Clomipramine Research Articles

Electromembrane extraction through a virtually rotating supported liquid membrane.

Electromembrane extraction (EME) of model analytes was carried out using a virtually rotating supported liquid membrane (SLM). The virtual (nonmechanical) rotating of the SLM was achieved using a novel electrode assembly including a central electrode immersed inside the lumen of the SLM and five counter electrodes surrounding the SLM. A particular electronic circuit was designed to distribute the potential among five counter electrodes in a rotating pattern. The effect of the experimental parameters on the recovery of the extraction was investigated for verapamil (VPL), trimipramine (TRP), and clomipramine (CLP) as the model analytes and 2-ethyl hexanol as the SLM solvent. The results showed that the recovery of the extraction is a function of the angular velocity of the virtual rotation. The best results were obtained at an angular velocity of 1.83 RadS(-1) (or a rotation frequency of 0.29 Hz).The optimization of the parameters gave higher recoveries up to 50% greater than those of a conventional EME method. The rotating also allowed the extraction to be carried out at shorter time (15 min) and lower voltage (200 V) with respect to the conventional extraction. The model analytes were successfully extracted from wastewater and human urine samples with recoveries ranging from 38 to 85%. The RSD of the determinations was in the range of 12.6 to 14.8%.

Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives

Chemoreceptor cells aggregating in clusters in the chicken thoracic aorta contain 5-hydroxytryptamine (5-HT) and have voltage-dependent ion channels and nicotinic acetylcholine receptors, which are characteristics typically associated with neurons. The aim of the present study was to investigate the effects of 5-HT uptake inhibitors, fluvoxamine, fluoxetine and clomipramine (CLM), and amphetamine derivatives, p-chloroamphetamine (PCA) and methamphetamine (MET), on endogenous 5-HT outflow from the isolated chick thoracic aorta in vitro. 5-HT was measured by using a HPLC system with electrochemical detection. The amphetamine derivatives and 5-HT uptake inhibitors caused concentration-dependent increases in endogenous 5-HT outflow. PCA was about ten times more effective in eliciting 5-HT outflow than MET. The 5-HT uptake inhibitors examined had similar potency for 5-HT outflow. PCA and CLM increased 5-HT outflow in a temperature-dependent manner. The outflow of 5-HT induced by PCA or 5-HT uptake inhibitors was independent of extracellular Ca2+ concentration. The 5-HT outflow induced by CLM, but not that by PCA, was dependent on the extracellular NaCl concentration. These results suggest that the 5-HT uptake system of 5-HT-containing chemoreceptor cells in the chicken thoracic aorta has characteristics similar to those of 5-HT-containing neurons in the mammalian central nervous system (CNS).

Adsorption and Micellization Behavior of Mixtures of Amphiphilic Drugs with Small Amounts of Bile Salts

AbstractBile acid salts are the most important biological surfactant-like molecules. These compounds play an active role in the cholesterol and lipid solubilization. They are also used as drug carriers. The salts give anionic amphiphilic moiety in aqueous solution and will interact strongly when mixed with cationic amphiphiles. With this aim we have investigated mixed systems of three bile acid salts (sodium cholate (NaC), sodium deoxycholate (NaDC) and sodium taurocholate (NaTC)) with two cationic drugs (adiphenine hydrochloride (ADP) and clomipramine hydrochloride (CLP)) by surface tension measurements. It was found that the two components mix nonideally, i.e., the cmc values of the mixtures decrease with the stoichiometric mole fraction (α1) of bile salts and are lower than cmc* values (cmc at ideal mixing condition). The interaction parameters, βmand βσ, come out to be negative and large in magnitude which is obvious from the fact that the two components are of opposite charge and would experience attractive interactions. The results suggest that the contribution of bile salts in the mixed micelles (X1m) is greater than both the α1and X1id(the contribution in ideal mixing condition). These components also form mixed interface where the contribution of bile salts is more than α1(i.e., X1σ> α1). The minimum area occupied by a monomer decreases with increase in the content of bile salts in the solution. This confirms that the opposite charges on the two components decrease the repulsion among the head groups. All the evaluated thermodynamic parameters (i.e., ΔG0m, ΔGex, ΔG°adsand Gmin) support the above explanations.

