Journal of Pharma and Pharmaceutical Sciences Indirect Determination of Process Impurity Cetrimonium Bromide in Neisseria meningitidis A/C/Y/W-135-DT Conjugate Vaccine by HPAEC-PAD Method

Abstract A validated High Performance Anion Exchange-Pulsed Amperometric Detection (HPAEC-PAD) indirect method is described to determine traces of process impurity cetrimonium bromide (CTAB) in Neisseria meningitidis A/C/Y/W-135-DT conjugate vaccine. Method reported here, measures the bromide ion present in CTAB. As part of impurity profiling, samples of crude and purified meningococcal four serogroup (A, C, W-135 and Y) polysaccharides and final vialed conjugate vaccine were analyzed for CTAB content. Vaccine grade pure polysaccharides, the control and the final vaccines both formulated in phosphate buffered saline (PBS) showed sub ppm levels of CTAB impurity. PBS used in this work showed detectable bromide levels presumably due to contamination originated from saline. The proposed method is very sensitive (LOD=0.04 ppm, LOQ =0.11 ppm), accurate, reproducible and compatible with polysaccharide and PBS environments

Next Generation Aryl Hydantoins as Antischistosomal Agents

Schistosomiasis, also known as “snail fever,” is both an acute and chronic disease spread by trematode flukes from the tropical parasitic worm genus Schistosoma. The flukes are spread via diseased freshwater snails, which release the parasites into the water column where they find a new human host. According to the World Health Organization (WHO), 99 million people were treated for schistosomiasis in 2017. The primary treatment used to combat schistosomiasis is the drug praziquantel (PZQ), but due to high drug pressure and widespread administration, its effectiveness has eroded because of rising drug resistance. Furthermore, PZQ is active against adult but not juvenile schistosomes, a potential factor regarding the frequently observed failed treatments. In 1980, the orally active hydantoin Ro 13-3978 was identified as a compound with antischistosomal activity. Although Ro 13-3978 is an effective inhibitor of schistosome growth, its antiandrogenic side effects on the host were undesirable. Utilizing the Ro 13-3978 scaffold as a starting point, we developed several libraries of structurally diverse analogs of Ro 13-3978. While numerous compounds identified exhibited good antischistosomal activity and lower antiandrogenic effects compared to Ro 13-3978, the desired potency was not achieved and a clear correlation between good activity/low side effects and compound structural features was indistinct. Building on this foundation, we reexamined the Ro 13-3978 SAR and designed a series of compounds to strategically separate the desired antischistosomal properties of aryl hydantoins from the undesirable antiandrogenic side effects. This research translated to the discovery of drug candidate 27 (AR102), which like Ro 13-3978, has high adult in vivo antischistosomal activity, but unlike Ro 13-3978, has substantial juvenile in vivo antischistosomal activity and no androgen receptor activity. Drug candidate 27 also possesses superior pharmacokinetic properties compared to Ro 13-3978. After scale-up synthesis, 27 is now progressing up the drug discovery ladder and we anticipate it will function as a new potent schistosomiasis treatment with broad-spectrum activity against multiple schistosome species and life stages

Chemical Reactions of Indole Alkaloids That Enable Rapid Access to New Scaffolds for Discovery

This graphical review provides a concise overview of indole alkaloids and chemical reactions that have been reported to transform both these natural products and derivatives to rapidly access new molecular scaffolds. Select biologically active compounds from these synthetic efforts are reported herein

One-Pot, Metal-Free Conversion of Anilines to Aryl Bromides and Iodides

A metal-free synthesis of aryl bromides and iodides from anilines via halogen abstraction from bromotrichloromethane and diiodomethane is described. This one-pot reaction affords aryl halides from the corresponding anilines in moderate to excellent yields without isolation of diazonium salts. The transformation has short reaction times, a simple workup, and insensitivity to moisture and air and avoids excess halogenation. DFT calculations support a S_RN1 mechanism. This method represents a convenient alternative to the classic Sandmeyer reaction

Characterizing Self-Reports of Self-Identified Patient Experiences with Methadone Maintenance Treatment on an Online Community during COVID-19

Background: The coronavirus disease (COVID-19) pandemic has impacted patients receiving methadone maintenance treatment (MMT) through opioid treatment programs (OTPs), especially because of the unique challenges of the care delivery model. Previously, documentation of patient experiences during emergencies often comes years after the fact, in part because there is a substantial data void in real-time. Methods: We extracted 308 posts that mention COVID-19 keywords on r/methadone, an online community for patients receiving MMT to share information, on Reddit occurring between January 31, 2020 and September 30, 2020. 215 of these posts self-report an impact to their MMT. Using qualitative content analysis, we characterized the impacts described in these posts and identified four emergent themes describing patients' experience of impacts to MMT during COVID-19. Results: The themes included (1) 54.4% of posts reporting impediments to accessing their methadone, (2) 28.4% reporting impediments to accessing physicial OTPs, (3) 19.5% reporting having to self-manage their care, and (4) 4.7% reporting impediments to accessing OTP providers and staff. Conclusions: Patients described unanticipated consequences to one-size-fits-all policies that are unevenly applied resulting in suboptimal dosing, increased perceived risk of acquiring COVID-19 at OTPs, and reduced interaction with OTP providers and staff. While preliminary, these results are formative for follow-up surveillance metrics for patients of OTPs as well as digitally-mediated resource needs for this online community. This study serves as a model of how social media can be employed during and after emergencies to hear the lived experiences of patients for informed emergency preparedness and response

Monitoring HIV testing and pre-exposure prophylaxis information seeking by combining digital and traditional data.

BackgroundPublic health is increasingly turning to non-traditional digital data to inform HIV prevention and control strategies. We demonstrate a parsimonious method using both traditional survey and internet search histories to provide new insights into HIV testing and pre-exposure prophylaxis (PrEP) information seeking that can be easily extended to other settings.MethodWe modeled how US internet search volumes from 2019 for HIV testing and PrEP compared against expected search volumes for HIV testing and PrEP using state HIV prevalence and socioeconomic characteristics as predictors. States with search volumes outside the upper and lower bound confidence interval were labeled as either over or under performing. State performance was evaluated by (a) Centers for Disease Control and Prevention designation as a hotspot for new HIV diagnoses (b) expanding Medicaid coverage.ResultsTen states over-performed in models assessing information seeking for HIV testing, while eleven states under-performed. Thirteen states over-performed in models assessing internet searches for PrEP information, while thirteen states under-performed. States that expanded Medicaid coverage were more likely to over perform in PrEP models than states that did not expand Medicaid coverage. While states that were hotspots for new HIV diagnoses were more likely to over perform on HIV testing searches.ConclusionOur study derived a method of measuring HIV and PrEP information seeking that is comparable across states. Several states exhibited information seeking for PrEP and HIV testing that deviated from model assessments. Statewide search volume for PrEP information was affected by a state's decision to expand Medicaid coverage. Our research provides health officials with an innovative way to monitor statewide interest in PrEP and HIV testing using a metric for information-seeking that is comparable across states

Monitoring HIV testing and pre-exposure prophylaxis information seeking by combining digital and traditional data.

BackgroundPublic health is increasingly turning to non-traditional digital data to inform HIV prevention and control strategies. We demonstrate a parsimonious method using both traditional survey and internet search histories to provide new insights into HIV testing and pre-exposure prophylaxis (PrEP) information seeking that can be easily extended to other settings.MethodWe modeled how US internet search volumes from 2019 for HIV testing and PrEP compared against expected search volumes for HIV testing and PrEP using state HIV prevalence and socioeconomic characteristics as predictors. States with search volumes outside the upper and lower bound confidence interval were labeled as either over or under performing. State performance was evaluated by (a) Centers for Disease Control and Prevention designation as a hotspot for new HIV diagnoses (b) expanding Medicaid coverage.ResultsTen states over-performed in models assessing information seeking for HIV testing, while eleven states under-performed. Thirteen states over-performed in models assessing internet searches for PrEP information, while thirteen states under-performed. States that expanded Medicaid coverage were more likely to over perform in PrEP models than states that did not expand Medicaid coverage. While states that were hotspots for new HIV diagnoses were more likely to over perform on HIV testing searches.ConclusionOur study derived a method of measuring HIV and PrEP information seeking that is comparable across states. Several states exhibited information seeking for PrEP and HIV testing that deviated from model assessments. Statewide search volume for PrEP information was affected by a state's decision to expand Medicaid coverage. Our research provides health officials with an innovative way to monitor statewide interest in PrEP and HIV testing using a metric for information-seeking that is comparable across states

Formation of 2‑Imino Benzo[<i>e</i>]‑1,3-oxazin-4-ones from Reactions of Salicylic Acids and Anilines with HATU: Mechanistic and Synthetic Studies

We describe a new 1-[Bis­(dimethylamino)­methylene]-1<i>H</i>-1,2,3-triazolo­[4,5-<i>b</i>]­pyridinium 3-oxide hexafluorophosphate (HATU)-mediated coupling reaction to produce 2-imino benzo­[<i>e</i>]-1,3-oxazin-4-ones from salicylic acids and anilines. Mechanistic studies support a reaction pathway in which HATU mediates carbon transfer to the initially formed salicylanilides to form in succession reactive tetramethylisouronium and <i>N</i>-acyl­(dimethyl)­isouronium intermediates, which then undergo imine–iminium exchange to generate the desired oxazinones

Diaryl Ureas as an Antiprotozoal Chemotype

We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N′-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD(7.4) values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no N,N′-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N′-diarylureas had antiprotozoal selectivities ≥10. One N,N′-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis