一种杂环类抗抑郁新药venlafaxine

传统的三环类抗抑郁药（TCA）和单胺氧化酶抑制剂（MAOI）常引起许多不良反应，如镇静、失眠、体位性低血压、尿潴留、恶心、呕吐及与食物的相互作用。理想的新型抗抑郁药疗效应与当前使用的药物相当，且无因不良反应而导致的不顺从用药问题。venlafaxine在抗抑郁作用方面与TCA，MAOI，选择性5－HT重摄取抑制剂相当，但其抗胆碱能、肾上腺素能和组胺能的不良反应轻微，因此美国食品和药品管理局（FDA）已正式批准投放市场。本文对venlafaxine的药理学、药效学、药动学、临床应用研究及其安全性和不良反应进行了介绍。

杂环类抗抑郁新药文拉法新(venlafaxine)的合成

目的 :改进新型杂环类抗抑郁药文拉法新 (venlafaxine)的合成方法。方法 :该化合物以对羟基苯乙酸为原料 ,经醚华、酰氯华、酰胺化格氏反应、还原、成盐等步骤制备而成。结果 :合成产物经元素分析、红外光谱、核磁共振谱、质谱和快原子轰击质谱等确证。结论

Irsogladine maleate and rabeprazole in non-erosive reflux disease: A double-blind, placebo-controlled study

AIM:To evaluate the efficacy of adding irsogladine maleate(IM) to proton-pump inhibitor(PPI) therapy in non-erosive reflux disease(NERD) treatment.METHODS:One hundred patients with NERD were recruited and randomized to receive rabeprazole plus IM(group I) or rabeprazole plus placebo(group P).The efficacy of the treatment was assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease(FSSG) and the short form(SF)-36 quality of life questionnaires after four weeks of treatment.We also assessed whether patients with NERD with minimal changes(grade M) had different responses to the therapies compared with patients who did not have minimal changes(grade N).RESULTS:Group I and group P showed significant improvements in their FSSG scores after the treatment(from 17.9 ± 7.9 to 9.0 ± 7.6, and from 17.7 ± 7.3 to 11.2 ± 7.9, respectively, P = 0.0001), but there was no statistically significant difference between the FSSG scores in group I and those in group P.Subgroup analysis showed that significant improvements in the FSSG scores occurred in the patients in group I who had NERD grade N(modified Los Angeles classification)(7.8 ± 7.4 vs 12.5 ± 9.8, P = 0.041).The SF-36 scores for patients with NERD grade N who had received IM and rabeprazole were significantly improved in relation to their vitality and mental health scores.CONCLUSION:The addition of IM to rabeprazole significantly improves gastroesophageal reflux diseasesymptoms and the quality of the lives of patients with NERD grade N.

新型抗抑郁药Venlafaxine

本文通过分析现今各种抗抑郁药的异同，并经由临床前及临床药理学研究报告之总结，介绍一种起效快、耐受性好、同时对５－ＨＴ和ＮＥ回收都有较强抑制作用新药Ｖｅｎｌａｆａｘｉｎｅ。

Effects of tanshinone Ⅱ sodium sulfonate plus cinepazide maleate on the hemorrheologic indexes and blood lipids in patients with acute cerebral infarction

BACKGROUND： The severity of cerebral infarction is associated with the increase of blood viscosity caused by hyperfibrinogenemia and hyperlipidemia, etc. Thus it has become one of the target for treating cerebral infarction to decrease blood viscosity by integrated Chinese and western medicine. OBJECTIVE： To investigate the influence and clinical therapeutic effects of cinepazide maleate combined with tanshinone Ⅱ A sodium sulfonate on the hemorrheologic indexes and blood lipids of patients with acute cerebral infarction, and compare the results with those of simple cinepazide maleate treatment. DESIGN： A non-randomized case-controlled observation. SETTINGS： Hebei North University; the Second Affiliated Hospitals of Hebei North University; the Third Affiliated Hospitals of Hebei North University, PARTICIPANTS： Eighty-six inpatients with cerebral infarction were selected from the infirmary, the Second and Third Affiliated Hospitals of Hebei North University from September 2004 to October 2006. They were all diagnosed to have acute cerebral infarction by CT or MRI, and accorded with the diagnostic standards for acute cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1995. Meanwhile, 40 teachers and medical staff of voluntary physical examinees were selected as the control group. Informed contents were obtained from all the patients and their relatives. METHODS： The patients were divided into combined treatment group （n=43） and simple treatment group （n=3）. In the combined treatment group, the patients were administrated with 160 mg cinepazide maleate injection （Beijing Four-ring Pharmaceutical, Co.,Ltd, No. H200220125; 80 mg/2 mL） added in 5% glucose, and 40 mg tanshinone Ⅱ sodium sulfonate （Shanghai No.1 Biochemical ＆ Pharmaceutical Co.,Ltd., No. H31022558, 10 mg/2 mL） added in 250 mL normal saline. In the simple treatment group, the patients were only administrated with cinepazide maleate 320 mg added in 5% glucose or 250 mL normal saline. They were treated for 1 or 2 courses, once a day, and 14 days as a course. The patients were detected before treatment and at 14 and 28 days after treatment respectively. ① Determination of hemorrheologic indexes： Whole blood viscosity was determined with LBY-N6B automatic hemorrheologic meter; Plasma viscosity with LBY-F200B automatic plasma viscosity meter; Volume of fibrinogen was determined by the method of 12.5% sodium nitrate depositing biuret reaction. ② Determination of blood lipids： The serum levels of total cholesterol （TC）, triglyceride （TG）, low density lipoprotein cholesterol （LDL-C） and high density lipoprotein cholesterol （HDL-C） were determined. ③ Severity of neurological deficit： The total score of neurological deficit score （NDS） ranged from 0 to 45 points, 0 - 15 points was taken as mild, 16 - 30 points as moderate and 31 - 45 points as severe.④ Evaluation of curative effects： Generally cured： NDS decreased by 91% - 100%, and disabled severity of grade 0; Significantly improved： NDS decreased by 46% - 90%, and disabled severity of grades 1 - 3; Improved： NDS decreased by 18% - 45%; No change： NDS decreased by less than 18%; Aggravated： NDS increased by more than 18%. Generally cured and significant improved were taken as significant effect. ⑤ The adverse events and side effects after medication were observed. MAIN OUTCOME MEASURES： ① Results of hemorrheologic indexes and blood lipids; ② NDS results in the combined treatment group and simple treatment group; ③ Therapeutic effects and adverse events. RESULTS： All the 86 patients with cerebral infarction and 40 healthy controls were involved in the analysis of results. ① Results of hemorrheologic indexes and blood lipids： The hemorrheologic indexes and blood lipids before treatment were manifested as abnormalities to different extents in both the combined treatment group and simple treatment group; The hemorrheologic indexes after treatment were obviously improved in both groups. But the hemorrheologic indexes were improved more obviously in the combined treatment group as compared with those in the simple treatment group （P 〈 0.05）; The levels of TC, TG and LDL-C after treatment in the combined treatment group were obviously lowered （P 〈 0.05）, whereas those in the simple treatment group were not significantly changed （P 〉 0.05）. ② NDS results： The NDS scores at 14 and 28 days after treatment in the combined treatment group [（6.23±2.34）, （4.27± 1.83） points] were obviously lower than those in the simple treatment group [（8.76±3.41）, （6.65±2.49） points, P 〈 0.05]. ③ Therapeutic effects and side effects： The total significant effective rates in the combined treatment group and simple treatment group were 93% and 81% respectively. In the combined treatment group, 1 case suffered from palpitation, dizziness and agrypnia. In the simple treatment group, 1 case suffered from palpitation, dizziness and agrypnia, 1 case had itch of skin. All the above symptoms disappeared gradually after the transfusing speed was adjusted to be slower. No drug withdrawal occurred in the patients due to the adverse events. CONCLUSION： Cinepazide maleate combined with tanshinon can obviously improve the abnormalities of hemorrheologic indexes and blood lipids and nerve function in patients with acute cerebral infarction, and its curative effect is faster than that of simple cinepazide maleate treatment.

Effect of Rosiglitazone Maleate on Inflammation Following Cerebral Ischemia/Reperfusion in Rats

In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5, 2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion, respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and inter- leukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swell- ing (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflam- matory response after ischemia-reperfusion in this model.

Sonochemical Synthesis of Maleated Rosin

The cycloaddition reaction of rosin and maleic anhydride under ultrasonic irradiation has been investigated. The results show that both isomerization and Diels-Alder cycloaddition reactions were accelerated remarkably. The sonochemical reaction reached equilibrium in 5-10 min at 110℃, comparing with regular synthesis of 4-5 h over 180℃.

