Buspirone: an update on a unique anxiolytic agent

Buspirone (Buspar) is a azaspirodecanedione anxiolytic agent. Its mechanism of action is extremely complex, but current investigations indicate that its main neuropharmacologic effects are mediated by the 5-HT1A receptors. Other neuroreceptor systems could be involved, as buspirone displays some affinity for DA2 autoreceptors and 5-HT2 receptors. It has been proposed that inhibition of synthesis and release of serotonin result through the combined interactions of neuroreceptors and secondary messenger systems. This action leads to inhibition of the firing rate of 5-HT-containing neurons in the dorsal raphe. From this novel profile, that differs from that of the benzodiazepines, buspirone lacks anticonvulsant and muscle-relaxant properties, and causes only minimal sedation. The drug is rapidly absorbed after oral administration, with a mean bioavailability of 3.9%. After a single oral dose, the mean elimination half-life is 2.1 hours. Buspirone is mainly bound to albumin and alpha 1-acid glycoprotein. It is metabolized to an active metabolite 1-(2-pyrimidinyl) piperazine (1-PP). The mean elimination half-life of 1-PP is 6.1 hours. Buspirone is indicated in the treatment of generalized anxiety disorders. Its efficacy is comparable to the benzodiazepines. Its use in depression and panic disorders requires further investigation. When combined with alcohol or given alone, psychomotor impairment was not detected. Abuse, dependence, and withdrawal symptoms have not been reported. The frequency of adverse effects is low, and the most common effects are headaches, dizziness, nervousness, and lightheadness. Buspirone should be added to drug formularies and could represent a significant addition in psychopharmacology.     

Honokiol, a putative anxiolytic agent extracted from magnolia bark, has no diazepam-like side-effects in mice

Use of the elevated plus-maze experiment and activity and traction tests in mice have revealed that seven daily treatments with 0.2 mg kg(-1) and higher doses of honokiol, a neolignane derivative extracted from Magnolia bark, had an anxiolytic effect without change in motor activity or muscle tone. Diazepam, 1 mg kg(-1), had the same anxiolytic potential as 0.2 mg kg(-1) honokiol but induced muscle relaxation. The aim of this study was to determine whether honokiol had diazepam-like side-effects. Mice treated with 1-10 mg kg(-1) diazepam, but not those treated with 0.1-2 mg kg(-1) honokiol, for 12 days showed withdrawal symptoms characterized by hyperactivity and running-fit when they were challenge-administered intraperitoneal flumazenil (10 mg kg(-1)) 24 h after the last treatment with diazepam. Oral diazepam (0.5-2 mg kg(-1), 10 min before) dose-dependently prolonged hexobarbital (100 mg kg(-1), i.p.)-induced sleeping, disrupted learning and memory, and inhibited (+)-bicuculline (40 mg kg(-1), i.p.)-induced death. Honokiol (0.2-20 mg kg(-1), p.o., 3 h before) had no such effects. The prolongation by diazepam (1 mg kg(-1)) of hexobarbital-induced sleeping was not modified by honokiol (0.2-20 mg kg(-1)). These results suggest that honokiol is less likely than diazepam to induce physical dependence, central depression and amnesia at doses eliciting the anxiolytic effect. It is also considered that honokiol might have no therapeutic effect in the treatment of convulsion.     

Pharmacological properties of tracazolate: a new non-benzodiazepine anxiolytic agent

Tracazolate (ICI 136,753, 4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester) demonstrated dose-related anticonflict activity in rats and mice. The potency of tracazolate appears to be one-quarter to one-half that of chlordiazepoxide. No tolerance to the anticonflict activity of either tracazolate or chlordiazepoxide was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide. Furthermore, based on rodent studies, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Unlike benzodiazepines, tracazolate enhances the binding of benzodiazepines to its receptor site. These results suggest that tracazolate is a novel agent with potential clinical utility as an anxiolytic drug.     

Dopaminergic effects of buspirone,a novel anxiolytic agent

The novel anxiolytic drug buspirone raised striatal levels of the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) 1 hr after oral administration. This effect was dose-dependent with a peak at 60 min. No changes were observed in the levels of 3-methyxytyramine (3MT), the extraneuronal metabolite of dopamine. Noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were not affected. Buspirone displaced [³H]spiroperidol from striatal binding sites, with an ic₅₀ (1.8 × 10^?7 M), comparable to that of clozapine ($\text{ic}{}_{50}\text{= 1.4 × 10}{}^{\mathrm{?7}}\text{M}$) but considerably lower than that of haloperidol (4.7 × 10^?9 M). Buspirone was only a weak inhibitor of dopamine-stimulated adenyl cyclase. Buspirone was not active on the binding of trifluoperazine to calmodulin and did not modify calmodulin-induced activation of phosphodiesterase (PDE). Repeated administration of buspirone did not increase the number of DA receptors. These data show that, although buspirone has antidopaminergic activity, it can hardly be classified as a classic neuroleptic agent.     

Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice

BACKGROUND AND PURPOSE: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. EXPERIMENTAL APPROACH: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. KEY RESULTS: NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg(-1)). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg(-1)) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. CONCLUSIONS AND IMPLICATIONS: We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.     

注射用氨溴索黏痰溶解与祛痰的疗效和安全性

目的:评价国产注射用氨溴索黏痰溶解与祛痰的疗效与安全性。方法:141例急、慢性呼吸道疾病病人随机分为2组,试验组70例,男∶女为38∶32,年龄(53±s14)a;对照组71例,男∶女为37∶34,年龄(51±13)a。试验组:国产注射用氨溴索30mg溶于5%～10%葡萄糖或氯化钠注射液100mL中静脉滴注,每日2次;对照组:进口氨溴索注射液30mg加于5%～10%葡萄糖或氯化钠注射液100mL中静脉滴注,每日2次。疗程均为5～7d。观察受试者治疗前后痰液性质、痰量变化以及咳嗽恢复日数,临床疗效,不良反应。结果:试验组与对照组比较,治疗后2组临床症状控制率为40%和53%,有效率为76%和79%P>0.05;痰液性质、痰量,恢复正常日数等指标2组间差异无显著意义,P>0.05;不良反应发生率分别为1.4%和1.4%,P>0.05。结论:国产注射用氨溴索是一种安全有效的促黏痰溶解与祛痰剂。     

Behavioral pharmacology of the pyrazoloquinoline CGS 9896, a novel putative anxiolytic

CGS 9896, a pyrazoloquinoline that displaces [³H]benzodiazepines from their CNS receptors, has been claimed to be a nonsedative anxiolytic in animals. However, conflicting results have been obtained with this compound in animal tests of anxiety and seizures. The present study reports the effects of CGS 9896 in three animal tests of anxiety, against seizures induced by picrotoxin and pentylenetetrazole, and on the holeboard test in rats. CGS 9896 (injected intraperitoneally) has an anxiolytic-like activity in the social interaction test (5--10 mg/kg) and in the elevated plus-maze (10--20 mg/kg) but not in the Vogel punished drinking procedure (5--10 mg/kg). CGS 9896 had potent anticonvulsant effects against pentylenetetrazole (total protection at 5 mg/kg) but was considerably less potent against picrotoxin-induced seizures (only 50% reduction at 40 mg/kg). CGS 9896 (10 mg/kg) caused significant reductions in spontaneous exploratory and locomotor behavior in the holeboard test in rats. In all test procedures, CGS 9896 was considerably less potent than the benzodiazepines diazepam or chlordiazepoxide. In conclusion, these data support the evidence suggesting that CGS 9896 possesses anxiolytic and anticonvulsant properties in rodents but suggest that caution should be observed in concluding that a compound is nonsedative on the basis of one or two measures.     

Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone

The present study evaluated the role of various neurotransmitter systems in mediating buspirone's blockade of the fear-potentiated startle effect, where acoustic startle amplitude is normally increased in the presence of a light previously paired with a shock. Large lesions of the dorsal and median raphe nuclei or IP injections of the serotonin antagonists cinanserin (10 mg/kg) or cyproheptadine (5 mg/kg) did not alter fear-potentiated startle, nor did these treatments prevent buspirone (5 or 10 mg/kg SC) from blocking fear-potentiated startle. The 5-HT_1A agonist 8-OH-DPAT (2.5–10.0) did not block fear-potentiated startle even at doses that produced a marked 5-HT syndrome. Another 5-HT_1A agonist, ipsapirone (10–20 mg/kg), blocked potentiated startle only at a very high dose (40 mg/kg).p-Chlorophenylalanine andp-chloroamphetamine did not alter fear-potentiated startle. Finally, pretreatment with the benzodiazepine receptor antagonist RO-15-1788 (1 mg/kg); the opiate antagonist naloxone (2 mg/kg) or the ₂-adrenergic antagonist yohimbine (5 mg/kg) did not reduce fear-potentiated startle, nor did they prevent buspirone from blocking fear-potentiated startle. Taken together, the data do not support the hypothesis that buspirone's anxiolytic effects are mediated by actions at 5-HT_1A receptors and more generally indicate that serotonergic neurons do not play an important role in fear-potentiated startle.     

Piperazine derivatives including the putative anxiolytic drugs,buspirone and ipsapirone,are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons

Summary Two putative anxiolytic drugs [ipsapirone (TVXQ 7821) and buspirone], structurally unrelated to benzodiazepines, have negligible ataxic and sedative side effects. These drugs are piperazine analogs which interact at 5-HT₁ binding sites. It is demonstrated here that these drugs and two other piperazine derivatives, trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (mCPP), are agonists at 5-HT_1A receptors, a subclass of the 5-HT₁ receptor, mediating inhibition of forskolin (100 M) stimulated adenylate cyclase in particulate fractions of guinea pig hippocampus as well as inhibition of the formation of cyclic AMP promoted by vasoactive intestinal polypeptide (0.1 M) plus forskolin (1 M) in mouse hippocampal neurons in primary culture. This study demonstrates that these piperazine based drugs act in both brain homogenate preparations and in intact neurons in a similar manner. The biochemical models described here may aid in the development of even more active drugs in this class.This work was supported by grants from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Direction des Recherches Etudes et Techniques (DRET, N°85/188) of the French Defense Ministry and by the Direction and Ministère de la Recherche Scientifique Send offprint requests to J. Bockaert at the above address     

The effects of umespirone as a potential anxiolytic and antipsychotic agent.

Umespirone was compared to buspirone, diazepam and clozapine as a potential anxiolytic and antipsychotic agent. In the mouse black and white test box, umespirone was considerably more potent than diazepam or buspirone to reduce aversive responding, tolerance to its effects was not observed and sedation was absent, a chronic treatment and withdrawal was not associated with an anxiogenic profile, and umespirone prevented the behavioural consequences of withdrawal from diazepam. Umespirone also had an anxiolytic profile of action in the tests of rat social interaction and in the marmoset exposed to a human threat. Both umespirone and clozapine reduced the hyperactivity induced by the infusion of dopamine into the nucleus accumbens of rat. In radioligand binding assays umespirone demonstrated nanomolar affinity for the alpha 1-adrenoceptor and the 5-HT1A and dopamine D2 receptors. It is concluded that umespirone may present as a novel psychotropic agent with anxiolytic and antipsychotic potential.     

Species differences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action

The effect of three anxiolytic drugs, indorenate, ipsapirone and diazepam, on the burying behaviour of rats and mice was studied. All three drugs induced a reduction in burying behaviour interpreted as a reduction in anxiety. However, a species difference in the diazepam sensitivity was found: rats showed a clear effect after 1.0 mg/kg while already at 0.25 mg/kg an action was observed in mice. The serotonergic anxiolytics produced similar responses at similar doses (2.5–5.0 mg/kg) in both species. The serotonergic antagonists, pindolol (3.1 mg/kg), alprenolol (5.0 mg/kg) and methiotepin (0.31 mg/kg), induced a slight reduction in the time spent burying but effectively counteracted the anxiolytic action of the serotonergic agonists in mice but not in rats. By contrast, in rats, the beta blocker, practolol (0.5 mg/kg), was the only drug effective in preventing the anxiolytic actions of ipsapirone. The combined treatment of indorenate and methiotepin resulted in an impairment of motor coordination and ambulatory behaviour in both species studied, thereby suggesting that the lack of effect of such combination was mediated by altering the motor behaviour. Finally, the reduction in ambulatory behaviour in mice produced by ipsapirone was effectively prevented by the antagonists methiotepin, pindolol and alprenolol indicating the involvement of a serotonergic receptor in this effect. From these results it is concluded that a different mechanism underlies the anxiolytic actions of indorenate and ipsapirone in mice and rats.     

Clinical study of the selective anxiolytic agent afobazol

A standard clinical trial including pharmaco-EEG investigation of the new selective anxiolytic afobazole was performed on a group of 30 patients with anxiety and anxious-asthenic disorders and premorbid individual asthenic profile traits. Afobazole exhibits the anxiolytic action with an activating component in the absence of sedative and myorelaxant effects. The clinical trial results confirmed good prospects of using the experimentally validated pharmacogenetic concept of anxioselectivity as a methodological approach to the design of new drugs possessing selective anxiolytic properties.     

Evidence for the involvement of the 5-HT1A receptor in the anxiolytic action of indorenate and ipsapirone

The systemic injection of diazepam (0.5 and 1.0 mg/kg), indorenate (5 and 10 mg/kg) and ipsapirone (2.5 and 5.0 mg/kg) reduced anxiety as tested in an exploratory avoidance model in mice. The injection of pindolol (2.0 mg/kg), alprenolol (5.0 mg/kg) or methiotepin (0.25 mg/kg) effectively prevented the anxiolytic action of indorenate and ipsapirone. The combined treatment of the antagonists with indorenate or ipsapirone did not reduce the motor activity, therefore suggesting that the inhibition of exploratory behaviour, after such combinations, was not mediated through a general motor impairment. Neither diazepam nor indorenate alone modified the motor activity; ipsapirone (5 and 2.5 mg/kg), however, reduced ambulation. This reduction was also prevented by administering pindolol, alprenolol or methiotepin. These observations suggest that the anxiolytic actions of indorenate and ipsapirone are mediated via stimulation of the 5-HT1A like receptor subtype.     

Effects of the putative anxiolytic SM-3997 on central monoaminergic systems

The effects of SM-3997 on central monoaminergic systems were evaluated by ex vivo measurement of monoamines and their metabolite levels in rat brain after intraperitoneal treatment of drugs and by in vitro measurement of monoamine uptake into rat brain slices. The effects of SM-3997 were also compared with those of other new nonbenzodiazepine anxiolytic compounds. SM-3997, buspirone, gepirone and ipsapirone showed no effects on serotonin uptake and dopamine uptake, and a weak inhibition of norepinephrine uptake at the concentration of 100 microM. SM-3997 decreased the serotonin metabolite (5-hydroxyindole-3-acetic acid) level without changing the serotonin level in hippocampus and increased dopamine metabolite (3,4-dihydroxyphenylacetic acid, homovanillic acid) level with no effect on the dopamine level in striatum. SM-3997 also produced an increase in the norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) level with a decrease in the norepinephrine levels in hippocampus. Similar effects on serotonin metabolites and norepinephrine metabolites were observed in several other regions. Although the serotonergic effect of SM-3997 was similar to that of buspirone, gepirone and ipsapirone, the dopaminergic effect of SM-3997 was much weaker than that of buspirone.     

Efficacy and safety of novel antipsychotics: a critical review

Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.     

