Search

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index 1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Context Ureteral stent-related symptoms (SRSs) are very common and may potentially influence the quality of life and functional capacity of patients. It remains unclear whether mirabegron has a place in the treatment of SRSs. Objective To summarize the evidence of mirabegron for the treatment for SRSs in adult patients. Evidence acquisition A systematic review of literature was performed using the PubMed, Embase, and Google Scholar databases. Studies published up to June 2021 that met the search terms (“mirabegron” OR “B3-agonist”) AND (“stent-related symptoms” OR “stent-related discomfort” OR “stent”) were considered. References from relevant sources were examined to identify additional sources for this review. Relevant studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The revised Cochrane tool “RoB 2” was used to assess the quality of included randomized clinical trials. Evidence synthesis Eight studies were selected for final quantitative and qualitative synthesis. The Ureteral Stent Symptom Questionnaire (USSQ) body pain score was significantly improved by mirabegron in five studies, although a pooled data analysis did not reveal any significant changes. The USSQ urinary symptom score was significantly improved by mirabegron in four independent studies as well as in the corresponding meta-analysis, while no changes were found in two studies. International Prostate Symptom Score was improved significantly by mirabegron in three independent studies as well as in the corresponding meta-analysis. The USSQ general health and the quality of life score were improved significantly by mirabegron on meta-analysis. Conclusions Mirabegron may have a beneficial effect on pain and urinary symptoms due to ureteral stents, although the evidence is based on low-quality studies. Patient summary In this report, we looked at the evidence of mirabegron for the treatment of ureteral stent-related symptoms. We found that mirabegron can potentially alleviate pain and bothersome urinary symptoms due to ureteral stents.

Aims Hyperuricaemia and gout are strongly related with traditional cardiovascular risk factors and vascular damage. This study aimed to assess whether febuxostat and allopurinol could differently influence carotid-femoral pulse wave velocity (cfPWV) in patients with gout and elevated serum uric acid (SUA) levels. Methods and results A multi-centre, multinational, phase IV, randomized, parallel-group, active-controlled, open-label trial with blind endpoints evaluation. One hundred and ninety-seven adults with gout and SUA levels ≥8 mg/dL were randomized to febuxostat or allopurinol in a 1:1 ratio for 36 weeks. The primary outcome was the comparison of the effects of febuxostat and allopurinol on changes in cfPWV. The mean cfPWV values at randomization and Week 36 were 8.69 and 9.00 m/s, respectively for subjects randomized to febuxostat and 9.02 and 9.05 m/s for subjects randomized to allopurinol. No statistically significant changes in cfPWV by treatment assignment were observed at any time point for any of the assessed parameters. More subjects who received febuxostat had serum urate concentrations ≤6 mg/dL following treatment (78.3% vs. 61.1% at Week 36, P = 0.0137). Treatment-emergent adverse events were reported by 51 (52.0%) patients randomized to febuxostat and 63 (62.5%) patients randomized to allopurinol. The majority of events were mild in both treatment groups and included gout flares and arthralgia. Conclusion In patients with gout and elevated SUA levels the arterial stiffness remained stable both with febuxostat and allopurinol. Febuxostat was more effective and faster than allopurinol in achieving the SUA target. Both treatments were safe and well tolerated.

Acute ischemic stroke continues to devastate millions of individuals worldwide. Current treatments work to restore blood flow but not rescue affected tissue. Our goal was to develop a combination of neuroprotective agents administered intra‐arterially following recanalization to target ischemic tissue. Using C57Bl/6J male mice, we performed tandem transient ipsilateral middle cerebral/common carotid artery occlusion, followed by immediate intra‐arterial pharmacotherapy administration through a standardized protocol. Two pharmacotherapy agents, verapamil and lubeluzole, were selected based on their potential to modulate different aspects of the ischemic cascade; verapamil, a calcium channel blocker, works in an acute fashion blocking L‐type calcium channels, whereas lubeluzole, an N‐methyl‐D‐aspartate modulator, works in a delayed fashion blocking intracellular glutamate trafficking. We hypothesized that combination therapy would provide complimentary and potentially synergistic benefit treating brain tissue undergoing various stages of injury. Physiological measurements for heart rate and pulse distention (blood pressure) demonstrated no detrimental effects between groups, suggesting that the combination drug administration is safe. Tissue analysis demonstrated a significant difference between combination and control (saline) groups in infarct volume, neuronal health, and astrogliosis. Although a significant difference in functional outcome was not observed, we did note that the combination treatment group had a greater percent change from baseline in forced motor movement as compared with controls. This study demonstrates the safety and feasibility of intra‐arterial combination therapy following successful recanalization and warrants further study.

Background: Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear. Objective: To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition. Methods: Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive group. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition. Results: PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake. Conclusion: Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of neurovascular unit are useful for identifying elderly individuals at risk of developing Alzheimer’s disease.

