A randomized double-blind placebo-controlled crossover-style trial of buspirone in functional dysphagia and ineffective esophageal motility.

PubMed

Aggarwal, Nitin; Thota, Prashanthi Nagavenkata; Lopez, Rocio; Gabbard, Scott

2018-02-01

Studies suggest that Ineffective Esophageal Motility (IEM) is the manometric correlate of Functional Dysphagia (FD). Currently, there is no accepted therapy for either condition. Buspirone is a serotonin modulating medication and has been shown to augment esophageal peristaltic amplitude in healthy volunteers. We aimed to determine if buspirone improves manometric parameters and symptoms in patients with overlapping IEM/FD. We performed a prospective, double-blind, placebo-controlled, crossover-style trial of 10 patients with IEM/FD. The study consisted of two 2-week treatment arms with a 2-week washout period. Outcomes measured at baseline, end of week 2, and week 6 include high resolution esophageal manometry (HREM), the Mayo Dysphagia Questionnaire-14 (MDQ-14), and the GERD-HRQL. The mean age of our 10 patients was 53 ± 9 years and 70% were female. After treatment with buspirone, 30% of patients had normalization of IEM on manometry; however, there was 30% normalization in the placebo group as well. Comparing buspirone to placebo, there was no statistically significant difference in the HREM parameters measured. There was also no statistically significant difference in symptom outcomes for buspirone compared to placebo. Of note, patients had a statistically significant decrease in the total GERD-HRQL total score when treated with placebo compared to baseline levels. Despite previous data demonstrating improved esophageal motility in healthy volunteers, our study shows no difference in terms of HREM parameters or symptom scores in IEM/FD patients treated with buspirone compared to placebo. Further research is necessary to identify novel agents for this condition. © 2017 John Wiley & Sons Ltd.

Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors

PubMed Central

Bergman, Jack; Roof, Rebecca A.; Furman, Cheryse A.; Conroy, Jennie L.; Mello, Nancy K.; Sibley, David R.; Skolnick, Phil

2016-01-01

Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (~98 and ~29 nM respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose–effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction. PMID:22827916

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

PubMed Central

Hanley, Michael J; Masse, Gina; Harmatz, Jerold S; Cancalon, Paul F; Dolnikowski, Gregory G; Court, Michael H; Greenblatt, David J

2013-01-01

Aim 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). Methods 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. Results 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). Conclusion 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. PMID:22943633

The immediate and the delayed effects of buspirone on zebrafish (Danio rerio) in an open field test: a 3-D approach.

PubMed

Maaswinkel, Hans; Zhu, Liqun; Weng, Wei

2012-10-01

Behavioral changes in zebrafish induced by acute administration of buspirone have been interpreted to be the result of reduced anxiety. The purpose of the current study was to determine whether the effects of short-term and mid-term habituation to an open field corroborated the anxiolytic hypothesis. We exposed single zebrafish for 60 min to 5 mgL buspirone and tested them twice, immediately after exposure and again 3.5 h later. Each session lasted 20 min. Distance from bottom of tank, velocity, duration freezing, distance from center and horizontal distribution, and preferred spatial location were analyzed with a 3-D tracking system. In the early session (starting at 10:30), 20 min habituation of control zebrafish only marginally increased distance from bottom, which was still 90% higher in zebrafish treated with buspirone. When extending the habituation to 3.5 h, the picture became more complex. Distance from bottom did not further increase in control zebrafish. More importantly, some signs of increased anxiety were present in the buspirone group, such as increased freezing, reduced velocity, and increased bottom-dwelling. However, analyzing data of individual fish excluded rebound anxiety as unlikely. The delayed effects might be drug side effects, such as motor impairment and/or dizziness. The immediate and the delayed effects of buspirone have the appearance to be unrelated. Copyright © 2012 Elsevier B.V. All rights reserved.

Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test.

PubMed

Lee, Kaziya M; Coelho, Michal A; Sern, Kimberly R; Class, MacKayla A; Bocz, Mark D; Szumlinski, Karen K

2017-01-01

Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swim test (FST) is employed as a predictor of antidepressant efficacy. However, over the past several years, our studies of alcohol withdrawal-induced negative affect consistently indicate the coincidence of increased anxiety-related behaviors on various behavioral tests with reduced immobility in the FST. Further, this behavioral profile correlates with increased mGlu5 protein expression within limbic brain regions. As the role for mGlu5 in anxiety is well established, we hypothesized that the reduced immobility exhibited by alcohol-withdrawn mice when tested in the FST might reflect anxiety, possibly a hyper-reactivity to the acute swim stressor. Herein, we evaluated whether or not the decreased FST immobility during alcohol withdrawal responds to systemic treatment with a behaviorally-effective dose of the prototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevance of the withdrawal-induced increase in mGlu5 expression for FST behavior by comparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negative allosteric modulator MTEP (3 mg/kg). Adult male C57BL/6J mice were subjected to a 14-day, multi-bottle, binge-drinking protocol that elicits hyper-anxiety and increases glutamate-related protein expression during early withdrawal. Control animals received only water. At 24hr withdrawal, animals from each drinking condition were subdivided into groups and treated with an IP injection of buspirone, MTEP, or vehicle, 30min prior to the FST. Drug effects on general locomotor activity were also assessed. As we reported previously, alcohol-withdrawn animals exhibited significantly reduced immobility in the FST compared to water controls. Both buspirone and MTEP significantly increased immobility in alcohol-withdrawn animals, with a modest increase also seen in water controls. No significant group differences were observed for

Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm.

PubMed

John, William S; Banala, Ashwini K; Newman, Amy H; Nader, Michael A

2015-04-01

The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers. The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self-administration (SA). Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01-0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N = 3/group). Monkeys received 5 days of treatment with either PG619 (0.1-3.0 mg/kg, i.v.) or buspirone (0.01-1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003-0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested. PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice. Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.

The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial.

PubMed

Karamanolis, George P; Panopoulos, Stylianos; Denaxas, Konstantinos; Karlaftis, Anastasios; Zorbala, Alexandra; Kamberoglou, Dimitrios; Ladas, Spiros D; Sfikakis, Petros P

2016-09-01

Acute administration of the oral 5-HT1A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc). Thirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged. Eight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively). Our findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment. Clinical

Buspirone before prenatal stress protects against adverse effects of stress on emotional and inflammatory pain-related behaviors in infant rats: age and sex differences.

PubMed

Butkevich, Irina P; Mikhailenko, Viktor A; Vershinina, Elena A; Otellin, Vladimir A; Aloisi, Anna Maria

2011-10-24

Prenatal stress strengthens tonic pain and provokes depression. The serotoninergic system is involved in these processes. We recently showed that maternal buspirone, a 5-HT1A receptor agonist, protects against the adverse effects of in utero stress on depression and pain in adult rat offspring. Using a similar maternal treatment with buspirone, we focus here on the infant stage, which is important for the correction of prenatal abnormalities. Maternal buspirone before restraint stress during the last week of pregnancy decreased the time of immobility in the forced swim test in the infant offspring. Prenatal stress increased formalin-induced pain in the second part of the time-course of the response to formalin in males of middle infancy but in the first part of the response in males of late infancy. The effect was reversed by maternal buspirone. Pain dominated in males of both middle and late infancy but the time-course of formalin pain in infant females revealed a slower development of the processes. The results show that the time-course of formalin-induced pain in infant rats reacts to prenatal stress in an age-dependent and sexually dimorphic manner. Our finding of opposite influences of prenatal stress and buspirone before prenatal stress on formalin-induced pain during the interphase indicates that functional maturity of the descending serotonergic inhibitory system occurs in late infancy males (11-day-olds), and 5-HT1A receptors participate in this process. The data provide evidence that maternal treatment with buspirone prior to stress during pregnancy alleviates depression-like and tonic pain-related behaviors in the infant offspring. Copyright © 2011 Elsevier B.V. All rights reserved.

Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.

PubMed

Azkona, Garikoitz; Sagarduy, Ainhoa; Aristieta, Asier; Vazquez, Nerea; Zubillaga, Verónica; Ruíz-Ortega, José Angel; Pérez-Navarro, Esther; Ugedo, Luisa; Sánchez-Pernaute, Rosario

2014-04-01

Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. In this study, we used a well-characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias. We then investigated the molecular substrates implicated in the anti-dyskinetic effect of buspirone, a 5HT1A partial agonist. Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor (DR)D3, ΔFosB and phospho (p)CREB, as well as an over-activation of the DRD1 signalling pathway, reflected by elevated ratios of phosphorylated DARPP32 and ERK2. Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose-dependent fashion. Buspirone (4 mg/kg) dramatically reduced the presence and severity of dyskinesias (by 83%) and normalized DARPP32 and ERK2 phosphorylation ratios, while the increases in DRD3, ΔFosB and pCREB observed in dyskinetic rats were not modified. Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development and optimization of buspirone oral osmotic pump tablet

PubMed Central

Derakhshandeh, K.; berenji, M. Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump–based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance. PMID:25657794

Development and optimization of buspirone oral osmotic pump tablet.

PubMed

Derakhshandeh, K; Berenji, M Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance.

Mass spectrometric investigation of buspirone drug in comparison with thermal analyses and MO-calculations

NASA Astrophysics Data System (ADS)

Zayed, M. A.; Fahmey, M. A.; Hawash, M. A.; El-Habeeb, Abeer A.

2007-06-01

The buspirone drug is usually present as hydrochloride form of general formula C 21H 31N 5O 2·HCl, and of molecular weight (MW) = 421.96. It is an analgesic anxiolytic drug, which does not cause sedative or depression of central nervous system. In the present work it is investigated using electron impact mass spectral (EI-MS) fragmentation at 70 eV, in comparison with thermal analyses (TA) measurements (TG/DTG and DTA) and molecular orbital calculation (MOC). Semi-empirical MO calculation, PM3 procedure, has been carried out on buspirone both as neutral molecule (in TA) and the corresponding positively charged species (in MS). The calculated MOC parameters include bond length, bond order, particle charge distribution on different atoms and heats of formation. The fragmentation pathways of buspirone in EI-MS lead to the formation of important primary and secondary fragment ions. The mechanism of formation of some important daughter ions can be illuminated from comparing with that obtained using electrospray ESIMS/MS mode mass spectrometer through the accurate mass measurement determination. The losses of the intermediate aliphatic part (CH 2) 4 due to cleavage of N-C bond from both sides is the primary cleavage in both techniques (MS and TA). The PM3 provides a base for fine distinction among sites of initial bond cleavage and subsequent fragmentation of drug molecule in both TA and MS techniques; consequently the choice of the correct pathway of such fragmentation knowing this structural session of bonds can be used to decide the active sites of this drug responsible for its chemical, biological and medical reactivity.

Gastric emptying and related symptoms in patients treated with buspirone, amitriptyline or clebopride: a "real world" study by 13C-octanoic Acid Breath Test.

PubMed

Caviglia, Gian P; Sguazzini, Carlo; Cisarò, Fabio; Ribaldone, Davide G; Rosso, Chiara; Fagoonee, Sharmila; Smedile, Antonina; Saracco, Giorgio M; Astegiano, Marco; Pellicano, Rinaldo

2017-12-01

Gastric motility is a key-factor in the pathogenesis of functional dyspepsia (FD). 13C-octanoic Acid Breath Test (OBT) is a tool used for measuring gastric emptying time in clinical setting. We aimed to investigate the variation in FD symptoms and OBT parameters after treatment with buspirone, amitriptyline or clebopride. Between Jan-2007 and Dec-2014, we enrolled 59 patients with FD unresponsive to first-line therapy with proton pump inhibitors and/or domperidone that underwent OBT before and after 3 months of buspirone (N.=32), amitriptyline (N.=16) or clebopride (N.=11) treatment. Early satiation severity was positively correlated with gastric half emptying time (t1/2) (r=0.3789, P=0.003) and gastric lag phase (r=0.3371, P=0.011), and negatively correlated with gastric emptying coefficient (r=-0.3231, P=0.015). A reduction in t1/2 measurement in association to postprandial fullness, and early satiation severity improvement was observed (P=0.009, P=0.005 and P<0.001, respectively). Patients treated with buspirone obtained both a decrease in t1/2 (P=0.005) and an amelioration in early satiation (P=0.001). Patients under amitriptyline treatment experienced an improvement in postprandial fullness (P=0.046), whereas no variation was reported in patients treated with clebopride. Patients with FD, non-responders to first-line therapy and reporting meal-related discomfort, may benefit from buspirone or amitriptyline-based therapies.

Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.

PubMed

Chouinard, G; Lefko-Singh, K; Teboul, E

1999-08-01

1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of alpha and beta half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.

Evaluation of buspirone for relapse-prevention in adults with cocaine dependence: An efficacy trial conducted in the real world

PubMed Central

Winhusen, Theresa; Brady, Kathleen T.; Stitzer, Maxine; Woody, George; Lindblad, Robert; Kropp, Frankie; Brigham, Gregory; Liu, David; Sparenborg, Steven; Sharma, Gaurav; VanVeldhuisen, Paul; Adinoff, Bryon; Somoza, Eugene

2012-01-01

Cocaine dependence is a significant public health problem for which there are currently no FDA-approved medications. Hence, identifying candidate compounds and employing an efficient evaluation process is crucial. This paper describes key design decisions made for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) study that uses a novel two-stage process to evaluate buspirone (60 mg/day) for cocaine-relapse prevention. The study includes pilot (N=60) and full-scale (estimated N=264) trials. Both trials will be randomized, double-blind, and placebo-controlled and both will enroll treatment-seeking cocaine-dependent participants engaged in inpatient/residential treatment and scheduled for outpatient treatment post-discharge. All participants will receive contingency management in which incentives are given for medication adherence as evaluated by the Medication Events Monitoring System (MEMS). The primary outcome measure is maximum days of continuous cocaine abstinence, as assessed by twice-weekly urine drug screens (UDS) and self-report, during the 15-week outpatient treatment phase. Drug-abuse outcomes include cocaine use as assessed by UDS and self-report of cocaine use, other substance use as assessed by UDS and self-report of substance use (i.e., alcohol and/or illicit drugs), cocaine bingeing, HIV risk behavior, quality of life, functioning, and substance-abuse treatment attendance. Unique aspects of the study include conducting an efficacy trial in community treatment programs, a two-stage process to efficiently evaluate buspirone, and an evaluation of mediators by which buspirone might exert a beneficial effect on relapse prevention. PMID:22613054

Evaluation of buspirone for relapse-prevention in adults with cocaine dependence: an efficacy trial conducted in the real world.

PubMed

Winhusen, Theresa; Brady, Kathleen T; Stitzer, Maxine; Woody, George; Lindblad, Robert; Kropp, Frankie; Brigham, Gregory; Liu, David; Sparenborg, Steven; Sharma, Gaurav; Vanveldhuisen, Paul; Adinoff, Bryon; Somoza, Eugene

2012-09-01

Cocaine dependence is a significant public health problem for which there are currently no FDA-approved medications. Hence, identifying candidate compounds and employing an efficient evaluation process is crucial. This paper describes key design decisions made for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) study that uses a novel two-stage process to evaluate buspirone (60 mg/day) for cocaine-relapse prevention. The study includes pilot (N=60) and full-scale (estimated N=264) trials. Both trials will be randomized, double-blind, and placebo-controlled and both will enroll treatment-seeking cocaine-dependent participants engaged in inpatient/residential treatment and scheduled for outpatient treatment post-discharge. All participants will receive contingency management in which incentives are given for medication adherence as evaluated by the Medication Events Monitoring System (MEMS). The primary outcome measure is maximum days of continuous cocaine abstinence, as assessed by twice-weekly urine drug screens (UDS) and self-report, during the 15-week outpatient treatment phase. Drug-abuse outcomes include cocaine use as assessed by UDS and self-report of cocaine use, other substance use as assessed by UDS and self-report of substance use (i.e., alcohol and/or illicit drugs), cocaine bingeing, HIV risk behavior, quality of life, functioning, and substance abuse treatment attendance. Unique aspects of the study include conducting an efficacy trial in community treatment programs, a two-stage process to efficiently evaluate buspirone, and an evaluation of mediators by which buspirone might exert a beneficial effect on relapse prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of buspirone on the immediate positive and delayed negative properties of intravenous cocaine as measured in the conditioned place preference test

PubMed Central

Ettenberg, Aaron; Bernardi, Rick E.

2007-01-01

In prior work, we have demonstrated that the behavioral effects of cocaine adhere to the predictions of the opponent-process theory of drug action. Animals develop conditioned place preferences for distinct locations paired with the immediate effects of IV cocaine, but learn to avoid places paired with the effects present 15-min post injection. It was of interest to assess the putative role of 5-HT in producing the negative properties of cocaine since cocaine acts to inhibit the reuptake of serotonin (5-HT) and since such actions have been associated with anxiogenic consequences. Male rats were administered a reinforcing dose of cocaine (1.0 mg/kg IV) and then placed – either immediately or after a 15-min delay -- into one side of a two-compartment (black-white) Conditioned Place Preference (CPP) box for 5-min. On alternate days, the animals received IV saline injections and were placed in the opposite side of the CPP box. This continued for eight days after which animals had experienced 4 pairings of cocaine with one side (black or white) of the CPP apparatus, and 4 saline pairings with the opposite side. Other groups of rats were treated identically except that 30-min prior to placement into the apparatus, these animals received an IP injection of saline or buspirone (a partial 5-HT1A agonist) at a dose that we have shown to be anxiolytic (2.5 mg/kg IP). Control animals experienced either buspirone or saline pretreatments without cocaine. Our results confirm that animals increase the time spent on the side paired with the immediate effects of cocaine (compared to baseline), but tend to avoid the side paired with effects present 15-min post-injection. Buspirone had no effect on the immediate rewarding properties of cocaine, but completely reversed the negative properties present 15-min post-cocaine. These results are consistent with the view that attenuation of 5-HT neurotransmission (via the autoreceptor agonist properties of buspirone) can reverse the negative

Effect of the 5-HT(1A) partial agonist buspirone on regional brain electrical activity in man: a functional neuroimaging study using low-resolution electromagnetic tomography (LORETA).

