3种选择性5-羟色胺再摄取抑制药代谢性相互作用的处方分析

目的 了解选择性5-羟色胺再摄取抑制药(SSRIs)氟西汀、舍曲林和帕罗西汀的合并用药情况,为临床合理用药提供参考. 方法 以代谢酶学为指导,从代谢性相互作用的角度对处方进行回顾性分析. 结果3种SSRIs的处方总量为1 985张,其中氟西汀并用CYP2C19抑制药或底物的处方9张,氟西汀、舍曲林和帕罗西汀并用CYP2D6底物或抑制药的处方分别为16,15和12张,氟西汀和舍曲林并用CYP3A4底物或抑制药的处方分别为69张和48张. 结论 避免与已有文献报道能抑制SSRIs代谢的药物合用,或选择无或很少相互作用的同类药物. 药师在SSRIs合并用药中应做好处方审查和患者用药教育,必要时对某些可疑相互作用药进行血药浓度监测.     

选择性5-羟色胺再摄取抑制剂与一些药物的相互作用

选择性的5-羟色胺（5-HT）再摄取抑制剂（SSRIs）属第三代抗抑郁药,疗效确切,安全性高,不良反应少。目前,在国内已成为第一线抗抑郁药,并对强迫症、厌食症有良效。国内用于临床的还有氟西汀、帕罗西汀、舍曲林。下面就探讨这三种SSRIs与一些药物的相互作用,为临床合理用药提供参考。ISSRIS和一些药物相互作用的主要机制SSRIS不诱导任何药物代谢酶。氟西订和帕罗西汀是肝微粒体酶P。。0强抑制剂,舍曲林此作用很弱,而三者的代谢物都具有抑制此酶的作用。然而,当它们与经此酶转化的药物（如某些三环类抗抑邯药、吩喀嗓类药物…     

56℃加热30min灭活血液标本对选择性5-羟色胺再摄取抑制剂治疗药物监测的影响

目的:评估新型冠状病毒肺炎疫情期间56℃加热30 min灭活血液标本对5-羟色胺再摄取抑制剂治疗药物监测的影响。方法:血清样品用乙腈蛋白沉淀法前处理,用液相色谱串联质谱法测定艾司西酞普兰、氟伏沙明、氟西汀、去甲氟西汀、帕罗西汀和舍曲林血清药物浓度,考察血液标本灭活前后基质效应、血清质控样品灭活后药物稳定性和临床血液标本灭活后对血清药物浓度的影响。结果:6个化合物灭活前后内标归一化基质效应无明显差别,艾司西酞普兰、氟伏沙明、氟西汀、去甲氟西汀和帕罗西汀在该灭活条件下可保持稳定,血液标本灭活后浓度无明显改变,舍曲林灭活后出现降解,而血液标本由于加热后溶血导致细胞内舍曲林扩散至血清中,其灭活后血清浓度反而增加。结论:艾司西酞普兰、氟伏沙明、氟西汀、去甲氟西汀和帕罗西汀的血液标本可用56℃加热30 min灭活处理,而舍曲林在该灭活条件下检测结果不准确。     

舍曲林、氟西汀及帕罗西汀治疗抑郁症的成本-效果分析

目的评价舍曲林、氟西汀及帕罗西汀3种抗抑郁药物治疗抑郁症的疗效及成本-效果。方法对A组（舍曲林）、B组（氟西汀）、C组（帕罗西汀）3种治疗方案进行成本-效果分析。结果A，B，C3种方案成本分别为334．74元、433．86元、489．30元，有效率分别为76．9％，82．3％，82．5％，成本-效果比分别为4．35，5．27，5．93，B，C方案相对于A方案的增量成本-效果比分别为18．36，27．60结论B方案为较佳治疗方案。     

我院2009—2012年抗抑郁药应用分析

目的通过我院门诊处方分析患者使用抗抑郁药物情况。方法随机抽取2009年1月—2010年1月、2010年1月—2011年1月及2011年1月—2012年1月于本院精神科专科门诊使用处方。结果根据用药金额与用药频度比值分析2009年前3为分别为氟哌噻吨/美利曲辛、氟西汀、帕罗西汀,2010年为氟哌噻吨/美利曲辛、氟西汀、帕罗西汀,2011年为氟哌噻吨/美利曲辛、帕罗西汀、氟西汀。结论单胺氧化酶抑制剂（MAOI）单药基本已不再使用。5-羟色胺再摄取抑制剂（SSRIs）使用最广,其他新型抗抑郁药有较快增长,氟哌噻吨/美利曲辛的复方制剂用药频度长期居首,值得推广。     

