Napo Pharmaceuticals (United States)

Chronic diarrhea presents a significant challenge for managing nutritional and electrolyte deficiencies, especially in children, given the higher stakes of impacting growth and developmental consequence. Congenital secretory diarrhea (CSD) compounds this further, particularly in the case of the activating variants of the guanylate-cyclase 2C (GUCY2C) gene. GUCY2C encodes for the guanylate-cyclase 2C (GC-C) receptor that activates the downstream cystic fibrosis transmembrane receptor (CFTR) that primarily drives the severity of diarrhea with an unclear extent of influence on other intestinal channels. Thus far, management for CSD primarily consists of mitigating nutritional, electrolyte, and volume deficiencies with no known pathophysiology-driven treatments. For activating variants of GUCY2C, experimental compounds have shown efficacy in vitro for direct inhibition of GC-C but are not currently available for clinical use. However, Crofelemer, a CFTR inhibitory modulator with negligible systemic absorption, can theoretically help to treat this type of CSD. Herein, we describe and characterize the clinical course of a premature male infant with a de novo missense variant of GUCY2C not previously reported and highly consistent with CSD. With multi-disciplinary family-directed decision-making, a treatment for CSD was evaluated for the first time to our knowledge with Crofelemer.

The utility of testing for urinary tract infection (UTI) in febrile infants with bronchiolitis is indeterminate. The objective of this study was to investigate if the incidence of UTIs in febrile infants 2 to 12 months of age with bronchiolitis is higher than the presumed incidence of asymptomatic bacteriuria and determine risk factors associated with UTIs in this population. This prospective multicenter cross-sectional study was conducted in the emergency departments of 6 children's hospitals between November 2011 and June 2015. We obtained a convenience sample of febrile infants with bronchiolitis 2 to 12 months of age who were tested for UTI. Patient characteristics analyzed included age, maximum temperature, duration of fever, ethnicity, sex, and circumcision status. A total of 442 patients (including 86 from a previously published pilot study) were enrolled. Mean age was 5.5 months, 65.2% were Latino, 50.9% were male, and 27.6% of male infants were circumcised. Urinary tract infections were found in 33 patients (7.69%, binomial; 95% confidence interval [CI], 5.19%-10.33%). Urinary tract infections were not related to age, height of temperature, duration of fever, or ethnicity. Uncircumcised males were significantly more likely to have UTIs than circumcised males (7.64% vs 0%, P = 0.03). Odds ratios (ORs) were lower for circumcised males but not uncircumcised males when compared with females (OR, 0.12; CI, 0.0-0.71; P = 0.01 vs OR, 0.77; CI, 0.33-1.74; P = 0.64). Febrile infants 2 to 12 months of age with bronchiolitis have a clinically significant incidence of UTI, suggesting that UTI evaluation should be considered in these patients.

In this chapter, we provide the details of an innovative two-stage, seamless adaptive clinical trial called ADVENT. This trial was conducted as a “final phase 3” clinical trial to establish the safety and efficacy of a first-in-class antidiarrheal agent, crofelemer, for the symptomatic relief of diarrhea in HIV patients receiving anti-retroviral therapy. Given that this was a trial with two-stage design that included a dose selection, it was necessary to demonstrate the strong control of Type 1 error. This was accomplished with a close testing procedure applied to combination tests that utilized the inverse normal combination function. We developed a one-sided significance testing procedure that ensures strong control of the Type 1 error at level 0.025. Using appropriate statistical methodology for combining the results from the two stages, a statistically significant outcome was obtained for the primary efficacy endpoint and crofelemer received marketing approval based on the ADVENT trial. While the authors acknowledge the importance of statistical methodology required to analyze the data from the ADVENT trial, this chapter also provides significant details on the clinical and regulatory challenges that were demanded for the conduct of this innovative, two-stage, adaptive clinical trial.