Tunable and sustained-release characteristics of venlafaxine hydrochloride from chitosan–carbomer matrix tablets based on in situ formed polyelectrolyte complex film coating

The objective of this study is to design sustained-release tablets using matrix technology, which can well control the release of highly water-soluble drugs with good system robustness and simple preparation process. Taking venlafaxine hydrochloride(VH) as a drug model, the feasibility of using chitosan(CS), carbomer(CBM) combination system to achieve this goal was studied. Formulation and process variables influencing drug release from CS–CBM matrix tablets were investigated. It was found that CS–CBM combination system weakened the potential influence of CS, CBM material properties and gastric emptying time on drug release profile. Demonstrated by direct observation, differential scanning calorimetry(DSC) and Fourier transform infrared spectroscopy(FTIR), in situ self-assembled polyelectrolyte complex(PEC) film was formed on the tablet surface during gastrointestinal tract transition, which contributed to the tunable and robust control of drug release. The sustained drug release behavior was further demonstrated in vivo in Beagle dogs, with level A in vitro and in vivo correlation(IVIVC) established successfully. In conclusion, CS–CBM matrix tablets are promising system to tune and control the release of highly water-soluble drugs with good system robustness.

Near-infrared chemical imaging for quantitative analysis of chlorpheniramine maleate and distribution homogeneity assessment in pharmaceutical formulations

Near infrared chemical imaging(NIR-CI)combines conventional near infrared(NIR)spectros-copy with chemical imaging,thus provides spectral and spatial information simult aneously.It could be utilized to visualize the spatial distribution of the ingredients in a sample.The data acquired using NIR CI instrument are hyperspectral data cube(hypercube)containing thousands of spectra.Chemometric methodologies are necessary to transform spectral information into chemical information.Partial least squares(PLS)method was performed to extract chemical information of chlorpheniramine maleate in pharmaceutical formulations.A series of samples which consisted of different CPM concentrations(w/w)were compressed and hypercube data were measured.The spectra extracted from the hypercube were used to establish the PLS model of CPM.The results of the model were R^(2)_(val)0.981,RMSEC 0.384%,RMSECV 0.483%,RMSEP 0.631%,indicating that this model was reliable.

治疗血小板减少症新药——马来酸阿凡泊帕(avatrombopag maleate)

马来酸阿凡泊帕(avatrombopag maleate)是血小板生成素受体激动药,最早由日本安斯泰来制药集团研制,几经授权,最后由美国Dova制药公司的子公司AkaRx制药公司完成新药研制,向美国食品药品管理局(FDA)提出新药上市申请,于2018年5月21日获准上市,商品名为Doptelet,用于患有血小板减少症并拟接受医疗或牙科手术的成人慢性肝病(CLD)患者。该文对马来酸阿凡泊帕的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。

Venlafaxine Dependence： A Case Report

Venlafaxine, an SNRI （serotonin-norepinephrine reuptake inhibitor） drug, is commonly used to treat depression. Although it is very rare, venlafaxine may lead to addiction or abuse in some patients. To date, there are very limited data available on venlafaxine addiction. The aim of this article is to draw an attention to dependence of venlafaxine in clinical practice. Significant point of this article is： Our patient was addicted by ＂high＂ doses of venlafaxine for getting high effects. Overdose of venlafaxine produces an amphethamine-like ＂high＂ with experiences of euphoria by its ability to increase neurotransmitter levels in addiction literature [1-3]. We present a man aged 42 years, who was referred to our clinic for detoxification from venlafaxine addiction. He had been taking venlafaxine upto 1,950-2,100 mg/day to get high for the past 10 years. Physicians must be careful when prescribing antidepressants to patients, especially those with a history of alcohol and/or drug addictions or abuse.

Synthesis and Characterization of a Cobalt Complex with Maleate and Pyridine

A new polymeric cobalt complex [Co(-male)(py)(H2O)]n (male = maleate; py = pyridine) 1 was prepared by cobalt chloride hexahydrate with disodium maleate and pyridine in an alcohol-aqueous solution. Single-crystal X-ray analysis has revealed that 1 crystallizes in the orthor- hombic system, space group Pnma with a = 18.001(1), b = 7.6001(6), c = 7.4731(6) ? V = 1022.4(1) 3, Z = 4, C9H9CoNO5, Mr = 270.10, Dc = 1.755 g/cm3, F(000) = 548, m(MoK? = 1.683 mm-1, S = 1.002, the final R = 0.0280 and wR = 0.0746 for 883 observed reflections with I > 2s(I). The structure analysis shows an approximate octahedral coordination environment of metal center. The Co(II) ions are bridged by maleic anions in a rare tetradentate coordination fashion with a syn-anti coplanar con- formation of the carboxyl group, forming a two-dimensional corrugated 2-D structure which is further attached into a three-dimensional framework via non-classical CH…O interactions between adjacent layers.

Long-term follow-up of a patient with venlafaxine-induced diurnal bruxism treated with an occlusal splint:A case report

BACKGROUND Bruxism is a jaw-muscle activity characterized by the clenching or grinding of teeth. It can be divided into nocturnal bruxism and diurnal bruxism(DB). DB secondary to antidepressants is rare and refractory. Reports associated with antidepressant-induced DB are mostly anecdotal without long-term follow-up.The effect of drug intervention on antidepressant-induced DB is still contested.We herein report the first case of successful treatment of venlafaxine-induced DB with an occlusal splint.CASE SUMMARY This case report describes detailed 7-year follow-up of a patient with venlafaxineinduced DB treated with an occlusal splint. The patient who complained about involuntary daytime tooth grinding after taking venlafaxine for a period of 4 mo and was diagnosed with venlafaxine-induced DB. Subsequently, an occlusal splint with modified bilateral buccal-pterygoid pads was used to treat his tooth grinding and to protect the dental structures from tooth wearing. The patient reported remission of symptoms after several months of treatment. His grinding activity was gradually and stably controlled after 2 years, with an almost complete recovery from DB after 6 years.CONCLUSION The maxillary buccal-pterygoid splint can be used as a noninvasive approach to treat venlafaxine-induced DB.

Study on Synthesis and Polymerization of Mono (isopropylmaleate oyloxyl) Diisopropoxyl Dysprosium

Mono(isopropyl maleate-oyloxyl) diisopropoxyl dysprosium(DM) was synthesized by the reaction of dysprosium isopropoxide with maleic anhydride. Dy-containing polymer(PDM) was obtained by the solution polymerization of DM using 2, 2'-azobisisobutyronitrile (AIBN) as an initiator. The kinetic study on the polymerization shows that the polymerization of DM exhibits high apparent activation energy(96.3 kJ.mol(-1)), indicating that the activity of DM is low for polymerization. The kinetic equation of polymerization can be expressed as R-P = k(P)C(DM)(1.23)c(AIBN)(0.82). The polymeric solid material shows excellent heat-stability and strong characteristic fluorescence of Dy3+, (4)Fg(9/2) --> H-6(15/2) and F-4(9/2) --> H-6(13/2).

Overdose of Venlafaxine with Mild Outcome

The antidepressant venlafaxine in overdose can lead to serotonin syndrome, seizures, QTc interval prolongation and can increase the risk of cardiac arrhythmias. It has been reported to be more toxic in overdose than other new antidepressants. We report a case of venlafaxine intoxication with a venlafaxine/O-desmethylvenlafaxine serum level of 2861/2670 ng/mL 22 h after ingestion. This is one of the so far highest survived venlafaxin serum levels. In contrast to other reported survived venlafaxin overdoses with high serum levels no clinical signs of intoxication were observed in our case. So venlafaxine overdose not necessarily leads to life-threatening signs of intoxication.

Development and Optimization of Venlafaxine Hydrochloride Sustained Release Triple Layer Tablets Adopting Quality by Design Approach

Purpose:Venlafaxine hydrochloride sustained release formulation increases patient compliance by reducing frequency of administration and it also reduces side effects like nausea and vomiting. Hence the objective of present investigation was to develop triple layer sustained release tablets of venlafaxine HCl using xanthan gum or polyethylene oxide. Methods:The venlafaxine HCl 150 mg sustained release tablets were prepared by wet granulation technique where drug was incorporated in middle layer with part of polymer. The barrier layers were composed of remaining polymer and other excipients. The granules and tablets were characterised. Optimized batches were also tested for drug release at different pH and in presence of ethanol, for kinetics of drug release and for water uptake/swelling. Results: Preliminary trials of monolayer tablet showed burst release due to high dose and solubility of venlafaxine HCl and hence triple layer tablets were developed. Granules of middle layer exhibited good flow properties. The comparative drug release to Effexor? XR capsule 150 mg could be achieved by modulating the concentration of polymer and diluents in middle layer as well as in barrier layers. Higher amount of polyethylene oxide was required as compared to xanthan gum which may be due to high water uptake and poor gel strength of polyethylene oxide. The optimized formulations showed pH independent drug release as well as ethanol had no effect on drug release. Effexor? XR capsule and optimized batches followed Weibull kinetics for drug release. The radar diagrams showed the comparable drug release to innovator in both the optimized formulations but point to point correlation was observed in batch with xanthan gum. Conclusion: The layered matrix tablets formulated successfully using hydrophilic polymers, xanthan gum or polyethylene oxide, to sustain the release of highly soluble drug like venlafaxine HCl.

Aqueous Diels-Alder Reactions of Cyclopentadicnc with Symmetric Diester of Fumarate or Maleate

Symmetric, diesters of cis- or trans- bicyclo[2,2,1]hept-5-ene-2,3-dicarboxylate were prepared by aqueous Diels-Alder reaction of cyclopentadiene with symmetric diester of fumarate or maleate.

Validation of a Capillary Electrophoresis Method for Analyzing Chlorphenamine Maleate-Based Drugs Using the Accuracy Profile Approach

This study aimed at validating an analytical method, using the accuracy profile approach, for the assay of chlorphenamine maleate by capillary electrophoresis. The validation was done using concentrations ranging between 75% and 125% of the target concentration of 600 mg/ml. Validation standards were prepared separately in triplicate for each series. Studied validation criteria were selectivity, linearity, trueness, precision (repeatability and intermediate precision), accuracy and limits of detection and quantification. The method was selective, with recoveries ranging between 99.55% and 99.84%. The relative standard deviations of repeatability and intermediate precision were <5%. The accuracy profile confirmed the performance of the assay method between 75% and 100% of the target concentration of 600 mg/ml. The detection and quantification limits were 5 mg/l and 15 mg/l respectively. This ecological and economical method was applied to identify and quantify chlorphenamine maleate in 3 samples of chlorphenamine maleate-based drugs provided by the Senegalese National Medicines Control Laboratory. All analyzed samples were in accordance with official standards.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C

BACKGROUND Entecavir(ETV)is a potent and selective nucleotide analog with significant activity against hepatitis B virus(HBV).ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV(Baraclude)when used in Chinese patients with chronic hepatitis B(CHB)in phase III clinical trials(Clinical Trials.gov number,NCT-01926288)at weeks 48,96,and 144.AIM To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C.METHODS In this double-blind study,we randomly assigned patients to receive 0.5 mg/d ETV(Group A)or ETV maleate(Group B)(ratio,1:1),each with a placebo tablet for 48 wk.Then,all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49.The primary efficacy endpoint was the reduction in HBV DNA levels from baseline.Secondary endpoints included the proportion of patients with undetectable HBV DNA(<20 IU/m L),serologic response,serum alanine aminotransferase(ALT)normalization and development of resistance mutations.RESULTS Two hundred eighteen patients who were hepatitis B e antigen(HBe Ag)positive and 57 who were HBe Ag negative were analyzed and predominantly presented with genotype B(49.82%)or C(48.73%).For the HBe Ag-positive CHB patients,the mean HBV DNA level decrease(6.61 Log10 IU/m L vs 6.69 Log10 IU/m L,P>0.05),viral suppression with HBV DNA<20 IU/m L(83.33%vs 79.17%,P>0.05)and HBe Ag seroconversion(28.77%vs 20.00%,P>0.05)occurred similarly between Groups A and B at week 192.However,there was a significant difference in the proportion of patients with normal ALT levels(91.14%vs 78.38%,P<0.05).For the HBe Ag-negative CHB patients,no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline(6.05 Log10 IU/m L vs 6.03 Log10 IU/m L,P>0.05),percentages of patients who achieved undetectable HBV DNA(100%vs 100%,P>0.05)and rates of ALT normalization(95.65%vs 100.00%,P>0.05).Safety and adverse event profiles were similar between Groups A and B.Two HBe Ag-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV.CONCLUSION Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

Square Wave Voltammetric Behavior of N,N-DiethyI-P-Nitroso Aniline an Indirect Method for Determination of Chlorpheniramin Maleate, Application of Pharmaceutical Formulations

The electrochemical behavior of N,N-diethyl-p-nitroso aniline was carried out using SWV （square wave voltammetric） at HMDE. A well defined reduction peak was observed at （-0.214） volt versus the reference electrode （Ag/AgC1/sat. KCI）, calibration curve was constructed in phosphate buffer （pH = 7.0）, the relationship is linear within the concentration range 1.283 × 10.5 M - 3.66 × 10.5 M with the correlation （R = 0.9923）. The serial addition ofCPM （chlorpheniramine maleate） leads to the decrease in the reduction current peak （Ip）, quantitatively, the plot of Alp （Ip - Ip） where, Ip： Peak current of N, N-diethyl-p-nitroso aniline alone, lp： peak current of N,N-diethyl-p-nitroso aniline in the presence of CPM, versus concentration is linear within the concentration range 0.984 × 10-6 M - 9.756 × 10-6 M, the correlation coefficient was 0.9954. The method was successfully applied to determine CPM in different types of pharmaceutical formulations, and compared with standard method from British Pharmacopeia [1].