Protein Binding of Doxepin and Desmethyldoxepin

Abstract: The protein binding of doxepin (DOX) and desmethyldoxepin (DDOX) were studied in serum and plasma samples from healthy volunteers and psychiatric patients. Binding was measured by equilibrium dialysis (16 hrs at 37°) and drug concentrations by radioimmunoassay. In addition, albumin and α₁-acid glycoprotein concentrations of the samples were measured by radial immunodiffusion. The mean ± SEM percentages of unbound DOX were: 20.4 ± 1.2 and 15.9 ± 1.2 in healthy subjects (n = 16) and patients (n= 15) respectively. and those of DDOX: 21.4 ± 0.9 and 19.0 ± 1.4 for healthy subjects and patients, respectively. There was a significant negative correlation between serum α₁-acid glycoprotein concentration and free fraction of DOX in both groups. In healthy subjects a significant negative correlation was also found between albumin concentrations and free fraction of both DOX and DDOX. Binding experiments with isolated protein fractions revealed that all of the total binding in plasma could be explained by binding to albumin and α₁-acid glycoprotein. The observed 2–4-fold interindividual variability in the free fractions of these drugs is probably less important than the much larger variability in the total serum concentrations.     

HPLC测定复方盐酸多塞平胶囊中盐酸多塞平与盐酸可乐定的含量

采用高效液相色谱法测定复方盐酸多塞平胶囊中盐酸多塞平与盐酸可乐定的含量。盐酸多塞平在５～３０μｇ／ｍｌ（ｒ＝０９９９８），盐酸可乐定在２～１２μｇ／ｍｌ（ｒ＝０９９９９）范围内，峰面积与其浓度呈良好线性关系；方法平均回收率分别为１００１８％（ＲＳＤ＝１０２％），１００３４％（ＲＳＤ＝１６３％）。结果表明，方法简便、快速、准确。     

多虑平治疗ⅢA型难治性前列腺炎40例疗效观察

目的观察多虑平治疗ⅢA型难治性前列腺炎的疗效。方法将40例通常方法治疗无效的难治性前列腺炎患者给以多虑平治疗。观察治疗前后的疗效和NIH-CPSI评分。结果治疗前后NIH-CPSI总分分别为(25.61±7.14)和(9.75±4.09),差别有统计学意义(P<0.01),有效率为77.5%。结论多虑平治疗ⅢA型难治性前列腺炎有较好疗效。     

盐酸多塞平乳膏的止痒和抗过敏作用

目的研究盐酸多塞平乳膏(Doxepinhydrochloridecream)的止痒、抗过敏作用。方法观察对4氨基吡啶(4AP)所致小鼠和磷酸组胺所致豚鼠皮肤瘙痒的影响;并观察对醋酸致小鼠腹腔毛细血管通透性及组胺所致大鼠皮肤血管扩张的抑制作用;以2,4-二硝基氯苯(DNCB)致小鼠迟发性过敏反应(DTH)和大鼠同种皮肤被动过敏反应,探讨抗过敏作用。结果小鼠皮肤涂抹盐酸多塞平乳膏(50、125、250mg·kg-1),对4AP所致皮肤的瘙痒有抑制作用;豚鼠皮肤涂抹盐酸多塞平乳膏(10、25、50mg·kg-1),对磷酸组胺所致皮肤瘙痒也有抑制作用。皮肤涂抹盐酸多塞平乳膏(10、25、50mg·kg-1和50、125、250mg·kg-1)可抑制磷酸组胺致大鼠皮肤毛细血管通透性增加和醋酸致小鼠腹腔毛细血管通透性增加。皮肤涂抹盐酸多塞平乳膏(50、125、250mg·kg-1和10、25、50mg·kg-1)可抑制2,4二硝基氯苯致小鼠迟发性变态反应和大鼠同种皮肤过敏反应。结论盐酸多塞平乳膏具有止痒、抑制致炎性物质所致毛细血管通透性增加和对Ⅰ、Ⅳ型变态反应有抑制作用。     

Single Dose Pharmacokinetics of Doxepin in Healthy Volunteers

Abstract: The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers. Doxepin (DOX) and desmethyldoxepin (DDOX) concentrations in serum (or plasma) and red blood cells (RBCs) were measured by radioimmunoassay. Peak serum concentrations of DOX were observed at 1–2 hours and they ranged between 59.1–107.4 nmol/1. DOX disappearance was biphasic with a mean distribution half-life of 2.0 hrs and elimination half-life of 17.9 hrs. The mean total apparent volume of distribution was 22.7 l/kg and plasma clearance 0.93 l/hr/kg. The estimated mean first-pass metabolism of DOX was 71 % assuming complete absorption. Peak DDOX concentrations were observed at 1–6 hours and they ranged between 35.0–117.8 nmol/1. DDOX elimination was monophasic with a mean apparent half-life of 28.5 hours. Equilibrium dialysis gave a mean protein binding of 75.5% for DOX and 76.0% for DDOX. A highly time dependent and interindividually variable RBC/plasma concentration ratio was observed for both substances. Initially the plasma concentrations were 3–4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma. The major reason for this seemed to be a slower elimination of both drugs from the erythrocytes than from plasma.     

