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Objectives: When malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations. However, questions remain regarding the optimal dosing. This study aimed to compare the mosquitocidal effect and pharmacokinetics of two-dose regimens of ivermectin for malaria vector control., Design: We conducted an open-label randomized control trial in Kenya, staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random-sequence generation, unstratified, with one block of six pharmacokinetics-only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n = 12), three daily doses (3-day regimen 300 mcg/kg, n = 6), albendazole (400 mg, n = 6), or no treatment (negative control, n = 6). Our primary outcome was Anopheles gambiae survival (time-to-event [days]) after blood feeding up to 10 days after drug administration. We also evaluated pharmacokinetics (peak plasma and capillary blood concentration, areas under the plasma and capillary blood concentration-time curve from time of last administration to time of last observation, time to reach peak plasma and capillary blood concentration, terminal elimination half-life) up to 7 days after treatment., Results: A total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion, with two participants not attending the visit on day 28. All drug regimens were well-tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10 days after treatment, the single dose presented superior longevity of effect (adjusted hazard ratio = 3.91; 95% confidence interval = 1.93-7.93; P <0.001) compared with the triple dose (adjusted hazard ratio = 1.79; 95% confidence interval = 0.88-3.62; P = 0.0.11). Albendazole had, overall, no mosquitocidal effect., Conclusions: It is unclear why a single dose led to increased bio-efficacy compared with a triple dose. We recommend trials investigating ivermectin mass drug administrations for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared with a 3-day regimen, leading to improved programmatic suitability., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Urinary tract catheters, including Double-J or ureteral stents, are prone to bacterial colonization forming biofilms and leading to asymptomatic bacteriuria. In the context of asymptomatic bacteriuria, endourological procedures causing mucosa-inducing lesions can lead to severe infections. Antibiotic prophylaxis is warranted, yet its efficacy is limited by biofilm formation on stents. Biofilms promote antibiotic tolerance, the capacity of genetically susceptible bacteria to survive a normally lethal dose of antimicrobial therapy. The UROPOT study evaluates the effectiveness of a first-in-type metabolism-based aminoglycoside potentiation for (i) preventing infectious complications of asymptomatic bacteriuria during mucosa lesion-inducing endourological procedures and (ii) assessing its anti-tolerance efficacy., Methods: The UROPOT trial is a phase I/II single-center (Lausanne University Hospital (CHUV), Switzerland) randomized double-blinded trial. Over 2 years, patients with asymptomatic Escherichia coli and/or Klebsiella pneumoniae bacteriuria, undergoing endourological procedures, will be randomly allocated to one of three treatment arms (1:1:1 randomization ratio, 30 patients per group) to evaluate the efficacy of mannitol-potentiated low-dose amikacin compared to established standard treatments (ceftriaxone or amikacin standard dose). Patients will be recruited at the CHUV Urology Outpatient Clinic. The primary outcome is the comparative incidence of postoperative urinary tract infections (assessed at 48 h) between the investigational amikacin/mannitol therapy and standard (ceftriaxone or amikacin) antibiotic prophylaxis, defined by specific systemic symptoms and/or positive blood and/or urine culture. Secondary outcomes include assessing microbiological eradication through anti-biofilm activity, sustained microbiological eradication, and mannitol and antibiotics pharmacokinetics in blood and urine. Safety outcomes will evaluate the incidence of adverse events following amikacin/mannitol therapy and postoperative surgical complications at postoperative day 14., Discussion: UROPOT tests a novel antimicrobial strategy based on "metabolic potentiation" for prophylaxis enabling aminoglycoside dose reduction and targeting biofilm activity. The anti-biofilm effect may prove beneficial, particularly in patients who have a permanent stent in situ needing recurrent endourological manipulations strategies in preventing infections and achieving sustained microbiological eradication in pre-stented patients., Trial Registration: The protocol is approved by the local ethics committee (CER-VD, 2023-01369, protocole 2.0) and the Swiss Agency for Therapeutic Products (Swissmedic, 701,676) and is registered on the NIH's ClinicalTrials.gov (trial registration number: NCT05761405). Registered on March 07, 2023., (© 2024. The Author(s).)

This study aimed to determine cefazolin target attainment in patients with invasive Staphylococcus aureus ( S. aureus ) infections and to develop a population pharmacokinetic (PK) model. Adult patients with invasive S. aureus infections treated with cefazolin bolus infusions were included. Unbound and total trough and mid-dose cefazolin concentrations were measured, and strain-specific MICs were determined. The primary outcome was the proportion of patients attaining 100% f T >MIC at all time points evaluated. A population PK model was developed, using non-linear mixed-effects modelling. Overall, 51 patients were included, with a total of 226 unbound and total cefazolin concentrations measured (mean: 4.4 per patient). The median daily dosage in patients with an estimated glomerular filtration rate of >60 mL/min/m 2 was 8 g. The median age was 74 years (interquartile range (IQR) 57-82) and 26% were female. A history of chronic kidney disease and acute kidney injury were present in 10/51 (19.6%) and 6/51 (11.7%), respectively. Achievement of 100% f T >MIC occurred in 86% of the patients and decreased to 45% when a target of 100% f T >4xMIC was evaluated. The mean unbound cefazolin fraction was 27.0% (standard deviation (SD) 13.4). Measured and estimated mean cefazolin trough concentrations differed significantly [13.1 mg/L (SD 23.5) vs. 7.4 mg/L (SD 7.9), p < 0.001]. In the population PK model, elevated estimated creatinine clearance and bolus instead of continuous application were covariates for target non-attainment. In conclusion, cefazolin target achievement was high, and the measurement of the unbound cefazolin concentration may be favored. The Monte Carlo simulations indicated that target attainment was significantly improved with continuous infusion.

Introduction: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. This study investigated the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes., Aims and Methods: In this randomized, double-blind, within-subject crossover study, 20 non-nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20 mg/mL, nicotine salt 20 mg/mL, nicotine salt 40 mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed., Results: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0 ng/mL (1.6-27.3), 5.4 ng/mL (1.9-18.7), and 3.0 ng/mL (1.3-8.8) for nicotine salt 40 mg/mL, nicotine salt 20 mg/mL and free-base 20 mg/mL, respectively). All groups reached Cmax 2.0-2.5 minutes (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed., Conclusions: Free-base 20 mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20 mg/mL, while 40 mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation., Implications: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine-free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40 mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and nonsmokers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background: Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients., Objectives: To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens., Methods: Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling., Results: Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin., Conclusions: By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Ivermectin (22,23-dihydroavermectin B 1a : H 2 B 1a ) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A "post-ivermectin effect" has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect., Methods: Ivermectin was incubated in the presence of recombinant human cytochrome P 450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (C max ) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days., Results: Human CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1-M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H 2 B 1a ) was mainly produced by CYP3A5. Both desmethyl-H 2 B 1a (M1) and hydroxy-H 2 B 1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H 2 B 1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at C max levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h)., Conclusion: In conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the "post-ivermectin effect"., (© 2023. The Author(s).)

Background: Residual malaria transmission is the result of adaptive mosquito behavior that allows malaria vectors to thrive and sustain transmission in the presence of good access to bed nets or insecticide residual spraying. These behaviors include crepuscular and outdoor feeding as well as intermittent feeding upon livestock. Ivermectin is a broadly used antiparasitic drug that kills mosquitoes feeding on a treated subject for a dose-dependent period. Mass drug administration with ivermectin has been proposed as a complementary strategy to reduce malaria transmission., Methods: A cluster randomized, parallel arm, superiority trial conducted in two settings with distinct eco-epidemiological conditions in East and Southern Africa. There will be three groups: human intervention, consisting of a dose of ivermectin (400 mcg/kg) administered monthly for 3 months to all the eligible population in the cluster (>15 kg, non-pregnant and no medical contraindication); human and livestock intervention, consisting human treatment as above plus treatment of livestock in the area with a single dose of injectable ivermectin (200 mcg/kg) monthly for 3 months; and controls, consisting of a dose of albendazole (400 mg) monthly for 3 months. The main outcome measure will be malaria incidence in a cohort of children under five living in the core of each cluster followed prospectively with monthly RDTs DISCUSSION: The second site for the implementation of this protocol has changed from Tanzania to Kenya. This summary presents the Mozambique-specific protocol while the updated master protocol and the adapted Kenya-specific protocol undergo national approval in Kenya. BOHEMIA will be the first large-scale trial evaluating the impact of ivermectin-only mass drug administration to humans or humans and cattle on local malaria transmission TRIAL REGISTRATION: ClinicalTrials.gov NCT04966702 . Registered on July 19, 2021. Pan African Clinical Trials Registry PACTR202106695877303., (© 2023. The Author(s).)

Drug interactions with other drugs are a well-known phenomenon. Similarly, however, pre-existing drug therapy can alter the course of diseases for which it has not been prescribed. We performed network analysis on drugs and their respective targets to investigate whether there are drugs or targets with protective effects in COVID-19, making them candidates for repurposing. These networks of drug-disease interactions (DDSIs) and target-disease interactions (TDSIs) revealed a greater share of patients with diabetes and cardiac co-morbidities in the non-severe cohort treated with dipeptidyl peptidase-4 (DPP4) inhibitors. A possible protective effect of DPP4 inhibitors is also plausible on pathophysiological grounds, and our results support repositioning efforts of DPP4 inhibitors against SARS-CoV-2. At target level, we observed that the target location might have an influence on disease progression. This could potentially be attributed to disruption of functional membrane micro-domains (lipid rafts), which in turn could decrease viral entry and thus disease severity.

As of October 2021, neither established agents (e.g., hydroxychloroquine) nor experimental drugs have lived up to their initial promise as antiviral treatment against SARS-CoV-2 infection. While vaccines are being globally deployed, variants of concern (VOCs) are emerging with the potential for vaccine escape. VOCs are characterized by a higher within-host transmissibility, and this may alter their susceptibility to antiviral treatment. Here we describe a model to understand the effect of changes in within-host reproduction number R 0 , as proxy for transmissibility, of VOCs on the effectiveness of antiviral therapy with molnupiravir through modeling and simulation. Molnupiravir (EIDD-2801 or MK 4482) is an orally bioavailable antiviral drug inhibiting viral replication through lethal mutagenesis, ultimately leading to viral extinction. We simulated 800 mg molnupiravir treatment every 12 h for 5 days, with treatment initiated at different time points before and after infection. Modeled viral mutations range from 1.25 to 2-fold greater transmissibility than wild type, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R 0 , making highly transmissible VOCs more sensitive to antiviral therapy. Total viral load was reduced by up to 70% in highly transmissible variants compared to 30% in wild type if treatment was started in the first 1-3 days post inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible SARS-CoV-2 variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schöning, Kern, Chaccour and Hammann.)

The adenosine monophosphate activated protein kinase (AMPK) is critical in the regulation of important cellular functions such as lipid, glucose, and protein metabolism; mitochondrial biogenesis and autophagy; and cellular growth. In many diseases-such as metabolic syndrome, obesity, diabetes, and also cancer-activation of AMPK is beneficial. Therefore, there is growing interest in AMPK activators that act either by direct action on the enzyme itself or by indirect activation of upstream regulators. Many natural compounds have been described that activate AMPK indirectly. These compounds are usually contained in mixtures with a variety of structurally different other compounds, which in turn can also alter the activity of AMPK via one or more pathways. For these compounds, experiments are complicated, since the required pure substances are often not yet isolated and/or therefore not sufficiently available. Therefore, our goal was to develop a screening tool that could handle the profound heterogeneity in activation pathways of the AMPK. Since machine learning algorithms can model complex (unknown) relationships and patterns, some of these methods (random forest, support vector machines, stochastic gradient boosting, logistic regression, and deep neural network) were applied and validated using a database, comprising of 904 activating and 799 neutral or inhibiting compounds identified by extensive PubMed literature search and PubChem Bioassay database. All models showed unexpectedly high classification accuracy in training, but more importantly in predicting the unseen test data. These models are therefore suitable tools for rapid in silico screening of established substances or multicomponent mixtures and can be used to identify compounds of interest for further testing.

Background: Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively., Methods: We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification., Results: Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin., Conclusion: There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin.

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01-1 μg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0-19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1-5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7-14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods., Competing Interests: The authors have declared that no competing interests exist.

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro , an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo , host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kern, Schöning, Chaccour and Hammann.)

Aims: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban., Methods: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract., Results: The geometric mean ratios for the area under the concentration-time curve and C max of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding T max (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping., Conclusion: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban., (© 2020 British Pharmacological Society.)

Background: Clinical risk scores and machine learning models based on routine laboratory values could assist in automated early identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients at risk for severe clinical outcomes. They can guide patient triage, inform allocation of health care resources, and contribute to the improvement of clinical outcomes., Methods: In- and out-patients tested positive for SARS-CoV-2 at the Insel Hospital Group Bern, Switzerland, between February 1st and August 31st ('first wave', n = 198) and September 1st through November 16th 2020 ('second wave', n = 459) were used as training and prospective validation cohort, respectively. A clinical risk stratification score and machine learning (ML) models were developed using demographic data, medical history, and laboratory values taken up to 3 days before, or 1 day after, positive testing to predict severe outcomes of hospitalization (a composite endpoint of admission to intensive care, or death from any cause). Test accuracy was assessed using the area under the receiver operating characteristic curve (AUROC)., Results: Sex, C-reactive protein, sodium, hemoglobin, glomerular filtration rate, glucose, and leucocytes around the time of first positive testing (- 3 to + 1 days) were the most predictive parameters. AUROC of the risk stratification score on training data (AUROC = 0.94, positive predictive value (PPV) = 0.97, negative predictive value (NPV) = 0.80) were comparable to the prospective validation cohort (AUROC = 0.85, PPV = 0.91, NPV = 0.81). The most successful ML algorithm with respect to AUROC was support vector machines (median = 0.96, interquartile range = 0.85-0.99, PPV = 0.90, NPV = 0.58)., Conclusion: With a small set of easily obtainable parameters, both the clinical risk stratification score and the ML models were predictive for severe outcomes at our tertiary hospital center, and performed well in prospective validation.

Background: Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset., Methods: Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose ( n  = 12) or placebo ( n  = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022., Findings: All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p  = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 ( p  = 0·24 for gene E; p  = 0·18 for gene N) and day 7 ( p  = 0·16 for gene E; p  = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment ( p  = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001)., Interpretation: Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials., Funding: ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra., Competing Interests: JLDP reports speaker fees from Pfizer and MSD as well as research grants from Novartis, outside the scope of the submitted work. No other competing interests were disclosed, (© 2021 The Author(s).)

Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean C max 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

Background: Ivermectin is an older anthelminthic agent that is being studied more intensely given its potential for mass drug administration against scabies, malaria and other neglected tropical diseases. Its pharmacokinetics (PK) remain poorly characterized. Furthermore, the majority of PK trials are performed under fasted-state dosing conditions, and the effect of food is therefore not well known. To better plan and design field trials with ivermectin, a model that can account for both conditions would be valuable., Objectives: To develop a PK model and characterize the food effect with single oral doses of ivermectin., Patients and Methods: We performed a population-based PK analysis of data pooled from two previous trials of a single dose of 12 mg ivermectin, one with dosing after a high-fat breakfast (n=12) and one with fasted-state dosing (n=3)., Results: The final model described concentration-time profiles after fed and fasted dosing accurately, and estimated the food effect associated with relative bioavailability to 1.18 (95% CI 1.10-1.67)., Conclusions: In this analysis, the effect of a high-fat breakfast compared with a fasted-state administration of a single oral dose of 12 mg ivermectin was minimal., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ivermectin is deployed in mass drug administration (MDA) campaigns to control parasitic diseases in the tropics, with billions of treatments having been administered in the last three decades. Simple blood sampling tools, like the dried blood spots (DBS) technique, are needed to monitor treatments in such challenging settings. Thus, we developed a fully automated method for the analysis of ivermectin in DBS microsamples, including a bioanalytical and clinical validation. Automated extraction was carried out using a DBS-MS 500 autosampler which was coupled to a LC-MS/MS system. DBS were extracted with 20 μL solvent and eluted on a C8 analytical column. Analysis was performed by multiple reaction monitoring in the positive mode. Automated DBS extraction resulted in consistent recoveries (62.8 ± 4.3%) and matrix effects (68.0 ± 8.1%) between different donors and concentration levels. Intra- and inter-day accuracy and precision deviations were ≤15%, while samples with hematocrits from 20 to 60% could be quantified reliably. The achieved sensitivity of 1 ng/mL in DBS samples is sufficient to analyze ivermectin at the dose given (single oral administration of 12 mg) over a period of at least 72 h post treatment. Importantly, DBS samples are stable after one-month storage at room temperature (accuracy: 88.8-96.2%), thus samples collected in the field must not be shipped on dry ice. Ivermectin concentrations in venous and capillary blood agreed strongly, with a mean difference of -4.8%. Moreover, the drying process of DBS did not alter the analysis and importantly plasma concentrations can be estimated from DBS data using the hematocrit and red blood cell partitioning as correction factor. Our method enables uncomplicated sample collection and shipment as well as automated analysis of large amounts of samples, which is key to surveying MDA campaigns in remote settings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions., Methods: Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system., Results: Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low., Conclusions: Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aims: The anthelminthic ivermectin is receiving new attention as it is being repurposed for new indications such as mass drug administrations for the treatment of scabies or in malaria vector control. As its pharmacokinetics are still poorly understood, we aimed to characterize the population pharmacokinetics of ivermectin in plasma and dried blood spots (DBS), a sampling method better suited to field trials, with special focus on the influence of body composition and enterohepatic circulation., Methods: We performed a clinical trial in 12 healthy volunteers who each received a single oral dose of 12 mg ivermectin, and collected peripheral venous and capillary DBS samples. We determined ivermectin concentrations in plasma and DBS by liquid chromatography tandem mass spectrometry using a fully automated and scalable extraction system for DBS sample processing. Pharmacokinetic data were analysed using non-linear mixed effects modelling., Results: A two-compartment model with a transit absorption model, first-order elimination, and weight as an influential covariate on central volume of distribution and clearance best described the data. The model estimates (inter-individual variability) for a 70 kg subject were: apparent population clearance 7.7 (25%) l h -1 , and central and peripheral volumes of distribution 89 (10%) l and 234 (20%) l, respectively. Concentrations obtained from DBS samples were strongly linearly correlated (R 2  = 0.97) with plasma concentrations, and on average 30% lower., Conclusion: The model accurately depicts population pharmacokinetics of plasma and DBS concentrations over time for oral ivermectin. The proposed analytical workflow is scalable and applicable to the requirements of mass drug administrations., (© 2018 The British Pharmacological Society.)

Drug-induced liver injury (DILI) is the most common cause of acute liver failure and often responsible for drug withdrawals from the market. Clinical manifestations vary, and toxicity may or may not appear dose-dependent. We present several machine-learning models (decision tree induction, k-nearest neighbor, support vector machines, artificial neural networks) for the prediction of clinically relevant DILI based solely on drug structure, with data taken from published DILI cases. Our models achieved corrected classification rates of up to 89%. We also studied the association of a drug's interaction with carriers, enzymes and transporters, and the relationship of defined daily doses with hepatotoxicity. The results presented here are useful as a screening tool both in a clinical setting in the assessment of DILI as well as in the early stages of drug development to rule out potentially hepatotoxic candidates., (© 2018 John Wiley & Sons, Ltd.)

Background: Considering the negative effects of stress on health, there is a growing interest in stress-reducing interventions. The present study examines the effects of a fixed combination of valerian, passion flower, lemon balm, and butterbur extracts (Ze 185) on biological and affective responses to a standardized psychosocial stress paradigm., Purpose: The aim of the present study was to investigate the efficacy of Ze 185 on cortisol and anxiety stress responses to acute psychosocial stress in healthy subjects., Study Design: This study was a randomized, placebo-controlled, double blind study with 3 parallel groups., Methods: 72 healthy male participants were randomized to 3 groups (Ze 185, placebo or no treatment) during 4 days prior to a standardized psychosocial stress paradigm. Principle outcomes were salivary cortisol and self-reported anxiety responses to stress assessed at the fourth day., Results: The stress paradigm induced significant and large cortisol and self-reported anxiety responses. Groups did not differ significantly in their salivary cortisol response to stress, but participants in the Ze 185 condition showed significantly attenuated responses in self-reported anxiety in comparison to placebo (F(3, 41) = 3.33, p = 0.03) and no treatment (F(3, 43) = 2.77, p = 0.05)., Conclusion: The results show that Ze 185 significantly attenuated the subjective emotional stress response during an acute stress situation, without affecting biological stress responses. Given that a circumscribed biological stress response is to be considered as an adaptive mechanism, Ze 185 reduces self-reported anxiety response to stress without affecting assumingly adaptive biological stress responses., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Pyrrolizidine alkaloids (PAs) are characteristic metabolites of some plant families and form a powerful defense mechanism against herbivores. More than 600 different PAs are known. PAs are ester alkaloids composed of a necine base and a necic acid, which can be used to divide PAs in different structural subcategories. The main target organs for PA metabolism and toxicity are liver and lungs. Additionally, PAs are potentially genotoxic, carcinogenic and exhibit developmental toxicity. Only for very few PAs, in vitro and in vivo investigations have characterized their toxic potential. However, these investigations suggest that structural differences have an influence on the toxicity of single PAs. To investigate this structural relationship for a large number of PAs, a quantitative structural-activity relationship (QSAR) analysis for hepatotoxicity of over 600 different PAs was performed, using Random Forest- and artificial Neural Networks-algorithms. These models were trained with a recently established dataset specific for acute hepatotoxicity in humans. Using this dataset, a set of molecular predictors was identified to predict the hepatotoxic potential of each compound in validated QSAR models. Based on these models, the hepatotoxic potential of the 602 PAs was predicted and the following hepatotoxic rank order in 3 main categories defined (1) for necine base: otonecine > retronecine > platynecine; (2) for necine base modification: dehydropyrrolizidine ≫ tertiary PA = N-oxide; and (3) for necic acid: macrocyclic diester ≥ open-ring diester > monoester. A further analysis with combined structural features revealed that necic acid has a higher influence on the acute hepatotoxicity than the necine base., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective: Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD., Methods: We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling., Results: Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups., Conclusions: The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance., Trial Registration: NCT02308969, NCT01878942.

Rationale: Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared. Methods: Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg), and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of amphetamine, subjective effects, and vital signs were repeatedly assessed. The pharmacokinetic parameters were determined using compartmental modeling. Results: The increase in plasma concentrations of amphetamine had a 0.6 ± 0.6 h (mean ± SD) longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration, but no differences in maximal concentrations or total exposure (AUC) were found between the two treatments. Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with D-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence) were observed after lisdexamfetamine administration compared with D-amphetamine administration. Lisdexamfetamine and D-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects. Conclusion: The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to D-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as D-amphetamine. The study was registered at ClinicalTrials.gov (NCT02668926).

Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.

Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways.

2,5-Dimethoxy-4(n)-propylphenethylamine (2C-P) is a synthetic phenethylamine derivative belonging to the large family of the so-called 2C drugs. These compounds can differ significantly in receptor affinity, potency and duration of action, and an important structural difference is the ligand in the 4 position of the phenyl ring, such as propyl in 2C-P or bromine in 2,5-dimethoxy-4-bromophenethylamine (2C-B). The 2C drugs are known for their hallucinogenic properties. We present a case of a 19-year-old male admitted to the emergency department with severe hallucinations, mydriasis, tachycardia, agitation and confusion following the use of a substance sold as 2C-B. By using liquid chromatography-mass spectrometry, the more potent substance 2C-P was detected and quantified. On the basis of two blood sample concentrations, the estimated elimination half-life was 19 h. This case report illustrates and discusses the differences in potency and duration of action of 2C drugs., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nicotine substitution is a mainstay component in smoking cessation schemes. Current products including patches are poorly effective mainly because they do not give smokers the same pharmacokinetic profile of nicotine as cigarette consumption. This work evaluates a new computer operated delivery system for time controlled pulsatile transdermal administration of nicotine in a phase I clinical trial with twelve heavy smoking male volunteers. The device was affixed to the ventral side of the leading lower arm of the subjects and was programmed to deliver two pulses of drug within 16h with three delivery rates in a consecutive dose escalation study. Tolerability of the three increasing doses of nicotine was established. Plasma concentration of nicotine exhibited two peaks and one trough and reached therapeutically effective levels that behaved linearly with the drug load concentration of the device. In vivo input rate, delivered amount and elimination kinetics were deduced by pharmacokinetic modeling to analyze device performance. Timing, dose and duration of delivery were controlled by system operation parameters. Hence, feasibility of controlled pulsatile delivery of nicotine at predetermined intervals was demonstrated. After additional optimization, preprogrammed or on demand administration to meet individualized and circadian replacement needs should improve smoking cessation efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Adverse drug events pose a great risk to patients, are an everyday clinical problem and can have potential/ega/ consequences. Computerized physician order entry or computerized provider order entry (CPOE} in combination with clinical decision support systems {CDSS) are popular and aim to reduce prescribing errors as well as identifying potentially harmful drug drug interactions. The quantifiable benejit these systems bring to patients, has however, yet to be definitively proven. This article focusses on the current standpoint of CPOE-/CDSS, their risks and benefits, the potential for improvement and their perspectives for the future.