我院病区药房抗抑郁药物临床应用分析

目的了解该院抗抑郁药物应用情况。方法统计病区药房2010年1月1日-12月31日抗抑郁药种类、年消耗金额,并依据每种药物的限定日剂量(DDD),计算出每种药物的用药频度(DDDs)和药物日消耗费用(DDE),并由此进行分析和讨论。结果该院抗抑郁药物DDDs的排序依次为氟哌噻吨美利曲辛(黛力新)、帕罗西汀、舍曲林、氟西汀、多塞平、阿米替林。DDE的排序依次为帕罗西汀、氟西汀、舍曲林、黛力新、多塞平、阿米替林。结论黛力新在该院病区药房用药频度最高;帕罗西汀、氟西汀、舍曲林DDDs紧随黛力新,而DDE相对较高;多塞平、阿米替林的DDDs和DDE值均偏低。抗抑郁药物利用指数(DUI)均≤1,无药物滥用情况。     

强迫症的药物治疗进展

强迫症的识别相对容易,治疗常较困难,常用的一线药物为氟西汀、氟伏沙明、帕罗西汀或舍曲林,二线药物为氯丙咪嗪、文拉法辛缓释剂、西酞普兰、米氮平等,三线药物为静脉注射氯丙咪嗪和口服反苯环丙胺.本文综述强迫症药物治疗的新进展,以期指导临床用药.     

舍曲林、氟西汀和帕罗西汀对抑郁症患者的生活质量和经济负担的影响

目的研究舍曲林、氟西汀和帕罗西汀对抑郁症患者的生活质量和经济负担的影响.方法采用随机、双盲的方法分别应用舍曲林、氟西汀和帕罗西汀对71例抑郁症患者进行分组治疗,通过生活质量指数量表评定其生活质量及经济负担.结果3组治疗后生活质量均较治疗前有明显改善;治疗前、后3组之间的生活质量和经济负担无显著性差异.结论舍曲林、氟西汀和帕罗西汀都是良好的抗抑郁药,3种药物对抑郁症患者的生活质量和经济负担的影响是相似的.     

氟西汀与抗精神病药相互作用

氟西汀是抗抑郁药的一线药,可与典型抗精神病药物、非典型抗精神病药物发生药物相互作用.氟西汀通过抑制细胞色素P450酶CYP2D6、CYP2C9、CYP3A4、CYP2C19、CYP1A2等,使其血药浓度升高,增加抗精神病药物的不良反应.临床应重视氟西汀与抗精神病药物的相互作用.     

4种抗抑郁药的经济学评价

目的:评价4种抗抑郁药治疗抑郁症的经济性的优劣。方法:采用循证医学方法收集氟西汀、帕罗西汀、文拉法辛和西酞普兰治疗抑郁症的药物经济学评价文献,提取各文献中有关成本-效果比的数据,综合分析两两药物间的经济性。结果:氟西汀的经济性与帕罗西汀差异无统计学意义;文拉法辛的经济性显著优于氟西汀;西酞普兰的经济性与氟西汀差异无统计学意义;文拉法辛的经济性显著优于帕罗西汀;西酞普兰的经济性与帕罗西汀差异无统计学意义;文拉法辛的经济性显著优于西酞普兰。结论:文拉法辛治疗抑郁症的经济性最优,与其他3种药物比较差异均具有统计学意义,西酞普兰、氟西汀和帕罗西汀之间差异则无统计学意义。     

Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract

Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug, such as tamoxifen, by decreasing the formation of active metabolites of this drug. Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.     

Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions

AIMS

The study aimed to investigate the clinical adherence to drug label recommendations on important drug–drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education.

METHODS

This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals ≥15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline.

RESULTS

Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively).

CONCLUSIONS

Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.     

Clinically significant drug interactions with antidepressants in the elderly

Pharmacological treatment of depression in old age is associated with an increased risk of adverse pharmacokinetic and pharmacodynamic drug interactions. Elderly patients may have multiple disease states and, therefore, may require a variety of other drugs. In addition to polypharmacy, other factors such as age-related physiological changes, diseases, genetic constitution and diet may alter drug response and, therefore, predispose elderly patients to adverse effects and drug interactions. Antidepressant drugs currently available differ in their potential for drug interactions. In general, older compounds, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have a higher potential for interactions than newer compounds, such as selective serotonin reuptake inhibitors (SSRIs) and other relatively novel agents with a more specific mechanism of action. In particular, TCAs and MAOIs are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients. Moreover, TCAs may be susceptible to pharmacokinetic interactions when given in combination with inhibitors or inducers of the cytochrome P450 (CYP) isoenzymes involved in their metabolism. Because of a more selective mechanism of action, newer antidepressants have a low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs, venlafaxine or nefazodone, are coadministered with other serotonergic agents. Newer agents have a differential potential for pharmacokinetic interactions because of their selective effects on CYP isoenzymes. Within the group of SSRIs, fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine predominantly affects CYP1A2 and CYP2C19 activity. Therefore, these agents should be closely monitored or avoided in elderly patients treated with substrates of these isoforms, especially those with a narrow therapeutic index. On the other hand, citalopram and sertraline have a low inhibitory activity on different drug metabolising enzymes and appear particularly suitable in an elderly population. Among other newer antidepressants, nefazodone is a potent inhibitor of CYP3A4 and its combination with substrates of this isoform should be avoided.     

Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers

The selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine have varying degrees of potency in inhibiting the hepatic cytochrome P450 (CYP) 2D6 enzyme. However, the time course for maximum inhibition to occur or for inhibition to dissipate when dosing is discontinued, requires clarification. In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p < 0.01), but the latter were not significantly different from each other (p > 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p < 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine > sertraline >or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. These data define the time course of a persistent effect that fluoxetine, sertraline, and paroxetine have on CYP2D6 following drug discontinuation and should be considered when initiating therapy with a CYP2D6 substrate.     

The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes.

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.     

CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6

STUDY OBJECTIVE: To assess the correlation between plasma concentrations of four commonly administered selective serotonin reuptake inhibitors (SSRIs) and the magnitude of cytochrome P450 (CYP) 2D6 inhibition. DESIGN: Prospective analysis. SETTING: University-affiliated research laboratory. PATIENTS: Thirty-two healthy, drug-free volunteers. INTERVENTION: Subjects were randomized to four groups and received daily administration of either fluoxetine 60 mg (as a loading dose), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg for 8 days. MEASUREMENTS AND MAIN RESULTS: The urinary concentration ratio of dextromethorphan:dextrorphan (interpreted as an in vivo index of CYP2D6 activity) was determined for each subject before and after the 8 days of receiving SSRIs. Plasma SSRI trough concentrations were measured on days 6-9. The CYP2D6 genotype was determined in a subject with an undetectable paroxetine concentration. Inhibition of CYP2D6 correlated significantly with plasma concentrations of paroxetine and fluoxetine. In contrast, no significant correlations emerged between CYP2D6 inhibition and plasma concentrations of sertraline or fluvoxamine. The subject with an undetectable paroxetine concentration was found to carry at least three functional CYP2D6 genes. CONCLUSIONS: For paroxetine and fluoxetine, plasma concentrations and dosage strongly influence the magnitude of enzyme inhibition. The potential of paroxetine (a CYP2D6 substrate) as an inhibitor may be affected by the genotypes and metabolic capacities of individual subjects.     

Pharmacokinetics of Selective Serotonin Reuptake Inhibitors: Clinical Relevance

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective class of drugs for treatment of depressive and obsessive-compulsive disorders. Among this class of drugs, pharmacodynamic actions, antidepressant efficacy and adverse effect profiles are remarkably similar. However, pharmacokinetic profiles of SSRIs are substantially different especially with respect to pharmacokinetically mediated drug-drug interactions. For example, fluoxetine and paroxetine produce clinically significant inhibition of cytochrome P450 2D6 at their usually effective antidepressant dose, whereas citalopram, fluvoxamine or sertraline do not. There is also a substantial difference between SSRIs with respect to their capacity to inhibit other cytochrome P450 enzymes including 1A2, 2C19, 3A4 and possibly 2C9/10. The inhibition of these enzymes can reduce the clearance of concomitantly administered drugs which are dependent on oxidative metabolism mediated by these enzymes as a necessary prerequisite for their subsequent elimination. The accumulation of unusually high levels of such drugs can result in an increase in nuisance and/or more serious, even life-threatening, adverse effects depending on the pharmacology of the co-prescribed drug. Knowledge of these issues will enable clinicians to predict and make appropriate dose adjustments to avoid potential drug-drug interactions that otherwise could result in toxicity.     

CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.     

The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat

Rationale: Endogenous opioid systems within the mesencephalic periaqueductal gray matter (PAG) appear to be intricately involved in many affective, defensive, submissive, and reflexive responses, and these systems are activated by aversive stimuli. Objectives: The present experiments evaluated the influence of opioid receptors within the PAG on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Methods: Defeat stress consisted of: (1) an aggressive confrontation with a ”resident” stimulus rat in which the experimental ”intruder” rat exhibited escape, defensive and submissive behaviors [i.e. upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident rat with a wire mesh screen for ca. 25 min. Defeat stress was immediately followed by an experimental session with thermal antinociceptive and tactile startle stimuli (20 psi airpuffs). Results: The μ opioid receptor agonist morphine (0.3, 1, 3 μg IC) attenuated startle-induced USV and the tail-flick reflex in socially inexperienced and defeated rats, with both groups of rats demonstrating equal sensitivity to morphine. Morphine decreased defeat-induced USV and increased the display of the crouch posture in defeated rats; these morphine effects in socially inexperienced and defeated rats were re- versed with the opioid receptor antagonist naltrexone (0.1 mg/kg IP). Conclusions: These results reveal that the ventrolateral PAG is an important site in which μ opioid receptor agonists such as morphine mediate affective vocal and submissive responses, yet this structure is not critical in the display of defeat stress-augmented effects of morphine. Endogenous opioid mechanisms appear to participate in the organization of defensive behavior, namely, to facilitate a shift from active to passive forms of coping. Received: 9 November 1998 / Final version: 29 April 1999