Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.

Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p < 0.01). For these drugs, significantly more women were found in patients using maprotiline, lamotrigine (not carbamazepine) and in the groups of antidepressants, tricyclics and anticonvulsants (p < 0.01). Women were more vulnerable to CADRs (67% in cases and 56% in non-cases, p < 0.01). The significantly higher rate of CADRs in women was mainly observed under age of 50 years, i.e. during female reproductive years. In a multivariate logistic regression, female sex, the diagnostic group ICD F1 (substance abuse), maprotiline, carbamazepine, lamotrigine and clomethiazole were identified as risk factors of CADRs. The case/non-case approach allowed to identify risk factors based on empirical data rather than experts' evaluations. The new findings of substance abuse and clomethiazole as risk factors for CADRs have to be confirmed in further studies. Since CADRs can be life-threatening, it is important to be aware of risk factors, especially women during their reproductive period and with lamotrigine treatment.

Depressive disorders are often associated with cognitive biases. In this study, we investigated, in an animal model, whether cognitive judgement bias, measured as a stable and enduring behavioural trait, could modulate the effects of antidepressant drugs on other cognitive processes associated with depression. For this purpose, we identified rats displaying 'pessimistic' and 'optimistic' traits in a series of ambiguous-cue interpretation (ACI) tests. Subsequently, in the preclinical version of the probabilistic reversal-learning (PRL) test, allowing multiple reversals within a test session, we compared the effects of acute administration of 5 different antidepressant (AD) drugs (agomelatine, escitalopram, clomipramine, mirtazapine and venlafaxine) on cognitive flexibility and sensitivity to positive/negative feedback in optimistic and pessimistic animals. We report that, following acute treatment with agomelatine, the proportion of lose-shift behaviours in the PRL test was significantly reduced in pessimistic animals compared to optimists. We also demonstrate that acute treatment with another antidepressant drug, mirtazapine, significantly increased the sensitivity of rats to positive feedback, as indexed by the increased proportion of win-stay behaviour following probabilistic reward. This effect was independent of cognitive bias and was associated with a reduced number of reversals made by the animals. Three other tested drugs had no significant effects on behavioural measures assessed in our study.

Hatching is an important phase of the development of pulmonate gastropods followed by the adult-like extracapsular foraging life. Right before hatching the juveniles start to display a rhythmic radula movement, executed by the buccal complex, consisting of the buccal musculature (mass) and a pair of the buccal ganglia. In order to have a detailed insight into this process, we investigated the serotonergic regulation of the buccal (feeding) rhythm in 100% stage embryos of the pond snail, Lymnaea stagnalis, applying quantitative immunohistochemistry combined with the pharmacological manipulation of the serotonin (5-HT) synthesis, by either stimulating (by the 5-HT precursor 5-hydroxytryptophan, 5-HTP) or inhibiting (by the 5-HT synthesis blocker para-chlorophenylalanine, pCPA) it. Corresponding to the direction of the drug effect, significant changes of the fluorescence intensity could be detected both in the cerebral ganglia and the buccal complex. HPLC-MS assay demonstrated that 5-HTP increased meanwhile pCPA decreased the 5-HT content both of the central ganglia and the buccal complex. As to the feeding activity, 5-HTP induced only a slight (20%) increase, whereas the pCPA resulted in a 20% decrease of the radula protrusion frequency. Inhibition of 5-HT re-uptake by clomipramine reduced the frequency by 75%. The results prove the role of both central and peripheral 5-HTergic processes in the regulation of feeding activity. Application of specific receptor agonists and antagonists revealed that activation of a 5-HT1-like receptor depressed the feeding activity, meanwhile activation of a 5-HT6,7-like receptor enhanced it. Saturation binding plot of [3H]-5-HT to receptor and binding experiments performed on membrane pellets prepared from the buccal mass indicated the presence of a 5-HT6-like receptor positively coupled to cAMP. The results suggest that 5-HT influences the buccal (feeding) rhythmic activity in two ways: an inhibitory action is probably exerted via 5-HT1-like receptors, while an excitatory action is realized through 5-HT6,7-like receptors.

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.

Various drugs are available for lifelong and acquired premature ejaculation (PE), but only dapoxetine and FortacinTM have been officially registered. On the other hand, all sorts of pharmacologically not-investigated over-the-counter-products (OTCs) are used by men with complaints of PE with normal ejaculation time durations (subjective PE). There is a need to critically review the current state of registered and nonregistered drugs for PE. Areas covered: In this review, the authors use the guideline of the International Society for Sexual Medicine (ISSM) for the treatment of PE and provide evidence-based recommendations for the pharmacotherapy of lifelong and acquired PE. This should always be accompanied by psychoeducation, counseling, and information about common and rare side effects of the various available drugs. Expert opinion: As long as subjective PE is not officially recognized as the third PE subtype, registration authorities will continue to demand drugs for subjective PE to be studied in men with lifelong PE. This is unfortunate as the method and design of studies of drugs for subjective PE differ from those of lifelong PE but also because drugs for subjective PE need to be investigated in men with subjective PE and not in men with lifelong PE.