Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo.Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method.Results: CPL500036 inhibited PDE10A at an IC50 of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC50 of 9.2 µM. Despite inhibiting hERG tail current at an IC25 of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg.Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.
Aim of the studyTo check the degree of acceptance of, inclination for, and barriers in genetic testing for gene mutations that increase the risk of breast and ovarian cancers among female residents of WarsawMaterial and methodsThis study involved 562 women between 20 and 77 years of age, all of whom were patients visiting gynaecologists practising in clinics in the City of Warsaw. The studied population was divided into six age categories. The study method was a diagnostic poll conducted with the use of an original questionnaire containing 10 multiple-choice questions.ResultsNearly 70% of the women showed an interest in taking a test to detect predispositions to develop breast and ovarian cancer. More than 10% did not want to take such a test, while every fifth women was undecided. No statistically significant differences between the respondents’ willingness to pay and education were found (p = 0.05). The most frequent answer given by women in all groups was that the amount to pay was too high. Such an answer was given by 52.17% of women with primary education, 65.22% of women with vocational education, 58.61% of women with secondary education, and 41.62% of women with higher education.ConclusionsWomen with a confirmed increased risk of developing breast and/or ovarian cancer due to inter alia the presence of BRCA1 and BRCA2 gene mutations should pay particular attention to 1st and 2nd level prophylaxis.
Articles reporting research may be full length or brief reports. These should report original research findings within the journal's scope. Papers should generally be a maximum of 4000 words in length, excluding tables, references, and abstract and key points of the article, whilst it is recommended that the number of references should not exceed 30. Review PapersComprehensive, authoritative, reviews within the journal's scope. There are two types of review papers:-systematic review papers: respond to a specific research question, accrue from criterion-based selection of sources, include a quantitative synthesis and a statistical method (meta-analysis), and should adhere to PRISMA guidelines. Guidelines used for abstracting data and assessing data quality and validity should be noted in methods section. -narrative review papers: the research question may be broad, and the scope of this review is to discuss a specific topic and keep the readers up-to-date about it. This type of review does not necessarily include a methodological approach and its synthesis is usually qualitative. Narrative reviews should include in a developments section, with details regarding data sources used, keywords applied, time restrictions and study types selected. Developments should be based on actual review articles. All review papers should be generally less than 6000 words, excluding abstract, tables, figures and references. References should not exceed 50. Conclusion of the reviews should be specific and stem from the findings. Short ReportsBrief reports of data from original research. Short reports are shorter versions of original articles, may include one table or figure, should not exceed 1500 words, and it is recommended that the number of references should not exceed 15. Short reports are suitable for the presentation of research that extends previously published research, including the reporting of additional controls and confirmatory results in other settings, as well as negative results. Authors must clearly acknowledge any work upon which they are building, both published and unpublished.
Articles reporting research may be full length or brief reports. These should report original research findings within the journal's scope. Papers should generally be a maximum of 4000 words in length, excluding tables, references, and abstract and key points of the article, whilst it is recommended that the number of references should not exceed 30. Review PapersComprehensive, authoritative, reviews within the journal's scope. There are two types of review papers:-systematic review papers: respond to a specific research question, accrue from criterion-based selection of sources, include a quantitative synthesis and a statistical method (meta-analysis), and should adhere to PRISMA guidelines. Guidelines used for abstracting data and assessing data quality and validity should be noted in methods section. -narrative review papers: the research question may be broad, and the scope of this review is to discuss a specific topic and keep the readers up-to-date about it. This type of review does not necessarily include a methodological approach and its synthesis is usually qualitative. Narrative reviews should include in a developments section, with details regarding data sources used, keywords applied, time restrictions and study types selected. Developments should be based on actual review articles. All review papers should be generally less than 6000 words, excluding abstract, tables, figures and references. References should not exceed 50. Conclusion of the reviews should be specific and stem from the findings. Short ReportsBrief reports of data from original research. Short reports are shorter versions of original articles, may include one table or figure, should not exceed 1500 words, and it is recommended that the number of references should not exceed 15. Short reports are suitable for the presentation of research that extends previously published research, including the reporting of additional controls and confirmatory results in other settings, as well as negative results. Authors must clearly acknowledge any work upon which they are building, both published and unpublished.
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