41 results on '"Toong C"'
Search Results
2. P462 Upfront infliximab dose intensification for secondary loss of response in IBD: similar efficacy to dose interval shortening with the added advantage of early clinical and pharmacokinetic predictors of response
- Author
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Srinivasan, A, primary, De Cruz, P, additional, Sam, M, additional, Toong, C, additional, and van Langenberg, D, additional
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- 2022
- Full Text
- View/download PDF
3. Degradation kinetics of C-Phycocyanin under isothermal and dynamic thermal treatments
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Faieta, M., Toong, C., Corradini, M. G., Ludescher, R. D., and Pittia, P.
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Hot Temperature ,Phycocyanin ,Water ,Degradation kinetics ,Thermal stability ,General Medicine ,C-phycocyanin ,Photophysical properties ,Analytical Chemistry ,Dynamic heating ,Luminescence spectroscopy ,Kinetics ,Food Science - Abstract
C-Phycocyanin (C-PC) represents an alternative to artificial blue/green dyes in food products. This study characterized and gained insights into C-PC thermal stability mechanisms and provided a model to estimate its thermal degradation. Aqueous solutions of C-PC (0.3 μM, pH:6.1) were isothermally heated at 45-80 °C. C-PC degradation was monitored based on the photophysical properties of its lumiphores (phycocyanobilins and aromatic aminoacids-AAs). While C-PC was stable at 45 °C, less than 10 min at 80 °C sufficed to degrade most of it. The thermal degradation curves were characterized using the Weibull model, which was validated with data obtained under non-isothermal conditions. Deviations between estimated and experimental values were lower than 8%. Hypsochromic shifts of the AAs' spectra (from 340 to 315 nm) and increase (30%) in anisotropy at λexc = 280 and 520 nm suggest that colour losses are not solely associated with alterations of the chromophore but also with conformational changes and possible aggregation of the protein subunits.
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- 2021
4. Population Pharmacokinetics of Metformin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus: Simulation of Doses According to Renal Function
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Duong, Janna K., Kumar, Shaun S., Kirkpatrick, Carl M., Greenup, Louise C., Arora, Manit, Lee, Toong C., Timmins, Peter, Graham, Garry G., Furlong, Timothy J., Greenfield, Jerry R., Williams, Kenneth M., and Day, Richard O.
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- 2013
- Full Text
- View/download PDF
5. Prospective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol
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Gu, B, De Gregorio, M, Pipicella, JL, Vande Casteele, N, Andrews, JM, Begun, J, Connell, W, D'Souza, B, Gholamrezaei, A, Hart, A, Liew, D, Radford-Smith, G, Rimola, J, Sutherland, T, Toong, C, Woods, R, Wu, Y, Xuan, W, Williams, AJ, Ng, W, Ding, NS, Connor, S, Gu, B, De Gregorio, M, Pipicella, JL, Vande Casteele, N, Andrews, JM, Begun, J, Connell, W, D'Souza, B, Gholamrezaei, A, Hart, A, Liew, D, Radford-Smith, G, Rimola, J, Sutherland, T, Toong, C, Woods, R, Wu, Y, Xuan, W, Williams, AJ, Ng, W, Ding, NS, and Connor, S
- Abstract
INTRODUCTION: Perianal fistulising Crohn's disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy. METHODS AND ANALYSIS: Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18-80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate. ETHICS AND DISSEMINATION: Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia. TRIAL REGISTRATION N
- Published
- 2021
6. Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group studyResearch in context
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Guy de Bruyn, Joyce Wang, Annie Purvis, Martin Sanchez Ruiz, Haritha Adhikarla, Saad Alvi, Matthew I. Bonaparte, Daniel Brune, Agustin Bueso, Richard M. Canter, Maria Angeles Ceregido, Sachin Deshmukh, David Diemert, Adam Finn, Remi Forrat, Bo Fu, Julie Gallais, Paul Griffin, Marie-Helene Grillet, Owen Haney, Jeffrey A. Henderson, Marguerite Koutsoukos, Odile Launay, Federico Martinon Torres, Roger Masotti, Nelson L. Michael, Juliana Park, Doris Maribel Rivera-Medina, Natalya Romanyak, Chris Rook, Lode Schuerman, Lawrence D. Sher, Fernanda Tavares-Da-Silva, Ashley Whittington, Roman M. Chicz, Sanjay Gurunathan, Stephen Savarino, Saranya Sridhar, Allaw Mohammed, Babin Valérie, Babyak Jennifer, Ines Ben-Ghezala, Thomas Breuer, Corinne Breymeier, Anne Conrad, Ciarrah Holmqvist, Cristiana Costa-Araujo, Florence Coux, Christine Dellanno, Bertrand Dussol, Brandon Essink, Jesús Garrido, Pierre-Olivier Girodet, Claudia Gonzalez, Marie-Ange Grosbois, Justin Hammond, Chelsea He, Ciarrah Homlqvist, Kathy Hudzina, Mark Hutchens, Peta-Gay Jackson Booth, Arnel Joaquin, Rama Kandasamy, Jennifer Kasztejna, Michael Keefer, Murray Kimmel, Matthew Kresge, Fabrice Laine, Maeva Lefebvre, Denise Lopez, Malaborbor Perpetua Lourdes, Zoha Maakaroun-Vermesse, Caitlin Malishchak, Lisa Menard, Sandra Mendoza, Patrick Moore, Mounika Mulamalla, Patrick Mulholland, Jean-Francois Nicolas, Onyema Ogbuagu, Juan Ortiz, Ana Paula Perroud, Gina Peyton, Ya-Fen Purvis, Vanessa Raabe, Enrique Rivas, Nadine Rouphael, Beatrice Roy, Lola Sagot, Nessryne Sater, Howard Schwartz, Randall Severance, Jiayuan Shi, Magdalena Sobieszczyk, Charlene Stevens, Tran Phuong Thuy, Ramy Toma, Tina Tong, Sophie Tourneux, John Treanor, Núria Turet, Rachel Froget, Stephen Walsh, Judith White, Victor del Campo Perez, Lina Perez Breva, Pablo Rojo Conejo, Maria Belen Ruiz Antoraz, Toong Chin, Charlotte Fribbens, Adrian Phillipson, Rachel Kaminski, Stevan Emmett, Corey Hebert, Thomas Birch, Russell Roberson, Jeffrey Zacher, Sophie Gelu-Maury, Loron Loryne, and Yvonne Davis
- Subjects
AS03 adjuvant ,Beta ,Booster ,B.1.351 ,COVID-19 ,CoV2 preS dTM-AS03 ,Medicine (General) ,R5-920 - Abstract
Summary: Background: In a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18–55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18–55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18–55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18–55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58–29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71–46.95) (anti-B.1.351); and for BiV, 14.39 (11.39–18.28) (anti-D614G) and 34.18 (25.84–45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).
