Dion Coakley - Academia.edu (original) (raw)

Papers by Dion Coakley

Antimicrobial Agents and Chemotherapy, 2004

Molecular genetics and metabolism reports, Dec 1, 2015

Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a do... more Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age-and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (b~9000 μg/mL for b 2 years old patients, b7000 μg/mL for N2 years with BSA ≤1.3 m 2 , and b~5000 μg/mL for N2 years of age with BSA N 1.3 m 2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.

This article cites 13 articles, 8 of which can be accessed free at:

Molecular genetics and metabolism, 2016

Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle ... more Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900μmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]μmol/L) than patients with baseline glutamine ≤900μmol/L (26.6 [18.0]μmol/L). Glutamine values >900μmol/L during the study were associated with an approximate...

Antimicrobial Agents and Chemotherapy, Jul 1, 1994

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to a... more Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of <150 cells per ,ul) who received Ihl valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stablb without any changes in underlying HIV-related medications for .6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in .31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2004

Annals of Internal Medicine, 2003

Metabolic Brain Disease, 2016

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are c... more Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

Pharmaceutical Medicine, 2016

Background Current approaches to detection of drug-induced liver injury (DILI) are generally base... more Background Current approaches to detection of drug-induced liver injury (DILI) are generally based on changes from normal in biochemical liver tests. However, limited information is available regarding the proportion of patients with normal versus abnormal biochemical tests, the expected temporal pattern of biochemical abnormalities, or the applicability of current approaches to DILI detection for patients with pre-existing liver disease. Objective These analyses aimed to answer the following questions. (1) What proportion of patients have normal versus abnormal biochemical liver tests at study baseline? (2) What is the variability of these biochemical tests on repeat testing? (3) What proportion of patients meet current criteria for discontinuation of treatment? (4) Is an eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) approach likely to be useful in such a study population? Methods Biochemical liver test results from 178 patients with clinically decompensated cirrhosis who participated in a 4-month clinical trial of glycerol phenylbutyrate versus placebo for reduction in recurrence rate of hepatic encephalopathy were reviewed to determine fluctuation over time and the applicability of the US FDA DILI guideline and eDISH. Results In this cohort, the biochemical tests were frequently abnormal at baseline (aspartate aminotransferase [AST] 42 %, alanine aminotransferase [ALT] 71 %, bilirubin 67 %, international normalized ratio [INR] 62 %) and exhibited substantial variation both pre-dose and following enrollment and dosing. Up to 20 % of patients met current regulatory guidance criteria for consideration of interruption of drug treatment irrespective of treatment group assignment and whether tests were normal or abnormal at baseline, and an eDISH display approach appears unlikely to be informative. Conclusions Approaches to DILI detection in patients with pre-existing liver disease will require a more nuanced approach to recognize patterns of potential liver injury. Key Points Patients with clinically decompensated cirrhosis frequently have abnormal biochemical liver tests at baseline, thereby confounding application of current approaches for detecting drug-induced liver injury (DILI). Biochemical liver tests in patients with decompensated cirrhosis exhibit substantial variation over time, with or without exposure to study drug. The application of conventional guidance in diagnosing DILI in patients with hepatic impairment is problematic.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, Jun 18, 2015

There is controversy over the use of measuring blood levels of ammonia (NH3) in the management of... more There is controversy over the use of measuring blood levels of ammonia (NH3) in the management of patients with overt hepatic encephalopathy (HE). We performed a retrospective analysis of data from a randomized, double-blind study of 178 patients with cirrhosis given glycerol phenylbutyrate (an NH3-lowering agent) or placebo for 16 weeks. Blood samples were collected at baseline and on study days 7 and 14 and NH3 levels were measured. The probabilities of having an HE episode, based on ammonia values, were modeled using binary logistic regression. A Cox proportional model was used to determine the risk of HE episodes in patients with baseline fasting NH3 levels ≤1.5-fold the upper limit of normal (ULN) versus patients with fasting NH3 levels >1.5-fold the ULN. The risk and frequency of HE episodes and HE-related hospitalizations correlated with baseline (mean, 51 ± 6 μmol/L; ULN, 35 μmol/L) and on-study fasting levels of NH3, and increased sharply at levels >1.5-fold the ULN. ...

Molecular Genetics and Metabolism, 2015

Background-Health care outcomes have been increasingly assessed through health-related quality of... more Background-Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

Clinical Pharmacology in Drug Development, 2013

Clinical Pharmacology & Therapeutics, 1996

To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic... more To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic kidney failure. Three groups of patients with human immunodeficiency virus (HIV) infection were studied: group I, six men with normal kidney function (creatinine clearance > 90 ml/min/1.73 m2); group II, six men with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD); and group III, four men and two women with chronic renal failure receiving hemodialysis three times a week. A 300 mg dose of didanosine was administered orally and intravenously according to a two-period randomized crossover design. Patients in group III were studied between hemodialysis sessions during the crossover periods. In addition, patients in group III were studied in a third period after administration of a 300 mg oral dose of didanosine 4 hours before hemodialysis. After intravenous administration in group I, the mean (+/-SD) total clearance (CLT) was 13.0 +/- 1.6 ml/min/kg and the elimination half-life (t 1/2) was 1.56 +/- 0.43 hour. In groups II and III, the CLT decreased significantly to 3.4 +/- 1.2 and 3.2 +/- 1.2 ml/min/kg, respectively, whereas the t1/2 increased to 3.60 +/- 0.82 hours and 3.11 +/- 0.88 hours, respectively. The absolute bioavailability of didanosine in groups I, II, and III was 42% +/- 12%, 52% +/- 6%, and 38% +/- 11%, respectively, and did not differ significantly. CAPD had little effect on the removal of didanosine, whereas approximately 30% of the drug present in the body at the start of dialysis was eliminated by an average 3-hour dialysis session. The clearance of didanosine is impaired in patients with chronic renal failure. To compensate, the dose and schedule of administration should be adjusted. It is recommended that one-fourth of the total daily dose of didanosine be administered once a day in this patient population.

Clinical Biochemistry, 2014

On the cover of Percival Everett's 2001 novel Erasure is the black and white photo of a shirtless... more On the cover of Percival Everett's 2001 novel Erasure is the black and white photo of a shirtless African American man. His face is stern as he mugs the camera, gesturing with two downward pointing fingers that resemble a pointed gun. Another African American man's photo is on the back flap of the book. The paragraph beneath him says that this man is the author, an American-born writer and distinguished professor of English. The onedimensional picture represents a unique person, a human being with thoughts, experiences, dreams, and personal struggles. Yet only one of these pictures represents the source from which the story originated. The man on the back imagined and brought to life the man on the cover. However, French literary theorist Roland Barthes claims that it is writing that makes an author and not vice versa. The special voice of literature, explains Barthes (1977) in The Death of the Author, consists of "several indiscernible voices…to which we cannot assign a specific origin" (142). Yet, there is an origin to such voices. Exploring the author's personality, looking at the distinction between the conscious and the unconscious, and examining various doubling effects can provide a wealth of knowledge about the inner workings of a text. This paper will provide a Freudian analysis of Erasure in order to prove that Everett is, in fact, the two main characters he has created, as well as attempt to challenge the stigma of interpreting through a psychoanalytical lens, rather than treating writing and literature as manifest content without a dreamer. Since the first words were penned on parchment, readers have admired literary greats for their writing and ability to weave together intricate narratives that captivate and entertain. "There is very real pleasure that comes from surrendering to the discursive seductions of a masterful author" and there are few other ways, aside from a close psycholanalyical reading of a text, to delve into the psyche of a famous author in order to understand his or her genius (Whitby 2011). Nevertheless, many scholars have argued that psychoanalytical criticism is problematic. Barthes (1977) explains that an author "is never anything more than the man who writes […he] can only imitate a gesture that is always anterior, never original. His only power is to mix writings…in such a way as never to rest on any one of them" (146). In addition, literary scholar Terry Eagleton (2008) debatably claims that psychoanalytical literary criticism, as it pertains to the author or the work and the work's content, is "in fact the most limited" (155). This is disputable. Someone had to meditate on their ideas, construct the characters, piece together dialogue, and ultimately toil over the writing until it reached its full potential. Studying the author in order to gain better knowledge into the work of literature is critical because the author is first and foremost the source. While solely reading an author's biography as a means of criticism is

Genetics in medicine : official journal of the American College of Medical Genetics, Jan 11, 2014

Purpose:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic cr... more Purpose:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.Methods:The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.Results:Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations…

Molecular Genetics and Metabolism, 2013

are/were employees of Hyperion at the time of the study. D. Milikien is an employee of Accudata, ... more are/were employees of Hyperion at the time of the study. D. Milikien is an employee of Accudata, which was paid by Hyperion to perform the biostatistical analyses. None of the other authors have a financial interest in Hyperion, although payments were made by Hyperion to all investigators for services related to the clinical trials.

Molecular Genetics and Metabolism, 2012

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodi... more We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). Study Design-These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Results-Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5-31.8 g/day and of sodium phenylbutyrate ranging from 1.3-31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979%-5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881%-to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r=0.730, p<0.001) or as total 24-hour excretion (r=0.791 p<0.001), followed by plasma phenylacetylglutamine AUC 24-hour , plasma phenylacetic acid AUC 24-hour and phenylbutyric acid AUC 24-hour. Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. Conclusion-The findings are collectively consistent with substantial yet variable pre-systemic (1 st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

Molecular Genetics and Metabolism, 2014

To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle ... more To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.

The Journal of Pediatrics, 2013

Objectives-To examine ammonia levels, pharmacokinetics (PK), and safety of glycerol phenylbutyrat... more Objectives-To examine ammonia levels, pharmacokinetics (PK), and safety of glycerol phenylbutyrate (GPB, HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs). Study design-This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hr blood and urine sampling on NaPBA and again on a PBA-equimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD. Results-15 patients (8 ASL, 3 ASS, 3 OTC, 1 ARG) ages 2 months through 5 years enrolled in and completed the study. Daily ammonia exposure (24-hour AUC) was lower on GPB and met predefined non-inferiority criteria (ratio of means 0.79; 95% CI 0.593-1.055; p = 0.03 Wilcoxon; 0.07 t-test). Six patients experienced mild AEs on GPB; there were no SAEs or significant lab changes. Liver tests and ASA levels among patients with ASL were unchanged or improved on GPB. Eleven of 15 patients reported 35 symptoms on Day 1; 23 of these 35 symptoms improved or resolved on GPB. Mean systemic exposure to PBA, PAA and PAGN were similar and PAA exposure tended to be higher in the youngest children on both drugs. Urinary PAGN concentration was greater on morning voids and varied less over 24 hours on GPB versus NaPBA. Conclusions-GPB results in more evenly distributed urinary output of PAGN over 24 hours, was associated with fewer symptoms and offers ammonia control comparable with that observed with NaPBA in young children with UCDs.