Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study.

INTRODUCTION: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. METHODS: Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. RESULTS: A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. CONCLUSIONS: This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Clostridioides difficile incidence related to in-hospital cephalosporin use: a tale of two highly comparable hospitals.

Background: Antibiotic treatment is a well-known risk factor for healthcare facility-associated Clostridioides (Clostridium) difficile infection (HCF-CDI). Antibiotic stewardship programmes (ASPs) targeting high-risk antibiotics have been shown to decrease HCF-CDI incidence. HCF-CDI incidence is high in Nordic countries despite relatively low antibiotic use in hospital. Objectives: To determine if HCF-CDI incidence was modified by a hospital ASP that restricted cephalosporin use. Methods: The effects of an ASP on HCF-CDI incidence were evaluated in a two-centre setting using a retrospective design. We exploited a strategy of both individual case ascertainment based on chart reviews and aggregated data from the hospitals. Cases were attributed to the antibiotics given prior to disease onset, in proportion to the number of DDDs used. Three periods were studied: 2007 (before the ASP), 2012 and 2015. Results: At the ASP hospital, cephalosporin use decreased by 87% and the number of HCF-CDI/1000 hospital admissions decreased significantly from 2.25 (2007) to 1.16 (2015) (P = 0.0014). The corresponding results at the non-ASP hospital showed a non-significant increase from 2.09 to 2.38. A high number of cases could be attributed to cephalosporins at both hospitals. The increased use of other broad-spectrum antibiotics, e.g. piperacillin/tazobactam, at the ASP hospital was not associated with offsetting increases in attributable HCF-CDI cases. Conclusions: Decreased use of cephalosporins is an effective strategy to decrease HCF-CDI incidence over time in a setting with high incidence and low antibiotic use.

Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA.

There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

Regional Intestinal Permeability of Three Model Drugs in Human.

Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.

Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms.

The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.

Subcutaneous administration of nano- and microsuspensions of poorly soluble compounds to rats.

The aim of the present study was to evaluate and interpret the pharmacokinetic profiles of two compounds after subcutaneous (s.c.) administration. The compounds have similar physicochemical properties, but are a base (BA99) and an acid (AC88), respectively. The compounds were administered as nano- (5 and 500 µmol/kg) and microsuspensions (5 µmol/kg) s.c. to Sprague-Dawley rats. At the low dose, the exposure was higher for both compounds administered as nanocrystals compared to microparticles. The high dose of the compounds resulted in even higher exposure, but not in a dose-linear manner. The differences in exposure between nano- and microparticles were mainly ascribed to higher dissolution rate and improved solubility for smaller particles. In addition to differences in exposure, there were also differences in the elimination pattern. After s.c. injection of 5 µmol/kg of BA99 as nano- and microsuspensions, the elimination profile was similar as observed earlier after oral administration. However, after injection of the higher dose of BA99 and all formulations of AC88, an extended elimination profile was observed, forming a maintained plateau under the investigated time-period. Essentially, constant plasma levels were caused by a balanced equilibrium between total body clearance of the drug and supply rate of drug from the formulations.

Evaluation of exposure properties after injection of nanosuspensions and microsuspenions into the intraperitoneal space in rats.

In the present paper, BA99 and AC88 were used as model compounds for intraperitoneal (i.p.) administration to Sprague-Dawley rats. A major problem for the compounds, like many others newly developed pharmaceutical drugs, is the poor solubility in water. To solve solubility related problems, development of nanosuspensions is an attractive alternative. Both compounds are suitable for nanosuspensions, using the milling approach. After 2 weeks in freezer, the nanoparticles aggregated to form particles in the 400-2000 nm interval. However, following a 20 s ultrasonication step, the original particle sizes (about 200 nm) were obtained. Adding 5% mannitol before the samples were frozen abolished aggregation. It is also possible to freeze-dry the nanosuspension in the presence of 5% mannitol and re-disperse the formulation in water. Nanosuspensions of both compounds were injected i.p. to rats at 5 and 500 µmoL/kg. At the low dose, also a microsuspension was administered. I.p. administration resulted in overall improved C(max) for both AC88 and BA99 compared to s.c. and oral administration. I.p. is the preferred route of administration of tolerable drugs when a fast onset of action is desired and when a significant first passage metabolism occurs. The net charge of the active molecule appeared to affect the absorption kinetics. In the present work, the neutral molecule was favored over the negatively charged one.

Selective Janus kinase 1 inhibition resolves inflammation and restores hair growth offering a viable treatment option for alopecia areata.

Background: Janus Kinase (JAK) inhibition has recently demonstrated therapeutic efficacy in both restoring hair growth and resolving inflammation in Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. Objectives: We explored the possibility to separate the beneficial and adverse effects of JAK inhibition by selectively inhibiting JAK1 and thereby avoiding side effects associated with JAK2 blockade. Methods: The C3H/HeJ mouse model of AA was used to demonstrate therapeutic efficacy in vivo with different regimens of a selection of JAK inhibitors in regards to systemic versus local drug exposure. Human peripheral blood lymphocytes were stimulated in vitro to demonstrate translation to the human situation. Results: We demonstrate that selective inhibition of JAK1 produces fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ mouse model of AA. Furthermore, we show that topical treatment does not restore hair growth and that treatment needs to be extended well beyond that of restored hair growth in order to reach treatment-free remission. For translatability to human disease, we show that cytokines involved in AA pathogenesis are similarly inhibited by selective JAK1 and pan-JAK inhibition in stimulated human peripheral lymphocytes and specifically in CD8+ T cells. Conclusion: This study demonstrates that systemic exposure is required for efficacy in AA and we propose that a selective JAK1 inhibitor will offer a treatment option with a superior safety profile to pan-JAK inhibitors for these patients.

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma.

Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 µg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.

Development of a highly sensitive method using liquid chromatography-multiple reaction monitoring to quantify membrane P-glycoprotein in biological matrices and relationship to transport function.

The quantification of P-glycoprotein [P-gp, ABCB1, multidrug resistance 1 (MDR1)] protein in biological matrices is considered a key factor missing for useful translation of in vitro functional data to the in vivo situation and for comparison of transporter data among different in vitro models. In the present study a liquid chromatography (LC)-mass spectrometry method was developed to quantify P-gp membrane protein levels in different biological matrices. The amount of P-gp transporter protein was measured in Caco-2 cell monolayers and in inside-out human embryonic kidney (HEK)-MDR1 vesicles. From both in vitro systems, two preparations with different functionality were used. Transporter function was determined as digoxin efflux in Caco-2 cell monolayers and N-methylquinidine (NMQ) uptake in membrane vesicles, and, in addition, mRNA expression in the Caco-2 monolayers was measured. The results showed an excellent relationship between NMQ uptake functionality in inside-out HEK-MDR1 vesicles and protein contents. Similar concordance between the digoxin efflux and P-gp content in different Caco-2 cell cultures was observed, whereas mRNA levels are indicative of increased P-gp content and activity in older Caco-2 cultures, however, not yielding the same quantitative relationship. The results from both Caco-2 and HEK-MDR1 membrane vesicles confirm that the protein content is directly related to the level of activity in the respective system. The method presented here to quantify P-gp protein by LC-multiple reaction monitoring will facilitate the development of future methodologies to bridge between expression systems and cell/tissue models and to scale from in vitro models to whole organs.

Co-administration of a nanosuspension of a poorly soluble basic compound and a solution of a proton pump inhibitor--the importance of gastrointestinal pH and solubility for the in vivo exposure.

