HIGHLY EFFECTIVE LUNG DELIVERY OF A FULLY HUMAN MONOCLONAL ANTIBODY TARGETING PSEUDOMONAS AERUGINOSA FOLLOWING INTRA-NASAL ADMINISTRATION

A time-course study was performed to assess lung concentrations and bioactivities of a fully human monoclonal antibody (mAb) targeting Pseudomonas aeruginosa (PA) flagella type b (LST-007) following intra-nasal administration. Intra-nasal administration of LST-007 (5 mg/kg) resulted in high mAb concentrations (11 µg/ml) within the bronchoalveolar lavage (BAL) fluid at 15 min post-administration, which decreased to 3 µg/ml at 4 hr. In marked contrast, LST-007 concentrations in blood were 110 and 11 fold lower at the same time points. Scrutinization of BAL fluid demonstrated the presence of both intact and immunoreactive LST-007 towards PAO1 bacteria, which impeded bacterial motility, underscoring the maintenance of biological activity. These compelling data lay credence that intra-nasal and thus potential inhalation modes of administration might represent bona fide routes for a targeted mAb delivery to the lung environment and establishment of therapeutically effective concentrations. Such delivery approaches could help combat life-threatening, pneumonia infections caused by PA. KEY WORDS:Monoclonal antibody, intra-nasal, bronchoalveolar lavage; Pseudomonas aeruginos

From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation

Objectives The aim was to evaluate the activity of seven medicinal, anti-inflammatory plants at the hH4R with focus on defined chemical compounds from Curcuma longa. Materials Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH4R, Gai2 and Gb1c2 subunits. Methods From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxycinnamoyl) methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH4R. Results Compounds from C. longa were the most potent ligands at the hH4R. They exhibited estimated Ki values of 4.26–6.26 lM (1.57–2.31 lg/mL) (1); 6.66––8.97 lM (2.26–3.04 lg/mL) (2) and 10.24–14.57 lM (3.16–4.49 lg/ mL) (3) (95% CI). The estimated Ki value of the crude extract of curcumawas 0.50–0.81 lg/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a Ki value of 5.54 lMor2.04 lg/mL[95%CI (4.47–6.86 lM), (1.65–2.53 lg/mL)]. Conclusion Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH4R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened

Inhibitory capacity of Rhus coriaria L. extract and its major component methyl gallate on Streptococcus mutans biofilm formation by optical profilometry: Potential applications for oral health

Streptococcus mutans (S. mutans) bacterium is the most well recognized pathogen involved in pathogenesis of dental caries. Its virulence arises from its ability to produce a biofilm and acidogenicity, causing tooth decay. Discovery of natural products capable to inhibit biofilm formation is of high importance for developing health care products. To the best of our knowledge, in all previous scientific reports, a colorimetric assay was applied to test the effect of sumac and methyl gallate (MG) on S. mutans adherence. Quantitative assessment of the developed biofilm should be further performed by applying an optical profilometry assay, and by testing the effect on both surface roughness and thickness parameters of the biofilm. To the best of our knowledge, this is the first study to report the effect of sumac extract and its constituent MG on biofilm formation using an optical profilometry assay. Testing antibacterial activity of the sumac extract and its fractions revealed that MG is the most bioactive component against S. mutans bacteria. It reduced S. mutans biofilm biomass on the polystyrene surface by 68‑93%, whereas 1 mg/ml MG was able to decrease the biofilm roughness and thickness on the glass surface by 99%. MG also prevented a decrease in pH level by 97%. These bioactivities of MG occurred in a dose‑dependent manner and were significant vs. untreated bacteria. The findings are important for the development of novel pharmaceuticals and formulations of natural products and extracts that possess anti‑biofilm activities with primary applications for oral health, and in a broader context, for the treatment of various bacterial infections.The present study was supported by the Al‑Qasemi Research Foundation, the Ministry of Science, Technology and Space (Israel) and the Faculty of Medicine, Vilnius University (Lithuania)

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030