Background: The prospect of eliminating malaria is challenged by emerging insecticide resistance and vectors with outdoor and/or crepuscular activity. Ivermectin can simultaneously tackle these issues by killing mosquitoes feeding on treated animals and humans. A single oral dose, however, confers only short-lived mosquitocidal plasma levels., Methods: Three different slow-release formulations of ivermectin were screened for their capacity to sustain mosquito-killing levels of ivermectin for months. Thirty rabbits received a dose of one, two or three silicone implants containing different proportions of ivermectin, deoxycholate and sucrose. Animals were checked for toxicity and ivermectin was quantified periodically in blood. Potential impact of corresponding long-lasting formulation was mathematically modelled., Results: All combinations of formulation and dose released ivermectin for more than 12 weeks; four combinations sustained plasma levels capable of killing 50% of Anopheles gambiae feeding on a treated subject for up to 24 weeks. No major adverse effects attributable to the drug were found. Modelling predicts a 98% reduction in infectious vector density by using an ivermectin formulation with a 12-week duration., Conclusions: These results indicate that relatively stable mosquitocidal plasma levels of ivermectin can be safely sustained in rabbits for up to six months using a silicone-based subcutaneous formulation. Modifying the formulation of ivermectin promises to be a suitable strategy for malaria vector control.

Protein based films are nowadays also prepared with the aim of replacing expensive, crude oil-based polymers as environmentally friendly and renewable alternatives. The protein structure determines the ability of protein chains to form intra- and intermolecular bonds, whereas the degree of cross-linking depends on the amino acid composition and molecular weight of the protein, besides the conditions used in film preparation and processing. The functionality varies significantly depending on the type of protein and affects the resulting film quality and properties. This paper reviews the methods used in examination of molecular interactions in protein films and discusses how these intermolecular interactions can be quantified. The qualitative determination methods can be distinguished by structural analysis of solutions (electrophoretic analysis, size exclusion chromatography) and analysis of solid films (spectroscopy techniques, X-ray scattering methods). To quantify molecular interactions involved, two methods were found to be the most suitable: protein film swelling and solubility. The importance of non-covalent and covalent interactions in protein films can be investigated using different solvents. The research was focused on whey protein, whereas soy protein and wheat gluten were included as further examples of proteins.

Rationale: It has been proposed that green tea extract may have a beneficial impact on cognitive functioning, suggesting promising clinical implications. However, the neural mechanisms underlying this putative cognitive enhancing effect of green tea extract still remain unknown., Objectives: This study investigates whether the intake of green tea extract modulates effective brain connectivity during working memory processing and whether connectivity parameters are related to task performance., Material and Methods: Using a double-blind, counterbalanced, within-subject design, 12 healthy volunteers received a milk whey-based soft drink containing 27.5 g of green tea extract or a milk whey-based soft drink without green tea as control substance while undergoing functional magnetic resonance imaging. Working memory effect on effective connectivity between frontal and parietal brain regions was evaluated using dynamic causal modeling., Results: Green tea extract increased the working memory induced modulation of connectivity from the right superior parietal lobule to the middle frontal gyrus. Notably, the magnitude of green tea induced increase in parieto-frontal connectivity positively correlated with improvement in task performance., Conclusions: Our findings provide first evidence for the putative beneficial effect of green tea on cognitive functioning, in particular, on working memory processing at the neural system level by suggesting changes in short-term plasticity of parieto-frontal brain connections. Modeling effective connectivity among frontal and parietal brain regions during working memory processing might help to assess the efficacy of green tea for the treatment of cognitive impairments in psychiatric disorders such as dementia.

Introduction: Patients, in particular elderly ones, frequently receive more than one drug at a time. With each drug added to a regime, the number of potential drug-drug interactions (DDIs) increases by a power law. Early prediction of relevant interactions by computerized tools greatly aids clinicians and can guide their prescribing choices., Areas Covered: In this article, we discuss different types of DDIs, on which levels they can arise and what efforts have been made in the past to detect and predict them. The emphasis is on data mining technology and network analysis, but overlaps with traditional pharmacovigilance are also discussed. Finally, we discuss strategies to focus and simplify mining efforts to get meaningful results with less effort., Expert Opinion: The necessary technology for detecting adverse DDIs exists and is quite refined, although it is more often implied in lower risk scenarios (such as syntactic analysis in web searches and online libraries). Data mining for DDIs, on the other hand, still requires a great deal of human intervention, not only to validate the results but also, more importantly, to separate the relevant from the spurious. The fields of network analysis and graph theory show great promise but have not yet shown much beyond descriptive analyses.

Predicting blood-brain barrier (BBB) permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS) values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK) was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction) on both descriptor sets. Models with a corrected classification rate (CCR) of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO)-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP) and charge (polar surface area), which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component.

Introduction: Decision tree induction (DTI) is a powerful means of modeling data without much prior preparation. Models are readable by humans, robust and easily applied in real-world applications, features that are mutually exclusive in other commonly used machine learning paradigms. While DTI is widely used in disciplines ranging from economics to medicine, they are an intriguing option in pharmaceutical research, especially when dealing with large data stores., Areas Covered: This review covers the automated technologies available for creating decision trees and other rules efficiently, even from large datasets such as chemical libraries. The authors discuss the need for properly documented and validated models. Lastly, the authors cover several case studies in hit discovery, drug metabolism and toxicology, and drug surveillance, and compare them with other established techniques., Expert Opinion: DTI is a competitive and easy-to-use tool in basic research as well as in hit and drug discovery. Its strengths lie in its ability to handle all sorts of different data formats, the visual nature of the models, and the small computational effort needed for implementation in real-world systems. Limitations include lack of robustness and over-fitted models for certain types of data. As with any modeling technique, proper validation and quality measures are of utmost importance., (© 2012 Informa UK, Ltd.)

Chemical fingerprints encode the presence or absence of molecular features and are available in many large databases. Using a variation of the Ant Colony Optimization (ACO) paradigm, we describe a binary classifier based on feature selection from fingerprints. We discuss the algorithm and possible cross-validation procedures. As a real-world example, we use our algorithm to analyze a Plasmodium falciparum inhibition assay and contrast its performance with other machine learning paradigms in use today (decision tree induction, random forests, support vector machines, artificial neural networks). Our algorithm matches established paradigms in predictive power, yet supplies the medicinal chemist and basic researcher with easily interpretable results. Furthermore, models generated with our paradigm are easy to implement and can complement virtual screenings by additionally exploiting the precalculated fingerprint information.

Intestinal drug absorption in humans is a central topic in drug discovery. In this study, we use a broad selection of machine learning and statistical methods for the classification and numerical prediction of this key end point. Our data set is based on a selection of 458 small druglike compounds with FDA approval. Using easily available tools, we calculated one- to three-dimensional physicochemical descriptors and used various methods of feature selection (best-first backward selection, correlation analysis, and decision tree analysis). We then used decision tree induction (DTI), fragment-based lazy-learning (LAZAR), support vector machine classification, multilayer perceptrons, random forests, k-nearest neighbor and Naïve Bayes analysis to model absorption ratios and binary classification (well-absorbed and poorly absorbed compounds). Best performance for classification was seen with DTI using the chi-squared analysis interaction detector (CHAID) algorithm, yielding corrected classification rate of 88% (Matthews correlation coefficient of 75%). In numeric predictions, the multilayer perceptron performed best, achieving a root mean squared error of 25.823 and a coefficient of determination of 0.6. In line with current understanding is the importance of descriptors such as lipophilic partition coefficients (log P) and hydrogen bonding. However, we are able to highlight the utility of gravitational indices and moments of inertia, reflecting the role of structural symmetry in oral absorption. Our models are based on a diverse data set of marketed drugs representing a broad chemical space. These models therefore contribute substantially to the molecular understanding of human intestinal drug absorption and qualify for a generalized use in drug discovery and lead optimization.