PubMed

Anderer, P; Saletu, B; Pascual-Marqui, R D

2000-12-04

In a double-blind, placebo-controlled study, the effects of 20 mg buspirone - a 5-HT(1A) partial agonist - on regional electrical generators within the human brain were investigated utilizing three-dimensional EEG tomography. Nineteen-channel vigilance-controlled EEG recordings were carried out in 20 healthy subjects before and 1, 2, 4, 6 and 8 h after drug intake. Low-resolution electromagnetic tomography (LORETA; Key Institute for Brain-Mind Research, software: http://www.keyinst.unizh.ch) was computed from spectrally analyzed EEG data, and differences between drug- and placebo-induced changes were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux human brain atlas available as a digitized MRI (McConnell Brain Imaging Centre: http://www.bic.mni.mcgill.ca). At the pharmacodynamic peak (1st hour), buspirone increased theta and decreased fast alpha and beta sources. Areas of theta increase were mainly the left temporo-occipito-parietal and left prefrontal cortices, which is consistent with PET studies on buspirone-induced decreases in regional cerebral blood flow and fenfluramine-induced serotonin activation demonstrated by changes in regional cerebral glucose metabolism. In later hours (8th hour) with lower buspirone plasma levels, delta, theta, slow alpha and fast beta decreased, predominantly in the prefrontal and anterior limbic lobe. Whereas the results of the 1st hour speak for a slight CNS sedation (more in the sense of relaxation), those obtained in the 8th hour indicate activation. Thus, LORETA may provide useful and direct information on drug-induced changes in central nervous system function in man.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

PubMed

Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

2016-04-01

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Automated software-guided identification of new buspirone metabolites using capillary LC coupled to ion trap and TOF mass spectrometry.

PubMed

Fandiño, Anabel S; Nägele, Edgar; Perkins, Patrick D

2006-02-01

The identification and structure elucidation of drug metabolites is one of the main objectives in in vitro ADME studies. Typical modern methodologies involve incubation of the drug with subcellular fractions to simulate metabolism followed by LC-MS/MS or LC-MS(n) analysis and chemometric approaches for the extraction of the metabolites. The objective of this work was the software-guided identification and structure elucidation of major and minor buspirone metabolites using capillary LC as a separation technique and ion trap MS(n) as well as electrospray ionization orthogonal acceleration time-of-flight (ESI oaTOF) mass spectrometry as detection techniques. Buspirone mainly underwent hydroxylation, dihydroxylation and N-oxidation in S9 fractions in the presence of phase I co-factors and the corresponding glucuronides were detected in the presence of phase II co-factors. The use of automated ion trap MS/MS data-dependent acquisition combined with a chemometric tool allowed the detection of five small chromatographic peaks of unexpected metabolites that co-eluted with the larger chromatographic peaks of expected metabolites. Using automatic assignment of ion trap MS/MS fragments as well as accurate mass measurements from an ESI oaTOF mass spectrometer, possible structures were postulated for these metabolites that were previously not reported in the literature. Copyright 2006 John Wiley & Sons, Ltd.

Different MK-801 administration schedules induce mild to severe learning impairments in an operant conditioning task: role of buspirone and risperidone in ameliorating these cognitive deficits.

PubMed

Rapanelli, Maximiliano; Frick, Luciana Romina; Bernardez-Vidal, Micaela; Zanutto, Bonifacio Silvano

2013-11-15

Blockade of N-methyl-d-aspartate receptor (NMDA) by the noncompetitive NMDA receptor (NMDAR) antagonist MK-801 produces behavioral abnormalities and alterations in prefrontal cortex (PFC) functioning. Due to the critical role of the PFC in operant conditioning task learning, we evaluated the effects of acute, repeated postnatal injections of MK-801 (0.1mg/kg) on learning performance. We injected Long-Evans rats i.p. with MK-801 (0.1mg/kg) using three different administration schedules: injection 40 min before beginning the task (during) (n=12); injection twice daily for six consecutive days prior to beginning the experimental procedures (prior) (n=12); or twice daily subcutaneous injections from postnatal day 7 to 11 (postnatal) (n=12). Next, we orally administered risperidone (serotonin receptor 2A and dopamine receptor 2 antagonist, 1mg/kg) or buspirone (serotonin receptor 1A partial agonist, 10mg/kg) to animals treated with the MK-801 schedule described above. The postnatal and prior administration schedules produced severe learning deficits, whereas injection of MK-801 just before training sessions had only mild effects on acquisition of an operant conditioning. Risperidone was able to reverse the detrimental effect of MK-801 in the animals that were treated with MK-801 during and prior training sessions. In contrast, buspirone was only effective at mitigating the cognitive deficits induced by MK-801 when administered during the training procedures. The data demonstrates that NMDA antagonism disrupts basic mechanisms of learning in a simple PFC-mediated operant conditioning task, and that buspirone and risperidone failed to attenuate the learning deficits when NMDA neurotransmission was blocked in the early stages of the postnatal period. Copyright © 2013 Elsevier B.V. All rights reserved.

Lyophilized sustained release mucoadhesive chitosan sponges for buccal buspirone hydrochloride delivery: formulation and in vitro evaluation.

PubMed

Kassem, Mohamed A A; ElMeshad, Aliaa N; Fares, Ahmed R

2015-06-01

This work aims to prepare sustained release buccal mucoadhesive lyophilized chitosan sponges of buspirone hydrochloride (BH) to improve its systemic bioavailability. Chitosan sponges were prepared using simple casting/freeze-drying technique according to 3(2) factorial design where chitosan grade was set at three levels (low, medium, and high molecular weight), and concentration of chitosan solution at three levels (0.5, 1, and 2%). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h), and time for release of 50% BH (T50%) were chosen as dependent variables. Additional BH cup and core buccal chitosan sponge were prepared to achieve uni-directional BH release toward the buccal mucosa. Sponges were evaluated in terms of drug content, surface pH, scanning electron microscopy, swelling index, mucoadhesion strength, ex vivo mucoadhesion time, and in vitro drug release. Cup and core sponge (HCH 0.5E) were able to adhere to the buccal mucosa for 8 h. It showed Q8h of 68.89% and exhibited a uni-directional drug release profile following Higuchi diffusion model.

Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder.

PubMed

Bari, Naimat Kalim; Fazil, Mohammad; Hassan, Md Quamrul; Haider, Md Rafi; Gaba, Bharti; Narang, Jasjeet K; Baboota, Sanjula; Ali, Javed

2015-11-01

The present work discusses the preparation, characterization and in vivo evaluation of thiolated chitosan nanoparticles (TCS-NPs) of buspirone hydrochloride (BUH) for brain delivery through intranasal route. TCS NPs were prepared by ionic gelation method and characterized for various parameters. The NPs formed were having particle size of 226.7±2.52nm with PDI 0.483±0.031. Drug entrapment efficiency (EE) and loading capacity (LC) were found to be 81.13±2.8 and 49.67±5.5%. The cumulative percentage drug permeation through nasal mucosa was 76.21%. Bioadhesion study carried out on porcine mucin and showed a bioadhesion efficiency of 90.218±0.134%. Nose-to-brain delivery of placebo NPs was investigated by confocal laser scanning microscopy (CLSM) technique using rhodamine-123 as a marker. The brain concentration achieved after intranasal administration of TCS-NPs was 797.46±35.76ng/ml with tmax 120min which was significantly higher than achieved after intravenous administration on BUH solution 384.15±13.42ng/ml and tmax of 120min and intranasal administration of BUH solution 417.77±19.24ng/ml and tmax 60min. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of d-amphetamine, diazepam and buspirone on schedule-induced polydipsia suppressed by response-dependent and response-independent shock.

PubMed

Flores, P; Pellón, R

1998-03-01

Food deprived Wistar rats were exposed to a fixed time 60 s food schedule until they developed schedule-induced polydipsia. Rats were matched in pairs according to their licking rate, being designated experimental or yoked control at random. Every fifth lick by experimental rats was then followed by an electric shock (0.05, 0.1, or 0.2 mA) while the food schedule continued in operation. Yoked-control rats received the same shocks as experimental rats, but independently of their own licking. Drugs were then tested on the suppressed rates of licking. Diazepam (0.5-2.0 mg/kg) increased punished schedule-induced polydipsia, a result not observed in yoked controls. No increases in the licks per minute of experimental or control animals were found after d-amphetamine (0.25-4.0 mg/kg) or buspirone (0.5-8.0 mg/kg). In comparison with previous results it is concluded that the antipunishment effects of drugs on schedule-induced behaviour depend on the type of punishment contingency.

Functional and physiological effects of treadmill training induced by buspirone, carbidopa, and L-DOPA in clenbuterol-treated paraplegic mice.

PubMed

Ung, Roth-Visal; Rouleau, Pascal; Guertin, Pierre A

2012-05-01

Chronic spinal cord injury may be complicated by weight loss, muscle atrophy, and bone loss. The authors identified a combination pharmacotherapy using buspirone, carbidopa, and L-DOPA (BCD) that elicits bouts of locomotor-like movements in spinal cord-transected (Tx) mice. They then evaluated the effects of 8 weeks of treadmill training in Tx mice that received BCD or BCD + clenbuterol, a monoaminergic agent with anabolic properties, on locomotor function, muscle atrophy, adipose tissue loss, and bone density measures. Induced locomotor movement, adipose tissue, skeletal muscle, and femoral bone properties were compared in unoperated control mice, operated controls (untreated, untrained Tx mice), and 2 groups of treated, trained Tx mice (Tx + BCD, Tx + BCD + clenbuterol) that also received training. BCD- and BCD + clenbuterol-treated mice showed comparable levels of locomotor movements that significantly improved over time. Soleus muscle mass and soleus and extensor digitorum longus cross-sectional area significantly increased in both groups of BCD-treated mice, with greater effects in BCD + clenbuterol-treated animals. Fiber type conversion, adipose tissues, bone mineral density, and content were reduced in all Tx groups compared with unoperated control mice. These findings suggest that locomotor movement and muscle properties can be restored to near-normal levels after several weeks of BCD treatment, regular training, and clenbuterol in completely paraplegic animals.

Spectroscopic study of the reaction mechanism of buspirone interaction with iodine and tetracyanoethylene reagents and its applications.

PubMed

Zayed, M A; El-Habeeb, Abeer A

2009-06-01

The reactions between the drug buspirone (busp) in its base form and iodine amphoteric reagent (n-donor and/or sigma-acceptor) and with tetracyanoethylene as a pi-acceptor reagent (TCNE) have been studied spectrophotometrically at different reactant concentrations, time intervals, temperatures, and with different solvents and wavelengths, with the aim of selecting the conditions that give the most suitable molar extinction coefficients. This study aims chiefly to throw light on the nature of these reactions and to select the most proper conditions for spectrophotometric application of these reagents to determine this biologically active drug used in treating different diseases. The reaction mechanism involves the formation of busp-I(2) outer and inner sphere complexes. The separated busp-I(2) solid product obtained was investigated using elemental analyses, FT-IR, thermal analyses (TA) and electron ionization mass spectrometry (EI-MS) and was found to be biologically active. The reaction mechanism of busp-TCNE involves the formation of a charge transfer (CT) complex. The analytical parameters of the proposed spectrophotometric procedures were calculated. These procedures were applied in the analysis of busp in its formulations as a drug used to treat psychiatric illnesses. The values of the Sandell sensitivity, standard deviation (SD), relative standard deviation (RSD) and recovery percentage show the high sensitivity of these procedures. This study also presents a promising new busp-I(2) drug derivative that can be used more efficiently for the same purposes as its parent. It gives a clear idea about the possible metabolites and metabolic pathways of busp and its derivative that may occur in vivo. Copyright 2009 John Wiley & Sons, Ltd.

[Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets].

PubMed

Drabant, S; Klebovich, I; Gachályi, B; Renczes, G; Farsang, C

1998-09-01

Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were

The assessment and treatment of performance anxiety in musicians.

PubMed

Clark, D B; Agras, W S

1991-05-01

Performance anxiety in musicians may be severe enough to require intervention but has been the subject of relatively little clinical research. The authors' objectives were to describe the results of a comprehensive clinical and laboratory assessment and to perform a double-blind, placebo-controlled study comparing buspirone, cognitive-behavior therapy, and the combination of these treatments for performance anxiety. Ninety-four subjects were recruited by mass media announcements and were seen in a university-based outpatient psychiatric clinic. Assessments were 1) questionnaires for all 94 subjects, 2) diagnostic interview of 50 subjects, and 3) laboratory performance of 34 subjects. Treatment conditions were 1) 6 weeks of buspirone, 2) 6 weeks of placebo, 3) a five-session, group cognitive-behavior therapy program with buspirone, or 4) the cognitive-behavior therapy program with placebo. Treatment outcome measures included subjective anxiety ratings and heart rate measures during a laboratory performance, a questionnaire measure of performance confidence, and a blind rating of musical performance quality. All subjects fulfilled criteria for DSM-III-R social phobia. Of the 15 full-time professional musicians, ten had tried propranolol and three had stopped performing. Most of the subjects had substantial anxiety and heart rate increases during laboratory speech and musical performances. Cognitive-behavior therapy resulted in statistically significant reductions in subjective anxiety, improved quality of musical performance, and improved performance confidence. Buspirone was not an effective treatment. Cognitive-behavior therapy is a viable treatment approach for performance anxiety in musicians.

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

PubMed Central

Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J.; Kiferle, Lorenzo; Turkheimer, Federico E.; Bain, Peter; Molloy, Sophie; Piccini, Paola

2014-01-01

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549

Identification of Splice Variants as Molecular Markers in Parkinson’s Disease

DTIC Science & Technology

2006-09-01

cyclosporine, cisapride, astemizole; b. NMDA antagonists: e.g. amantadine, budipine, memantine, remacemide, dextromethorphan ; c. Any investigational...f. Drugs known to improve dyskinesias: amantadine, dextromethorphan , beta-blockers, fluoxitene, clozapine, quetiapine, olanzapine, buspirone, other

A New Paradigm for Evaluating Avoidance/Escape Motivation.

PubMed

Tsutsui-Kimura, Iku; Bouchekioua, Youcef; Mimura, Masaru; Tanaka, Kenji F

2017-07-01

Organisms have evolved to approach pleasurable opportunities and to avoid or escape from aversive experiences. These 2 distinct motivations are referred to as approach and avoidance/escape motivations and are both considered vital for survival. Despite several recent advances in understanding the neurobiology of motivation, most studies addressed approach but not avoidance/escape motivation. Here we develop a new experimental paradigm to quantify avoidance/escape motivation and examine the pharmacological validity. We set up an avoidance variable ratio 5 task in which mice were required to press a lever for variable times to avoid an upcoming aversive stimulus (foot shock) or to escape the ongoing aversive event if they failed to avoid it. We i.p. injected ketamine (0, 1, or 5 mg/kg) or buspirone (0, 5, or 10 mg/kg) 20 or 30 minutes before the behavioral task to see if ketamine enhanced avoidance/escape behavior and buspirone diminished it as previously reported. We found that the performance on the avoidance variable ratio 5 task was sensitive to the intensity of the aversive stimulus. Treatment with ketamine increased while that with buspirone decreased the probability of avoidance from an aversive stimulus in the variable ratio 5 task, being consistent with previous reports. Our new paradigm will prove useful for quantifying avoidance/escape motivation and will contribute to a more comprehensive understanding of motivation. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Effects of Nicotine Administration and Stress on Sensory-Gating Depend on Rat Strain and Sex

DTIC Science & Technology

1998-01-01

and cocaine (Harty & Davis, 1985), and decrease in response to ethanol (Pohorecky, Cagan, Brick, & Jaffe, 1976) and haloperidol (Mansbach, Geyer...dopamine agonists. Specifically, increased PPI has been found after treatment with haloperidol , raclopride, and buspirone (antagonists at the D2 receptor

Pharmacotherapy in the Developmental Disabilities: New Developments.

ERIC Educational Resources Information Center

Aman, Michael G.

1991-01-01

This paper identifies and evaluates emerging developments in the behavioral pharmacotherapy of people with developmental disabilities, including such medications as the opiate antagonists, fenfluramine, beta adrenergic blockers, buspirone, antipsychotics, amantadine hydrochloride, and antilibidinal drugs. The need for more well-designed drug…

Tricyclic and Tetracyclic Antidepressants for the Prevention of Frequent Episodic or Chronic Tension-Type Headache in Adults: A Systematic Review and Meta-Analysis.

PubMed

Jackson, Jeffrey L; Mancuso, Josephine M; Nickoloff, Sarah; Bernstein, Rebecca; Kay, Cynthia

2017-12-01

Tension-type headaches are a common source of pain and suffering. Our purpose was to assess the efficacy of tricyclic (TCA) and tetracyclic antidepressants in the prophylactic treatment of tension-type headache. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the ISI Web of Science, and clinical trial registries through 11 March 2017 for randomized controlled studies of TCA or tetracyclic antidepressants in the prevention of tension-type headache in adults. Data were pooled using a random effects approach. Among 22 randomized controlled trials, eight included a placebo comparison and 19 compared at least two active treatments. Eight studies compared TCAs to placebo, four compared TCAs to selective serotonin reuptake inhibitors (SSRIs), and two trials compared TCAs to behavioral therapies. Two trials compared tetracyclics to placebo. Single trials compared TCAs to tetracyclics, buspirone, spinal manipulation, transcutaneous electrical stimulation, massage, and intra-oral orthotics. High-quality evidence suggests that TCAs were superior to placebo in reducing headache frequency (weighted mean differences (WMD): -4.8 headaches/month, 95% CI: -6.63 to -2.95) and number of analgesic medications consumed (WMD: -21.0 doses/month, 95% CI: -38.2 to -3.8). TCAs were more effective than SSRIs. Low-quality studies suggest that TCAs are superior to buspirone, but equivalent to behavioral therapy, spinal manipulation, intra-oral orthotics, and massage. Tetracyclics were no better than placebo for chronic tension-type headache. Tricyclic antidepressants are modestly effective in reducing chronic tension-type headache and are superior to buspirone. In limited studies, tetracyclics appear to be ineffective in the prophylactic treatment of chronic tension-type headache.

Placebo Medication Use for Behavior Management in an Adult with Autism

ERIC Educational Resources Information Center

Kroeger, K. A.; Brown, Jennifer

2011-01-01

Buspar (buspirone) is an anxiolytic medication used to reduce symptoms associated with anxiety. The current study provides a case description of a man diagnosed with autistic disorder where Buspar was prescribed on an "as needed" basis in order to decelerate tantrum behavior associated with undifferentiated anxiety. After successful reduction of…

Comparison of the Effects of Typical and Atypical Anxiolytics on Learning in Monkeys and Rats,

DTIC Science & Technology

kg) and alprazolam (0.032-0.32 mg/kg) produced dose-dependent decreases in overall response rate in all subjects. However, with buspirone and 8-OH-DPAT...monkeys were variable across drugs and drug classes. Both 8-OH-DPAT and alprazolam produced large increases in percent errors in acquisition at doses

The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

PubMed Central

Paquette, Melanie A.; Foley, Katherine; Brudney, Elizabeth G.; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul

2010-01-01

Rationale Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. Objectives Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. Results Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin. Conclusions BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia. PMID:19283364

Thermoregulatory defense mechanisms.

PubMed

Sessler, Daniel I

2009-07-01

Core body temperature is normally tightly regulated by an effective thermoregulatory system. Thermoregulatory control is sometimes impaired by serious illness, but more typically remains intact. The primary autonomic defenses against heat are sweating and active precapillary vasodilation; the primary autonomic defenses against cold are arteriovenous shunt vasoconstriction and shivering. The core temperature triggering each response defines its activation threshold. Temperatures between the sweating and vasoconstriction thresholds define the inter-threshold range. The shivering threshold is usually a full 1 degrees C below the vasoconstriction threshold and is therefore a "last resort" response. Both vasoconstriction and shivering are associated with autonomic and hemodynamic activation; and each response is effective, thus impeding induction of therapeutic hypothermia. It is thus helpful to accompany core cooling with drugs that pharmacologically induce a degree of thermal tolerance. No perfect drug or drug combination has been identified. Anesthetics, for example, induce considerable tolerance, but are rarely suitable. Meperidine-especially in combination with buspirone-is especially effective while provoking only modest toxicity. The combination of buspirone and dexmedetomidine is comparably effective while avoiding the respiratory depression association with opioid administration.

Stimulation of serotonin-1A receptors in mammals to alleviate motion sickness and emesis induced by chemical agents

NASA Technical Reports Server (NTRS)

Lucot, James B. (Inventor); Crampton, George H. (Inventor)

1990-01-01

A method for the alleviation of both motion sickness and chemically-induced emesis is provided which includes the administration of a nontoxic, therapeutically effective amount of a composition which stimulates serotonin-1A receptors in a mammal in need of such treatment. The preferred compounds for use are buspirone and 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT).

Agonist-dependent modulation of G-protein coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus.

PubMed

Valdizán, Elsa Maria; Castro, Elena; Pazos, Angel

2010-08-01

5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific Galpha subtypes ([35S]GTPgammaS labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, p<0.05) in (+)8-OH-DPAT-induced [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 antibodies but not with anti-Galphao, anti-Galphai1, anti-Galphai2, anti-Galphaz or anti-Galphas antibodies. In contrast, in the presence of buspirone, significant [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 (50%, p<0.01), anti-Galphao (32%, p<0.01) and anti-Galphai2 (29%, p<0.05) antibodies, without any labelling with anti-Galphai1, anti-Galphaz or anti-Galphas. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8+/-4.9, pIC50 5.95+/-0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.

A Novel Animal Model for Panic Disorder: Attempted Reproduction of the Fear of Fear

DTIC Science & Technology

1999-11-04

and haloperidol . Buspirone, ipsapirone, flesi noxin, and 8- O H-DPAT (aI1 5HT IA agoni sts) strongly reduced USV in treated animals. T he 5HT 1A...Robinson & Shrol, 1989). Alprazolam (an effective anti-panic agent) and haloperidol (3 dopamine antagonist), produced similar profiles. Both drugs...identical to a drug serving as a negative control ( haloperidol ) suggests this model has poor predictive validity. Furthermore, the benzodiazepine

The olfactory hole-board test in rats: a new paradigm to study aversion and preferences to odors

PubMed Central

Wernecke, Kerstin E. A.; Fendt, Markus

2015-01-01

Odors of biological relevance (e.g., predator odors, sex odors) are known to effectively influence basic survival needs of rodents such as anti-predatory defensiveness and mating behaviors. Research focused on the effects of these odors on rats’ behavior mostly includes multi-trial paradigms where animals experience single odor exposures in subsequent, separated experimental sessions. In the present study, we introduce a modification of the olfactory hole-board test that allows studying the effects of different odors on rats’ behavior within single trials. First, we demonstrated that the corner holes of the hole-board were preferentially visited by rats. The placement of different odors under the corner holes changed this hole preference. We showed that holes with carnivore urine samples were avoided, while corner holes with female rat urine samples were preferred. Furthermore, corner holes with urine samples from a carnivore, herbivore, and omnivore were differentially visited indicating that rats can discriminate these odors. To test whether anxiolytic treatment specifically modulates the avoidance of carnivore urine holes, we treated rats with buspirone. Buspirone treatment completely abolished the avoidance of carnivore urine holes. Taken together, our findings indicate that the olfactory hole-board test is a valuable tool for measuring avoidance and preference responses to biologically relevant odors. PMID:26379516

[Comparison of in vitro model examinaitons with respect to drug release from suppositories].

PubMed

Regdon, G; Vágó, I; Mándi, E; Regdon, G; Erós, I

2000-04-01

9 lipophilic suppository bases with different physical-chemical parameters were examined. Buspiron-hydrochloride, an anxiolytic drug with good water-solubility was used--partly as a model--as a pharmacon, in a concentration of 10.0 mg/2.00 g. The rate and extent of in vitro drug release was monitored with static and dynamic methods. Kidney-dialysing membranes with various surfaces were used. The quantitative measurements were carried out spectrophotometrically and the amount of the diffused drug was determined at lambda = 298 nm. The mean values were calculated from 5 parallel measurements each time. The percentage values of in vitro relative availability revealed that the results of the two static diffusion studies did not differ significantly (p < 0.05) and were almost independent of the size of the membrane surface. The results of the dynamic diffusion method were well-reproducible but were vehicle-dependent. The process of release was characterized by the mathematical transformation of the release curves, while the correlation coefficients described the closeness of the relation. Two German vehicles, namely Witepsol H 15 with a medium hydroxyl value and Massa Estarinum 299, and a French vehicle, Suppocire AS2X were found to be excellent for the formulation of suppositories containing Buspiron-hydrochloride.

Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurones in vitro.

PubMed

Van den Hooff, P; Galvan, M

1992-08-01

1. The actions of 5-hydroxytryptamine (5-HT) and some 5-HT1A receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2. In the presence of tetrodotoxin (1 microM) to block any indirect effects, bath application of 5-HT (0.3-30 microM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3. The 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT1 receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4. 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50S were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 microM and buspirone 110 nM. 5. At a concentration of 3 microM, the putative 5-HT1A receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17.6. The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 microM) and the 5HT3 receptor antagonist, tropisetron (3 microM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization.7. It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.

Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder.

PubMed

Freeman, Ellen W

2004-01-01

This review focuses on current information about luteal phase administration (i.e. typically for the last 2 weeks of the menstrual cycle) of pharmacological agents for the treatment of premenstrual dysphoric disorder (PMDD). Compared with continuous administration, a luteal phase administration regimen reduces the exposure to medication and lowers the costs of treatment. Based on evidence from randomised clinical trials, SSRIs are the first-line treatment for PMDD at this time. Of these agents, sertraline, fluoxetine and paroxetine (as an extended-release formulation) are approved by the US FDA for luteal phase, as well as continuous, administration. Clinical trials of these agents and citalopram have demonstrated that symptom reduction is similar with both administration regimens. When used to treat PMDD, SSRI doses are consistent with those used for major depressive disorder. The medications are well tolerated; discontinuation symptoms with this intermittent administration regimen have not been reported. Other medications that have been examined in clinical trials for PMDD or severe premenstrual syndrome (PMS) using luteal phase administration include buspirone, alprazolam, tryptophan and progesterone. Buspirone and alprazolam show only modest efficacy in PMS (in some but not all studies), but there may be a lower incidence of sexual adverse effects with these medications than with SSRIs. Symptom reduction with tryptophan was significantly greater than with placebo, but the availability of this medication is strictly limited because of safety concerns. Progesterone has consistently failed to show efficacy for severe PMS/PMDD in large, randomised, placebo-controlled trials.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

PubMed

Ohyama, Masayo; Kondo, Maho; Yamauchi, Miki; Imanishi, Taiichiro; Koyama, Tsukasa

2016-12-01

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Anti-anxiety drugs reduce conflict-specific "theta"--a possible human anxiety-specific biomarker.

PubMed

McNaughton, Neil; Swart, Charles; Neo, Phoebe; Bates, Vanessa; Glue, Paul

2013-05-15

Syndromes of fear/anxiety are currently ill-defined, with no accepted human biomarkers for anxiety-specific processes. A unique common neural action of different classes of anxiolytic drugs may provide such a biomarker. In rodents, a reduction in low frequency (4-12 Hz; "theta") brain rhythmicity is produced by all anxiolytics (even those lacking panicolytic or antidepressant action) and not by any non-anxiolytics. This rhythmicity is a key property of the Behavioural Inhibition System (BIS) postulated to be one neural substrate of anxiety. We sought homologous anxiolytic-sensitive changes in human surface EEG rhythmicity. Thirty-four healthy volunteers in parallel groups were administered double blind single doses of triazolam 0.25mg, buspirone 10mg or placebo 1 hour prior to completing the stop-signal task. Right frontal conflict-specific EEG power (previously shown to correlate with trait anxiety and neuroticism in this task) was extracted as a contrast between trials with balanced approach-avoidance (stop-go) conflict and the average of trials with net approach and net avoidance. Compared with placebo, both triazolam and buspirone decreased right-frontal, 9-10 Hz, conflict-specific-power. Only one dose of each of only two classes of anxiolytic and no non-anxiolytics were tested, so additional tests are needed to determine generality. There is a distinct rhythmic system in humans that is sensitive to both classical/GABAergic and novel/serotonergic anxiolytics. This conflict-specific rhythmicity should provide a biomarker, with a strong pre-clinical neuropsychology, for a novel approach to classifying anxiety disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review.

PubMed

Berry-Bibee, Erin N; Kim, Myong-Jin; Simmons, Katharine B; Tepper, Naomi K; Riley, Halley E M; Pagano, H Pamela; Curtis, Kathryn M

2016-12-01

To examine whether the co-administration of hormonal contraceptives (HC) and psychotropic drugs commonly used to treat anxiety and/or depression results in safety or efficacy concerns for either drug. We searched PubMed and Cochrane libraries for clinical or pharmacokinetic (PK) studies that examined co-administration of any HC with psychotropic drugs [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), oral benzodiazepines, bupropion, mirtazapine, trazadone, buspirone, hydroxyzine, monoamine oxidase inhibitors (MAOIs), or atypical antipsychotics] in reproductive aged women. Of 555 articles identified, 22 articles (18 studies) met inclusion criteria. We identified 5 studies on SSRIs, four on TCAs, one on bupropion, three on atypical antipsychotics and five on oral benzodiazepines. No articles met inclusion criteria for SNRIs, mirtazapine, trazadone, buspirone, hydroxyzine or MAOIs. Overall, clinical studies did not demonstrate differences in unintended pregnancy rates when HCs were administered with and without psychotropic drugs or in psychotropic drug treatment outcomes when psychotropic drugs were administered with and without HCs. PK studies did not demonstrate changes in drug exposure related to contraceptive safety, contraceptive effectiveness or psychotropic drug effectiveness for most classes of psychotropic drugs. However, limited PK data raise concern for HCs increasing systemic exposure of amitriptyline and imipramine (both TCAs), theoretically posing safety concerns. Limited quality and quantity evidence on use of psychotropic drugs and HCs suggests low concern for clinically significant interactions, though no data exist specifically for non-oral formulations of HC. Given the high frequency of use for both HCs and psychotropic drugs among reproductive-age women in the US, this review highlights a need for further research in this area. Copyright © 2016 Elsevier Inc

The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.

PubMed

Li, Xia; Kaczanowska, Katarzyna; Finn, M G; Markou, Athina; Risbrough, Victoria B

2015-10-01

GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists. Published by Elsevier Ltd.

Does being drunk or high cause HIV sexual risk behavior? A systematic review of drug administration studies.

PubMed

Berry, Meredith S; Johnson, Matthew W

2018-01-01

HIV sexual risk behavior is broadly associated with substance use. Yet critical questions remain regarding the potential causal link between substance use (e.g., intoxication) and HIV sexual risk behavior. The present systematic review was designed to examine and synthesize the existing literature regarding the effects of substance administration on HIV sexual risk behavior. Randomized controlled experiments investigating substance administration and HIV sexual risk behavior (e.g., likelihood of condom use in a casual sex scenario) were included. Across five databases, 2750 titles/abstracts were examined and forty-three total peer reviewed published manuscripts qualified (few were multi-study manuscripts, and those details are outlined in the text). The majority of articles investigated the causal role of acute alcohol administration on HIV sexual risk behavior, although one article investigated the effects of acute THC administration, one the effects of acute cocaine administration, and two the effects of buspirone. The results of this review suggest a causal role in acute alcohol intoxication increasing HIV sexual risk decision-making. Although evidence is limited with other substances, cocaine administration also appears to increase sexual risk, while acute cannabis and buspirone maintenance may decrease sexual risk. In the case of alcohol intoxication, the pharmacological effects independently contribute to HIV sexual risk decision-making, and these effects are exacerbated by alcohol expectancies, increased arousal, and delay to condom availability. Comparisons across studies showed that cocaine led to greater self-reported sexual arousal than alcohol, potentially suggesting a different risk profile. HIV prevention measures should take these substance administration effects into account. Increasing the amount of freely and easily accessible condoms to the public may attenuate the influence of acute intoxication on HIV sexual risk decision-making. Copyright �

Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice.

PubMed

Rupniak, N M; Carlson, E C; Harrison, T; Oates, B; Seward, E; Owen, S; de Felipe, C; Hunt, S; Wheeldon, A

2000-06-08

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.

The drug treatment of delayed ejaculation

PubMed Central

Elsaied, Moustafa A.; Mostafa, Taymour

2016-01-01

Delayed ejaculation (DE) is an uncommon and a challenging disorder to treat. It is often quite concerning to patients and it can affect psychosocial well-being. Here we reviewed how DE is treated pharmacologically .We also highlighted specific settings where drugs could be introduced to medical practice. Electronic databases were searched from 1966 to February 2016, including PubMed MEDLINE, EMBASE, EBCSO Academic Search Complete, Cochrane Systematic Reviews Database, and Google Scholar using key words; delayed ejaculation, retarded ejaculation, inhibited ejaculation, drugs, treatment, or pharmacology. To achieve the maximum sensitivity of the search strategy and to identify all studies, we combined “delayed ejaculation” as Medical Subject Headings (MeSH) terms or keywords with each of “testosterone” or “cabergoline” or “bupropion” or “amantadine” or “cyproheptadine” or “midodrine” or “imipramine” or “ephedrine” or “pseudoephedrine” or “yohimbine” or “buspirone” or “oxytocin” or “bethanechol” as MeSH terms or keywords. There are a number of drugs to treat patients with DE including: testosterone, cabergoline, bupropion, amantadine, cyproheptadine, midodrine, imipramine, ephedrine, pseudoephedrine, yohimbine, buspirone, oxytocin, and bethanechol. Although there are many pharmacological treatment options, the evidence is still limited to small trials, case series or case reports. Review of literature showed that evidence level 1 (Double blind randomized clinical trial) studies were performed with testosterone, oxytocin, buspirone or bethanechol treatment. It is concluded that successful drug treatment of DE is still in its infancy. The clinicians need to be aware of the pathogenesis of DE and the pharmacological basis underlying the use of different drugs to extend better care for these patients. Various drugs are available to address such problem, however their evidence of efficacy is still limited and their

Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists.

PubMed

Winslow, J T; Insel, T R

1991-01-01

A modulatory role for serotonin has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9-11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT [+/-)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor. d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP.(ABSTRACT TRUNCATED AT 250 WORDS)

[The expressions of anxiety in the elderly. Their diagnosis and therapy].

