The Diagnostic Pathway of Hirschsprung's Disease in Paediatric Patients: A Single-Centre Experience.

BACKGROUND: The presenting symptoms of patients with Hirschsprung's disease (HD) are a failure to pass meconium, abdominal distension, and bilious vomiting. The gold standard diagnosis is a rectal biopsy to confirm aganglionosis. The aim of our study was to describe the diagnostic pathway of Hirschsprung's disease at our institution and document the indication for a rectal biopsy. METHODS: We have performed a prospective collection of all patients who underwent a rectal biopsy to exclude HD from December 2022 until September 2023 including. The following data were collected: patient's age, presenting symptoms, type of biopsy, failure rate, complications, and histopathological results. RESULTS: We identified 33 patients who underwent 34 rectal biopsies at 0.6 years of age. A total of 17 patients had a rectal suction biopsy (RSB), and 17 patients underwent a partial thickness under general anaesthesia (GA). 1/17 (6%) patients had an inconclusive RSB and subsequently underwent a biopsy under GA. Constipation and chronic abdominal distension plus vomiting were the most common presenting symptoms throughout all ages. Five patients (15%) had a rectal biopsy that was positive for HD. CONCLUSION: A protocolised approach to the assessment of infants and children with suspected HD ensures the appropriate utilisation of invasive procedures such as biopsy.

Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Development of a specialist ileoanal pouch surgery pathway: a multidisciplinary patient-centred approach.

Background: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard procedure for ulcerative colitis refractory to medical treatment, as an alternative to permanent end ileostomy. Gaining experience in pouch surgery is difficult as the procedure is performed infrequently. This study presents an institutional initiative to promote standardisation of multidisciplinary care in IPAA surgery. Methods: A dedicated pathway for patients who had an IPAA or are considering IPAA surgery was developed among colorectal surgeons, gastroenterologists, paediatric colorectal surgeons, inflammatory bowel disease (IBD) nurses, dietitians, stoma nurses, trainees in colorectal surgery. Pathway items were discussed and finalised via emails and videoconferences.The pathway included triaging of patients referred for IPAA surgery, preoperative IBD multidisciplinary team discussion and management plan for surgery, surgical review prior to surgery, peer to peer counselling, surgical technique, postoperative short-term and long-term follow-up, audit, research and training in IPAA surgery. Results: A multidisciplinary preoperative pathway was developed and a stepwise approach to minimally invasive ileoanal pouch surgery was formalised. A dedicated one-stop ileoanal pouch clinic was established integrating endoscopy and imaging on the same day of the consultation with the surgical and gastroenterology team. The clinic reviewed 72 patients over 24 months, and during the same time 36 patients underwent IPAA surgery at our institution. Conclusions: We have described our initial experience in establishing a specialist IPAA surgery pathway and have proposed outcome measures that we hope will support a subspecialty IPAA service.

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226.

Historical and Contemporary Management of Infantile Hepatic Hemangioma: A 30-year Single-center Experience.

OBJECTIVE: To describe outcome of infants with hemangioma(s) of the liver. SUMMARY OF BACKGROUND DATA: Infantile hepatic hemangiomas exhibit a diverse phenotype. We report our 30-year experience and describe optimal management based on precise radiological classification. METHODS: Retrospective review of 124 infants (66 female) 1986-2016. Categorical analysis with Chi2 and nonparametric comparison. Data expressed as median (range) and P < 0.05 considered significant. RESULTS: Lesions classified as focal (n = 70, 56%); multifocal (n = 47, 38%) or diffuse (n = 7, 6%) and of these 80(65%) were symptomatic (eg, cardiac failure n = 39, 31%; thrombocytopenia n = 12, 10%).Increased hepatic artery velocity was seen in 63 (56%). Median hepatic artery velocity was greatest in diffuse lesions [245 (175-376) cm/s vs focal 120 (34-242) cm/s vs multifocal 93 (36-313) cm/s; P = 0.0001]. Expectant management alone was followed in 55 (44%). Medical therapy was utilised in 57(46%) and sufficient for symptom control in 29/57 (51%). Propranolol therapy (from 2008) was sufficient for symptom control in 22/28 (79%). Surgery (hepatic artery ligation n = 26; resection n = 13; embolization n = 1) was required in 40 (32%). Median maximal lesion diameter was 3 (0.5-17.1) cm and greater in those requiring surgery (7 cm vs 4.9 cm; P = 0.04). The proportion requiring surgery decreased markedly in the propranolol era [pre-propranolol 25/48 (52%) vs post-propranolol 16/76 (21%) (P = 0.0003)]. Systematic follow-up with ultrasound to a median of 2.6 (0.02-16) years. CONCLUSIONS: A proportion of infantile hepatic hemangiomas remain asymptomatic permitting observation until resolution but the majority require complex multi-modal therapy. First-line pharmacotherapy with propranolol has reduced but not abolished the need for surgery.

Therapeutic strategies for stricturing Crohn's disease in childhood: a systematic review.

PURPOSE: Childhood stricturing Crohn's disease (CD) has significant morbidity. Interventions including resection, stricturoplasty and endoscopic balloon dilatation (EBD) are often required. Optimal intervention modality and timing, and use of adjuvant medical therapies, remains unclear. We aim to review the therapies used in paediatric stricturing CD. METHODS: A systematic review in accordance with PRISMA was performed (PROSPERO: CRD42020164464). Demographics, stricture features, interventions and outcomes were extracted. RESULTS: Fourteen studies were selected, including 177 patients (183 strictures). Strictures presented at 40.6 months (range 14-108) following CD diagnosis. Medical therapy was used in 142 patients for an average of 20.4 months (2-36), with a complete response in 11 (8%). Interventions were undertaken in 138 patients: 53 (38%) resections, 39 (28%) stricturoplasties, and 17 (12%) EBD. Complications occurred in 11% of resections, versus 15% stricturoplasties, versus 6% EBD (p = 0.223). At a median follow-up of 1.9 years (interquartile range 1.2-2.4) pooled stricture recurrence was 22%. Resection had 9% recurrence, versus 38% stricturoplasty, versus 47% EBD (p < 0.001). CONCLUSIONS: Resection is associated with a low incidence of recurrence and complications. There remains a paucity of evidence regarding adjuvant medical therapy and the role of EBD. We propose a minimum reported dataset for interventions in paediatric stricturing CD.

Intussusception in 2 Children With Severe Acute Respiratory Syndrome Coronavirus-2 Infection.

We note that intussusception was likely associated with severe acute respiratory syndrome coronavirus-2 infection in 2 infants in Wuhan and London. The intussusception was reduced by enemas in Wuhan; the outcome was fatal. The intussusception was not reduced by enemas in London and required surgery; the outcome was favorable.

A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology.

The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman-Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology.

Newly discovered variant of oesophageal atresia: 'Type Y'.

Multiple variations of oesophageal atresia (OA) have been described. We present two cases of a new variant of OA ('Type Y') where the fistula enters the trachea in a Y-shaped configuration. Awareness of this is important. Bronchoscopy will reveal a single fistula opening and therefore there will initially be no suspicion of anatomical variation. It may be that only one bifurcation of the 'Y' fistula is patent which poses a risk of incomplete fistula closure.

Phase I study of orally administered 14Carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies.

PURPOSE: Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. METHODS: Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. RESULTS: 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) < 1.2 h in all subjects). Overall, > 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each < 10% area under the concentration-time curve from zero to infinity (AUC0-∞)]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. CONCLUSIONS: The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.

The Lake Urmia environmental disaster in Iran: A look at aerosol pollution.

Lake Urmia (LU) once was the second largest hypersaline lake in the world, covering up to 6000km2, but has undergone catastrophic desiccation in recent years resulting in loss of 90% of its area and extensive coverage by playas and marshlands that represent a source of salt and dust. This study examines daily Aerosol Optical Depth (AOD) data from the Moderate Resolution Imaging Spectroradiometer (MODIS) between 2001 and 2015 over northwestern Iran, which encompasses LU. Intriguingly, salt emissions from the LU surface associated with ongoing desiccation do not drive the study region's AOD profile, whereas pollution transported from other regions and emissions around LU are more important. Signatures of increasing local crustal emissions are most evident outside of the peak dust season (January, February, and October) and on the periphery of LU. AOD has generally increased in the latter half of the study period with the onset of the AOD ramp-up starting a month earlier in the spring season when comparing 2009-2015 versus earlier years. Results indicate that suppression of emissions on the LU border is critical as the combined area of salt and salty soil bodies around LU have increased by two orders of magnitude in the past two decades, and disturbing these areas via activities such as grazing and salt harvesting on the lake surface can have more detrimental impacts on regional pollution as compared to benefits. These results have important implications for public health, climate, the hydrological cycle, and pollution control efforts.

Patient safety improvement interventions in children's surgery: A systematic review.

BACKGROUND: Adult surgical patient safety literature is plentiful; however, there is a disproportionate paucity of published safety work in the children's surgical literature. We sought to systematically evaluate the nature and quality of patient safety evidence pertaining to pediatric surgical practice. METHODS: Systematic search of MEDLINE and EMBASE databases and gray literature identified 1399 articles. Data pertaining to demographics, methodology, interventions, and outcomes were extracted. Study quality was assessed utilizing formal criteria. RESULTS: 20 studies were included. 14 (70%) comprised peer-reviewed articles. 18 (90%) were published in the last 4years. 13 (65%) described a novel intervention, and 7 (35%) described a modification of an existing intervention. Median patient sample size was 79 (29-1210). A large number (n=55) and variety (n=35) of measures were employed to evaluate the effect of interventions on patient safety. 15 (75%) studies utilized a checklist tool as a component of their intervention. 9 (45%) studies [comprising handoff tools (n=7); checklists (n=1); and multidimensional quality improvement initiatives (n=1)] reported a positive effect on patient safety. Quality assessment was undertaken on 14 studies. Quantitative studies had significantly higher quality scores than qualitative studies (61 [0-89] vs 44 [11-78], p=0.03). CONCLUSIONS: Pediatric surgical patient safety evidence is in its early stages. Successful interventions that we identified were typically handoff tools. There now ought to be an onus on pediatric surgeons to develop and apply bespoke pediatric surgical safety interventions and generate an evidence base to parallel the adult literature. LEVEL OF EVIDENCE: Level IV, Case series with no comparison group.

