Buspirone Research Articles

Buspirone attenuated methotrexate-induced hippocampal toxicity in rats by regulating Nrf2/HO-1, PPAR-γ, NF-κB/nNOS, and ROS/NLRP3/caspase-1 signaling pathways.

Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX-induced hippocampal neurotoxicity is a well-defined dose-limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX-induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5-HT1a receptor (5-HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti-inflammatory effects. The current study investigated BSP's potential anti-inflammatory and antioxidant effects in attenuating MTX-induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch-like ECH-associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase-1, and peroxisome proliferator-activated receptor expression. BSP dampened inflammation by reducing NO2 - , tumor necrosis factor-alpha, IL-6, and interleukin 1 beta levels mediated by downregulating NF-κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved-caspase-1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX.

Anxiolytic-like Effects and Quantitative EEG Profile of Palmitone Induces Responses Like Buspirone Rather Than Diazepam as Clinical Drugs.

Anxiety is a mental disorder with a growing worldwide incidence due to the SARS-CoV-2 virus pandemic. Pharmacological therapy includes drugs such as benzodiazepines (BDZs) or azapirones like buspirone (BUSP) or analogs, which unfortunately produce severe adverse effects or no immediate response, respectively. Medicinal plants or their bioactive metabolites are a shared global alternative to treat anxiety. Palmitone is one active compound isolated from Annona species due to its tranquilizing activity. However, its influence on neural activity and possible mechanism of action are unknown. In this study, an electroencephalographic (EEG) spectral power analysis was used to corroborate its depressant activity in comparison with the anxiolytic-like effects of reference drugs such as diazepam (DZP, 1 mg/kg) and BUSP (4 mg/kg) or 8-OH-DPAT (1 mg/kg), alone or in the presence of the GABAA (picrotoxin, PTX, 1 mg/kg) or serotonin 5-HT1A receptor antagonists (WAY100634, WAY, 1 mg/kg). The anxiolytic-like activity was assayed using the behavioral response of mice employing open-field, hole-board, and plus-maze tests. EEG activity was registered in both the frontal and parietal cortex, performing a 10 min baseline and 30 min recording after the treatments. As a result, anxiety-like behavior was significantly decreased in mice administered with palmitone, DZP, BUSP, or 8-OH-DPAT. The effect of palmitone was equivalent to that produced by 5-HT1A receptor agonists but 50% less effective than DZP. The presence of PTX and WAY prevented the anxiolytic-like response of DZP and 8-OH-DPAT, respectively. Whereas only the antagonist of the 5-HT1A receptor (WAY) inhibited the palmitone effects. Palmitone and BUSP exhibited similar changes in the relative power bands after the spectral power analysis. This response was different to the changes induced by DZP. In conclusion, brain electrical activity was associated with the anxiolytic-like effects of palmitone implying a serotoninergic rather than a GABAergic mechanism of action.

Buspirone, a 5-HT1A agonist attenuates social isolation-induced behavior deficits in rats: a comparative study with fluoxetine.

Social isolation is a potent stressor in both humans and animals that results in increased anger-like emotion, (anger in humans), aggression and suicidal ideation in humans [suicidal trait-related behavior in rats (STRB)]. The study's purpose was to compare the effects of buspirone (BUS) and fluoxetine (Flx) on social isolation-induced behavior deficits in rats. The male Wistar rats were randomized into six groups and caged individually for 14 days except for the non stress control (nSC) group. They were then divided into the following groups, stress control (SC), Flx (30), BUS (10), BUS (20) and BUS (40) and treated from day 14 to day 28. On the last day of treatment behavior parameters were recorded. Serum cortisol, blood pressure (BP) measurement, magnetic resonance imaging (MRI) of the rat's brain and brain-derived neurotrophic factor (BDNF) expression were performed. SC group showed a significant increase in anger-like emotion, aggression, irritability score, learned helplessness, increased cortisol level and reduced BDNF. These behavioral deficits were attenuated by BUS and Flx, Both were found to be equally beneficial in preventing anger-like emotions and aggression. Flx, which has been found to promote suicidal thoughts in people, did not reduce irritability in rats, showing that it did not affect it. BUS significantly improved all behavioral traits also reduced cortisol levels, significantly increased BDNF and normalized BP. Neuroimaging studies in SC brains showed a reduction in amygdala size compared to nSC, BUS treatment mitigated this reduction. Buspirone is effective in preventing social isolation induced behavioural-deficits.

