Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 23
Filter
1.
PLoS Biol ; 20(11): e3001873, 2022 11.
Article in English | MEDLINE | ID: mdl-36395326

ABSTRACT

In animal experiments, blinding (also known as masking) is a methodological strategy to reduce the risk that scientists, animal care staff, or other staff involved in the research may consciously or subconsciously influence the outcome. Lack of masking has been shown to correlate with an overestimation of treatment efficacy and false positive findings. We conducted exploratory interviews across academic and a commercial setting to discuss the implementation of masking at four stages of the experiment: during allocation and intervention, during the conduct of the experiment, during the outcome assessment, and during the data analysis. The objective was to explore the awareness, engagement, perceptions, and the barriers to implementing masking in animal experiments. We conducted multiple interviews, to explore 30 different experiments, and found examples of excellent practice but also areas where masking was rarely implemented. Significant barriers arose from the operational and informatic systems implemented. These systems have prioritised the management of welfare without considering how to allow researchers to use masking in their experiments. For some experiments, there was a conflict between the management of welfare for an individual animal versus delivering a robust experiment where all animals are treated in the same manner. We identified other challenges related to the level of knowledge on the purpose of masking or the implementation and the work culture. The exploration of these issues provides insight into how we, as a community, can identify the most significant barriers in a given research environment. Here, we offer practical solutions to enable researchers to implement masking as standard. To move forward, we need both the individual scientists to embrace the use of masking and the facility managers and institutes to engage and provide a framework that supports the scientists.


Subject(s)
Animal Experimentation , Research Personnel , Animals , Humans , Qualitative Research , Data Analysis , Academies and Institutes
2.
PLoS Biol ; 18(7): e3000410, 2020 07.
Article in English | MEDLINE | ID: mdl-32663219

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.


Subject(s)
Animal Experimentation , Guidelines as Topic , Research Report , Animals , Checklist
3.
PLoS Biol ; 18(7): e3000411, 2020 07.
Article in English | MEDLINE | ID: mdl-32663221

ABSTRACT

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.


Subject(s)
Animal Experimentation , Guidelines as Topic , Research Report , Animal Experimentation/ethics , Animal Husbandry , Animals , Confidence Intervals , Housing, Animal , Outcome Assessment, Health Care , Publications , Random Allocation , Reproducibility of Results , Sample Size
4.
J Physiol ; 598(18): 3793-3801, 2020 09.
Article in English | MEDLINE | ID: mdl-32666574

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the 'ARRIVE Essential 10,' which constitutes the minimum requirement, and the 'Recommended Set,' which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.


Subject(s)
Animal Experimentation , Animals , Checklist , Reproducibility of Results , Research Report
5.
Exp Physiol ; 105(9): 1459-1466, 2020 09.
Article in English | MEDLINE | ID: mdl-32666546

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.


Subject(s)
Animal Experimentation/standards , Guidelines as Topic , Animals , Checklist , Reproducibility of Results , Research Design
6.
PLoS Biol ; 15(9): e2003779, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28957312

ABSTRACT

Addressing the common problems that researchers encounter when designing and analysing animal experiments will improve the reliability of in vivo research. In this article, the Experimental Design Assistant (EDA) is introduced. The EDA is a web-based tool that guides the in vivo researcher through the experimental design and analysis process, providing automated feedback on the proposed design and generating a graphical summary that aids communication with colleagues, funders, regulatory authorities, and the wider scientific community. It will have an important role in addressing causes of irreproducibility.


Subject(s)
Internet , Research Design , Software , Feedback
7.
BMC Vet Res ; 16(1): 242, 2020 Jul 14.
Article in English | MEDLINE | ID: mdl-32660541

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.


