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Purpose: Positron emission tomography with the radioligand [¹¹C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [¹¹C]D-deprenyl´s usefulness as a marker of acute inflammation.

Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [¹¹C]D-deprenyl, [¹¹C]L-dideuterumdeprenyl and [¹⁸F]fluorodeoxyglucose were used.

Results: No [¹¹C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [¹¹C]D-deprenyl and [¹¹C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [¹⁸F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [¹⁸F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [¹¹C]D-deprenyl and [¹¹C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

Conclusions: Contrary to our expectations, of the three tracers only [¹⁸F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [¹¹C]D-deprenyl and [¹¹C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

Background: Sweden is among the top countries with the greatest use of e-prescriptions at a national level. A clinical decision support system called Electronic Expert Support (EES) is available at all pharmacies in Sweden to examine e-prescriptions in connection with the dispensing to prevent drug related problems (DRPs). DRPs result in patient suffering and substantial costs for society. The types of alerts generated for pediatric patients at Swedish pharmacies using EES-system has not been studied before, to the best of our knowledge. Aim: The aim of this research is to study the use of EES at pharmacies in Sweden for the pediatric population (ages 0-12 years), by describing what types of alerts for potential DRPs are generated, how they are handled and how the use of EES has changed over time. Method: Data on the number and categories of EES analyses, alerts, and resolved alerts was provided by the Swedish eHealth Agency. Results: The study shows that the use of EES has increased. The most common type of generated alert for a potential DRP among pediatric was high dose pediatric (30,3% of all alerts generated). The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication (45,8%). The most common reason for closing an alert was dialogue with patient for verification of the treatment (66,3% of all closed alerts). Conclusion: Knowledge of which type of alerts that are the most common may contribute to increased prescriber awareness of important potential DRPs. Future studies should investigate the clinical relevance of the generated alerts for the pediatric population.

The clinical support system Electronic Expert Support (EES) is available at all pharmacies in Sweden to examine electronic prescriptions when dispensing to prevent drug-related problems (DRPs). DRPs are common, and result in patient suffering and substantial costs for society. The aim of this research was to study the use of EES for the pediatric population (ages 0-12 years), by describing what types of alerts are generated for potential DRPs, how they are handled, and how the use of EES has changed over time. Data on the number and categories of EES analyses, alerts, and resolved alerts were provided by the Swedish eHealth Agency. The study shows that the use of EES has increased. The most common type of alert for a potential DRP among pediatric patients was regarding high doses in children (30.3% of all alerts generated). The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication (4.6% of the alerts were resolved). The most common reason for closing an alert was dialogue with patient for verification of the treatment (66.3% of all closed alerts). Knowledge of which type of alerts are the most common may contribute to increased prescriber awareness of important potential DRPs.

December 2019 the new pandemic Covid-19 sweeps the world and impose unmatched challenges on modern humanity, the virus started from Wuhan China and in just a few months the virus had spread to other countries and WHO (World Health Organization) called the disease a pandemic, Covid-19 is caused by the virus SARS-CoV -2 (severe acute respiratory syndrome-Coronavirus2), the virus is largely spread through human-to-human transmission, today more than 263 million people have been infected with the virus while more than 5 million have died.

SARS-CoV-2 is closely related to other viruses of the genus Betacoronavirus such as bat coronavirus BatCoV RaTG13 (~ 96% sequence identity) and SARS-CoV (~ 80% sequence identity), Coronavirus such as SARS-CoV and SARS-CoV -2 need main protease MPro (3CLPro), MPro is interesting as there are no similar proteases in humans, and it is vital for virus survival as it has essential role in processing and replicating polyproteins of viral RNA.

ML188 is a SARS-CoV MPro inhibitor, SARS-CoV and SARS-CoV -2 have 80% sequence identity, ML188 can be used as a starting point to analyze and improve MPro inhibitors that can be used against SARS-CoV -2.

In this study with the use of UGI reaction to synthesized and modified analog to ML188 by exchanging 3-pyridialkarboxaldehyd which is one of the 4 starting material the compound with 4-pyridilkarboxaldehyd. By changing the nitrogen position in the aromatic ring, we want to see if this change can increase or decrease the compound effectiveness and if it has deferent effect on SARS-CoV2.  

TLC and LC-MS are analysis method that is used to monitor the reaction and determine the purity of the reaction, column chromatography is used to purify the reaction mixture, NMR analysis both proton and carbon NMR is used to confirm the structure of our synthesized product. Result from the LCMS-Analyze showed a clear high peak with the exact mass of our Sought product but it also showed that the purification of the mixture didn’t happen fully thus we still had some impurities in the mixture. both the proton and carbon NMR results data were consistent with our compound structure. Now we need to test if this new compound can result to better inhibition in SARS-CoV2.

Background: Covid-19 is a serious infectious disease that was first discovered in China in 2019. The disease spread very quickly, infecting over 40 million globally and leading to more than a million deaths. The damage caused by the corona infection led to severe thromboembolic conditions that led to death. Therefore, anticoagulants were used in connection with corona to prevent the thromboembolic conditions. But has the use of anticoagulants in covid-19 patients really affected mortality?    Aim: To make a systematic review that explores whether anticoagulant use among COVID-19 patients affect mortality.    Methods: A systematic search was conducted September in 2022 of published studies on PubMed associated with mortality and use of anticoagulants in covid-19 patients. The articles reviewed were selected based on defined PICO and inclusion and exclusion criteria. Types of studies reviewed were cohort and case-control studies.    Results & conclusions:   A total of 20 different studies were studied and based on them it is concluded that anticoagulant treatment associated with lower mortality in severely ill covid-19 patients has been demonstrated. However, bleeding risk was observed in other covid-19 patients due to use of anticoagulants.

Chicken meat is among the common and relatively inexpensive source of protein consumed worldwide from the poultry industry. Many communities show concern regarding the procedure of slaughtering animals for meat consumption due to ethical, religious, or cultural reasons. Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) based untargeted metabolomics of 40 chicken meat samples were evaluated to differentiate meat samples based on slaughtering methods. Samples were grouped into, Zabiha (cutting neck without detaching spinal cord) and Non-Zabiha (completely detaching neck). A volcano plot reveals at least 150 features found significantly different between the two groups having >= 2-fold changes in intensities with p-values <= 0.05. Among them 05 identified and 25 unidentified metabolites have clear differences in peak intensities. The identified features can be employed to differentiate meat obtained from different slaughtering methods. A characteristic pattern based on principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) was observed among the groups. The results will benefit Halal certification, food safety, and security agencies to curb food fraud. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of King Saud University.

Introduction:  The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain),  the brain free fraction (fu,brain) and  the plasma free fraction (fu,p).

Aim:  This study has three purposes, to calculate Kp,uu,brain from publications in humans,  to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different  brain regions or not.

Materials and Methods:  The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.

Results:  Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats.  Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.

Conclusions:  No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain  or Kp,uu,brain  in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain  in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.

Introduction: Febrile neutropenia (FN) is a frequent complication of chemotherapy use in cancer patients. There is evidence to suggest that the time to antibiotic administration is associated with increase survival and effective clinical outcome. The Australian consensus guidelines for the management of FN in adult cancer patients recommends treatment within 30 minutes to patients with features of systemic compromise. A study performed at The Alfred Hospital in 2010 revealed a median time of 145 minutes to first antibiotic administration. A new guideline was therefore developed and education was implemented. This study was conducted to evaluate the intervention. Aim: To determine time to first antibiotic prescribing and administration for patients with suspected FN presenting to the Alfred Emergency and Trauma centre. Materials and Methods: The electronic medical record of 112 episodes of suspected FN presenting between March and August 2012 were reviewed.  Data were retrospective collected according to a FN data spreadsheet. An observational study were also performed at  The Alfred Emergency and Trauma centre during October and November 2012 to determine time to first antimicrobial prescribing, because this data could not be collected from the electronic medical record. Results: The median time from presentation to antibiotic prescribing was 68 minutes. The median time from presentation to antibiotic administration was 121 minutes. Conclusions: The implementation of the new guidelines has reduced the time with 16.6%, but the target first antibiotic administration within 30 minutes has not been reached.

This article stands to introduce microwave assisted extraction (MAE) as a more effective method for extraction of Anastatica hierochuntica (L) essential oils (EOs) compared to traditional hydrodistillation (HD) and steam distillation (SD) methods. Analysis of EOs by gas chromatography-mass spectrometry (GC/MS) showed significant differences in the constituents and percentages of the obtained oils. Using MAE and HD obtained oxygenated monoterpenes 50.79 % whereas SD obtained sesquiterpene hydrocarbons 79.84 % as major contents of the extracted oils. This is the first report of EO composition of the aerials parts of A. heirochunatica. It offered several advantages of MAE technique as a green method with shorter extraction time (60 min) and better yield.

Objective: Beehive air therapy is recognized as a potential remedy for treating asthma, bronchitis, lung fibrosis, and respiratory tract infections. Developed countries in which beehive air therapy is currently authorized include Germany, Hungary, Slovenia, and Austria. However, scientific proof of its efficacy is lacking which warrants further chemical and biological analyses as a proof of concept. In this study, bee-hive air volatile profile was determined for the first time along with its individual components (bees, venom, honey, and beeswax).

Methods: Volatile compounds were collected from beehive air using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). Antimicrobial assay of the air released from 4 beehive products was further performed against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and multi drug-resistant Staphylococcus aureus (MRSA) using the in vitro agar-well diffusion and microtiter plate assays.

Results and conclusions: A total of 56 volatile compounds were identified from beehive air, venom, bee insect and wax air including 6 fatty acids, 6 alcohols, 10 aldehydes, 5 esters, 1 ether, 9 hydrocarbons, 1 phenol, 7 ketones, 1 nitrogenous compound and 10 terpenes. The most abundant constituents were short-chain fatty acids (26.32%) while the lowest were the nitrogenous compounds (0.82%). The principal component analysis (PCA) scores plot of the UPLC/MS dataset showed the similarity of the beehive air to the insect bee's aroma profile. With regards to antimicrobial assay, beehive air and venom exerted the strongest antimicrobial activity among the examined bee products against S. aureus, K. pneumoniae, A. baumannii, and MRSA in agar-well diffusion assay but failing to exert an effect using microtiter plate assay as in case of bee venom against the aforementioned bacteria.

Bee venom (BV) is a typical toxin secreted by stingers of honeybee workers. BV and BV therapy have long been attractive to different cultures, with extensive studies during recent decades. Nowadays, BV is applied to combat several skin diseases, such as atopic dermatitis, acne vulgaris, alopecia, vitiligo, and psoriasis. BV is used extensively in topical preparations as cosmetics and used as dressing for wound healing, as well as in facemasks. Nevertheless, the safety of BV as a therapeutic choice has always been a concern due to the immune system reaction in some people due to BV use. The documented unfavorable impact is explained by the fact that the skin reactions to BV might expand to excessive immunological responses, including anaphylaxis, that typically resolve over numerous days. This review aims to address bee venom therapeutic uses in skin cosmetics.

