Abstract:The pharmacodynamics and elimination kinetics of escalating doses (1.5-12 mg/kg) of hyaluronan (HA) infusions were studied in healthy human volunteers. Metabolic breakdown of serum HA and associated adverse events were monitored throughout the study. The HA-binding capacities of circulating CD4+ and CD8+ T lymphocytes, CD19+ Blymphocytes and CD14+ peripheral blood monocytes (PBMC) were also quantified. Breakdown of infused HA into small fragments (<37 kDa) were not detected and adverse events related to HA infusions were infrequent and non-serious in nature. Binding of FITC-HA was greatest to CD14+ monocytes and the binding capacity of these cells for FITC-HA was significantly increased by the final HA infusion. At that time, binding to CD14+ monocytes was related to serum HA levels suggesting a close relationship between PK and PD of serum HA. Drug level analysis demonstrated a disproportional increase in the area under the serum concentration vs. time curve with increasing HA dose. The observed non-linear HA kinetics appears to result from a saturable elimination process as revealed by pharmacokinetic modeling. These results have implications for the use of injected HA for drug delivery or in imaging applications.
INTRODUCTION: MAP US was a global multicenter randomized trial comparing the efficacy and safety of RHB-104, a fixed-dose oral combination of clarithromycin, rifabutin and clofazimine against MAP infection, in moderately to severely active Crohn's disease (CD). We report evaluations of efficacy, symptom improvement and exposure-response by individual RHB-104 components. METHODS: Patients with active CD (CDAI ≥220 and ≤450) and failure with conventional therapies were randomized 1:1 to RHB-104 or placebo for up to 52 Wks. Concomitant corticosteroids, immunosuppressives (IS) and anti-TNF agents were permitted. The primary endpoint was clinical remission (CDAI <150) at Wk 26. Secondary endpoints included clinical response at Wk 26 (CDAI decrease ≥100 points), early remission at Wk 16 and remission at Wk 52. A population pharmacokinetic (PK) and exposure-response analysis was performed based on PK assessments and remission at Wk 26; a subset of patients underwent colonoscopy at baseline and Wk 26. RESULTS: 331 subjects were randomized at 92 sites. The proportion achieving remission at Wk 26 (36.7% vs 23%, P = .007), remission at Wk 16 (42.2% vs 29.1%, P = .015) and response at Wk 26 (44% vs 30.9%, P = .017) were significantly greater with RHB-104 vs placebo. The superiority of RHB-104 was more pronounced in patients receiving RHB-104 with concomitant anti-TNF or IS treatment. Despite the small numbers (n = 35), a greater proportion of RHB-104 patients achieved endoscopic response by SES-CD 50 (28.6% vs 4.8%, P = .11). Differences in fecal calprotectin (FCP) increased over time (Figure 1); improvements in PRO-2 symptoms appeared by Wk 4 and reached significance by Wk 16 (Figure 2). A significantly greater proportion of patients receiving RHB-104 achieved clinical remission with at least a 50% reduction from baseline in either FCP or CRP concentration at Wk 16 (25.9% vs 9.7%, P = .0002), Wk 26 (21.1% vs 9.1%, P = .0003) and Wk 52 (16.9% vs 7.9%, P = .02). Exposure-response modeling demonstrated the combination of the individual components of RHB-104 contributed to the higher rate of remission compared to placebo and that the probability of achieving remission was most sensitive to clofazimine. CONCLUSION: RHB-104 demonstrated meaningful improvement in efficacy and biomarkers of active inflammation, with exposure-response for each drug component, early onset of response and benefit in patients with and without concomitant anti-TNF or IS therapy.
Chronic cyclosporine nephrotoxicity is a poorly understood drug side-effect characterized by renal cortical interstitial scarring. To evaluate procollagen mRNA levels as an early factor in the development of this form of renal fibrosis, we measured renal procollagen alpha 1 (I), alpha 1 (III), alpha 1 (IV) and beta-actin mRNA levels in rats treated with cyclosporine (CsA) or the olive oil vehicle (OO) for one or four weeks. Renal morphology was similar without atrophy or fibrosis in one week CsA and OO and four week OO rats. Four week CsA rats had focal cortical interstitial fibrosis and tubular atrophy. Cortical procollagen alpha 1 (I) mRNA levels were increased in CsA versus OO rats at one week (P less than 0.02) and four weeks (P less than 0.02). One week medullary procollagen alpha 1 (I) and all other one week medullary, and one and four week cortical procollagen and beta-actin mRNA levels were no different in CsA versus OO rats. The early increase in renal cortical procollagen alpha 1 (I) mRNA levels precedes renal morphologic abnormalities, and may represent an important step in the pathogenesis of cyclosporine-induced renal cortical fibrosis.
Patients who develop hepatic decompensation with ascites have a poor prognosis and often experience other complications including spontaneous bacterial peritonitis, hepatic encephalopathy and variceal bleeding. We hypothesised that smartphone (SP)-enabled remote monitoring of patients with ascites may enable early detection of infection and acute decompensation, facilitate timely intervention and improve patient outcomes. Aim: We aimed to design, develop and implement a remote monitoring system (RMS) for outpatients with cirrhotic ascites. Method: We undertook surveys with patients and hepatologists to quantify the demand for a RMS and identify issues regarding implementation. A smartphone and a web-based application were developed as a RMS. Patients used the RMS in a 6-week prospective non-randomised trial. Results: We surveyed 27 patients (mean age 56 years, 18 (67%) were male, 16 (59%) had Childs Pugh B cirrhosis, and 20 (74%) had a history of alcoholic liver disease) and 5 hepatologists. There were 19 patients (70%) who reported that they would use a RMS. The RMS was used by 10 patients for a mean 53.8days (11-70), who entered 20.6 (0-71) updates. A total of 18 automated alerts occurred. 22% of automated alerts resulted in clinically significant changes to management, such as inpatient admission n=1 (6%), early outpatient appointment n=1 (6%) and reinforced adherence n=2 (11%). Conclusion: We have successfully designed an internet-enabled RMS for outpatients with cirrhotic ascites that could be used as an adjunct to existing outpatient services. Future studies will optimise the alert thresholds, assess long-term patient adoption and quantify clinical impact.
This article documents the continued gender disparities evident across U.S. higher education. While more women than men attend college and now obtain the majority of undergraduate, master's, and doctoral degrees, women continue to be underrepresented in senior-level institutional leadership roles. This phenomenon is particularly evident among the member institutions of the Council for Christian Colleges & Universities (CCCU). Given that the CCCU's 108 U.S. member campuses serve a collective student body that is more than 60% female, such gender imbalances are striking, especially noting the commitment of Christ-centered campuses to foster organizational climates that value diversity and promote the success and well-being of all students. Data over a 12-year period (1998-2010) have been collected to document trends in the gender composition of the seniorlevel leadership teams on these campuses. Over that period, the average number of individuals serving at vice presidential or higher levels across these institutions increased from 5.3 to 5.9. The percent of men grew 20% over the period, while the percent of women serving on those leadership teams grew 161%-from 8.4% to 17% of the total serving in these senior leadership positions. On average across these campuses, the mean of male senior leaders in 2010 was 4.9; the mean of women serving was just under 1.0 (.99). The background, results, and discussion/implications sections present trends and themes related to the composition of CCCU presidents' leadership teams, with suggestions offered for changing the face of senior leadership in member institutions.Gender equity continues to be elusive in many sectors of U.S. society, despite a majority of women now participating in the labor force and more women than men attending college. Overall,
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