Interactions of dextromethorphan with theN-methyl-d-aspartate receptor-channel complex: single channel recordings

The actions of dextromethorphan (DXM) on the 50 pS conductance state of theN-methyl-d-aspartate (NMDA) receptor-operated channel were studied using outside-out patches obtained from cultured rat hippocampal pyramidal neurons. DXM (5–50 μM) had no effect on the amplitudes of unitary currents but caused concentration-dependent reductions in channel mean open times and the frequency of channel openings. Channel open probability was reduced in a concentration-dependent manner by DXM and was one-half of the control value at a DXM concentration of 6 μM, with the patch potential held at −60 mV. An IC₅₀ value of 4 μM was obtained for the reduction by DXM of NMDA-evoked rises in [Ca²⁺]_i in cultured rat hippocampal pyramidal neurons loaded with Fura-2. The results were consistent with drug block of the open NMDA channel with an onward (blocking) rate constant of 7.7 × 10⁶ M⁻¹ · s⁻¹ (at −60 mV). The estimated unblocking rate constant was about 10 s⁻¹, a value considerably higher compared to the off-rate constant found for dizocilpine block of the NMDA channel.     

Adverse events associated with pediatric exposures to dextromethorphan

Study objective: Dextromethorphan is the most common over-the-counter (OTC) antitussive medication. We sought to characterize adverse events associated with dextromethorphan in children <12 years old from a surveillance program of OTC cough/cold medication exposures.

Methods: This is a retrospective case series of oral exposures to dextromethorphan with ≥1 adverse event from multiple U.S. sources (National Poison Data System, FDA Adverse Event Reporting System, manufacturer safety reports, news/media, medical literature) reported between 2008 and 2014. An expert panel determined the relationship between exposure and adverse events, estimated dose ingested, intent of exposure, and identified contributing factors to exposure.

Results: 1716 cases contained ≥1 adverse event deemed at least potentially related to dextromethorphan; 1417 were single product exposures. 773/1417 (55%) involved only one single-ingredient dextromethorphan product (dextromethorphan-only). Among dextromethorphan-only cases, 3% followed ingestion of a therapeutic dose; 78% followed an overdose. 69% involved unsupervised self-administration and 60% occurred in children <4 years old. No deaths or pathologic dysrhythmias occurred. Central nervous system [e.g., ataxia (N?=?420)] and autonomic symptoms [e.g., tachycardia (N?=?224)] were the most common adverse events. Flushing and/or urticarial rash occurred in 18.1% of patients. Dystonia occurred in 5.4%.

Conclusions: No fatalities were identified in this multifaceted surveillance program following a dextromethorphan-only ingestion. Adverse events were predominantly associated with overdose, most commonly affecting the central nervous and autonomic systems.     

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

含对乙酰氨基酚的感冒药及柴芩清宁胶囊对脂多糖和干酵母大鼠发热模型的解热作用研究

目的 研究含对乙酰氨基酚的西药对乙酰氨基酚片、复方氨酚烷胺片、美扑伪麻片及中成药柴芩清宁胶囊对脂多糖（LPS）及干酵母大鼠发热模型的解热作用。方法 制备大鼠100 μg/kg LPS及20%干酵母发热模型;乙酰氨基酚片、复方氨酚烷胺片、美扑伪麻片高、中、低剂量分别为205.67、102.83、51.42 mg/kg,以对乙酰氨基酚计;柴芩清宁胶囊高、中、低剂量分别为1110.60、555.30、277.65 mg/kg,以胶囊内容物质量表示,ig给药。观察大鼠体温变化,计算平均最大体温上升高度（△T）及体温反应指数（TRI）,绘制平均升温曲线。结果 对乙酰氨基酚片、复方氨酚烷胺片、美扑伪麻片及柴芩清宁胶囊各剂量组对LPS及干酵母大鼠发热模型均具有显著解热作用,且均存在一定剂量效应关系。结论 对乙酰氨基酚片、复方氨酚烷胺片、美扑伪麻片及柴芩清宁胶囊对LPS及干酵母大鼠发热模型均有一定解热作用,3种西药的解热作用起效快但是作用时间短,而柴芩清宁胶囊表现为起效慢但是作用时间长。     

术前肌注右美沙芬对全麻术后拔管时呛咳反应的影响

目的 观察术前肌注右美沙芬(dextromethorphan,DM)对阻塞性睡眠呼吸暂停综合征(OSAS)患者全麻术后拔管时呛咳反应的影响.方法 选择40例OSAS拟在全麻下行腭咽成型术(UPPD)患者,ASA Ⅰ～Ⅱ级,随机分为对照组及DM组,每组20例,术前30 min分别肌注5 ml生理盐水或DM 0.3 mg/kg,手术结束后拔管过程中观察各组呛咳反应的程度及不良反应.结果 手术结束后拔管时,DM组与对照组比较,DM组呛咳反应程度明显低于对照组.结论 术前30 min肌肉注射DM 0.3 mg/kg可降低OSAS患者全麻下行UPPP术后呛咳反应的程度.     

高效液相色谱法测定人血中氢溴酸右美沙芬浓度

目的研究氢溴酸右美沙芬在健康志愿者体内的血药浓度。方法采用高效液相色谱法测定8例健康受试者口服右美沙芬糖浆和片剂后不同时间血浆中的美沙芬浓度。结果右美沙芬在5--500 ng/ml浓度范围内呈良好线性关系（r=0.9965）。结论本法精密,准确,可用于氢溴酸右美沙芬的药动学研究。     

应用大鼠肝微粒体筛选对细胞色素P4502D6有抑制作用的中药

目的从17种中药(单体、提取物和注射液)中快速筛选出对细胞色素P4502D6(CYP2D6)亚型有抑制作用的中药,建立高通量筛选对CYP2D6有抑制作用中药的技术平台。方法取大鼠空白肝微粒体,分别加入17种中药,HPLC法测定大鼠肝微粒体中CYP2D6的探针药物右美沙芬(DM)的代谢率,通过代谢率降低的现象初步筛选出能抑制肝微粒体中CYP2D6代谢的药物。结果槲皮素、黄芩苷、厚朴提取物、清开灵注射液、盐酸川芎嗪注射液可明显降低DM的代谢率(P<0.01)。结论初步筛选出槲皮素、黄芩苷、厚朴提取物、清开灵注射液、盐酸川芎嗪注射液这5种中药可抑制肝微粒体CYP2D6酶活性。此方法可作为高通量筛选对CYP2D6活性有抑制作用中药的技术平台。     

Premedication with dextromethorphan provides posthemorrhoidectomy pain relief

PURPOSE: Previous studies have shown that N-methyl-D-aspartate receptor antagonists provide a preemptive analgesic effect in humans. This study was designed to examine whether premedication with dextromethorphan, an N-methyl-D-aspartate antagonist, also provided a preemptive analgesic effect that improved postoperative pain management. METHODS: Sixty patients who were American Society of Anesthesiologists status I and II scheduled for hemorrhoidectomy (modified Whitehead procedure) were included in the study. Patients were randomly assigned to the control and study groups. For the control group patients received chlorpheniramine maleate (20 mg), a component of the injection form of dextromethorphan, intramuscular injection 30 minutes before skin incision. In the study group dextromethorphan 40 mg containing 20 mg chlorpheniramine maleate (intramuscular) was given as premedication 30 minutes before skin incision. Pethidine (1 mg/kg, intramuscular) was given for pain relief as required postoperatively. The time to first pethidine injection, total pethidine consumption, worst pain score, and pethidine-related side effects were recorded for 48 hours postoperatively. RESULTS: The times to first pethidine injection (mean ± standard error of the mean) were 5.2±3 and 19.6±6 hours in the control and study groups, respectively. Total pethidine consumption was 140±11.3 and 63.5±11.8 mg in the control and study groups. The worst visual analog scale pain scores were 7.4±0.2 and 5.6±0.3 in the control and study groups during the two-day observation. The numbers of patients who required pethidine injection were 29 and 20 in the control and study groups, respectively. Two patients suffered pethidine-related side effects, such as nausea, vomiting, dizziness, and headache, in the control group, and no patient complained of any side effect in the study group. CONCLUSION: We found that dextromethorphan premedication provided a preemptive analgesic effect, thus producing reduced postoperative pain and pethidine requirement and improved recovery from hemorrhoidectomy.Supported by grants from the Tri-Service General Hospital (TSGH-C89-057) and National Health Research Institute of Taiwan, Republic of China (NHRI-GT-EX89B909P).     

A new method for evaluating antitussives in cats using an electrode-cannula.

An emplaced laryngo-tracheal electrode-cannula was employed to induce and to measure cough in cats anesthetized with either sodium pentobarbital or Dial--urethane. Carbetapentane citrate, codeine sulfate and dextromethorphan hydrobromide were tested for antitussive action by this method. Relative antitussive potency obtained in order of decreasing effectiveness was dextromethorphan hydrobromide, codeine sulfate and carbetapentane citrate.     

NMDA antagonist modulation of morphine antinociception in female vs. male rats

NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague–Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 °C hotplate and tail withdrawal assays 15–120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.