Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis.

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 µm) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solid-state characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose-response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 µg/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 µg/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 µg/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization.

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections.

Distal esophagus is the most commonly involved site for strictures in patients with eosinophilic esophagitis.

While strictures are common in eosinophilic esophagitis (EoE), there are few data on stricture distribution and characteristics. Our primary aim was to characterize strictures by location in the esophagus in EoE and associated clinical, endoscopic, and histologic features. This was a retrospective study from the UNC EoE Clinicopathologic Database of subjects with esophageal strictures or narrowing from 2002 to 2017. Strictures were categorized as distal esophagus/gastroesophageal junction, mid-esophagus, proximal esophagus, or diffusely narrowed. Stricture location was assessed and compared with clinical, endoscopic, and histologic features, and also with treatment response to diet or topical steroids. Efficacy of combination therapy with dilation and intralesional steroid injection was assessed in a sub-group of patients with strictures. Of 776 EoE cases, 219 (28%) had strictures, 45% of which were distal, 30% were proximal, 5% were mid-esophageal, and 20% had diffuse narrowing. Those with mid-esophageal strictures were younger (P = 0.02) and had shorter symptom duration (P < 0.01). Those with diffuse esophageal narrowing were more likely to be women (57%) and have abdominal pain (25%). There was no association between other clinical, endoscopic, and histologic findings and treatment response based on stricture location. Fourteen patients (8%) received intralesional triamcinolone injection and subsequently achieved a higher mean dilation diameter after injection (13.7 vs. 15.5 mm; P < 0.01). In conclusion, almost half of strictures in EoE patients were in the distal esophagus. Therefore, EoE should be a diagnostic consideration in patients with focal distal strictures and not presumed to be secondary to gastroesophageal reflux disease.

Long-term Continued Proton Pump Inhibitor Use is Common in Patients Diagnosed with Eosinophilic Esophagitis Despite Failure of Histologic Response: Data from a two-centre study: Long-term PPI Use in Patients with EoE.

Background and Aims: Treatment paradigms for proton pump inhibitors (PPIs) in eosinophilic esophagitis (EoE) are evolving. We aimed to determine patterns of long-term PPI use after EoE diagnosis in PPI histologic non-responders. Methods: We conducted a retrospective review at University of Colorado (UCH) and University of North Carolina (UNC) of EoE patients who were histologic non-responders to PPIs. Data were extracted from electronic medical records related to demographics, PPI use, and reasons for continuing or stopping PPI. Results: Of 67 patients in the UCH cohort, PPIs were initially discontinued in 9 (13%). Of 58 remaining on PPI, 48% were not instructed to discontinue therapy and 26% continued for symptom improvement. Of 675 patients at UNC, PPI was stopped in 185 (27%). Of patients remaining on PPI, 15% were not told to discontinue therapy and 62% were continued for symptom improvement. At last contact, >50% of patients remained on PPI at both centres with most common reasons for continuation being symptom improvement and not telling patients to discontinue. In the UNC cohort, clinical features associated with remaining on PPI included children younger than 18 years (p=0.01), males (p<0.001), heartburn symptoms (p<0.001) and hiatal hernia (p=0.004). Patients with dysphagia were less likely to remain on PPIs (p<0.001). Conclusions: Long-term PPI use is common in EoE patients even without histologic response. Failure to instruct patients to discontinue therapy was a common reason for long-term use, thus PPI use should be revisited in all EoE patients to confirm clinical benefit.

Compounded Oral Viscous Budesonide is Effective and Provides a Durable Response in Eosinophilic Esophagitis.

AIM: Because no approved medications exist for eosinophilic esophagitis (EoE), patients must use off-label drugs or create their own formulations. We assessed the efficacy of a standardized compounded budesonide suspension for treatment of EoE. MATERIALS AND METHODS: We conducted a retrospective cohort study of EoE patients at the University of North Carolina treated with compounded budesonide dispensed by a specialty compounding pharmacy. Outcomes (symptomatic global response [yes/no], endoscopic response [% with individual findings], and histologic response [absolute eosinophil count; % with <15 eos/hpf])were assessed after the initial and last treatment in our system. RESULTS: We identified 48 patients treated with compounded budesonide (mean age 33.6; 69% male; 96% white; 2.4 mg mean initial dose). After a mean length of follow-up of 17.0 months (range: 4.2 - 56.3), there was a significant decrease in symptoms of dysphagia (95% vs. 32%, p < 0.001), improvements in heartburn (37% vs. 11%, p=0.06) and global symptom response (81%). The median of the peak eosinophil counts decreased from 55 to 20 eos/hpf (p<0.001) with 42% achieving a response of <15 eos/hpf. Esophageal candidiasis was rare (6%). In the 18 patients with prior non-response to corticosteroids or dietary elimination, 83% had symptomatic and 38% had histologic response. CONCLUSION: Compounded budesonide suspension produced a durable symptomatic, endoscopic, and histologic response in a cohort followed for more than a year. Many patients previously refractory to prior therapy responded to compounded budesonide. This formulation can be used clinically until there are approved drugs with esophageal formulations for EoE.

Management of Serrated Polyps of the Colon.

PURPOSE OF REVIEW: The purpose of this review is to summarize the management of serrated colorectal polyps (SPs), with a particular focus on the most common premalignant SP, sessile serrated adenoma or polyp (SSA/P). These lesions present a challenge for endoscopists with respect to detection and resection, and are also susceptible to pathologic misdiagnosis. RECENT FINDINGS: Patients with SSA/Ps are at an increased risk of future colorectal neoplasia, including advanced polyps and cancer. Reasonable benchmarks for SP detection rates are 5-7% for SSA/Ps and 10-12% for proximal SPs. Certain endoscopic techniques such as chromoendoscopy, narrow band imaging, water immersion, and wide-angle viewing may improve SSA/P detection. Emerging endoscopic techniques such as underwater polypectomy, suction pseudopolyp technique, and piecemeal cold snare polypectomy are helpful tools for the endoscopist's armamentarium for removing SSA/Ps. Proper orientation of SSA/P specimens can improve the accuracy of pathology readings. Patients with confirmed SSA/Ps and proximal HPs should undergo surveillance at intervals similar to what is recommended for patients with conventional adenomas. Patients with SSA/Ps may also be able to lower their risk of future polyps by targeting modifiable risk factors including tobacco and alcohol use and high-fat diets. NSAIDs and aspirin appear to be protective agents. SPs and SSA/Ps in particular are important colorectal cancer precursors that merit special attention to ensure adequate detection, resection, and surveillance.

Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control.

We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (≤4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p-value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT.