辣椒素对文拉法辛药动学影响研究

目的：考察辣椒素对文拉法辛及其活性代谢物O-去甲基文拉法辛体内药动学的影响。方法：选取10只健康SD大鼠，采用自身对照方法，考察单剂量给予盐酸文拉法辛（20.25 mg·kg^-1）（对照组）以及连续7 d灌胃辣椒素后再给予盐酸文拉法辛（实验组）的药动学差异。采用已验证的液相色谱-串联质谱法（LC-MS/MS）测定血浆中文拉法辛及O-去甲基文拉法辛的浓度，经DAS 3.2.4软件计算药动学参数，SPSS软件计算两组实验的差异是否具有显著性。结果：对照组和实验组大鼠血浆中文拉法辛的AUC_0-10、C_max、T_max、t_1/2分别为（780.81±709.76）μg·L^-1·h^-1和（1037.84±582.63）μg·L^-1·h^-1、（517.57±462.46）μg·L^-1和（876.64±301.79）μg·L^-1、（0.32±0.20）h和（0.25±0.09）h、（1.00±0.84）h和（0.89±0.18）h；O-去甲基文拉法辛的AUC_0-10、C_max、T_max、t_1/2分别为（163.60±77.93）μg·L^-1·h^-1和（240.41±62.69）μg·L^-1·h^-1、（96.83±46.51）μg·L^-1和（182.52±46.40）μg·L^-1、（0.46±0.30）h和（0.25±0.06）h、（1.19±0.32）h和（2.65±1.58）h；其中实验组的AUC_0-10、C_max均增加，差异具有显著性。结论：辣椒素增加文拉法辛的吸收，提高生物利用度，即能影响文拉法辛的体内药动学过程。     

The effects of gepirone on neuroendocrine function and temperature in humans

The effects of the selective 5-HT_1A receptor agonist gepirone (10 and 20 mg orally) on neuroendocrine function and temperature were assessed using a single-blind cross-over design in 12 healthy male volunteers. Gepirone significantly increased plasma levels of ACTH,-endorphin, cortisol, prolactin and growth hormone. Following gepirone there was a significant decrease in body temperature and moderate increases in subjective reports of light-headedness, nausea and drowsiness. Our results are consistent with studies in rodents suggesting that 5-HT_1A receptor agonists increase ACTH and prolactin secretion and decrease body temperature. Further investigations are needed to determine if the neuroendocrine and temperature effects of gepirone in humans are mediated by 5-HT_1A receptors.     

盐酸文拉法辛缓释片人体药动学和生物等效性研究

目的建立测定文拉法辛血浆药物浓度的HPLC荧光检测法,研究盐酸文拉法辛缓释片在人体的药动学和评价生物等效性.方法48例青年健康志愿受试者(单次给药24例,多次给药24例),分别单次和多次交叉口服文拉法辛参比制剂75 mg和受试制剂75 mg,采用HPLC法测定给药后不同时间点血浆中文拉法辛和O-去甲文拉法辛经时血药浓度,采用DAS 2.0进行药动学参数计算.结果单次和多次口服盐酸文拉法辛缓释片的血药浓度-时间曲线符合一室开放模型.单次口服受试制剂和参比制剂后文拉法辛的Tmax分别为(6.5±1.9)与(6.3±1.4)h,t1/2分别为(11.6±4.9)与(11.7±4.3)h,AUC0～1分别为(1 840.0±1 153.1)和(1 956.O±1 201.2)μg·h·L-1;O-去甲文拉法辛的Tmax分别为(12.0±6.0)与(10.3±6.1)h,t1/2分别为(18.9±4.8)与(20.3±6.2)h,AUG0-t分别为(1 356.8±344.1)和(1 382.8±287.3)μg·h·L-1;文拉法辛和O-去甲文拉法辛的生物利用度分别为(94.3±13.3)%和(99.3±20.4)%.多次口服受试制剂和参比制剂6 d后文拉法辛的AUCss分别为(1 488.9±863.3)和(1 630.7±962.2)μg·h·L-1,Tmax分别为(7.0±1.6)与(6.7±1.8)h,DF分别为(114.63±27.05)和(110.94±24.25);O-去甲文拉法辛的AUCss分别为(528.3±220.6)和(568.3±251.1)μg·h·L-1,Tmax分别为(7.7±2.1)与(7.3±1.9)h,DF分别为(70.12±21.63)和(71.67±24.27);文拉法辛和O-去甲文拉法辛的生物利用度分别为(93.2±17.7)%和(95.9±17.0)%.结论经方差分析和t检验,证明两制剂生物等效.     

The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects

Recently, much interest has been given to the role of glutamatergic N-methyl-D-aspartate receptors (NMDA) in sensory gating, such as prepulse inhibition (PPI) and reduction of the P50 evoked response potential (ERP). Currently, mainly animal data are available describing the role of NMDA receptors in these stimulus evaluation processes. Human data are virtually lacking and are potentially important, for instance for the understanding of sensory gating deficits observed in schizophrenia. Therefore, the effects of the NMDA antagonist ketamine, in a dose of 0.3 mg/kg IV, on concurrent assessment of PPI and P50 reduction was studied in 18 healthy male volunteers. Ketamine was administered in a pseudo-steady state model with a subacute loading dose. In addition, the effects of ketamine on behavior, vital signs, homovanillic acid (HVA) plasma levels and secretion of cortisol and luteinizing hormone (LH) were also determined. Ketamine did not significantly alter PPI or the reduction of the P50 ERP. A small but significant increase in Brief Psychiatric Rating Scale (BPRS) total scores and BPRS composite scores “thinking disorder” and “withdrawal/retardation” was observed. Several subjects experienced visual perceptional alterations, but complex hallucinations did not occur. Ketamine induced mild analgesia and coordination problems. In addition, ketamine induced a marked rise in cortisol secretion, while LH secretion was not affected. Finally, systolic and diastolic, blood pressure and heart rate increased during ketamine infusion. Although in humans NMDA receptors may not be involved in the regulation of PPI and P50 reduction, the most likely explanation for the lack of effect of ketamine on these sensory gating paradigms is the dose used in this experiment. However, using a higher dose is hampered by the aspecificity of racemic ketamine. Future studies should use the enantiomer S-ketamine, which is more specific to NMDA receptors, to evaluate the involvement of NMDA receptors in these neurophysiological processes further. Received: 4 August 1997/Final version: 7 November 1997     

Pharmacokinetics and endocrine effects of terguride in healthy subjects

Summary Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i. v. dose of 50 g and on the first and seventh day of an oral treatment with 250 g, 500 g and 750 g b. d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH) — stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA.Following the i. v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml·min^–1·kg^–1. the oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6-OH cortisol.     

高效液相色谱-荧光法测定人血浆中文拉法辛及相对生物利用度

目的建立人血浆中文拉法辛的HPLC-荧光测定法，研究2种文拉法辛胶囊的相对生物利用度。方法以拉呋替丁为内标，血浆样品萃取后经Diamonsil C18柱分离，流动相为乙腈-磷酸盐缓冲液（磷酸调pH为5．95）25：75（v／v），荧光检发射波长（Ex）为276nm，检测波长（EM）为598nm。18名健康志愿者采用随机交叉方式分别单剂量口服文拉法辛胶囊100mg后研究两者的相对生物利用度。结果血浆中文拉法辛与内源性杂质分离完全，在5．1～490．7μg·L^-1浓度与峰面积比线性良好，回归方程为：Y=0．074X＋0．0285（r^2=0．9998），最低定量限为5．1μg·L^-1；文拉法辛绝对回收率为98．6％～100．5％（n=20），内标绝对回收率为84．2％～85．7％（n=20），方法回收率为89．3％～108．7％（n=15），日内精密度（RSD）〈3．6％（n=15），日间精密度（RSD）〈9．6%（n=15）。单次服用100mg文拉法辛胶囊T或R后的AUC0-24。分别为（1146．4±339．6）和（1132．9±311．3）μg·h·L^-1；Cmax分别为（167．7±49．1）和（177．6±47．8）μg·L^-1；tmax分别为（1．9±0．3）和（1．8±0．6）h。与R相比，T的相对生物利用度为（103．7％±13．3％）。结论该法简单，准确度高，灵敏度好。方差分析结果两制剂的主要药动学参数之间无明显差异，两者为生物等效制剂。     

Cardiovascular effects of high dose venlafaxine XL in patients with major depressive disorder

OBJECTIVE: To assess cardiovascular safety profile of high dose Venlafaxine XL in patients with major depression. METHOD: Effects of high dose venlafaxine (mean 346.15 mg;) on the cardiovascular system in 37 patients with major depressive disorder were evaluated: BP, ECG (PR, QT, QRSD and QTc intervals) and heart rate. RESULTS: 12.5% of patients developed hypertension after starting treatment with venlafaxine. There was an association between heart rate and the dose of venlafaxine although not statistically significant. There was no association between dose of venlafaxine and PR, QT, QRSD and QTc intervals. One patient on 300 mg who was hypertensive and on other medications that may prolong QTc, had mildly prolonged QTc. However this was not clinically significant. CONCLUSION: This study of subjects on high dose venlafaxine (mean 346.15 mg; range 225-525 mg) did not demonstrate any clinical or statistically significant effects on electrocardiogram (ECG) parameters including PR, QT, QRSD and QTc interval.     

抗抑郁药文拉法辛对精神分裂症阴性症状、社会功能恢复的临床疗效研究

目的:探讨抗抑郁药文拉法辛对精神分裂症患者的治疗效果。方法:回顾性分析2013年11月-2015年1月收治的64例精神分裂症患者的临床资料,其中,对照组采用利培酮治疗,而观察组采取文拉法辛联合利培酮治疗,比较2组患者的阴性症状、社会功能恢复情况以及不良事件发生情况。结果:治疗后,观察组与对照组患者的PANSS阴性症状、PSP评分均较治疗前出现明显改善,且在12周时,观察组患者的以上指标改善效果均优于对照组,组间差异具有统计学意义(P<0.05);2组不良反应发生率最高的主要为锥体外系副反应但组间各项相比,差异均无统计学意义(P>0.05)。结论:抗抑郁药文拉法辛可有效改善精神分裂症患者的阴性症状,提高患者的认知能力,从而较大程度改善患者的社会功能,促进患者的预后,其疗效显著且安全可靠,值得临床应用。     

Blockade of 5-Hydroxytryptamine and noradrenaline uptake by venlafaxine: a comparative study with paroxetine and desipramine

1. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5-HT and NA reuptake to those of the selective 5-HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine.
2. Administered acutely, venlafaxine dose-dependently prolonged the time required for a 50% recovery (RT₅₀) of the firing activity of dorsal hippocampus CA₃ pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT₅₀ values for 5-HT, while desipramine was more potent than venlafaxine at increasing the RT₅₀ values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT₅₀ values for 5-HT compared to that of NA.
3. A two-day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT₅₀ values for both 5-HT and NA applications. The RT₅₀ values for 5-HT were significantly increased at a dose of 10 mg kg⁻¹ day⁻¹, whereas those for NA were increased at a dose of 20 mg kg⁻¹ day⁻¹, consistent with the data obtained following the acute administration of venlafaxine.
4. Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.

     

反相高效液相色谱法测定血浆中文拉法辛浓度

目的 :建立高效液相色谱法检测人血浆中文拉法辛浓度。方法 :血浆样品经石油醚 乙醚 (2∶1 )提取后 ,有机相再用50mmol·L- 1盐酸反萃取并浓缩进样。色谱柱为氰基柱 (2 50× 4.6mm ,5μm) ,乙腈 -0 .1mol·L- 1NH4 H2 PO4 (2 5∶75)为流动相 ,UV检测波长 2 2 9nm。结果 :文拉法辛血浆最低检测浓度 1 0 μg·L- 1,线性范围 2 5～ 80 0 μg·L- 1,萃取回收率 75.5%～79.3%,加样回收率 97.4%～ 1 0 1 .2 %,日内RSD 4.87%～ 6 .39%,日间RSD 7.55%～ 1 0 .80 %。结论 :该法准确可靠 ,已用于临床患者文拉法辛血药浓度测定。     

Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers

AIMS: Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. METHODS: Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. RESULTS: The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. CONCLUSIONS: These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.     

The effects of venlafaxine on autonomic functions in healthy volunteers

Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition.     

杂环类抗抑郁新药文拉法新(venlafaxine)的合成

目的：改进新型杂环类抗抑郁药文拉法新（ｖｅｎｌａｆａｘｉｎｅ）的合成方法。方法：该化合物以对羟基苯乙酸为原料,经醚华、酰氯华、酰胺化格氏反应、还原、成盐等步骤制备而成。结果：合成产物经元素分析、红外光谱、核磁共拓谱、质谱和快原子轰击质谱等确证。结论：此合成路线是完全可行的。     

The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose

AIMS

To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination.

METHODS

Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t₉₀) of seizure, respectively.

RESULTS

A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03–0.08), 0.19 (0.09–0.35) and 0.75 (0.30–0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25–0.89), 0.71 (0.35–1.22) and 0.25 (0.08–0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t₉₀ values for first seizure was 26 h and was not affected by dose or decontamination procedure.

CONCLUSION

SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring.     

阿立哌唑合用文拉法辛治疗难治性抑郁症

目的探讨阿立哌唑合用文拉法辛治疗难治性抑郁症的疗效和安全性。方法将72例难治性抑郁症病人随机分成阿立哌唑合用文拉法辛组(研究组,n=36)与单用文拉法辛组(对照组,n=36),文拉法辛剂量:起始25 mg,bid,7～10 d内加至175～300 mg·d~(-1);阿立哌唑剂量:5 mg·d~(-1),治疗6 wk。用HAMD,HAMA,TESS量表评定疗效和不良反应。结果2组间HAMD,HAMA于wk 1,2,6末减分率比较差异均有非常显著意义(P<0.01),6 wk末研究组有效率86%,对照组56%,2组差异有显著意义(P<0.05),不良反应均表现较轻,大多出现在治疗早期,经对症治疗逐渐缓解。结论阿立哌唑合用文拉法辛治疗难治性抑郁症的疗效优于单用文拉法辛,且耐受性好。     

Psychomotor,respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers

Summary Actions and interactions of buprenorphine (BUP) and amitriptyline (AMI) on performance and respiration were studied double-blind and cross-over in 12 healthy volunteers. After one-week pretreatments with AMI or placebo, the subjects received on Day 8 placebo, BUP or AMI so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute BUP, 4) subchronic AMI + acute BUP and 5) subchronic AMI. The subacute treatments were started at two-week intervals.A Mapleson D rebreathing circuit including a pneumotachograph and an infrared capnograph was employed to study drug effects on respiration. Minute volume and end-tidal carbon dioxide as well as psychomotor performance were measured and the blood samples taken on Day 8 before the drug intake and 2 and 4 h thereafter. The performance tests included tracking, choice reaction, flicker fusion, exophoria, nystagmus, digit symbol substitution and the subjective assessment of mood.BUP depressed respiration, and subchronic AMI increased this depression. Both BUP and acute AMI 50 mg each alone impaired various measures of performance and rendered the subjects drowsy, feeble, mentally slow and muzzy but subchronic AMI did not enhance BUP effects. BUP increased plasma prolactin levels similarly after both pretreatments.The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.     

Biochemical,neurophysiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine

Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O-desmethyl compound Wy-45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β-adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring-hydroxylated metabolite Wy-47,877 and the N-desmethyl metabolite Wy-45, 494 were also active in reserpine hypothermia, but Wy-45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy-45,233. None of the seven metabolites tested exhibited significated binding at dopamine-2, muscarinic cholinergic, α-1-adrenergic, histamine-1, or opiate (μ) receptors. These results suggest that Wy-45,233, the O-desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side-effect profile of venlafaxine.     

Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition

The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1–30 mg/kg, i.p.), a balanced serotonergic–noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3–100 mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03–10 mg/kg, i.p.) and desipramine (1–30 mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3–10 mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic–noradrenergic reuptake inhibition by dual SNRIs, or SSRI–NRI combinations, produces synergistic analgesic efficacy.     

抗抑郁药文拉法辛的药代动力学研究进展

文拉法辛是已在中国上市的抗抑郁药，为第1个5-羟色胺和去甲肾上腺素再摄取双重抑制剂（SNRIs），由于其疗效肯定、起效快、副作用小、耐受性好，而备受关注。本文主要就文拉法辛在人体内的吸收、分布、代谢、排泄的药物动力学特征和给药方案、年龄、性别、肝肾功能损害等因素对这些过程的影响及与其他药物的相互作用做一综述。