receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at

Antibiotics represent one of the main discoveries of the last century that changed the treatment of a large array of infections in a significant way. However, increased consumption has led to an exposure of bacterial communities and ecosystems to a large amount of antibiotic residues. This paper aims to provide a brief overview of the primary drivers associated with antibiotic occurrence in the environment. Furthermore, we attempted to summarize the behavior of antibiotic residues in the environment and the necessity of their detection and quantification. Also, we provide updated scientific and regulatory facts about environmental antibiotic discharge and environmental and human antibiotics risk assessment. We propose that environmental antibiotic contamination should be diminished beginning from regulating the causes of occurrence in the environment (such as antibiotic consumption) and ending with regulating antibiotic discharge and risk assessment. Some important intermediate steps are represented by the detection and quantification of the antibiotics and the characterization of their behavior in the environment, which could come to support future regulatory decisions.

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A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [(3)H]histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.

RationaleSecond-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.ObjectiveThe purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.MethodsUsing [11C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.ResultsA monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing.ConclusionThis PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4382-y) contains supplementary material, which is available to authorized users.

Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.

Rationale A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D2-like receptors in ameliorating these cognitive deficits, and pre-clinical studies suggest that D3-receptor-preferring compounds can exert pro-cognitive effects. Objective The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D3-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits. Methods One group of wild-type or D3-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting. Results PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D3-receptor knockout mice. Conclusions In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D3 receptors contribute to this effect.