化疗所致恶心呕吐(chemotherapy induced nausea and vomiting,CINV)是肿瘤患者化疗过程中最常见的不良反应。5-HT_(3)受体拮抗剂类药物被推荐为抗CINV的一线用药。但5-HT_(3)受体拮抗剂药物目前临床常用剂型以口服和静脉给药为主,其中...化疗所致恶心呕吐(chemotherapy induced nausea and vomiting,CINV)是肿瘤患者化疗过程中最常见的不良反应。5-HT_(3)受体拮抗剂类药物被推荐为抗CINV的一线用药。但5-HT_(3)受体拮抗剂药物目前临床常用剂型以口服和静脉给药为主,其中静脉注射给药易产生不良反应且需要专业医护操作,口服给药有首过效应,尤其是化疗后严重呕吐患者无法口服用药,所以目前临床常用剂型具有一定的缺陷,临床应用受到限制。经皮给药系统具有避免胃肠道首过效应、毒副作用小、病人依从性好等优点,所以抗肿瘤所致恶心呕吐药物的经皮给药系统受到人们的广泛关注和研究。本研究就5-HT_(3)受体拮抗剂类药物的经皮给药制剂国内外研究现状进行综述,为该类药物的新制剂和新给药途径研发提供借鉴和参考。展开更多
5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated ca...5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.展开更多
Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study i...Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.展开更多
文摘化疗所致恶心呕吐(chemotherapy induced nausea and vomiting,CINV)是肿瘤患者化疗过程中最常见的不良反应。5-HT_(3)受体拮抗剂类药物被推荐为抗CINV的一线用药。但5-HT_(3)受体拮抗剂药物目前临床常用剂型以口服和静脉给药为主,其中静脉注射给药易产生不良反应且需要专业医护操作,口服给药有首过效应,尤其是化疗后严重呕吐患者无法口服用药,所以目前临床常用剂型具有一定的缺陷,临床应用受到限制。经皮给药系统具有避免胃肠道首过效应、毒副作用小、病人依从性好等优点,所以抗肿瘤所致恶心呕吐药物的经皮给药系统受到人们的广泛关注和研究。本研究就5-HT_(3)受体拮抗剂类药物的经皮给药制剂国内外研究现状进行综述,为该类药物的新制剂和新给药途径研发提供借鉴和参考。
基金supported by the National Natural Science Foundation of China(Nos.82071516,32171065,91949105,and 81771227)the Innovation Capability Support Program of Shannxi Province in China(No.2020TD-037)the Fundamental Research Funds for the Central Universities(Nos.GK202105001,GK202205019,and CK202205022),China.
文摘5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.
基金This work was supported by National Natural Science Foundation of China(30873064)Foundation of Key Laboratory of Bio-pharmaceutical-engineering(Harbin Medical University),Ministry of Education(2010-07).
文摘Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.