- Published
- 2023
- Full Text
- View/download PDF
7. Degradation kinetics of phycocyanin under isothermal and dynamic heating
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Faieta, M., Toong, C., Corradini, M. G., Ludescher, R. D., and Pittia, P
- Published
- 2017
8. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases
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Mitrev, N, Vande Casteele, N, Seow, CH, Andrews, JM, Connor, SJ, Moore, GT, Barclay, M, Begun, J, Bryant, R, Chan, W, Corte, C, Ghaly, S, Lemberg, DA, Kariyawasam, V, Lewindon, P, Martin, J, Mountifield, R, Radford-Smith, G, Slobodian, P, Sparrow, M, Toong, C, van Langenberg, D, Ward, MG, Leong, RW, Mitrev, N, Vande Casteele, N, Seow, CH, Andrews, JM, Connor, SJ, Moore, GT, Barclay, M, Begun, J, Bryant, R, Chan, W, Corte, C, Ghaly, S, Lemberg, DA, Kariyawasam, V, Lewindon, P, Martin, J, Mountifield, R, Radford-Smith, G, Slobodian, P, Sparrow, M, Toong, C, van Langenberg, D, Ward, MG, and Leong, RW
- Abstract
Background: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. Aim: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. Methods: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. Results: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. Conclusion: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.
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- 2017
9. Therapeutic drug monitoring-guided biological drug therapy in inflammatory bowel disease: Consensus statements of the Australian Inflammatory Bowel Disease Association (AIBDA) and Gastroenterological Society of Australia (GESA).
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Ward M.G., Toong C., Van Langenberg D., Leong R.W., Moore G., Mitrev N., Vande Casteele N., Seow C., Andrews J.M., Connor S.J., Barclay M., Begun J., Bryant R., Chan W., Corte C., Ghaly S., Lemberg D.A., Kariyawasam V., Lewindon P., Martin J., Mountifield R., Radford-Smith G., Slobodian P., Sparrow M., Ward M.G., Toong C., Van Langenberg D., Leong R.W., Moore G., Mitrev N., Vande Casteele N., Seow C., Andrews J.M., Connor S.J., Barclay M., Begun J., Bryant R., Chan W., Corte C., Ghaly S., Lemberg D.A., Kariyawasam V., Lewindon P., Martin J., Mountifield R., Radford-Smith G., Slobodian P., and Sparrow M.
- Abstract
Introduction: Therapeutic drug monitoring (TDM)-guided biological drug therapy in inflammatory bowel disease (IBD) may improve clinical outcomes and reduce treatment cost, beyond fixed or clinically guided dosing. TDM of biological drugs involves measurement of drug levels and antidrug antibodies, and data are most comprehensive for TDM of anti-tumor necrosis factor (TNF) agents. Reactive TDM is performed during treatment failure to elicit mechanisms of failure and guide appropriate treatment changes (dose escalation versus changing to another agent), while proactive TDM is performed routinely in patients who maintain response in order to optimize drug levels and prevent future disease flares and loss of response. We produced consensus statements based on current evidence to aid implementation of TDM-guided therapy of biological drugs in IBD. Method(s): Consensus statements were produced via a modified Delphi method. A steering committee invited Australian and international experts in IBD and TDM of biological drugs. A literature search aided the steering committee in producing an initial draft of the consensus statements. Two rounds of online voting were undertaken, with modification of statements following each round based on voting results and feedback. On a final face-to-face voting round, each statement was presented, modified, and voted on. Panelists voted on their level of agreement with individual statements as follows: A) agree without reservation; B) agree with minor reservation; C) agree with major reservation; D) disagree with some reservation; E) disagree without reservation; or F) reserved. Statements with >= 80% agreement with no or only minor reservation met criteria for consensus. Level of evidence and grade of recommendation for each statement was agreed upon based on National Health and Medical Research Council (NHMRC) recommendations. Result(s): Of 26 panel nominees, 25 accepted to participate in this project, including the following: 18 Australi
- Published
- 2017
10. A bioequivalence comparison of two formulations of rifampicin (300- vs 150-mg capsules): An open-label, randomized, two-treatment, two-way crossover study in healthy volunteers
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Rokiah Pendek, Roma Choudhury Basu, Zamri Chik, Toong C. Lee, and Zahurin Mohamed
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Chemistry, Pharmaceutical ,Population ,Cmax ,Administration, Oral ,Capsules ,Bioequivalence ,Pharmacology ,Gastroenterology ,Drug Administration Schedule ,Dosage form ,Young Adult ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,education ,Antibiotics, Antitubercular ,Chromatography, High Pressure Liquid ,Antibacterial agent ,education.field_of_study ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Crossover study ,Therapeutic Equivalency ,Female ,Rifampin ,business ,Rifampicin ,medicine.drug - Abstract
Background: Rifampicin is a semisynthetic antibiotic derivative of rifamycin used worldwide for the treatment of various forms of tuberculosis. Objective: The objective of this study was to compare, under fasting conditions in healthy volunteers, the rate and extent of absorption of a generic rifampicin capsule in oral dosage form versus the proprietary equivalent formulation for the purpose of registration approval of the test formulation. Methods: This was an open-label, randomized, 2-treatment, 2-way crossover study with an 8-week washout period between the 2 study arms. Healthy volunteers received a 300-mg capsule of the test formulation (Idaman Pharma Manufacturing Sdn. Bhd.) or two 150-mg capsules of the reference formulation. Blood samples were collected predose and at 45 minutes and 1.25, 1.5, 2, 2.25, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours postdose. Plasma concentrations of rifampicin and its metabolite, 25-desacetyl rifampicin, were analyzed using a validated HPLC method. The formulations were considered bioequivalent if the 90% CIs for C max and AUC were within the predetermined bioequivalence range (80%–125%, according to the guidelines of the US Food and Drug Administration, or 75%–133% for Cmax only, as set by the European Commission-European Medicines Agency and the National Pharmaceutical Control Bureau of Malaysia). Tolerability was assessed by verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects (serious or mild) were recorded on adverse-event forms. Results: Fourteen healthy subjects (10 males, 4 females) with a mean age of 22.6 years (range, 20–28 years) and a mean body mass index of 22.2 kg/m 2 (range, 18.3-29.9 kg/m2) were enrolled in the study; all 14 completed the trial as outlined in the protocol. The mean values for C max , T max , AUC 0–24 , and AUC 0−∞ ) with the test formulation of rifampicin were 7.20 μg/mL, 1.32 hours, 37.12 μg/mL · h, and 39.69 μg/mL · h, respectively; for the reference formulation, the values were 7.65 μg/mL, 1.71 hours, 38.92 μg/mL · h, and 42.24 μg/ mL · h. For 25-desacetyl rifampicin, the mean values for C max , T max , AUC 0−24 , and AUC 0−∞ ) with the test formulation were 0.63 μg/mL, 3.45 hours, 4.92 μg/mL · h, and 6.27 μg/mL · h; for the reference formulation, the values were 0.7 μg/mL, 3.27 hours, 5.23 μg/mL · h, and 6.84 μg/mL · h. For rifampicin, the 90% CIs for the test formulation/reference formulation ratio for the logarithmic transformations of both C max and AUC 0−∞ ) were within the bioequivalence limit of 80% to 125% (80.9109.7 and 80.7–103.2, respectively). For 25-desacetyl rifampicin, the 90% CI for the test formulation/reference formulation ratio for the logarithmic transformations of AUC 0–24 (80.0–104.7) was within the bioequivalence limit of 80% to 125%. However, the 90% CI for C max (78.4–102.2) was outside this limit but still within the acceptance limit for Cmax when adhering to the bioequivalence range of 75% to 133%. No adverse events were reported during the study. Conclusions: This study found that the 300-mg test capsule and the 150-mg reference capsules of rifampicin met the regulatory criteria for assuming bioequivalence in these fasting healthy volunteers. Both formulations appeared to be well tolerated in the population studied.
- Published
- 2010
11. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults
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Timothy M. E. Davis, Sam Salman, Daryl Bendel, Toong C. Lee, and David Templeton
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Drug ,Adult ,Male ,Adolescent ,media_common.quotation_subject ,medicine.medical_treatment ,Population ,Administration, Sublingual ,Dihydroartemisinin ,Absorption (skin) ,Pharmacology ,Clinical Therapeutics ,Drug Administration Schedule ,Antimalarials ,Young Adult ,Pharmacokinetics ,medicine ,Humans ,Pharmacology (medical) ,Artemether ,education ,media_common ,education.field_of_study ,business.industry ,Artemisinins ,Healthy Volunteers ,Bioavailability ,Infectious Diseases ,Sublingual spray ,business ,medicine.drug - Abstract
The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (≥1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (≥1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.
- Published
- 2015
12. Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria
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Sam Salman, Toong C. Lee, Daryl Bendel, Timothy M. E. Davis, and David Templeton
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Male ,medicine.medical_treatment ,Population ,Administration, Sublingual ,Dihydroartemisinin ,Pharmacology ,Clinical Therapeutics ,Antimalarials ,Pharmacokinetics ,Medicine ,Humans ,Pharmacology (medical) ,Artemether ,Adverse effect ,education ,education.field_of_study ,business.industry ,Infant ,Liter ,medicine.disease ,Artemisinins ,Bioavailability ,Malaria ,Infectious Diseases ,Child, Preschool ,Africa ,Female ,business ,medicine.drug - Abstract
The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197–3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14 ), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.
- Published
- 2014
13. Periextubation caffeine in preterm neonates: A randomized dose response trial
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Vicki Flenady, David I. Tudehope, Bruce G. Charles, A.D. Shearman, Toong C. Lee, and PA Steer
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Male ,Apnea ,Respiratory System Agents ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Caffeine ,Intensive care ,Heart rate ,Intubation, Intratracheal ,medicine ,Humans ,Theophylline ,Citrates ,Dosing ,Dose-Response Relationship, Drug ,business.industry ,Infant, Newborn ,Doxapram ,Drug Combinations ,Caffeine citrate ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Central Nervous System Stimulants ,Female ,medicine.symptom ,business ,Ventilator Weaning ,Infant, Premature ,medicine.drug - Abstract
Objective: To compare the effectiveness of three dosing regimens of caffeine for preterm infants in the periextubation period. Methods: A randomized double-blind clinical trial of three dosing regimens of caffeine citrate ( 3, 15 and 30 mg/kg) for periextubation management of ventilated preterm infants was undertaken. Infants born 48 h were eligible for the study. Caffeine citrate was given as a once daily dose for a period of 6 days commencing 24 h prior to a planned extubation, or within 6 h of an unplanned extubation. The primary outcome measure was extubation failure, defined as neonates who were unable to be extubated within 48 h of caffeine loading or who required reventilation or doxapram dose within 7 days of caffeine loading. Continuous recordings of oxygen saturation and heart rate were undertaken in a subgroup of enrolled infants. Results: A total of 127 babies were enrolled into the study ( 42, 40, 45, in the 3, 15, and 30 mg/kg groups, respectively). No statistically significant difference was demonstrated in the incidence of extubation failure between dosing groups ( 19, 10, and 11 infants in the 3, 15, and 30 mg/kg groups, respectively), however, infants in the two higher dose groups had statistically significantly less documented apnoea than the lowest dose group. Of the 37 neonates with continuous pulse oximetry recordings, those on higher doses of caffeine recorded a statistically significantly higher mean heart rate, oxygen saturations and less time with oxygen saturations < 85%. Conclusions: This trial indicated there were short-term benefits of decreased apnoea in the immediate periextubation period for ventilated infants born < 32 weeks gestation receiving higher doses of caffeine. Further studies with larger numbers of infants assessing longer-term outcomes are necessary to determine the optimal dosing regimen of caffeine in preterm infants.
- Published
- 2003
14. Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation
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Glen J. Harte, Peter H. Gray, Toong C. Lee, Peter A Steer, Vicki Flenady, and Bruce G. Charles
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Volume of distribution ,education.field_of_study ,medicine.drug_class ,business.industry ,Birth weight ,Population ,Gestational age ,NONMEM ,Anesthesiology and Pain Medicine ,Pharmacokinetics ,Sedative ,Anesthesia ,medicine ,Midazolam ,education ,business ,medicine.drug - Abstract
Background Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. Methods Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. Results Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. Conclusions Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.
- Published
- 1999
15. Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates
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Glen J. Harte, Peter H. Gray, Toong C. Lee, Bruce G. Charles, and PA Steer
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Male ,Myoclonus ,genetic structures ,medicine.drug_class ,Midazolam ,medicine.medical_treatment ,Population ,Pain ,Hemodynamics ,Blood Pressure ,Pharmacokinetics ,Heart Rate ,mental disorders ,Humans ,Infant, Very Low Birth Weight ,Medicine ,Infusions, Intravenous ,education ,reproductive and urinary physiology ,Mechanical ventilation ,Analysis of Variance ,education.field_of_study ,business.industry ,Infant, Newborn ,Respiration, Artificial ,Treatment Outcome ,Blood pressure ,Cerebral blood flow ,Cerebrovascular Circulation ,Sedative ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Female ,business ,Anesthetics, Intravenous ,Blood Flow Velocity ,Infant, Premature ,Follow-Up Studies ,medicine.drug - Abstract
To evaluate the effects of intravenous midazolam on haemodynamic variables and cerebral blood flow velocity (CBFV) and to determine the pharmacokinetics using a population approach in very low birthweight (VLBW) ventilated infants.Physiological variables were measured at predetermined times in 10 infants with birthweightor = 1500 g following a bolus dose of intravenous midazolam (0.1 mg/kg). Heart rate, mean arterial blood pressure (MAP) and transcutaneous CO2 (TcPCO2) were recorded and CBFV was assessed by Doppler ultrasound. Midazolam concentrations were also measured and pharmacokinetic parameters determined using a population modelling package.No change in heart rate occurred during the study period, while the MAP decreased by 3 mmHg 5 min after midazolam administration compared to baseline values. A non-significant fall in TcPCO2 was seen at 20 min. Mean CBFV decreased from the baseline by 12% at 5 min, then returning to predose values. Midazolam concentrations were in the range shown to be effective in sedation of paediatric intensive care infants with the elimination being delayed in comparison to older children.As only minor cerebral and haemodynamic effects were found with the use of midazolam in stable ventilated preterm infants, it appears to be a safe, short-term sedative agent.
- Published
- 1997
16. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function
- Author
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Janna K. Duong, Jerry R. Greenfield, Carl M. J. Kirkpatrick, Toong C Lee, Richard O. Day, Peter Timmins, Manit Arora, Timothy J. Furlong, Kenneth M. Williams, Garry G. Graham, Shaun S. Kumar, and Louise C Greenup
- Subjects
Adult ,medicine.medical_specialty ,endocrine system diseases ,Adolescent ,Renal function ,Pharmacology ,Gastroenterology ,Models, Biological ,Polymorphism, Single Nucleotide ,White People ,Young Adult ,Pharmacotherapy ,Pharmacokinetics ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Hypoglycemic Agents ,Pharmacology (medical) ,Tissue Distribution ,Dosing ,Renal Insufficiency ,Young adult ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Malaysia ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Membrane Transport Proteins ,Middle Aged ,medicine.disease ,Metformin ,Diabetes Mellitus, Type 2 ,Nonlinear Dynamics ,Delayed-Action Preparations ,business ,medicine.drug - Abstract
Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function.Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit.Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations.The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.
- Published
- 2013
17. Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea
- Author
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T. C. Grant, PA Steer, Toong C. Lee, Bruce G. Charles, and Vicki Flenady
- Subjects
medicine.medical_specialty ,Time Factors ,Apnea ,medicine.drug_class ,Population ,Theophylline ,Pharmacokinetics ,Bronchodilator ,Humans ,Medicine ,Pharmacology (medical) ,Neonatology ,education ,Retrospective Studies ,Pharmacology ,Volume of distribution ,education.field_of_study ,business.industry ,Infant, Newborn ,Infant ,Gestational age ,NONMEM ,Anesthesia ,business ,medicine.drug - Abstract
1. Theophylline is commonly used in neonatology for the treatment and prophylaxis of apnoea of prematurity, and during ventilator weaning. 2. NONMEM was used to study the population pharmacokinetics of intravenous and oral theophylline from retrospective drug monitoring data in 82 premature neonates, weighing < 1500 g at birth, and < or = 32 weeks gestational age. 3. Clearance (CL), volume of distribution (V), and oral bioavailability (F1) from liquid preparations were modelled alone, and under the influence of demographic and clinical covariates, assuming a 1-compartment model with first-order elimination. 4. The final population models with influential co-variates were as follows: CL (1h-1) = 0.0000123 *body weight (g) + 0.000377 *postnatal age (days); V (1) = 0.000937 *body weight (g); F = 0.918. 5. The CL was lower and V was higher than previously reported for less premature neonates, term babies, and older children. 6. Predictive performance of the population models was evaluated by Bayesian forecasting in a similar, but independent cohort of 30 infants. There was statistically insignificant bias and imprecision between measured and predicted serum theophylline concentrations. 7. Based on the validated population models, recommended maintenance theophylline dosages are provided for infants aged between 2 and 50 days, and weighing 700 to 2000 g.
- Published
- 1996
18. Measurement by HPLC of Midazolam and its Major Metabolite 1-Hydroxymidazolam in Plasma of Very Premature Neonates
- Author
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Toong C. Lee and Bruce G. Charles
- Subjects
Pharmacology ,Chromatography ,Elution ,Metabolite ,Clinical Biochemistry ,Isopropyl alcohol ,General Medicine ,Biochemistry ,High-performance liquid chromatography ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Pharmacokinetics ,Drug Discovery ,medicine ,Midazolam ,Molecular Biology ,Phosphoric acid ,Climazolam ,medicine.drug - Abstract
A simple, selective high-performance liquid chromatographic method with ultraviolet detection at 220 nm is described for quantitation of midazolam and its primary metabolite 1-hydroxymidazolam in 100 microL plasma samples from premature infants. A mobile phase of acetonitrile:tetrahydrofuran:phosphate buffer (0.01 M, pH 6.7) (35:5:60 v/v) was pumped at 1 mL/min through a C8 Symmetry (150 x 3.9 mm) column. Plasma (100 microL) was extracted with 10% v/v isopropyl alcohol in dichloromethane containing 25 ng/mL climazolam (internal standard, IS) followed by back extraction into phosphoric acid (0.02 M). 1-Hydroxymidazolam, midazolam, and climazolam (IS) were eluted at 4.9, 7.4, 8.4 min, respectively. Recoveries were > 70%. Calibration curves in blank plasma were linear (r > 0.999) from 12.5 to 800 ng/mL. Within-day and between-day imprecision (CV%) was 1.8-6.5%, and 4.1-8.8%, respectively. Inaccuracy was 12.3%. Application of the method was demonstrated by a pharmacokinetic analysis of midazolam and 1-hydroxymidazolam in plasma drawn from 15 premature neonates after a single intravenous dose of midazolam (0.1 mg/kg).
- Published
- 1996
19. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria
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Salman, Sam, primary, Bendel, Daryl, additional, Lee, Toong C., additional, Templeton, David, additional, and Davis, Timothy M. E., additional
- Published
- 2015
- Full Text
- View/download PDF
20. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults
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Salman, Sam, primary, Bendel, Daryl, additional, Lee, Toong C., additional, Templeton, David, additional, and Davis, Timothy M. E., additional
- Published
- 2015
- Full Text
- View/download PDF
21. Population pharmacokinetics of intravenous amoxicillin in very low birth weight infants
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Peter A Steer, Nicola Debuse, Vicki Flenady, Yupaporn Preechagoon, Toong C. Lee, and Bruce G. Charles
- Subjects
Male ,Metabolic Clearance Rate ,Population ,Pharmaceutical Science ,Physiology ,Penicillins ,Pharmacokinetics ,Blood plasma ,medicine ,Humans ,Infant, Very Low Birth Weight ,education ,Antibacterial agent ,education.field_of_study ,business.industry ,Infant, Newborn ,Gestational age ,Amoxicillin ,Drug interaction ,Low birth weight ,Anesthesia ,Injections, Intravenous ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
The population pharmacokinetics of amoxicillin were determined in 40 very premature infants (or = 32 week gestational age,1500 g birth weight) who were receiving intravenous amoxicillin (50 mg/ kg, every 12 h) during the first days after birth. Serum amoxicillin concentrations were measured by HPLC. Clearance (CL) and volume of distribution (Vd) were modeled alone and under the influence of demographic and clinical covariates with a 1-compartment model with first-order elimination. The final population models with influential covariates were: CL(L/h) = 0.0000610 x body weight (g) and CL (L/h) = 0.0000805 x body weight (g), for infants also receiving gentamicin and not receiving gentamicin, respectively; Vd(L) = 0.678. The interpatient standard deviation (SD) for CL was 0.0351 L/h, and for Vd was 0.365 L. The intrapatient variability (SD) among observed and model-predicted serum concentrations was 13.7 mg/L. Evaluation of the predictive performance of this model in another group of infants (n = 16) indicated statistically insignificant bias (p0.05) of 3 mg/L among pairs of observed and Bayesian-predicted amoxicillin concentrations. The average population CL was smaller, but the average Vd and terminal half-life (t1/2) were larger than previously reported for healthy adults.
- Published
- 1997
22. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity
- Author
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Toong C. Lee, A.D. Shearman, Vicki Flenady, Peter A Steer, and Bruce G. Charles
- Subjects
Male ,genetic structures ,Apnea ,medicine.medical_treatment ,Gestational Age ,chemistry.chemical_compound ,Pharmacokinetics ,Predictive Value of Tests ,Caffeine ,medicine ,Humans ,Pharmacology (medical) ,Theophylline ,Single-Blind Method ,Prospective Studies ,Prospective cohort study ,Infusions, Intravenous ,Apnea of prematurity ,Chromatography, High Pressure Liquid ,Pharmacology ,Chemotherapy ,business.industry ,Infant, Newborn ,Gestational age ,Reproducibility of Results ,medicine.disease ,respiratory tract diseases ,chemistry ,Anesthesia ,Female ,medicine.symptom ,business ,Infant, Premature ,medicine.drug - Abstract
The study the population pharmacokinetics of caffeine after intravenous administration to premature infants with apnea.A prospective, blinded parallel study in which daily caffeine citrate doses of 30, 15, and 3 mg/kg were administered over 7 days by intermittent intravenous infusion. Arterial blood samples (three to six per patient) were assayed for caffeine content by means of HPLC. Population pharmacokinetic modeling was performed with NONMEM.Clearance (L/hr) = (0.00000399 . current weight [grams]) + (0.000128 . postnatal age [days]). For gestational age28 weeks, volume of distribution (L) = (0.000764 . weight [grams] + (0.0468 . postnatal age [days]); for gestational ageor = 28 weeks, volume of distribution (L) = (0.000755 . weight [grams]) + (0.0224. postnatal age [days]). Interpatient variability (coefficient of variation, in percent) was approximately 25% for clearance and approximately 11% for volume of distribution. Intrapatient error (standard deviation) was 3.9 mg/L. There was insignificant bias between observed and model-predicated serum caffeine concentrations in a separate group of 30 infants.Caffeine was well tolerated at all doses. Clearance was markedly lower and volume of distribution was higher than the values reported previously for term infants and adults. Both parameters were significantly influenced by postnatal age and current body weight, whereas volume of distribution in infants28 weeks' gestational age was higher than that in more premature babies. The predictive performance and the clinical application of the derived population models was satisfactorily shown.
- Published
- 1997
23. Saliva as a valid alternative to serum in monitoring intravenous caffeine treatment for apnea of prematurity
- Author
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Peter A Steer, Toong C. Lee, Bruce G. Charles, and Vicki Flenady
- Subjects
Male ,medicine.medical_specialty ,Saliva ,Apnea ,Loading dose ,chemistry.chemical_compound ,Double-Blind Method ,Predictive Value of Tests ,Internal medicine ,Caffeine ,Enzyme Multiplied Immunoassay Technique ,medicine ,Humans ,Pharmacology (medical) ,Theophylline ,Apnea of prematurity ,Chromatography, High Pressure Liquid ,Pharmacology ,medicine.diagnostic_test ,business.industry ,Maintenance dose ,Infant, Newborn ,medicine.disease ,Endocrinology ,chemistry ,Therapeutic drug monitoring ,Injections, Intravenous ,Central Nervous System Stimulants ,Female ,Drug Monitoring ,business ,Infant, Premature ,medicine.drug ,Blood sampling - Abstract
Caffeine is a potentially useful alternative to theophylline for the treatment and prevention of apnea of prematurity because of its lower toxicity and longer terminal half-life. Monitoring of salivary caffeine concentrations is less invasive than blood sampling, especially in very sick premature neonates. Caffeine citrate-3 mg/kg, 15 mg/kg, or 30 mg/kg-was administered once daily for 7 days in a randomized, parallel design to 59 newborn, premature infants with an initial loading dose of twice the maintenance dose. Serum and saliva samples (131 pairs) were collected and assayed by high-performance liquid chromatography (HPLC) for caffeine content. Measurable caffeine concentrations in serum ranged from 0.28 to 93.3 mg/L and in saliva from 0.35 to 91.5 mg/L. The mean ratio of the saliva-to- serum concentrations was 0.924. There was no significant difference in precision between the serum and salivary data. The mean serum caffeine concentration was 29.9 mg/L, and the mean salivary concentration was 27.7 mg/L, indicating a small negative bias for saliva versus serum monitoring. Salivary caffeine concentration monitoring is a satisfactory alternative to blood sampling across a wide range of caffeine doses used to treat apnea.
- Published
- 1996
24. Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam During Mechanical Ventilation: Midazolam Neonatal Pharmacokinetics
- Author
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LEE, TOONG C., primary, CHARLES, BRUCE G., additional, HARTE, GLEN J., additional, GRAY, PETER H., additional, STEER, PETER A., additional, and FLENADY, VICKI J., additional
- Published
- 2000
- Full Text
- View/download PDF
25. Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation
- Author
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Lee, Toong C., primary, Charles, Bruce G., additional, Harte, Glen J., additional, Gray, Peter H., additional, Steer, Peter A., additional, and Flenady, Vicki J., additional
- Published
- 1999
- Full Text
- View/download PDF
26. Population Pharmacokinetics of Intravenous Amoxicillin in Very Low Birth Weight Infants
- Author
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CharlesX, Bruce G., primary, Preechagoon, Yupaporn, additional, Lee, Toong C., additional, Steer, Peter A., additional, Flenady, Vicki J., additional, and Debuse, Nicola, additional
- Published
- 1997
- Full Text
- View/download PDF
27. Saliva as a Valid Alternative to Serum in Monitoring Intravenous Caffeine Treatment for Apnea of Prematurity
- Author
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Lee, Toong C., primary, Charles, Bruce G., additional, Steer, Peter A., additional, and Flenady, Vicki J., additional
- Published
- 1996
- Full Text
- View/download PDF
28. Population pharmacokinetics of intravenous amoxicillin in very low birth weight infants
- Author
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Charles, Bruce G., Preechagoon, Yupaporn, Lee, Toong C., Steer, Peter A., Flenady, Vicki J., and Debuse, Nicola
- Abstract
The population pharmacokinetics of amoxicillin were determined in 40 very premature infants (≤32 week gestational age, <1500 g birth weight) who were receiving intravenous amoxicillin (50 mg/kg, every 12 h) during the first days after birth. Serum amoxicillin concentrations were measured by HPLC. Clearance (CL) and volume of distribution (Vd) were modeled alone and under the influence of demographic and clinical covariates with a 1-compartment model with first-order elimination. The final population models with influential covariates were: CL (L/h) = 0.0000610 · body weight (g) and CL (L/h) = 0.0000805 · body weight (g), for infants also receiving gentamicin and not receiving gentamicin, respectively; Vd (L) = 0.678. The interpatient standard deviation (SD) for CL was 0.0351 L/h, and for Vd was 0.365 L. The intrapatient variability (SD) among observed and model-predicted serum concentrations was 13.7 mg/L. Evaluation of the predictive performance of this model in another group of infants (n = 16) indicated statistically insignificant bias (p > 0.05) of 3 mg/L among pairs of observed and Bayesian-predicted amoxicillin concentrations. The average population CL was smaller, but the average Vd and terminal half-life (t
1/2 ) were larger than previously reported for healthy adults.- Published
- 1997
29. Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.
- Author
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Srinivasan A, De Cruz P, Sam M, Toong C, and van Langenberg DR
- Subjects
- Humans, Infliximab therapeutic use, Gastrointestinal Agents therapeutic use, Cohort Studies, Prospective Studies, Treatment Outcome, Crohn Disease drug therapy
- Abstract
Background: The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses., Methods: A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5 mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5 mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response., Results: Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02 ug/mL, P = 0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P > 0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36 ug/mL, P < 0.01), 12 (8.94 vs 5.96 ug/mL, P = 0.02) and 30 (3.89 vs 6.35 ug/mL, P = .0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P = 0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P = 0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P = 0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P = 0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6 ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P < 0.05) predicted nonresponse at week 32., Conclusion: Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response., (© 2023 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
30. Serum protein electrophoresis and rheumatoid factor analysis is an effective screening strategy for cryoglobulinaemia.
- Author
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Stoyanov A, Toong C, Kong Y, Chen R, and Urriola N
- Subjects
- Humans, Cryoglobulins, Rheumatoid Factor, Retrospective Studies, Electrophoresis, Paraproteins, Cryoglobulinemia diagnosis
- Abstract
Accurate serum cryoglobulin detection is important to allow prompt treatment but laboratory testing requires stringent pre-analytical conditions and has long turnaround times. Serum protein electrophoresis (EPG) for paraproteinaemia and rheumatoid factor (RF) analysis may offer an effective initial screening strategy for the presence of cryoglobulinaemia. We retrospectively assessed the sensitivity of ancillary EPG and RF testing for the presence of serum cryoglobulinaemia in 586 eligible cryoglobulin positive samples received at the Royal Prince Alfred and Liverpool Hospital immunopathology laboratories over an 11-year period. Ninety-one percent of all cryoglobulin positive samples had either a detectable paraprotein or RF activity, with greatest sensitivity for type I and type II cryoglobulins (97% and 98%, respectively). The sensitivity remained high irrespective of whether EPG and RF analysis was performed with the same, or different, pre-analytical collection conditions to the cryoglobulin collection (92% vs 90%, p=0.46). Only two patients with detected cryoglobulins and no associated paraprotein or RF activity had clinical features of cryoglobulinaemia and neither required treatment. This study demonstrates that serum EPG and RF analysis has high sensitivity for the detection of clinically relevant cryoglobulinaemia, even when not collected under ideal pre-analytical conditions, and potentially offers a prompt and effective screening strategy., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
31. Monoclonal antibody interference in electrophoresis.
- Author
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Malik S and Toong C
- Subjects
- Humans, Electrophoresis methods, Antibodies, Monoclonal
- Published
- 2023
- Full Text
- View/download PDF
32. Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.
- Author
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Liu Z, Julsgaard M, Zhu X, Martin J, Barclay ML, Cranswick N, Gibson PR, Gearry RB, van der Giessen J, Connor SJ, Rosella O, Grosen A, Toong C, Flanagan E, Wieringa JW, Janneke van der Woude C, and Bell SJ
- Subjects
- Child, Female, Humans, Infant, Infant, Newborn, Pregnancy, Bayes Theorem, Prospective Studies, Tumor Necrosis Factor Inhibitors therapeutic use, Vaccination, Maternal Exposure, Adalimumab therapeutic use, Inflammatory Bowel Diseases drug therapy, Infliximab therapeutic use, Vaccines, Attenuated administration & dosage
- Abstract
Background and Aims: For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy., Methods: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included., Results: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/., Conclusions: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
33. Degradation kinetics of C-Phycocyanin under isothermal and dynamic thermal treatments.
- Author
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Faieta M, Toong C, Corradini MG, Ludescher RD, and Pittia P
- Subjects
- Kinetics, Water, Hot Temperature, Phycocyanin
- Abstract
C-Phycocyanin (C-PC) represents an alternative to artificial blue/green dyes in food products. This study characterized and gained insights into C-PC thermal stability mechanisms and provided a model to estimate its thermal degradation. Aqueous solutions of C-PC (0.3 μM, pH:6.1) were isothermally heated at 45-80 °C. C-PC degradation was monitored based on the photophysical properties of its lumiphores (phycocyanobilins and aromatic aminoacids-AAs). While C-PC was stable at 45 °C, less than 10 min at 80 °C sufficed to degrade most of it. The thermal degradation curves were characterized using the Weibull model, which was validated with data obtained under non-isothermal conditions. Deviations between estimated and experimental values were lower than 8%. Hypsochromic shifts of the AAs' spectra (from 340 to 315 nm) and increase (>30%) in anisotropy at λexc = 280 and 520 nm suggest that colour losses are not solely associated with alterations of the chromophore but also with conformational changes and possible aggregation of the protein subunits., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
34. Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency.
- Author
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Yap JY, Moens L, Lin MW, Kane A, Kelleher A, Toong C, Wu KHC, Sewell WA, Phan TG, Hollway GE, Enthoven K, Gray PE, Casas-Martin J, Wouters C, De Somer L, Hershfield M, Bucciol G, Delafontaine S, Ma CS, Tangye SG, and Meyts I
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Adolescent, Adult, Agammaglobulinemia blood, Agammaglobulinemia genetics, Aged, Cell Differentiation, Child, Child, Preschool, Dendritic Cells immunology, Humans, Infant, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins deficiency, Intercellular Signaling Peptides and Proteins genetics, Killer Cells, Natural immunology, Middle Aged, Severe Combined Immunodeficiency blood, Severe Combined Immunodeficiency genetics, Young Adult, Agammaglobulinemia immunology, B-Lymphocytes immunology, Severe Combined Immunodeficiency immunology, T-Lymphocytes immunology
- Abstract
Purpose: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes., Methods: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls., Results: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4
+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56brigh t immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients., Conclusion: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
35. Prospective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol.
- Author
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Gu B, De Gregorio M, Pipicella JL, Vande Casteele N, Andrews JM, Begun J, Connell W, D'Souza B, Gholamrezaei A, Hart A, Liew D, Radford-Smith G, Rimola J, Sutherland T, Toong C, Woods R, Wu Y, Xuan W, Williams AJ, Ng W, Ding NS, and Connor S
- Subjects
- Adult, Australia, Gastrointestinal Agents therapeutic use, Humans, Infliximab therapeutic use, Prospective Studies, Randomized Controlled Trials as Topic, Treatment Outcome, Crohn Disease complications, Crohn Disease drug therapy, Rectal Fistula drug therapy, Rectal Fistula etiology
- Abstract
Introduction: Perianal fistulising Crohn's disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy., Methods and Analysis: Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18-80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate., Ethics and Dissemination: Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results., Competing Interests: Competing interests: NVC reports grants and personal fees from Takeda, grants and personal fees from UCB, grants from R-Biopharm, personal fees from Celltrion, personal fees from Prometheus, outside the submitted work. JA reports lecture fees, grants, Boards, Consultancies for Abbott, AbbVie, Allergan, Anatara, AstraZeneca, Bayer, Celegene, Ferring, Gilead, Hospira, Immuninc, ImmunsanT, Janssen, MSD, Nestle, Progenity, Pfizer, Shire, Takeda and Vifor, grants from the Royal Adelaide Hospital Research Fund, outside the submitted work. JB reports personal fees from Abbvie, personal fees from Pfizer, personal fees from BMS, grants and personal fees from Janssen, personal fees from Takeda, personal fees from Gilead, personal fees from Microba, grants and personal fees from Ferring, outside the submitted work. ALH has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and serves on the Global Steering Committee for Genentech, outside the submitted work. DL reports consultancy fees from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Sanofi, grants from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, CSL-Behring, Novartis, Pfizer, Sanofi and Shire, and travel expenses from AstraZeneca and Bayer; outside the submitted work. GR-S reports fees to his institute from Ferring Australia, grants and fees to his institute from Janssen, fees to his institute from Takeda, fees to his institute from Pfizer, fees to his institute from AbbVie, outside the submitted work. JR reports grants from AbbVie, personal fees from Takeda, personal fees from Gilead, grants from Genentech, personal fees from Alimentiv, personal fees from Janssen, during the conduct of the study. TS reports personal fees from Seimens Workshop, personal fees from Bayer, outside the submitted work. CT reports grants from Janssen, grants from Pfizer, grants from MSD, outside the submitted work; and is a director of laboratory that performs therapeutic drug monitoring for infliximab. A-JW reports grants and personal fees from Ferring, personal fees and non-financial support from AbbVie, personal fees from Janssen, personal fees and non-financial support from Takeda, outside the submitted work. WN received grants from Janssen and Pfizer, during the conduct of the study; grants and personal and speaker fees from AbbVie, Takeda, Grants from Ferring and Shire unrelated to the submitted work. NSD reports personal fees from AbbVie, personal fees from Pfizer, personal fees from BMS, personal fees from Janssen, outside the submitted work. SC reports grants from Janssen, grants from Pfizer, during the conduct of the study; grants and personal fees from AbbVie, educational support from Aspen/Orphan Australia, grants and personal fees from Ferring, personal fees from Gilead, grants and personal fees from Janssen, personal fees from Novartis, grants, personal fees and educational support from Pfizer, grants, personal fees and educational support from Shire/Takeda, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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36. Comparison of three commercially available ELISA assays for anti-infliximab antibodies.
- Author
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West TA, Sam M, and Toong C
- Subjects
- Antibodies immunology, Drug Monitoring, Humans, Inflammatory Bowel Diseases immunology, Infliximab blood, Reagent Kits, Diagnostic, Antibodies blood, Enzyme-Linked Immunosorbent Assay methods, Inflammatory Bowel Diseases drug therapy, Infliximab analysis
- Abstract
Three commercially available assays for the measurement of antibodies to infliximab (ATI) are approved for clinical use in Australia: Promonitor anti-infliximab (Grifols), Lisa Tracker anti-infliximab (Theradiag) and Ridascreen anti-IFX (R-Biopharm). All are bridging ELISA assays. Measurement of ATI has been incorporated into treatment algorithms for assessing loss of response to infliximab in patients with inflammatory bowel disease, but results obtained by the three ATI assays have not been systematically compared. We performed a series of experiments to allow comparison of results between the assays. Forty-two patient samples known to be positive for ATI by the Lisa Tracker assay were run on the Promonitor assay in singlicate, of which 26 were run on the Ridascreen assay in duplicate, according to the manufacturers' instructions. The Spearman correlation coefficient for all three pairwise assay comparisons was 0.95. Results were not numerically comparable between the assays. The coefficient of variation (CV) was 2.3% for the Lisa Tracker assay, 7.6% for the Promonitor assay and 7.4% for the Ridascreen assay. The presence of infliximab interfered with all three assays in a dose dependent manner. The cut-point for loss of response to infliximab dose intensification, previously demonstrated to be 200 ng/mL on the Lisa Tracker assay, is equivalent to approximately 60 ng/mL on the Ridascreen assay and between 22.9 and 41 AU/mL on the Promonitor assay. All three assays are suitable for clinical use., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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37. Therapeutic drug monitoring in inflammatory bowel disease reduces unnecessary use of infliximab with substantial associated cost-savings.
- Author
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Wu Y, Lin B, Thilakanathan C, Lehmann P, Xuan W, Mohsen W, Toong C, Williams AJ, Ng W, and Connor S
- Subjects
- Australia, Cost Savings, Drug Monitoring, Gastrointestinal Agents therapeutic use, Humans, Infliximab therapeutic use, Colitis, Ulcerative drug therapy, Inflammatory Bowel Diseases drug therapy
- Abstract
Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR)., Aims: To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX., Methods: Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing., Results: Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing., Conclusion: Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped., (© 2019 Royal Australasian College of Physicians.)
- Published
- 2021
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38. Gastric Cancer Screening in Common Variable Immunodeficiency.
- Author
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van der Poorten DK, McLeod D, Ahlenstiel G, Read S, Kwok A, Santhakumar C, Bassan M, Culican S, Campbell D, Wong SWJ, Evans L, Jideh B, Kane A, Katelaris CH, Keat K, Ko Y, Lee JA, Limaye S, Lin MW, Murad A, Rafferty M, Suan D, Swaminathan S, Riminton SD, Toong C, and Berglund LJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Biopsy, Common Variable Immunodeficiency etiology, Early Detection of Cancer, Female, Gastritis, Atrophic complications, Gastroscopy, Helicobacter Infections complications, Helicobacter Infections microbiology, Humans, Male, Mass Screening, Metaplasia, Middle Aged, Neoplasm Staging, Precancerous Conditions, Prevalence, Public Health Surveillance, Risk Assessment, Risk Factors, Stomach Neoplasms diagnosis, Surveys and Questionnaires, Young Adult, Common Variable Immunodeficiency complications, Common Variable Immunodeficiency epidemiology, Stomach Neoplasms epidemiology, Stomach Neoplasms etiology
- Abstract
Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p < 0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.
- Published
- 2018
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39. Anti-synthetase syndrome associated with anti PL-12 and anti-Signal recognition particle antibodies and a necrotizing auto-immune myositis.
- Author
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Malkan A, Cappelen-Smith C, Beran R, Griffith N, Toong C, Wang MX, and Cordato D
- Subjects
- Adult, Anti-Inflammatory Agents therapeutic use, Autoimmune Diseases pathology, Cyclophosphamide therapeutic use, Female, Humans, Immunization, Passive, Immunosuppressive Agents therapeutic use, Immunotherapy, Muscle Weakness etiology, Muscle Weakness pathology, Myositis pathology, Necrosis, Prednisolone therapeutic use, Syndrome, Treatment Outcome, Autoantibodies immunology, Autoimmune Diseases etiology, Ligases immunology, Myositis etiology, Signal Recognition Particle immunology
- Abstract
We report a 37-year-old woman with a 2 month history of proximal muscle weakness and extremely high creatine kinase (21,808 U/L) due to necrotizing auto-immune myositis (NAM) in association with anti-synthetase syndrome. Myositis-specific auto-immune antibody panel was positive for anti-Signal recognition particle and anti-PL-12. CT scan of the chest confirmed interstitial lung disease. Prednisolone, intravenous immunoglobulin and cyclophosphamide therapy was given with gradual improvement. This patient is notable for the unusual combination of NAM and anti-synthetase syndrome with the rare finding of two myositis-specific autoantibodies, which directed testing for associated extramuscular features and management with more aggressive immunotherapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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40. Use of cardiac MR imaging to evaluate the presence of myocarditis in autoimmune myositis: three cases.
- Author
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Toong C, Puranik R, and Adelstein S
- Subjects
- Adult, Autoimmune Diseases complications, Autoimmune Diseases immunology, Contrast Media therapeutic use, Electrocardiography, Female, Gadolinium DTPA therapeutic use, Humans, Male, Middle Aged, Myocarditis complications, Myocarditis immunology, Myositis complications, Myositis immunology, Radiography, Thoracic, Troponin T blood, Autoimmune Diseases diagnosis, Magnetic Resonance Imaging methods, Myocarditis diagnosis, Myositis diagnosis
- Abstract
Cardiac involvement in patients with idiopathic inflammatory myopathies (autoimmune myositis) is important to detect because it confers an increased risk of mortality. However, detection of myocardial involvement is hampered by a lack of sensitivity of traditional non-invasive methods, and the finding of elevated cardiac troponin T levels that may be due to regenerating skeletal muscle, rather than myocardial damage. Here, we describe three cases of inflammatory myositis with elevated troponin T levels, and non-specific echocardiographic and ECG findings. Cardiac MR imaging was useful in the evaluation for the presence of myocarditis or alternative cardiac pathology.
- Published
- 2012
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41. Clearing the complexity: immune complexes and their treatment in lupus nephritis.
- Author
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Toong C, Adelstein S, and Phan TG
- Abstract
Systemic lupus erythematosus (SLE) is a classic antibody-mediated systemic autoimmune disease characterised by the development of autoantibodies to ubiquitous self-antigens (such as antinuclear antibodies and antidouble-stranded DNA antibodies) and widespread deposition of immune complexes in affected tissues. Deposition of immune complexes in the kidney results in glomerular damage and occurs in all forms of lupus nephritis. The development of nephritis carries a poor prognosis and high risk of developing end-stage renal failure despite recent therapeutic advances. Here we review the role of DNA-anti-DNA immune complexes in the pathogenesis of lupus nephritis and possible new treatment strategies aimed at their control.
- Published
- 2011
- Full Text
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