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Article ; Online: Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes.

Jordaan, Pierre / Dumotier, Bérengère / Traebert, Martin / Miller, Paul E / Ghetti, Andre / Urban, Laszlo / Abi-Gerges, Najah

Toxicological sciences : an official journal of the Society of Toxicology

2021 Volume 180, Issue 2, Page(s) 356–368

Abstract: Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase ... ...

Abstract	Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antiviral Agents/administration & dosage ; Antiviral Agents/adverse effects ; Azithromycin/administration & dosage ; Azithromycin/adverse effects ; Cardiotoxicity ; Chloroquine/administration & dosage ; Chloroquine/adverse effects ; Female ; Humans ; Hydroxychloroquine/administration & dosage ; Hydroxychloroquine/adverse effects ; Male ; Middle Aged ; Myocytes, Cardiac/drug effects ; Risk Assessment ; SARS-CoV-2 ; United States ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Hydroxychloroquine (4QWG6N8QKH) ; Azithromycin (83905-01-5) ; Chloroquine (886U3H6UFF)
Language	English
Publishing date	2021-01-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfaa194
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Article: Programmed cell death in the coccoid green microalga Ankistrodesmus densus Korshikov (Sphaeropleales, Selenastraceae)

Barreto Filho, Marcelo M. / Durand, Pierre M. / Andolfato, Nathan E. / Jordaan, Anine / Sarmento, Hugo / Bagatini, Inessa L.

European journal of phycology. 2022 Apr. 03, v. 57, no. 2

2022

Abstract: Reports of programmed cell death (PCD) across the taxonomic spectrum of photosynthetic unicellular organisms raise questions concerning its ecological and evolutionary roles. However, prior to ecological studies or evolutionary interpretations, it is ... ...

Abstract	Reports of programmed cell death (PCD) across the taxonomic spectrum of photosynthetic unicellular organisms raise questions concerning its ecological and evolutionary roles. However, prior to ecological studies or evolutionary interpretations, it is essential to document phenotypic changes associated with PCD at the single-cell level, since death-related responses vary between taxa and within a single taxon depending on environmental stimuli. Here, we report responses to rapidly changing light, temperature and fluctuations in macronutrients in the model selenastracean green microalga Ankistrodesmus densus (Chlorophyta, Chlorophyceae, Sphaeropleales). We used stringent, but environmentally appropriate, conditions of prolonged darkness, nitrogen starvation (4 days), heat (1 h at 44°C) and cold shock (3 h at 2 ± 2°C). PCD phenotypes were examined by ultrastructural changes, phosphatidylserine (PS) externalization and DNA degradation. Flow cytometric Annexin V FITC analyses revealed that darkness and nitrogen-deprived cultures had significantly higher proportions of cells with PS externalization compared with controls (p < 0.05). Heat and cold treatments did not affect PS externalization (p = 0.44 and p = 0.99, respectively). Transmission electron microscopy (TEM) of light-deprived cells demonstrated, among other ultrastructural changes, marked cytoplasmic vacuolization suggesting a subtype of PCD known as vacuolar cell death. Nitrogen-starved cells had less vacuolization but presented more typical ultrastructural markers of PCD such as chromatin condensation and marginalization. In contrast, the more severe heat and cold shock treatments resulted in necrotic-like features. These findings suggest that prolonged darkness and nitrogen starvation induce PCD in a small (8.4 3.5 and 7.42 2.6%, respectively) but significant (p < 0.05) fraction of the A. densus population. Documenting these different death-related phenotypes depending on different environmental inducers is essential for interpreting ecological studies. Furthermore, our data support the hypothesis that autophagic/vacuolar cell death (VCD), which is central to organism homeostasis in plants (Streptophyta), occurs in Chlorophyta. VCD probably arose long before the evolution of multicellularity in plants. HIGHLIGHTSDarkness and nitrogen deprivation induce different programmed cell death markers in Ankistrodesmus densus; Plant vacuolar-like cell death occurs in Chlorophyta; There is crossover between the vacuolar and apoptosis-like death morphotypes.
Keywords	Ankistrodesmus ; DNA ; Sphaeropleales ; algology ; chromatin ; cold ; cold stress ; death ; flow cytometry ; heat ; homeostasis ; microalgae ; morphs ; nitrogen ; phenotype ; phosphatidylserines ; photosynthesis ; programmed cell death ; starvation ; temperature ; vacuoles
Language	English
Dates of publication	2022-0403
Size	p. 193-206.
Publishing place	Taylor & Francis
Document type	Article
ZDB-ID	1481147-9
ISSN	1469-4433 ; 0967-0262
ISSN (online)	1469-4433
ISSN	0967-0262
DOI	10.1080/09670262.2021.1938240
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Comparing QT interval variability of semiautomated and high-precision ECG methodologies in seven thorough QT studies-implications for the power of studies intended for definitive evaluation of a drug's QT effect.