In Sigfridsson et al. (2011, Drug Dev Ind Pharm, 37:243-251), there was no difference in plasma concentration of BA99 when administering the drug as nanosuspension or microsuspension and analyzing the blood samples by liquid chromatography-mass spectrometry. This was related to the dissolved amount of drug in the gastric tract, which was high enough to support fast absorption when the drug reached the small intestine. One single physicochemical property (pK(a), about 3 for BA99) abolished the benefit of small particles. These results were further confirmed in the present study, where a proton pump inhibitor, AZD0865, was used to elevate the gastric pH and then drastically decreased the gastric solubility. In this way, BA99 could be considered as a model compound for a neutral substance. By increasing the gastric pH to 5-6 and 8-9, respectively, in rats, the plasma concentrations of BA99, after administering nanosuspensions, were unchanged compared with untreated (i.e. no AZD0865) animals. For microsuspensions of the test compound, on the other hand, the exposure of BA99 was 2- to 3-fold lower than for nanosuspensions at both pHs. Moreover, the blood concentrations of BA99 administered as microsuspension were also 2- to 3-fold lower compared with untreated (no AZD0865) individuals receiving both nanoparticles and microparticles of BA99. Obviously, for neutral compounds, with similar physicochemical properties as the present compound, size reduction will be crucial for increased plasma exposure. For basic compounds, with similar physicochemical properties as the present compound, the crucial step for absorption is the dissolution and solubility in the gastric tract.

Particle size reduction and pharmacokinetic evaluation of a poorly soluble acid and a poorly soluble base during early development.

AIM: The aim of the present study was to find out if nanosuspensions were a better choice compared with microsuspensions, for the present substances with water solubility in the order of 2-3 µM (pH 6.8, small intestinal pH) and no permeability limitations. The ambition was also to understand what the higher solubility in the stomach for BA99 means in terms of absorption properties of the substance. METHOD: The pharmacokinetic parameters of a poorly soluble acid (AC88) and a poorly soluble base (BA99) administered orally as nanosuspensions have been compared with those from microsuspensions using rat as in vivo species. RESULTS: A significant difference was observed between the two suspensions for AC88 already at the lowest dose, 5 µmol/kg (the particle size of the nanosuspensions and the microsuspensions was about 200 nm and 14 µm, respectively). These results were further confirmed at a high dose (500 µmol/kg). However, for BA99, there were no significant differences between the two formulations at any dose investigated (the particle size of the nanosuspensions and the microsuspensions was about 280 nm and 12 µm, respectively). CONCLUSIONS: The study demonstrated a clear correlation between particle size and in vivo exposures for an acidic compound, the nanosuspensions providing the highest exposure. For a basic compound, on the other hand, with the present properties and doses, a microsuspension was sufficient. In the latter case, the higher solubility at gastric pH, because of the basic pK(a), limits the need for particle reduction.

Lung pharmacokinetics of inhaled and systemic drugs: A clinical evaluation.

BACKGROUND AND PURPOSE: Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration. EXPERIMENTAL APPROACH: Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings. KEY RESULTS: Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles. CONCLUSION AND IMPLICATIONS: Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.

Airway Epithelial Lining Fluid and Plasma Pharmacokinetics of Inhaled Fluticasone Propionate and Salmeterol Xinafoate in Mechanically Ventilated Pigs.

Background: The lower respiratory tract of the landrace pig has close anatomical and physiological similarities with that of the human, and hence, for inhalation studies this species is well suited for biopharmaceutical research. Methods: The objective of this study was to evaluate pharmacokinetics in pigs following one dose of Diskus™ Seretide™ forte device, labeled 500/50 fluticasone propionate (FP) and salmeterol xinafoate (SX), respectively. The PreciseInhale™ (PI) instrument was used to actuate the inhaler for in vitro testing and aerosol dosing to pigs. In vitro, the aerosol was characterized with a cascade impactor with respect to mass median aerodynamic diameter, geometric standard deviation, and fine particle dose. In vivo, dry powder inhalation exposure was delivered as a short bolus dose, to anesthetized and mechanically ventilated landrace pigs. In addition to plasma PK, PK assessment of airway epithelial lining fluid (ELF) was used in this study. ELF of the depth of three to fourth airway generation of the right lung was accessed using standard bronchoscopy and a synthetic absorptive matrix. Results and Conclusions: Dry powder inhalation exposures with good consistency and well characterized aerosols to the pig lung were achieved by the use of the PreciseInhale™ instrument. Drug concentrations of ELF for both FP and SX were demonstrated to be four to five orders of magnitude higher than its corresponding systemic plasma drug concentrations. Clinical PK following inhalation of the same dose was used as benchmark, and the clinical study did demonstrate similar plasma PK profiles and drug exposures of both FP and SX as the current pig study. Two factors explain the close similarity of PK (1) similiar physiology between species and (2) the consistency of dosing to animals. To conclude, our study demonstrated the utility and translational potential of conducting PK studies in pigs in the development of inhaled pharmaceuticals.

Particle size reduction for improvement of oral absorption of the poorly soluble drug UG558 in rats during early development.

BACKGROUND: The exposure of UG558 was not good enough using traditional microsuspensions. AIM: The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 microM (pH 6.8, small intestinal pH) and no permeability limitations. METHODS: UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously. RESULTS: The particle size of the nanosuspensions was about 190 nm and about 12 microm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 micromol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 micromol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 micromol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed. CONCLUSIONS: The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.

[Neonatal suppurative parotitis]. / Neonatal purulent parotit ovanlig men potentiellt allvarlig infektion - God prognos med intravenös antibiotikabehandling tidigt.

Neonatal suppurative parotitis is a rare condition characterized by swelling, pain and erythema over the parotid gland. There may be a purulent exsudate from the Stensen duct. The predominant etiology is Staphylococcus aureus but cases with gram negative bacteria and streptococci have been reported. Most cases are managed conservatively with intravenous antibiotic therapy, and early treatment reduces risks of complications like sepsis and intraglandular abscess. We report two cases of neonatal suppurative parotitis; two 14-days-old males, both with one day history of parotid swelling and erythema. In one of them purulent exudate could be extracted from the Stensen duct. One of them had positive blood culture with Staphylococcus aureus. Ultrasound examination showed an enlarged parotid gland but no abscess. Growth of Staphylococcus aureus was found in both cases and the patients responded well to intravenous antibiotic therapy.

[Learning methods in general practice]. / Fortbildningen sedd ur ett allmänmedicinskt perspektiv - Svensk förening för allmänmedicin har tagit fram riktlinjer för allmänläkarna.

The Swedish Association of General Practice has published a set of guidelines for general practitioner's (GPs') learning in general practice/family medicine. This article is a summary of principles, guidelines and applications regarding Swedish GPs' continuing professional development (CPD). We argue that reflection on own practice, reflection with colleagues in small groups and use of written learning plans and portfolios for courses and lectures are important parts of CPD and should be increasingly used and supported by employers. Collection of CME credits for certification purposes does not ensure that educational measures have been effective. Statements of recurring CPD should be incorporated in contracts between health care authorities and health care units.

Education, decision support, feedback and a minor reward: a novel antimicrobial Stewardship intervention in a Swedish paediatric emergency setting.

Background: Sweden enjoys a favourable situation with regard to antimicrobial resistance. However, healthcare costs are expected to increase exponentially, along with increased morbidity and mortality, due to the emergence of resistant bacterial strains. Our aim was to design an antimicrobial stewardship programme suitable for Scandinavian settings. Methods: A quasi-experimental pre-post study was conducted in a Swedish paediatric emergency department, evaluating adherence to national guidelines for acute otitis media and acute tonsillitis. The programme consisted of educational outreach, decision support, feedback, and a minor reward upon reaching a pre-defined adherence rate. Results: The largest impact, significant for both diagnoses, was on the practice of refraining from antibiotic use when recommended. The other variables evaluated showed no significant improvement for either condition; however, in most cases, pre-interventional adherence was already high. Conclusions: This relatively easily implementable ASP intervention showed a significant effect on correctly refraining from the use of antibiotics. Previous interventions in Scandinavia either failed to accomplish this or have been more logistically difficult. The combination of education, decision support, email-based feedback and a minor reward, offers an alternative. Future research will be needed to assess whether the result is sustainable, as well as to identify additional barriers to the judicious use of antibiotics not addressed in this study.

Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2.

The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound 1, guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound 28, which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement in vivo was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.

Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma.

While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.