Lack of pharmacokinetic interaction between valproic acid and a traditional Chinese medicine, Paeoniae Radix, in healthy volunteers

BACKGROUND AND OBJECTIVE: In addition to the standard antiepileptic drugs, traditional Chinese medicines (TCMs) are used for the treatment of epilepsy in oriental countries. The interactions between antiepileptic drugs and TCMs represent a potential problem in clinical application. Because valproic acid (VPA), one of the most widely prescribed antiepileptic drugs, may be administered concomitantly with Paeoniae Radix (PR), one of the famous TCMs, in some epileptic patients, the present study was conducted to evaluate the influences of PR on the pharmacokinetics of VPA. METHOD: The pharmacokinetics of VPA were investigated in a randomized, open-label, two-way crossover study. Six healthy volunteers received the following treatments in a crossover design: (i) 1.2 g extract powder of Paeoniae Radix once daily for 7 days and one 200 mg VPA gastro-resistant tablet on day 7 and (ii) one 200 mg VPA gastro-resistant tablet alone on day 7. Serial plasma samples were obtained on day 7. Total and free (unbound) VPA plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). Safety measures included laboratory tests (haematology, serum chemistry and urinalysis) and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters were performed with the Student paired t-test. RESULTS: Overall clinical safety was satisfactory. The mean maximum plasma concentration of VPA was attained at within 6 h after oral administration of VPA alone and 3-4 h after oral administration of VPA in combination with PR. The plasma level of VPA declined with a half-life of 11.71 and 11.91 h, respectively. No statistically significant difference was obtained in any of the pharmacokinetic parameters (Tmax, Cmax, AUC, t1/2, MRT, CL/F and Vd/F) of VPA between the two treatments. Also, there was no significant difference in the protein binding rates of VPA. CONCLUSION: PR did not significantly affect the absorption, distribution, metabolism and elimination of VPA in healthy volunteers.     

阿立哌唑与喹硫平对精神分裂症患者临床疗效及认知功能的影响

目的探讨阿立哌唑与喹硫平对首发精神分裂症患者临床疗效及认知功能的影响。方法将82例首发精神分裂症患者随机分为两组,研究组42例,口服阿立哌唑治疗,对照组40例,口服喹硫平治疗,观察8周。于治疗前及治疗第1周、4周、8周末采用阳性与阴性症状量表评定临床疗效;于治疗前及治疗8周末,采用韦氏记忆量表中的再认、图片、联想及背数分量表评定认知功能。结果治疗后两组阳性与阴性症状量表评分均较治疗前有显著下降（P〈0．01）,同期两组评分比较差异均无显著性（P〉0．05）。治疗8周末,两组韦氏记忆量表再认、图片、联想、背数分量表评分均较治疗前显著提高（P〈0．05或0．01）,但研究组较对照组提高更显著（P〈0．05或0．01）。结论阿立哌唑与喹硫平治疗首发精神分裂症患者疗效显著且相当,但阿立哌唑改善患者的认知功能优于喹硫平。     

Putative mechanisms of cognitive decline with implications for clinical research and practice

Multiple intrinsic and extrinsic mechanisms contribute to vulnerability of cognitive decline and nurses play a significant role in assisting individuals and families to use strategies for healthy cognitive aging. The objective of this narrative review is to provide a synthesis of the intrinsic and extrinsic mechanisms of cognitive decline and conditions that are associated with cognitive decline. Well‐established intrinsic mechanisms of cognitive decline include aging, apolipoprotein E (APOE) ε4 carrier status, SORL1 mutations, neuroinflammation, mitochondrial dysfunction, amyloid deposition, and demyelination. Extrinsic risk factors include obesity, diabetes, hypertension, elevated lipid panel, metabolic syndrome, depression, traumatic brain injury, substance use, heart failure, and stroke. The various definitions of cognitive decline as well as the intrinsic and extrinsic factors that impact cognition as humans age should be incorporated in future clinical research studies. Nurses may use this information to help patients make lifestyle choices regarding cognitive health.     

齐拉西酮与喹硫平对精神分裂症患者疗效和认知功能的影响

目的：探讨齐拉西酮与喹硫平对精神分裂症患者的临床疗效和认知功能的影响。方法将60例精神分裂症患者随机分为两组,每组30例,分别口服齐拉西酮和喹硫平治疗,观察12周。采用阳性与阴性症状量表评定临床疗效,副反应量表评定不良反应,公认认知功能成套测验评定认知功能。结果治疗后两组阳性与阴性症状量表评分较治疗前显著降低（P＜0．01）,公认认知功能成套测验评分均较治疗前显著升高（P＜0．01）,同期两组间比较差异均无显著性（P＞0．05）;两组不良反应发生率比较差异无显著性（P＞0．05）。结论齐拉西酮与喹硫平治疗精神分裂症疗效显著,安全性高,均能有效改善患者的认知功能。     

Reversible cognitive decline accompanies migraine and cluster headaches

Vascular headaches, including migraine, cluster, and migrainous transformation to chronic daily headaches, are disabling. During and shortly after headache intervals, difficulties are reported in concentration, comprehension, and communication, not accounted for by nausea, photophobia, or sonophobia. These interfere with interpersonal relations and performance at work with economic loss. The hypothesis tested and reported here is that cognitive impairments comprise an important part of vascular headache diatheses. One hundred ninety-six otherwise normative subjects suffering from migraine or cluster, but not tension-type, headaches (136 women, 63 men; mean age, 46 years) participated in an outpatient prospective trial. One hundred thirty-three patients had migraine without aura, 39 migraine with aura, 11 periodic cluster (by IHS criteria), and 13 had migrainous transformation into chronic daily headaches. Neuropsychological testing was compared with and without headaches, by combined Mini-Mental Status Examination (MMSE), Cognitive Capacity Screening Examination (CCSE), and Hamilton Depression Rating Scale (HDRS). During headache intervals, significant decline was measured in both CCSE and MMSE scores (P <. 001) without HDRS change in all types of vascular headache and independent of headache severity, which often improved, or associated physical symptoms. Cognitive decline was promptly relieved by serotonin agonists and sleep. Disorders of cerebral serotoninergic projection systems appear to cause these reversible cognitive impairments.     

奎硫平与氯氮平对精神分裂症的疗效及认知功能影响的比较研究

目的探讨奎硫平与氯氮平对精神分裂症的疗效及认知功能的影响。方法将120例精神分裂症患者随机分为两组,每组各60例．研究组给予奎硫平治疗,对照组给予氯氮平治疗,疗程8w。与治疗前及治疗2w．4w,6w,8w末采用潘氏量表和副反应量表评定临床疗效及不良反应。结果研究组显效率为78．3％,总有效率为95．0％;对照组显效率为75．0％,总有效率为90．0%,两组总体疗效相当（P〉0.05）。研究组认知功能的改善较对照组显著,治疗2W末差异有显著性（P〈0.05）．4w,6w．8w末差异均有极显著性（P〈0.01）。研究组不良反应较对照组发生率低．且程度轻。结论奎的平治疗精神分裂症疗效显著,能显著改善患者的认知功能,安全性高,依从性好。     

Efficacy and tolerability of intravenous valproic acid in acute adolescent migraine

OBJECTIVE: To describe the efficacy and tolerability of rapid intravenous valproic acid (VPA) infusions in children with severe migraine headache. BACKGROUND: Intravenous VPA is an emerging treatment option for acute migraine headache. Adult data suggests both efficacy and tolerability of rapid VPA infusions as abortive therapy, but little data exist in children. METHODS: We conducted a retrospective chart review of all children who received intravenous VPA at The Children's Hospital Headache Clinic during an 18--month study period. Baseline intensity of headache pain, time at which maximum relief was attained, pain reduction following therapy, dose and duration of VPA infusion(s), patient's pulse, blood pressure, respiratory rate, and pulse oximetry were collected. Adverse events were also recorded. RESULTS: Thirty-one children (age=15+/- 2 years; 81% female) requiring 58 clinic visits and 71 VPA infusions were included. Most visits (n=45; 78%) resulted in only one dose of VPA (976+/- 85 mg infused over 12+/- 4 minutes) for desired pain relief. Percent pain reduction in those children was 39.8%, with time to maximum relief of 63+/- 31 minutes. Some children required a second dose of 500 mg (n=13 visits; 22%), that was infused over 14+/- 6 minutes and produced a 57% reduction in pain intensity from baseline. VPA infusions were well tolerated. Adverse events described included cold sensation (1), dizziness (3), nausea (1), possible absence seizure (1), paraesthesia (2), and tachycardia (2). CONCLUSIONS: Rapid infusion of intravenous VPA is generally well tolerated and may play a role in the management of children with acute migraine headache. Prospective, controlled trials to further investigate this treatment in children are warranted.     

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem

A 55-year-old woman was diagnosed with pneumonia and was treated with meropenem; 5 days later she developed epileptic seizures. She had been treated with valproic acid for 16 years to control her epileptic seizures. Her serum valproic acid concentration was low during treatment with meropenem than previously recorded despite an increase of valproic dose. As soon as administration of meropenem was withdrawn, valproic acid concentration increased to previous levels and her seizures stopped. Meropenem decreases valproic acid concentration, and may promote the development of epileptic seizures in previously controlled epileptic patients. The acute lowering of serum valproate produced by meropenem probably precludes their concomitant use.     

Somnambulism due to probable interaction of valproic acid and zolpidem

OBJECTIVE: To report a case of somnambulism due to a probable interaction between valproic acid and zolpidem in a patient with no prior personal or family history of somnambulism. CASE SUMMARY: A 47-year-old white man with a history of bipolar disorder was being maintained on citalopram 40 mg once daily and zolpidem 5 mg at bedtime. During treatment, he developed manic symptoms and was started on adjunctive valproic acid therapy. Soon after this, he developed episodes of somnambulism, which stopped when valproic acid was discontinued. On rechallenge with valproic acid, somnambulism returned. DISCUSSION: To our knowledge, this is the first report in the literature describing a probable interaction between valproic acid and zolpidem leading to somnambulism. Even though valproic acid has been associated with sleep changes, there are no published reports of somnambulism with this agent. Zolpidem has been associated with somnambulism, but our patient did not experience this when he was on zolpidem monotherapy. However, within 2 days of starting adjunctive valproic acid, sleepwalking occurred. It stopped after valproic acid was withdrawn. On rechallenge with valproic acid, sleepwalking recurred. However, when zolpidem was discontinued and valproic acid was continued, somnambulism did not occur. An assessment on the Naranjo probability scale suggests probable pharmacokinetic or pharmacodynamic interactions between the 2 medications. CONCLUSIONS: Valproic acid and zolpidem are generally safe medications that are commonly prescribed and often used together. No interactions have been previously reported with combined use of valproic acid and zolpidem. This case suggests a probable interaction between these 2 agents that can have a serious consequence, somnambulism. This could be frightening to patients and put them in danger. Recognition of such interactions that place patients at risk for potentially serious adverse events is imperative for appropriate care.     