Wasps, members of the order Hymenoptera, are distributed in different parts of the world, including Brazil, Thailand, Japan, Korea, and Argentina. The lifestyles of the wasps are solitary and social. Social wasps use venom as a defensive measure to protect their colonies, whereas solitary wasps use their venom to capture prey. Chemically, wasp venom possesses a wide variety of enzymes, proteins, peptides, volatile compounds, and bioactive constituents, which include phospholipase A2, antigen 5, mastoparan, and decoralin. The bioactive constituents have anticancer, antimicrobial, and anti-inflammatory effects. However, the limited quantities of wasp venom and the scarcity of advanced strategies for the synthesis of wasp venom's bioactive compounds remain a challenge facing the effective usage of wasp venom. Solid-phase peptide synthesis is currently used to prepare wasp venom peptides and their analogs such as mastoparan, anoplin, decoralin, polybia-CP, and polydim-I. The goal of the current review is to highlight the medicinal value of the wasp venom compounds, as well as limitations and possibilities. Wasp venom could be a potential and novel natural source to develop innovative pharmaceuticals and new agents for drug discovery.

Bakgrund: Hjälpämne definieras som de inaktiva ingredienserna som tillsätts till läkemedel och som inte är avsedda att utöva terapeutiska effekter. Majoriteten av läkemedelsprodukter innehåller hjälpämne där hjälpämnena utgör ca. 50% av totala vikten av de fasta beredningsformerna. Hjälpämnen används för att överkomma de begränsningar som den farmaceutiska substansen har men även för att möjliggör hantering och användning av en läkemedelsberedning samt underlätta frisättningsegenskaper. Forskning har visat att hjälpämne är mer än inerta komponenter, utan hjälpämne har förmågan att reagera med andra ingredienser i formuleringen och påverka läkemedelsabsorptionen. Syftet: Att beskriva med hjälp av exempel hur hjälpämne kan påverka läkemedelsabsorptionen. Uppsatsen kommer att fokusera på vissa delprocesser av absorptionen. Metod: En allmän litteraturstudie där 18 artiklar inkluderades. Analysen av artiklarna resulterade i teman. Resultat: Tre huvudteman formulerades. Hjälpämnes effekter på absorptionsvariabler utifrån dess egenskaper där studier har visat att egenskaper hos hjälpämne kan avspegla om dessa kommer att bidra till en förbättrad eller försämrad absorption. Hjälpämnes effekter på transportproteiner där det framkom att hjälpämne modulerar aktiviteter av en del effluxtransportörer. Koncentrationsberoende effekter av hjälpämne på läkemedelsabsorption där koncentrationen av hjälpämne är en avgörande faktor för en förbättrad respektive försämrad absorption. Diskussion: Hjälpämnens effekter kan inte generaliseras, även inom en viss läkemedelsklass. Mycket forskning i in-vivo är nödvändigt för att förbättra förståelsen och utveckling av hjälpämne samt deras inverkan på läkemedelsabsorption.

Background: Defined daily dose (DDD) is a unit that gives an estimate of drug utilization. The DDDs that are developed today are only based on adult’s drug use. That means that the DDDs for adults may not necessarily apply to children. 

Aim: To calculate recommended daily dose for boys and girls in different ages and compare it with DDD for adults for paracetamol, phenoxymethylpenicillin, desloratadine and melatonin.  

Methods: This descriptive cross-sectional study was conducted September-October 2021. Boys and girls in ages 1, 5, 12 and 16 years were included. Data was retrieved from FASS.se, tillväxtkurvor.se and WHO Collaborating Centre for Drug Statistics Methodology. 

Results: The children’s daily doses are lower than DDD for adults for paracetamol for all ages, phenoxymethylpenicillin for ages 1, 5 and 12 and desloratadine for ages 1 and 5. The daily doses of phenoxymethylpenicillin aged 16 are higher than DDD for adults. Daily doses for melatonin and desloratadine age 12 and 16 were the same as DDD for adults. Paracetamol and phenoxymethylpenicillin have variations in the daily doses for the children. Girls in all ages except from 12 years and the youngest children had lowers doses. Desloratadine ages 1 and 5 had the same dose and ages 12 and 16 had the same dose. For melatonin the children received the same doses. 

Conclusion: The calculated recommended daily doses for children are to some extent in line with WHO DDDs. In order to use WHO DDDs in children, it is important to have knowledge of which drugs and ages they can be applied for.  

Gastropods comprise approximately 80% of molluscans, of which land snails are used variably as food and traditional medicines due to their high protein content. Moreover, different components from land snails exhibit antimicrobial activities. In this study, we evaluated the antifungal activity of soft tissue extracts from Helix aspersa against Candida albicans, Aspergillus flavus, and Aspergillus brasiliensis by identifying extract components using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Two concentrations of three extracts (methanol, acetone, and acetic acid) showed antifungal activity. Both acetone (1 g/3 mL) and acetic acid extracts (1 g/mL) significantly inhibited C. albicans growth (p = 0.0001, 5.2 +/- 0.2 mm and p = 0.02, 69.7 +/- 0.6 mm, respectively). A. flavus and A. brasiliensis growth were inhibited by all extracts at 1 g/mL, while inhibition was observed for acetic acid extracts against A. brasiliensis (p = 0.02, 50.3 +/- 3.5 mm). The highest growth inhibition was observed for A. flavus using acetic acid and acetone extracts (inhibition zones = 38 +/- 1.7 mm and 3.1 +/- 0.7 mm, respectively). LC-MS-MS studies on methanol and acetone extracts identified 11-alpha-acetoxyprogesterone with a parent mass of 372.50800 m/z and 287.43500 m/z for luteolin. Methanol extracts contained hesperidin with a parent mass of 611.25400 m/z, whereas linoleic acid and genistein (parent mass = 280.4 and 271.48900 m/z, respectively) were the main metabolites.

 Abstract:

This study investigates the complex interaction between melittin, a cationic amphiphilic peptide found in bee venom, and cardiolipin-based liposomes. By using steady-state fluorescence measurements, the research aims to delineate the binding dynamics of melittin within the framework of cardiolipin-based liposomes. In addition, the investigation includes DSPE-PEG2000 to evaluate its impact on liposomal stability, with particular focus on the role of PEG lipids in preventing structural perturbations. Methodologically, fluorescence studies that include binding experiments and induced leakage studies provide nuanced insights into the intricacies of melittin-liposome interactions. Melittin's ability to maintain a favorable peptide/lipid ratio ensures efficient encapsulation in the liposomal environment. The strategic introduction of PEG lipids successfully reduces H2 phase formation and thereby preserves the structural integrity of PEGylated liposomes after melittin encapsulation. These findings underscore the stability and efficacy of liposomal carriers for cationic amphiphilic peptides, exemplified by melittin. This study contributes valuable insights into the optimization of liposomal formulations, particularly in the area of controlled drug delivery systems and broader biomedical applications

Background: Although the chemistry of heteroaromatic monoamino azoles has been surveyed more than once in the last decade, the chemistry of the di- and triaminoazoles has not been reviewed. In this article we will survey the synthesis, chemistry and utility of the diaminoazoles. In this review, the chemistry of the diaminoazoles as well as their most important utilities will be surveyed. Objective: The review focuses on recent progress in diaminoazoles (i.e. diaminopyrazoles, diaminoimidazoles, diaminotriazoles and diaminothiazole) with especial references to diaminopyrazoles. The synthesis as well as pharmaceutical utilities are reported. There are several methods for synthesis of diaminopyrazoles. 3,5-Diaminopyrazole and its derivatives are prepared through the reaction of malononitrile or arylhydrazononitrile with hydrazine derivatives. 3,4-Diaminopyrazoles are prepared via nitration of 3-aminopyrazole with subsequent reduction of the produced compound. The diaminopyrazoles have several applications in cosmetic and pharmaceutical industries. They also have useful utilities as a constituent in oxidative hair dyes. Conclusion: We managed to report the common methods for the synthesis of diaminoazoles with especial reference to aminopyrazoles that are prepared through the reaction of malononitrile or hydrazononitriles with hydrazine derivatives. Some important applications that include pharmaceutical utilities such as hair dye constituents are reported.

Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.

Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.