As a well-known extraction procedure, electromembrane extraction (EME) was combined with electro-assisted liquid-liquid microextraction (EA-LLME) in the present work, which resulted in a promising method. This hyphenated sample preparation method, named EME-EA-LLME, was followed by GC for the determination of two model analytes (clomipramine and imipramine). The effective parameters of both EME and EA-LLME (such as organic solvent, pH of acceptor and sample solutions, voltage and extraction time) were optimized. The proposed EME-EA-LLME procedure demonstrated good linearity with coefficients of determination, R2 ≥ 0.998 over the concentration range of 0.5-750 ng/mL. Limit of detection for both analytes was 0.15 ng/mL. The corresponding repeatability ranged from 6.9 to 12.2% (n = 3). The high enrichment factors were obtained as 770.3 and 561.4 for imipramine and clomipramine, respectively. The advantages of this tandem sample preparation method were low detection limits, simplicity, low cost, and short analysis time (<10 min). Finally, the optimized method was used to extract and determine the analytes in urine and wastewater samples. Overall, the results revealed that the developed EME-EA-LLME procedure had better extraction efficiency in comparison with EME and EA-LLME alone.

We investigated the effect of the tricyclic antidepressant clomipramine on voltage-dependent K+ (Kv) channels in native rabbit coronary arterial smooth muscle cells. Our results showed that clomipramine inhibited vascular Kv channels in a concentration-dependent manner, with an IC50 value of 8.61 ± 4.86 μM and a Hill coefficient (n) of 0.58 ± 0.07. The application of 10 μM clomipramine did not affect the activation curves of the Kv channels; however, the inactivation curves of the Kv channels were shifted toward a more negative potential. The clomipramine-induced inhibition of Kv currents was not changed by the application of train pulses (1 or 2 Hz), which demonstrated that clomipramine inhibited Kv current in a state (use)-independent manner. Pretreatment with the Kv1.5 and Kv2.1 inhibitors, DPO-1 and guangxitoxin, respectively, partially reduced the clomipramine-induced inhibition of Kv currents. Therefore, we concluded that clomipramine inhibited vascular Kv channels in a concentration-dependent, but state (use)-independent manner, regardless of its own function.

Anxiety is the most prevalent mental disorder among adults in the United States and females tend to have significantly higher rates of anxiety compared with men. Common treatments for anxiety include usage of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, however, sex differences in the efficacy of these drugs exist. In this study, we were interested in determining if acutely manipulating serotonin mechanisms at the whole-animal level affects cellular metabolism and oxidative stress in primary fibroblast cells from clomipramine-treated Sprague-Dawley rats. Our groups included a female and male control group that was injected with a saline solution, a female and male group that was injected with a low dosage of clomipramine, and a female and male group of rats that were injected with a high dosage of clomipramine. We then compared cellular oxygen consumption rates, rates of glycolysis and oxidative stress parameters in primary fibroblasts grown from each of the groups described above. We found that clomipramine-treated rats had significantly lower rates of glycolysis and glycolytic capacity, regardless of sex. Coupling efficiency was significantly higher in male rats compared with female rats across treatment groups. Our data suggest that in female rats reduced glutathione (GSH) is nonsignificantly reduced, yet lipid peroxidation (LPO) damage still accumulates, meaning that enzymatic antioxidants may be acting to reduce any continual increases in LPO damage. This is a metabolically costly process that may be happening because of our drug treatments. Our results provide further evidence of sex differences in the behavioral and metabolic responses to short-term clomipramine treatment. Continued investigation into these sex differences may reveal their potential for improving our understanding of how different therapeutic interventions may be better suited for treating males and females.

A large number of Food and Drug Administration (FDA)-approved drugs have been found to inhibit the cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacological targets, their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA-approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that antidepressants imipramine and clomipramine and antipsychotic drug thioridazine also directly interact with EBOV GP and determine the mode of interaction by crystallographic analysis of the complexes. The compounds bind within the same pocket as observed for other, chemically divergent complexes but with different binding modes. These details should be of value for the development of potent EBOV inhibitors.

Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.

A large number of antidepressant drugs are available across the world. All have been compared against placebo, and many have been compared with some but not all other antidepressants. There is therefore little information about a hierarchy of the efficacy and acceptability of these drugs. About 9 years ago, a network meta-analysis attempted to rank the efficacy and acceptability of 12 newer antidepressant drugs in adults with major depressive disorder. Very recently, this network meta-analysis was updated to include 21 antidepressant drugs, most of which were introduced during the 1980s and afterward. The present article explains what meta-analysis and network meta-analysis do, summarizes the important findings of the 21-antidepressant network meta-analysis, and offers comments on the findings. In general, it appears that antidepressant drugs are associated with clinically significant superiority over placebo with regard to response and remission rates; that almost all antidepressants do not differ from placebo with regard to all-cause discontinuation; that escitalopram, mirtazapine, amitriptyline, venlafaxine, and paroxetine are associated with better response rates than certain other antidepressants; that reboxetine, trazodone, and fluoxetine are associated with poorer response rates than certain other antidepressants; that agomelatine, escitalopram, and vortioxetine are associated with lower all-cause discontinuation than certain other antidepressants; and that clomipramine, reboxetine, and duloxetine are associated with higher all-cause discontinuation than certain other antidepressants. Whereas this conclusion is necessarily subjective, escitalopram could be a first choice in the balance of efficacy and acceptability, and reboxetine, the last choice. The strengths and limitations of the network meta-analysis are examined, and some comments on the findings are offered.

Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) observed in laboratory animals is proposed as a model of TTM. The neurobiological basis of TTM is unclear, but involves striatal hyperactivity and hypoactivation of the prefrontal cortex.