This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Increased life expectancy and high costs of medicines and medical care have led to the use of herbal products. However, these items may contain toxic compounds that have an impact on public health. We will focus on the regulatory aspects and differences of these products marketed in the North American region (USA-Mexico-Canada) from government websites and selected literature. Mexico has an ancestral tradition of using plants for the treatment, improvement, and maintenance of human health as compared with Canada and the USA Currently, the use of herbal products in this region has a regulatory framework. The legal framework in these three countries is related to their history, idiosyncrasies, socio-economic and cultural aspects. Therefore, there are different public policies for herbal products consumed in the region. Mexico has a more specific classification of these products. In Canada, all herbal products are classified as natural health products and the safety and efficacy must be scientifically proven. In the USA, the development of botanical drugs is very recent. In particular, both herbal products classified as food supplements in Mexico and dietary supplements in the USA may have risks in both safety and efficacy.

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood–brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery.

Giardia duodenaliscauses giardiasis, a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole (MTZ) and albendazole (ABZ). The emergence of ABZ resistance in this parasite has prompted studies to elucidate the molecular mechanisms underlying this phenomenon.G.duodenalistrophozoites convert ABZ into its sulfoxide (ABZSO) and sulfone (ABZSOO) forms, despite lacking canonical enzymes involved in these processes, such as cytochrome P450s (CYP450s) and flavin-containing monooxygenases (FMOs). This study aims to identify the enzyme responsible for ABZ metabolism and its role in ABZ resistance inG.duodenalis. We first determined that the iron-containing cofactor heme induces higher mRNA expression levels of flavohemoglobin (gFlHb) inGiardiatrophozoites. Molecular docking analyses predict favorable interactions of gFlHb with ABZ, ABZSO and ABZSOO. Spectral analyses of recombinant gFlHb in the presence of ABZ, ABZSO and ABZSOO showed high affinities for each of these compounds withK_dvalues of 22.7, 19.1 and 23.8 nM respectively. ABZ and ABZSO enhanced gFlHb NADH oxidase activity (turnover number 14.5 min^-1), whereas LC-MS/MS analyses of the reaction products showed that gFlHb slowly oxygenates ABZ into ABZSO at a much lower rate (turnover number 0.01 min^-1). Further spectroscopic analyses showed that ABZ is indirectly oxidized to ABZSO by superoxide generated from the NADH oxidase activity of gFlHb. In a similar manner, the superoxide-generating enzyme xanthine oxidase was able to produce ABZSO in the presence of xanthine and ABZ. Interestingly, we find that gFlHb mRNA expression is lower in albendazole-resistant clones compared to those that are sensitive to this drug. Furthermore, all albendazole-resistant clones transfected to overexpress gFlHb displayed higher susceptibility to the drug than the parent clones. Collectively these findings indicate a role for gFlHb in ABZ conversion to its sulfoxide and that gFlHb down-regulation acts as a passive pharmacokinetic mechanism of resistance in this parasite.

Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy.