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Article ; Online: Use of the Actiwatch-Mini® in dog safety studies as an early indicator for drug-induced behavioural changes.

Cools, Frank / Kopljar, Ivan / Fetene, Tekle / Borghys, Herman

Journal of pharmacological and toxicological methods

2020 Volume 104, Page(s) 106896

Abstract: Introduction: Clinical observations are routinely used to address drug-induced behavioural changes in dogs. To deal with the limitations of this methodology, we evaluated Actiwatch-Mini® as a tool to monitor continuously locomotor activity in dogs and ... ...

Abstract	Introduction: Clinical observations are routinely used to address drug-induced behavioural changes in dogs. To deal with the limitations of this methodology, we evaluated Actiwatch-Mini® as a tool to monitor continuously locomotor activity in dogs and to provide objective parameters that could be linked to behavioural changes after compound administration. Methods: Eight Beagles were equipped with Actiwatch-Mini®. As a reference drug, a PDE2-inhibitor was administered daily for six days at doses known to cause minor or severe behavioural changes. Results: While traditional observation showed no behavioural changes - except sedation - dogs receiving 0.5 mg/kg/day, showed significant increases in % immobile time (+15.8%) and mean length of immobile phases (+1.2 min) but no change in number of immobile phases (+2.2). At 1 mg/kg/day, light to severe changes in behaviour were present. Actiwatch-Mini® recorded an increase in mean length of immobile phases (+1.9 min) and a decrease in mean number of immobile phases (-7.4) in the first four hours after each dosing while total % immobile time was not significantly increased (+4.9%). Discussion: Actiwatch-Mini® was able to detect changes in immobility parameters in dogs dosed with a PDE2-inhibitor while no or only minor behavioural changes were observed. The system can be used for continuously monitoring the activity of dogs, to provide objective scores for evaluation of activity. It provides an inexpensive and low labour-intensive method for detecting changes in activity and possible early indications of drug-induced behavioural changes.
MeSH term(s)	Animals ; Behavior, Animal/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors ; Dogs ; Female ; Male ; Monitoring, Physiologic/instrumentation ; Monitoring, Physiologic/methods ; Motor Activity/drug effects ; Phosphodiesterase Inhibitors/administration & dosage ; Phosphodiesterase Inhibitors/toxicity ; Time Factors
Chemical Substances	Phosphodiesterase Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 2 (EC 3.1.4.17)
Language	English
Publishing date	2020-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2020.106896
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Use of the Actiwatch-Mini® in dog safety studies as an early indicator for drug-induced behavioural changes

Cools, Frank / Kopljar, Ivan / Fetene, Tekle / Borghys, Herman

Journal of pharmacological and toxicological methods. 2020 July, Aug., v. 104

2020

Abstract: Clinical observations are routinely used to address drug-induced behavioural changes in dogs. To deal with the limitations of this methodology, we evaluated Actiwatch-Mini® as a tool to monitor continuously locomotor activity in dogs and to provide ... ...

Abstract	Clinical observations are routinely used to address drug-induced behavioural changes in dogs. To deal with the limitations of this methodology, we evaluated Actiwatch-Mini® as a tool to monitor continuously locomotor activity in dogs and to provide objective parameters that could be linked to behavioural changes after compound administration.Eight Beagles were equipped with Actiwatch-Mini®. As a reference drug, a PDE2-inhibitor was administered daily for six days at doses known to cause minor or severe behavioural changes.While traditional observation showed no behavioural changes - except sedation - dogs receiving 0.5 mg/kg/day, showed significant increases in % immobile time (+15.8%) and mean length of immobile phases (+1.2 min) but no change in number of immobile phases (+2.2). At 1 mg/kg/day, light to severe changes in behaviour were present. Actiwatch-Mini® recorded an increase in mean length of immobile phases (+1.9 min) and a decrease in mean number of immobile phases (−7.4) in the first four hours after each dosing while total % immobile time was not significantly increased (+4.9%).Actiwatch-Mini® was able to detect changes in immobility parameters in dogs dosed with a PDE2-inhibitor while no or only minor behavioural changes were observed. The system can be used for continuously monitoring the activity of dogs, to provide objective scores for evaluation of activity. It provides an inexpensive and low labour-intensive method for detecting changes in activity and possible early indications of drug-induced behavioural changes.
Keywords	dogs ; drugs ; locomotion ; sedation ; toxicology
Language	English
Dates of publication	2020-07
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2020.106896
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: High-Throughput Screening Assay for Detecting Drug-Induced Changes in Synchronized Neuronal Oscillations and Potential Seizure Risk Based on Ca 2+ Fluorescence Measurements in Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neuronal 2D and 3D Cultures

