Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation

Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety.Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs).Results: The cohort comprised 22,969 patients (mean age: 80–86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42–0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53–0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30–0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09–2.29]).Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.

Pharmacokinetics of chloroquine and primaquine in healthy volunteers

Background Vivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods. Methods Three trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC–MS/MS method in accordance with current international regulatory requirements for bio-analytical methods. Results In total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80–125% in all cases, the formulations tested were bioequivalent. Conclusions In conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

Bioavailability Enhancement of Vitamin E TPGS Coated Liposomes of Nintedanib Esylate Formulation Developed Using Quality by Design Approach

PurposeNintedanib esylate (NE) is a kinase inhibitor designated for the cure of non-small cell lung cancer suffers from first-pass metabolism which resulted in low oral bioavailability (~4.7%). The intent of this exploration was to increase the oral bioavailability of NE by means of TPGS coated liposomes. MethodsThe NE-loaded TPGS coated liposomes were formulated by high-speed homogenization by optimizing process parameters like phospholipids: cholesterol molar ratio, drug loading and sonication time through the design of experiments. The drug's behaviour was studied using a variety of techniques, including physicochemical characterization, in-vitro and in-vivo studies. ResultsThe NE-liposomes had a particle size of 125±6.68 nm, entrapment efficiency of 88.64±4.12% and zeta potential of +46±2.75 mV. X-ray diffraction analysis revealed that NE had been converted to an amorphous state, while transmission electron microscope images showed spherical shape and smooth coating of TPGS on surface of liposomes. The formulation showed Higuchi kinetics with sustained drug release of 88.72 ± 3.40% in 24 hours. Cellular uptake of C-6 labelled liposomes was observed in A-549 cells and cytotoxicity testing revealed that NE-liposomes were more effective than marketed formulation Ofev®. Formulation remained in simulated fluids and for three months in stability chamber and. Liposomal oral bioavailability was ~6.23 times greater in sprague dawley male rats compared to marketed formulation Ofev®, according to in-vivo pharmacokinetic data. ConclusionNE-Liposomal formulations are better for oral administration compared to the marketed capsules because of the prolonged drug release and increased oral bioavailability as a result, the developed formulation can become a successful strategy in cancer chemotherapy.

Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42–1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5–2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75–1.5 mg/kg/12 h for P. aeruginosa and 1–1.5 mg/kg/12 h for A. baumannii and K. pneumoniae were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.

Nanoparticles use for Delivering Ursolic Acid in Cancer Therapy: A Scoping Review

Ursolic acid is a natural pentacyclic triterpenoid that exerts a potent anticancer effect. Furthermore, it is classified as a BCS class IV compound possessing low permeability and water solubility, consequently demonstrating limited bioavailability in addition to low therapeutic effectiveness. Nanoparticles are developed to modify the physical characteristics of drug and can often be produced in the range of 30–200 nm, providing highly effective cancer therapy due to the Enhanced Permeation and Retention (EPR) Effect. This study aims to provide a review of the efficacy and safety of various types of Ursolic Acid-loading nanoparticles within the setting of preclinical and clinical anticancer studies. This literature study used scoping review method, where the extracted data must comply with the journal inclusion criteria of within years of 2010–2020. The identification stage produced 237 suitable articles. Duplicate screening was then conducted followed by the initial selection of 18 articles that had been reviewed and extracted for data analysis. Based on this review, the use of nanoparticles can be seen to increase the anticancer efficacy of Ursolic Acid in terms of several parameters including pharmacokinetic data, survival rates and inhibition rates, as well as the absence of serious toxicity in preclinical and clinical trials in terms of several parameters including body weight, blood clinical chemistry, and organ histipathology. Based on this review, the use of nanoparticles has been able to increase the anticancer efficacy of Ursolic Acid, as well as show the absence of serious toxicity in preclinical and clinical trials. Evenmore, the liposome carrier provides development data that has reached the clinical trial phase I. The use of nanoparticle provides high potential for Ursolic Acid delivery in cancer therapy.

A Critical Review of the Pharmacokinetics and Pharmacodynamics of Opioid Medications Used in Avian Patients

Opioid drugs are used to manage moderate to severe pain in mammals and avian species. In dosing opioids for a particular species, it is optimal to use dosing regimens based on pharmacokinetics or pharmacodynamics studies conducted in the same species as variability in the physiology among different species may result in differences in drug pharmacokinetics and pharmacodynamics. Unfortunately, dosing regimens are typically extrapolated from closely related avian species or even mammals, which is unideal. Therefore, this critical review aims to collate and evaluate the dosing regimens of selected opioids: tramadol, hydromorphone, buprenorphine, butorphanol, and fentanyl, in avian species and its related safety, efficacy and pharmacokinetic data. Our review found specific dosing regimens not described in the Exotic Animal Formulary for tramadol used in Indian Peafowl (Pavo cristatus), Muscovy Duck (Cairina moschata) and Hispaniolan Parrot (Amazona ventralis); hydromorphone used in Orange-winged Parrot (Amazona amazonica); buprenorphine used in Cockatiel (Nymphicus hollandicus), American Kestrel (Falco sparverius) and Grey Parrot (Psittacus erithacus); and butorphanol used in Hispaniolan Parrot (Amazona ventralis), Broiler Chicken and Indian Peafowl (Pavo cristatus). Cockatiel appeared to not experience analgesic effects for hydromorphone and buprenorphine, and American Kestrel exhibited sex-dependent responses to opioids. The selected opioids were observed to be generally safe, with adverse effects being dose-dependent.

Visualizing Phytochemical-Protein Interaction Networks: Momordica charantia and Cancer

The in silico study of medicinal plants is a rapidly growing field. Techniques such as reverse screening and network pharmacology are used to study the complex cellular action of medicinal plants against disease. However, it is difficult to produce a meaningful visualization of phytochemical-protein interactions (PCPIs) in the cell. This study introduces a novel workflow combining various tools to visualize a PCPI network for a medicinal plant against a disease. The five steps are 1) phytochemical compilation, 2) reverse screening, 3) network building, 4) network visualization, and 5) evaluation. The output is a PCPI network that encodes multiple dimensions of information, including subcellular location, phytochemical class, pharmacokinetic data, and prediction probability. As a proof of concept, we built a PCPI network for bitter gourd (Momordica charantia L.) against colorectal cancer. The network and workflow are available at https://yumibriones.github.io/network/. The PCPI network highlights high-confidence interactions for further in vitro or in vivo study. The overall workflow is broadly transferable and can be used to visualize the action of other medicinal plants or small molecules against other diseases.

Improved Bioavailability of Poorly Water-Soluble Drug by Targeting Increased Absorption through Solubility Enhancement and Precipitation Inhibition

Itraconazole (ITZ) is a class II drug according to the biopharmaceutical classification system. Its solubility is pH 3-dependent, and it is poorly water-soluble. Its pKa is 3.7, which makes it a weak base drug. The aim of this study was to prepare solid dispersion (SD) pellets to enhance the release of ITZ into the gastrointestinal environment using hot-melt extrusion (HME) technology and a pelletizer. The pellets were then filled into capsules and evaluated in vitro and in vivo. The ITZ changed from a crystalline state to an amorphous state during the HME process, as determined using DSC and PXRD. In addition, its release into the gastrointestinal tract was enhanced, as was the level of ITZ recrystallization, which was lower than the marketed drug (Sporanox®), as assessed using an in vitro method. In the in vivo study that was carried out in rats, the AUC0–48h of the commercial formulation, Sporanox®, was 1073.9 ± 314.7 ng·h·mL−1, and the bioavailability of the SD pellet (2969.7 ± 720.6 ng·h·mL−1) was three-fold higher than that of Sporanox® (*** p < 0.001). The results of the in vivo test in beagle dogs revealed that the AUC0–24h of the SD-1 pellet (which was designed to enhance drug release into gastric fluids) was 3.37 ± 3.28 μg·h·mL−1 and that of the SD-2 pellet (which was designed to enhance drug release in intestinal fluids) was 7.50 ± 4.50 μg·h·mL−1. The AUC of the SD-2 pellet was 2.2 times higher than that of the SD-1 pellet. Based on pharmacokinetic data, ITZ would exist in a supersaturated state in the area of drug absorption. These results indicated that the absorption area is critical for improving the bioavailability of ITZ. Consequently, the bioavailability of ITZ could be improved by inhibiting precipitation in the absorption area.

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

IntroductionChagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs.Methods and analysisNew ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping.Ethics and disseminationThe TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions.Trial registration numberNCT03981523.