Radioimmunoassay for Atropine and l-Hyoscyamine

Abstract: A simple, specific and sensitive radioimmunoassay is described for atropine (dl-hyoscyamine) and l-hyoscyamine. Antiserum was obtained from rabbits immunized with an immunogen prepared by coupling l-hyoscyamine to human serum albumin. By using ³H-atropine as tracer, the assay can detect atropine and l-hyoscyamine concentrations down to 9 nmol/1 (2.5 ng/ml)in a 0.1 ml serum or plasma sample, The recovery of atropine was near 100% when the drug was added at different concentrations to normal, pooled human plasma. Atropine and l-hyoscyamine are recognized equally well by the antibodies, but some other structurally related drugs (homatropine, scopolamine) and atropine hydrolysis products (tropine, tropic acid) do not interfere. The usefulness of the method in pharmacokinetic studies was shown by assaying atropine concentrations in serial serum samples from two patients, who were given 1.3 mg atropine in connection with anaesthesia. A biexponential serum decay curve was demonstrated in both cases with a very rapid distribution phase (t 1/2 0.63 and 1.38 min.) and a much slower elimination phase (t 1/2A 1.86 and 2.09 hrs.).     

RP－HPLC法同时测定血浆中阿普唑仑和多虑平

本文首次采用反相ＨＰＬＣ法同时测定人血浆中阿普唑仑和多虑平。血浆样品在碱性条件下用乙酸乙酯提取，有机相在氮气下吹干，残渣用５０μｌ甲醇溶解，ＨＰＬＣ流动相为甲醇－０．０５ｍｏｌ／Ｌ醋酸铵缓冲液（内含１．０％三乙胺，ｐＨ５．０）（６０：４０），在２５４ｎｍ进行检测。阿普唑仑的线性范围为０～１００μｇ／Ｌ，ｒ＝０．９９８５，平均回收率为７７．３％，ＲＳＤ为３．２％～６．２％；多虑平的线性范围为０～５００μｇ／Ｌ，ｒ＝０．９９５７，平均回收率为９７．２％，ＲＳＤ为３．１％～６．２％。阿普唑仑和多虑平的最低检出限分别为１．２ｎｇ和４ｎｇ。本法简便、快速、灵敏、准确，适用于阿普唑仑和多虑平血药浓度的同时监测及临床药理学研究。     

Doxepin protects cultured neurons against oxidative stress-induced injury

INTRODUCTION Oxidative stress is defined as loss of balance inthe body for the generation of oxygen free radicals, oras cytotoxicity induced by accumulation of reactive oxy-gen species due to overuptake of exotic oxidizing agent[1] . It is recognized that some central nervous diseasessuch as cerebral ischemia, Parkinson’s disease andAlzheimer’s disease are related to accumulation of freeradicals[2]. Doxepin (Dox), a tricycline anti-depressant,is known to have protective effects on acut…     

多塞平治疗非器质性病因的咽异感症60例

目的 :探讨多塞平治疗非器质性病因的咽异感症的疗效。方法 :6 0例经过中西医药物及方法治疗无效的非器质性病因的病人 ,加用多塞平 2 5～5 0mg ,tid ,疗程 7～ 14d。结果 :临床治愈 2 9例(4 8% ) ,有效 2 4例 (4 0 % ) ,无效 7例 (12 % )。结论 :多塞平治疗非器质性病因的咽异感症有一定疗效 ,不良反应轻。     

多塞平加氟桂利嗪治疗难治性功能性消化不良

目的 :观察多塞平加氟桂利嗪治疗难治性功能性消化不良 (FD)的疗效。方法 :应用随机开放性的自身交叉对照试验 ,6 3例病人分为AB组和BA组 ,轮替给予A方案和B方案先后治疗各 4wk。A方案给多塞平 12 .5mg ,po ,bid +2 5mg ,po ,qn ;氟桂利嗪 5mg ,po ,qn。B方案给西沙必利 5mg ,po ,tid ;雷尼替丁 0 .3g ,po ,qn。A和B方案间隔 3wk执行 ,2组病人在A和B方案均完成后 ,相同方案的症状评分结果合并 ,再比较症状改善情况及有效率。结果 :治疗后 2方案的症状积分下降均有非常显著意义 (P <0 .0 1) ;2方案间比较 ,A方案症状积分非常显著低于B方案 (P <0 .0 1) ,症状总积分减分率达有效者 ,A方案 75 % ,非常显著高于B方案 4 4% (P <0 .0 1)。结论 :多塞平加氟桂利嗪是治疗难治性FD的有效方案。     