Recent data suggest direct oral anticoagulants are as safe and efficacious as warfarin among select patients with valvular heart disease and atrial fibrillation (AF). However, real-world treatment patterns of AF stroke prophylaxis in the setting of valvular AF are currently unknown. Accordingly, using the prospective, ambulatory National Cardiovascular Data Registry Practice Innovation and Clinical Excellence (PINNACLE) Registry, we sought to characterize overall use, temporal trends in use, and the extent of practice-level variation in the use of any direct oral anticoagulant and warfarin among patients with valvular AF from January 1, 2013, to March 31, 2019.

Background In the absence of head-to-head trials, we performed an indirect treatment comparison of the β3-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB). Methods PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively. Results After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC50 values in the range of 6.31 to 49.89 μM compared to standard drug acarbose (IC50 = 750.0 ± 10.0 μM). Enzyme kinetic studies on 9c, 9g, and 9m as the most potent compounds revealed that these compounds were uncompetitive inhibitors into α-glycosidase. Docking studies confirmed the important role of benzoimidazole and triazole rings of the synthesized compounds to fit properly into the α-glycosidase active site. This study showed that this scaffold can be considered as a highly potent α-glycosidase inhibitor. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10310-7.

Background Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. Methods This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. Results 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. Conclusions This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments.

Direct oral anticoagulants (DOACs) are widely used for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, the differences in safety and effectiveness among four DOACs, dabigatran, rivaroxaban, apixaban, and edoxaban, in Japanese patients have not been clarified. Therefore, we conducted a retrospective cohort study to directly compare the safety and effectiveness among the four DOACs using the Japan Medical Data Center (JMDC) claims database. We identified 3823 patients with NVAF who started receiving a DOAC between March 2011 and June 2017. The safety outcome was major bleeding (a composite outcome of intracranial, gastrointestinal, respiratory, or renal/urinary tract bleeding) and the effectiveness outcome was the composite of ischemic stroke including transient ischemic attack (TIA) or systemic embolism. We constructed a Cox proportional hazard model to calculate the hazard ratio (HR) for all four DOAC combinations. The risk of major bleeding was significantly lower in the dabigatran group than in the apixaban group (HR, 0.55; 95% confidence interval (CI), 0.31-0.93; p = 0.03). In contrast, there was no significant difference in the risk of major bleeding among the other DOACs. In the composite risk of ischemic stroke including TIA or systemic embolism, there was no significant difference among the four DOACs. This study suggested that in the current use of DOACs in Japanese patients with NVAF, dabigatran had a significantly lower risk of major bleeding than apixaban, but there was no significant difference in effectiveness among the four DOACs.

PURPOSE The safety of mirabegron 50mg monotherapy was comprehensively assessed versus placebo for overactive bladder. METHODS A systematic literature search was conducted up to June, 2020 using PUBMED, EMBASE and Cochrane Library. Randomized controlled trials evaluating safety of mirabegron in overactive bladder were collected, and safety was assessed according to 15 adverse events. Adverse events were widely selected to be assessed if they could be calculated. Heterogeneity among studies was assessed by using the χ2 test based on the Q and I2 tests. Pooled effect sizes were calculated using fixed model if I2

The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications.

Purpose: We aimed to investigate the clinical performance of edoxaban for the treatment of pulmonary embolism (PE) in hospitalized COVID-19 patients. Methods: We conducted a retrospective analysis selecting hospitalized patients with COVID-19 admitted to our Institution from 20 May 2020 to 20 November 2020 with computer tomography (CT) detected PE at admission, treated with edoxaban after initial parenteral therapy. Clinical outcomes were compared between patients with and without ARDS at admission and between those with and without CT confirmed PE resolution. Results: 50 patients were included. Mean follow-up was 42.5±10days. No baseline differences were found between patients with ARDS (30%) and those without ARDS at admission. Patients with PE resolution (84%) were younger (P =0.03), had a shorter duration of fondaparinux therapy (9.9±3.8 vs 15.8±7.5days; P =0.0015) and length of hospitalization (36±8 vs 46±9days: P =0.0023) compared with those without PE resolution. 2 patients experienced major bleedings. At multivariate analysis the time to edoxaban switch was the only predictor of the PE resolution (HR: 0.92; 95% C.I. 0.86 to 0.99). Conclusion: Edoxaban was an effective and safe treatment for acute PE in COVID-19 setting.

To observe the efficacy and safety of Mirabegron in patients with distal, ureteral stones ≤ 10 mm. A total of 90 patients with distal ureteral stones ≤ 10 mm were prospectively randomized into two groups. Forty-five cases in the study group and 45 cases as control. The stone-free rates (SFRs) and renal colic episodes between two groups were compared at the 1st, 2nd and 4th week end by imaging examinations. All of 90 patients were randomly assigned to two groups. In patients with ≤ 5 mm stones, the SFRs in the 1st week (63.6% vs. 33.3%, P = 0.040), the 2nd week (86.4% vs. 54.2%, P = 0.018), and the 4th week (90.9% vs. 66.7%, P = 0.046) after treatment were all significantly higher than that in the control group by the stratification analysis of stone size. Even though SFRs were all higher for patients with > 5 mm stones in study group, there was no statistically significant difference (All P > 0.05). In terms of renal colic episodes, the frequency of occurrence of the study group was significantly lower than that of the control group and need less antalgic. The MET with Mirabegron has a significant role in improve SFR for the patients with distal ureteral stones ≤ 5 mm and no effect in > 5 mm stones. Furthermore, Mirabegron reduces the need for antalgic in ≤ 10 mm stones with low incidence of adverse effects.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a significant threat to human health. Despite its similarity to related coronaviruses, there are currently no specific treatments for COVID-19 infection, and therefore there is an urgent need to develop therapies for this and future coronavirus outbreaks. Formation of the cap at the 5′ end of viral RNA has been shown to help coronaviruses evade host defenses. Nonstructural protein 14 (nsp14) is responsible for N7-methylation of the cap guanosine in coronaviruses. This enzyme is highly conserved among coronaviruses and is a bifunctional protein with both N7-methyltransferase and 3′-5′ exonuclease activities that distinguish nsp14 from its human equivalent. Mutational analysis of SARS-CoV nsp14 highlighted its role in viral replication and translation efficiency of the viral genome. In this paper, we describe the characterization and development of a high-throughput assay for nsp14 utilizing RapidFire technology. The assay has been used to screen a library of 1771 Food and Drug Administration (FDA)-approved drugs. From this, we have validated nitazoxanide as a selective inhibitor of the methyltransferase activity of nsp14. Although modestly active, this compound could serve as a starting point for further optimization.

Current treatments for Chagas disease have a limited impact during the chronic stage and trigger severe side effects. Treatments target Trypanosoma cruzi, the etiological agent of the disease. The aims of this study were to evaluate the trypanocidal activity of four 2-phenylbenzothiazole derivatives (BZT1–4) in vitro by using the infectious and non-infectious forms of T. cruzi (trypomastigotes and epimastigotes, respectively) and to test the most promising compound (BZT4) in vivo in mice. Additionally, the toxicological profile and possible neuronal damage were examined. In relation to trypomastigotes, BZT4 was more selective and effective than the reference drug (benznidazole) during this infective stage, apparently due to the synergistic action of the CF3 and COOH substituents in the molecule. During the first few hours post-administration of BZT4, parasitemia decreased by 40% in an in vivo model of short-term treatment, but parasite levels later returned to the basal state. In the long-term assessment, the compound did not produce a significant antiparasitic effect, only attaining a 30% reduction in parasitemia by day 20 with the dose of 16 mg/kg. The toxicity test was based on repeated dosing of BZT4 (administered orally) during 21 days, which did not cause liver damage. However, the compound altered the concentration of proteins and the proteinic profile of neuronal cells in vitro, perhaps leading to an effect on the central nervous system. Further research on the low trypanocidal activity in vivo compared to the better in vitro effect could possibly facilitate molecular redesign to improve trypanocidal activity.

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.

Introduction:Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. Areas covered:We analyze selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the results that suggested a potential survival benefit of low-dose aspirin and colchicine when used for COVID-19. Expert opinion:Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that are unfortunately currently at best of second choice after paracetamol, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their anti-inflammatory and immunomodulatory properties. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials., GRAPHICAL ABSTRACT

OBJECTIVES To compare the 1-year continuation rate and discontinuation factors between vibegron and mirabegron in patients with neurogenic and nonneurogenic overactive bladder. METHODS Continuation or discontinuation of the target drugs and reasons for discontinuation as well as patients' grounds and adverse effects were evaluated retrospectively from the medical records between September 2018 and December 2020. After selecting patients according to the inclusion and exclusion criteria, 180 cases taking mirabegron and 132 taking vibegron were adjusted for intergroup variability by propensity score matching. We performed Cox proportional hazards regression for the 1-year continuation rate and Fine-Gray proportional hazards regression for the 1-year cumulative incidence of discontinuation events. Subgroup analysis was also performed for the background factors related to the 1-year continuation rate. RESULTS The 1-year continuation rate was 83.8% for vibegron and 58.2% for mirabegron, and the hazard ratio was 0.32 (95% CI: 0.18-0.57, P

A class of quinazolone thiazoles was identified as new structural scaffolds for potential antibacterial conquerors to tackle dreadful resistance. Some prepared compounds exhibited favorable bacteriostatic efficiencies on tested bacteria, and the most representative 5j featuring the 4-trifluoromethylphenyl group possessed superior performances against Escherichia coli and Pseudomonas aeruginosa to norfloxacin. Further studies revealed that 5j with inappreciable hemolysis could hinder the formation of bacterial biofilms and trigger reactive oxygen species generation, which could take responsibility for emerging low resistance. Subsequent paralleled exploration discovered that 5j not only disintegrated outer and inner membranes to induce leakage of cytoplasmic contents but also broke the metabolism by suppressing dehydrogenase. Meanwhile, derivative 5j could intercalate into DNA to exert powerful antibacterial properties. Moreover, compound 5j gave synergistic effects against some Gram-negative bacteria in combination with norfloxacin. These findings indicated that this novel structural type of quinazolone thiazoles showed therapeutic foreground in struggling with Gram-negative bacterial infections.

Objectives This analysis from the PERSPECTIVE (a Prospective, Non‐interventional Registry Study of Patients Initiating a Course of Drug Therapy for Overactive Bladder) study evaluated treatment persistence with mirabegron or antimuscarinics over a 12‐month period. Methods Participants were adults diagnosed with overactive bladder (OAB) by their health care provider (HCP), who were initiating mirabegron or antimuscarinic treatment. The HCP made all treatment decisions, and patients were followed for 12 months with no mandatory scheduled visits. Information requests were sent to patients at baseline and months 1, 3, 6, and 12. Patients were nonpersistent if they switched, discontinued, or added OAB medications/therapies to their initial treatment. Reasons for discontinuation and switching patterns were investigated. Results Overall, 1514 patients were included (613 mirabegron and 901 antimuscarinic initiators). Persistence rates decreased steadily over time in both groups. A low proportion of patients added or switched medication at each time point. Unadjusted Kaplan‐Meier analysis showed similar persistence rates for both groups. When the data were adjusted for patient characteristics (age, sex, and OAB treatment status), mirabegron initiators had higher persistence rates. No significant differences were noted in unadjusted median time to end of persistence. However, end of treatment persistence by any cause was longer with mirabegron (median: 9.5 vs 6.7 months for antimuscarinics). HCPs stated that the most common reasons for nonpersistence were no symptomatic improvement and side effect aversion. Conclusions Treatment persistence was longer for mirabegron compared with antimuscarinic initiators after controlling for patient characteristics. End of treatment persistence by any cause was also longer with mirabegron.

Background: A significant proportion of patients with clinically diagnosed Alzheimer’s Disease (AD) and an even higher proportion of patients with amnestic mild cognitive impairment (aMCI) do not show evidence of amyloid deposition on Positron Emission Tomography (PET) with amyloid-binding tracers such as 11C-labeled Pittsburgh Compound B (PiB). Objective: This study aimed to identify clinical, neuropsychological and neuroimaging factors that might suggest amyloid neuropathology in patients with clinically suspected AD or aMCI. Methods: Forty patients with mild to moderate AD and 23 patients with aMCI who were clinically diagnosed in our memory clinic and had PiB PET scans were included. Clinical, neuropsychological, and imaging characteristics, such as Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMH) on MRI and metabolic pattern on 18F-labeled fluorodeoxyglucose (FDG) PET, were compared between patients with PiB positive and negative PET results for AD, aMCI, and all subjects combined, respectively. Results: Compared with PiB positive patients, PiB negative patients had a higher prevalence of hypertension history, better performance on the Mini-Mental State Examination, the Rey Auditory Verbal Learning Test, and the Judgement of Line Orientation, lower score of MTA, and were less likely to have temporoparietal-predominant hypometabolism on FDG PET. Affective symptoms were less common in PiB negative patients diagnosed with AD, and the Animal Fluency Test score was higher in PiB negative patients diagnosed with aMCI. Conclusion: In patients with clinically diagnosed AD or aMCI, absence of a history of hypertension, deficits in verbal learning and memory, visuospatial function, semantic verbal fluency, presence of affective symptoms, MTA on MRI, and temporoparietal hypometabolism on FDG PET suggested amyloid deposition in the brain.

Background The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor–positive (HR+), human epidermal growth factor receptor‐2–negative (HER2−), PIK3CA‐mutated advanced breast cancer (ABC), after cyclin‐dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real‐world setting. Materials and Methods Patients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real‐world patient cohort who received standard‐of‐care from a deidentified clinico‐genomics database (CGDB). Primary and secondary endpoints were to compare progression‐free survival (PFS), estimated by the Kaplan‐Meier method, and the proportion of patients remaining progression‐free at 6 months, respectively, between the two cohorts. Results A total of 855 patients with PIK3CA‐mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2‐targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real‐world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real‐world cohort, and 6‐month PFS was 54.6% versus 40.1%, respectively. Conclusion Matched/weighted analysis comparing BYLieve with the real‐world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2−, PIK3CA‐mutant ABC after CDK4/6i treatment. Implications for Practice Approximately 40% of patients with hormone receptor–positive (HR+), human epidermal growth factor receptor‐2–negative (HER2−) advanced breast cancer (ABC) have PIK3CA‐mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α‐selective phosphatidylinositol‐3‐kinase inhibitor, demonstrated significantly improved progression‐free survival in SOLAR‐1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real‐world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2−, PIK3CA‐mutant ABC in the post‐CDK4/6i setting., This article reports the efficacy of treatment with alpelisib combined with fulvestrant in a cohort of patients with PIK3CA‐mutated breast cancer compared with the effectiveness of real‐world standard treatments in the post‐CDK4/6i setting using data from a deidentified clinico‐genomics database (CGDB).