Pregabalin: a new anxiolytic

Pregabalin (S-[+]-3-isobutylgaba) was designed as a lipophilic GABA (γ-aminobutyric acid) analogue substituted at the 3′-position in order to facilitate diffusion across the blood–brain barrier. It was originally developed as an anticonvulsant agent, however it has been shown to be effective in the treatment of several disorders including hyperalgesia and behavioural disorders. Although its exact mode of action remains unclear, pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor, gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the α₂δ subunit of voltage-dependent calcium channels, widely distributed throughout the peripheral and central nervous system. Pregabalin appears to produce an inhibitory modulation of neuronal excitability. In healthy volunteers, it is rapidly absorbed with peak blood concentrations within 1 h and it has a bioavailability of ～ 90%. In preclinical trials of anticonvulsant activity, pregabalin is three to ten times more potent than gabapentin. It is well-tolerated and associated with dose-dependent adverse effects (ataxia, dizziness, headache and somnolence) that are mild-to-moderate and usually transient. There are no known pharmacokinetic drug–drug interactions reported to date. Preliminary animal and human studies showed beneficial effects in both ethological and conflict models of anxiety, as well as having some sleep-modulating properties. In Phase II and III trials, pregabalin shows promising anxiolytic action when compared to placebo in generalised anxiety disorder, social phobia and panic disorder.     

Pregabalin: a new anxiolytic

Pregabalin (S-[+]-3-isobutylgaba) was designed as a lipophilic GABA (gamma-aminobutyric acid) analogue substituted at the 3'-position in order to facilitate diffusion across the blood-brain barrier. It was originally developed as an anticonvulsant agent, however it has been shown to be effective in the treatment of several disorders including hyperalgesia and behavioural disorders. Although its exact mode of action remains unclear, pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor, gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the alpha(2)delta subunit of voltage-dependent calcium channels, widely distributed throughout the peripheral and central nervous system. Pregabalin appears to produce an inhibitory modulation of neuronal excitability. In healthy volunteers, it is rapidly absorbed with peak blood concentrations within 1 h and it has a bioavailability of approximately 90%. In preclinical trials of anticonvulsant activity, pregabalin is three to ten times more potent than gabapentin. It is well-tolerated and associated with dose-dependent adverse effects (ataxia, dizziness, headache and somnolence) that are mild-to-moderate and usually transient. There are no known pharmacokinetic drug-drug interactions reported to date. Preliminary animal and human studies showed beneficial effects in both ethological and conflict models of anxiety, as well as having some sleep-modulating properties. In Phase II and III trials, pregabalin shows promising anxiolytic action when compared to placebo in generalised anxiety disorder, social phobia and panic disorder.     

Efficacy and safety of telavancin: a systematic review and meta-analysis

The emergence and rapid spread of multidrug-resistant gram-positive bacteria has become a vital and serious medical problem. A literature search was conducted in PubMed, EMBASE, and Elsevier databases to identify relevant publications. To calculate the risk ratios (RRs) with 95% confidential intervals (CIs), a fixed- or random-effects model was applied based on the heterogeneity across studies. Five studies containing seven RCTs were included in this meta-analysis. Regarding cSSTIs, HAP, SAB, there was no statistically significant difference in the rate of clinical cure between telavancin and vancomycin or standard therapy in intention-to-treat population (ITT) (RR 1.01, 95% CI 0.97–1.05, P = 0.72; FEM) and clinically evaluable population (CE) (RR 1.01, 95% CI 0.98–1.04, P = 0.41; FEM). However, telavancin was more effective than vancomycin or standard therapy in MRSA eradication rate (RR 1.08, 95% CI 1.02–1.14, P = 0.009; FEM). Regarding the safety profile, no statistically significant differences were found in all-cause mortality (9.0% vs. 8.4%; RR 1.07, 95% CI 0.88–1.31, P = 0.49; FEM) and overall adverse events (77.0% vs. 72.3%; RR 1.08, 95% CI 0.98–1.20, P = 0.12; FEM) between telavancin and vancomycin or standard therapy. Pooled data from cSSTIs, HAP and SAB studies on telavancin indicated higher rates of adverse-event related withdrawals (7.7% vs. 5.4%; RR 1.43, 95% CI 1.12–1.83, P = 0.05; FEM) and creatinine elevation (10.0% vs. 5.1%; RR 1.95, 95% CI 1.53–2.48, P<0.00001; FEM)than vancomycin or standard therapy.Telavancin and vancomycin or standard therapy are equally effective for the treatment of cSSTIs, HAP and SAB, and telavancin might be an option for the treatment of difficult-to-treat serious infections caused by MRSA. However, telavancin is associated a higher incidence of creatinine elevation and adverse-event related withdrawals.