- Uptake and metabolism of the antidepressants sertraline, clomipramine and trazodone in a garden cress (Lepidium sativum) model. [Journal Article]
- EElectrophoresis 2018 Feb 10
- Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts o...
Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts on non-target organisms including plants. Due to these facts investigations of the uptake and metabolism of pharmaceuticals in organisms is an emerging research area. The present study demonstrates the analysis of three selected antidepressants (sertraline, clomipramine and trazodone) as well as metabolites and transformation products in a cress model (Lepidium sativum). Cress was treated with tap water containing 10 mg L-1of the parent drugs. Employing an analytical approach based on HPLC coupled with quadrupole-time-of-flight or Orbitrap mass spectrometry in MS and MS² mode, in total 14 substances were identified in the cress extracts. All three parent drugs were taken up by the cress and translocated from the roots to the leaves in specific patterns. In addition to this, eleven metabolite species were identified. They were generated by hydroxylation, demethylation, conjugation with amino acids or combinations of these mechanisms. Finally, the inclusion of control cultures in the experimental setup allowed for a differentiation of "true" metabolites generated by the cress and transformation products generated by plant-independent mechanisms. This article is protected by copyright. All rights reserved.
- Early postnatal treatment with clomipramine induces female sexual behavior and estrous cycle impairment. [Journal Article]
- PBPharmacol Biochem Behav 2018 Jan 31; 166:27-34
- Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation ...
Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems.
- Joint effects of nine antidepressants on Raphidocelis subcapitata and Skeletonema marinoi: A matter of amine functional groups. [Journal Article]
- ATAquat Toxicol 2018; 196:117-123
- Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target or...
Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target organisms justify the growing concern of both the public and regulatory authorities. These emerging pollutants do not occur as isolated compounds but rather as multi-component mixtures, which may lead to increased adverse effects compared to individual compounds. Freshwater and marine algae seem particularly sensitive to pharmaceuticals, including antidepressants. Studies assessing the toxicity of antidepressant mixture to algae focused mainly on binary mixtures of selective serotonin reuptake inhibitors. In the present experiment, the freshwater algae Raphidocelis subcapitata (formerly known as Pseudokirchneriella subcapitata) and the marine diatom Skeletonema marinoi were exposed to equitoxic mixtures of 9 antidepressants (fluvoxamine, fluoxetine, sertraline, duloxetine, venlafaxine, clomipramine, amitriptyline, and citalopram) at different concentrations. The growth inhibition was measured. Results showed that the toxicity of this mixture was higher than the effects of each individual component, highlighting simple additivity or synergistic effects, whereas tested concentrations were below the 10% inhibition concentration (IC10) of each compound. Moreover, the QSAR analysis highlighted that antidepressants would act through narcosis (non-specific mode of action) towards the two species of algae. However, more specific effects can be observed by differentiating compounds with a primary/secondary amine from those with a tertiary amine. These mixture effects on algal species have to be assessed, especially since any impacts on phytoplankton could ultimately impact higher trophic levels (less food, secondary poisoning).
- Fast and easy extraction of antidepressants from whole blood using ionic liquids as extraction solvent. [Journal Article]
- TTalanta 2018 Apr 01; 180:292-299
- This study aims to prove that ionic liquids (ILs) can be used as extraction solvents in a liquid-liquid microextraction, coupled to LC-MS/MS, for the quantification of a large group of antidepressant...
This study aims to prove that ionic liquids (ILs) can be used as extraction solvents in a liquid-liquid microextraction, coupled to LC-MS/MS, for the quantification of a large group of antidepressants in whole blood samples. The sample preparation procedure consisted of adding 1.0mL aqueous buffer pH 3.0 and 60µL of IL (1-butyl-3-methylimidazolium hexafluorophosphate) to 1.0mL whole blood. Subsequently, a 5-min rotary mixing step was performed followed by centrifugation. The lower IL phase was collected, diluted 1:10 in methanol and 10µL was injected into the LC-MS/MS. The following analytes were included in the full-quantitative method: agomelatine, amitriptyline, bupropion, clomipramine, dosulepin, doxepin, duloxetine, escitalopram, fluoxetine, imipramine, maprotiline, mianserin, mirtazapine, nortriptyline, paroxetine, reboxetine, trazodone and venlafaxine. Selectivity was checked for 10 different whole blood matrices. Additionally, possible interferences of deuterated standards or other antidepressants were evaluated. Overall, no interferences were found. For each analyte a matrix-matched calibration curve was constructed (7 levels, n = 6), covering therapeutic and low toxic concentrations. Accuracy and precision were evaluated over eight days, at three concentration levels (n = 2). Bias, repeatability and intermediate precision results met with the proposed validation criteria, except for fluvoxamine, which was therefore only included in the semi-quantitative method. LOQs were set at the lowest calibrator concentration and LOD values were - for most analytes - within a range of 1-2ng/mL. Recoveries (RE) and matrix effects (ME) were evaluated for five types of donor whole blood, at two concentration levels. RE values were within a range of 53.11-132.98%. ME values were within a range of 61.92-123.24%. In conclusion, this study proves the applicability of ILs as extraction solvents for a large group of antidepressants in complex whole blood matrices.
