Prediction of Sublingual Bioavailability of Buprenorphine in Newborns with Neonatal Abstinence Syndrome—a case study on physiological and developmental changes using NONMEM and SIMCYP

Poster presented at 2009 American College of Clinical Pharmacology conference in Orlando. April 24-28. Background: About 55 to 94% of infants born to opioid dependent mothershave neonatal abstinence syndrome (NAS). Buprenorphine (BUP) is usedclinically as an analgesic and a detoxification agent and a maintenancetreatment for opioid dependence. No data, however, has been reported about the use of sublingual administration of BUP below the age of 4 year, especially for term infants with NAS. Objectives: Characterize pharmacokinetics (PK) of BUP in newborn patients;Evaluate the developmental changes in newborns in order to assist dosingoptimization in ongoing clinical studies. Methods: In silico prediction of PK behavior and physiological development in newborn patients were evaluated using SIMCYP. Intravenous clearance was predicted through physiologically based simulation method in SIMCYP. Basedon sublingual clearance obtained from a one compartmental model developedpreviously using NONMEM, individual changes of sublingual bioavailability were evaluated with physiological development in the first one and half month during the newborn period. Results: Intrinsic clearance of BUP in newborns were incorporated into enzymekinetic data obtained from literature. Change of sublingual bioavailability fornewborns was evaluated with bioavailability-postmenstrual age profiles.Sublingual bioavailability of BUP was estimated as 8.9--56.6% in newborn patients studied during the first one and half postnatal month. Conclusion: Developmental considerations for the PK of BUP in newborns are important for the characterization of the dose-exposure relationship. We have evaluated this from “bottom-up” and “top-down” approaches with SIMCYP and NONMEM respectively and found these approaches to be complementary andvaluable for clinical trial design and routine clinical care. Presumably theywould facilitate rational decision making in pediatric drug development as well

Cost‐effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144625/1/bju14151_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144625/2/bju14151.pd

Can endoscopic ultrasound or magnetic resonance cholangiopancreatography replace ERCP in patients with suspected biliary disease? A prospective trial and cost analysis

ERCP is the gold standard for pancreaticobiliary evaluation but is associated with complications. Less invasive diagnostic alternatives with similar capabilities may be cost-effective, particularly in situations involving low prevalence of disease. The aim of this study was to compare the performance of endoscopic ultrasound (EUS) with magnetic resonance cholangiopancreatography (MRCP) and ERCP in the same patients with suspected extrahepatic biliary disease. The economic outcomes of EUS-, MRCP-, and ERCP-based diagnostic strategies were evaluated. METHODS : Prospective cohort study of patients referred for ERCP with suspected biliary disease. MRCP and EUS were performed within 24 h before ERCP. The investigators were blinded to the results of the alternative imaging studies. A cost-utility analysis was performed for initial ERCP, MRCP, and EUS strategies for these patients. RESULTS : A total of 30 patients were studied. ERCP cholangiogram failed in one patient, and another patient did not complete MRCP because of claustrophobia. The final diagnoses ( n = 28 ) were CBD stone (mean = 4 mm; range = 3–6 mm) in five patients; biliary stricture in three patients, and normal biliary tree in 20. Two patients had pancreatitis after therapeutic ERCP, one after precut sphincterotomy followed by a normal cholangiogram. EUS was more sensitive than MRCP in the detection of choledocolithiasis (80% vs 40%), with similar specificity. MRCP had a poor specificity and positive predictive value for the diagnosis of biliary stricture (76%/25%) compared to EUS (100%/100%), with similar sensitivity. The overall accuracy of MRCP for any abnormality was 61% (95% CI = 0.41–0.78) compared to 89% (CI = 0.72–0.98) for EUS. Among those patients with a normal biliary tree, the proportion correctly identified with each test was 95% for EUS and 65% for MRCP ( p < 0.02 ). The cost for each strategy per patient evaluated was $1346 for ERCP,$1111 for EUS, and $1145 for MRCP. CONCLUSIONS : In this patient population with a low disease prevalence, EUS was superior to MRCP for choledocholithiasis. EUS was most useful for confirming a normal biliary tree and should be considered a low-risk alternative to ERCP. Although MRCP had the lowest procedural reimbursement, the initial EUS strategy had the greatest cost-utility by avoiding unnecessary ERCP examinations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73885/1/j.1572-0241.2001.04245.x.pd