Learning Curves in Pediatric Minimally Invasive Surgery: A Systematic Review of the Literature and a Framework for Reporting.

AIMS: There exists a learning curve (LC) with the adoption of any minimally invasive surgical (MIS) technique with implications for training, implementation, and evaluation. A standardized approach to describing and analyzing LCs in pediatric MIS is lacking. We sought to determine how pediatric MIS LCs are quantified and present a framework for reporting. METHODS: Systematic search of MEDLINE and EMBASE 1985-October 2015 for articles describing MIS in the pediatric population and presenting formal analysis of the LC. Articles screened by two independent reviewers. RESULTS: Twenty-nine articles (n = 17 general abdominal/thoracic, n = 12 urological) from an 18-year period (1997-2015) were included representing 3345 procedures (n = 3116 laparoscopic, n = 10 thoracoscopic, n = 219 robotic). Seven (24%) were prospective, three multicenter. Twenty-two (76%) presented data pertaining to >1 operating surgeon. Operative time was the most commonly employed surrogate of proficiency (n = 26 [90%] studies). Twenty (69%) described >1 LC outcome measure. Sixteen additional measures were described, including conversion (n = 12 studies); blood loss (n = 4 studies); complications (n = 10 studies); and postoperative outcomes (n = 14 studies). Three studies assessed impact of LC on trainees and one considered economic impact. LCs were presented in tabular form (n = 14 studies) and graphically (n = 19). Eleven (38%) studies undertook statistical appraisal utilizing comparative statistics (n = 8 studies) and regression analysis (n = 4 studies). CONCLUSIONS: Multiple outcome measures of proficiency are employed in reporting pediatric MIS experience and analysis of LCs is inconsistent. A standardized multioutcome approach to reporting should be encouraged. In addition, attempts should be made to quantify the impact on trainee involvement. We present an idealized framework for reporting.

Contemporary pediatric surgical training in the UK.

INTRODUCTION: Pediatric surgical trainees worldwide face pressures from expansion of programs and training positions, subspecialization, regionalization, restrictions of working hours, and rigid training criteria. The era of apprenticeship training has long gone, and surgical education needs to be responsive and adapt to newer challenges. The aim of this study was to examine the teaching provision component of pediatric surgical training in the UK. METHOD: A national teaching survey was sent to UK pediatric surgery trainees in 2010 and compared to results of a repeat survey in 2015. Analysis was carried out to compare type of teaching, trends in teaching delivery, quality, and attendance over time. RESULTS: Regional variability was noted in teaching programs. Both provision of educational activities and ability to attend teaching improved between 2010 and 2015. Despite this, overall trainee satisfaction remained low, with 50% and 52% of respondents describing their teaching as "good" or "excellent" in 2010 and 2015, respectively (P=0.84). Seventy-five percent of centers provided simulation training, and 25% of respondents had regional teaching provided. Survey response rate was comparable between 2010 and 2015. CONCLUSION: Variability in national educational provision was observed. We suggest regular national audit of educational activity and responsive adaption to external pressures on training if competent surgeons are to be the product of contemporary pediatric surgery training programs.

Outcome of abstracts presented at the British Association of Paediatric Surgeons congresses (1999-2008).

BACKGROUND: Abstracts presented at the British Association of Paediatric Surgeons annual congress have the potential to influence practice. However, it is not known what percentage of accepted abstracts actually go on to withstand peer review and be published in the literature. METHODS: Abstract books were reviewed for the period 1999 to 2008. A MEDLINE search using keywords from title and authors' names was used to identify subsequent publication. Categorical analysis for variation and trend with P < .05 was accepted as significant. Data were expressed as median (interquartile range). RESULTS: During the 10-year period, 862 abstracts were presented orally and were derived from 36 countries, with a median of 18 (17-19) countries represented each year. Of these, 375 (43%) abstracts originated from 25 United Kingdom (UK) institutions with most (45%) from London and specifically the Institute of Child Health/Great Ormond Street Hospital (n = 118, 14%). The annual median number of presentations was 81 (74-97). This fell during the first half of the decade but is now rising with a significant increase in the UK proportion (P = .001). Thirty (27-35) abstracts per year (overall, n = 302) were subsequently published with the proportion (36% [33%-39%]) remaining remarkably consistent over the period. Abstracts were published in a range of 26 journals, but most (69%) were published in the Journal of Pediatric Surgery. CONCLUSIONS: The publication rate of the British Association of Paediatric Surgeons congress and hence entry into the "evidence base" as published material is consistent at just over one third of submissions. Whether this represents a waste of scientific endeavor or further refinement of quality is a moot point.

SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. WHAT THIS STUDY ADDS: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. AIMS: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. METHODS: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers. RESULTS: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. CONCLUSIONS: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.

Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.