Crofelemer is a novel first in class compound extracted, isolated and purified from the stem bark latex of the widespread pioneer tree species Croton lechleri, (Sangre de Drago). The natural distribution of this species includes the Northwest Amazon regions of Colombia, Ecuador, Peru, Bolivia and adjacent regions of the Brazil. The latex of this species has been utilized by numerous indigenous peoples of the western Amazon basin orally for the treatment of diarrhea, topically for wound healing and many other therapeutic applications. Crofelemer is an acid-labile oligomeric proanthocyanidin. The primary monomers include (+)-gallocatechin; (-)-epigallocatechin; (+)-catechin and (-)-epicatechin. The oligomer predominantly contains 7–11 linked monomers in varying ratios and an average molecular weight ranges from 1800 to 2200 Da. A new drug application (NDA) for crofelemer for the treatment of HIV/AIDS related chronic diarrhea was submitted on December 5, 2011 to the US FDA and was granted a 6 month priority review designation. Crofelemer's antidiarrheal activity is mediated primarily through its action on two chloride channels. Specifically the compound reduces fluid loss and Cl- secretion through inhibition of both the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium activated Cl- channels (CaCC) in the intestinal epithelium. The drug has minimal systemic absorption and has demonstrated an excellent safety profile in global clinical trials with >2,000 patients dosed across multiple trials conducted in numerous countries. Most recently crofelemer demonstrated excellent efficacy and safety in a pivotal Phase 3 trial in HIV patients (ADVENT) in reducing secretory diarrhea with a p-value of 0.0096. Clinical trials have also been conducted at the International Center for Diarrheal Disease Research (ICDDR) in Dhaka, Bangladesh, demonstrating significant reduction in fluid loss in patients with cholera-induced diarrhea, a life-threatening condition that most recently killed 7,000 people Haiti. One goal of Napo is to make certain that crofelemer can be made available to help save lives in cholera outbreaks wherever they may occur in the world.

This paper introduces an improved best-fit back-calculation technique based on deflection predictions obtained using finite element method (FEM) simulations (i.e., computer program EverFE), rather than generic theoretical deflection predictions. It is based on minimizing the squared error between falling weight deflectometer (FWD) measured deflections and FEM predicted deflections. It assumes that the modulus of the portland concrete is known and gives a closed-form solution for the reaction modulus k of the layers supporting the concrete slab. The results were compared to those obtained by the best-fit method used for the Long Term Pavement Performance (LTPP) program. The comparison was in terms of the mean absolute error between measured and estimated deflections. The latter were obtained using the slab reaction moduli back-calculated by the two methods. Comparing the back-calculated reaction moduli to the ones obtained by the plate loading test was less conclusive. Overall, the results support that the additional work required in modeling the slab and the loading configuration at the time FWD measurements are taken is worthwhile.

Around the world, publicly owned and run health services face challenges. In poor countries in particular, health services are characterized by such problems as inadequate infrastructure and equipment, frequent shortages of medicines and supplies, and low quality of care. Increasingly, both developed- and developing-country governments are embracing public-private partnerships to harness private financing and expertise to achieve public policy goals. An innovative form of these partnerships is the public-private integrated partnership, which goes a step further than more common hospital building and maintenance arrangements, by combining infrastructure renewal with delivery of clinical services. We describe the benefits and risks inherent in such integrated partnerships and present three case studies that demonstrate innovative design. We conclude that these partnerships have the potential to improve access, quality, and efficiency in health care. More such partnerships should be launched and rigorously evaluated, and their lessons should be widely shared to guide policy makers in the effective use of this model.

In this piece about the future role of the probation service the author follows the Churchillian adage of looking back in order to go forward. He considers the experience of the service under the Labour Government, in particular the impact of the National Offender Management Service (NOMS) ‘project’, before going on to examine the intentions — good and bad — of the Coalition Government. Inevitably, it is necessary to ponder the likely substantial cuts to the probation service in line with the broader cuts to the public sector promised in the budget announcements but the author concludes by focusing on the potential opportunity for the service if a more progressive sentencing policy is pursued.