Objectives To evaluate whether the long-term usage of mirabegron, which was reported to have potential side effects on male reproductive organs in animal studies, was harmful to spermatogenesis in human testis. Methods Thirty consecutive patients with spinal cord injury (20-48 years old) who performed clean intermittent catheterization were involved in this study. Ten patients were treated with mirabegron (50 mg/d) for more than 2 years and refrained from using an antimuscarinic agent due to the side effects of constipation and dry mouth. Twenty patients were treated with neither anticholinergic agents nor mirabegron. All underwent conventional testicular sperm extraction. The sperm recovery rate and histopathologic findings of the retrieved testicular tissue were compared between both groups. Results We found no difference in the sperm recovery rate (P = .083) between both groups. Spinal cord injury patients treated with mirabegron had better spermatogenesis than those not treated with mirabegron (P Conclusions From these data, we conclude that the therapeutic dose of mirabegron had no harmful effect on spermatogenesis in spinal cord injury patients of reproductive age.

Ponesimod is a sphingosphine-1-phosphate receptor modulator being developed for the treatment of multiple sclerosis. The effects of disease-modifying treatments on magnetic resonance imaging (MRI) lesions in relapsing multiple sclerosis accurately predict effects on clinical relapses, therefore MRI lesion counts are generally accepted efficacy endpoints in phase II clinical studies of multiple sclerosis disease-modifying treatments. Here, we characterize the effect of ponesimod systemic exposure on the cumulative number of T1 gadolinium-enhancing (Gd+) lesions and the annualized relapse rate in a phase IIb study. This study assessed the cumulative number of new Gd+ lesions on T1-weighted MRI scans (primary endpoint) at weeks 12, 16, 20, and 24 and the annualized relapse rate (secondary endpoint). The effect of the demographic and prognostic covariates of sex, age, weight, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were explored. Analyses were performed using NONMEM, Version 7.3.0 (ICON plc). An increase in ponesimod exposure led to a statistically significant decrease in the cumulative T1 Gd+ lesions on MRI from week 12 to 24 of treatment. Increasing the ponesimod daily dose beyond 20 mg did not provide significant additional benefits. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were associated with a higher number of new cumulative T1 Gd+ from week 12 to 24 of treatment. This analysis shows a relationship between ponesimod exposure and the cumulative number of new T1 Gd+ lesions. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Score at baseline were not found to be importantly associated with the magnitude of ponesimod effect, and consequently, there is no indication from these analyses that dosage adjustments based on the explored covariates are warranted. ClinicalTrials.gov Identifier: NCT01006265, registration date 1 November, 2009.

Giardia intestinalis is a worldwide parasite. Drugs used for the treatment of giardiasis are metronidazole, albendazole and nitazoxanide. The development of drug resistance is an obstacle to the effective treatment. Resistance mechanisms in some parasites involve the participation of ATP-binding cassette (ABC) transporter superfamily. To find if the ATP-binding cassette genes are overexpressed in trophozoites treated with albendazole or nitazoxanide. A search for ATP-binding cassette genes in Giardia sequence database (GiardiaDB) was done and six genes were selected. Trophozoites treated with albendazole or nitazoxanide and the expression of these six ABC genes was quantitated by real-time RT-PCR. The ABC-C1 gene was selected, and a fragment cloned. The ABC-C1 protein was expressed, and polyclonal antibodies were elicited in mice to detect the protein in treated trophozoites, finally a docking analysis was performed for ABC-C1 and tizoxanide interaction. Bioinformatics analysis showed that the ATP-binding cassette (ABC) topology is present in the six proteins. The qRT-PCR revealed that the ABC-C1 gene was overexpressed in cells incubated with nitazoxanide or albendazole. Confocal analysis showed that ABC-C1 protein levels increased in trophozoites with both treatments but was higher with nitazoxanide. The mark was detected heavily in the periphery of the cells. Using a docking analysis, it was found that the nitazoxanide metabolite, tizoxanide was docked close to the ATP-binding region as well as in the exit tunnel, located in the transmembrane region. These findings in Giardia intestinalis, support the possible role of ABC-C1 in drug efflux.

Summary Background Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. Methods This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov , NCT03056755 . Findings Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5–15·9). 61 (50·4%; 95% CI 41·2–59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. Interpretation BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Funding Novartis Pharmaceuticals.

The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non‐randomized controlled trial included 62 patients on the triple combination treatment versus 51 age‐ and sex‐matched patients on routine supportive treatment. all of them confirmed cases by positive reverse‐transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS‐COV2 from the nasopharynx in a shorter time than symptomatic therapy.

Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein—Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (<

In patients with atrial fibrillation, incomplete adherence to anticoagulants increases risk of stroke. Non-warfarin oral anticoagulants (NOACs) are expensive; we evaluated whether higher copayments are associated with lower NOAC adherence.Using a national claims database of commercially-insured patients, we performed a cohort study of patients with atrial fibrillation who newly initiated a NOAC from 2012 to 2018. Patients were stratified into low ($35), medium ($35-$59), or high (≥$60) copayments and propensity-score weighted based on demographics, insurance characteristics, comorbidities, prior health care utilization, calendar year, and the NOAC received. Follow-up was 1 year, with censoring for switching to a different anticoagulant, undergoing an ablation procedure, disenrolling from the insurance plan, or death. The primary outcome was adherence, measured by proportion of days covered (PDC). Secondary outcomes included NOAC discontinuation (no refill for 30 days after the end of NOAC supply) and switching anticoagulants. We compared PDC using a Kruskal-Wallis test and rates of discontinuation and switching using Cox proportional hazards models.After weighting patients across the 3 copayment groups, the effective sample size was 17,558 patients, with balance across 50 clinical and demographic covariates (standardized differences0.1). Mean age was 62 years, 29% of patients were female, and apixaban (43%), and rivaroxaban (38%) were the most common NOACs. Higher copayments were associated with lower adherence (P.001), with a PDC of 0.82 (Interquartile range [IQR] 0.36-0.98) among those with high copayments, 0.85 (IQR 0.41-0.98) among those with medium copayments, and 0.88 (IQR 0.41-0.99) among those with low copayments. Compared to patients with low copayments, patients with high copayments had higher rates of discontinuation (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.08-1.19; P.001).Among atrial fibrillation patients newly initiating NOACs, higher copayments in commercial insurance were associated with lower adherence and higher rates of discontinuation in the first year. Policies to lower or limit cost-sharing of important medications may lead to improved adherence and better outcomes among patients receiving NOACs.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran.

Background: Thiazolopyrimidine analogues are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. Objective: To report the synthesis of novel bromothiazolopyrimidine derivatives and the study of both molecular modeling and in-vitro anticancer activity. Methods: Novel bromothiazolopyrimidine derivatives 5-18 have been prepared from 2-bromo-3-(4- chlorophenyl)-1-(3,4-dimethylphenyl)-propenone 3 as a key starting compound. The anti-cancer activities of the new compounds were evaluated against HepG2, MCF-7, A549 and HCT116 cell lines. Results: The compounds 16, 17 and 18 showed cytotoxic and growth inhibitory activities on both colon and lung cells. The cytotoxic activities of the novel synthetic compounds 8, 9, 11, 16, 17 and 18 were due to CDC25 phosphatases inhibition as shown by the enzymatic binding assay. Although compounds 8, 9 and 11 have only demonstrated CDC25B phosphatases inhibition. Conclusion: The novel bromothiazolopyrimidine derivatives showed promising in vitro anticancer activities against colon cancer HCT116 and lung cancer A549 cell lines comparable to the anticancer drug doxorubicin.

The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated.Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve.The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study.Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

INTRODUCTION: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. METHODS: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein e4 (APOE e4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. RESULTS: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non-carriers. DISCUSSION: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.

AIM The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. METHODS We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. RESULTS While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. CONCLUSION These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

Purpose Recently, guidelines recommended the use of direct oral anticoagulants (DOACs) for the management of non-valvular atrial fibrillation (NVAF). Postoperative atrial fibrillation (POAF) is the most common post-surgical complication of cardiac surgery, but the efficacy and safety of DOAC for POAF have rarely been investigated. We conducted a prospective observational study to investigate the efficacy and safety of DOAC administered immediately after POAF. Materials and methods In all, 135 patients that experienced POAF after cardiac surgery were treated with a DOAC. Primary endpoints were either bleeding or thromboembolic events. Secondary endpoints included changes in hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (APTT), serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and pleural/pericardial effusion. Results Patients were treated with apixaban (n = 31), edoxaban (n = 87), and rivaroxaban (n = 17). Major bleeding (p = 0.011) and gastrointestinal (GI) bleeding (p = 0.047) were significantly more frequent in the rivaroxaban group. Stroke was observed in one rivaroxaban group patient and none in the other two groups. Conclusion DOAC as anticoagulation therapy for the early intervention of POAF following cardiac surgery is associated with a low incidence of major bleeding; a favorable safety profile and excellent efficacy were demonstrated for DOAC. Furthermore, our results indicate that the safety and efficacy of apixaban and edoxaban are better than rivaroxaban.

OBJECTIVE To analyze the safety of mirabegron add-on therapy in men with overactive bladder symptoms concurrently receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia. METHODS The Phase 4 PLUS study comprised a 4-week run-in period (tamsulosin [0.4 mg]) and a 12-week randomized treatment period (add-on treatment: mirabegron [25 mg] or placebo). Doses were increased to mirabegron 50 mg or matched placebo after 4 weeks. Safety assessments: treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms, and changes in postvoid residual volume and maximum urinary flow (Qmax). RESULTS The safety analysis set included 352 tamsulosin plus mirabegron (TAM + MIRA) and 354 tamsulosin plus placebo (TAM + PL) patients. The frequency of overall TEAEs was higher with TAM + PL, although a higher incidence of drug-related TEAEs was observed with TAM + MIRA. Most TEAEs were mild or moderate in severity. Drug-related serious TEAEs were reported for 3 patients (2 TAM + MIRA patients: acute myocardial infarction with cerebral infarction and angina pectoris, 1 TAM + PL patient: lacunar stroke). Hypertension, headache, and nasopharyngitis were the most common TEAEs. Special interest TEAEs were infrequently reported. The most common was urinary retention and 2 TAM + MIRA patients required catheterization (neither led to discontinuation). No major changes in blood pressure or pulse rate were noted and similar electrocardiogram parameters were observed for both groups. Changes in mean postvoid residual volume and Qmax were not clinically meaningful. CONCLUSION No unexpected safety concerns were noted in men receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia who subsequently received mirabegron add-on therapy.

