美罗培南与丙戊酸药物相互作用的病例报道与分析

近期我院在开展丙戊酸血药浓度监测中发现个别住院患儿的丙戊酸血药浓度结果异常,远低于丙戊酸的正常治疗浓度。排除了患儿服药依从性,我们发现患儿丙戊酸血药浓度偏低可能与使用美罗培南有关。通过文献检索,可以得知此药物不良反应已经得到国外很多学者重视,并做了大量机制研究。我们阐述了丙戊酸体内代谢过程,总结了上述两种药物潜在的作用机制,临床应引起重视,避免类似情况的再次发生。     

美罗培南致血浆丙戊酸钠浓度异常1例

患者,男,4岁4个月。因发热3 d、抽搐4次入院。患儿3 d前出现发热,至当地医院行输液治疗,输液中出现抽搐,发作时呈双眼上翻,四肢抖动,口吐白沫,面色发绀,最长持续约15 min自行缓解,遂送我院急诊,给予相关对症支持治疗后仍见抽搐发作,为进一步治疗转入我院神经内科。     

美罗培南降低丙戊酸钠稳态血药浓度的临床分析

目的： 分析美罗培南降低丙戊酸钠（VPA）血药浓度的影响程度及变化规律,为临床合理用药提供借鉴和参考。方法：回顾性分析我院住院患者23例,记录患者的基本信息、用药信息,VPA血药浓度等,分析两药合用后VPA血药浓度下降的幅度和程度,及VPA血药浓度的变化规律;并依据两药合用前VPA的血药浓度,将患者分为3组,VPA血药浓度50~60 mg?L-1组（n=13例）,VPA血药浓度60~70 mg?L-1组（n=6例）,VPA血药浓度＞70 mg?L-1组（n=4例）,探讨VPA血药浓度降低的程度和幅度是否呈浓度依赖性。结果：美罗培南与VPA合用24 h内,6例患者中有5例VPA血药浓度均降低到治疗浓度范围以下,合用24~48 h后所有患者VPA血药浓度均降到治疗浓度范围以下。未合用前VPA血药浓度越高,合用后VPA血药浓度下降幅度越大,VPA最低浓度波动5.9~15.7 mg?L-1之间,均降到了治疗浓度范围以下。停用美罗培南1~7 d后,7例患者中有2例VPA血药浓度恢复到了治疗浓度范围以上,7~14 d内13例患者VPA浓度均恢复到治疗浓度范围以上。结论：美罗培南降低VPA血药浓度主要发生在两药合用24 h内,个别病例会延迟到48 h。合用后VPA血药浓度下降幅度呈浓度依赖性,最低VPA血药浓度无浓度依赖性。停用美罗培南7~14 d后,VPA血药浓度基本都可恢复到治疗浓度范围以上。     

美罗培南降低患者丙戊酸钠血药浓度的临床分析

摘 要 目的：分析美罗培南降低丙戊酸钠（VPA）稳态血药浓度的程度及变化规律,为临床合理用药提供参考。 方法: 收集我院2015年1月~2018年12月合用美罗培南和丙戊酸钠的患者信息,分析两药合用后 VPA 血药浓度下降幅度;根据患者的族别、两药合用前VPA的给药剂量和给药途径将纳入患者进行分组,比较不同族别及在不同剂量和不同给药方式下VPA与美罗培南合用,VPA血药浓度变化情况;对患者的VPA血药浓度下降百分数和年龄进行相关性分析。 结果: 17例患者在联合使用美罗培南和VPA后,VPA血药浓度均降到治疗浓度范围以下,下降幅度为37.18%~99.26%,平均（69.66±17.91）%;两药合用后,VPA使用剂量分别为0.4 g bid,0.5 g bid,0.8 g bid的3组患者的VPA血药浓度均降到了最低治疗浓度范围以下,下降幅度分别为（65.10±19.12）%,（68.15±24.18）%,（75.60±12.64）%,3组间差异无统计学意义（P＞0.05）;口服和静脉使用VPA合用美罗培南后,VPA血药浓度下降幅度分别为（68.15±24.18）%和（70.12±16.77）%,两组间差异无统计学意义（P＞0.05）;汉族与维吾尔族患者的VPA血药浓度下降百分数分别为（72.29±17.28）%和（63.60±22.86）%,两组间差异无统计学意义（P＞0.05）;VPA血药浓度下降百分数与年龄的相关系数为-0.055,两者相关性不大。 结论: VPA与美罗培南两药合用可显著降低VPA血药浓度,临床上应避免两者联用。患者的族别、年龄、VPA不同给药剂量和给药途径在两药合用后对VPA血药浓度下降幅度影响不大。     

美罗培南可能降低丙戊酸疗效

西班牙Francisco Javier Coves-Orts等报告了1例可能由丙戊酸与美罗培南相互作用而导致癫痫控制不利的病例。该患者21岁，女性，因新发强直阵挛性癫痫大发作被送往急诊科并转送至重症监护病房，接受24小时连续静脉输注丙戊酸1000mg治疗。入院第6天患者血清丙戊酸浓度为52．5μg／mL。患者于第18天开始接受静脉美罗培南1g，tid治疗。     

美罗培南致血丙戊酸浓度降低1例

患者,男,57岁,汉族,因“脑出血术后5月伴意识障碍”于2009年4月25日入院。入院诊断：左侧基底节区脑出血并破入脑室术后,气管切开术后肺部感染,症状性癫痫。入院后检查血常规：RBC3．29×10^12·L^-1,HGB103g·L^-1,WBC4．73×10^9·L^-1,N43．5％,其余无明显异常。生化指标：GGT432IU·L^-1,GLU6．29mmol·L^-1,DBIL10．99μmol．L^-1,其余无明显异常。入院予改善循环,抗感染,抗癫痫及综合康复治疗。     

美罗培南致丙戊酸血药浓度显著降低的案例分析

目的:分析丙戊酸(VPA)血药浓度显著降低原因,为癫痫持续发作患者制订详细的药物调整方案。方法:临床药师参与疑难癫痫案例治疗,根据血药浓度变化规律,为药物相互作用判断提供依据,为后续治疗方案提供参考。结果:通过VPA血药浓度监测,临床药师发现VPA血药浓度变化规律,确定美罗培南致VPA血药浓度显著降低,并经过后续治疗方案调整后,患者癫痫症状得以控制。结论:美罗培南可迅速、大幅降低VPA血药浓度,有必要加强两者相互作用的监护。     

美罗培南联用丙戊酸钠致癫痫发作1例

<正>1病历摘要患者男,62岁,9小时前无明显诱因下骑电动车时摔倒,头面部着地,具体不详。倒地后出现心跳,呼吸骤停,急救人员到场后予以心肺复苏和支持治疗,送往我院急诊。急查CT示：左侧额叶脑沟可疑高密度影,右侧眶上部额骨骨折,右侧上颌窦前外侧壁可疑骨折,右侧上颌窦腔内、鼻腔内积液积血,双侧筛窦积液。     

1例临床药师参与美罗培南联用丙戊酸钠的临床实践

目的 总结临床药师参与1例颅脑术后患者美罗培南联用丙戊酸钠的临床实践,为患者合理用药提供参考建议。 方法 临床药师通过分析1例颅脑术后美罗培南联用丙戊酸钠引起丙戊酸钠血药浓度明显下降的案例,提出血药浓度监测和给药方案建议,并通过文献复习为后续相似的案例提供用药参考。 结果与结论 碳青霉烯类药物联用丙戊酸钠可导致丙戊酸钠血药浓度明显下降,临床可通过调整抗癫痫药物、抗感染药物或加强患者的监测,取得良好的治疗效果。     

美罗培南致丙戊酸钠血药浓度降低的3例临床分析

目的:分析美罗培南降低丙戊酸钠(VPA)血药浓度的变化规律。方法:测定患者VPA血药浓度在合用美罗培南前后及停药后的变化,观察患者癫痫发作情况及其浓度是否可剂量依赖性回升。结果:3例患者的VPA血药浓度在合用美罗培南后下降幅度均大于70%。例1有癫痫发作;例2在美罗培南合用24 h即降至低点,停药后7 d回升至单用VPA水平;例3在VPA增量后浓度未回升。结论:美罗培南可明显降低VPA血药浓度并为非剂量调控性,临床上宜尽量避免两者合用。     

Potential interaction between valproic acid and doripenem

A potential interaction between valproate (VPA) and doripenem leading to decreased valproic acid concentrations in two patients is described. In the first patient case, a 54-year-old female presented to the emergency department following a seizure episode after stopping her medications a few days prior. She was given a 1500 mg (23 mg/kg) intravenous (IV) bolus dose of valproate and restarted on her home regimen of divalproex sodium 750 mg daily which quickly resulted in valproic acid blood concentrations within the reference range. The patient was later started on doripenem 500 mg IV every 8 hours and subsequent valproic acid concentrations decreased by 62%. The second patient was a 54-year-old female transferred from an outlying facility following a motor vehicle accident. The patient was receiving valproate 1250 mg IV every 8 hours for seizure prophylaxis following a traumatic brain injury. She developed pneumonia and was started on doripenem 500mg IV every 8 hours. Valproic acid concentrations decreased by 69% within two days. This case report describes two patients receiving concomitant valproate and doripenem resulting in a 62% and 69% reduction in valproic acid concentration.     

