Oral Buspirone Research Articles

A Case Report of Low-Dose Steroid Induced Psychosis in an Older Adult with Rheumatoid Arthritis

IntroductionRheumatoid arthritis (RA) is typically known for its intra-articular manifestations in the joints, and steroids are considered one of the first-line medications for it. Steroids are known for neuropsychiatric manifestations, but it is rarely reported in low-dose steroids.Objectives We describe a case of psychosis in an older adult with RA precipitated by low-dose prednisone with no past history of neuropsychiatric symptoms from steroids in the past five years.MethodsMiss X is a 63-year-old female with past history of RA, major depressive disorder, hypothyroidism, chronic obstructive pulmonary disease, and hypertension, presented with one-week history of irritable mood, increased psychomotor agitation, decreased need for sleep and appetite, and delusions of grandeur and persecution. Her depression had been treated with oral duloxetine 60mg twice daily, oral buspirone 10mg at night, and oral trazodone 150mg at night. She did have a urinary tract infection a week prior, but the psychotic symptoms persisted with antibiotic treatment. Miss X had also been on a monthly taper regimen of low-dose oral prednisone for RA (from 15mg to 5mg) for the past three months and had completed the regimen one week ago. On mental status examination, she was alert and oriented to time, place, and person. Her mood was irritable with lability. She demonstrated tangential speech along with persecutory and grandiose delusions. Attention and concentration was normal with intact immediate and remote memory and impaired recent memory. Abstract ability, judgment, and insight were impaired. Physical examination and vital signs were within normal limits. Laboratory investigations of complete blood count, urine analysis, urine drug screen, thyroid function panel, renal function panel, hepatic function panel, serum sodium, potassium, calcium, thiamine, vitamin B12, folate, and vitamin D did not show any significant abnormalities.ResultsMiss X was admitted to the inpatient psychiatric unit with the diagnosis of medication-induced psychotic disorder, with onset after medication use as per The Diagnostic and Statistical Manual of Mental Disorders 5th edition- Text Revision. Oral olanzapine 10mg at night and oral lithium 300mg twice daily was started along with her home medications of oral duloxetine 60 mg twice daily and oral trazodone 150mg at night. During hospital stay, oral olanzapine was gradually increased to 15mg in the night but had to be reduced back to 10mg in the night due to sedation. Miss X’s symptoms improved during hospital stay and she was discharged on the 13th day of hospitalization with the same psychotropic medication regimen.ConclusionsOur case demonstrates the need for caution in prescribing steroids in older adults as it can precipitate neuropsychiatric symptoms even with a change in use or after withdrawal of steroids.Disclosure of InterestNone Declared

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial.

Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF. The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate-severe CA [nocturnal apnoea-hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1week, with a crossover design (1week of wash-out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14-73%, P=0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P=0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone-related serious adverse events. Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF.

Acute and Chronic Laryngeal Deficits Following Cervical Spinal Cord Injury

Laryngeal dysfunction is a common symptom following cervical spinal cord injury (cSCI) and currently there are no effective pharmacological interventions or behavioral treatments. The larynx is the primary valve controlling entrance into the trachea and lungs via opening and closing of the vocal folds. Although not well studied following cSCI, it is understood that laryngeal deficits during swallow often produce aspiration of food/liquid, significantly increasing risk of pneumonia. Our previous terminal electrophysiology experiments using freely breathing sodium pentobarbital anesthetized cats with acute hemisections at the 3rd cervical spinal level (C3) showed immediate alterations in laryngeal activity. These alterations persisted for 4 hours (testing duration). The serotonin (5‐HT1A) receptor agonist 8‐OH‐DPAT was delivered via the vertebral artery at low (3 □g/kg) and/or high (30 □g/kg) doses. This agonist altered behavior‐specific muscle recruitment patterns. In particular, the high dose restored laryngeal activity across breathing and swallow, which could be reversed with the competitive antagonist WAY100635 (0.5 mg/kg). In the current study, we tested if alterations seen acutely in laryngeal activity persist chronically, and if the 8‐OH‐DPAT clinical‐correlate buspirone (Buspar) would produce similar therapeutic results. Adult female cats underwent C3 hemisections and recovered for 4 or 8 weeks. Laryngeal endoscopy was performed weekly under isofluorane (3%) during normocapnia and hypercapnia (5% CO2). Asynchronous vocal fold movement was seen in all animals, defined by unilateral movement delays, and the extent of opening and closing of the glottis became variable. In a subset of animals, oral buspirone (5 mg) was given with food. One hour later, repeat endoscopic evaluation revealed full resolution of laryngeal function with synchronized movements during normocapnia and hypercapnia. Most importantly, with termination of buspirone dosing, laryngeal dysfunction returned. This work shows that the anesthetized preparation effectively identifies upper airway dysfunction early and chronically after C3 SCI, and that it can be used as a pre‐clinical model for novel therapeutic interventions. Results also indicate that buspirone is a high‐priority target for additional investigation as a therapeutic intervention after cSCI.Support or Funding InformationThis work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Veterans Affairs Rehabilitation, Research and Development RCSB9249S (DRH), Kentucky Spinal Cord and Head Injury Research Trust, Rebecca F. Hammond Endowment (DRH), and the Commonwealth of Kentucky Challenge for Excellence.

Evaluation of the Role of P-glycoprotein (P-gp)-Mediated Efflux in the Intestinal Absorption of Common Substrates with Elacridar, a P-gp Inhibitor, in Rats.

P-glycoprotein (P-gp) has been shown previously to contribute to the intestinal absorption of verapamil, diltiazem, tacrolimus, colchicine and indinavir in situ; however, its contribution in vivo is unknown. The present study aimed to evaluate the in vivo involvement of P-gp using elacridar as its inhibitor to distinguish the contribution of P-gp from cytochrome P450 (CYP) 3A. Fexofenadine (5mg/kg) and buspirone (1mg/kg) were used as probe substrates of P-gp and CYP3A, respectively. Each dual substrate (1 or 2mg/kg) was orally administered to rats after elacridar pre-treatment (3mg/kg). Additionally, verapamil, diltiazem or tacrolimus was orally co-administered with fexofenadine. Elacridar drastically increased the area under the plasma concentration-time curve (AUC0-t) of oral fexofenadine by 8.6-fold; however, it did not affect the AUC0-t of oral buspirone. Therefore, elacridar inhibited P-gp without affecting CYP3A. The absorption of oral verapamil, diltiazem and tacrolimus was not influenced by elacridar pre-treatment, and the increase in the AUC0-t of fexofenadine was approximately 3-fold when co-administered with each substrate; the minimal effect of elacridar was attributable to the limited contribution of P-gp but not to their self-inhibition against the transporter. Conversely, elacridar significantly increased the AUC0-t of colchicine (5.3-fold) and indinavir (2.0-fold), indicating that P-gp contributes to their absorption. Elacridar is useful for distinguishing the contribution of P-gp from CYP3A to the absorption of drugs in rats. The in vivo contribution of P-gp is minimal for high permeable compounds owing to their fraction absorbed of nearly 1.0.

The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

IntroductionA new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition.AimThe aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B).Methods19 healthy women took T+B under fed and fasted conditions during 2 overnight visits. The blood was sampled over a 24-hour period to determine the pharmacokinetics of buspirone and its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). Total testosterone levels were also assessed, at 5 time points and for quality control purposes only, as sublingual testosterone uptake is not expected to be influenced by prior food intake.Main Outcome MeasurePK profiles of buspirone and 1-PP.ResultsFor buspirone, the 90% confidence intervals (CIs) of the observed fed/fasted ratios for the plasma area under the curve (AUC)0-last, AUC0-inf, and Cmax after administration of T+B were not contained within the prespecified bounds of 80% and 125%, except for the lower bound of AUC0-inf. However, the 90% CIs of the observed fed/fasted ratios for the plasma AUC0-last, AUC0-inf, and Cmax of 1-PP were contained within the prespecified bounds, with the exception of the upper bound for Cmax. The mean AUCs and Cmax for 1-PP did not differ between fed and fasted conditions.ConclusionsAdministration of T+B after high-caloric food intake increased the bioavailability of buspirone but did not result in differences in Tmax when compared with fasted conditions. Both in fed and fasted conditions, T+B was generally well tolerated and safe. Exposure of 1-PP in fed and fasted conditions was comparable in both conditions. These results demonstrate that T+B can safely and effectively be used in both fed and fasted states.Gerritsen J, Bloemers J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects. J Sex Med 2020;8:186–194.