Meiser, Karin / Jordaan, Pierre / Latypova, Sasha / Darpo, Borje

Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc

2016 Volume 22, Issue 1

Abstract: Background: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects.: Methods: Variability data from investigational, placebo and ...

Abstract	Background: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects. Methods: Variability data from investigational, placebo and moxifloxacin treatments from seven thorough QT studies performed by the same sponsor were analyzed with the objective to compare the performance of two commonly used approaches for ECG interval measurements: semiautomated (SA) and the high-precision QT (HPQT) analysis. Five studies were crossover and two parallel. Harmonized procedures were implemented to ensure similar experimental conditions across studies. ECG replicates were extracted serially from continuous 12-lead recordings at predefined time points from subjects supinely resting. The variability estimates were based on the time-point analysis of change-from-baseline QTcF as the dependent variable for the standard primary analysis of previous thorough QT studies. The residual variances were extracted for each study and ECG technique. Results: High-precision QT resulted in a substantial reduction in ∆QTc variability as compared to SA. A reduction in residual variability or approximately 50% was achieved in both crossover and parallel studies, both for the active comparison (drug vs. placebo) and for assay sensitivity (moxifloxacin vs. placebo) data. Conclusions: High-precision QT technique significantly reduces QT interval variability and thereby the number of subjects needed to exclude small effects in QT studies. Based on this assessment, the sample size required to exclude a QTc effect >10 ms with 90% power is reduced from 35 with SA to 18 with HPQT, if a 3 ms underlying drug effect is assumed.
MeSH term(s)	Adult ; Anti-Bacterial Agents/therapeutic use ; Electrocardiography/drug effects ; Female ; Fluoroquinolones/pharmacology ; Healthy Volunteers ; Heart Conduction System/drug effects ; Heart Rate/drug effects ; Humans ; Male ; Moxifloxacin ; Research Design
Chemical Substances	Anti-Bacterial Agents ; Fluoroquinolones ; Moxifloxacin (U188XYD42P)
Language	English
Publishing date	2016-12-19
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1325530-7
ISSN	1542-474X ; 1082-720X
ISSN (online)	1542-474X
ISSN	1082-720X
DOI	10.1111/anec.12416
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Zs.A 4953: Show issues

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Article ; Online: Tackling sport-related concussion: effectiveness of lowering the maximum legal height of the tackle in amateur male rugby - a cross-sectional analytical study.

van Tonder, Riaan / Starling, Lindsay / Surmon, Sean / Viviers, Pierre / Kraak, Wilbur / Boer, Pieter-Henk / Jordaan, Esme / Hendricks, Sharief / Stokes, Keith A / Derman, Wayne / Brown, James Craig

Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention

2022 Volume 29, Issue 1, Page(s) 56–61

Abstract: Objective: Rugby union ('rugby') is popular globally, with most of its participants being amateur. Concern regarding sport-related concussion (SRC) sustained during rugby is increasing. SRC occurs most frequently in the tackle, yet few interventions ... ...

Abstract	Objective: Rugby union ('rugby') is popular globally, with most of its participants being amateur. Concern regarding sport-related concussion (SRC) sustained during rugby is increasing. SRC occurs most frequently in the tackle, yet few interventions have aimed to mitigate this risk factor. This study investigated the influence of a lowered legal tackle height on SRC incidence in amateur rugby. Design: Cross-sectional analytical study: 2018 (control-standard tackle height) and 2019 (intervention-lowered legal tackle height) seasons. Setting: South African collegiate student rugby competition. Participants: Between 800 and 900 male amateur student players (age: 20±1.6 years) in each year. Intervention: Maximum legal tackle height lowered from line of the shoulder on the ball carrier to the line of the armpit. Outcome measures: Number of overall (medical attention) and time-loss (≥1 day lost) injuries, head injuries and SRCs in 2018 and 2019 (dependent variables); events associated with injury incidents (independent variables). Results: There was no statistically significant difference in incidences of time-loss injuries (IRR: 0.79; 95% CI: 0.6 to 1.1; p=0.13), head injuries (IRR: 0.83; 95% CI: 0.5 to 1.3; p=0.42) and SRC (IRR: 0.69; 95% CI: 0.4 to 1.2; p=0.20). In 2018 and 2019, most time-loss head injuries (57%, n=43) and SRCs (55%, n=26) occurred during the tackle. Conclusions: Despite a trend towards reducing injuries, head injuries and SRC, lowering maximum legal tackle height to armpit level did not change SRC incidence in this amateur male rugby cohort. Most time-loss head injuries and SRCs occurred during the tackle. Further tackle-related interventions to reduce SRC incidence require investigation.
MeSH term(s)	Humans ; Male ; Adolescent ; Young Adult ; Adult ; Athletic Injuries/epidemiology ; Athletic Injuries/prevention & control ; Cross-Sectional Studies ; Football/injuries ; Brain Concussion/epidemiology ; Brain Concussion/prevention & control ; Brain Concussion/complications ; Craniocerebral Trauma/epidemiology ; Craniocerebral Trauma/prevention & control ; Incidence
Language	English
Publishing date	2022-12-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1433667-4
ISSN	1475-5785 ; 1353-8047
ISSN (online)	1475-5785
ISSN	1353-8047
DOI	10.1136/ip-2022-044714
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Zs.A 4910: Show issues

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Article: Cardiac markers--optimising proBNP in cardiac diagnosis and management.

Jordaan, Pierre J

Cardiovascular journal of South Africa : official journal for Southern Africa Cardiac Society [and] South African Society of Cardiac Practitioners

2005 Volume 16, Issue 4, Page(s) 192–193

MeSH term(s)	Cardiovascular Diseases/diagnosis ; Natriuretic Peptide, Brain/blood ; Peptide Fragments/blood ; Protein Precursors/blood ; Sensitivity and Specificity
Chemical Substances	Peptide Fragments ; Protein Precursors ; pro-brain natriuretic peptide (1-76) ; Natriuretic Peptide, Brain (114471-18-0)
Language	English
Publishing date	2005-07
Publishing country	South Africa
Document type	Editorial
ZDB-ID	2027189-X
ISSN	1015-9657
ISSN	1015-9657
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Zs.A 4813: Show issues

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Article ; Online: A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.

Vormfelde, Stefan Viktor / Pezous, Nicole / Lefèvre, Gilbert / Kolly, Carine / Neumann, Ulf / Jordaan, Pierre / Ufer, Mike / Legangneux, Eric

Clinical and translational science

2020 Volume 13, Issue 6, Page(s) 1316–1326

Abstract: Umibecestat, an orally active β-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR ... ...

Abstract	Umibecestat, an orally active β-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA).
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Dose-Response Relationship, Drug ; Electrocardiography/drug effects ; Female ; Heart Rate/drug effects ; Humans ; Long QT Syndrome/chemically induced ; Long QT Syndrome/diagnosis ; Male ; Middle Aged ; Moxifloxacin/administration & dosage ; Oxazines/administration & dosage ; Oxazines/adverse effects ; Randomized Controlled Trials as Topic ; Young Adult
Chemical Substances	Oxazines ; Umibecestat (4612B80545) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46) ; Moxifloxacin (U188XYD42P)
Language	English
Publishing date	2020-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12832
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Article ; Online: Analysis of unipolar electrograms in rabbit heart demonstrated the key role of ventricular apicobasal dispersion in arrhythmogenicity.

Guérard, Nicolas / Jordaan, Pierre / Dumotier, Bérengère

Cardiovascular toxicology

2014 Volume 14, Issue 4, Page(s) 316–328

Abstract: Reduced repolarization reserve and increased transmural dispersion of repolarization (TDR) are known risk factors for Torsade de Pointes development, but less is known about the role of apex-to-base (apicobasal) repolarization in arrhythmogenesis. Three ... ...

Abstract	Reduced repolarization reserve and increased transmural dispersion of repolarization (TDR) are known risk factors for Torsade de Pointes development, but less is known about the role of apex-to-base (apicobasal) repolarization in arrhythmogenesis. Three needles were inserted in rabbit left ventricle to record unipolar electrograms from endocardium to epicardium and base to apex. Total repolarization interval (TRI) and peak-to-end repolarization interval (Tp) were assessed after quinidine (n = 6) and D,L-sotalol (n = 6) perfusion in combination with the IKs inhibitor chromanol 293B. About 30 µM D,L-sotalol increased TRI and Tp more at the base (TRI + 40 ± 4 %; Tp +89 ± 11 %) relative to the apex (TRI + 28 ± 3 %, Tp + 30 ± 8 %). Similar results were obtained with quinidine: TRI and Tp increased more at the base compared to the apex. No significant differences were recorded from the endocardium to the epicardium. Our results show that combined IKr + IKs block prolonged TRI and Tp significantly more at the ventricular base than at the apex, in the absence of transmural dispersion of refractoriness. Regional changes in TRI and Tp indicate the contribution of apicobasal dispersion to arrhythmogenicity compared to TDR in a rabbit heart model.
MeSH term(s)	Animals ; Anti-Arrhythmia Agents/pharmacology ; Antioxidants/metabolism ; Arrhythmias, Cardiac/etiology ; Chromans/pharmacology ; Electrophysiologic Techniques, Cardiac ; Endocardium/physiopathology ; Pericardium/physiopathology ; Quinidine/pharmacology ; Rabbits ; Sotalol/pharmacology ; Sulfonamides/pharmacology ; Torsades de Pointes/etiology
Chemical Substances	Anti-Arrhythmia Agents ; Antioxidants ; Chromans ; Sulfonamides ; 6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane (163163-23-3) ; Sotalol (A6D97U294I) ; Quinidine (ITX08688JL)
Language	English
Publishing date	2014-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036765-X
ISSN	1559-0259 ; 1530-7905
ISSN (online)	1559-0259
ISSN	1530-7905
DOI	10.1007/s12012-014-9254-2
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Zs.A 5817: Show issues

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Article: High Concussion Rate in Student Community Rugby Union Players During the 2018 Season: Implications for Future Research Directions.

Brown, James Craig / Starling, Lindsay Toyah / Stokes, Keith / Viviers, Pierre / Jordaan, Esme / Surmon, Sean / Derman, Elton Wayne

Frontiers in human neuroscience

2019 Volume 13, Page(s) 423

Abstract: Collision sports, such as Rugby Union ("Rugby") have a particularly high risk of injury. Of all injuries common to collision sports, concussions have received the most attention due to the potentially negative cognitive effects in the short- and long- ... ...

Abstract	Collision sports, such as Rugby Union ("Rugby") have a particularly high risk of injury. Of all injuries common to collision sports, concussions have received the most attention due to the potentially negative cognitive effects in the short- and long-term. Despite non-professional Rugby players comprising the majority of the world's playing population, there is relatively little research in this population. Stellenbosch Rugby Football Club ("Maties"), the official rugby club of Stellenbosch University, represents one of the world's largest non-professional Rugby clubs, making this an ideal cohort for community-level injury surveillance. The aim of this study was to describe the incidence and events associated with concussion in this cohort. Baseline demographics were obtained on the 807 male student Rugby non-professional players who registered for the 10-week long 2018 season, which comprised 101 matches and 2,915 of exposure hours. All match-related injuries were captured by the medical staff of Stellenbosch Campus Health Service on an electronic form developed from the consensus statement for injury recording in Rugby. The mean age, height and weight of this cohort were 20 ± 2 years, 182 ± 7 cm and 88 ± 14 kg, respectively. Overall, there were 89 time-loss injuries, which equated to an injury rate of 30.6 per 1,000 match hours [95% confidence intervals (CIs): 24.2-36.9], or about one injury per match. The most common injury diagnosis was "concussion" (
Language	English
Publishing date	2019-12-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2425477-0
ISSN	1662-5161
ISSN	1662-5161
DOI	10.3389/fnhum.2019.00423
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Article ; Online: The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors.

Coker, Shodeinde A / Hurwitz, Herbert I / Sharma, Sunil / Wang, Ding / Jordaan, Pierre / Zarate, Juan Pablo / Lewis, Lionel D

Cancer chemotherapy and pharmacology

2019 Volume 84, Issue 2, Page(s) 383–392

Abstract: Purpose: To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors.: Methods: This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered ... ...

Abstract	Purpose: To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors. Methods: This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12 h apart and one dose in the morning on day 2. Two doses of lapatinib 2000 mg were administered orally on day 3, 12 h apart and one dose in the morning on day 4. Twelve-lead digital ECGs were extracted from continuous Holter recordings at pre-specified time points over the 24-h period on days 2 and 4. Venous blood samples for lapatinib concentrations were obtained immediately following the ECGs. Results: A maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8 ms (90% CI 4.1, 13.4) occurred approximately 10 h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9 ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60 ms on lapatinib or placebo. The geometric mean lapatinib C Conclusions: These data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000 mg. This study confirms the need for caution in patients with solid tumors treated with lapatinib, and who are concomitantly receiving drugs that are strong CYP3A inhibitors and/or prolong the QTc.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cross-Over Studies ; Female ; Humans ; Lapatinib/pharmacology ; Lapatinib/therapeutic use ; Male ; Middle Aged ; Neoplasms/drug therapy ; Neoplasms/pathology ; Young Adult
Chemical Substances	Antineoplastic Agents ; Lapatinib (0VUA21238F)
Language	English
Publishing date	2019-06-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-019-03880-9
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Zs.A 1420: Show issues

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Article ; Online: Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies.

Pivonello, Rosario / Muscogiuri, Giovanna / Holder, Geoffrey / Paul, Michaela / Sarp, Severine / Lesogor, Anastasia / Jordaan, Pierre / Eisinger, Johannes / Colao, Annamaria

Endocrine

2017 Volume 60, Issue 1, Page(s) 65–72

Abstract: Purpose: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled ... ...

Abstract	Purpose: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety. Methods: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries. Results: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia. Conclusions: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.
MeSH term(s)	Adult ; Aged ; Cholelithiasis/chemically induced ; Diabetic Retinopathy/drug therapy ; Diarrhea/chemically induced ; Double-Blind Method ; Female ; Humans ; Hypertension/chemically induced ; Hypoglycemia/chemically induced ; Male ; Middle Aged ; Octreotide/adverse effects ; Octreotide/therapeutic use
Chemical Substances	Octreotide (RWM8CCW8GP)
Language	English
Publishing date	2017-11-07
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial
ZDB-ID	1194484-5
ISSN	1559-0100 ; 1355-008X ; 0969-711X
ISSN (online)	1559-0100
ISSN	1355-008X ; 0969-711X
DOI	10.1007/s12020-017-1448-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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