癫痫患者丙戊酸与拉莫三嗪药代动力学相互作用研究

目的 考察癫痫患者合用丙戊酸(VPA)与拉莫三嗪(LTG)的药代动力学相互作用.方法 将纳入的癫痫患者随机分为3组:VPA组276例、LTG组254例和合用组334例.VPA组患者每天口服VPA 500～1000 mg,LTG组每天口服LTG 100～200 mg,合用组用VPA+LTG.高效液相色谱-质谱联用法测定V...     

Plasma protein binding interaction between phenytoin and valproic acid in vitro.

1 Valproic acid or phenytoin were added to fresh human serum in varying concentrations and their binding characteristics determined by the method of Scatchard (1949). 2 Changes in serum albumin binding were investigated for phenytoin in the presence of 280, 560, 1050 and 2100 mumol l-1 valproic acid, and for valproic acid in the presence of 40, 120, 280 and 480 mumol l-1 phenytoin. 3 Phenytoin appeared to bind to a single site on the albumin molecule and could be competitively displaced from this site by concentrations of valproic acid above 280 mumol l-1. 4 At high concentrations of valproic acid, the affinity of phenytoin for albumin was greatly decreased but the number of available binding sites was increased from one to four. 5 Valproic acid was bound to two high affinity and five low affinity binding sites but the latter were not detectable at valproic acid concentrations below 2100 mumol l-1. 6 Phenytoin displaced valproic acid from its high affinity binding sites, although this was statistically significant only at a concentration of 480 mumol l-1 phenytoin.     

Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats.

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM, and doripenem [S-4661; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5'-diphosphate D-glucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.     

汉族、蒙古族、维吾尔族、哈萨克族丙戊酸血药浓度监测结果回顾性分析

目的:探讨比较汉族、蒙古族、维吾尔族、哈萨克族4个不同民族丙戊酸血药浓度监测结果的差异。方法:采用回顾性研究方法,对某院282例次丙戊酸血药浓度监测结果按民族进行统计分析。结果:丙戊酸在汉、蒙、维、哈4个民族中浓度低于有效血药浓度的占比分别为28.81%,50.00%,45.68%,51.16%,在有效浓度范围内的占比分别为60.17%,45.00%,48.15%,41.86%,高于有效血药浓度的占比分别为11.02%,5.00%,6.17%,6.98%。结论:丙戊酸代谢在不同人群中存在民族差异,在同民族中也存在个体差异,使用丙戊酸盐进行个体化治疗时最好进行血药浓度监测,以便达到更好的临床疗效。     

Interaction between valproic acid and carbapenem antibiotics

The serum concentration of valproic acid (VPA) in epilepsy patients decreased by the administration of carbapenem antibiotics, such as meropenem, panipenem or imipenem, to a sub-therapeutic level. This review summarized several case reports of this interaction between VPA (1-4 g dose) and carbapenem antibiotics to elucidate the possible mechanisms decreasing VPA concentration by carbapenem antibiotics. Studies to explain the decrease were carried out using rats by the following sites: absorption of VPA in the intestine, glucuronidation in the liver, disposition in blood and renal excretion. In the intestinal absorption site, there are two possible mechanisms: inhibition of the intestinal transporter for VPA absorption by carbapenem antibiotics, and the decrease of beta-glucuronidase supplied from enteric bacteria, which were killed by antibiotics. This is consistent with a view that the decrease of VPA originated from VPA-Glu, relating to entero-hepatic circulation. The second key site is in the liver, because of no decreased in VPA level by carbapenem antibiotics in hepatectomized rats. There are three possible mechanisms in the liver to explain the decreased phenomenon: first, decrease of the UDPGA level by carbapenem antibiotics. UDPGA is a co-factor for UDP-glucuronosyltransferase (UGT)-mediated glucuronidation of VPA. Second, the direct activation of UGT by carbapenem antibiotics. This activation was observed after pre-incubation of human liver microsomes with carbapenem antibiotics. Third, the inhibition of beta-glucuronidase in liver by carbapenem antibiotics and the decreased VPA amount liberated from VPA-Glu. The third site is the distribution of VPA in blood (erythrocytes and plasma). Plasma VPA distributed to erythrocytes by the inhibition of transporters (Mrp4), which efflux VPA from erythrocytes to plasma, by carbapenem antibiotics. The increase of renal excretion of VPA as VPA-Glu depends on the increase of VPA-Glu level by UGT. One or a combination of some factors in these mechanisms might relate to the carbapenem-mediated decrease of the plasma VPA level.