P3525Buspirone effect on chemoreflex and central apneas in heart failure

Abstract Background Increased chemosensitivity to carbon dioxide (CO2) is an important trigger of central apneas in heart failure (HF), contributing to HF progression and mortality. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity, thus preventing CA in patients with HF. Methods Sixteen patients with systolic HF (age 71.3±5.8 years, left ventricular ejection fraction 29.8±7.8%) and moderate-severe central apneas (nighttime apnea/hypopnea index AHI≥15 events/hour) underwent a double-blind, placebo-controlled, cross over, randomized study of oral buspirone administration (45 mg/day for 1 week). Results Buspirone reduced CO2 chemosensitivity compared to placebo (1.2 IR [1.1–1.5] vs. 2.0 [1.6–2.2] L/min/mmHg, p=0.008). Furthermore, buspirone improved: the AHI at nighttime (16.5 [8.5–24.7] vs. 27.5 [23.0–37.3] events/hour, p=0.002), and daytime (8.0 [2.3–11.5] vs. 11.5 [6.3–18.8] events/hour, p=0.006); the central apnea index at nighttime (4.0 [1.0–19.0] vs. 12.5 [8.3–27.3] events/hour, p=0.01) and daytime (1.0 [0.0–3.0] vs. 4.0 [1.3–6.0] events/hour, p=0.009); and the oxygen desaturation index at nighttime (4.7 [1.0–11.0] vs. 20.0 [8.7–26.5] events/hour, p=0.004) and daytime (0.2 [0.1–0.7] vs. 1.2 [0.3–4.8] events/hour, p=0.005). Buspirone showed a good safety profile and had no effect on neurohormones, arrhythmias, exercise capacity and mood/daytime sleepiness. Conclusion Buspirone reduces CO2 chemosensitivity and inhibits central apneas both during the day and the night in patients with systolic HF.

Bergamottin can be used to assess CYP3A-mediated intestinal first-pass metabolism without affecting P-glycoprotein-mediated efflux in rats

1. We investigated whether bergamottin would be useful for evaluating CYP3A-mediated intestinal metabolism in rats utilising its characteristics as a mechanism-based inhibitor of CYP3A.2. Buspirone and fexofenadine, probe substrates of CYP3A and P-glycoprotein (P-gp), respectively, were orally co-administered to rats with bergamottin (2.5 mg/kg) or orally administered 2 h after bergamottin pre-treatment. The effect of bergamottin pre-treatment on hepatic CYP3A specifically was investigated with intravenous administration of buspirone. The kobs of bergamottin for CYP3A was calculated based on the portal unbound Cmax.3. Co-administration of bergamottin significantly increased the AUC0–inf for buspirone and fexofenadine by 1.6-fold and 1.7-fold, respectively, indicating that bergamottin inhibited both CYP3A and P-gp.4. Bergamottin pre-treatment significantly elevated the AUC0–inf of oral buspirone by 3.7-fold but exerted no effect on the pharmacokinetics of intravenous buspirone, indicating that bergamottin pre-treatment selectively inhibited CYP3A-mediated intestinal metabolism without affecting the hepatic CYP3A. These findings were supported by the result that the kobs (0.00000118 min−1) of bergamottin for CYP3A was lower than the kdeg (0.0005 min−1) for CYP3A. Furthermore, bergamottin pre-treatment did not affect the pharmacokinetics of oral fexofenadine, suggesting that P-gp was not influenced.5. These profiles of bergamottin enable the convenient assessment of CYP3A-mediated intestinal metabolism.

Comparative Evaluation of Efficacy of Oral Diazepam and Buspirone in Reducing Anxiety and Discomfort in Mandibular Third Molar Surgery-In Vivo Study

Comparative Evaluation of Efficacy of Oral Diazepam and Buspirone in Reducing Anxiety and Discomfort in Mandibular Third Molar Surgery-In Vivo Study

26 Feasibility of therapeutic hypothermia in stemi: single UK heart attack centre experience

Background Primary PCI is the gold standard treatment for acute STEMI, but reperfusion injury limits its beneficial effect on infarct size (IS). In experimental studies, therapeutic hypothermia (HT) consistently reduces IS caused by reperfusion injury, but translation into clinical practice remains a challenge. The purpose of our study (part of COOL AMI EU study) was to assess the feasibility of integrating pre-reperfusion HT using an intravascular temperature management system (Thermogard XP, ZOLL, USA) into routine clinical practice without a significant delay in door-to-balloon (DTB) time. Methods Patients with STEMI presenting within 6 h of symptoms onset and planned for PPCI were prospectively enrolled. TH was implemented by intravenous infusion (IV) of cold saline and a heat-exchange balloon catheter inserted via the right femoral vein. Oral buspirone and IV pethidine were used to control shivering. HT was continued for a total time of 3 h, followed by passive rewarming. Results 18 patients were successfully recruited. The average age was 60.3 years and 94.4% were male. The DTB time was 40.6 min. There was an increase of 3.6 min compared with the mean DTB time of 37 min for patients who underwent PPCI and did not received HT. Mean temperature at reperfusion was 34.4 ° C. There were no adverse events related to the use of the heat-exchange catheter or the implementation of hypothermia. Conclusion Hypothermia is feasible and safe in STEMI patients without significant delay in door-to-balloon time.

Effects on behavioural variables of oral versus transdermal buspirone administration in cats displaying urine marking

ABSTRACTUrine marking in cats is one of the most recurrent pathologies observed in clinical consults. The cause can be (amongst others) stress, anxiety, litter box aversion, hormonal disturbance, or territoriality or other responses to other cats. In addition to environmental enrichment, treatment consists of sterilization and/or the use of pheromones, and in some cases is complemented with drug therapy; the use of buspirone is considered appropriate. The goal of this study was to evaluate, with a clinical study, significant differences between oral and transdermal buspirone administration. Individual evaluation and directed selection established two experimental groups. Patients in Group 1 were given buspirone tablets and patients in Group 2 were given buspirone in the form of pluronic lecithin organogel. Effects were evaluated after 35 days of treatment. Statistical analysis of results indicated no significant differences between oral and transdermal administration on the reduction in frequency of urine marking. Nevertheless, a significant reduction in marking frequency was observed following treatment (p < .05) for both forms of buspirone administration.

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 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.

Effects of intramuscular and oral buspirone on physiology and behavior in monkeys

Effects of intramuscular and oral buspirone on physiology and behavior in monkeys

In Vitro and In Vivo Evaluation of the Effect of Puerarin on Hepatic Cytochrome P450-Mediated Drug Metabolism

Puerarin (8-β-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a major pharmacological component of Puerariae Radix, the root of Pueraria lobata. We investigated the effect of puerarin on hepatic cytochrome P450-mediated drug metabolism in rats and humans. The in vitro cytochrome P450 inhibitory effect of puerarin in human and rat liver microsomes was evaluated using the following model cytochrome P450 substrates: phenacetin for CYP1A, diclofenac for CYP2C, dextromethorphan for CYP2D, and testosterone for CYP3A. The in vivo pharmacokinetics of intravenous and oral buspirone, a probe substrate for CYP3A, was studied with single simultaneous intravenous coadministration of puerarin in rats. In the in vitro cytochrome P450 inhibition study, the rate of disappearance of testosterone was significantly reduced in the presence of 10 µM PU, while that of other cytochrome P450 substrates was not significantly affected in both human and rat liver microsomes, suggesting that puerarin inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and rat systems (IC50 = 15.5 ± 3.9 µM). After intravenous administration of buspirone with single simultaneous coadministration of intravenous puerarin at a dose of 10 mg/kg in rats, the total area under the plasma concentration-time curve from time zero to time infinity was increased while time-averaged total body clearance decreased. When buspirone was orally administered in rats with the 10 mg/kg intravenous puerarin coadministration, both total area under the plasma concentration-time curve from time zero to time infinity and the extent of absolute oral bioavailability were significantly increased. Therefore, results of the in vitro microsomal and in vivo pharmacokinetic studies suggest the possible inhibition of hepatic CYP3A-mediated drug metabolism by puerarin administration, potentially leading to metabolism-mediated herb-drug interactions with clinical significance.

Therapeutic doses of buspirone block D3 receptors in the living primate brain

Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5mg/kg) blocked both [11C]PHNO and [11C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15min and rapid wash-out over 2-6h. In contrast, oral buspirone (3mg/kg) significantly blocked [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3h, but had minimal effects on [11C]raclopride binding (28-37% at 1h and 10% at 3h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.

Somatodendritic 5-hydroxytryptamine1A(5-HT1A) autoreceptor function in major depression as assessed using the shift in electroencephalographic frequency spectrum with buspirone

Positron emission tomography and post-mortem studies of the number of somatodendritic 5-hydroxytryptamine(1A) (5-HT(1A)) autoreceptors in raphé nuclei have found both increases and decreases in depression. However, recent genetic studies suggest they may be increased in number and/or function. The current study examined the effect of buspirone on the electroencephalographic (EEG) centroid frequency, a putative index of somatodendritic 5-HT(1A) receptor functional status, in a cohort of medication-free depressed patients and controls. A total of 15 depressed patients (nine male) and intelligence quotient (IQ)-, gender- and age-matched healthy controls had resting EEG recorded from 29 scalp electrodes prior to and 30, 60 and 90 min after oral buspirone (30 mg) administration. The effect of buspirone on somatodendritic 5-HT(1A) receptors was assessed by calculating the EEG centroid frequency between 6 and 10.5 Hz. The effect of buspirone on postsynaptic 5-HT(1A) receptors was assessed by measuring plasma growth hormone, prolactin and cortisol concentrations. Analysis of variance revealed a significantly greater effect of buspirone on the EEG centroid frequency in patients compared with controls (F1,28 = 6.55, p = 0.016). There was no significant difference in the neuroendocrine responses between the two groups. These findings are consistent with an increase in the functional status of somatodendritic, but not postsynaptic, 5-HT1A autoreceptors, in medication-free depressed patients in line with hypotheses based on genetic data. This increase in functional status would be hypothesized to lead to an increase in serotonergic negative feedback, and hence decreased release of 5-HT at raphé projection sites, in depressed patients.

Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers

The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9). A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ. BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50 ) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration-time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03). The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9.

Buspirone transdermal administration for menopausal syndromes, in vitro and in animal model studies

Menopausal syndromes can seriously disturb the quality of women's life. In this work, we have investigated transdermal administration of buspirone, a 5-HT 1A receptor agonist, for treatment of the major menopausal syndrome, hot flushes. To the best of our knowledge, this is the first time buspirone has been proposed for the treatment of hot flushes. We designed a buspirone transdermal system containing the drug in an ethosomal carrier. Pharmacokinetic data in rats following transdermal administration indicate that buspirone was present in plasma for 12 h, reaching a C max value of 120.07 ± 86.97 ng/ml after 2 h. A F rel value of 0.89 was estimated for transdermal vs. oral buspirone. The effect of transdermal buspirone on hot flushes was evaluated in ovariectomized rats by monitoring tail skin temperature changes. Temperature alleviation (1.6 ± 0.7 °C) to normal values was observed 3 h post-buspirone administration with the effect lasting for at least 3 h. Histological examination of the skin at the application site indicated that transdermal ethosomal buspirone is safe. The significant findings presented here encourage further studies with ethosomal buspirone transdermal system for treatment of menopausal syndromes.

Successful management of psychogenic alopecia with buspirone in a crossbreed cat

A 1-year-old male crossbreed cat was presented for evaluation of alopecia in dorsal lumbar and sacral regions. The owner had moved to his current residence 2 months prior to the admission date. It seemed that the cat was uncomfortable in this new place. The client noticed excessive vocalisation, restlessness, unusual over-licking and self-grooming. One month after moving to the current residence, the owner brought an African grey parrot to the house. These events seem to have increased the cat’s anxiety, and the owner noticed excessive grooming and other signs of anxiety, such as vocalisation and restlessness. The behaviour of abnormal licking resulted in alopecia in the dorsal trunk. Dermatophyte culture, skin scrapes and acetate strip examinations were negative for dermatophytes, parasites and yeasts. A tentative diagnosis of feline psychogenic alopecia was made based on history and clinical findings. Treatment with clomipramine resulted in urinary retention. Due to history of drug therapy, urinary retention was expected as an anticholinergic effect of using clomipramine. The clomipramine therapy was stopped, and the cat was then treated with oral buspirone. The selected drug was significantly effective in controlling the animal’s anxiety and overgrooming behaviour.

The Effect of Oral Buspirone, Pyridostigmine, and Bethanechol on Esophageal Function Evaluated With Combined Multichannel Esophageal Impedance-manometry in Healthy Volunteers

There is limited information on medications with promotility effects on the esophagus. Studies in healthy volunteers have shown the potential role of the direct cholinergic agonist bethanechol and the serotonin receptor agonist buspirone in improving esophageal motility. It has been also shown that an acetylcholinesterase inhibitor, the short-acting drug edrophonium administered intravenously caused a greater increase in the esophageal contraction amplitude and duration than bethanechol. Edrophonium cannot be used as a promotility therapy owing to short duration of action and lack of oral administration. The use of another acetylcholinesterase inhibitor pyridostygmine with longer duration of action has not been studied. The aim of the study was to evaluate the effect of oral pyridostygmine (60 mg), buspirone (20 mg), and bethanechol (25 mg) on esophageal function assessed by combined multichannel intraluminal impedance-esophageal manometry. Ten healthy volunteers were enrolled in a double blind randomized 3-period crossover study. Multichannel intraluminal impedance-esophageal manometry recorded esophageal pressures and bolus transit data during 6 liquid and 6 viscous swallows at baseline and 20, 40, and 60 minutes after the randomized oral administration of each drug. Blinded analysis found significant increases in mean distal esophageal amplitude for liquid swallows from baseline to 60 minutes postdosing after pyridostygmine (87.6 vs. 118.0 mm Hg, P<0.001), buspirone (85.1 vs. 101.9 mm Hg, P<0.05), and bethanechol (87.6 vs. 118.8 mm Hg, P<0.01). Only pyridostygmine showed a significant decrease in mean distal onset velocity for liquid swallows at 60 minutes postdosing (3.4 vs. 2.3 cm/s, P<0.01) and increase in total bolus transit time at 60 minutes postdosing (7.9 vs. 9.3 s, P<0.05). All 3 agents significantly increased mean lower esophageal sphincter residual pressure for liquid swallows at 20, 40, and 60 minutes postdosing. Increased lower esophageal sphincter resting pressure was not significant. Similar results were found with viscous swallows. Oral pyridostygmine, buspirone, and bethanechol enhance esophageal motility with pyridostygmine appearing to have the greatest effect. A potential effect on improving esophageal function and symptoms in patients requires further study.