Towards the design of combination therapy for the treatment of enterovirus infections

We report here on a comparative study of the activity of 10 enterovirus inhibitors against poliovirus 1, enterovirus 71 and human rhinovirus 14. Three of the selected molecules (Pleconaril, BTA-798 and V-073) are in clinical development. The in vitro antiviral activity of pairwise combinations of inhibitors indicated that most combinations resulted in an additive to slightly synergistic antiviral activity. However, the combination of ribavirin with a nucleoside polymerase inhibitor resulted in a pronounced antagonistic effect.     

The Emotional Stroop task: A comparison between schizophrenic subjects and controls

The colour-word Emotional Stroop task (ES task) has been proposed to assess the interferences between emotion and attention. Using this task, first, we examined how attention (using reaction times) can be modified by emotionally relevant words in schizophrenics as compared with controls as a function of the emotional significance of the word; second, we tested the assumption that schizophrenics with the most negative symptoms will show higher impairment in relationship to negative emotional words. In general, schizophrenics were slower to react. In both groups, mean reaction times were slower for emotional as compared with neutral words. No significant differences were observed between negative and positive words either in schizophrenics (n = 21) or in controls (n = 20). Even in the most negative schizophrenic patients, there were no differences between negative and positive words. There were no significant interactions between type of stimulus and any clinical variables (PANSS negative or non negative categorization, etc.). Also, there were no statistically significant correlations between reaction times and neuroleptic dosage or anhedonia scores. In conclusion, schizophrenia patients showed the same degree of interference from emotional words as compared with controls. Moreover, patients with a higher level of negative symptoms did not differently experience positive and negative words.     

Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin

The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects.     

Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure-activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N(1) H-C(2) (=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N(1) position) is not tolerated.     

Chronic rhinosinusitis with and without nasal polyps: What is the difference?

Chronic rhinosinusitis is a heterogeneous group of chronic sinus diseases that may consist of clearly different disease entities. Further investigation of the pathomechanisms of chronic rhinosinusitis and the introduction of appropriate disease markers have recently facilitated disease classification. Evaluation of inflammatory cell profiles, the differentiation of T-effector cells, characterization of remodeling processes such as fibrosis or edema formation, and innate or adaptive immunity products such as Toll-like receptors and immunoglobulins all provide tools to identify distinct disease entities within the group of chronic sinus diseases. This disease differentiation will not only increase our knowledge of the pathophysiology of sinusitis but may lead to new diagnostic and therapeutic strategies specifically targeted and adapted to the diagnosed disease entity.