A comparison of visual assessment and semi-quantification for the diagnostic and prognostic use of [18F]flortaucipir PET in a memory clinic cohort.

PURPOSE: [18F]Flortaucipir PET is a powerful diagnostic and prognostic tool for Alzheimer's disease (AD). Tau status definition is mainly based in the literature on semi-quantitative measures while in clinical settings visual assessment is usually preferred. We compared visual assessment with established semi-quantitative measures to classify subjects and predict the risk of cognitive decline in a memory clinic population. METHODS: We included 245 individuals from the Geneva Memory Clinic who underwent [18F]flortaucipir PET. Amyloid status was available for 207 individuals and clinical follow-up for 135. All scans were blindly evaluated by three independent raters who visually classified the scans according to Braak stages. Standardized uptake value ratio (SUVR) values were obtained from a global meta-ROI to define tau positivity, and the Simplified Temporo-Occipital Classification (STOC) was applied to obtain semi-quantitatively tau stages. The agreement between measures was tested using Cohen's kappa (k). ROC analysis and linear mixed-effects models were applied to test the diagnostic and prognostic values of tau status and stages obtained with the visual and semi-quantitative approaches. RESULTS: We found good inter-rater reliability in the visual interpretation of tau Braak stages, independently from the rater's expertise (k>0.68, p<0.01). A good agreement was equally found between visual and SUVR-based classifications for tau status (k=0.67, p<0.01). All tau-assessment modalities significantly discriminated amyloid-positive MCI and demented subjects from others (AUC>0.80) and amyloid-positive from negative subjects (AUC>0.85). Linear mixed-effect models showed that tau-positive individuals presented a significantly faster cognitive decline than the tau-negative group (p<0.01), independently from the classification method. CONCLUSION: Our results show that visual assessment is reliable for defining tau status and stages in a memory clinic population. The high inter-rater reliability, the substantial agreement, and the similar diagnostic and prognostic performance of visual rating and semi-quantitative methods demonstrate that [18F]flortaucipir PET can be robustly assessed visually in clinical practice.

Pharmacodynamics assessment of ß-carboline from the roots of Psammosilene tunicoides as analgesic compound.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Psammosilene tunicoides (W. C. Wu et C. Y. Wu) is a well-known medicinal herb for the treatment of pain, hemostasia and rheumatoid arthritis among Chinese people. AIM OF THE STUDY: The present study aimed to investigate the antinociceptive activity and mechanism of ß-carboline alkaloids 1-4 which were extracted from the roots of P. tunicoides. MATERIALS AND METHODS: The analgesic effects were evaluated using peripheral and central pain mouse models of nociception, including the formalin test and the tail flick test. The levels of glutamic acid (Glu) and nitric oxide (NO) in cerebellar cortexes and spinal cords (L4-6) were determined. The anti-inflammatory of all compounds were then assessed on RAW264.7 cells. RESULTS: Our results showed that compounds 1-4 had significant analgesic effects on both phases of formalin test of mice. Furthermore, all compounds showed suppressive effects on Glu in the brain and NO levels in the brain cortex and the spinal cord. Except for compound 1, the others could extend the pain threshold of hot water tail-flick in mice. In addition, compounds 2 and 3 (60 µmol/kg) could decrease GABAAα1 protein levels in spinal cord. All compounds exhibited anti-inflammatory effects by inhibiting lipopolysaccharide (LPS)-induced NO production in RAW264.7 cells with half-maximal inhibitory concentration (IC50) 1.1-34.9 µM. CONCLUSION: ß-carboline alkaloids from the roots of P. tunicoides had significant analgesic activity by both central and peripheral mechanisms. Our findings suggested that regulating the release of NO or Glu or GABAα1 are some of the mechanisms of analgesic activity of ß-carboline alkaloids.

Assessment of the intracavernosal injection platelet-rich plasma in addition to daily oral tadalafil intake in diabetic patients with erectile dysfunction non-responding to on-demand oral PDE5 inhibitors.

This study aimed to evaluate the effectiveness of ICI of platelet-rich plasma (PRP) in addition to daily oral tadalafil intake in diabetic erectile dysfunction (ED) patients non-responding to PDE5 inhibitors. Overall, 48 patients complaining of ED non-responding to on-demand PDE5 inhibitors were allocated into 2 equal groups, diabetics and non-diabetics that were given a daily dose of 5 mg tadalafil plus vardenafil 20 mg on demand during the study besides being subjected to 3 doses of ICI of PRP, 4 weeks apart. Responses to on-demand PDE5 inhibitors, International index of erectile function-5 (IIEF-5) score, erection hardness scores (EHS) and pharmaco-dynamic duplex studies were assessed. After PRP injections, 33% and 50% of cases were satisfied with on-demand PDE5 inhibitors, respectively, whereas 41% and 66% of them showed improved EHS response. Compared with baseline scores, the mean IIEF-5 scores were significantly improved after PRP therapy in the diabetic ED group (12.1 vs. 8.04, p = 0.003) as well as in the non-diabetic ED group (14.8 vs. 10.2, p = 0.001) linked to pharmaco-penile duplex readings. Both good and fair diabetic control exhibited significant responses to ICI therapy of PRP compared with bad controlled cases. The significant improvement included; the IIEF-5 score increase (86.7%, 126% vs. 16.1%), improved EHS as well as penile duplex readings. Baseline HbA1C demonstrated a significant negative correlation with IIEF-5 score before (p = 0.019) and after PRP therapy (p = 0.002) respectively. It could be concluded that ICI of PRP could be an effective therapy for treating ED patients non-responding to on-demand oral PDE5 treatment.

Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective.

Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer's disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field.

Redox-Neutral and Atom-Economic Route to ß-Carbolines via Gold-Catalyzed [4 + 2] Cycloaddition of Indolylynamides and Cyanamides.

Gold(I)-catalyzed [4 + 2] cycloaddition of indolylynamides and cyanamides (aminonitriles) is an efficient redox-neutral and atom-economic route to diversely substituted 1,3-diamino-ß-carbolines. The protocol operates under mild conditions (Ph3PAuNTf2 5 mol %, DCE, 60 °C) with a good tolerance to functional groups (23 examples and yields up to 98%). The obtained ß-carboline systems represent a versatile synthetic platform with modifiable substituents for successive functionalizations. Control experiments indicate the crucial role of both the nature of reactants and the identity of employed catalysts in the developed cycloaddition.

Assessment of Tau Pathology as Measured by 18F-THK5317 and 18F-Flortaucipir PET and Their Relation to Brain Atrophy and Cognition in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD. OBJECTIVE: We aimed to investigate the discriminative ability of 18F-THK5317 and 18F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition. METHODS: Two cohorts, each including 29 participants (healthy controls [HC], prodromal AD, and AD dementia patients), underwent 18F-THK5317 or 18F-flortaucipir PET, T1-weighted MRI, and neuropsychological assessment. For each subject, we quantified regional 18F-THK5317 and 18F-flortaucipir uptake within six bilateral and two composite regions of interest. We assessed global brain atrophy for each individual by quantifying the brain volume index, a measure of brain volume-to-cerebrospinal fluid ratio. We then quantified the discriminative ability of regional 18F-THK5317, 18F-flortaucipir, and brain volume index between diagnostic groups, and their associations with cognition in patients. RESULTS: Both 18F-THK5317 and 18F-flortaucipir outperformed global brain atrophy in discriminating between HC and both prodromal AD and AD dementia groups. 18F-THK5317 provided the highest discriminative ability between HC and prodromal AD groups. 18F-flortaucipir performed best at discriminating between prodromal and dementia stages of AD. Across all patients, both tau tracers were predictive of RAVL learning, but only 18F-flortaucipir predicted MMSE. CONCLUSION: Our results warrant further in vivo head-to-head and antemortem-postmortem evaluations. These validation studies are needed to select tracers with high clinical validity as biomarkers for early diagnosis, prognosis, and disease staging, which will facilitate their incorporation in clinical practice and therapeutic trials.

Synthesis and Assessment of Fused ß-Carboline Derivatives as Kappa Opioid Receptor Agonists.

The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-ß-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused ß-carboline derivatives, which were investigated for their κ-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC50 values of 46±19 and 134±9 nM, respectively. Moreover, compound-induced KOR signaling studies suggested both compounds to be extremely G-protein-biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time-dependent manner, which was completely blocked by the KOR-selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.

Socioeconomic Status Mediates Racial Differences Seen Using the AT(N) Framework.

OBJECTIVES: African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non-Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences. METHODS: Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs-fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area-based SES were included in mediation analyses. RESULTS: Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f2 = 0.05, p < 0.001). SES mediated the relationship between race and cortical volumes. There were no significant race effects for amyloid, tau, or rs-fc signature. INTERPRETATION: Modifiable factors, such as differences in social contexts and resources, particularly area-level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254-265.

Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes.

Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants: This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-ß plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

Phosphodiesterase Type-5 Inhibitor Prescription Patterns in the United States Among Men With Erectile Dysfunction: An Update.

BACKGROUND: While phosphodiesterase type-5 inhibitors (PDE5Is) are highly effective for the treatment of erectile dysfunction (ED) and well tolerated, updated data on prescription patterns have been limited in real-world settings. AIM: To describe men in the United States who are prescribed PDE5Is for ED treatment and to evaluate patterns of initiation, switching, and treatment overlap. METHODS: This retrospective claims study used MarketScan Commercial and Medicare Supplement Databases from January 1, 2010, to December 31, 2015, to identify initial PDE5I claims (index date) for sildenafil, tadalafil, and/or vardenafil. Adults aged ≥18 years with ED were identified between July 1, 2010, and December 31, 2014, allowing for a 6-month preindex and 12-month follow-up period from the index date. OUTCOMES: Outcomes included patient demographics and treatment-related patterns after treatment initiation. RESULTS: A total of 106,206 identified patients met all inclusion criteria. Of these, 51,694, 40,193, and 14,319 had initial claims for sildenafil, tadalafil, and vardenafil, respectively. Mean age was 50.35 years, and comorbidities included dyslipidemia (44.17%), hypertension (43.09%), diabetes (15.32%), and depression (10.61%). More patients (48.67%) initiated on sildenafil than tadalafil (37.85%) or vardenafil (13.48%). Rate of switching was lower in the 60 days after the end of day supply of the initial prescription in the sildenafil cohort (2.71%) compared with the tadalafil (2.81%) and vardenafil (3.88%) cohorts (P < .001 for sildenafil vs tadalafil or vardenafil). Treatment overlap was lower in the sildenafil cohort (0.35%) than in the tadalafil (0.75%) and vardenafil (0.62%) groups (P < .001 for sildenafil vs tadalafil or vardenafil). CLINICAL IMPLICATIONS: These findings provide insight into updated patterns of PDE5I prescriptions in the United States and may aid in clinical decision-making. STRENGTHS & LIMITATIONS: Strengths include the large sample size, long data coverage period, and the real-world nature of the study. Limitations include the retrospective study design, use of data collected with a primary focus of claims, and lack of further details regarding reasons that drive switching. Actual rates of ED and impact on prescription patterns may be underestimated because the claims database only captured patients electing to visit a health-care provider. CONCLUSION: Among men with ED in the United States, rates of switching and treatment overlap were low for all PDE5Is but were found to be the lowest for sildenafil compared with tadalafil and vardenafil. Mulhall JP, Chopra I, Patel D, et al. Phosphodiesterase Type-5 Inhibitor Prescription Patterns in the United States Among Men With Erectile Dysfunction: An Update. J Sex Med 2020;17:941-948.

Activation of Anxiogenic Circuits Instigates Resistance to Diet-Induced Obesity via Increased Energy Expenditure.

Anxiety disorders are associated with body weight changes in humans. However, the mechanisms underlying anxiety-induced weight changes remain poorly understood. Using Emx1Cre/+ mice, we deleted the gene for brain-derived neurotrophic factor (BDNF) in the cortex, hippocampus, and some amygdalar subregions. The resulting mutant mice displayed impaired GABAergic transmission and elevated anxiety. They were leaner when fed either a chow diet or a high-fat diet, owing to higher sympathetic activity, basal metabolic rate, brown adipocyte thermogenesis, and beige adipocyte formation, compared to control mice. BDNF re-expression in the amygdala rescued the anxiety and metabolic phenotypes in mutant mice. Conversely, anxiety induced by amygdala-specific Bdnf deletion or administration of an inverse GABAA receptor agonist increased energy expenditure. These results reveal that increased activities in anxiogenic circuits can reduce body weight by promoting adaptive thermogenesis and basal metabolism via the sympathetic nervous system and suggest that amygdalar GABAergic neurons are a link between anxiety and metabolic dysfunction.

Scan-Time Corrections for 80-100-min Standardizetd Uptake Volume Ratios to Measure the 18F-AV-1451 Tracer for Tau Imaging.

The 18F-AV-1451 PET tracer binds to tau, an Alzheimer's disease biomarker. The standardized uptake value ratio (SUVR) 80-100 min window is widely used to quantify tau binding, although 18F-AV-1451 continues increasing relative to a reference region in regions with tau deposition. Left uncorrected, acquisition time inaccuracies can lead to errors from -4% to 6% in 20-min SUVR measurements in subjects with Alzheimer's disease. In 40 subjects with scans from 75-115 min following 18F-AV-1451 injection, we created 20-min reconstructions (4×5 min) of start-times ranging from 75-85 min, as proxies of offset scans and calculated the mean in regions of interest (ROIs). We developed a segmented least squares (SLS) method to obtain error-minimizing weighting coefficients for 18F-AV-1451 ROIs that best predict SUVR 80-100 from weighted means of SUVRs from offset start-times. We compared residual errors of our SLS method to those in: 1) uncorrected offset 20-min-SUVRs; 2) the mean of five-min frames within the 80-100 window; and 3) a least-squares interpolation method. We evaluated errors induced by start-time offset on SUVRs for each method. TheSLS, which corrected using least-squares coefficients of 5-min components, consistently reduced errors across all offset starttimes. Effect size analysis for simulated clinical longitudinal 18F-AV-1451 drug trials showed that uncorrected 20-min offset SUVRs would require up to 20% more participants to detect treatment effects compared with using SLS. Correction of SUVR scan-time errors by SLS minimizes errors compared with other correction methods and may be extended to other scanners and tracers.

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Assessment of toxicity and differential antimicrobial activity of methanol extract of rhizome of Simaba ferruginea A. St.-Hil. and its isolate canthin-6-one.

ETHNOPHARMACOLOGICAL RELEVANCE: Simaba ferruginea A. St.-Hil., Simaroubaceae, popularly known as "calunga" is a typical subtropical shrub used in Central Brazil mainly for infection, anti-inflammatory, analgesic and gastric duodenal-ulcers. It presents in its composition the alkaloid canthin-6-one, an alkaloid indole ß-carboxylic. AIM: This study aims to investigate the toxicity, antimicrobial activities of methanol extract of Simaba ferruginea (MESf) and canthin-6-one by using different experimental models. METHODS: The present study evaluated the phytochemical analysis by high performance liquid chromatography (HPLC), toxicological potential of MESf and canthin-6-one, using the cytotoxicity, genotoxicity assays with CHO-K1 cells and in vivo acute test in mice. Antimicrobial activity was evaluated by the broth microdilution assays, while the antimicrobial mechanism of action was also assessed using different in vitro bacterial and fungal models. RESULTS: The HPLC analysis of MESf revealed the presence of canthin-6-one, kaempferol and morin. Differential in vitro toxicities were observed between MESf and canthin-6-one. In the cytotoxicity assay, MESf presented toxicity against CHO-K1, while canthin-6-one did not. In the case of in vitro genotoxicity, both showed to be potentially genotoxic. In the in vivo toxicity study, both MESf (up to 1000 mg/kg) and cantin-6-one (up to 100 mg/kg) caused no toxicologically relevant alterations and are thus considered not to be toxic. MESf was shown to be relatively safe with NOAEL (100 mg/kg) when administrate in mice. Both MESf and canthin-6-one also showed differential antimicrobial activities. On one hand, MESf demonstrated good spectrum of antibacterial action against Staphylococcus aureus (MIC 12.5 µg/mL) and Escherichia coli (MIC 25 µg/mL) and moderate activity against Enterococcus faecalis and Shigella flexneri (MIC 200 µg/mL) but no antifungal effect. On the hand, canthin-6-one showed no antibacterial activity, except against Staphylococcus aureus (100 µg/mL), but potent in vitro fungicidal activity against clinically important Aspergillus niger and Candida species at MFC intervals ranging from 3.12 to 25 µg/mL. Both MESf and canthin-6-one were bacteriostatic in action. MESf antimicrobial mechanism of actions are associated with changes in the permeability of bacterial membranes, evidenced by the increased entry of hydrophobic antibiotic in Shigella flexneri, intense K+ efflux (Shigella flexneri, Staphylococcus aureus) and nucleotides leakage (Staphylococcus aureus). In the antifungal mode of action, canthin-6-one inhibited Saccharomyces cerevisiae growth and including alteration in the cell membrane of Neurospora crassa. CONCLUSION: The results of this work demonstrated the differential antimicrobial activities of MESf and its alkaloid isolate, canthin-6-one with antibacterial and antifungal activities, respectively. The present study support the popular use of Simaba ferruginea in combatting afflictions related to bacterial infections, and demonstrate that canthin-6-one as a promising antifungal agent. Both MESf and canthin-6-one are considered non-toxic based on the in vitro toxicological study.

Assessment of Extent and Role of Tau in Subcortical Vascular Cognitive Impairment Using 18F-AV1451 Positron Emission Tomography Imaging.

Importance: Amyloid-ß (Aß), tau, and cerebral small vessel disease (CSVD), which occasionally coexist, are the most common causes of cognitive impairments in older people. However, whether tau is observed in patients with subcortical vascular cognitive impairment (SVCI), as well as its associations with Aß and CSVD, are not yet established. More importantly, the role of tau underlying cognitive impairments in SVCI is unknown. Objective: To investigate the extent and the role of tau in patients with SVCI using 18F-AV1451, which is a new ligand to detect neurofibrillary tangles in vivo. Design, Setting, and Participants: This cross-sectional study recruited 64 patients with SVCI from June 2015 to December 2016 at Samsung Medical Center, Seoul, Korea. The patients had significant ischemia on brain magnetic resonance imaging, defined as periventricular white matter hyperintensity at least 10 mm and deep white matter hyperintensity at least 25 mm. We excluded 3 patients with SVCI owing to segmentation error during AV1451 positron emission tomography analysis. Main Outcomes and Measures: We calculated CSVD scores based on the volumes of white matter hyperintensities, numbers of lacunes, and microbleeds using magnetic resonance imaging data. The presence of Aß was assessed using fluorine 18-labeled (18F) florbetaben positron emission tomography. Tau was measured using 18F-AV1451 positron emission tomography. We determined the spreading order of tau by sorting the regional frequencies of cortical involvement. We evaluated the complex associations between Aß, CSVD, AV1451 uptake, and cognition in patients with SVCI. Results: Of the 61 patients with SVCI, 44 (72.1%) were women and the mean (SD) age was 78.7 (6.3) years. Patients with SVCI, especially patients with Aß-negative SVCI, showed higher AV1451 uptake in the inferior temporal areas compared with normal control individuals. In patients with SVCI, Aß positivity and CSVD score were each independently associated with increased AV1451 uptake in the medial temporal and inferior temporal regions, respectively. Involvement frequency of AV1451 uptake in the fusiform gyrus, inferior temporal, and precuneus regions were higher than that in the parahippocampal region. In patients with SVCI, higher AV1451 uptake in the inferior temporal and medial temporal regions correlated with worse language and general cognitive function. In patients with SVCI, Aß positivity and CSVD score each correlated with worse general cognitive function, which was completely mediated by AV1451 uptake in the entorhinal cortex and inferior temporal gyrus, respectively. Conclusions and Relevance: Our findings suggest that in SVCI, both Aß and CSVD were independently associated with increased tau accumulation. Furthermore, tau burden played a pivotal role because it was the final common pathway for the cognitive impairment in patients with SVCI.

Quality Assessment of Kumu Injection, a Traditional Chinese Medicine Preparation, Using HPLC Combined with Chemometric Methods and Qualitative and Quantitative Analysis of Multiple Alkaloids by Single Marker.

Kumu injection (KMI) is a common-used traditional Chinese medicine (TCM) preparation made from Picrasma quassioides (D. Don) Benn. rich in alkaloids. An innovative technique for quality assessment of KMI was developed using high performance liquid chromatography (HPLC) combined with chemometric methods and qualitative and quantitative analysis of multi-components by single marker (QAMS). Nigakinone (PQ-6, 5-hydroxy-4-methoxycanthin-6-one), one of the most abundant alkaloids responsible for the major pharmacological activities of Kumu, was used as a reference substance. Six alkaloids in KMI were quantified, including 6-hydroxy-ß-carboline-1-carboxylic acid (PQ-1), 4,5-dimethoxycanthin-6-one (PQ-2), ß-carboline-1-carboxylic acid (PQ-3), ß-carboline-1-propanoic acid (PQ-4), 3-methylcanthin-5,6-dione (PQ-5), and PQ-6. Based on the outcomes of twenty batches of KMI samples, the contents of six alkaloids were used for further chemometric analysis. By hierarchical cluster analysis (HCA), radar plots, and principal component analysis (PCA), all the KMI samples could be categorized into three groups, which were closely related to production date and indicated the crucial influence of herbal raw material on end products of KMI. QAMS combined with chemometric analysis could accurately measure and clearly distinguish the different quality samples of KMI. Hence, QAMS is a feasible and promising method for the quality control of KMI.

Pittsburgh Compound B and AV-1451 positron emission tomography assessment of molecular pathologies of Alzheimer's disease in progressive supranuclear palsy.

INTRODUCTION: Little is known about Alzheimer's disease molecular proteins, beta-amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features. METHODS: Thirty probable PSP participants underwent MRI, [18F]AV-1451 PET and Pittsburgh compound B (PiB) PET. Apolipoprotein (APOE) genotyping was also performed. A global PiB standard-uptake value ratio (SUVR) was calculated. AV-1451 SUVRs were calculated for a set of Alzheimer's disease (AD)-related regions and a set of PSP-related regions. Voxel-level analyses were conducted to assess for differences in AV-1451 uptake patterns and MRI atrophy between PiB(+) and PiB(-) cases compared to 60 normal PiB(-) controls. Statistical testing for correlations and associations between variables of interest were also performed. RESULTS: Twelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy. CONCLUSION: Beta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP.

A rapid and simple method for the determination of psychoactive alkaloids by CE-UV: application to Peganum Harmala seed infusions.

The ß-carboline alkaloids of the harmala (HAlks) group are compounds widely spread in many natural sources, but found at relatively high levels in some specific plants like Peganum harmala (Syrian rue) or Banisteriopsis caapi. HAlks are a reversible Mono Amino Oxidase type A Inhibitor (MAOI) and, as a consequence, these plants or their extracts can be used to produce psychotropic effects when are combined with psychotropic drugs based on amino groups. Since the occurrence and the levels of the HAlks in natural sources are subject to significant variability, more widespread use is not clinical but recreational or ritual, for example B. caapi is a known part of the Ayahuasca ritual mixture. The lack of simple methods to control the variable levels of these compounds in natural sources restricts the possibilities to dose in strict quantities and, as a consequence, limits its use with pharmacological or clinical purposes. In this work, we present a fast, simple, and robust method of quantifying simultaneously the six HAlks more frequently found in plants, i.e., harmine, harmaline, harmol, harmalol, harmane, and norharmane, by capillary electrophoresis instruments equipped with the more common detector UV. The method is applied to analyze these HAlks in P. Harmala seeds infusion which is a frequent intake form for these HAlks. The method is validated in three different instruments in order to evaluate the transferability and to compare the performances between them. In this case, harmaline, harmine, and harmol were found in the infusion samples. Copyright © 2016 John Wiley & Sons, Ltd.

Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-ß-carboline (Pinoline) and Melatonin-Pinoline Hybrids.

6-Methoxy-1,2,3,4-tetrahydro-ß-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-ß-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.

Management of ED under the "severe distress" criteria in the NHS: a real-life study.

INTRODUCTION: The United Kingdom is unusual in that a significant proportion of patients with erectile dysfunction (ED) have their treatment fully reimbursed by the National Health Service (NHS). This may have consequences for the choice of treatment and for compliance with treatment. AIMS: The aim of this study was to evaluate the use and cost implications of phosphodiesterase type 5 inhibitor in an NHS setting. METHODS: Basic demographics and data on ED management for patients treated from January 2000 to April 2011 were obtained from a prospectively accrued database. We reviewed drug usage and costs as well as switching between drugs. Patients were given the choice of all available therapies and were followed up annually. MAIN OUTCOME MEASURES: Switching, compliance, and costs of treating ED under the "severe distress" criteria in the NHS were reviewed for this study. RESULTS: Two thousand one hundred fifty-nine patients qualified for reimbursed therapy. Two hundred twenty-six patients were excluded from further analysis owing to missing data. Patients were followed up on an annual basis. The mean patient age was 60.2 years (min 23, max 90), and the mean follow-up was 50.8 months (min 1, max 127). Six hundred ninety-six were started on sildenafil, 990 on tadalafil, 163 on vardenafil, and 84 on intracavernosal alprostadil. Eighteen percent of patients initially started on the scheme and stopped medication unilaterally. Of the patients, 12.3% changed their medication during follow-up. The cost of drugs increased year by year from £257,100 in 2007 to £352,519 in 2011. CONCLUSIONS: Our real-life observational study shows that in our institution, dropout of therapy is unusual. We hypothesize that this reflects, in part, the reimbursement issue. We also found that switching between drugs was unusual, although there are several possible explanations for that. Although this is a successful system for the patients, the hospital, which bears the costs of medication, is finding this an increasing economic drain.