Radioimmunoassay for 2,4-dichlorophenoxyacetic acid

Antisera to 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide, have been obtained from rabbits following immunization with various 2,4-D-protein conjugates. Employing [¹²⁵I] 2,4-D-tyramine as the radioligand for the antisera, very poor assay sensitivity was achieved because of a much higher affinity of the antibodies to the tracer. When using [6-³H] 2,4-D(specific radioactivity 465 GBq/mmol) a sensitive and specific radioimmunoassay (RIA) for 2,4-D could be developed, which allows determination directly in water, plasma and urine samples. Levels as low as approximately 100 pg (450 femtomoles) of 2,4-D can be detected. The antiserum is fairly specific for 2,4-D. Other related phenoxycarboxylic acids and dichlorophenol showed a cross-reactivity smaller than 10%. After a single administration of 2,4-D (0.91 mg/100 g body weight, orally) to rats, plasma and urine levels were determined at different times. Results correspond to those found in the literature, thus indicating the utility of the RIA. Further applications and limitations are discussed.     

复方盐酸多塞平乳膏的制备与质量控制

目的 :研究复方盐酸多塞平乳膏的制备与质量控制方法。方法 :将盐酸多塞平与醋酸曲安奈德制成复方制剂 ,并分别采用紫外法、高效液相色谱法进行含量测定。结果 :在实验浓度范围内吸收值、峰面积分别与浓度呈良好的线性关系 ,r=0 9999。结论 :本方法简单、方便 ,可用于该制剂的质量控制     

Prostaglandins and the Cardiotoxic Effects of Doxepin in Rabbits and Guinea-pigs

Abstract: Intravenous administration of tricyclic antidepressants to rabbits leads to dysrhythmias largely attributable to their non-specific membrane effects. Further experiments with doxepin (Dx) were conducted to assess an eventual contribution by prostaglandins (PG) to these events. Dx infused intravenously to conscious or anaesthetized guinea-pigs proved as cardiotoxic as amitriptyline hut more toxic than protriptyline, thus confirming our previous results in rabbits. PG F₂α given intravenously before or during the Dx infusion failed to antagonize cardiotoxicity. In conscious rabbits, pretreatment with drugs (aminophenazon, indomethacin, tolfenamic acid) known to inhibit PG synthesis failed to modify the Dx cardiotoxicity asalsodid PG F₂α which elevated blood pressure, however. PG F₂α also failed to counteract the ouabain cardiotoxicity in anaesthetized guinea-pigs and major Ba⁺⁺ -induced dysrhythmias in conscious rabbits. Our results suggest that a) at least Dx induced dysrhythmias are unresponsive to PGs, and that b) previous speculations about PGsas antiarrhythmic agents may be exaggerated.     

盐酸多塞平乳膏人体透皮吸收试验

目的 :比较进口与国产5 %盐酸多塞平乳膏的人体透皮吸收效果。方法 :采用高效液相色谱法测定血药浓度 ,8位健康男性受试者按交叉试验设计 ,以进口的5 %盐酸多塞平乳膏为对照品 ,对比研究国产5 %盐酸多塞平乳膏的人体透皮吸收效果。结果 :连续8d于受试者前臂皮肤涂抹相同剂量的盐酸多塞平乳膏试验品和对照品后进行测定 ,两组血药浓度均较低 ,无显著性差异。结论 :国产5 %盐酸多塞平乳膏的人体透皮吸收效果可达国外同类品种水平 ,且安全、有效     

前列腺素F2α放射免疫分析及其应用

A specific antibody against prostaglandin F_2α (PGF_2α) was obtained from rabbits immunized with PGF_2α conjugated to bovine thyroglobulin (BTG) by N, N-Carbonyl-diimidazole (CDI). A sensitive, accurate, precise and convenient radioimmunoassay for PGF_2α has been established in our laboratory by use of this antibody, and the normal levels of PGF_2αin plasma and tissues of human and animals were measured.     

放射免疫法测定血清抗生长激素抗体

目的 建立人血清抗生长激素（GH）抗体放射免疫测定法。方法 （1）以聚丙烯酰胺凝胶电泳、放射自显影,鉴定人重组生长激素（r-hGH)及其单抗纯度、检验r-hGH在^125I标记后是否改变其与抗GH抗体形成免疫复合物的能力。（2）将^125I标记r-hGH与血清于37℃水浴孵育3h,经三次非特异性洗脱,测定并计算出^125I结合率,并观察75例原发性生长激素缺乏症患儿接受r-hGH治疗前后不同时期共263份血清抗GH抗体阳性变化。结果 （1）r-hGH及其单抗为电泳纯,^125Ir-hGH可与其抗体形成免疫复合物。（2）测得阳性标本61例,阳性率23．2％。结论 该测定方法可用于人血清抗生长激素抗体水平测定,敏感、可靠、方便。     

多塞平(71例)与胰酶(32例)治疗肠易激综合征的比较

目的 :观察多塞平治疗肠易激综合征 (IBS)的临床疗效 ,进一步探讨IBS的病因和治疗原则。方法 :1 0 3例IBS病人 ,其中多塞平组 71例 [男性 32例 ,女性 39例 ,年龄 (46±s 1 3)a] ,给予多塞平 2 5mg ,po,qn;胰酶组 32例 [男性 1 8例 ,女性 1 4例 ,年龄 (48± 1 1 )a ] ,给予胰酶 1 50mg,po,tid;均以 8wk为一个疗程。利用症状等级评分表和SF 36健康调查量表对治疗前后的肠道症状和生活质量进行评估 ,观察疗效。结果 :多塞平组和胰酶组的总有效率分别为 86 % (61 / 71 )和 44 % (1 4 / 32 ) ,两组相比差异有非常显著意义 (P <0 .0 1 ) ,多塞平组各亚型之间疗效比较差异无显著意义 (P >0 .0 5)。多塞平治疗后病人的生活质量有所提高 ,以总体健康、活力和精神健康纬度积分为明显。结论 :多塞平对IBS病人肠道症状也有较好的治疗作用 ,且能改善病人的生活质量。     

唾液中白细胞介素-6的放射免疫测定法探讨

目的　探讨唾液中白细胞介素 - 6的放射免疫测定方法和人唾液中白细胞介素 - 6浓度水平。方法　以柠檬酸作为刺激物 ,间断吐出法收集 2 6份健康男性的唾液。用放射免疫法测定白细胞介素 - 6浓度。结果　方法相对标准偏差 (RSD)为 4 .8% ,回收率在 93.8%～ 10 5 %。 2 6名健康男性调度员唾液中白细胞介素 - 6为 0 .18± 7.3× 10 -2 ng/ml,并符合正态分布。结论　用放射免疫法测定人唾液中白细胞介素 - 6浓度可行     

The N-Demethylation of the Doxepin Isomers Is Mainly Catalyzed by the Polymorphic CYP2C19

Purpose. This study was conducted to identify the cytochrome P450s (CYPs) responsible for the metabolism of the cis- and trans-isomers of the tricyclic antidepressant doxepin to its pharmacologically active N-desmethylmetabolite by in vitro techniques. Methods. The doxepin N-demethylation was studied by means of pooled human liver microsomes and chemical inhibitors, recombinant human (rh)-CYPs, and geno- and phenotyped human liver microsomes. Results. The N-demethylation of both isomers was inhibited most prominently by tranylcypromine (CYP2C19) to more than 50%. Furafylline (CYP1A2) and sulfaphenazole (CYP2C9) inhibited the N-demethylation to a lesser extent while quinidine (CYP2D6) or troleandomycine (CYP3A4) had no effect. Rh-CYP2C19, -CYP1A2, and -CYP2C9 were able to N-demethylate cis- and trans-doxepin. Only traces of trans-desmethyldoxepin were detectable when CYP3A4 was used. The maximum velocity in the cis- and trans-doxepin N-demethylation was significantly (P < 0.05) lower in microsomes with low CYP2C19 activity (345 ± 44 and 508 ± 75 pmol/min/mg protein, respectively) compared to those with high CYP2C19 activity (779 ± 132 and 1189 ± 134 pmol/min/mg). Conclusion. The present study demonstrates a significant contribution of the polymorphic CYP2C19 to the N-demethylation of doxepin. CYP2C9 and CYP1A2 play a minor role and CYP3A4 does not contribute substantially.     

Radioimmunoassay of Hair for Determination of Cocaine,Heroin, and Marijuana Exposure: Comparison with Self-Report

Radioimmunoassay of hair (RIAH) was compared with self-report for cocaine, heroin, and marijuana in two populations: 109 persons entering residential drug user treatment and 86 at follow-up posttreatment. Among treatment entrants, 89% of 87 RIAH cocaine-positives and 96% of 45 RIAH heroin-positives were confirmed by self-report. However, among those followed-up posttreatment, only 51% of 43 RIAH cocaine-positives and 67% of 18 RIAH heroin-positives were so confirmed. Whereas 95% of 104 self-reports of cocaine use in the combined population were confirmed by RIAH, only 69% of 80 self-reports of heroin use were. Self-report and RIAH for marijuana were weakly associated.