Subject(s)
Animal Experimentation , Guidelines as Topic , Research Report , Animals , Checklist
8.
Handb Exp Pharmacol ; 257: 55-69, 2020.
Article in English | MEDLINE | ID: mdl-31707471

ABSTRACT

Preclinical studies using animals to study the potential of a therapeutic drug or strategy are important steps before translation to clinical trials. However, evidence has shown that poor quality in the design and conduct of these studies has not only impeded clinical translation but also led to significant waste of valuable research resources. It is clear that experimental biases are related to the poor quality seen with preclinical studies. In this chapter, we will focus on hypothesis testing type of preclinical studies and explain general concepts and principles in relation to the design of in vivo experiments, provide definitions of experimental biases and how to avoid them, and discuss major sources contributing to experimental biases and how to mitigate these sources. We will also explore the differences between confirmatory and exploratory studies, and discuss available guidelines on preclinical studies and how to use them. This chapter, together with relevant information in other chapters in the handbook, provides a powerful tool to enhance scientific rigour for preclinical studies without restricting creativity.


Subject(s)
Research Design , Animals , Biomedical Research/standards
9.
J Transl Med ; 12: 327, 2014 Dec 10.
Article in English | MEDLINE | ID: mdl-25491123

ABSTRACT

BACKGROUND: Rodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis. METHODS: The biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues. RESULTS: In anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9-39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0-120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9-39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve. CONCLUSIONS: Peripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists.


Subject(s)
Appetite Depressants/pharmacology , Emetics/pharmacology , Hypoglycemic Agents/pharmacology , Peptides/pharmacology , Venoms/pharmacology , Animals , Blood Glucose/metabolism , Exenatide , Ferrets , Male
10.
Exp Physiol ; 95(7): 768-73, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20360423

ABSTRACT

In humans, motion sickness is associated with disruption of normal gastric myoelectric activity, and it has been proposed that this results from an imbalance of autonomic nervous system activity. We used the established Suncus murinus (house musk shrew) model of motion-induced emesis to investigate the effect of horizontal motion on gastric myoelectric activity (recorded using telemetry) and the involvement of the abdominal vagi. Surgical vagotomy increased baseline dysrhythmia and reduced the dominant power of the gastric myoelectric signals. In response to motion, normal gastric myoelectric activity was reduced in sham-operated animals but not in vagotomized animals. Vagotomy, however, failed to affect motion-induced emesis. In conclusion, motion had a differential effect in sham-operated and vagotomized animals, which is consistent with the hypothesis that motion-induced dysrhythmia arises from an autonomic nervous system imbalance.


Subject(s)
Motion Sickness/physiopathology , Vagus Nerve/physiology , Animals , Autonomic Nervous System/physiology , Male , Membrane Potentials/physiology , Shrews , Stomach/physiology , Telemetry , Vomiting/etiology
11.
BMJ Open Sci ; 4(1): e100115, 2020 Jul 20.
Article in English | MEDLINE | ID: mdl-34095516

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into two sets, the 'ARRIVE Essential 10', which constitutes the minimum requirement, and the 'Recommended Set', which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

12.
Br J Pharmacol ; 177(16): 3617-3624, 2020 08.
Article in English | MEDLINE | ID: mdl-32662519

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.


Subject(s)
Animal Experimentation , Animals , Checklist , Reproducibility of Results , Research Design , Research Report
13.
Elife ; 92020 03 04.
Article in English | MEDLINE | ID: mdl-32127131

ABSTRACT

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.


Subject(s)
Biomedical Research/education , Biomedical Research/methods , Biomedical Research/standards , Research Design/standards , Humans
14.
J Cereb Blood Flow Metab ; 40(9): 1769-1777, 2020 09.
Article in English | MEDLINE | ID: mdl-32663096

ABSTRACT

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

15.
F1000Res ; 7: 591, 2018.
Article in English | MEDLINE | ID: mdl-29862024

ABSTRACT

This editorial introduces the NC3Rs gateway, which publishes articles and reviews on new models and technologies emerging from NC3Rs-funded research. The aim is to raise awareness about these approaches, increase confidence in their capability, and provide sufficient information to facilitate their uptake by others.

17.
J Cereb Blood Flow Metab ; 37(11): 3488-3517, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28797196

ABSTRACT

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).


Subject(s)
Animal Welfare/standards , Brain Ischemia/pathology , Stroke/pathology , Animals , Disease Models, Animal , Guidelines as Topic , Humans , Infarction, Middle Cerebral Artery/pathology
18.
PLoS One ; 6(9): e24439, 2011.
Article in English | MEDLINE | ID: mdl-21931717

ABSTRACT

Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds--denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers--capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9 ± 4.0 µM) > quinine hydrochloride (IC(50) = 44.3 ± 6.8 µM) > denatonium benzoate (IC(50) = 129 ± 4 µM) > phenylthiourea (IC(50) = 366 ± 5 µM) > copper sulphate (IC(50) = 1433 ± 3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general.


Subject(s)
Chemotaxis , Dictyostelium/metabolism , Taste , Animals , Capsaicin/pharmacology , Cell Movement , Dose-Response Relationship, Drug , Emetics , Genome , Inhibitory Concentration 50 , Movement , Proteins/chemistry , Quinine/pharmacology , Stomach/drug effects
19.
Toxicol Lett ; 192(3): 402-7, 2010 Feb 15.
Article in English | MEDLINE | ID: mdl-19931602

ABSTRACT

Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only at doses that have adverse effects on the cardiovascular system and on temperature homeostasis. In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator, olvanil (0.05-5 mg/kg, s.c., 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5 mg/kg, i.p.) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature. Cisplatin induced an acute (day 1: 48.0+/-18.3 retches+vomits) and delayed (day 2: 111.7+/-35.5; day 3: 147.5+/-20.2 retches+vomits) emetic response that was associated with reduced food (-98.7% at day 3, P<0.001) and water consumption (-70.2% at day 3, P<0.001) and progressive weight loss (-12.0% at day 3, P<0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (P>0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0.05 mg/kg (P<0.05) and 19.9% at 0.5 mg/kg (P<0.05). Cisplatin did not alter body temperature (basal: 37.7+/-0.1 degrees C) or heart rate (basal: 233.7+/-5.5 beats per min (BPM); P>0.05), but hypothermia (-1.6 degrees C) and increases in locomotor activity (50-90%) were recorded in animals concomitantly treated with olvanil (P<0.05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin.


Subject(s)
Antineoplastic Agents/adverse effects , Capsaicin/analogs & derivatives , Cisplatin/adverse effects , TRPV Cation Channels/agonists , Vomiting/drug therapy , Animals , Body Temperature/drug effects , Capsaicin/pharmacology , Drinking/drug effects , Eating/drug effects , Ferrets , Heart Rate/drug effects , Male , Motor Activity/drug effects , Vomiting/chemically induced
20.
Neuropharmacology ; 58(2): 383-91, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19825380

ABSTRACT

Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05-5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants. In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-emetic activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-emetic properties via central and/or peripheral mechanisms after peripheral administration.


Subject(s)
Antiemetics/pharmacology , Capsaicin/analogs & derivatives , TRPV Cation Channels/metabolism , Vomiting/drug therapy , Animals , Antiemetics/administration & dosage , Antiemetics/adverse effects , Apomorphine , Arachidonic Acids/pharmacology , Behavior, Animal/drug effects , Blood Pressure/drug effects , Body Temperature/drug effects , Capsaicin/administration & dosage , Capsaicin/adverse effects , Capsaicin/pharmacology , Cisplatin , Copper Sulfate , Diterpenes/adverse effects , Diterpenes/pharmacology , Dose-Response Relationship, Drug , Ferrets , Heart Rate/drug effects , Male , TRPV Cation Channels/agonists , Vomiting/chemically induced
SELECTION OF CITATIONS
SEARCH DETAIL