Development of an automated DNA purification module using a micro-fabricated pillar chip

We present a fully automated DNA purification module comprised of a micro-fabricated chip and sequential injection analysis system that is designed for use within autonomous instruments that continuously monitor the environment for the presence of biological threat agents. The chip has an elliptical flow channel containing a bed (3.5 &times; 3.5 mm) of silica-coated pillars with height, width and center-to-center spacing of 200, 15, and 30 &micro;m, respectively, which provides a relatively large surface area (ca. 3 cm2) for DNA capture in the presence of chaotropic agents. We have characterized the effect of various fluidic parameters on extraction performance, including sample input volume, capture flow rate, and elution volume. The flow-through design made the pillar chip completely reusable; carryover was eliminated by flushing lines with sodium hypochlorite and deionized water between assays. A mass balance was conducted to determine the fate of input DNA not recovered in the eluent. The device was capable of purifying and recovering Bacillus anthracis genomic DNA (input masses from 0.32 to 320 pg) from spiked environmental aerosol samples, for subsequent analysis using polymerase chain reaction-based assays.<br /

Human Jejunal Permeability of Cyclosporin A: Influence of Surfactants on P-Glycoprotein Efflux in Caco-2 Cells

Purpose. The purpose of this work was to determine the jejunal permeability of cyclosporin A (CsA) in humans and whether formulation variables modulate the effects of P-glycoprotein (P-gp) on the permeability of CsA in Caco-2 cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41496/1/11095_2004_Article_464398.pd

Interactive Effects of Climate Change with Nutrients, Mercury, and Freshwater Acidification on Key Taxa in the North Atlantic Landscape Conservation Cooperative Region

The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public-private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using a case study approach, we focused on 3 stressors with sufficient NA LCC region-specific information for an informed discussion. We describe GCC interactions with a contaminant (Hg) and 2 complex environmental phenomena-freshwater acidification and eutrophication. We also prepared taxa case studies on GCC- and GCC-contaminant/nutrient/process effects on amphibians and freshwater mussels. Several avian species of high conservation concern have blood Hg concentrations that have been associated with reduced nesting success. Freshwater acidification has adversely affected terrestrial and aquatic ecosystems in the Adirondacks and other areas of the region that are slowly recovering due to decreased emissions of N and sulfur oxides. Eutrophication in many estuaries within the region is projected to increase from greater storm runoff and less denitrification in riparian wetlands. Estuarine hypoxia may be exacerbated by increased stratification. Elevated water temperature favors algal species that produce harmful algal blooms (HABs). In several of the region\u27s estuaries, HABs have been associated with bird die-offs. In the NA LCC region, amphibian populations appear to be declining. Some species may be adversely affected by GCC through higher temperatures and more frequent droughts. GCC may affect freshwater mussel populations via altered stream temperatures and increased sediment loading during heavy storms. Freshwater mussels are sensitive to un-ionized ammonia that more toxic at higher temperatures. We recommend studying the interactive effects of GCC on generation and bioavailability of methylmercury and how GCC-driven shifts in bird species distributions will affect avian exposure to methylmercury. Research is needed on how decreases in acid deposition concurrent with GCC will alter the structure and function of sensitive watersheds and surface waters. Studies are needed to determine how GCC will affect HABs and avian disease, and how more severe and extensive hypoxia will affect fish and shellfish populations. Regarding amphibians, we suggest research on 1) thermal tolerance and moisture requirements of species of concern, 2) effects of multiple stressors (temperature, desiccation, contaminants, nutrients), and 3) approaches to mitigate impacts of increased temperature and seasonal drought. We recommend studies to assess which mussel species and populations are vulnerable and which are resilient to rising stream temperatures, hydrological shifts, and ionic pollutants, all of which are influenced by GCC