Study of phospholipid-induced phase-separation in amphiphilic drugs

Phase separation of five amphiphilic drugs in 10 mM phosphate buffer with added phospholipids has been studied. The drugs used are tricyclic antidepressants (amitriptyline hydrochloride, imipramine hydrochloride, and clomipramine hydrochloride) and phenothiazines (promethazine hydrochloride and promazine hydrochloride). Depending on the nature and structure of studied compounds, the phospholipids caused different effects on the clouding behavior. Cardiolipin decreased the cloud point for all drugs. With amitriptyline, all the additives lowered the cloud points, whereas the clomipramine showed opposite tendency. Imipramine and promethazine led to similar extremal behaviour of cloud point, although promazine, which is structurally similar to promethazine, did not show the same tendency. Thermodynamic analysis of the experimental data suggested that the process of clouding is entropically driven.

The bio-distribution of the antidepressant clomipramine is modulated by chronic stress in mice: effects on behavior.

Major depression (MD) is one of the most common psychiatric disorders, severely affecting the quality of life of millions of people worldwide. Despite the availability of several classes of antidepressants, treatment efficacy is still very variable and many patients do not respond to the treatment. Clomipramine (CMI), a classical and widely used antidepressant, shows widespread interindividual variability of efficacy, while the environmental factors contributing to such variability remain unclear. We investigated whether chronic stress modulates the bio-distribution of CMI, and as a result the behavioral response to CMI treatment in a mouse model of chronic social defeat stress (CSDS). Our results show that stress exposure increased anxiety-like and depressive-like behaviors and altered the stress response. Chronic defeat stress furthermore significantly altered CMI bio-distribution. Interestingly, CMI bio-distribution highly correlated with anxiety-like and depressive-like behaviors only under basal conditions. Taken together, we provide first evidence demonstrating that chronic stress exposure modulates CMI bio-distribution and behavioral responses. This may contribute to CMI’s broad interindividual variability, and is especially relevant in clinical practice.

Highly Sensitive and Validated Spectrophotometric Technique for the Assay of Some Antidepressant Drugs

The present paper describes a simple, rapid, reproducible, and highly sensitive spectrophotometric method for the determination of the tricyclic antidepressant drugs: amitriptyline hydrochloride (AMT), imipramine hydrochloride (IMH), clomipramine hydrochloride (CPH) and desipramine hydrochloride (DPH) in pure and in pharmaceutical preparations. The method is based on the bromination of the above drugs with known excess of bromine. The unreacted bromine is determined based on its ability to bleach the dye methyl red quantitatively at 520 nm. Regression analysis of Beer–Lambert plots showed a good correlation in the concentration range 0.0–2.5, 0–1.4, 0–1.4, and 0–1.0 μg/ml for AMT, IMH, CPH, and DPH, respectively. The molar absorptivity values were found to be 0.65 × 105, 1.41 × 105, 1.93 × 105, and 2.96 × 105l/mol/cm, with the corresponding Sandell’s sensitivity values were 0.0048, 0.0022, 0.0018, and 0.0010 μg/cm2 for AMT, IMH, CPH, and DPH, respectively. The limits of detection (LOD) and quantification (LOQ) are also reported for the developed method. Intra- and inter-day accuracy and precision was established according to the current ICH guidelines. Application of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the proposed method was confirmed by applying the standard addition technique, and the results obtained are in good agreement with those obtained by the official method.

A simple dried blood spot method for therapeutic drug monitoring of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, clomipramine, and their active metabolites using LC-MS/MS

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8min. The assay was linear in the range 20–500µg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and<15% at other concentrations. The initial LLOQ was 20µg/L however for CMP and DMCP it was increased to 40µg/L. The blood volume per spot did not influence the results, but a low hematocrit (≤ 30%) was associated with a>15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method.

Abstract 327: Targeting autophagy overcomes enzalutamide resistance in castrate-resistant prostate cancer cells and improves therapeutic response in a xenograft model

Abstract Androgen deprivation or treatment with the androgen receptor signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or biclutamide induces autophagy in androgen-dependent and castration resistant CaP (CRPC) cell lines. This autophagic process is mediated by AMPK activation and the suppression of mTOR through Raptor phosphorylation (Serine 792). Using autophagy modulators such as clomipramine (CMI) or metformin in combination with ENZA drastically reduces the cell survival in the colony formation assay. Metformin in combination with ENZA causes AR degradation, which is inhibited by proteasome inhibitor MG132. Transcriptome deep sequencing of parental and ENZA resistant C4-2B cells was carried out to examine differential gene expression pattern that may be related to their ability to survive under constant high exposure to ARSI. In-vivo studies with mice orthotopically implanted with ENZA resistant cells demonstrates that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduces tumor growth when compared to control groups (p&amp;lt;0.005). Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in- vitro and in-vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen resistance setting.This work is supported in part by Stand Up To Cancer - Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant. This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Citation Format: Joy C. Yang, Hao G. Nguyen, Hsing-Jien Kung, Xu-Bao Shi, Derya Tilki, Ralph W. deVere White, Allen C. Gao, Christopher P. Evans. Targeting autophagy overcomes enzalutamide resistance in castrate-resistant prostate cancer cells and improves therapeutic response in a xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 327. doi:10.1158/1538-7445.AM2014-327

Effect of clomipramine combine sleep deprivation on depression rat behavior and hippocampal CA3 neuron apoptosis

Objective To analyze the effect of clomipramine combine sleep deprivation on depression rat behavior and hippocampal CA3 neuron apoptosis. Methods Chronic unpredictable mild stimulation was used to establish 40 depression model rats. They were randomly divided into depression group, clomipramine group (5 mg/kg orally), sleep deprivation group (36 h continuous full sleep deprivation), chlorpromazine combination of sleep deprivation group, and then selected 10 rats as control group. Open-field test and water maze test were used to test rats' behavioral change after 28 days intervention. RT-PCR, Western blot were used to detect the GDNF and Bcl-2 expression of hippocampal CA3 neurons. TUNEL assay was performed to test hippocampal CA3 neuron apoptosis ratios in each group. Results Open-field test level score, vertical score and latency of combination group were (75.6±7.3), (26.4±4.3), (1.1±0.2), and showed no significant difference with those of control group((79.4±6.8), (28.6±5.7), (1.0±0.4)) after 28 d intervention (P>0.05), while the level score, vertical score were significantly higher than those in other three groups(P 0.05). Sleep deprivation group' apoptotic rate was the highest (55±6)%, significantly higher than the control group and the combination group ((14±3)% and (19±4)%). Conclusion Clomipramine combined sleep deprivation can improve the ability of rat model of depression and suppression of acts of hippocampal CA3 neuron apoptosis, and its effect may be related to increased hippocampal CA3 GDNF, Bcl-2 level. Key words: Clomipramine; Sleep deprivation; Depression; Hippocampus

AB53. Efficacy and safety of nasal spray containing clomipramine hydrochloride in treatment of men with premature ejaculation

ObjectiveThe aim of the study is to evaluate the efficacy and safety of nasal spray, containing Clomipramine hydrochloride (Clom spray) in the treatment of men with premature ejaculation (PE).Material and MethodsAfter the approval of the National Ethics Committee, from 2011 to 2013, in Republican Specialized Center of Urology examined and treated 54 patients with premature ejaculation, who were appointed Clomipramine hydrochloride 5mg as a nasal spray in both nostrils for 1 hour before sexual intercourse (on demand) for 8-weeks (group A). The second group consisted of 22 patients with placebo (distilled water nasal spray in both nostrils for 1 hour before sexual intercourse for 8-weeks)—group B. All patients were included in the study according to the strict inclusion and exclusion criteria. The prototype of our study was the research of Wei Lu et al. “Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride” (2007y). The primary endpoint was score of China Index of Premature Ejaculation (CIPE) and the measurement of intravaginal ejaculation latency time (IELT), secondary endpoints include mean intercourse satisfaction domain and adverse drug effects.ResultsInitial values CIPE in the group A made 28.9+3.6 points, in group B, 30.1+4.1 points. Initial values IELT in the group A made 28.3+2.3sec, in group B, 30.8+1.9sec. The final values CIPE in group A made 40.3+8.1 (+39.4%) points (P<0.01), while in group B, 32.4+6.1 (+2.2%). The final values IELT in group A made 82.6+4.2 (291.9%) sec, and group B-43.6 (+41.5%) seconds. The greatest changes of studied parameters (CIPE and IELT) achieved among patients receiving Clomipramine hydrochloride 5 mg as a nasal spray in both nostrils for 1 hour before sexual intercourse (on demand) during 8-weeks (group A). As for indicators of group B (placebo), some changes also took place in this group, but they are not on a reliable basis.We also compared the results of IELT and CIPE of groups with each together. Moreover, all indicators of group A were statistically higher than the rates in group B (P<0.01). It should be noted that tolerability was good. No serious side effects, that would require the withdrawal of the drug were not observed. Two patients from group A (3.7%) had nasal congestion that did not require the use of other drugs to resolve it.ConclusionsThis study showed that Clom spray was more efficacious than placebo and well tolerated. Adverse reactions were mild and self-limited. Further studies with different groups of patients are necessary to draw final conclusions on the efficacy and role of Clom spray in the treatment of PE.

The Effects of Suanzaoren decoction on hippocampus, cortex BDNF and TrKB geneexpression in depression rats

Objective To investigate the effect of Suanzaoren Decoction on hippocampus, cortex BDNF and TrKB gene expression in depression model rats. Methods Depression rat models were established by social-isolated raise and chronic stress stimulation. Suanzaoren decoction was administrated to the models. RT-PCR was adopted to detect the expression of mRNA BDNF and TrKB genes. Results The mRNA expression of BDNF and TrKB in cortex of Suanzaoren decoction high dose group、medium dose group and clomipramine group（0.213±0.094, 0.639±0.023, 1.032±0.015, 1.089±0.014, 1.580±0.012, 1.860±0.019）were all higher than the model group（0.032±0.008, 0.001±0.000）, showing a significant difference among four groups （P〈0.01）, and the mRNA expression of BDNF and TrKB in hippocampus of Suanzaoren decoction high dose group, medium dose group and clomipramine group（0.213±0.094, 0.639±0.023, 1.032±0.015, 1.089±0.014, 1.580± 0.012, 1.860±0.019）were higher than the model group （0.021±0.015, 0.125±0.013）, there was a significant difference between four groups（P〈0.01）. Compared with the model group, the mRNA expression of low-dose group of Suanzaoren decoction in both cortex and hippocampus of BDNF and TrKB was not significantly different to the model group（P>0.05）. Conclusion Suanzaoren decoction can increase the expression of BDNF and TrKB gene, promote neuronal proliferation, and resist depression. Key words: Depression; Suanzaoren Decoction; BDNF; TrKB

Long-term effects of sertraline on clinical symptoms, executive and occupational functions of patients with obsessive-compulsive disorder

Objective To explore the long-term effects of sertraline on clinical symptoms, executive and occupational functions of patients with obsessive-compulsive disorder. Methods By randomly grouped, 48 cases with obsessive-compulsive disorder were treated with sertraline as the study group and 44 cases treated with clomipramine as the control one. They were maintained with relative stable drug dosage after ill-condition improving, and all the subjects were also treated with psychological treatment and rehabilitation activities. The incidences of obsessive-compulsive symptoms before and after 2, 4, 6 and 8 weeks of treatment were investigated and compared. Yale-Brown obsessive-compulsive scale(Y-BOCS) were used to evaluate the efficacy according to the Y-BOCS reducing rate. The trail making test A and B(TMT-A and TMT-B), Stroop test and the Social Disability Screening Schedule (SDSS) were used at 8th weekend and 2 year's follow-up to evaluate and compare the two groups’ executive and occupational functions. Results The incidences of 4 weeks’ obsessive symptoms (62.5%)and 6 weeks’ compulsive symptoms(18.8%) showed significantly lower in the study group than those in the control one (81.8% and 38.6%, P 0.05). The clinical efficacy also showed no statistical difference between the two groups(P>0.05). After two years’ treatment, the times of TMT-B((46.4±6.4)s) and Stroop-CW((132.2±14.9)s) of the study group showed significantly shorter than those of the control ((49.3±6.5)s, (138.8±15.7)s, P<0.05), and the total score and occupational function score of SDSS were significantly lower (P<0.01) but the employment rates (72.9%)higher in the study group than those in the control (47.7%, P<0.05). The total side-effect rate of the study group (12.5%) showed significantly lower than that of the control (43.2%, P<0.05). Conclusion Sertraline is as effective as clomipramine for treatment clinical symptoms of obsessive-compulsive disorder. But it shows better long-term efficacy in improving executive and occupational social functions. Key words: Obsessive-compulsive disorder; Sertraline; Executive function; Social function

Study on the interaction between amphiphilic drug and bovine serum albumin: A thermodynamic and spectroscopic description

Herein we report the interaction of amphiphilic drug clomipramine hydrochloride (CLP—a tricyclic antidepressant) with bovine serum albumin (BSA) studied by fluorescence, UV–vis, and circular dichroism (CD) spectroscopic techniques. Clomipramine hydrochloride is used to treat a variety of mental health problems. The quenching rate constant (kq) values, calculated according to the fluorescence data, decrease with increase in temperature indicating the static quenching procedure for the CLP–BSA interaction. The association binding constants (KA), evaluated at different conditions, and the thermodynamic parameters (free energy, enthalpy and entropy changes) indicate that the hydrophobic forces play a major role in the binding interaction of drug. The interaction of BSA with CLP was further confirmed by UV absorption spectra. Blue shift of position was detected due to the complex formation between the BSA–CLP. The molecular distance, r0, between donor (BSA) and acceptor (CLP) was estimated by fluorescence resonance energy transfer (FRET) whose value (4.47nm) suggests high probability of static quenching interaction. The CD results prove the conformational changes in the BSA on binding with the drug. Thus, the results supply qualitative and quantitative understanding of the binding of BSA to CLP, which is important in understanding their effect as therapeutic agents.

Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model

Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen-resistance setting.

Physicochemical Studies of Aqueous Amphiphilic Drug + Hydrotrope Solutions

Abstract The micellization and interfacial behaviours of two amphiphilic drugs (adephinine and clomipramine hydrochlorides) in the presence of hydrotropes (sodium salicylate and sodium benzoate) have been investigated by surface tension measurements. Micellar and interfacial compositions at different stoichiometeric mole fractions of the hydrotropes have been evaluated using Rubingh's and Rosen's models. Synergism was found in mixed micelles as well as in mixed monolayers. Thermodynamic parameters (ΔG mic o , ΔG ex, G min , ΔG ads o ) indicate that mixed systems are more stable than the individual systems with CLP-hydrotrope &gt; ADP-hydrotrope systems.

ANTIDEPRESSANT DRUGS: HIGHLY SENSITIVE AND VALIDATED SPECTROPHOTOMETRIC TECHNIQUE

A simple, rapid, selective and highly sensitive spectrophotometric method is described for the quantitative determination of the tricyclic antidepressant drugs, desipramine hydrochloride (DPH), clomipramine hydrochloride (CPH) and imipramine hydrochloride (IMH) in pure and in pharmaceutical preparations. The proposed method is based on the bromination of above drugs with known excess of bromine. The unreacted bromine is determined based on its ability to bleach the dye Eiochrome blue black R quantitatively at 530 nm for all the three drugs obeying Beer’s law in the range, 0.0 – 8, 0.0 – 10 and 0.0 – 9.0 µg ml-1 for DPH, CPH and IMH, respectively. The molar absorptivity values were found to be 1.61 × 104, 1.62 × 104 and1.57 × 104 l mol-1cm-1, respectively with the corresponding Sandell’s sensitivity values 0.0187, 0.0216 and 0.0202 µg cm-2. The limits of detection and (LOD) and quantification (LOQ) are also reported for the developed method. Intra- and inter-day precision and accuracy of the method were established according to the current ICH guidelines. Applications of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the procedure was confirmed by applying the standard addition technique and the results were evaluated in terms of Student’s t-test and variance ratio F-test to find out the significance of proposed method over the reference method.

EPA-1745 – Plasma clomipramine levels in adult obsessive-compulsive disorder patients

The aim of this study was to explore the possible relationship between plasma clomipramine (CMI) and its major metabolite (DMCMI) levels and related parameters, and clinical features in OCD patients. Twenty-six OCD outpatients (13 men, 13 women), suffering from OCD were consecutively enrolled in the study. The severity of OCD was assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The measurements were carried out after four weeks and six months from the beginning of the treatment. The drug levels were measured by a HPLC method developed by us. The correlations between biological and clinical parameters were analyzed by means of the Spearman's correlation coefficient. The Mann-Whitney test was used for comparing biological and clinical variables between men and women. The results showed that CMI levels were related to the doses at the two assessment times. A significant and positive correlation was detected at the beginning between the DMCMI/ratio and the Y-BOCS total score, however this was true only for men, where the similar correlations were measured also with the Y-BOCS subscale. After six months of CMI, men showed a significant improvement of the compulsions. These findings would highlight the potential impact of assessing CMI plasma levels and their relationships with specific symptoms, as well as the influence of the gender on the drug response.

Secondary metabolismin in Annonaceae: potencial source of drugs

Several species of Annona (Annonaceae) are used in traditional Mexican medicine by their anti-anxiety, anticonvulsant and tranquilizing properties. It has been reported that the alkaloids isolated from some species of the Annona have affinity to serotonergic 5-HT1A receptors and modulate dopaminergic transmission, which is involved in depressive disorders. In this review it is showed the results of the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice. The antidepressant-like effect was evaluated in the forced swimming test. To elucidate a possible mechanism of action, experiments of synergism with antidepressant drugs, such as imipramine (IMI), clomipramine (CLIMI), and fluoxetine (FLX), were carried out. The neurotransmitter content (DA: dopamine, 5HT: serotonin and its metabolites, HVA: homovanillic acid and 5HIAA:5-hydroxyindoleacetic) in the whole brain of mice were also determined by HPLC method. The results showed that repeated treatment with TA produced antidepressant-like effects in mice. This effect was not related to an increase in locomotor activity. Administration of TA facilitated the antidepressant effect of IMI and CLIMI as well as increased the turnover of DA and 5-HT. The alkaloids: 1,2-dimethoxy-5, 6.6 to 7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine were the main constituents of TA.

Field-amplified sample injection coupled with pseudo-isotachophoresis technique for sensitive determination of selected psychiatric drugs in human urine samples after dispersive liquid–liquid microextraction

A field-amplified sample injection (FASI) technique was elaborated for fast and sensitive determination of selected central nervous system drugs in human urine samples. Factors affecting the sensitivity enhancement, such as background electrolyte (BGE) and the analytical matrix composition were optimized and discussed. Pseudo-isotachophoresis (p-ITP) mechanism contribution in preconcentration mechanism was discussed. All separations were performed in uncoated fused silica capillaries 50μm×57cm at 22kV. The optimized analytical matrix was composed of 0.25mM HCOOH in 90% (v/v) methanol, while BGE contained 45mM TRIS/HCl (pH 2.20). The head-column injection was performed in 0.25mM HCOOH water solution (3s, 3.45kPa). Sample was introduced into the capillary by electrokinetic injection (70s, 5kV) followed by short BGE plug (3s, 3.45kPa). Seven psychiatric drugs (olanzapine, prochlorperazine dimaleate, trifluoperazine dihydrochloride, perphenazine, promazine hydrochloride, clomipramine hydrochloride, and chlorprothixene hydrochloride) were separated in about 6min. The elaborated method was additionally supported with dispersive liquid–liquid microextraction (DLLME) technique which in summary with FASI provided about 8000–13,000-fold sensitivity enhancement in comparison to the capillary zone electrophoresis (CZE) method with standard hydrodynamic injection (5s, 3.45kPa).

Clinical effect of venlafaxine combined with methylphenidate hydrochloride on narcolepsy

This study aims to explore the clinical effect of venlafaxine sustained-release capsules combined with methylphenidate hydrochloride tablets on narcolepsy. Thirty-eight cases of narcoleptic patients were randomly divided into venlafaxine combined with methylphenidate hydrochloride treatment group (observation group, N = 19) and methylphenidate hydrochloride and clomipramine treatment group (control group, N = 19). After a total of 12-week treatment, clinical curative effect and adverse drug reactions were observed in 2 groups of patients. The results showed that effective rate of the treatment for excessive daytime sleepiness (EDS) in observation group was higher than that of the control group (15/19 vs 8/19, P = 0.044), and effective rate of the treatment for cataplexy in observation group was higher than that of the control group (13/19 vs 6/19, P = 0.048). The rate of adverse drug reactions in observation group was lower than that in the control group (χ2 = 8.889, P = 0.003). It was indicated that venlafaxine combined with methylphenidate had good curative effect on narcolepsy with EDS and cataplexy symptoms. doi：10.3969/j.issn.1672-6731.2013.11.010