PubMed

Scapicchio, P L

1995-10-01

Among the most common manifestations of anxiety in the elderly are those associated with neurological disorders. The etiology is often unclear, as anxiety and agitation may be a consequence of insight into the cognitive impairment rather than the direct expression of the neurological deficit. Benzodiazepines are the treatment of choice, particularly the 3-OH compounds that are non oxidised and without active metabolites. Concern about the use of benzodiazepines in the elderly may have been overstated. If used judiciously this class of drugs can prove extremely helpful in reducing day-time anxiety and night-time insomnia. Other medications that are commonly used to treat agitation and disruptive behaviour in demented elderly patients include antipsychotics, beta-blockers, trazodone, buspirone, anticonvulsants.

A systematic review of treatments for anxiety in youth with autism spectrum disorders.

PubMed

Vasa, Roma A; Carroll, Laura M; Nozzolillo, Alixandra A; Mahajan, Rajneesh; Mazurek, Micah O; Bennett, Amanda E; Wink, Logan K; Bernal, Maria Pilar

2014-12-01

This study systematically examined the efficacy and safety of psychopharmacological and non-psychopharmacological treatments for anxiety in youth with autism spectrum disorders (ASD). Four psychopharmacological, nine cognitive behavioral therapy (CBT), and two alternative treatment studies met inclusion criteria. Psychopharmacological studies were descriptive or open label, sometimes did not specify the anxiety phenotype, and reported behavioral activation. Citalopram and buspirone yielded some improvement, whereas fluvoxamine did not. Non-psychopharmacological studies were mainly randomized controlled trials (RCTs) with CBT demonstrating moderate efficacy for anxiety disorders in youth with high functioning ASD. Deep pressure and neurofeedback provided some benefit. All studies were short-term and included small sample sizes. Large scale and long term RCTs examining psychopharmacological and non-psychopharmacological treatments are sorely needed.

[Documented effects of SSRI preparations in anxiety].

PubMed

Allgulander, C

1998-05-20

The article consists in a review of the clinical evidence for treating anxiety disorders with selective serotonin re-uptake inhibitors (SSRIs). Sufficient documentation now exists to support the use of SSRIs in treating panic and obsessive-compulsive disorders, and in Sweden moclobemide is now approved for use in treating social phobia, and buspirone for use in treating generalised anxiety disorder. Further documentation of the treatment of post-traumatic stress disorder with SSRIs is probably to be expected. Benzodiazepines remain the most commonly used anxiolytics. Although persistent adverse sexual reactions, and withdrawal symptoms upon abrupt termination of medication, are notable side effects of SSRIs, patients become measurably more self-confident and focused, and manage risks more adequately. This underscores the need of further research into the interrelationship of personality traits and anxiety symptoms.

Serotonergic mechanisms in emesis

NASA Technical Reports Server (NTRS)

Lucot, J. B.; Crampton, G. H.

1988-01-01

The observation that the cerebrospinal fluid of cats which are susceptible to motion sickness contained lower baseline levels of 5-hydroxyindoleacetic acid, among other constituents, led to the hypothesis that serotonin inhibits emesis. The hypothesis was tested by administration of the serotonin-1A agonists buspirone and 8-OH-DPAT before motion testing in cats susceptible to motion sickness. Both drugs blocked motion sickness in a dose-dependent fashion. To determine if these drugs blocked emesis elicited by other stimuli, they were administered before subcutaneous administration of the alpha-2 noradrenergic agonist, xylazine. Both drugs also blocked xylazine-induced emesis. It was concluded that the stimulation of serotonin-1A receptors inhibits emesis elicited by the two stimuli and that this mechanism may exert a general antiemetic effect.

Behavioral effects of plant-derived essential oils in the geller type conflict test in mice.

PubMed

Umezu, T

2000-06-01

The present study was conducted to further explore plant-derived essential oils that possess an anticonflict effect using the Geller type conflict test in ICR mice. The benzodiazepine anxiolytic diazepam increased the response (lever pressing) rate during the alarm period (i.e., an anticonflict effect), but the 5-HT1A partial agonist buspirone did not. Oils of juniper, cypress, geranium and jasmine did not produce any effect in this test. Frankincense oil decreased the response rate during the safe period at 1600 mg/kg, but did not exhibit any effect on the response rate during the alarm period. In contrast, lavender oil increased the response rate during the alarm period in a dose-dependent manner in the same manner as diazepam. These results indicate that not only rose oil but also lavender oil possess an anticonflict effect in mice.

Facilitation by 8-OH-DPAT of passive avoidance performance in rats after inactivation of 5-HT1A receptors

PubMed Central

Otano, Ana; García-Osta, Ana; Ballaz, Santiago; Frechilla, Diana; Del Río, Joaquín

1999-01-01

Pretraining administration of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT 0.1 mg kg−1), a 5-HT1A receptor agonist, or buspirone (1 mg kg−1), a 5-HT1A receptor partial agonist, markedly impaired passive avoidance retention in rats 24 h later. The effect of 8-OH-DPAT was prevented by the 5-HT1A receptor antagonists, NAN-190 and WAY-100635, at doses without any intrinsic effect.N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ 10 mg kg−1), an alkylating agent that inactivates different G-protein coupled receptors, impaired retention performance when given 48 h pretraining. The disruptive effect of EEDQ was reversed by 8-OH-DPAT or buspirone, given 30 min before training.Non-specific actions did not account for 8-OH-DPAT-induced reversal of the EEDQ effect since no significant difference in locomotor activity or in pain threshold was found between rats receiving EEDQ or EEDQ+8-OH-DPAT.When NAN-190 (1 mg kg−1) or WAY-100635 (0.5 mg kg−1) were given before 8-OH-DPAT to EEDQ-pretreated animals, the reversal by 8-OH-DPAT of EEDQ-induced retention impairment was still more pronounced. However, no EEDQ reversal by 8-OH-DPAT was found when 5-HT1A receptors were protected by WAY-100635 (10 mg kg−1) 30 min before EEDQ.In the hippocampus of EEDQ-treated rats, 5-HT7 receptors were less inactivated than 5-HT1A receptors and significant increases were found in 5-HT1A but not in 5-HT7 receptor mRNA levels. Ritanserin and methiothepin (10 mg kg−1 each), antagonists with higher affinity at 5-HT7 than at 5-HT1A receptors, prevented the retention impairment induced by EEDQ but did not significantly protect against 5-HT7 receptor inactivation.The results indicate that the facilitatory effect of 8-OH-DPAT is not mediated through 5-HT1A receptors and suggest that other 8-OH-DPAT-sensitive receptors could be involved in the dual effect of 8-OH-DPAT on passive avoidance performance in rats. PMID:10588924

Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments

PubMed Central

Connors, Kristin A.; Valenti, Theodore W.; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S.; Brooks, Bryan W.; Gould, Georgianna G.

2014-01-01

The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitolizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [3H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of simalarly Gαi/o-coupled cannabinoid receptors. [3H] 8-OH-DPAT specific binding was 176 ± 8, 275 ± 32, and 230 ± 36 fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [3H] WIN55,212-2 binding density was higher in those same brain regions at 6 ± 0.3, 5.5 ± 0.4 and 7.3 ± 0.3 pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50 mg/L), or dietary exposure to WIN55,212-2 (7 μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p < 0.05). Acute exposure to WIN55,212-2 at 0.5-50 mg/L, reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID

75 FR 64310 - Determination That BUSPAR (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-19

..., Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness AGENCY: Food and Drug... reasons of safety or effectiveness. This determination means that FDA will not begin procedures to... withdraws or suspends approval of the drug's NDA or ANDA for reasons of safety or effectiveness or if FDA...

Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

PubMed

Gillman, P Ken

2010-02-01

The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats.

PubMed

Kanno, Hitomi; Sekiguchi, Kyoji; Yamaguchi, Takuji; Terawaki, Kiyoshi; Yuzurihara, Mitsutoshi; Kase, Yoshio; Ikarashi, Yasushi

2009-09-01

Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats. The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured. PCA reduced not only the 5-HT concentration but also the high K(+)-induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the

Nitric Oxide and Anxiety.

PubMed

Gulati, K; Rai, N; Ray, A

2017-01-01

Anxiety is a common neuropsychiatric disorder which affects both physical and mental health. Complex neurobiological mechanisms are involved in the genesis of anxiety, and the drugs used to date, though effective, are not free from shortcomings. Conventional agents like the classical benzodiazepines and the atypical nonbenzodiazepine agents like buspirone have their own limitations. There is thus need to explore newer neurochemical pathways to develop efficacious and safer drugs for the disorder. Nitric oxide (NO) is a unique neuromodulator substance, with the ability to influence and modulate several other conventional messengers which play an important role in anxiety. The currently available experimental and clinical data indicate that NO may be involved in the regulation of anxiety-like behavior induced by a variety of stimuli. These studies have explored the pharmacological and biochemical basis of nitrergic mechanisms in anxiety, and the data available are equivocal. This chapter reviews the research data available in this specific area and suggests that in view of the nature of the existing data, there is considerable scope for future research in this field. © 2017 Elsevier Inc. All rights reserved.

Reevaluating Antidepressant Selection in Patients With Bruxism and Temporomandibular Joint Disorder.

PubMed

Rajan, Royce; Sun, Ye-Ming

2017-05-01

Temporomandibular joint disorder (TMD) is a broad pain disorder that refers to several conditions affecting the temporomandibular joint of the jaw and the muscles of mastication. As with most pain disorders, a high prevalence of depression and anxiety is associated with TMD. Research has shown that selective serotonin reuptake inhibitors (SSRIs), the first-line drug therapy for major depressive disorder, may not be suitable for TMD patients because SSRIs can induce teeth-grinding, otherwise known as bruxism. This is problematic because bruxism is believed to further exacerbate TMD. Therefore, the purpose of this literature review is to better understand the mechanism of SSRI-induced bruxism, as well as discuss alternative antidepressant options for treating depression and anxiety in patients with bruxism and TMD. Alternative classes of antidepressants reviewed include serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, and monoamine oxidase inhibitors. Findings indicate that dopamine agonists and buspirone are currently the most effective medications to treat the side effects of SSRI-induced bruxism, but results regarding the effectiveness of specific antidepressants that avoid bruxism altogether remain inconclusive.

Treatment of anxiety disorders

PubMed Central

Bandelow, Borwin; Michaelis, Sophie; Wedekind, Dirk

2017-01-01

Anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, social anxiety disorder, and others) are the most prevalent psychiatric disorders, and are associated with a high burden of illness. Anxiety disorders are often underrecognized and undertreated in primary care. Treatment is indicated when a patient shows marked distress or suffers from complications resulting from the disorder. The treatment recommendations given in this article are based on guidelines, meta-analyses, and systematic reviews of randomized controlled studies. Anxiety disorders should be treated with psychological therapy, pharmacotherapy, or a combination of both. Cognitive behavioral therapy can be regarded as the psychotherapy with the highest level of evidence. First-line drugs are the selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Benzodiazepines are not recommended for routine use. Other treatment options include pregabalin, tricyclic antidepressants, buspirone, moclobemide, and others. After remission, medications should be continued for 6 to 12 months. When developing a treatment plan, efficacy, adverse effects, interactions, costs, and the preference of the patient should be considered. PMID:28867934

Weight Bearing Over-ground Stepping in an Exoskeleton with Non-invasive Spinal Cord Neuromodulation after Motor Complete Paraplegia.

PubMed

Gad, Parag; Gerasimenko, Yury; Zdunowski, Sharon; Turner, Amanda; Sayenko, Dimitry; Lu, Daniel C; Edgerton, V Reggie

2017-01-01

We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 year) and completely absent of vision (>15 year) using two novel strategies-transcutaneous electrical spinal cord stimulation at selected sites over the spine as well as pharmacological neuromodulation by buspirone. We also asked whether these neuromodulatory strategies could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics, CA) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation and drug enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton along with changes in autonomic functions including cardiovascular and thermoregulation. Based on these data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the over-ground step training in an exoskeleton, combined with transcutaneous electrical spinal cord stimulation either without or with pharmacological modulation.

Comparison of TiO2 photocatalysis, electrochemically assisted Fenton reaction and direct electrochemistry for simulation of phase I metabolism reactions of drugs.

PubMed

Ruokolainen, Miina; Gul, Turan; Permentier, Hjalmar; Sikanen, Tiina; Kostiainen, Risto; Kotiaho, Tapio

2016-02-15

The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for simulation of phase I metabolism of drugs was studied by comparing the reaction products of buspirone, promazine, testosterone and 7-ethoxycoumarin with phase I metabolites of the same compounds produced in vitro by human liver microsomes (HLM). Reaction products were analysed by UHPLC-MS. TiO2 photocatalysis simulated the in vitro phase I metabolism in HLM more comprehensively than did EC-Fenton or EC. Even though TiO2 photocatalysis, EC-Fenton and EC do not allow comprehensive prediction of phase I metabolism, all three methods produce several important metabolites without the need for demanding purification steps to remove the biological matrix. Importantly, TiO2 photocatalysis produces aliphatic and aromatic hydroxylation products where direct EC fails. Furthermore, TiO2 photocatalysis is an extremely rapid, simple and inexpensive way to generate oxidation products in a clean matrix and the reaction can be simply initiated and quenched by switching the UV lamp on/off. Copyright © 2015 Elsevier B.V. All rights reserved.

Perinatal Anxiety: Approach to Diagnosis & Management in the Obstetric Setting.

PubMed

Thorsness, Katie R; Watson, Corey; Larusso, Elizabeth M

2018-05-24

Anxiety is common in women during the perinatal period, manifests with various symptomatology and severity, and is associated with significant maternal morbidity and adverse obstetrical and neonatal outcomes. Given the intimate relationship and frequency of contact, the obstetric provider is optimally positioned to create a therapeutic alliance and manage perinatal anxiety. Time constraints, absence of randomized controlled trials, mixed quality of data, and concern for potential adverse reproductive outcomes all limit clinicians' ability to initiate informed risk-benefit discussions. Clear understanding of the role of the obstetric provider in the identification, stabilization, and initiation of medication and/or referral to psychotherapy for women with perinatal anxiety disorders is critical to maternal and neonatal wellbeing. Informed by our clinical practice as perinatal psychiatric providers, we have provided a concise summary of current research on the approach to treatment of perinatal anxiety disorders in the obstetric setting, including psychotherapy and supportive interventions, primary and adjuvant psychiatric medication, and general prescribing pearls. Medications examined include antidepressants, benzodiazepines, sedative-hypnotics, antihistamines, quetiapine, buspirone, propranolol, and melatonin. Further research into management of perinatal anxiety, particularly psychopharmacological management, is warranted. Copyright © 2018 Elsevier Inc. All rights reserved.

Medication Discovery for Addiction: Translating the Dopamine D3 Receptor Hypothesis

PubMed Central

Newman, Amy Hauck; Blaylock, Brandi L.; Nader, Michael A.; Bergman, Jack; Sibley, David R.; Skolnick, Phil

2013-01-01

The dopamine D3 receptor (D3R) has been investigated as a potential target for medication development to treat substance use disorders (SUDs) with a particular focus on cocaine and methamphetamine. Currently, there are no approved medications to treat cocaine and methamphetamine addiction and thus developing pharmacotherapeutics to compliment existing behavioral strategies is a fundamental goal. Novel compounds with high affinity and D3R selectivity have been evaluated in numerous animal models of drug abuse and favorable outcomes in nonhuman primate models of self-administration and relapse have provided compelling evidence to advance these agents into the clinic. One approach is to repurpose drugs that share the D3R mechanism and already have clinical utility, and to this end buspirone has been identified as a viable candidate for clinical trials. A second, but substantially more resource intensive and risky approach involves the development of compounds that exclusively target D3R, such as GSK598809 and PG 619. Clinical investigation of these drugs or other novel D3R-selective agents will provide a better understanding of the role D3R plays in addiction and whether or not antagonists or partial agonists that are D3R selective are effective in achieving abstinence in this patient population. PMID:22781742

An update on pharmacotherapy of autism spectrum disorder in children and adolescents.

PubMed

Goel, Ritu; Hong, Ji Su; Findling, Robert L; Ji, Na Young

2018-02-01

To date, no medication is proven to be effective in treating core symptoms of autism spectrum disorder (ASD). Psychotropic medications are widely used to target emotional and behavioural symptoms in ASD. This article reviewed evidence for pharmacotherapy, novel therapeutic agents, and Complementary and Alternative Medicine (CAM) in children and adolescents with ASD. Currently, only risperidone and aripiprazole have been approved by the US Food and Drug Administration (FDA) for treatment of irritability associated with ASD in children and adolescents. However, associated metabolic side-effects are concerning. Evidence supports use of methylphenidate and atomoxetine for attention deficit hyperactivity disorder (ADHD) symptoms and clonidine and guanfacine ER appear to be helpful. SSRIs are poorly tolerated and lack evidence in reducing restricted repetitive behaviours (RRB), anxiety, and depression. Buspirone shows promise in the treatment of RRB. The evidence is inconsistent for the effectiveness of anti-epileptic medications. Recent studies of glutamatergic, Gamma-aminobutyric acid (GABA)ergic, and cholinergic agents and oxytocin show inconsistent results. Despite wide use of CAM agents, the evidence is inconclusive. Melatonin can be helpful in reducing sleep problems. Overall, the evidence is limited for pharmacotherapy in children with ASD, and side-effects with long-term use can be burdensome.

Evaluation and management of esophageal manifestations in systemic sclerosis.

PubMed

Denaxas, Konstantinos; Ladas, Spyros D; Karamanolis, George P

2018-01-01

Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high-resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities.

Pharmacological Management of Anxiety Disorders in the Elderly

PubMed Central

Crocco, Elizabeth A.; Jaramillo, Sindy; Cruz-Ortiz, Caroline; Camfield, Katherine

2017-01-01

Opinion Statement Anxiety disorders are common in the elderly. Additionally, anxiety symptoms often accompany co-morbid psychiatric, medical, as well as neurodegenerative diseases in the older population. Anxiety in the elderly, often accompanied by depression, can lead to worsening physical, cognitive and functional impairments in this vulnerable population. Antidepressants are considered first line treatment. Both SSRIs and SNRIs are efficacious and well-tolerated in the elderly. Some SSRIs are strong inhibitors of the cytochrome P450 hepatic pathway whereas others have less potential for drug interaction. Those antidepressants with more favorable pharmacokinetic profiles should be considered first-line in the treatment of anxiety. Mirtazapine and vortioxetine are also considered safe treatment options. Buspirone may have benefit, but lacks studies in elderly populations. Although tricyclic/tetracyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) may be effective in the elderly, their side effect and safety profiles are suboptimal and thus are not recommended in late-life. Benzodiazepines and beta blockers should generally be avoided when treating anxiety in the elderly. There is not enough evidence to support the use of antipsychotics or mood stabilizers given their risk of problems in both the long and short term. In addition, antipsychotics have a black box warning for increased mortality in elderly patients with dementia. PMID:28948135

Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents.

PubMed

Lalonde, Robert; Strazielle, Catherine

2010-06-01

Two 5HT(1A) receptor agonists and chlordiazepoxide were examined in open-field, elevated plus maze, and emergence tests. At doses with no effect in the open-field, chlordiazepoxide increased open and open/total arm visits as well as open arm duration in the elevated plus maze, whereas 5HT(1A) receptor agonists showed an anxiolytic response on a single measure. The anxiolytic action of chlordiazepoxide was limited to the less active BALB/c strain. Unlike the 5HT(1A) receptor agonists, chlordiazepoxide was also anxiolytic in the emergence test, once again only in BALB/c and not C57BL/6J mice. Significant correlations were found between emergence latencies and specific indicators of anxiety in the elevated plus-maze in chlordiazepoxide-treated but not in mice treated with buspirone and 8-OH-DPAT. These results indicate that elevated plus-maze and emergence tests depend on benzodiazepine receptors. In contrast, 5HT(1A) receptor agonists were ineffective in the emergence test and no correlation was found between emergence latencies and specific indicators of anxiety in the elevated plus-maze. Though superficially similar, the emergence test seems to tap into a partially separate facet of anxiety.

Evaluation and management of esophageal manifestations in systemic sclerosis

PubMed Central

Denaxas, Konstantinos; Ladas, Spyros D.; Karamanolis, George P.

2018-01-01

Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high-resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities. PMID:29507463

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Generalized Anxiety Disorder.

PubMed

Abejuela, Harmony Raylen; Osser, David N

2016-01-01

This revision of previous algorithms for the pharmacotherapy of generalized anxiety disorder was developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. Algorithms from 1999 and 2010 and associated references were reevaluated. Newer studies and reviews published from 2008-14 were obtained from PubMed and analyzed with a focus on their potential to justify changes in the recommendations. Exceptions to the main algorithm for special patient populations, such as women of childbearing potential, pregnant women, the elderly, and those with common medical and psychiatric comorbidities, were considered. Selective serotonin reuptake inhibitors (SSRIs) are still the basic first-line medication. Early alternatives include duloxetine, buspirone, hydroxyzine, pregabalin, or bupropion, in that order. If response is inadequate, then the second recommendation is to try a different SSRI. Additional alternatives now include benzodiazepines, venlafaxine, kava, and agomelatine. If the response to the second SSRI is unsatisfactory, then the recommendation is to try a serotonin-norepinephrine reuptake inhibitor (SNRI). Other alternatives to SSRIs and SNRIs for treatment-resistant or treatment-intolerant patients include tricyclic antidepressants, second-generation antipsychotics, and valproate. This revision of the GAD algorithm responds to issues raised by new treatments under development (such as pregabalin) and organizes the evidence systematically for practical clinical application.

Marijuana Neurobiology and Treatment

PubMed Central

Elkashef, Ahmed; Vocci, Frank; Huestis, Marilyn; Haney, Margaret; Budney, Alan; Gruber, Amanda; el-Guebaly, Nady

2008-01-01

Marijuana is the number one illicit drug of abuse worldwide and a major public health problem, especially in the younger population. The objective of this article is to update and review the state of the science and treatments available for marijuana dependence based on a pre-meeting workshop that was presented at ISAM 2006. At the workshop, several papers were presented addressing the neurobiology and pharmacology of marijuana and treatment approaches, both psychotherapy and medications, for marijuana withdrawal. Medicolegal and ethical issues concerning marijuana medical use were also discussed. Concise summaries of these presentations are incorporated in this article, which is meant to be an updated review of the state of the science. Major advances have been made in understanding the underpinning of marijuana dependence and the role of the CNS cannabinoid system, which is a major area for targeting medications to treat marijuana withdrawal and dependence, as well as other addictions. Behavioral therapies are efficacious for facilitating abstinence from marijuana. Nefazadone, Marinol, and buspirone are showing early positive signals for efficacy in ameliorating marijuana withdrawal symptoms. Effective psychotherapeutic approaches are available and promising medications studies need to be confirmed in outpatient trials. The next few years looking promising for translational research efforts to make treatment widely accessible to patients with marijuana dependence. PMID:19042204

Anxiolytic effects of the aqueous extract of Uncaria rhynchophylla.

PubMed

Jung, Ji Wook; Ahn, Nam Yoon; Oh, Hye Rim; Lee, Bo Kyung; Lee, Kang Jin; Kim, Sun Yeou; Cheong, Jae Hoon; Ryu, Jong Hoon

2006-11-24

The purpose of this study was to characterize the putative anxiolytic-like effects of the aqueous extract of hooks with stem of Uncaria rhynchophylla using the elevated plus maze (EPM) and the hole-board apparatus in rats and mice. Control rats were treated with an equal volume of saline, and positive control rats with buspirone (1 mg/kg). Single or repeated treatments of the aqueous extract of Uncaria rhynchophylla (200 mg/kg/day, p.o.) for 7 days significantly increased the time-spent and entries into open arms of the EPM, and reduced the time-spent and entries into the closed arms versus saline controls (P<0.05). However, no changes in spontaneous locomotor activity or myorelaxant effects were observed versus saline controls. In the hole-board test, repeated treatment with the aqueous extract of Uncaria rhynchophylla (100 or 200 mg/kg/day, p.o.) significantly increased the number of head-dips (P<0.05). In addition, the anxiolytic-like effects of Uncaria rhynchophylla extract as assessed using the EPM test were abolished by WAY 100635 (0.3 mg/kg, i.p.), a 5-HT(1A) receptor antagonist. These results suggest that Uncaria rhynchophylla is an effective anxiolytic agent, and acts via the serotonergic nervous system.

Pharmacotherapy for anxiety and comorbid alcohol use disorders.

PubMed

Ipser, Jonathan C; Wilson, Don; Akindipe, Taiwo O; Sager, Carli; Stein, Dan J

2015-01-20

anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review. A systematic review is a standardised evaluation of all research studies that address a particular clinical issue.Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi(2) and I(2) heterogeneity statistics. We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting.Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male.There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI

Disruption of Epithalamic Left-Right Asymmetry Increases Anxiety in Zebrafish.

PubMed

Facchin, Lucilla; Duboué, Erik R; Halpern, Marnie E

2015-12-02

Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left-right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the epithalamus in the regulation of stress responses in zebrafish. Copyright © 2015 the authors 0270-6474/15/3515847-13$15.00/0.

Direct-to-consumer prescription drug advertising and the public.

PubMed

Bell, R A; Kravitz, R L; Wilkes, M S

1999-11-01

Drug manufacturers are intensely promoting their products directly to consumers, but the impact has not been widely studied. Consumers' awareness and understanding of, attitudes toward, and susceptibility to direct-to-consumer (DTC) drug advertising were examined. Random-digit dialing telephone survey with a random household member selection procedure (completion and response rates, 58% and 69%, respectively). Respondents were interviewed while they were at their residences. Complete data were obtained from 329 adults in Sacramento County, California. Outcome measures included awareness of advertisements for 10 selected drugs, misconceptions about DTC advertising, attitudes toward DTC ads, and behavioral responses to such promotions. The influence of demographic characteristics, health status, attitudes, beliefs, and media exposure on awareness and behaviors was examined. On average, respondents were aware of advertisements for 3.7 of the 10 drugs; awareness varied from 8% for Buspar (buspirone) to 72% for Claritin (loratadine). Awareness was associated with prescription drug use, media exposure, positive attitudes toward DTC advertising, poorer health, and insurance status. Substantial misconceptions were revealed; e.g., 43% thought that only "completely safe" drugs could be advertised. Direct-to-consumer advertisements had led one third of respondents to ask their physicians for drug information and one fifth to request a prescription. Direct-to-consumer advertisements are reaching the public, but selectively so, and affecting their behaviors. Implications for public policy are examined.

LC-ESI-MS/MS analysis and pharmacokinetics of 6'-hydroxy justicidin A, a potential antitumor active component isolated from Justicia procumbens, in rats.

PubMed

Qiu, Feng; Zhou, Shujun; Fu, Shujun; Kong, Weijun; Yang, Shihai; Yang, Meihua

2012-11-01

A sensitive and accurate LC-ESI-MS/MS method was developed and validated of for the determination of 6'-hydroxy justicidin A (HJA), a potential antitumor active component isolated from Justicia procumbens in rat plasma using a simple liquid-liquid extraction (LLE) method for sample preparation. Chromatographic separation was achieved on an Agilent Zorbax-C(18) column (2.1 mm × 50 mm, 3.5 μm) using a step gradient program with the mobile phase of 0.1% formic acid aqueous solution and acetonitrile with 0.1% formic acid. HJA and IS (buspirone) were detected using electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. This method demonstrated good linearity and did not show any endogenous interference with the active compound and IS peaks. The lower limit of quantification (LLOQ) of HJA was 0.50 ng/ml in 50 μl rat plasma. The developed and validated method has been successfully applied to the quantification and pharmacokinetic study of HJA in rats after intravenous and oral administration of 0.25 mg/kg HJA. The oral bioavailability (F) of HJA was estimated to be 36.0±13.4% with an elimination half-life (t(1/2)) value of 1.04±0.20 h. Copyright © 2012 Elsevier B.V. All rights reserved.

Advances in pharmacotherapy for treating female sexual dysfunction.

PubMed

Nappi, Rossella E; Cucinella, Laura

2015-04-01

'Female sexual dysfunction' (FSD) is an umbrella term comprising a range of common disorders, including hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction, which are multidimensional by nature and often coexisting. Psychological and contextual factors have a significant influence on organic components of sexual response and behavior and a tailored medical approach to sexual symptoms is inevitably limited. The paper reports the most recent advances in pharmacotherapy for women taking into account the biopsychosocial model. Hormone therapy, including estrogens, testosterone, tibolone and dehydroepiandrosterone, are discussed in term of efficacy and safety in postmenopausal women both for female sexual interest/arousal disorder (FSIAD) and genito-pelvic pain/penetration disorder. Ospemifene, a selective estrogen receptor modulator, approved to treat dyspareunia at menopause, is also discussed. Data on psychoactive agents for treatment of FSIAD in premenopausal women are discussed, including the potential use of on-demand combined hormonal (testosterone) and non-hormonal (buspirone or sildenafil) treatments to address possible neurophysiological profiles of women. We are still waiting for an approved pharmacotherapy for FSD. This is not the result of gender inequality in sexual medicine, but it reflects the need of balancing benefits and risks in order to provide effective and safe treatments to women of any age.

Treatment of Comorbid Alcohol Dependence and Anxiety Disorder: Review of the Scientific Evidence and Recommendations for Treatment

PubMed Central

Gimeno, Carmen; Dorado, Marisa Luisa; Roncero, Carlos; Szerman, Nestor; Vega, Pablo; Balanzá-Martínez, Vicent; Alvarez, F. Javier

2017-01-01

Patients with alcohol-use disorders (AUDs) have a high prevalence of anxiety disorders (AnxDs). “Co-occurring disorders” refers to the coexistence of an AUD and/or drug related disorders with another non-addictive psychiatric disorder. The aim of this study was to assess the effectiveness of psychopharmacological treatments and psychotherapy in patients with AUD and AnxD and to propose recommendations for the treatment of patients with comorbid AnxDs and AUDs. Randomized clinical trials, meta-analyses, and clinical guidelines were retrieved from PubMed, Embase, and Cochrane databases. Paroxetine was found to be effective in social anxiety patients with alcohol dependence. Selective serotonin reuptake inhibitors (SSRIs), especially sertraline, showed effective results in posttraumatic stress disorder and in comorbid AnxD–AUD. However, SSRIs should be used with caution when patients are actively drinking because they may increase alcohol consumption. Buspirone, gabapentin, and pregabalin were found to be effective in comorbid AnxD–AUD. The treatment of dual AnxDs should start as early as possible. Since AUDs and AnxDs can reinforce each other, treatments targeting both pathologies can be effective. Women suffer from higher levels of stress and AnxDs than men, and they are also more vulnerable to maintaining alcohol consumption levels. Further research is needed in this comorbid patient population, including the study of different types of patients and gender perspectives. PMID:29018367

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

PubMed

Lauterbach, Edward C; Victoroff, Jeff; Coburn, Kerry L; Shillcutt, Samuel D; Doonan, Suzanne M; Mendez, Mario F

2010-01-01

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Pharmacological Treatment of Cannabis Dependence

PubMed Central

Weinstein, A.M.; Gorelick, David A.

2011-01-01

Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability), those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA). Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. PMID:21524266

An improved human anxiety process biomarker: characterization of frequency band, personality and pharmacology

PubMed Central

Shadli, S M; Glue, P; McIntosh, J; McNaughton, N

2015-01-01

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4–12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis. PMID:26670284

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

PubMed

Bijlsma, Elisabeth Y; Chan, Johnny S W; Olivier, Berend; Veening, Jan G; Millan, Mark J; Waldinger, Marcel D; Oosting, Ronald S

2014-06-01

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling. © 2013 Elsevier Inc. All rights reserved.

The 5-HT1A Receptor and the Stimulus Effects of LSD in the Rat

PubMed Central

Reissig, C.J.; Eckler, J.R.; Rabin, R.A.; Winter, J.C.

2005-01-01

Rationale It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). Objectives The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD. Methods 12 Male F-344 rats were trained in a two-lever, fixed ratio10, food reinforced task with LSD (0.1 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg; SC; 30 min. pretreatment). Results In combination tests stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635. Conclusions These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD. PMID:16025319

Direct-to-Consumer Prescription Drug Advertising and the Public

PubMed Central

Bell, Robert A; Kravitz, Richard L; Wilkes, Michael S

1999-01-01

OBJECTIVE Drug manufacturers are intensely promoting their products directly to consumers, but the impact has not been widely studied. Consumers' awareness and understanding of, attitudes toward, and susceptibility to direct-to-consumer (DTC) drug advertising were examined. DESIGN Random-digit dialing telephone survey with a random household member selection procedure (completion and response rates, 58% and 69%, respectively). SETTING Respondents were interviewed while they were at their residences. PARTICIPANTS Complete data were obtained from 329 adults in Sacramento County, California. MEASUREMENTS AND MAIN RESULTS Outcome measures included awareness of advertisements for 10 selected drugs, misconceptions about DTC advertising, attitudes toward DTC ads, and behavioral responses to such promotions. The influence of demographic characteristics, health status, attitudes, beliefs, and media exposure on awareness and behaviors was examined. On average, respondents were aware of advertisements for 3.7 of the 10 drugs; awareness varied from 8% for Buspar (buspirone) to 72% for Claritin (loratadine). Awareness was associated with prescription drug use, media exposure, positive attitudes toward DTC advertising, poorer health, and insurance status. Substantial misconceptions were revealed; e.g., 43% thought that only “completely safe” drugs could be advertised. Direct-to-consumer advertisements had led one third of respondents to ask their physicians for drug information and one fifth to request a prescription. CONCLUSIONS Direct-to-consumer advertisements are reaching the public, but selectively so, and affecting their behaviors. Implications for public policy are examined. PMID:10571712

Pharmacological treatments of cerebellar ataxia.

PubMed

Ogawa, Masafumi

2004-01-01

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.

Gender differences in cannabis use disorder treatment: Change readiness and taking steps predict worse cannabis outcomes for women.

PubMed

Sherman, Brian J; Baker, Nathaniel L; McRae-Clark, Aimee L

2016-09-01

Gender differences in cannabis use and cannabis use disorder have been established. Regarding treatment, some evidence suggests that women are less responsive, though the mechanisms are not well understood. Motivation to change and self-efficacy are associated with better outcomes overall, and may help explain gender differences in cannabis use outcomes. A secondary data analysis of a double-blind placebo controlled trial of buspirone treatment for cannabis dependence (N=175) was conducted. Self-report assessments of motivation to change, self-efficacy, and other clinical correlates were completed at baseline, and cannabis use was measured throughout the study. There was a significant interaction between gender and taking steps on abstinence. Counter to hypothesis, higher taking steps reduced likelihood of achieving abstinence among women; there was no association among men. Subsequently, taking steps was associated with self-efficacy and quantity of use among men, and cannabis related problems among women. There was a significant interaction between gender and readiness to change on creatinine adjusted cannabinoid levels. Change readiness was positively associated with cannabinoid levels among women, but not men. Motivation to change and initiation of change behavior predict worse cannabis outcomes in women. Men and women differ in what motivates change behavior. Social desirability, neurobiology, and treatment type may impact these effects. Gender differences in cannabis use and treatment responsiveness must be considered in future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, C.J.; Ahlgren, P.C.; O'Neill, C.