Interactive Effects of Climate Change with Nutrients, Mercury, and Freshwater Acidification on Key Taxa in the North Atlantic Landscape Conservation Cooperative Region

The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public–private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using a case study approach, we focused on 3 stressors with sufficient NA LCC regionspecific information for an informed discussion. We describe GCC interactions with a contaminant (Hg) and 2 complex environmental phenomena—freshwater acidification and eutrophication. We also prepared taxa case studies on GCCand GCC-contaminant/nutrient/process effects on amphibians and freshwater mussels. Several avian species of high conservation concern have blood Hg concentrations that have been associated with reduced nesting success. Freshwater acidification has adversely affected terrestrial and aquatic ecosystems in the Adirondacks and other areas of the region that are slowly recovering due to decreased emissions of N and sulfur oxides. Eutrophication in many estuaries within the region is projected to increase from greater storm runoff and less denitrification in riparian wetlands. Estuarine hypoxia may be exacerbated by increased stratification. Elevated water temperature favors algal species that produce harmful algal blooms (HABs). In several of the region\u27s estuaries, HABs have been associated with bird die-offs. In the NA LCC region, amphibian populations appear to be declining. Some species may be adversely affected by GCC through higher temperatures and more frequent droughts. GCC may affect freshwater mussel populations via altered stream temperatures and increased sediment loading during heavy storms. Freshwater mussels are sensitive to un-ionized ammonia that more toxic at higher temperatures. We recommend studying the interactive effects of GCC on generation and bioavailability of methylmercury and how GCC-driven shifts in bird species distributions will affect avian exposure to methylmercury. Research is needed on how decreases in acid deposition concurrent with GCC will alter the structure and function of sensitive watersheds and surface waters. Studies are needed to determine how GCC will affect HABs and avian disease, and how more severe and extensive hypoxia will affect fish and shellfish populations. Regarding amphibians, we suggest research on 1) thermal tolerance and moisture requirements of species of concern, 2) effects of multiple stressors (temperature, desiccation, contaminants, nutrients), and 3) approaches to mitigate impacts of increased temperature and seasonal drought. We recommend studies to assess which mussel species and populations are vulnerable and which are resilient to rising stream temperatures, hydrological shifts, and ionic pollutants, all of which are influenced by GCC

Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs

Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: Lack of prediction by the erythromycin breath test

The CYP3A subfamily of cytochromes P450 metabolize many medications and environmental contaminants. CYP3A4 and, in 25% of patients, CYP3A5 seem to be the major CYP3A genes expressed in adult liver. Hepatic levels of CYP3A4 can be estimated by the erythromycin breath test and vary at least 10-fold among patients. CYP3A4 has also been shown to be present in small bowel where it is responsible for significant "first-pass" metabolism of orally administered substrates. However, it is not known whether there is significant interindividual variability in the intestinal expression of CYP3A4, or whether the liver and intestinal catalytic activities of CYP3A4 correlate within an individual. It is also not known whether CYP3A5 is expressed in the small intestine. To address these questions, we administered the erythromycin breath test to 20 patients and obtained biopsies from their small bowel. There was a 6-fold variation in CYP3A catalytic activity (midazolam hydroxylation), an 11-fold variation in CYP3A4 protein content, and an 8-fold variation in CYP3A4 mRNA content in intestinal biopsies. There was an excellent correlation between intestinal CYP3A4 protein level and catalytic activity (r = 0.86; p = 0.0001); however, neither parameter significantly correlated with hepatic CYP3A4 activity as measured by the erythromycin breath test result (r = 0.27; p = 0.24 and r = 0.33; p = 0.15, respectively). We also found that CYP3A5 protein was readily detectable in biopsies from 14 (70%) of the patients, indicating that CYP3A5 is commonly expressed in human small intestine

Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs

Purpose . To compare gene expression profiles and drug permeability differences in Caco-2 cell culture and human duodenum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41490/1/11095_2004_Article_450750.pd