华山版听觉词语学习测验在主观认知下降和轻度认知障碍患者中的应用初探

摘要 目的：探索华山版听觉词语记忆测验（auditory verbal learning test-Huashan version,AVLT-H）在主观认知下降（subjective cognitive decline, SCD）和轻度认知障碍（mild cognitive impairment,MCI）患者记忆功能障碍中的应用价值。方法：筛查招募的老年人,根据入组标准分为三组,即正常组、SCD组和MCI组,并完成神经心理学测试简易智能精神状态检查（mini-mental status examination,MMSE）、北京版蒙特利尔认知评估量表（Montreal Cognitive Assessment-Beijing version,MoCA-BJ）及AVLT-H,从而获得MMSE、MOCA、AVLT-H的即刻回忆N1、N2、N3、延迟回忆N4、N5、线索回忆N6及再认N7得分;结果：①三组老年人的神经心理学测试发现MMSE、MoCA及AVLT各项评分均存在显著性差异（P<0.0167）。采用Bonferroni法校正显著性水平的事后两两比较发现,MMSE和MoCA评分在SCD与NC之间（P<0.001）、MCI与NC之间（P<0.001）均有显著性差异,在MCI与SCD之间无显著性差异;N1评分在MCI与NC之间（P=0.013）、MCI与SCD之间（P=0.001）均有显著性差异,在SCD与NC之间无显著性差异;N2、N3、N4、N5、N6及N7评分在MCI与NC之间（P<0.001）、MCI与SCD之间（P<0.001）均有显著性差异,在SCD与NC之间无显著性差异。②分别以NC组和SCD组为状态变量对MMSE、MoCA和AVLT-H得分进行曲线下面积检测,发现对于区分MCI和SCD,AVLT-H各项得分具有较大的曲线下面积,且敏感度和特异度较高,N1和N7的敏感度最高;对于区分MCI和NC,AVLT-H和MoCA得分具有较大的曲线下面积,且敏感度和特异度均较高,N4、N6和N7的敏感度最高。 结论：AVLT-H可完善MMSE、MoCA对于MCI和SCD的界定诊断,值得将AVLT-H作为MCI和SCD的常规评估方法,即联合使用AVLT-H、MMSE或MoCA可提高其诊断的准确性。     

Acute seizures due to a probable interaction between valproic acid and meropenem

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.     

Population pharmacokinetics of intravenous valproic acid in Korean patients

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.     

Successful reintroduction of valproic acid after the occurrence of pancytopenia

Background

Valproic acid is associated with a variety of hematologic abnormalities, most commonly thrombocytopenia. Pancytopenia is much less common and potentially much more serious. Little is known about the natural course of valproate-induced pancytopenia.

Case summary

We present a patient who developed pancytopenia while taking valproic acid for bipolar illness. After failing to respond to several other mood stabilizers, valproic acid was cautiously reintroduced with close hematologic monitoring. The pancytopenia has not recurred in the past 6 months.

Conclusions

Pancytopenia may not represent an absolute contraindication to continuing valproate therapy, although caution is warranted.     

利培酮 奥氮平 奎硫平对康复期精神分裂症认知功能的影响

目的 探讨利培酮、奥氮平、奎硫平对康复期精神分裂症患者认知功能和社会功能的影响. 方法 将60例康复期精神分裂症患者随机分为三组,每组20例,分别口服利培酮、奥氮平、奎硫平治疗,观察12周.于治疗前及治疗12周末采用韦氏记忆量表、威斯康星卡片分类测验、连线测验、个人和社会功能量表、阳性与阴性症状量表及临床病情严重程度量表进行测评,并与60名健康体检者（对照组）进行对比分析. 结果 治疗前三组患者威斯康星卡片分类测验、连线测验及韦氏记忆量表的各项认知功能指标评分与对照组均有显著性差异（P＜0.05或0.01）;治疗后三组患者连线测验-B连线时间评分显著低于治疗前（P＜0.05或0.01）,而威斯康星卡片分类测验、连线测验-A连线时间、连线测验-A错误数、连线测验-B错误数及韦氏记忆量表记忆商评分与治疗前比较均无显著变化（P＞0.05）,且威斯康星卡片分类测验、连线测验-B错误数及韦氏记忆量表记忆商评分仍与对照组有显著性差异（P＜0.05或0.01）.治疗12周末,三组患者临床病情严重程度量表评分均较治疗前有显著下降（P＜0.05）;奎硫平组阳性与阴性症状量表总分减分值显著低于利培酮组和奥氮平组（P＜0.05）;三组不良反应均轻微. 结论 利培酮、奥氮平、奎硫平均能改善康复期精神分裂症患者的部分认知功能和社会功能,疗效相当,但短期内对执行功能及韦氏记忆量表记忆商无显著改善.     