IMR-32 and SK-N-MC cells were found to contain ({sup 3}H)quinuclidinyl benzilate specific binding sites inhibited by pirenzepine in a manner suggesting the presence of both M1-type and M2-type muscarinic receptor recognition sites. Neither cell had detectable ({sup 3}H)8-OH-DPAT binding sites. Carbachol stimulated the rate of inositol phospholipid breakdown in IMR-32 and SK-N-MC human neuroblastoma cells with an EC{sub 50} value of about 50 {mu}M in both cases. Pirenzepine inhibited the carbachol stimulated inositol phospholipid breakdown in both cells with Hill slopes of unity and IC{sub 50} values of 15 nM (IMR-32) and 12 nM (SK-N-MC). The 5-HT{sub 1A} receptor agonistmore » 8-OH-DPAT competitively inhibited carbachol-stimulated inositol phospholipid breakdown with pA{sub 2} values of 5.78 (IMR-32) and 5.61 (SK-N-MC). The 5-HT agonists 5-MeODMT and buspirone at micromolar concentrations inhibited carbachol-stimulated breakdown in IMR-32 cells. The inhibition by 8-OH-DPAT and 5-MeODMT was not affected by preincubation with (-)alprenolol. 5-HT was without effect on either basal or carbachol-stimulated breakdown. It is concluded that IMR-32 and SK-N-MC neuroblastoma cells express muscarinic M1-type but not serotoninergic receptors coupled to phosphoinositide-specific phospholipase C. 8-OH-DPAT acts as a weak antagonist at these muscarinic receptors.« less

Shortage of psychotropic medications in community pharmacies in Saudi Arabia: Causes and solutions.

PubMed

Al-Ruthia, Yazed Sulaiman; Mansy, Wael; Barasin, Mohammad; Ghawaa, Yazeed Mohammad; AlSultan, Mohammed; Alsenaidy, Mohammad A; Alhawas, Solaiman; AlGhadeer, Sultan

2017-07-01

Background: Patients with mental disorders, such as depression and anxiety, who seek medical care in private psychiatric clinics in Riyadh, Saudi Arabia, have recently expressed concerns to doctors about difficulty in filling psychotropic medications, such as Amitriptyline and Aripiprazole, at retail community pharmacies. Objectives: The aim of this study was to investigate whether there is a shortage of some commonly prescribed psychotropic medications in retail community pharmacies in Saudi Arabia, and if so, to explore the possible reasons behind the shortage of these medications. Methods: The availability of 28 commonly prescribed psychotropic medications was checked in multiple retail community pharmacies in 4 different regions of Saudi Arabia. Further, potential reasons behind the shortage of some psychotropic medications in retail community pharmacies were also explored. Results: Amitriptyline, Amoxapine, Aripiprazole, Bupropion, Buspirone, Duloxetine, Haloperidol, Hydroxyzine, Lithium, Prochlorperazine, Procyclidine, Promethazine, Thioridazine, Trazodone, and Trifluoperazine were unavailable in over half of the 248 community pharmacies surveyed. Four possible reasons behind the shortage of these medications were reported by 31 pharmacists working in different retail community pharmacies' purchasing departments, with a majority (58.06%) reporting the primary reason for a shortage of these medications that they are slow-moving items with low profit margins. Conclusions: The findings of this study should expedite the reform process in both the Ministry of Health and the Saudi Food and Drug Authority (SFDA) to publish and enforce an essential list of medications for retail community pharmacies, which should include the most commonly prescribed psychotropic medications.

[Effect of anshen jielu recipe in intervening cerebral metabolism in rats with generalized anxiety disorder using magnetic resonance spectroscopy].

PubMed

Tang, Qi-sheng; Li, Ning; Luo, Bin

2011-01-01

To study the metabolic change in brain of rats with generalized anxiety disorder (GAD) and the intervention effect with Anshen Jielu Recipe (AJR) on it. Eight rats selected from 32 Wistar rats as normal group, the others were established as GAD model by using uncertainty empty water bottles method. Then the GAD rats were randomly divided into the model group (saline, by gastrogavage), the control group [buspirone hydrochloride, 2.0 mg/(kg x d), by gastrogavage], the treatment group [AJR, 12.5 g/(kg x d), by gastrogavage], 8 in each group, all were treated for 7 days. The concentration of cerebral metabolites, including N-acetyl aspartate (NAA), choline (Cho), creatine (Cr) and glutamate (Glu), in bilateral prefrontal cortex and hippocampus were measured using high-field strong super-conductivity (7.0T) animal MRI; and the ratio of NAA/Cr, Cho/Cr and Glu/Cr were calculated. The effect of AJR intervention was evaluated by changes of MRI before and after rats being treated with AJR for 7 days. Rats with GAD showed lowered ratios of NAA/Cr and Cho/Cr, and elevated Glu/Cr ratio in the right prefrontal cortex than those in normal rats. After AJR intervention, the abnormal changes in the three indices were restored to certain extents. AJR has apparent antianxiety effect in rats with GAD, with the effect initiation faster than that in the control group. Its mechanism is probably correlated with the regulation of abnormal metabolism in the brain.

Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic.

PubMed

Sanger, D J; Zivkovic, B

1994-01-01

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of a platform in an automated open-field to enhance assessment of anxiety-like behaviors in mice.

PubMed

Pogorelov, Vladimir M; Lanthorn, Thomas H; Savelieva, Katerina V

2007-05-15

The present report describes a setup for simultaneously measuring anxiety-like behaviors and locomotor activity in mice. Animals are placed in a brightly lit, standard automated open-field (OF) in which a rectangular ceramic platform 8 cm high covers one quadrant of the floor. Mice preferred to stay under the platform, avoiding the area with bright illumination. Activities under and outside the platform were measured for 5 min. Chlordiazepoxide and buspirone dose-dependently increased time spent outside the platform (L-Time) and the light distance to total OF distance ratio (L:T-TD) in both genders without changing total OF distance. By contrast, amphetamine decreased L-Time and L:T-TD in males, thus displaying an anxiogenic effect. Imipramine was without selective effect on L-Time or L:T-TD, but decreased total OF distance at the highest dose indicative of a sedative effect. Drug effects were also evaluated in the OF without platform using conventional anxiety measures. Introduction of the platform into the OF apparatus strongly enhanced the sensitivity to anxiolytics. Comparison of strains differing in activity or anxiety levels showed that L-Time and L:T-TD can be used as measures of anxiety-like behavior independent of locomotor activity. Changes in motor activity are reflected in the total distance traveled under and outside the platform. Therefore, the platform test is fully automated, sensitive to both anxiolytic and anxiogenic effects of drugs and genetic phenotypes with little evidence of gender-specific responses, and can be easily utilized by most laboratories measuring behavior.

Shivering Treatments for Targeted Temperature Management: A Review

PubMed Central

Jain, Akash; Gray, Maria; Slisz, Stephanie; Haymore, Joseph; Badjatia, Neeraj; Kulstad, Erik

2018-01-01

ABSTRACT Background: Shivering is common during targeted temperature management, and control of shivering can be challenging if clinicians are not familiar with the available options and recommended approaches. Purpose: The purpose of this review was to summarize the most relevant literature regarding various treatments available for control of shivering and suggest a recommended approach based on latest data. Methods: The electronic databases PubMed/MEDLINE and Google Scholar were used to identify studies for the literature review using the following keywords alone or in combination: “shivering treatment,” “therapeutic hypothermia,” “core temperature modulation devices,” and “targeted temperature management.” Results: Nonpharmacologic methods were found to have a very low adverse effect profile and ease of use but some limitations in complete control of shivering. Pharmacologic methods can effectively control shivering, but some have adverse effects, such that risks and benefits to the patient have to be balanced. Conclusion: An approach is provided which suggests that treatment for shivering control in targeted temperature management should be initiated before the onset of therapeutic hypothermia or prior to any attempt at lowering patient core temperature, with medications including acetaminophen, buspirone, and magnesium sulfate, ideally with the addition of skin counterwarming. After that, shivering intervention should be determined with the help of a shivering scale, and stepwise escalation can be implemented that balances shivering treatment with sedation, aiming to provide the most shivering reduction with the least sedating medications and reserving paralytics for the last line of treatment. PMID:29278601

Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology.

PubMed

Bhidayasiri, Roongroj; Fahn, Stanley; Weiner, William J; Gronseth, Gary S; Sullivan, Kelly L; Zesiewicz, Theresa A

2013-07-30

To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy? PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966-2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence. Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells.

PubMed

Kim, Hye-Young H; Korade, Zeljka; Tallman, Keri A; Liu, Wei; Weaver, C David; Mirnics, Karoly; Porter, Ned A

2016-05-16

A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS.

AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease.

PubMed

Ivachtchenko, Alexandre V; Lavrovsky, Yan; Ivanenkov, Yan A

2016-03-07

Within the past decade several novel targets have been indicated as key players in Alzheimer-type dementia and associated conditions, including a "frightening" memory loss as well as severe cognitive impairments. These proteins are deeply implicated in crucial cell processes, e.g., autophagy, growth and progression, apoptosis, and metabolic equilibrium. Since recently, 5-HT6R has been considered as one of the most prominent biological targets in AD drug therapy. Therefore, we investigated the potential procognitive and neuroprotective effects of our novel selective 5-HT6R antagonist, AVN-211. During an extensive preclinical evaluation the lead compound demonstrated a relatively high therapeutic potential and improved selectivity toward 5-HT6R as compared to reference drug candidates. It was thoroughly examined in different in vivo behavioral models directly related to AD and showed evident improvements in cognition and learning. In many cases, the observed effect was considerably greater than that determined for the reported drugs and drug candidates, including memantine, SB-742457, and Lu AE58054, evaluated under the same conditions. In addition, AVN-211 showed a similar or better anxiolytic efficacy than fenobam, rufinamide, lorazepam, and buspirone in an elevated plus-maze model, elevated platform, and open field tests. The compound demonstrated low toxicity and no side effects in vivo, an appropriate pharmacokinetic profile, and stability. In conclusion, AVN-211 significantly delayed or partially halted the progressive decline in memory function associated with AD, which makes it an interesting drug candidate for the treatment of neurodegenerative and psychiatric disorders. Advanced clinical trials are currently under active discussion and in high priority.

Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review.

PubMed

Goldstein, Irwin; Kim, Noel N; Clayton, Anita H; DeRogatis, Leonard R; Giraldi, Annamaria; Parish, Sharon J; Pfaus, James; Simon, James A; Kingsberg, Sheryl A; Meston, Cindy; Stahl, Stephen M; Wallen, Kim; Worsley, Roisin

2017-01-01

The objective of the International Society for the Study of Women's Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels. Symptoms include lack or loss of motivation to participate in sexual activity due to absent or decreased spontaneous desire, sexual desire in response to erotic cues or stimulation, or ability to maintain desire or interest through sexual activity for at least 6 months, with accompanying distress. Treatment follows a biopsychosocial model and is guided by history and assessment of symptoms. Sex therapy has been the standard treatment, although there is a paucity of studies assessing efficacy, except for mindfulness-based cognitive behavior therapy. Bupropion and buspirone may be considered off-label treatments for HSDD, despite limited safety and efficacy data. Menopausal women with HSDD may benefit from off-label testosterone treatment, as evidenced by multiple clinical trials reporting some efficacy and short-term safety. Currently, flibanserin is the only Food and Drug Administration-approved medication to treat premenopausal women with generalized acquired HSDD. Based on existing data, we hypothesize that all these therapies alter central inhibitory and excitatory pathways. In conclusion, HSDD significantly affects quality of life in women and can effectively be managed by health care providers with appropriate assessments and individualized treatments. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

An Automated High-Throughput Metabolic Stability Assay Using an Integrated High-Resolution Accurate Mass Method and Automated Data Analysis Software.

PubMed

Shah, Pranav; Kerns, Edward; Nguyen, Dac-Trung; Obach, R Scott; Wang, Amy Q; Zakharov, Alexey; McKew, John; Simeonov, Anton; Hop, Cornelis E C A; Xu, Xin

2016-10-01

Advancement of in silico tools would be enabled by the availability of data for metabolic reaction rates and intrinsic clearance (CLint) of a diverse compound structure data set by specific metabolic enzymes. Our goal is to measure CLint for a large set of compounds with each major human cytochrome P450 (P450) isozyme. To achieve our goal, it is of utmost importance to develop an automated, robust, sensitive, high-throughput metabolic stability assay that can efficiently handle a large volume of compound sets. The substrate depletion method [in vitro half-life (t1/2) method] was chosen to determine CLint The assay (384-well format) consisted of three parts: 1) a robotic system for incubation and sample cleanup; 2) two different integrated, ultraperformance liquid chromatography/mass spectrometry (UPLC/MS) platforms to determine the percent remaining of parent compound, and 3) an automated data analysis system. The CYP3A4 assay was evaluated using two long t1/2 compounds, carbamazepine and antipyrine (t1/2 > 30 minutes); one moderate t1/2 compound, ketoconazole (10 < t1/2 < 30 minutes); and two short t1/2 compounds, loperamide and buspirone (t½ < 10 minutes). Interday and intraday precision and accuracy of the assay were within acceptable range (∼12%) for the linear range observed. Using this assay, CYP3A4 CLint and t1/2 values for more than 3000 compounds were measured. This high-throughput, automated, and robust assay allows for rapid metabolic stability screening of large compound sets and enables advanced computational modeling for individual human P450 isozymes. U.S. Government work not protected by U.S. copyright.

Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder.

PubMed

Stock, Eileen M; Zeber, John E; McNeal, Catherine J; Banchs, Javier E; Copeland, Laurel A

2018-04-01

In 2012, the Food and Drug Administration issued Drug Safety Communications on several drugs associated with QT prolongation and fatal ventricular arrhythmias. Among these was citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for depression and commonly used for posttraumatic stress disorder (PTSD). Evaluation of the risk for QT prolongation among other psychotropic drugs for individuals with PTSD remains limited. Explore psychotropic drugs associated with QT prolongation among veterans with PTSD. Patients in the Veterans Health Administration in 2006-2009 with PTSD and QT prolongation (176 cases) were matched 1:4 on age, gender, visit date and setting, and physical comorbidity. Classification trees assessed QT prolongation risk among prescribed medications (n=880). Receipt of any drug with known risk of QT prolongation varied by group (23% QT cases vs 15% control, p<0.01). Psychotropic medications conferring significant risks included ziprasidone (3% vs 1%, p=0.02) and buspirone (6% vs 2%, p=0.01). Increased risk was not observed for the SSRIs, citalopram and fluoxetine. Classification trees found that sotalol and amitriptyline carried greater risk among cardiac patients and methadone, especially if prescribed with quetiapine, among noncardiac patients. Per adjusted survival model, patients with QT prolongation were at increased risk for death (hazard ratio=1.60; 95% CI=1.04-2.44). Decision models are particularly advantageous when exploring nonlinear relationships or nonadditive interactions. These findings may potentially affect clinical decision-making concerning treatment for PTSD. For patients at higher risk of QT prolongation, antidepressants other than amitriptyline should be considered. Medications for comorbid conditions should also be closely monitored for heightened QT prolongation risk.

Antidepressant-like effects of alnespirone (S 20499) in the learned helplessness test in rats.

PubMed

Mac Sweeney, C P; Lesourd, M; Gandon, J M

1998-03-19

The effects of the new chroman derivative, alnespirone (S 20499), which is a selective 5-HT1A receptor agonist, were investigated in an animal model of depression, the learned helplessness test. Rats previously submitted to a session of 60 inescapable electric foot shocks (learned helpless controls) exhibited a deficit in escape performance in three subsequent shuttle-box sessions. Alnespirone was administered twice daily via the oral route (2.5, 5, 10, 20 mg kg(-1) day(-1)). It was shown to protect against the elevation in escape failures caused by exposure to the uncontrollable aversive situation at 5 and 10 mg kg(-1) day(-1) p.o. (13+/-2 and 10+/-3 escape failures, respectively, vs. 9+/-2 escape failures in control rats). In addition, alnespirone had a tendency to elevate the number of intertrial crossings during the resting periods, depending on the dose and day on which the avoidance task was performed (15+/-2 intertrial crossings at the dose of 5 mg kg(-1) day(-1), vs. 5+/-2 intertrial crossings for the helpless control rats, on the second day). In comparison, imipramine (64 mg kg(-1) day(-1) p.o.) provided marked protection on all three days of the avoidance task and tended to increase the number of intertrial crossings during the resting periods on the second and the third days. It is concluded that alnespirone exerts antidepressant-like properties in the learned helplessness test in rats, in a manner similar to 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone, other 5-HT1A receptor agonists.

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cosgrove, Benjamin D.; Cell Decision Processes Center, Massachusetts Institute of Technology, Cambridge, MA; Biotechnology Process Engineering Center, Massachusetts Institute of Technology, Cambridge, MA

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF,more » IFN{gamma}, IL-1{alpha}, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1{alpha}, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.« less

Increase in work productivity of depressed individuals with improvement in depressive symptom severity.

PubMed

Trivedi, Madhukar H; Morris, David W; Wisniewski, Stephen R; Lesser, Ira; Nierenberg, Andrew A; Daly, Ella; Kurian, Benji T; Gaynes, Bradley N; Balasubramani, G K; Rush, A John

2013-06-01

The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity. Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time. Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression. Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to

New trends in the treatment of nicotine addiction.

PubMed

Sliwińska-Mossoń, Mariola; Zieleń, Iwona; Milnerowicz, Halina

2014-01-01

The aim of this study was to discuss the therapeutic substances used to treat nicotine addiction, not registered in Poland. This paper presents the results of the latest clinical trials and the possibility of their use in the treatment of nicotine addiction. The first two discussed drugs clonidine and nortriptyline are recommended by clinical practice guidelines AHRQ (Agency for Healthcare Research and Quality) as the substance of the second line in the fight against addiction. Nortriptyline belongs to tricyclic antidepressants. Its mechanism of action is the inhibition of the reuptake of norepinephrine. It is suggested as the antagonist of activity of nicotinic receptors. The results confirm its efficacy in the treatment of nicotine addiction, but many side effects limit its use. Clonidine acts presumably by inhibition of sympathetic hyperactivity characteristic of symptoms associated with nicotine rehab. The remaining compounds under discussion, such as: venlafaxine, fluoxetine, moclobemide and rimonabant, are not registered in any country with an indication to use in the treatment of nicotine addiction, however, due to the mechanism in which they act, the possibility of their use in the treatment of this disease is considered. The possibility of using anxiolytics such as: buspirone, diazepam, meprobamate and beta-blockers: metoprolol and oxprenolol is also considered in order to treat the anxiety appearing as one of the symptoms of abstinence. An interesting proposal to combat nicotine addiction are vaccines--NicVAX, CYT002-NicQb and TA-NIC. Currently, they are in clinical phase I and II of their development. Their operation would be based on the induction of specific antibodies that bind nicotine in the plasma, thus prevent it reaching the nicotinic receptors. Preliminary results confirm the possible positive effects in the prevention and treatment of nicotine addiction.

The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature.

PubMed

Moll, Jennifer L; Brown, Candace S

2011-04-01

The monoamine neurotransmitters serotonin, dopamine, and norepinephrine play an important role in many medical and psychological conditions, including sexual responsiveness and behavior. Pharmacological agents that modulate monoamines may help alleviate sexual dysfunction. To provide an overview of pharmacological agents that modulate monoamines and their use in the treatment of sexual dysfunction. EMBASE and PubMed search for articles published between 1950 and 2010 using key words "sexual dysfunction,"monoamines,"monoaminergic receptors," and "generic names for pharmacological agents." To assess the literature evaluating the efficacy of monoamine pharmacologic agents used in the treatment of sexual dysfunction. The literature primarily cites the use of monoaminergic agents to treat sexual side effects from serotonergic reuptake inhibitors (SSRIs), with bupropion, buspirone and ropinirole providing the most convincing evidence. Controlled trials have shown that bupropion improves overall sexual dysfunction, but not frequency of sexual activity in depressed and nondepressed patients. Nefazodone and apomorphine have been used to treat sexual dysfunction, but their use is limited by significant side effect and safety profiles. New research on pharmacologic agents with subtype selectivity at dopaminergic and serotonergic receptors and those that possess dual mechanisms of action are being investigated. There has been tremendous progress over the past 50 years in understanding the role of monoamines in sexual function and the effect of pharmacologic agents which stimulate or antagonize monoaminergic receptors on sexual dysfunction. Nevertheless, large, double-blind, placebo-controlled studies evaluating the efficacy of currently available agents in populations without comorbid disorders are limited, preventing adequate interpretation of data. Continued research on sexual function and specific receptor subtypes will result in the development of more selective

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

PubMed

Thompson, Trey; Grabowski-Boase, Laura; Tarantino, Lisa M

2015-06-01

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. Copyright © 2015 Elsevier Inc. All rights reserved.

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.

PubMed

Rush, A John; Fava, Maurizio; Wisniewski, Stephen R; Lavori, Philip W; Trivedi, Madhukar H; Sackeim, Harold A; Thase, Michael E; Nierenberg, Andrew A; Quitkin, Frederic M; Kashner, T Michael; Kupfer, David J; Rosenbaum, Jerrold F; Alpert, Jonathan; Stewart, Jonathan W; McGrath, Patrick J; Biggs, Melanie M; Shores-Wilson, Kathy; Lebowitz, Barry D; Ritz, Louise; Niederehe, George

2004-02-01

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month

Thermal effects of whole head submersion in cold water on nonshivering humans.

PubMed

Pretorius, Thea; Bristow, Gerald K; Steinman, Alan M; Giesbrecht, Gordon G

2006-08-01

This study isolated the effect of whole head submersion in cold water, on surface heat loss and body core cooling, when the confounding effect of shivering heat production was pharmacologically eliminated. Eight healthy male subjects were studied in 17 degrees C water under four conditions: the body was either insulated or uninsulated, with the head either above the water or completely submersed in each body-insulation subcondition. Shivering was abolished with buspirone (30 mg) and meperidine (2.5 mg/kg), and subjects breathed compressed air throughout all trials. Over the first 30 min of immersion, exposure of the head increased core cooling both in the body-insulated conditions (head out: 0.47 +/- 0.2 degrees C, head in: 0.77 +/- 0.2 degrees C; P < 0.05) and the body-exposed conditions (head out: 0.84 +/- 0.2 degrees C and head in: 1.17 +/- 0.5 degrees C; P < 0.02). Submersion of the head (7% of the body surface area) in the body-exposed conditions increased total heat loss by only 10%. In both body-exposed and body-insulated conditions, head submersion increased core cooling rate much more (average of 42%) than it increased total heat loss. This may be explained by a redistribution of blood flow in response to stimulation of thermosensitive and/or trigeminal receptors in the scalp, neck and face, where a given amount of heat loss would have a greater cooling effect on a smaller perfused body mass. In 17 degrees C water, the head does not contribute relatively more than the rest of the body to surface heat loss; however, a cold-induced reduction of perfused body mass may allow this small increase in heat loss to cause a relatively larger cooling of the body core.

The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major Depressive Disorder

PubMed Central

Sahli, Zeyad T.; Banerjee, Pradeep; Tarazi, Frank I.

2016-01-01

ABSTRACT Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide, and according to the STAR*D trial, only 33% of patients with MDD responded to initial drug therapy. Augmentation of the leading class of antidepressant treatment, selective serotonin reuptake inhibitors (SSRIs), with the 5-HT1A receptor agonist buspirone has been shown to be effective in treating patients that do not respond to initial SSRI therapy. This suggests that newer treatments may improve the clinical picture of MDD. The US Food and Drug Administration (FDA) approved the antidepressant drug vilazodone (EMD 68843), a novel SSRI and 5-HT1A receptor partial agonist. Vilazodone has a half-life between 20–24 hours, reaches peak plasma concentrations at 3.7–5.3 hours, and is primarily metabolized by the hepatic CYP450 3A4 enzyme system. Areas covered: The authors review the preclinical and clinical profile of vilazodone. The roles of serotonin, the 5-HT1A receptor, and current pharmacotherapy approaches for MDD are briefly reviewed. Next, the preclinical pharmacological, behavioral, and physiological effects of vilazodone are presented, followed by the pharmacokinetic properties and metabolism of vilazodone in humans. Last, a brief summary of the main efficacy, safety, and tolerability outcomes of clinical trials of vilazodone is provided. Expert opinion: Vilazodone has shown efficacy versus placebo in improving depression symptoms in several double-blind, placebo-controlled trials. The long-term safety and tolerability of vilazodone treatment has also been established. Further studies are needed that directly compare patients treated with an SSRI (both with and without an adjunctive 5-HT1A partial agonist) versus patients treated with vilaozodone. PMID:26971593

Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings.

PubMed

Le Foll, Bernard; Collo, Ginetta; Rabiner, Eugenii A; Boileau, Isabelle; Merlo Pich, Emilio; Sokoloff, Pierre

2014-01-01

The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction. © 2014 Elsevier B.V. All rights reserved.

Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations.

PubMed

Luauté, Jacques; Plantier, David; Wiart, Laurent; Tell, Laurence

2016-02-01

The agitation crisis in the awakening phase after traumatic brain injury (TBI) is one of the most difficult behavioral disorders to alleviate. Current treatment options are heterogeneous and may involve excessive sedation. Practice guidelines are required by professionals in charge of TBI patients. Few reviews were published but those are old and based on expert opinions. The purpose of this work is to propose evidence-based guidelines to treat the agitation crisis. The elaboration of these guidelines followed the procedure validated by the French health authority for good practice recommendations, close to the Prisma statement. Guidelines were elaborated on the basis of a systematic and critical review of the literature. Twenty-eight articles concerning 376 patients were analyzed. Recommendations are: when faced with an agitation crisis, the management strategy implies to search for an underlying factor that should be treated such as pain, acute sepsis, and drug adverse effect (expert opinion). Physical restraints should be discarded when possible (expert opinion). Neuroleptic agent with a marketing authorization can be used in order to obtain a quick sedation so as to protect the patient from himself, closed ones or the healthcare team but the duration should be as short as possible (expert opinion). The efficacy of beta-blockers and antiepileptics with mood regulation effects like carbamazepine and valproate yield the most compelling evidence and should be preferably used when a background regimen is envisioned (grade B for beta-blocker and C for antiepileptics). Neuroleptics, antidepressants, benzodiazepines, buspirone may be prescribed but are considered second-line treatments (expert opinion). This study provides a strategy for treating the agitation crisis based on scientific data and expert opinion. The level of evidence remains low and published data are often old. New studies are essential to validate results from previous studies and test new drugs and

Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands.

PubMed

Rorick-Kehn, Linda M; Hart, John C; McKinzie, David L

2005-12-01

Accumulating evidence suggests that drugs acting on the glutamatergic system may represent promising novel therapeutic targets for the treatment of anxiety disorders. The stress-induced hyperthermia paradigm has been used widely to model some of the physiological symptoms associated with anxiety disorders and has produced results that are predictive of clinical efficacy. We have modified this paradigm to measure the autonomic consequences of stress induced by the fear of predation in mice. To evaluate the efficacy of several classes of metabotropic and ionotropic glutamate receptor ligands, as well as known anxiolytics and psychotropic comparators, in attenuating predatory-stress-induced hyperthermia. Male DBA/2 mice were implanted with radiotelemetric transmitters in the peritoneal cavity to measure stress-related increases in core body temperature, following placement in a novel cage containing soiled rat shavings. Clinically active compounds such as chlordiazepoxide (5-10 mg/kg), alprazolam (0.3-3 mg/kg), and buspirone (10-30 mg/kg) exhibited an anxiolytic profile. Assessment of glutamatergic agents indicated that the mGlu1 receptor antagonist LY456236 (10-30 mg/kg), mGlu5 receptor antagonist MPEP (10-30 mg/kg), mGlu2/3 receptor agonist LY354740 (3-10 mg/kg), mGlu2 receptor potentiator LY566332 (30 and 100 mg/kg), mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (30-60 mg/kg), competitive NMDA receptor antagonist LY235959 (1 mg/kg), AMPA receptor antagonist GYKI-52466 (10-20 mg/kg), and glycine transporter-1 (GlyT-1) inhibitor ALX-5407 (3-10 mg/kg) dose-dependently attenuated stress-induced hyperthermia. The AMPA receptor potentiator LY451646, iGlu5 kainate receptor antagonist LY382884, glycine(B) receptor partial agonist D: -cycloserine, and GlyT-1 inhibitor ORG-24461 were ineffective in this model. Select metabotropic and ionotropic glutamate receptor ligands exhibited an anxiolytic profile, as measured by the attenuation of stress-induced hyperthermia

Development and evaluation of fixed dose bi therapy sublingual tablets for treatment stress hypertension and anxiety

PubMed Central

El-Nabarawi, Mohamed A.; Tayel, Saadia A.; Soliman, Nadia A.; Abo Enin, Hadel A.

2013-01-01

Objective: A stress induced rise in the blood pressure. Some believe that patients with hypertension are characterized by a generalized state of increased anxiety. Aim: The purpose of this study is to prepare a fixed dose bi therapy using bisoprolol hemifumarate (BH) as antihypertensive drug and buspirone hydrochloride (BuHCl) as anxiolytic drug, which can be used to treat both diseases concomitantly. Using sublingual tablets is hopeful to improve the BuHCl poor oral bioavailability and to facilitate administration to patients experiencing problems with swallowing. Materials and Methods: A total of 5mg BH and 10mg BuHCl were selected based on compatibility study. A 3×22 full factorial design was adopted for the optimization of the tablets prepared by direct compression method. The effects of the filler type, the binder molecular weight, and the binder type were studied. The prepared formulae were evaluated according to their physical characters as hardness, friability, disintegration time (new modified method and in vivo disintegration time) and wetting properties. In vitro drugs dissolute, permeation through the buccal mucosa and the effect of storage were analyzed by a new valid high pressure liquid chromatography (HPLC) method. Bioavailability study of the selected formula study was carried out and followed by the clinical. Results: The optimized tablet formulation showed accepted average weight, hardness, wetting time, friability, content uniformity, disintegration time (less than 3 min). Maximum drug release could be achieved with in 10 min. In addition enhancing drug permeation through the buccal mucosa and, the maximum concentration of the drug that reached the blood was in the first 10 min which means a rapid onset of action and improved the extent of both drug's absorption. Conclusion: The results revealed that sublingual (F6) tablets containing both drugs would maintain rapid onset of action, and increase bioavailability. BuHCl with BH can be attributed

The cannabis withdrawal syndrome: current insights

PubMed Central

Bonnet, Udo; Preuss, Ulrich W

2017-01-01

The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to

Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options.

PubMed

Croft, Harry A

2017-12-01

The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD. To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD. Searches of the Medline database for articles on serotonin and female sexual function. Relevant articles from the peer-reviewed literature were included. Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT] 1A receptor agonist and 5-HT 2A receptor antagonist), is currently approved for the treatment of HSDD. The central serotonin system is 1 biochemical target for medications intended to treat HSDD. This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system

Comparison of hippocampal G protein activation by 5-HT(1A) receptor agonists and the atypical antipsychotics clozapine and S16924.

PubMed

Newman-Tancredi, A; Rivet, J-M; Cussac, D; Touzard, M; Chaput, C; Marini, L; Millan, M J

2003-09-01

This study employed [(35)S]guanosine 5'- O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT(1A) receptors with those of reference agonists at postsynaptic 5-HT(1A) receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, E(max), values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC(50)) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT(1A) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT(1A) receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding, consistent with partial agonist properties. In [(35)S]GTPgammaS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT(1A) receptors, was more potent in the septum (pEC(50) approximately 6.5) than in the dentate gyrus of the hippocampus (pEC(50) approximately 5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 microM) did not enhance [(35)S]GTPgammaS labelling in any structure, S16924 (10 micro M) modestly increased [(35)S]GTPgammaS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 microM)-stimulated [(35)S]GTPgammaS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G

Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

PubMed

Newman-Tancredi, A; Gavaudan, S; Conte, C; Chaput, C; Touzard, M; Verrièle, L; Audinot, V; Millan, M J

1998-08-21

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical

An LC-MS/MS method for the simultaneous determination of 15 antipsychotics and two metabolites in hair and its application to rat hair.

PubMed

Sim, Juhyun; Kim, Eunmi; Yang, Wonkyung; Woo, Sanghee; In, Sangwhan

2017-05-01

In recent years, the inappropriate use of antipsychotics by young Korean men has become a social problem. As military service exemptions are given for mental illness, some men pose as mental health patients to avoid military service. In order to verify the authenticity of mental illnesses, we developed simultaneous analytical methods for the detection of 15 antipsychotics and 2 of their metabolites in hair using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The target drugs were modafinil, atomoxetine, aripiprazole, benztropine, buspirone, duloxetine, gabapentin, oxcarbazepine, topiramate, escitalopram, paliperidone, ziprasidone, lamotrigine, clonazepam, levetiracetam, and metabolites of oxcarbazepine and clonazepam. To remove possible contaminants on the hair surface, hair samples were washed twice with methanol and distilled water, and then were extracted with methanol overnight at 38°C. Desipramine-d 3 was used as an internal standard. LC-MS/MS analysis was performed on an Agilent 1290 Infinity UHPLC coupled to an AB Sciex Qtrap ® 5500 MS/MS. The total chromatographic run time was 14min. The following validation parameters were evaluated: selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, matrix effect, and recovery. The LOD and LOQ values for all analytes, except modafinil, ranged from 0.2 to 10pg/mg hair and from 0.2 to 20pg/mg hair, respectively. Good linearity was achieved for most of the analytes in the range of 20-200pg/mg hair. The method showed acceptable precision and accuracy, which were less than 15%, as well as satisfactory matrix effects and recoveries. Furthermore, this method was also applied to the analysis of rat hair samples. The study in rats showed that the concentrations of atomoxetine and aripiprazole in pigmented hair were significantly higher than those in non-pigmented hair. However, no significant difference was observed in the concentration of topiramate between

Quantitative methods in electroencephalography to access therapeutic response.

PubMed

Diniz, Roseane Costa; Fontenele, Andrea Martins Melo; Carmo, Luiza Helena Araújo do; Ribeiro, Aurea Celeste da Costa; Sales, Fábio Henrique Silva; Monteiro, Sally Cristina Moutinho; Sousa, Ana Karoline Ferreira de Castro

2016-07-01

Pharmacometrics or Quantitative Pharmacology aims to quantitatively analyze the interaction between drugs and patients whose tripod: pharmacokinetics, pharmacodynamics and disease monitoring to identify variability in drug response. Being the subject of central interest in the training of pharmacists, this work was out with a view to promoting this idea on methods to access the therapeutic response of drugs with central action. This paper discusses quantitative methods (Fast Fourier Transform, Magnitude Square Coherence, Conditional Entropy, Generalised Linear semi-canonical Correlation Analysis, Statistical Parametric Network and Mutual Information Function) used to evaluate the EEG signals obtained after administration regimen of drugs, the main findings and their clinical relevance, pointing it as a contribution to construction of different pharmaceutical practice. Peter Anderer et. al in 2000 showed the effect of 20mg of buspirone in 20 healthy subjects after 1, 2, 4, 6 and 8h after oral ingestion of the drug. The areas of increased power of the theta frequency occurred mainly in the temporo-occipital - parietal region. It has been shown by Sampaio et al., 2007 that the use of bromazepam, which allows the release of GABA (gamma amino butyric acid), an inhibitory neurotransmitter of the central nervous system could theoretically promote dissociation of cortical functional areas, a decrease of functional connectivity, a decrease of cognitive functions by means of smaller coherence (electrophysiological magnitude measured from the EEG by software) values. Ahmad Khodayari-Rostamabad et al. in 2015 talk that such a measure could be a useful clinical tool potentially to assess adverse effects of opioids and hence give rise to treatment guidelines. There was the relation between changes in pain intensity and brain sources (at maximum activity locations) during remifentanil infusion despite its potent analgesic effect. The statement of mathematical and computational

[Mechanism of action of antidepressants and therapeutic perspectives].

PubMed

Bourin, M; David, D J P; Jolliet, P; Gardier, A

2002-01-01

. Knowledge of the existence of links between neurotransmitter systems and the discovery of the most specific target, 5-HT receptors, should lead to improvements in antidepressant therapy. Developing drugs using innovative mechanisms such as directly acting on 5-HT receptors (5-HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment of depression. The use of antidepressants in anxiety disorders such as obsessional compulsive disorders and even generalised anxiety, highlights the distinction between antidepressants and classic anxiolytics such as benzodiazepines, or even buspirone.

Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.

PubMed

Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier

2008-02-26

Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507

Systematic evaluation of commercially available ultra-high performance liquid chromatography columns for drug metabolite profiling: optimization of chromatographic peak capacity.

PubMed

Dubbelman, Anne-Charlotte; Cuyckens, Filip; Dillen, Lieve; Gross, Gerhard; Hankemeier, Thomas; Vreeken, Rob J

2014-12-29

The present study investigated the practical use of modern ultra-high performance liquid chromatography (UHPLC) separation techniques for drug metabolite profiling, aiming to develop a widely applicable, high-throughput, easy-to-use chromatographic method, with a high chromatographic resolution to accommodate simultaneous qualitative and quantitative analysis of small-molecule drugs and metabolites in biological matrices. To this end, first the UHPLC system volume and variance were evaluated. Then, a mixture of 17 drugs and various metabolites (molecular mass of 151-749Da, logP of -1.04 to 6.7), was injected on six sub-2μm particle columns. Five newest generation core shell technology columns were compared and tested against one column packed with porous particles. Two aqueous (pH 2.7 and 6.8) and two organic mobile phases were evaluated, first with the same flow and temperature and subsequently at each column's individual limit of temperature and pressure. The results demonstrated that pre-column dead volume had negligible influence on the peak capacity and shape. In contrast, a decrease in post-column volume of 57% resulted in a substantial (47%) increase in median peak capacity and significantly improved peak shape. When the various combinations of stationary and mobile phases were used at the same flow rate (0.5mL/min) and temperature (45°C), limited differences were observed between the median peak capacities, with a maximum of 26%. At higher flow though (up to 0.9mL/min), a maximum difference of almost 40% in median peak capacity was found between columns. The finally selected combination of solid-core particle column and mobile phase composition was chosen for its selectivity, peak capacity, wide applicability and peak shape. The developed method was applied to rat hepatocyte samples incubated with the drug buspirone and demonstrated to provide a similar chromatographic resolution, but a 6 times higher signal-to-noise ratio than a more traditional UHPLC

Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-Brain Interaction): A Rome Foundation Working Team Report.

PubMed

Drossman, Douglas A; Tack, Jan; Ford, Alexander C; Szigethy, Eva; Törnblom, Hans; Van Oudenhove, Lukas

2018-03-01

Central neuromodulators (antidepressants, antipsychotics, and other central nervous system-targeted medications) are increasingly used for treatment of functional gastrointestinal disorders (FGIDs), now recognized as disorders of gut-brain interaction. However, the available evidence and guidance for the use of central neuromodulators in these conditions is scanty and incomplete. In this Rome Foundation Working Team report, a multidisciplinary team summarized available research evidence and clinical experience to provide guidance and treatment recommendations. The working team summarized the literature on the pharmacology of central neuromodulators and their effects on gastrointestinal sensorimotor function and conducted an evidence-based review on their use for treating FGID syndromes. Because of the paucity of data for FGIDs, we included data for non-gastrointestinal painful disorders and specific symptoms of pain, nausea, and vomiting. This information was combined into a final document comprising a synthesis of available evidence and recommendations for clinical use guided by the research and clinical experience of the experts on the committee. The evidence-based review on neuromodulators in FGID, restricted by the limited available controlled trials, was integrated with open-label studies and case series, along with the experience of experts to create recommendations using a consensus (Delphi) approach. Due to the diversity of conditions and complexity of treatment options, specific recommendations were generated for different FGIDs. However, some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone α2δ ligand

Development and evaluation of a multiple-plate fraction collector for sample processing: application to radioprofiling in drug metabolism studies.

PubMed

Barros, Anthony; Ly, Van T; Chando, Theodore J; Ruan, Qian; Donenfeld, Scott L; Holub, David P; Christopher, Lisa J

2011-04-05

Microplate scintillation counters are utilized routinely in drug metabolism laboratories for the off-line radioanalysis of fractions collected during HPLC radioprofiling. In this process, the current fraction collection technology is limited by the number of plates that can be used per injection as well as the potential for sample loss due to dripping or spraying as the fraction collector head moves from well to well or between plates. More importantly, sample throughput is limited in the conventional process, since the collection plates must be manually exchanged after each injection. The Collect PAL, an innovative multiple-plate fraction collector, was developed to address these deficiencies and improve overall sample throughput. It employs a zero-loss design and has sub-ambient temperature control. Operation of the system is completely controlled with software and up to 24 (96- or 384-well) fraction collection plates can be loaded in a completely automated run. The system may also be configured for collection into various-sized tubes or vials. At flow rates of 0.5 or 1.0 mL/min and at collection times of 10 or 15s, the system precisely delivered 83-μL fractions (within 4.1% CV) and 250-μL fractions (within 1.4% CV), respectively, of three different mobile phases into 12 mm × 32 mm vials. Similarly, at a flow rate of 1 mL/min and 10s collection times, the system precisely dispensed mobile phase containing a [(14)C]-radiolabeled compound across an entire 96-well plate (% CV was within 5.3%). Triplicate analyses of metabolism test samples containing [(14)C]buspirone and its metabolites, derived from three different matrices (plasma, urine and bile), indicated that the Collect PAL produced radioprofiles that were reproducible and comparable to the current technology; the % CV for 9 selected peaks in the radioprofiles generated with the Collect PAL were within 9.3%. Radioprofiles generated by collecting into 96- and 384-well plates were qualitatively comparable

Drug Discovery Targeting Serotonin G Protein-Coupled Receptors in the Treatment of Neuropsychiatric Disorders

NASA Astrophysics Data System (ADS)

Felsing, Daniel E.

Clinical data show that activation of 5-HT2C G protein-coupled receptors (GPCRs) can treat obesity (lorcaserin/BelviqRTM) and psychotic disorders (aripiprazole/Abilify.), including schizophrenia. 5-HT2C GPCRs are members of the 5-HT2 sub-family of 5-HT GPCRs, which include 5-HT2A, 5-HT2B, and 5-HT 2C GPCRs. 5-HT2C is structurally similar to 5-HT2A and 5-HT2B GPCRs, but activation of 5-HT2A and/or 5-HT 2B causes deleterious effects, including hallucinations and cardiac valvulopathy. Thus, there is a challenge to develop drugs that selectively activate only 5-HT2C. Prolonged activation of GPCRs by agonists reduces their function via a regulatory process called desensitization. This has clinical relevance, as 45% of drugs approved by the FDA target GPCRs, and agonist drugs (e.g., morphine) typically lose efficacy over time due to desensitization, which invites tolerance. Agonists that cause less desensitization may show extended clinical efficacy as well as a more acceptable clinical dose range. We hypothesized that structurally distinct agonists of the 5-HT2C receptor may cause varying degrees of desensitization by stabilizing unique 5-HT2C receptor conformations. Discovery of 5-HT2C agonists that exhibit minimal desensitization is therapeutically relevant for the pharmacotherapeutic treatment of chronic diseases such as obesity and psychotic disorders. The 5-HT7 receptor has recently been discovered as a druggable target, and selective activation of the 5-HT7 receptor has been shown to alleviate locomotor deficits in mouse models of Rett Syndrome. Additionally, buspirone has been shown to display therapeutically relevant affinity at 5-HT 1A and is currently in phase II clinical trials to treat stereotypy in children with autism. The 5-PAT chemical scaffold shows high affinity towards the 5-HT7 and 5-HT1A receptors. Modulations around the 5-phenyl moiety were able to improve selectivity in binding towards the 5-HT 7 receptor, whereas modulations of the alkyl chains

Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD.

PubMed

Thorkelson, Gregory; Bielefeldt, Klaus; Szigethy, Eva

2016-06-01

noradrenaline reuptake and has moderate efficacy for depression, and some small support for use in fatigue and smoking cessation. Buspirone has an indication for generalized anxiety disorder though studies show only a minimal benefit. It has some growing evidence for use in functional dyspepsia. Most of these agents have physiological effects on the brain, immune system, and gastrointestinal tract (with the exception of bupropion) hence their therapeutic and side effects manifested in these systems. Antidepressant medications are frequently prescribed for depression, anxiety disorders, and chronic pain syndromes, but overall support for their efficacy is modest at best. Psychological interventions have growing support for having much more robust effects without the side effects of antidepressants and should be considered first-line treatment or at least an adjunct to psychotropic medications for these conditions.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

PubMed

Tuiten, Adriaan; van Rooij, Kim; Bloemers, Jos; Eisenegger, Christoph; van Honk, Jack; Kessels, Rob; Kingsberg, Sheryl; Derogatis, Leonard R; de Leede, Leo; Gerritsen, Jeroen; Koppeschaar, Hans P F; Olivier, Berend; Everaerd, Walter; Frijlink, Henderik W; Höhle, Daniël; de Lange, Robert P J; Böcker, Koen B E; Pfaus, James G

2018-02-01

In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (�

[Treatment of a serious autistic disorder in a child with Naltrexone in an oral suspension form].

PubMed

Desjardins, S; Doyen, C; Contejean, Y; Kaye, K; Paubel, P

2009-04-01

CLINICAL BACKGROUND: Autism is a developmental disorder that is usually diagnosed in early childhood. According to ICD-10 criteria, autism can be characterized by delays in language skills, by impaired social interaction, verbal or non-verbal communication and by repetitive, stereotyped or severely restricted activities and interests. The causes of autism are not yet elucidated, but both genetics and environment seem to play a role in 10 to 25% of autism cases. Several biochemical abnormalities, such as impairment of serotoninergic, catecholinergic, dopaminergic, and opioid systems have been reported. Autism therapies are designed to treat symptoms, and medication can be associated with psychoeducational and environmental interventions. Generally, the medications that are currently used are not intended for autism, and must be used with caution and selected according to the type and intensity of symptoms. The most common medication consists of psychotropic therapies by administration of dopaminergic and/or serotoninergic receptor antagonists (haloperidol, risperidone, clomipramine). Several drugs, such as anxiolytics (buspirone), mood stabilisers (lithium, sodium valproate), vitamins (vitamins B6, B12) or opioid antagonists (naltrexone) can be prescribed, in second intention, in cases of severe behavioural disorders. The prescription of opioid antagonists is based on the possible implication of an opioid system disorder observed in some cases. Nevertheless, several clinical studies reveal its variable effectiveness. Naltrexone is a competitive antagonist of opioid receptors OPRM1, OPRD1 and OPRK1. In France, this drug is prescribed for treating opioid and alcohol dependence. Moreover, several studies describe naltrexone as a possible treatment of autistic children in cases of developmental disorder and hyperactivity. In the Child and Adolescent Psychopathology Department of Sainte-Anne's Hospital, autistic children benefit from a multidisciplinary treatment program

Pharmacotherapies for cannabis dependence

PubMed Central

Marshall, Kushani; Gowing, Linda; Ali, Robert; Le Foll, Bernard

2015-01-01

evidence for all of the pharmacotherapies investigated, and for many of the outcomes the quality was downgraded due to small sample sizes, inconsistency and risk of attrition bias. The quantitative analyses that were possible, combined with general findings of the studies reviewed, indicate that SSRI antidepressants, mixed action antidepressants, atypical antidepressants (bupropion), anxiolytics (buspirone) and norepinephrine reuptake inhibitors (atomoxetine) are probably of little value in the treatment of cannabis dependence. Preparations containing THC are of potential value but, given the limited evidence, this application of THC preparations should be considered still experimental. Further studies should compare different preparations of THC, dose and duration of treatment, adjunct medications and therapies. The evidence base for the anticonvulsant gabapentin and the glutamatergic modulator N-acetylcysteine is weak, but these medications are also worth further investigation. PMID:25515775

Miscellaneous treatments for antipsychotic-induced tardive dyskinesia.

PubMed

Soares-Weiser, Karla; Rathbone, John; Ogawa, Yusuke; Shinohara, Kiyomi; Bergman, Hanna

2018-03-19

participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. This review has found that the use of valbenazine or extract

[Review of psychopharmacological treatments in adolescents and adults with autistic disorders].

PubMed

Baghdadli, A; Gonnier, V; Aussilloux, C

2002-01-01

behaviours. Nevertheless, these studies have used small size sample and have not been replicated. Category II. This category correspond to drugs supposed to be active on neurochemical disturbances found in autism but their target symptoms are not autism specific signs as defined by the ICD 10. Buspirone: This serotonine agonist may have a good impact on emotional disorders and sleeping confusions. Methylphenidate: Most of the current studies about this noradrenergic drug concern children. The results are variable. Paradoxical effects may exist in children with severe mental retardation. Propanolol: Some isolated studies habe reported its efficiency on behavioural disturbances. Clonidine: This adrenergic drug treats efficiently some cases of aggressive behaviour and hyperactivity. Category III. This category contains a wide range of drugs, vitamins or method used in autism after sporadic observations of their positive effects. Secretine: An important improvement has been reported in isolated cases. However, controlled studies in children do not confirm these results. Vitamines B6, B12 and Magnesium: An improvement in socialization and in behavioural disorders have been reported in some cases, but these results are not yet confirmed. Lithium, Carbamazépine, Valproate: Results of some case studies have found it to be efficient in cyclic disorders. Gluten and casein free diet: An improvement of social behaviour have been reported by some parents after these diets. No controlled study has validated this observation. Conclusion - There is no consensus on the use of psychopharmacological treatments in autism. Although there exist many clinical observations, only few controlled studies have validated the efficiency and safety of these treatments. At the present time and until having sufficient studies, drugs are generally limited to severe disorders, for which usual psycho-educational approaches are insufficient.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

PubMed

Vogel, Adam P; Folker, Joanne; Poole, Matthew L

2014-10-28

low dose of the intervention), in heterogenous groups of degenerative cerebellar ataxias. Three compounds were studied in two trials each: a levorotatory form of 5-hydroxytryptophan (L-5HT), idebenone and thyrotropin-releasing hormone tartrate (TRH-T); each of the other compounds (riluzole, varenicline, buspirone, betamethasone, coenzyme Q10 with vitamin E, α-tocopheryl quinone and erythropoietin) were studied in one trial. The 14th trial, involving a mixed group of participants with spinocerebellar ataxia, compared the effectiveness of nonspecific physiotherapy and occupational therapy within an inpatient hospital setting to no treatment. No studies utilised traditional speech therapies. We defined the primary outcome measure in this review as the percentage change (improvement) in overall speech production immediately following completion of the intervention or later, measured by any validated speech assessment tool. None of the trials included speech as a primary outcome or examined speech using any validated speech assessment tool. Eleven studies reported speech outcomes derived from a subscale embedded within disease rating scales. The remaining three studies used alternative assessments to measure speech, including mean time to produce a standard sentence, a subjective rating of speech on a 14-point analogue scale, patient-reported assessment of the impact of dysarthria on activities of daily living and acoustic measures of syllable length. One study measured speech both subjectively as part of a disease rating scale and with further measures of speech timing. Three studies utilised the Short Form-36 Health Survey (SF-36) and one used the Child Health Questionnaire as measures of general quality of life. A further study utilised the Functional Independence Measure to assess functional health.Five studies reported statistically significant improvement on an overall disease rating scale in which a speech subscale was included. Only three of those studies provided

[Neurobiology and pharmacotherapy of social phobia].

PubMed

Aouizerate, B; Martin-Guehl, C; Tignol, J

2004-01-01

symptoms (eg, tachycardia, sweating and dry mouth). However, they are not effective in the generalized form of social phobia. Other pharmacologic alternatives seem helpful for the management of social phobia, including venlafaxine, gabapentin, bupropion, nefazodone or augmentation with buspirone. Preliminary studies point to promising effects of these agents. Larger controlled clinical trials are now needed to confirm their potential role in the treatment of social phobia.