Scalable and selective deuteration of (hetero)arenes

Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. For this purpose, many efficient methodologies have been developed that allow for the small-scale synthesis of selectively deuterated compounds. Due to the development of deuterated compounds as active drug ingredients, there is a growing interest in scalable methods for deuteration. The development of methodologies for large-scale deuterium labelling in industrial settings requires technologies that are reliable, robust and scalable. Here we show that a nanostructured iron catalyst, prepared by combining cellulose with abundant iron salts, permits the selective deuteration of (hetero)arenes including anilines, phenols, indoles and other heterocycles, using inexpensive D2O under hydrogen pressure. This methodology represents an easily scalable deuteration (demonstrated by the synthesis of deuterium-containing products on the kilogram scale) and the air- and water-stable catalyst enables efficient labelling in a straightforward manner with high quality control.

A Smartphone Application as an Exploratory Endpoint in a Phase 3 Parkinson’s Disease Clinical Trial: A Pilot Study

<b><i>Background:</i></b> Smartphones can generate objective measures of Parkinson’s disease (PD) and supplement traditional in-person rating scales. However, smartphone use in clinical trials has been limited. <b><i>Objective:</i></b> This study aimed to determine the feasibility of introducing a smartphone research application into a PD clinical trial and to evaluate the resulting measures. <b><i>Methods:</i></b> A smartphone application was introduced part-way into a phase 3 randomized clinical trial of inosine. The application included finger tapping, gait, and cognition tests, and participants were asked to complete an assessment battery at home and in clinic alongside the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). <b><i>Results:</i></b> Of 236 eligible participants in the parent study, 88 (37%) consented to participate, and 59 (27 randomized to inosine and 32 to placebo) completed a baseline smartphone assessment. These 59 participants collectively completed 1,292 batteries of assessments. The proportion of participants who completed at least one smartphone assessment was 61% at 3, 54% at 6, and 35% at 12 months. Finger tapping speed correlated weakly with the part III motor portion (<i>r</i> = −0.16, left hand; <i>r</i> = −0.04, right hand) and total (<i>r</i> = −0.14) MDS-UPDRS. Gait speed correlated better with the same measures (<i>r</i> = −0.25, part III motor; <i>r</i> = −0.34, total). Over 6 months, finger tapping speed, gait speed, and memory scores did not differ between those randomized to active drug or placebo. <b><i>Conclusions:</i></b> Introducing a smartphone application midway into a phase 3 clinical trial was challenging. Measures of bradykinesia and gait speed correlated modestly with traditional outcomes and were consistent with the study’s overall findings, which found no benefit of the active drug.

Nocebo effect in multiple system atrophy: systematic review and meta-analysis of placebo-controlled clinical trials

Background Nocebo effect is prevalent among neurological diseases, resulting in low adherence and treatment outcome. We sought to examine the nocebo effect in randomized controlled trials (RCTs) in multiple system atrophy (MSA). Methods We searched RCTs in MSA from Medline since September, 2021. RCTs for drug treatment conducted in adult MSA patients with more than 5 cases in each treatment arm were included. We assessed the number of dropout due to placebo intolerance. We also did a symptomatic/disease-modifying subgroup analysis based on two different treatment purposes. The STATA software was used for statistical analysis. Overall heterogeneity was assessed using the Cochran Q and I2. Results Data were extracted from 11 RCTs fulfilling our search criteria. Of 540 placebo-treated patients, 64.2% reported at least one adverse event (AE) and 7.5% reported dropout because of AEs. The chance of dropping out because of an AE and experiencing at least one AE did not differ between placebo and active drug treatment arms. Besides, the pooled nocebo dropout rate in the symptomatic subgroup was similar to that of the disease-modifying subgroup. Conclusion In MSA RCTs, nocebo dropout rate was not at a low level among neurological disorders. Nocebo effect was an important reason of dropout because of AE in placebo and active drug treatment arms. Different treatment purposes may not influence nocebo effect.

Biosimilars monoclonal antibodies in the therapy of inflammatory bowel diseases An important milestone in the development of Crohn’s disease and ulcerative colitis therapy, or just a sophisticated generic?

Summary: In 2013, EMA approved the fi rst biosimilar infl iximab CT-P13 for clinical practice in all indications of the original infl iximab. Since 2015, biosimilar infl iximab has been extensively used in patients with Crohn‘s disease and ulcerative colitis also in the Czech Republic. Biosimilar infl iximab is very similar to the original infl iximab in terms of its macromolecular structure, and its clinical eff ects, adverse events and immunogenicity are identical to those of the original infl iximab. Biosimilar biologics which have been introduced in clinical practice signifi cantly reduced therapeutic costs and improved access to an innovative therapy and facilitated a new therapeutic strategy, with pro-active drug monitoring and fl exibility in dosing. Biosimilars are associated with a signifi cant improvement in the therapeutic armamentarium, which makes them one of the important therapeutic milestones in the treatment of infl ammatory bowel disease. Key words: bio similars – bio logic therapy – Crohn’s disease – ulcerative colitis

Farnesol abrogates biofilm- and efflux pump- associated genes in drug resistant Candida auris strains

Background: Candida auris, a decade old Candida species, has been identified globally as a significant nosocomial multidrug resistant (MDR) pathogen responsible for causing invasive outbreaks. Biofilms and over expression of efflux pumps such as Major Facilitator Superfamily and ATP Binding Cassette are known to cause multidrug resistance in Candida species, including C. auris. Therefore, targeting these factors may prove an effective approach to combat MDR in C. auris. Methods: In this study, 25 clinical isolates of C. auris from different hospitals of South Africa were used. Antifungal susceptibility profile of all the isolates against commonly used drugs was determined following CLSI recommended guidelines. Rhodamine-6-G extracellular efflux and intracellular accumulation assays were used to study active drug efflux mechanism. We further studied the role of farnesol in modulating development of biofilms and drug efflux in C. auris. Down-regulation of biofilm- and efflux pump- associated genes by farnesol was also investigated. CLSM analysis for examining C. auris biofilm architecture among treated and untreated isolates. Results: Most of the isolates (twenty-two) were found resistant to FLZ whereas five were resistant to AmB. All the isolates were found capable of biofilm formation and ornamented with active drug efflux mechanism. The MIC for planktonic cells ranged from 62.5-125 mM and for sessile cells was 125 mM (0 h and 4 h biofilm) and 500 mM (12 h and 24 h biofilm), CLSM studies also confirmed these findings. Farnesol also blocked efflux pumps and down-regulated biofilm- and efflux pump- associated genes. Conclusion: Modulation of biofilm- and efflux pump- associated genes by farnesol represent a promising approach in combating C. auris infection.

Monitored therapy of sporadic mycobacteriosis caused by Mycobacterium genavense in Atlantic canaries (Serinus canaria) and Bengalese finch (Lonchura striata)

Introduction Mycobacteriosis is a significant disease of companion and wild birds which causes emaciation and widely distributed lesions, as well as being a potential zoonosis. Its primary aetiological agents in birds are Mycobacterium avium subsp. avium and the fastidious Mycobacterium genavense. This study monitored the therapy of birds naturally infected with Mycobacterium genavense to gain understanding of its effectiveness and the interrelation of co-infections with the disease course and pharmacotherapy. Material and Methods Five Atlantic canaries (Serinus canaria) and one Bengalese finch (Lonchura striata) with tentative diagnoses of mycobacteriosis resulting from M. genavense infection were treated twice daily with clarithromycin at 40 mg/kg, ethambutol at 30 mg/kg, and moxifloxacin at 10 mg/kg for 6 months. Two canaries were also found to be carriers of Cryptosporidium galli. Mycobacteria in faecal samples of all birds were investigated by bacterioscopy and quantitative PCR. Results Molecular tests yielded positive results for up to four months after treatment initiation for M. genavense and Cryptosporidium, but microscopy failed to detect the latter after four weeks in specimens from one canary. Co-infections with polyomavirus (in all birds) and circovirus and bornavirus (in canaries) were diagnosed. Two birds died during treatment and one was euthanised because of other disease, 1 month after treatment completion. Three canaries were in relatively good health a year after treatment. Conclusion Canary circovirus and polyomavirus co-infection may suppress the immune system and this may facilitate the development of mycobacteriosis. The set of drugs used led to the complete cure of mycobacteriosis in three canaries. In one bird the disease returned. Clarithromycin was the active drug against C. galli. Molecular methods serve well to monitor mycobacteriosis therapy and identify M. genavense and C. galli carriage.

Influence of Structural, Electronic and Spin Properties of ND[NV] - Surface Group Conjugates on Formation of Their Biological Activity: Quantum Chemical Simulations

To estimate possible biological activity of conjugates based on nanodiamond with an NV center inside (ND[NV]), with various functional groups located on its surface, their structural, electronic, and spin properties were calculated using the PM6 method. The energy gap between HOMO and LUMO of the complex was used as a main indicator of biological activity. It has been shown that complexes with OH or H groups attached to the (111) surface are most stable in an aqueous medium. Analysis of spin density and HOMO and LUMO localization shows that complexes ND[NV] may be not just an inert carrier of a biologically active drug or means of visualizing drug delivery, but are also directly involved in the formation of the biological activity of the conjugate.

Diagnosis of Behavioral Symptoms of Dementia and CNS-Active Drug Use Among Diverse Persons Living With Dementia

Approximately 90% of persons living with dementia (PLWD) experience behavioral and psychological symptoms of dementia (BPSD). Studies demonstrated high use of central nervous system (CNS) active drugs in nursing homes; one recent study documented high use among community-dwelling PLWD. Racial/ethnic disparities in BPSD diagnosis and CNS-active drug use, however, are unknown. We quantified disparities in BPSD diagnoses and CNS-active drug use using 100% Medicare Part A and B claims, 2017-2019, and Part D, 2018-2019. Beneficiaries were ages 65 and older in 2017, community-dwelling, and had a dementia diagnosis (n=801,597). We estimated models of CNS-active drug use to quantify racial/ethnic differences adjusting for confounders. Among PLWD, 66% had a BPSD diagnosis and 65% were taking a CNS-acting drug. Asians/Pacific Islanders were less likely to have a BPSD diagnosis (55%) than other groups, particularly affective diagnoses (40%). Whites were most likely to have any diagnosis (67%). Blacks were most likely to have hyperactivity diagnoses (7%). Antidepressants were most commonly used drug class (44%). Thirteen percent used an antipsychotic. Models adjusted for age, sex, comorbid conditions, dual-eligibility and BPSD diagnoses, showed non-Whites were less likely to use any CNS-active drug than Whites, but Blacks and Hispanics were slightly more likely to use antipsychotics. We found racial/ethnic differences in BPSD diagnoses and CNS-active drug use. Whether these disparities are due to differences in BPSD symptoms, health-care access or care-seeking remains an important question. Further study of disparity in outcomes associated with use will inform risk and benefit of CNS-active drugs use among PLWD.