- A systematic review of evidence-based treatment strategies for obsessive-compulsive disorder resistant to first-line pharmacotherapy. [Journal Article]
- CMCurr Med Chem 2017 Dec 22
- CONCLUSIONS: Treatment-resistant OCD remains a significant challenge to psychiatrists. To date, the most effective strategy is the addition of antipsychotics (aripiprazole and risperidone) to SRIs; another effective strategy is CBT addition to medications. Other strategies, such as the switch to another first-line treatment or the switch to intravenous administration are promising but need further confirmation in double-blind studies. The addition of medications other than antipsychotics remains to be studied, as several negative studies exist and positive ones need confirmation (only 1 positive study).
- Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. [Journal Article]
- NCNat Commun 2017 Dec 19; 8(1):1990
- The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress...
The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood-brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.
- Psychotropics and Male Reproduction. [Journal Article]
- AEAdv Exp Med Biol 2017; 1034:63-101
- Psychotropic drugs, including antidepressants, antipsychotics, and anticonvulsants, all have negative effects on sexual function and semen quality. These adverse events vary among men and are less pr...
Psychotropic drugs, including antidepressants, antipsychotics, and anticonvulsants, all have negative effects on sexual function and semen quality. These adverse events vary among men and are less pronounced for some medications, allowing their effects to be managed to some extent. Use of specific serotonin reuptake inhibitors (SSRIs) is prevalent in men of reproductive age; and application to treat premature ejaculation increases the number of young men on SSRI therapy. Oxidative damage to sperm can result from prolonged residence in the male reproductive tract. The increase in ejaculatory latency seen with SSRIs likely underlies some of their negative effects on semen quality, including higher sperm DNA fragmentation, seen in all SSRIs evaluated thus far. These medications increase prolactin (PRL) levels in some men, and this is often credited with inhibitory effects on male reproduction; however, testosterone levels are generally normal, reducing the likelihood of direct HPG axis inhibition by PRL. The tricyclic antidepressants have also been shown to increase PRL levels in some studies but not in others. The exception is the tricyclic antidepressant clomipramine, which profoundly increases PRL levels and may depress semen quality. Other antidepressants modulating synaptic levels of serotonin, norepinephrine, and/or dopamine may have toxicity similar to SSRIs, but most have not been evaluated. In limited studies, norepinephrine-dopamine reuptake inhibitors (NDRIs) and serotonin agonist/reuptake inhibitors (SARIs) have had minimal effects on PRL levels and on sexual side effects. Antipsychotic medications increase PRL, decrease testosterone, and increase sexual side effects, including ejaculatory dysfunction. The greatest evidence is for chlorpromazine, haloperidol, reserpine, risperidone, and thioridazine, with less effects seen with aripiprazole and clozapine. Remarkably few studies have looked at antipsychotic effects on semen quality, and this is an important knowledge gap in reproductive pharmacology. Lithium increases PRL and LH levels and decreases testosterone although this is informed by few studies. The anticonvulsants, many used for other indications, generally decrease free or bioavailable testosterone with variable effects on the other reproductive hormones. Valproate, carbamazepine, oxcarbazepine, and levetiracetam decrease semen quality; other anticonvulsants have not been investigated for this adverse reaction. Studies are required evaluating endpoints of pregnancy and offspring health for psychotropic medications.
- Tolerability and adequate therapeutic dosage of oral clomipramine for the treatment of premature ejaculation: A randomized, double-blind, placebo-controlled, fixed-dose, parallel-grouped clinical study. [Journal Article]
- IJInt J Impot Res 2017 Dec 04
- To evaluate the adequate therapeutic dosage of clomipramine 15 mg/day and clomipramine 30 mg/day in male patients with premature ejaculation (PE), this study enrolled men aged 20-65 years who met dia...
To evaluate the adequate therapeutic dosage of clomipramine 15 mg/day and clomipramine 30 mg/day in male patients with premature ejaculation (PE), this study enrolled men aged 20-65 years who met diagnostic criteria for PE including Intravaginal Ejaculation Latency Time (IELT) less than 2 min for at least 75% of their sexual intercourses. Subjects received placebo, clomipramine 15 mg, or clomipramine 30 mg prn (2~6 h before intercourse) for 4 weeks. Efficacy was assessed using fold change, percentile change, and mean change of IELT, as well as Drug Coitus Interval Time (DCIT). A total of 101 patients were randomized into the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group. Analyses of fold changes of IELT in each group revealed that the IELT of both the clomipramine 15 mg group and clomipramine 30 mg group was significantly increased 4 weeks after administration than the placebo group. Adverse events were reported by 11.76, 32.35, and 57.57% of patients in the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group, respectively. Most common adverse events in the clomipramine treatment groups were gastrointestinal disorders and psychiatric disorders of mild to moderate severity. On-demand regimen of clomipramine 15 mg resulted in a significant improvement in IELT and was superior to a regimen of clomipramine 30 mg in terms of risk-to-benefit ratio.
- Suitability of 1-hexyl-3-methylimidazolium ionic liquids for the analysis of pharmaceutical formulations containing tricyclic antidepressants. [Journal Article]
- JCJ Chromatogr A 2017 Nov 27
- The reversed-phase chromatographic behaviour of six tricyclic antidepressants (amitryptiline, clomipramine, doxepin, imipramine, nortryptiline and maprotiline) was examined in this work with acetonit...
The reversed-phase chromatographic behaviour of six tricyclic antidepressants (amitryptiline, clomipramine, doxepin, imipramine, nortryptiline and maprotiline) was examined in this work with acetonitrile-water mobile phases, in the absence and presence of the ionic liquids 1-hexyl-3-methylimidazolium chloride and 1-hexyl-3-methylimidazolium tetrafluoroborate, which have interesting features for the separation of basic compounds, in terms of peak shape combined with reduced retention. Tricyclic antidepressants are low polarity drugs that strongly associate to the alkyl chains of conventional stationary phases. They are also positively charged in the usual working pH range (2-8) in reversed-phase liquid chromatography, due to their strong basic character. In consequence, they may interact with the residual ionised silanols present in conventional silica-based stationary phases, which is translated in stronger retention, and tailed and broad peaks. A simple chromatographic procedure for the control of tricyclic antidepressants in pharmaceutical formulations was developed using a C8 column and a mobile phase containing 30% acetonitrile/10 mM 1-hexyl-3-methylimidazolium chloride at pH 3, with UV detection. Intra- and inter-day precisions were usually below +1.0%, and intra- and inter-day bias (trueness) ranged between ‒2.1% and +2.4%, and between ‒3.0% and +2.3%, respectively. Sample preparation was simple and only required solubilisation and filtration previous to injection.
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- Molecular network-selected pharmacogenomics in a case of bipolar spectrum disorder. [Journal Article]
- PPharmacogenomics 2017; 18(18):1631-1642
- Personal genomic analysis was used for molecular diagnosis and pharmacogenomics in a 53-year-old female suffering from alternating depressive and dysphoric episodes. A total of 52 genes and 108 SNPs ...
Personal genomic analysis was used for molecular diagnosis and pharmacogenomics in a 53-year-old female suffering from alternating depressive and dysphoric episodes. A total of 52 genes and 108 SNPs were analyzed in the whole genome. Results from the pharmacogenomic analysis were consistent with the pharmacological history and indicate mutations associated with low monoaminergic tone, but also a hyperactive 5HT2A receptor, a feature that associates to a high probability of developing a bipolar condition, especially under 5-hydroxytryptamine potentiating pharmacology. This aligns with the patient developing dysphoria with high clomipramine. The pharmacokinetic genomics pointed out to some absorption, distribution, metabolism, and excretion (ADME) alterations that can lower or nullify drug's activity. A personalized regimen was proposed, with a positive outcome after 1 year.