主观认知下降的结构和功能磁共振成像研究进展

主观认知下降被认为是阿尔茨海默病连续体的第一个临床表现,先于轻度认知障碍。其认知变化以微妙的认知下降和补偿性的认知努力为特征,且已经被证明是阿尔茨海默病的高危阶段。研究患有主观认知下降的人群对于理解早期阿尔茨海默病的病理机制和识别主观认知下降相关的生物标志物很重要,且早期诊断和干预可以有效改善患者的预后。随着正电子发射断层扫描和磁共振成像等先进神经成像技术的出现,越来越多的证据揭示了与主观认知下降症状相关的大脑结构和功能改变。本研究主要从结构磁共振成像、扩散张量成像、功能磁共振成像、机器学习角度分析主观认识下降的诊断、预测病情方面的研究现状进行了综述,以期为揭示其神经生理机制及早期诊断提供影像学依据。     

喹硫平对帕金森病患者伴精神症状和认知功能的影响

目的 探讨喹硫平治疗帕金森病患者伴精神症状的临床疗效以及对认知功能的影响.方法 将49例帕金森病伴精神症状患者随机分为两组.研究组27例,口服喹硫平治疗;对照组22例,口服安慰剂治疗.观察8周.于治疗前及治疗第2周、8周末,采用简明精神病量表评定精神症状改善状况;同时测定P300电位内源性成分N2、P3波潜伏期及P3波幅.结果 研究组治疗2周末起简明精神病量表评分较治疗前有显著下降(P＜0.01),对照组治疗8周末有显著下降(P＜0.05);研究组治疗各时段均较对照组下降更显著(P＜0.01).研究组治疗2周、8周末,P300中N2、P3波潜伏期较治疗前显著缩短(P＜0.01),P3波幅较治疗前显著升高(P＜0.05);对照组则无显著改变(P＞0.05).研究组治疗2周、8周末,N2、P3波潜伏期较对照组显著缩短(P＜0.01),而P3波幅较对照组显著升高(P＜0.05).结论 喹硫平能有效改善帕金森病的精神症状和认知功能.     

辛伐他汀和丙戊酸钠对K562细胞增殖和凋亡的影响

目的 实验以人K562细胞株为研究对象,观察辛伐他汀及丙戊酸钠对K562细胞的增殖和凋亡的影响.方法 实验分3组,辛伐他汀组,丙戊酸钠组,辛伐他汀+丙戊酸钠组,以等客积的RPMI1640培养液为空白对照组.经瑞士-姬姆萨(Wright-Giemsa)染色,光镜下观察经辛伐他汀和丙戊酸钠处理后细胞的形态改变.MTT法检测细胞增殖抑制率.用AnnexinV-FITC/PI双重标记,经流式细胞仪检测细胞凋亡率的变化.结果 与对照组比较,10、20、40μmol/L辛伐他汀作用K562细胞48小时后凋亡半分别为(17.36±1.91)%、(23.26±2.35)%、(34.15±2.54)%;72小时后凋亡率分别为(31.43±2.15)%、(49.42±1.05)%、(56.57±3.06)%.1、2、4 mmol/L丙戊酸钠作用48小时后细胞凋亡率分别为(14.30±1.39)%、(22.90±2.35)%、(39.79±2.65)%;72小时后凋亡率分别为(22.79±2.31)%、(34.67±2.78)%、(49.51±2.37)%.细胞凋亡率随浓度和时问的增加而升高.结论 辛伐他汀和丙戊酸钠均可对K562细胞发挥增殖抑制和诱导凋亡作用,两者联合应用有一定增效作用.