercised when risperidone is used concomitantly with other centrally acting drugs and alcohol.
Ripardone may antagonize the effects of levodopa and dopamine agonists.
When risperidone is used in combination with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased to twice the patient’s usual dose. When enzyme inducers such as carbamazepine are discontinued, the dose of risperidone may need to be reduced [see Drug Interactions (7.1)]. A similar situation may occur when risperidone is used in combination with other enzyme inducers (e.g., phenytoin sodium, rifampin, and phenobarbital).
Prolonged use of clozapine and risperidone may reduce the clearance of risperidone.
For more complete data on risperidone interactions (of 10 items), please visit the HSDB record page.

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Hepatotoxicity
Up to 30% of patients taking risperidone long-term may experience liver dysfunction, usually within the first 8 weeks of treatment. Elevations in ALT are usually mild and transient and may return to normal with continued use. More pronounced elevations in ALT and alkaline phosphatase, with or without symptoms, and jaundice have been reported in some patients. Damage typically occurs within days of starting risperidone and resolves rapidly upon discontinuation. There are also reports of acute liver injury with jaundice occurring in some patients months or even years after starting risperidone. Serum enzyme elevations are usually cholestatic, but hepatocellular and mixed cases have also been reported. Immune allergic reactions (rash, fever, eosinophilia) are rare; one case of risperidone-induced autoimmune hepatitis has been reported, but most cases do not have autoimmune characteristics.

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Use during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that low concentrations of risperidone in breast milk are observed when pregnant women take up to 6 mg daily. Infants ingesting risperidone through breast milk have been reported to experience sedation, growth retardation, restlessness, tremors, abnormal muscle movements, and respiratory depression. Due to limited published experience and a lack of long-term follow-up data regarding the use of risperidone during lactation, alternative medications may be preferred, especially for breastfed newborns or premature infants. A systematic review of second-generation antipsychotics concluded that, due to limited available data and the fact that risperidone is more readily excreted into breast milk compared to other medications, it appears appropriate to use risperidone as a second-line treatment during lactation. A safety rating system indicated that cautious use of risperidone during lactation is feasible. Infant somnolence, weight gain, tremors, respiratory rate, abnormal muscle movements, and developmental milestones should be monitored, especially in cases of concurrent use of other antipsychotics.
◉ Effects on Breastfed Infants
One woman took 4 mg of risperidone daily while breastfeeding. Her infant showed no developmental abnormalities in all examinations before 9 months of age. Another mother took 6 mg of risperidone daily while breastfeeding. Her infant showed no developmental abnormalities in all examinations before 12 months of age.
Two women who took 4 mg and 1.5 mg of risperidone daily, respectively, breastfed their infants at 3.3 months and 6 weeks of age, respectively. Both infants showed normal developmental milestones, and no adverse reactions were reported.
A woman started taking risperidone 2 mg daily one week postpartum, increasing to 3 mg daily after 10 days. She breastfed her infant six times a day. The infant underwent five weeks of inpatient observation, and a pediatric neurologist assessed that the infant's development was normal. No sedation or other adverse reactions were observed in the infant. After three months of risperidone treatment, both mother and infant were in good health.
An infant was exclusively breastfed for three months while the mother was taking 1 mg risperidone daily. Pediatric examination revealed no neurological or physical abnormalities in the infant, and the infant interacted normally.
In a telephone follow-up study, 124 mothers who were taking benzodiazepines while breastfeeding reported any signs of sedation in their infants. One mother taking 0.75 mg risperidone, 15 mg flurazepam, 0.25 mg clonazepam (twice daily), and 1 mg bupropion daily reported sedation in her breastfed infant. A woman diagnosed with schizophrenia took 1.5 mg of risperidone daily during late pregnancy and postpartum (breastfeeding duration not specified) while breastfeeding her full-term infant. Two weeks postpartum, due to a relapse of symptoms, haloperidol 0.8 mg/day was added. At this dose, the infant did not experience adverse reactions. However, due to a relapse of symptoms, the haloperidol dose was increased to 1.5 mg/day. Three days later, the infant developed excessive sedation, feeding difficulties, and motor retardation. Pediatric evaluation revealed no medical cause for these symptoms. After discontinuation of breastfeeding, the infant's symptoms completely resolved within 5 days. The infant's symptoms may have been caused by the combination of medications. A prospective cohort study conducted in a maternal and infant psychiatric ward in India followed seven infants who were exposed to risperidone through breast milk; most infants received partial supplemental therapy. One infant's mother took 4 mg of risperidone and 2 mg of lorazepam, and the infant experienced sedation, which resolved after discontinuation of lorazepam. An infant whose mother was taking risperidone 4 mg and trihexyphenidyl 2 mg daily and receiving electroconvulsive therapy developed constipation. The infants were followed up for 1 to 3 months after discharge. One infant had stunted growth in weight, one had stunted growth in height, one had intellectual disability, and another had both motor and intellectual disabilities. A woman with bipolar disorder was taking risperidone 2 mg orally at bedtime, 50 mg of long-acting risperidone intramuscularly every 2 weeks, citalopram 20 mg orally daily, and benzalkonium chloride 0.5 mg orally daily. She continued taking the same medications during pregnancy. Her infant was born at 35 weeks of gestation and was breastfed (the extent and duration of breastfeeding were not specified). The infant was developing well at 16 months of age, with all developmental milestones met. Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotics Pregnancy Registry were compared with a breastfeeding control group (n = 818) who were not taking second-generation antipsychotics. Among patients taking second-generation antipsychotics, 60.4% were concurrently taking two or more psychotropic medications. Pediatric case reviews showed no adverse reactions in infants, regardless of whether they received monotherapy or combination therapy with second-generation antipsychotics. The number of women taking risperidone was not reported. A premature infant, weighing 2.75 kg at 35 weeks gestation, received 2 minutes of assisted ventilation on a portable ventilator due to respiratory distress and received continuous oxygen for the first 18 hours after birth. Breastfeeding began on the second day after birth. On day 12, the mother began taking risperidone at 1 mg daily for the treatment of psychotic episodes. On day 13, the infant's respiratory rate decreased to 16 breaths/min without respiratory distress, and continuous positive airway pressure (CPAP) was administered for 12 hours, followed by gradual weaning and formula feeding. On day 15, the mother resumed breastfeeding, but the infant experienced respiratory depression again. The feeding method was changed to expressing breast milk before taking risperidone, feeding formula 6 hours after each dose, and then resuming direct breastfeeding. Respiratory depression did not recur for the next two days. The infant was discharged on day 24 and instructed to continue the previous feeding method. The respiratory depression was likely caused by risperidone in the breast milk.
A woman diagnosed with undifferentiated schizophrenia took 4 to 5 mg of risperidone and 2 mg of trihexyphenidyl daily during five pregnancies. She breastfed each infant for 20 to 24 months. None of the children experienced adverse developmental consequences. As of the time of this writing, the three oldest children (aged 26, 23, and 22) have completed their education and entered the workforce, while the two youngest children (aged 15 and 19) are performing well academically.

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◉ Effects on lactation and breast milk
Patients taking risperidone may experience elevated serum prolactin levels, gynecomastia, and galactorrhea. In one case, a 19-year-old male developed gynecomastia and galactorrhea while taking fluvoxamine, despite normal prolactin levels. A meta-analysis of three studies found that risperidone induced gynecomastia at a 4.3-fold higher risk than quetiapine. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed. One study compared breastfeeding mothers on second-generation antipsychotics registered with the National Atypical Antipsychotic Pregnancy Registry (n = 576) with a control group of breastfeeding mothers with a primary diagnosis of major depressive disorder and anxiety disorder (n = 818). The control group typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but not second-generation antipsychotics. Among the women taking second-generation antipsychotics, 60.4% were also taking more than one other psychotropic medication, compared to 24.4% in the control group. Among women taking second-generation antipsychotics, 59.3% reported having breastfed, compared to 88.2% in the control group. At 3 months postpartum, 23% of women taking second-generation antipsychotics were still exclusively breastfeeding, compared to 47% in the control group. No reports were found regarding the number of women taking risperidone.
◈ What is risperidone?
Risperidone is a medication used to treat mental illnesses such as schizophrenia, bipolar disorder, and depression. It can be administered orally or by injection. Risperidone belongs to the atypical or second-generation antipsychotic class. Brand names for risperidone include Risperdal®, Risperdal Consta®, and Perseris®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy.
◈ I am taking risperidone. Will it affect my ability to get pregnant?
In some people, risperidone may increase levels of a hormone called prolactin. High levels of prolactin can suppress ovulation (the process by which the ovary releases an egg during the menstrual cycle). This can make it more difficult to conceive. If you have any concerns, your healthcare provider can test your prolactin levels.
◈ Does taking risperidone increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. Based on reviewed studies, risperidone is not expected to increase the risk of miscarriage.
◈ Does taking risperidone increase the risk of birth defects?
There is a 3-5% risk of birth defects at the start of each pregnancy. This is called background risk. Based on reviewed studies, risperidone is not expected to increase the risk of birth defects above the background risk.
◈ Does taking risperidone during pregnancy increase the risk of other pregnancy-related problems?
Based on reviewed studies, risperidone may lead to low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Risperidone may cause weight gain and blood sugar problems in pregnant women, increasing the risk of gestational diabetes. For more information about gestational diabetes, please see our fact sheet: https://mothertobaby.org/fact-sheets/diabetes-pregnancy/.
◈ I need to take risperidone throughout my pregnancy. Will it cause withdrawal symptoms in my baby after birth?
Taking certain medications during pregnancy can cause temporary symptoms in newborns shortly after birth, sometimes referred to as withdrawal symptoms. It is currently unclear whether taking risperidone alone increases the risk of withdrawal symptoms in newborns. Similar medications are associated with a risk of withdrawal symptoms, so infants exposed to risperidone around the time of delivery should be closely monitored for symptoms such as muscle stiffness or weakness, lethargy, irritability, tremors, difficulty breathing, and feeding difficulties. In most cases, these symptoms resolve on their own within a few days and do not have long-term health effects. It is important that your healthcare provider knows you are taking risperidone so that your baby can receive optimal care should symptoms occur.
◈ Will taking risperidone during pregnancy affect my child's future behavior or learning abilities?
Currently, there are no studies showing whether risperidone causes behavioral or learning problems in children.
◈ Is it safe to breastfeed while taking risperidone?
Information regarding the use of risperidone while breastfeeding is limited. Small amounts of risperidone can be detected in breast milk when taken up to 6 mg daily. A small number of breastfed infants exposed only to risperidone (up to 6 mg daily) have not reported side effects. Your infant may be at higher risk of side effects if you are taking risperidone with other medications. If you suspect your infant has any symptoms (drowsiness, feeding difficulties, irritability, or unusual movements), contact your child's healthcare provider. The product label for risperidone advises against using this medication while breastfeeding. However, the benefits of using risperidone may outweigh the potential risks. Your healthcare provider can discuss the use of risperidone with you and the best treatment option for you. Be sure to consult your healthcare provider about all questions regarding breastfeeding.
◈ If a man takes risperidone, will it affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
Taking risperidone may increase prolactin levels in the body, which may affect fertility. Currently, there is no research indicating whether risperidone increases the risk of birth defects on top of background risk. Generally, medication exposure to a father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Father Exposure” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. J Neurosci Res. 2000 Jun 15;60(6):783-94.

[2]. J Pharmacol Exp Ther. 2001 May;297(2):711-7.

[3]. Schizophr Res,?007, 92(1-3), 108-115.

[4]. Neuropsychopharmacology. 2007 Apr;32(4):757-64.

[5]. Brain Res. 2002 Dec 6;957(1):144-51.

[6]. Clin Exp Pharmacol Physiol. 2002 Nov;29(11):980-9.

Therapeutic Uses
Antipsychotic; Dopamine antagonist; Serotonin antagonist. Risperdone (Risperdal) is indicated for the treatment of schizophrenia. Its efficacy has been demonstrated in 4 short-term trials in adults, 2 short-term trials in adolescents (13 to 17 years of age), and 1 long-term maintenance treatment trial in adults. /US Product Label/ Risperdone in combination with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Its efficacy has been demonstrated in one short-term trial in adults. /US Product Label/ Risperdone is indicated for the treatment of autism-related irritability symptoms, including aggression, intentional self-harm, temper tantrums, and rapid mood swings. Its efficacy has been demonstrated in 3 short-term trials in children and adolescents (5 to 17 years of age). /US Product Label Includes/ Risperdone is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Efficacy has been demonstrated in two short-term trials in adults and one short-term trial in children and adolescents (10 to 17 years of age). /US product label contains/

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Drug Warning
/Black Box Warning/ Warning: Increased mortality in patients with dementia-related psychosis. Patients with dementia-related psychosis receiving antipsychotic medication have an increased risk of death. Risperdone (Risperdal) is not approved for the treatment of dementia-related psychosis.
Like other antipsychotics (such as phenothiazines), risperdone is associated with tardive dyskinesia. Although some studies have shown a lower risk of tardive dyskinesia with atypical antipsychotics, it is unclear whether there is a difference in the potential for tardive dyskinesia among different antipsychotics. In an open-label study, the annual incidence of tardive dyskinesia was 0.3% in patients with schizophrenia who received approximately 8–9 mg of oral risperdone daily for at least one year. The prevalence of this syndrome appears to be highest in older patients, particularly women. The risk of developing tardive dyskinesia and its potential for irreversibility appears to increase with the duration and cumulative dose of antipsychotic medication; however, the syndrome can occur even after relatively short periods of low-dose treatment, although much less frequently. Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom cluster that has been reported in patients taking antipsychotic medication. NMS requires immediate discontinuation of the medication and intensive symptomatic and supportive care. Dose-related somnolence is a common side effect of risperidone treatment. In studies using direct questioning or checklists to detect adverse events, approximately 8% of adult patients with schizophrenia taking 16 mg of risperidone daily reported somnolence, compared to 1% in patients taking placebo. For more complete data on risperidone (41 total), please visit the HSDB record page. Pharmacodynamics: The primary action of risperidone is to reduce the activity of dopaminergic and serotonergic pathways in the brain, thereby alleviating symptoms of schizophrenia and mood disorders. Compared to dopamine D2 receptors in the brain, risperidone has a higher binding affinity for serotonin 5-HT2A receptors. The binding affinity of risperidone to D2 receptors is lower than that of first-generation antipsychotics, which have very high affinity for D2 receptors. Compared to previous antipsychotics, risperidone alleviates extrapyramidal symptoms, likely due to its moderate affinity for dopamine D2 receptors. Antipsychotics have long been thought to primarily act on neurons or neural networks, including synaptic networks. However, this study shows that antipsychotics, particularly risperidone, can exert anti-inflammatory effects by inhibiting microglia activation. Therefore, antipsychotics may have a potential therapeutic effect on schizophrenia by reducing the inflammatory response in microglia, thereby inhibiting neurogenesis and oligodendrocyte formation. These results may provide new insights into treatment strategies for schizophrenia. Drugs that can inhibit microglia activation may also be beneficial in the treatment of schizophrenia. To further investigate, the molecular mechanism of risperidone’s inhibitory effect on microglial activation should be elucidated in detail, and in vivo studies should be conducted to verify the current results. [3] The mechanism of P-gp transport and inhibition has been studied extensively for many years. Various hypotheses have been proposed to explain the molecular mechanism of P-gp’s interaction with its substrates or inhibitors. However, due to the presence of multiple drug-binding sites on P-gp, it remains a challenge to establish a universally accepted model to reconcile data from different laboratories. Studies have shown that there are at least four drug-binding sites on P-gp. These sites can be divided into two categories: transport sites, where drugs can be transported across the cell membrane; and regulatory sites, which can alter the function of P-gp (Martin et al., 2000). In addition, some drugs can inhibit P-gp activity by reducing intracellular ATP supply and inhibiting P-gp ATPase activity (Batrakova et al., 2001). Given that risperidone/RSP and PALI appear to be both P-gp substrates and inhibitors, their competitive binding to P-gp with other substrates may be one of the mechanisms by which they inhibit P-gp. However, other mechanisms cannot be ruled out, and further research is needed to elucidate the molecular basis of the interaction between RSP and PALI and P-gp. [4] This study failed to provide a definitive explanation for the changes in food intake in rats injected with risperidone from evidence involving dopamine and/or 5-HT receptor antagonism. However, the reduced weight gain in rats injected with risperidone (0.5 mg/kg) may be partly due to increased energy expenditure, as evidenced by the significant increase in UCP-1 mRNA expression in brown adipose tissue (BAT). In humans, BAT is present in newborns but is reduced in adults and has a smaller effect. This may partially explain the difference in the effect of risperidone on weight gain in rodents and humans. In this study, we demonstrated for the first time that risperidone injection induces the expression of leptin mRNA in white adipose tissue (WAT) and UCP-1 mRNA in brown adipose tissue (BAT) in rats. However, we failed to provide a reasonable explanation for these increases in expression. Therefore, our next task is to elucidate the mechanism by which risperidone induces the increased expression levels of these gene mRNAs in adipose tissue. ^[6]

C23H27FN4O2

410.48

410.211

C, 67.30; H, 6.63; F, 4.63; N, 13.65; O, 7.80

106266-06-2

Risperidone-d4; 1020719-76-9; Risperidone hydrochloride; 666179-74-4; Risperidone mesylate; 666179-96-0

5073

White to off-white solid powder

1.4±0.1 g/cm3

572.4±60.0 °C at 760 mmHg

170°C

300.0±32.9 °C

0.0±1.6 mmHg at 25°C

1.677

2.88

0

6

4

30

731

0

FC1C([H])=C([H])C2=C(C=1[H])ON=C2C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C2=C(C([H])([H])[H])N=C3C([H])([H])C([H])([H])C([H])([H])C([H])([H])N3C2=O)C([H])([H])C1([H])[H]

RAPZEAPATHNIPO-UHFFFAOYSA-N

InChI=1S/C23H27FN4O2/c1-15-18(23(29)28-10-3-2-4-21(28)25-15)9-13-27-11-7-16(8-12-27)22-19-6-5-17(24)14-20(19)30-26-22/h5-6,14,16H,2-4,7-13H2,1H

3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)