Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (−)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects

The 2024 Outline of Fungi and fungus-like taxa

With the simultaneous growth in interest from the mycological community to discover fungal species and classify them, there is also an important need to assemble all taxonomic information onto common platforms. Fungal classification is facing a rapidly evolving landscape and organizing genera into an appropriate taxonomic hierarchy is central to better structure a unified classification scheme and avoid incorrect taxonomic inferences. With this in mind, the Outlines of Fungi and fungus-like taxa (2020, 2022) were published as an open-source taxonomic scheme to assist mycologists to better understand the taxonomic position of species within the Fungal Kingdom as well as to improve the accuracy and consistency of our taxonomic language. In this paper, the third contribution to the series of Outline of Fungi and fungus-like taxa prepared by the Global Consortium for the Classification of Fungi and fungus-like taxa is published. The former is updated considering our previous reviews and the taxonomic changes based on recent taxonomic work. In addition, it is more comprehensive and derives more input and consensus from a larger number of mycologists worldwide. Apart from listing the position of a particular genus in a taxonomic level, nearly 1000 notes are provided for newly established genera and higher taxa introduced since 2022. The notes section emphasizes on recent findings with corresponding references, discusses background information to support the current taxonomic status and some controversial taxonomic issues are also highlighted. To elicit maximum taxonomic information, notes/taxa are linked to recognized databases such as Index Fungorum, Faces of Fungi, MycoBank and GenBank, Species Fungorum and others. A new feature includes links to Fungalpedia, offering notes in the Compendium of Fungi and fungus-like Organisms. When specific notes are not provided, links are available to webpages and relevant publications for genera or higher taxa to ease data accessibility. Following the recent synonymization of Caulochytriomycota under Chytridiomycota, with Caulochytriomycetes now classified as a class within the latter, based on formally described and currently accepted data, the Fungi comprises 19 Phyla, 83 classes, 1,220 families, 10,685 genera and ca 140,000 species. Of the genera, 39.5% are monotypic and this begs the question whether mycologists split genera unnecessarily or are we going to find other species in these genera as more parts of the world are surveyed? They are 433 speciose genera with more than 50 species. The document also highlights discussion of some important topics including number of genera categorized as incertae sedis status in higher level fungal classification. The number of species at the higher taxonomic level has always been a contentious issue especially when mycologists consider either a lumping or a splitting approach and herein we provide figures. Herein a summary of updates in the outline of Basidiomycota is provided with discussion on whether there are too many genera of Boletales, Ceratobasidiaceae, and speciose genera such as Colletotrichum. Specific case studies deal with Cortinarius, early diverging fungi, Glomeromycota, a diverse early divergent lineage of symbiotic fungi, Eurotiomycetes, marine fungi, Myxomycetes, Phyllosticta, Hymenochaetaceae and Polyporaceae and the longstanding practice of misapplying intercontinental conspecificity. The outline will aid to better stabilize fungal taxonomy and serves as a necessary tool for mycologists and other scientists interested in the classification of the Fungi

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Spatial Distribution of Heavy Metals in Sediments of the Negombo Lagoon, Sri Lanka

Heavy metals accumulate in the sediments of aquatic environments due to poor water solubility. Their toxic effect poses a significant threat to living organisms. Negombo Lagoon, a vital aquatic ecosystem in Sri Lanka, has become vulnerable to heavy metals mainly from urbanization-related anthropogenic activities. Previous research in this respect has sampling points restricted to the boundary area. Since the heavy metal concentration is a static parameter, continuous research needs to keep the data updated. This study aims to investigate the spatial distribution of several heavy metals (Cr, Ni, Co, Cu, As, Cd, and Pb) in the surficial sediment of the Negombo Lagoon. Fifteen grab sediment samples were collected from the lagoon and analyzed for heavy metal concentration and grain size. The range of concentrations of each metal in test samples were between (78.07 - 222.68 mg/kg) Cr, (376.7-1298.05 mg/kg) Ni, (15.875-43.74 mg/kg) Co, (32.45-112.79 mg/kg) Cu, (20.17-55.81 mg/kg) As, (0.30-1.4 mg/kg) Cd, and (16.57-70.97 mg/kg) Pb. Heavy metal concentrations and sediment grain sizes show significant spatial variation over the Negombo lagoon area. Heavy metals were highly concentrated in locations, where finer sediments are accumulated (i.e., towards the eastern and southern part of the lagoon). Heavy metal concentrations were found to be increased with the decreasing grain size. High heavy metal concentrations are also found at places where there is a river discharge. Among the sources which feed heavy metals into Negombo Lagoon anthropogenic activities such as municipal and industrial waste disposal, rapid urbanization, shipping, and naval activities etc. have a significant impact.</jats:p