Hua-Rong Lu / Manabu Seo / Mohamed Kreir / Tetsuya Tanaka / Rie Yamoto / Cristina Altrocchi / Karel van Ammel / Fetene Tekle / Ly Pham / Xiang Yao / Ard Teisman / David J. Gallacher

Cells, Vol 12, Iss 958, p

2023 Volume 958

Abstract: Drug-induced seizure liability is a significant safety issue and the basis for attrition in drug development. Occurrence in late development results in increased costs, human risk, and delayed market availability of novel therapeutics. Therefore, there ... ...

Abstract	Drug-induced seizure liability is a significant safety issue and the basis for attrition in drug development. Occurrence in late development results in increased costs, human risk, and delayed market availability of novel therapeutics. Therefore, there is an urgent need for biologically relevant, in vitro high-throughput screening assays (HTS) to predict potential risks for drug-induced seizure early in drug discovery. We investigated drug-induced changes in neural Ca 2+ oscillations, using fluorescent dyes as a potential indicator of seizure risk, in hiPSC-derived neurons co-cultured with human primary astrocytes in both 2D and 3D forms. The dynamics of synchronized neuronal calcium oscillations were measured with an FDSS kinetics reader. Drug responses in synchronized Ca 2+ oscillations were recorded in both 2D and 3D hiPSC-derived neuron/primary astrocyte co-cultures using positive controls (4-aminopyridine and kainic acid) and negative control (acetaminophen). Subsequently, blinded tests were carried out for 25 drugs with known clinical seizure incidence. Positive predictive value (accuracy) based on significant changes in the peak number of Ca 2+ oscillations among 25 reference drugs was 91% in 2D vs. 45% in 3D hiPSC-neuron/primary astrocyte co-cultures. These data suggest that drugs that alter neuronal activity and may have potential risk for seizures can be identified with high accuracy using an HTS approach using the measurements of Ca 2+ oscillations in hiPSC-derived neurons co-cultured with primary astrocytes in 2D.
Keywords	hiPSC neurons ; 2D ; 3D ; high throughput screening HTS ; Ca 2+ neuronal oscillations ; neuronal active drugs ; Biology (General) ; QH301-705.5
Subject code	333
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking

Ivan Kopljar / Hua Rong Lu / Karel Van Ammel / Martin Otava / Fetene Tekle / Ard Teisman / David J. Gallacher

Stem Cell Reports, Vol 11, Iss 6, Pp 1365-

2018 Volume 1377

Abstract: Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the ... ...

Abstract	Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening. : Kopljar and colleagues developed a scoring system to evaluate the potential cardiac hazard of drugs using a hiPSC-CM-based screening assay. This approach allows translation of various pharmacological responses in hiPSC-CMs into a single hazard label. Early evaluation of thousands of new chemical entities within drug discovery and development should enhance the development of new drugs with a favorable cardio-safety profile. Keywords: cardiomyocytes, stem cells, drug discovery and development, drug screening, cardiac safety, cardiac hazard, pharmacology, arrhythmia, torsade de pointes, hERG
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Macrofilaricidal efficacy of single and repeated oral and subcutaneous doses of flubendazole in Litomosoides sigmodontis infected jirds.

Marc P Hübner / Alexandra Ehrens / Marianne Koschel / Bettina Dubben / Franziska Lenz / Stefan J Frohberger / Sabine Specht / Ludo Quirynen / Sophie Lachau-Durand / Fetene Tekle / Benny Baeten / Marc Engelen / Charles D Mackenzie / Achim Hoerauf

PLoS Neglected Tropical Diseases, Vol 13, Iss 1, p e

2019 Volume 0006320

Abstract: Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a ... ...

Abstract	Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	630
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

Chelsea Fischer / Iosune Ibiricu Urriza / Christina A Bulman / K C Lim / Jiri Gut / Sophie Lachau-Durand / Marc Engelen / Ludo Quirynen / Fetene Tekle / Benny Baeten / Brenda Beerntsen / Sara Lustigman / Judy Sakanari

PLoS Neglected Tropical Diseases, Vol 13, Iss 1, p e

2019 Volume 0006787

Abstract: River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are ... ...

Abstract	River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	630
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Measuring chronic care management experience of patients with diabetes

Hanneke Drewes / Janneke van Til-de Jong / Jeroen Struijs / Caroline Baan / Fetene Tekle / Bert Meijboom / Gert Westert

International Journal of Integrated Care, Vol 12, Iss

PACIC and PACIC+ validation

2012 Volume 8

Abstract: Background: The patient assessment of chronic illness care (PACIC) is a promising instrument to evaluate the chronic care experiences of patients, yet additional validation is needed to improve its usefulness. Methods: A total of 1941 patients with ... ...

Abstract	Background: The patient assessment of chronic illness care (PACIC) is a promising instrument to evaluate the chronic care experiences of patients, yet additional validation is needed to improve its usefulness. Methods: A total of 1941 patients with diabetes completed the questionnaire. Reliability coefficients and factor analyses were used to psychometrically test the PACIC and PACIC+ (i.e., PACIC extended with six additional multidisciplinary team functioning items to improve content validity). Intra-Class Correlations were computed to identify the extent to which variation in scores can be attributed to GP practices. Results: The PACIC and PACIC+ showed a good psychometric quality (Cronbach's alpha's > 0.9). Explorative factor analyses showed inconclusive results. Confirmative factor analysis showed that none of the factor structures had an acceptable fit (RMSEA > 0.10). In addition, 5.1 to 5.4 percent of the total variation was identified at the GP practice level. Conclusion: The PACIC and PACIC+ are reliable instruments to measure the chronic care management experiences of patients. The PACIC+ is preferred because it also includes multidisciplinary coordination and cooperation - one of the central pillars of chronic care management - with good psychometric quality. Previously identified subscales should be used with caution. Both PACIC instruments are useful in identifying GP practice variation.
Keywords	chronic care model ; patient experience ; chronic care management ; integrated care ; diabetes ; PACIC ; Medicine (General) ; R5-920
Subject code	650
Language	English
Publishing date	2012-10-01T00:00:00Z
Publisher	Ubiquity Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Measuring chronic care management experience of patients with diabetes

Hanneke Drewes / Janneke van Til-de Jong / Jeroen Struijs / Caroline Baan / Fetene Tekle / Bert Meijboom / Gert Westert

International Journal of Integrated Care, Vol 12, Iss

PACIC and PACIC+ validation

2012 Volume 8

Abstract	Background: The patient assessment of chronic illness care (PACIC) is a promising instrument to evaluate the chronic care experiences of patients, yet additional validation is needed to improve its usefulness. Methods: A total of 1941 patients with diabetes completed the questionnaire. Reliability coefficients and factor analyses were used to psychometrically test the PACIC and PACIC+ (i.e., PACIC extended with six additional multidisciplinary team functioning items to improve content validity). Intra-Class Correlations were computed to identify the extent to which variation in scores can be attributed to GP practices. Results: The PACIC and PACIC+ showed a good psychometric quality (Cronbach's alpha's > 0.9). Explorative factor analyses showed inconclusive results. Confirmative factor analysis showed that none of the factor structures had an acceptable fit (RMSEA > 0.10). In addition, 5.1 to 5.4 percent of the total variation was identified at the GP practice level. Conclusion: The PACIC and PACIC+ are reliable instruments to measure the chronic care management experiences of patients. The PACIC+ is preferred because it also includes multidisciplinary coordination and cooperation - one of the central pillars of chronic care management - with good psychometric quality. Previously identified subscales should be used with caution. Both PACIC instruments are useful in identifying GP practice variation.
Keywords	chronic care model ; patient experience ; chronic care management ; integrated care ; diabetes ; PACIC ; Medicine (General) ; R5-920
Subject code	650
Language	English
Publishing date	2012-10-01T00:00:00Z
Publisher	Ubiquity Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

PLoS Neglected Tropical Diseases, Vol 13, Iss 1, p e

2019 Volume 0006356

Abstract: The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of ...

Abstract	The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve ...
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	630
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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