Buspirone loaded solid lipid nanoparticles for amplification of nose to brain efficacy: Formulation development, optimization by Box-Behnken design, in-vitro characterization and in-vivo biological evaluation

The strategies to avoid blood brain barrier are been explored to improve brain targeting therapeutics in order to ensure potential prospects of nose to brain delivery. In this research work, Buspirone (BUS) loaded solid lipid nanoparticles (SLNs) for nose to brain delivery were prepared by solvent free technique and optimized by three factors and three levels Box- Behnken design. The three independent variables viz, drug (BUS) to lipid (Compritol® 888 ATO) ratio (labeled A), surfactant concentration (tween 80+ poloxamer, 2:1- labeled B) and sonication time (labeled C) were selected in range of 1:3–1:5, 1–2% and 5–15 min respectively. Their influences on particle size (nm, labeled Y1), Polydispersity index (PDI, labeled Y2) and % entrapment efficiency (labeled Y3) were observed. Optimized batch (B-OP3) showed spherical morphology possessing the value of particle size, PDI, zeta potential, entrapment efficiency, and in-vitro drug release as 218.60 ± 9.18 nm, 0.305 ± 0.012, −26.47 ± 2.36 mV, 70.13 ± 4.21% and 93.36 ± 8.63% respectively. BUS-SLNs displayed superior ex-vivo permeation profiles as compared to BUS-Sol. X-ray diffraction and differential scanning calorimetry spectra do not display the characteristic peak of BUS, thus recommending the entrapment of drug in lipid core. AUC 0-∞ in the brain for BUS-SLNs i.n was found to be 2.18 times more than BUS-Sol i.n and 2.66 times more than BUS-SLNs i.v., thus supporting improved targeting efficiency of developed SLNs. The value of drug targeting efficiency (DTE) percentage to brain (882.59%) and nose to brain direct transport (DTP) percentage (88.67%) for BUS-SLNs i.n was higher as compared to BUS-Sol i.n (DTE = 238.63%, DTP = 58.09%). Furthermore, confocal laser scanning microscopy study confirmed that brain targeting of BUS-SLNs was better than BUS-Sol when administered intranasally. Finally, results revealed that SLNs establish itself as a potential drug delivery system for brain delivery of BUS via intranasal route.

Buccal Buspirone as add-on Therapy to Omeprazole Versus Omeprazole in Treatment of Gastroesophageal Reflux Diseases (GERD).

Proton pump inhibitors (PPIs) are recommended as first line treatments for gastroesophageal reflux disease (GERD). Failure to PPIs has been mentioned as a problem in pharmacotherapy of GERD. The present study compared the symptom relief, quality of life (QoL) and adverse drug reactions (ADRs) of omeprazole plus buccal buspirone with that of omeprazole alone.This was a prospective, randomized trial between buccal buspirone (10 mg/d) plus omeprazole (20 mg/d) and omeprazole (20 mg/d) plus placebo administered for 4 weeks to patients with GERD symptoms. Patients who had GERD symptoms enrolled in this study. 67 patients were randomly assigned to either the buspirone plus omeprazole group (n = 33) or the placebo plus omeprazole group (n = 34). Finally, 58 patients completed the study (29 in each group). Treatment response rates in each drug group were evaluated according to the Frequency Scale for the Symptoms of GERD (FFSG). The QoL and ADRs have been also evaluated too.The treatment score rates for symptom relief according to the FFSG were 7.13 ± 5.13 in the buspirone group and 15.34 ± 8.17 in the placebo group. Regarding FFSG score, there is a significant difference between the groups (p < 0.0001). QoL were 6.86 ± 6.65 and 27.2 ± 20.95 in placebo and buspirone group, respectively after four weeks and there is a significant difference in two groups ( p < 0.0001).The total incidence of ADRs were similar in the buspirone and placebo groups (p = 0.36).A combination of buccal buspirone plus omeprazole may be a more effective treatment for GERD than omeprazole alone.

Buspirone-associated Movement Disorder: A Literature Review.

Buspirone (BUS) belongs to the azapirone chemical class. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of BUS-associated movement disorders (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 25 reports containing 65 cases were assessed. The MD associated with BUS were: dyskinesia in 14 cases, 10 of akathisia, 8 of myoclonus, 6 of Parkinsonism, and 6 of dystonia. The cases not clearly defined were 7 tension, 14 incoordination, and the undefined number of dyskinesia, tics, and Parkinsonism. The mean age was 45.23 years (range: 15-74). The male was the predominant sex in 60.86% and the most common BUS-indication was anxiety disorder. The mean BUS-dose was 42.16 mg (range: 5-100). The time from the beginning of BUS administration to the MD onset was one month or less in 76%. The time from BUS withdrawal to complete recovery was within one month in 87.5%. The most common management was BUS withdrawal. In 16 patients the follow-up was reported: 14 had a full recovery, but in two (1 dyskinesia + 1 dystonia) the symptoms continued after the BUS withdrawal. MD associated with BUS were scarcely reported in the literature. Moreover, in the majority of cases, no clear description of the clinical profile, neurological examination, or the time data of the movement disorder onset and recovery were given.

Research on the clinical effect of Jiuwei-Zhenxin granules and buspirone hydrochloride tablets for geriatric anxiety patients

Objective To investigate the clinical efficacy of Jiuwei-Zhenxin granules and buspirone hydrochloride tablets for geriatric anxiety patients. Methods A total of 136 elderly anxiety patients who met the inclusion criteria were randomly divided into two groups with 68 patients in each group. Patients in the control group were treated with butyrocyclone hydrochloride tablets, while the patients in the treatment group were treated with Jiuwei-Zhenxin granules on the basis of control group. Both groups were treated for 4 weeks. The average R-R interval standard deviation at 24 h (SDNN), the standard deviation of the mean normal R-R interval value for every 5 minutes in 24 h (SDANN) and mean square root of inter-period difference between adjacent R-R at 24h (RMSSD) were measured by heart rate variation analyzer. The 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) were detected using ELISA. The HAMA scale was used to evaluate anxiety and adverse reactions. Results After treatment, the SDNN (132.04 ± 30.17 ms vs. 107.23 ± 23.44 ms, t=16.901), RMSSD (70.12 ± 21.85 ms vs. 46.43 ± 20.09 ms, t=20.367) and SDANN (136.45 ± 27.18 ms vs. 125.62 ± 20.92 ms, t=6.945) of the treatment group were significantly higher than those of the control group (P<0.01). The serum 5-HT (119.69 ± 10.24 ng/L vs. 142.26 ± 13.71 ng/L, t=21.523), NE (126.47 ± 20.15 ng/L vs. 205.84 ± 23.12 ng/L, t=35.776), DA (130.12 ± 15.95 ng/ml vs. 156.47 ± 15.09 ng/ml, t=14.198) were significantly lower than those of the control group (P<0.01). The HAMA scores of the treatment group at week 1, 2, 3 and 4 after treatment were significantly lower than those of the control group (t=2.105, 4.116, 4.270, 3.369, P<0.05). Conclusions The Jiuwei-Zhenxin granules combined with buspironone hydrochloride tablets can reduce the anxiety of elderly anxiety patients, and its mechanism may be related to regulating the body's neurotransmitter to inhibit autonomic nervous dysfunction and reduce anxiety. Key words: Anxiety disorders; Aged; Jiuwei-Zhenxin granules; Butyrocyclosterone hydrochloride tablets; Receptors, neurotransmitter; Heart rate

Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis.

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n=4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

Electrochemiluminescence Quantification of Amine Functionalized Drugs at Ru(bpy)32+/poly(4-amino-diphenylamine) Sensor Incorporated with AuNPs: Potential Analysis of Ephedrine

An electrochemiluminescence (ECL) sensor based on a sandwich gold nanoparticles (AuNPs) linkage species amid luminescence molecules, [Ru(bpy)3]2+, doped at a pre-alkaline poly(4-aminodiphenylamine), t-Padpa, film has been employed for the quantification of some tertiary amines including buspirone (BUS), triprolidine (TPL), diphenhydramine (DPH) and chlorpheniramine (CPM). The proposed sensor (Ru.AuNPs.Ru.t-Padpa/GCE) showed high sensitivity and good stability with limit of detection (LOD) low enough for successful application and determination of above drugs in their pharmaceutical formulation. The relationship between the observed ECL intensity and the structural attribute of these drugs was justified by the type of attached nitrogen functionalities, the presence of electron donating or electron withdrawing groups and the extent of anodic potential. The potential analysis of ephedrine (EPH), a secondary amine, proceeded by in-situ derivatization reaction with formaldehyde to produce a strongly ECL susceptible aminol intermediate. Variation of EPH concentration at constant amount of formaldehyde significantly enhances ECL signals and drops the LOD of EPH into 1.2 ng/mL. Real sample analysis of EPH was satisfactorily recovered regardless of drug matrixes and presence of interference species. The protocol of sensor construction along with the reductive addition reaction confirms that the present ECL approach meets the highest demand required for EPH analysis.

Effects of paroxetine hydrochloride combined with buspirone on HAMD and serum BDNF and 5-HT levels in patients with depression

Objective To investigate the effect of paroxetine hydrochloride combined with buspirone in patients with depression. Methods A retrospective study was performed on 74 cases of patients with depression who were admitted from March 2014 to June 2016.Patients were randomly divided into the normal group and the observation group, with 37 cases in each group.Patients in the normal group were given treatment of paroxetine hydrochloride, the others in the observation group were given treatment of paroxetine hydrochloride combined with buspirone, and both groups were treated for 2 months.The scores of depression(HAMD)were compared between the two groups at admission, 1 month and 2 months after treatment.After the end of treatment, the clinical efficacy of the two groups was compared, the changes of serum BDNF and 5-HT levels, the occurrence of adverse reactions and the life quality were observed at the time of admission and after treatment. Results After 1 month and 2 months, the scores of HAMD were lower than those before treatment, the HAMD score in the observation group was lower than that in the normal group(P 0.05); There was no statistically significant difference in physical role, emotional function, social function, energy, general health, mental health, physical pain and body function between the two groups(P>0.05); after 2 months of treatment, patients of the observation group were superior to those of the normal group in physical role, emotional function, social function, energy, general health, mental health, physical pain and body function(P<0.05). Conclusion Buspirone combined with paroxetine hydrochloride has a significant effect on patients with depression, which can effectively alleviate the degree of depression in patients with increasing serum BDNF and 5-HT content, improve the treatment effect and life quality without increasing the risk of adverse reactions. Key words: Paroxetine hydrochloride; Buspirone; Depression; HAMD score; Serum factor

Application of a cocktail approach to screen cytochrome P450 BM3 libraries for metabolic activity and diversity.

In the present study, the validity of using a cocktail screening method in combination with a chemometrical data mining approach to evaluate metabolic activity and diversity of drug-metabolizing bacterial Cytochrome P450 (CYP) BM3 mutants was investigated. In addition, the concept of utilizing an in-house-developed library of CYP BM3 mutants as a unique biocatalytic synthetic tool to support medicinal chemistry was evaluated. Metabolic efficiency of the mutant library towards a selection of CYP model substrates, being amitriptyline (AMI), buspirone (BUS), coumarine (COU), dextromethorphan (DEX), diclofenac (DIC) and norethisterone (NET), was investigated. First, metabolic activity of a selection of CYP BM3 mutants was screened against AMI and BUS. Subsequently, for a single CYP BM3 mutant, the effect of co-administration of multiple drugs on the metabolic activity and diversity towards AMI and BUS was investigated. Finally, a cocktail of AMI, BUS, COU, DEX, DIC and NET was screened against the whole in-house CYP BM3 library. Different validated quantitative and qualitative (U)HPLC-MS/MS-based analytical methods were applied to screen for substrate depletion and targeted product formation, followed by a more in-depth screen for metabolic diversity. A chemometrical approach was used to mine all data to search for unique metabolic properties of the mutants and allow classification of the mutants. The latter would open the possibility of obtaining a more in-depth mechanistic understanding of the metabolites. The presented method is the first MS-based method to screen CYP BM3 mutant libraries for diversity in combination with a chemometrical approach to interpret results and visualize differences between the tested mutants.Graphical abstractGeneral worklfow in screening mutant enzyme libraries for catalytic efficiency and diversityElectronic supplementary materialThe online version of this article (doi:10.1007/s00216-015-9241-x) contains supplementary material, which is available to authorized users.

The clinical observation of estradiol valerate and drospirenone applying in missed abortion and curettage before and after operation

Objective To observe the clinical effects of estradiol valerate and drospirenone applying in missed abortion and curettage before and after operation. Methods 160 patients with missed abortion parallel curettage were chosen, who were randomly divided into the observation group and control group by the number table method.Two groups of patients were oral misoprostol 400 g before uterine curettage 1 h, and then were treated with ultrasonic curettage after filling the bladder and postoperative routine use of antibiotics for 3 D. 3 D before the curettage, observation group were treated with oral estradiol valerate 4 mg for 3 D, 2times a day..After curettage of the day, drospirenone orally was given for 1 tablet every night, used in conjunction a cycle for 3weeks.The control group before and after curettage were given without estradiol valerate and drospirenone.Operation time, bleeding volume, postoperative bleeding time and bleeding volume, the time of the first menstrual cycle, endometrial repair and postoperative complications were observed in the two groups. Results In the control group, operation time, intraoperative bleeding volume, for the first time the resumption of menstruation tide time, endometrial thickness, postoperative complication rate were (6.05±0.49)min, (50.88±9.18)mL, (36.51±1.95)d, (4.08±0.56)mm and 15.0%; the data of the observation group were (4.46±0.45)min, (35.63±8.24)mL, of (29.28±1.57)d, (6.11±0.76)mm and 3.8%.The operation time, intraoperative bleeding volume, for the first time the resumption of menstruation tide time, endometrial thickness, postoperative complication rate differences of the two groups were statistically significant(t=-11.264, -16.643, -24.93, 19.151, χ2=5.959, all P<0.05). Conclusion Giving estradiol valerate and flexor buspirone before and after missed abortion and curettage, can effectively improve the short-term and long-term complications of uterine curettage, and improve the clinical efficacy of dilatation and curettage. Key words: Abortion, missed; Curettage; Estradiol valerate; Drospirenone

Modulation of Cytochrome P450 Activity by 18β-Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats.

The aim of this study was to elucidate the inhibition mechanism of 18β-glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC50 of 20.1 ± 10.7 μM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration-time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12-1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A-mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A-mediated drug metabolism in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

The significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction: The necessity of combination therapy of radix Aconiti

Ethnopharmacological relevanceWutou (WT, Radix Aconiti), the mother root of Aconitum carmichaelii Debx., is a famous Chinese herb against rheumatoid arthritis. In Chinese clinics, PWT is often prepared as a decoction in combination with other herbs, such as Wutou decoction (WTD). The present study aimed to compare the effects of PWT single herb and WTD on CYP3A activity ex vivo and in vivo. Materials and methodsIn the ex vivo study, CYP3A activity was determined by using testosterone (Tes) as a specific probe. Levels of Tes and its metabolite 6β-hydroxytestosterone (6β-OH-Tes) were measured using a validated ultra-performance liquid chromatography (UPLC) method. CYP3A protein and mRNA levels were measured by using Western blot and real-time PCR, respectively. In the in vivo study, CYP3A activity was determined by using buspirone (BP) as a specific probe. The plasma concentrations of BP and its primary metabolites, namely, 1-(2-pyrimidinyl) piperazine (1-PP) and 6′-hydroxybuspirone (6′-OH-BP), were determined using a validated UPLC-tandem mass spectrometry (UPLC/MS/MS) method. ResultsCompared with the control group, the formation rates of 6β-OH-Tes from Tes ex vivo significantly decreased in groups treated with PWT at the tested doses, and this decrease was accompanied by a striking decrease in CYP3A protein and mRNA levels. However, a significant increase was observed in the ratios in the WTD groups compared with PWT single herb groups. In vivo, both formation ratios of 6′-OH-BP and 1-PP from BP showed no significant change in the WTD group. ConclusionsPWT can significantly inhibit CYP3A activity ex vivo at the tested doses because of the down-regulation of CYP3A protein and mRNA expression levels. WTD can significantly reverse the inhibition caused by PWT. WTD also had no significant effect on CYP3A activity in vivo. Results implied that the use of PWT as a part of the WTD prescription rather than PWT single herb is more appropriate in clinics.

Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice

Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains.

The influences of aconitine, an active/toxic alkaloid from aconitum, on the oral pharmacokinetics of CYP3A probe drug buspirone in rats.

Aconitine (AC), an active/toxic alkaloid from Aconitum species, is commonly present in Traditional Chinese Medicine (TCM) prescriptions because of the great effectiveness of Aconitum for the treatment of rheumatoid arthritis, cardiovascular diseases, and tumors in clinic. Buspirone (BP) is a sensitive CYP3A probe drug that is administered through oral/intravenous routes as recommended by the U.S. Food and Drug Administration. This study aims to investigate the influences of AC (0.125 mg/kg, oral) on first-pass (intestinal and hepatic) CYP3A activity by using oral BP as the probe in rats. The pharmacokinetics of oral buspirone hydrochloride at different doses (12.5, 25, and 50 mg/kg) were conducted. The pharmacokinetics of oral BP in rats pretreated with single dose or multiple doses (7-day) of AC were investigated. The plasma concentrations of BP and its major metabolites [1-(2-pyrimidinyl)piperazine (1-PP) and 6'-hydroxybuspirone (6'-OH-BP)] were determined. The formation ratios of 1-PP and 6'-OH-BP from BP (AUC0-∞ of 1-PP/AUC0-∞ of BP and AUC0-∞ of 6'-OH-BP/AUC0-∞ of BP values) showed no alternation when the dose of BP changed. Single dose of AC decreased the AUC0-∞ of BP by 53% but increased the formation ratio of 6'-OH-BP by 74% (P<0.05). Multiple AC exposure increased the AUC0-∞ of BP by 110%, and the formation ratios of 1-PP and 6'-OH-BP from BP were increased by 229% and decreased by 95%, respectively (P<0.05). Conclusively, single/multiple AC exposure did not alter the first-pass CYP3A activity when using oral BP as probe in rats. Nevertheless, multiple AC exposure had markedly changed the production of BP metabolites.

Pinelliae rhizoma, a toxic chinese herb, can significantly inhibit CYP3A activity in rats.

Raw Pinelliae Rhizoma (RPR) is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP) and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA), are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes) and buspirone (BP) were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug–drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions.

Modulation of Hepatic Cytochrome P450 Enzymes by Curcumin and its Pharmacokinetic Consequences in Sprague-dawley Rats.

Background:Curcumin (CUR) is a polyphenolic component derived from an herbal remedy and dietary spice turmeric (Curcuma longa).Objective:The aim of this study was to investigate inhibitory effects of CUR on in vitro cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single CUR dose in rats.Materials and Methods:An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral CUR in rats.Results:In the in vitro CYP inhibition study, CUR inhibited the CYP3A-mediated metabolism of testosterone (TES) with a half maximal inhibitory concentration of 11.0 ± 3.3 μM. However, the impact of a single oral CUR dose on the pharmacokinetics of BUS in rats is limited, showing that CUR cannot function as an inhibitor for CYP3A-mediated drug metabolism in vivo.Conclusion:To the best of our knowledge, our results are the first reported data regarding the inhibition of in vitro CYP3A-mediated metabolism of TES and the in vivo impact of a single CUR dose on the pharmacokinetics of BUS in rats. Further study is required to draw a confirmative conclusion on whether CUR can be a clinically relevant CYP3A4 inhibitor.SUMMARY CUR can inhibit the in vitro CYP3A-mediated metabolism of TES in RLM. However, the impact of a single oral CUR dose on the pharmacokinetics of BUS in rats is limited, showing that CUR cannot function as an inhibitor for CYP3A-mediated drug metabolism in vivo.

Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation

Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior – has robust 5-HT fibers and reciprocal connections with the hypothalamic–pituitary–adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment and the PAG neural correlates of the behavior remain largely unknown. In this study, the effects of acute and chronic treatments with buspirone (BUSP) and escitalopram (ESCIT) on anxiety-related behaviors were tested in an open-field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural-endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos-ir. No significant differences were found in behaviors and CORT after chronic treatment. In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment.

Coadministration of Pinellia ternata Can Significantly Reduce Aconitum carmichaelii to Inhibit CYP3A Activity in Rats.

Chuanwu (CW), the mother root of Aconitum carmichaelii Debx., is a traditional Chinese medicine (TCM) for treating traumatic injuries, rheumatoid arthritis, and tumors. CW coadministered with banxia (BX), the root of Pinellia ternata, is also widely prescribed in clinical practice. However, the mechanism of this combination is yet deciphered. Current study aimed to investigate the effects of CW, including raw chuanwu (RCW) and processed chuanwu (PCW) alone, as well as CW coadministered with BX on CYP3A activity. Buspirone (BP) and testosterone (Tes) were used as specific probe substrates in vivo and ex vivo, respectively. CYP3A activity was determined by the metabolites formation ratios from the substrates. Compared with those in the control group, the metabolites formation ratios significantly decreased in the RCW and PCW alone groups, accompanied by a marked decrease in CYP3A protein and mRNA levels. However, there was a significant increase in those ratios in the RCW-BX and PCW-BX groups compared to the RCW and PCW alone groups. The results indicated that both RCW and PCW can inhibit CYP3A activity in rats because of downregulation of CYP3A protein and mRNA levels. Decreases in CYP3A activity can be reversed by coadministration with BX.