Background Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. In Brazil, even though low-molecular-weight heparin (LMWH) is the gold standard of care for the management of cancer-associated thrombosis (CAT), its cost limits its use and therefore warfarin is commonly prescribed. Direct oral anticoagulants (DOACs), such as edoxaban, have been introduced as an alternative in this setting. Objective The aim of this study was to compare the cost-effectiveness of edoxaban with LMWH (Model 1) and warfarin (Model 2) to support clinicians and hospitals when choosing an anticoagulant to manage CAT. Materials and methods Cost-effectiveness analyses were performed using Markov state-transition models over a timeframe of 5 years, in a hypothetical, 64 years-old patients cancer population with an index VTE event. Transition probabilities, costs, quality-adjusted life years (QALYs) and risk reductions were either derived from the literature, estimated or calculated. A willingness-to-pay limit of 3 Gross Domestic Product (GDP) per head was used. Deterministic and probabilistic sensitivity analyses were performed for robustness. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained. Results Model 1 base case analysis demonstrated dominance of edoxaban compared to LMWH, with an ICER of $5204.46, representing cost saved per QALY lost. In Model 2, edoxaban was associated with a $736.90 cost increase vs. warfarin, with an ICER of $2541.03. Sensitivity analyses confirmed base-case results. Conclusion Edoxaban represents a cost-saving alternative to LMWH for the management of CAT and is cost-effective vs. warfarin.

The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay is one of the most commonly used assays to assess cell proliferation and cytotoxicity, but i...

The effect of edoxaban on plasma prothrombin fragment 1+2 (PTF1+2), a sensitive maker of in vivo thrombin generation, has not been fully investigated in nonvalvular atrial fibrillation (NVAF). We compared plasma PTF1+2 levels between 25 NVAF patients receiving warfarin and 100 NVAF patients receiving edoxaban and additionally analyzed the association between plasma PTF1+2 levels and the dose of edoxaban. Plasma PTF1+2 levels were significantly higher in patients receiving edoxaban than in those receiving warfarin (141.5 ± 50.0 pmol/l vs 93.1 ± 55.7 pmol/l, p0.001). The prevalence of plasma PF1+2 levels above the upper limit (229 pmol/l) of the normal range did not differ between the 2 groups (4% vs 4%), whereas the prevalence of plasma PTF1+2 levels below the lower limit (69 pmol/l) of the normal range was significantly lower in patients receiving edoxaban than in those receiving warfarin (1% vs 48%, p0.001). Multiple linear regression analysis identified age and warfarin treatment as independent variables associated with the plasma PTF1+2 level. In a subgroup analysis, plasma PTF1+2 levels were significantly higher in 58 receiving edoxaban of 30 mg/day than in 42 receiving edoxaban of 60 mg/day (157.6 ± 50.8 pmol/l vs 121.6 ± 39.8 pmol/l, p = 0.01); however, after adjusting for confounding factors, the dose of edoxaban was not independently associated with the plasma PTF1+2 level. In conclusion, edoxaban sufficiently inhibits thrombin generation unrelated to its dose in NVAF, although its inhibitory effect is weaker compared with warfarin.

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

Non–vitamin K antagonist oral anticoagulants (NOACs) are a widely prescribed treatment to prevent stroke in patients with nonvalvular atrial fibrillation, and a therapy and preventative measure to prevent recurrences following venous thromboembolism. Optimal use of NOACs requires a thorough knowledge of the pharmacology of these drugs, as well as an understanding of patient factors affecting their use. The 4 NOACs—dabigatran, apixaban, edoxaban, and rivaroxaban are available in a range of doses suitable for differing indications and with a variety of dose reduction criteria. Identification of the correct dose is one of the key challenges in the individualization of treatment. Elderly patients with atrial fibrillation are at a greater risk of both ischemic and bleeding events than younger patients. Consequently, it is essential to achieve balance in anticoagulation strategies. Medication adherence to NOACs is important for safe and effective treatment, particularly in elderly populations. A growing body of evidence shows that once-daily dosing improves adherence and persistence to therapy, without having an impact on bleeding risk.

The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.

Schizophrenia is a severe brain disorder with an excess morbidity and mortality partly due to a higher incidence of metabolic disturbances and cardio-vascular events. The exposure to antipsychotic treatment has been observed linked to these metabolic abnormalities. This study explores the metabolic effects of aripiprazol, quetiapine and ziprasidone in drug-naïve patients with a first-episode of psychosis, at long-term. Two-hundred and two patients with first-episode of psychosis were included in the study. Patients were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Clinical, sociodemographic and anthropometric measures, as well as lipid and glyceamic parameters, were recorded at baseline and after three years of initiating antipsychotic treatment. Body weight and BMI increased significantly after 3 years of follow-up (F = 35.0, p, The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de Salud Carlos III PI020499, PI050427, PI060507; Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004; SENY Fundació Research Grant CI 2005–0308007; and Fundación Marqués de Valdecilla API07/011.

Background Antithrombotic drugs decrease stroke risk in patients with atrial fibrillation, but they increase bleeding risk, particularly in older adults at high risk for falls. We aimed to determine the most cost-effective antithrombotic therapy in older adults with atrial fibrillation who are at high risk for falls. Methods We conducted a mathematical modelling study from July 2019 to March 2020 based on the Ontario, Canada, health care system. We derived the base-case age, sex and fall risk distribution from a published cohort of older adults at risk for falls, and the bleeding and stroke risk parameters from an atrial fibrillation trial population. Using a probabilistic microsimulation Markov decision model, we calculated quality-adjusted life years (QALYs), total cost and incremental cost-effectiveness ratios (ICERs) for each of acetylsalicylic acid (ASA), warfarin, apixaban, dabigatran, rivaroxaban and edoxaban. Cost data were adjusted for inflation to 2018 values. The analysis used the Ontario public payer perspective with a lifetime horizon. Results In our model, the most cost-effective antithrombotic therapy for atrial fibrillation in older patients at risk for falls was apixaban, with an ICER of $8517 per QALY gained (5.86 QALYs at $92 056) over ASA. It was a dominant strategy over warfarin and the other antithrombotic agents. There was moderate uncertainty in cost-effectiveness ranking, with apixaban as the preferred choice in 66% of model iterations (given willingness to pay of $50 000 per QALY gained); edoxaban, 30 mg, was preferred in 31% of iterations. Sensitivity analysis across ranges of age, bleeding risk and fall risk still favoured apixaban over the other medications. Interpretation From a public payer perspective, apixaban is the most cost-effective antithrombotic agent in older adults at high risk for falls. Health care funders should implement strategies to encourage use of the most cost-effective medication in this population.

Introduction: Nitazoxanide has shown efficacy in vitro against coronavirus infections (MERS, SARS, SARS-CoV-2). The aim of this report is to describe the results of treating COVID-19 positive patients with nitazoxanide in three clinical settings: pregnancy/puerperium, hospitalized patients in an Internal Medicine Service and in an ambulatory setting. Methodology: This was a prospective follow-up and report of COVID-19 cases in three different situations, pregnant women, hospitalized patients receiving medical attention in an Internal Medicine Service and ambulatory patients residing in Toluca City, and Mexico City. Results: The experience with a first group of 20 women, pregnant (17) or in immediate puerperium (3) was successful in 18 cases with two unfortunate deaths. The five cases treated in an Internal Medicine service showed a positive outcome with two patients weaned from mechanical ventilation. Of the remaining 16 patients treated in an ambulatory setting, all got cured. Nitazoxanide seems to be useful against SARS-CoV-2, not only in an early intervention but also in critical condition as well as in pregnancy without undesired effects for the babies. As an adjunctive therapy budesonide was used that seems to contribute to the clinical improvement. Conclusions: Nitazoxanide could be useful against COVID-19 as a safe and available regimen to be tested in a massive way immediately.

Objectives To investigate the cardiovascular safety of mirabegron add‐on treatment to tamsulosin in male patients with residual overactive bladder symptoms. Methods This was a post hoc analysis of MATCH, the first double‐blind, placebo‐controlled study comparing mirabegron and placebo as add‐on therapy to tamsulosin for treatment of overactive bladder in men with lower urinary tract symptoms. The analysis focused on treatment‐emergent adverse events relating to the cardiovascular system or blood pressure, and changes in vital signs during 12 weeks of follow‐up. Results Cardiovascular‐related treatment‐emergent adverse events were reported by 6/566 patients, although only one serious treatment‐emergent adverse event was related to treatment (unstable angina in the tamsulosin + placebo group). Hypertension (two patients) and increased blood pressure (one patient) were reported in the tamsulosin + placebo group, but there were no blood pressure‐related treatment‐emergent adverse events among tamsulosin + mirabegron patients. There were no clinically meaningful changes from baseline in blood pressure, and changes in pulse rate were small (+1.2 bpm in the tamsulosin + mirabegron group). Increased pulse rate was more frequent with tamsulosin + mirabegron than with tamsulosin + placebo in older patients, although within the normal range. Conclusions Cardiovascular‐related adverse events were uncommon in both treatment groups. Mirabegron is a well‐tolerated add‐on therapy to tamsulosin in Japanese and Korean males with residual overactive bladder symptoms.