Abstract
The discipline of safety pharmacology can impact all stages of drug discovery and development from early target identification to regulatory approval. One of the key deliverables for safety pharmacology is the GLP studies to support Phase I clinical trials primarily in healthy volunteers but also in patients. The so-called core package of studies (investigating the adverse pharmacodynamic effects on the respiratory, cardiovascular, and central nervous systems) is well characterized and well served using normal healthy animals. Characterizing the phenotype of genetically modified animals may be useful to understand the hazards associated with a target modulation. Examples of when, and when not, the phenotype of knockout animals correlates with that observed with pharmacological agents in normal healthy animals and humans are given. For a number of years, some animal models of human disease (e.g., models of heart failure and cardiac arrhythmia) have been applied to safety pharmacology, and some show a different safety profile from that observed in normal healthy animals and as such may have the potential to increase the confidence in safety in the patient population. However, there are also examples where the translation of these models to humans has been far from perfect. Animal models of human disease have been used for decades in drug discovery, and similar translational challenges have been reviewed at length in the scientific literature. If we are to be successful in broadening the use of animal models of human disease in safety pharmacology, the learnings of many years of experience in drug discovery should be applied. Consideration must be given to both the internal and external validities of these models.
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Adan RAH, Tiesjema B, Hillebrand JJG, La Fleur SE, Kas MJH, de Krom M (2006) The MC4 receptor and control of appetite. Br J Pharmacol 149:815–827. https://doi.org/10.1038/sj.bjp.0706929
Anon (2000) ICHS7A: safety pharmacology studies for human pharmaceuticals. CPMP/ICH/539/00. London. https://database.ich.org/sites/default/files/S7A_Guideline.pdf
Anon (2005) ICHS7B: the nonclinical evaluation of the potential for delayed repolarisation (QT interval prolongation) by human pharmaceuticals. https://database.ich.org/sites/default/files/S7B_Guideline.pdf
Anon (2022) ICH E14/S7B implementation working group clinical and nonclinical evaluation of QT/QTc interval prolongation and proarrhythmia potential. Questions and answers. https://database.ich.org/sites/default/files/E14-S7B_QAs_Step4_2022_0221.pdf
Anon. CreibleMeds. https://crediblemeds.org
Baldrick P (2021) Core battery safety pharmacology testing – an assessment of its utility in early drug development. J Pharmacol Toxicol Methods. https://doi.org/10.1016/j.vascn.2021.107055
Baublits J, Vargas HM, Engwall MJ (2021) The in vivo QTc core assay: an evaluation of QTc variability, detection sensitivity and implications for the improvement of conscious dog and non-human primate telemetry studies. J Pharmacol Toxicol Methods. https://doi.org/10.1016/j.vascn.2021.107067
Behn D, Potter MJ (2001) Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the γ-subunit of phosphodiesterase. Invest Ophthalmol Vis Sci 42:523–527
Bhatt S, Northcott C, Wisialowski T, Li D, Steidl-Nichols J (2019) Preclinical to clinical translation of hemodynamic effects in cardiovascular safety pharmacology studies. Toxicol Sci 169:272–279. https://doi.org/10.1093/toxsci/kfz035
Borkowski AH, Barnes DC, Blanchette DR, Castellanos FX, Klein DF, Wilson DA (2011) Interaction between delta opioid receptors and benzodiazepines in CO2-induced respiratory response in mice. Brain Res 1396:54–59. https://doi.org/10.1016/j.brainres.2011.04.042
Bowes J, Rolf MG, Valentin J-P, Hamon V, Crawford M, Jean T (2006) Pharmacological and pharmaceutical profiling: new trends. The process of new drug discovery and development, 2nd edn. Informa Healthcare USA Inc
Brockman SK, Manlove A (1965) Cardiodynamics of complete heart block. Cardiology 16:72–83
Butz GM, Davisson RL (2001) Long-term telemetric measurement of cardiovascular parameters in awake mice: a physiological genomics tool. Physiol Genomics. https://doi.org/10.1152/physiolgenomics.2001.5.2.89
Caulfield MP, Birdsall NJM (1998) International union of pharmacology. XVII Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290
Corander MP, Fenech M, Coli AP (2009) Science of self-preservation. How melanocortin action in the brain modulates body weight, blood pressure and ischemic damage. Circulation 120:2260–2268. https://doi.org/10.1161/CIRCULATIONAHA.109.854612
D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath (2000) Mutation of the receptor kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–651. https://doi.org/10.1093/hmg/9.4.645
DaSilva JK, Breidenbach L, Deats T, Li D, Trenen K, Dinklo T, Kervyn S, Teuns G, Traebert M, Hempel K (2020) Nonclinical species sensitivity to convulsions: an IQ DruSafe consortium working group initiative. J Pharmacol Toxicol Methods. https://doi.org/10.1016/j.vascn.2020.106683
De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N (2002) Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes. Drug Saf 25:263–286. https://doi.org/10.2165/00002018-200225040-00004
Del Rio CL (2020) Animal models of human disease. Presentation to the annual meeting of the safety pharmacology society
Del Rio CL, Henze MP, Wong FL, Evanchik MJ, Divekar A, Gifford LM, Ferhaan A, Green EM (2017) Abstract 20770: a novel mini-pig genetic model of hypertrophic cardiomyopathy: altered myofilament dynamics, hyper-contractility, and impaired systolic/diastolic functional reserve in vivo. Circulation 136:A20770
Del Rio CL, Yadav A, Ferguson BS, Zambataro C, Smit T, Rohert F, Swart J, Guo L-J, Hargraves A, Grinde J, Sridhar V (2019) Abstract 14585: chronic treatment with mavacamten-like myosin-modulator (MYK-581) blunts disease progression in a mini-pig model of non-obstructed hypertrophic cardiomyopathy: in vivo evidence for improved relaxation and functional reserve. Circulation 140:A14585
Duncan JL, LaVail MM, Yasumura D, Matthes MT, Yang H, Trautmann N, Chappelow AV, Feng W, Earp HS, Matsushima GK, Vollrath D (2003) An RCS-like retinal dystrophy phenotype in Mer knockout mice. Invest Opthalmol Vis Sci 44:826–838. https://doi.org/10.1167/iovs.02-0438
Ewart L, Aylott M, Deurinck M, Engwall M, Gallacher DJ, Geys H, Jarvis P, Ju H, Leishman D, Leong L, McMahon N, Mead A, Milliken A, Suter W, Teisman A, Ammel KV, Vargas H, Wallis R, Valentin J-P (2014) The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative. Toxicol Sci 142:427–435. https://doi.org/10.1093/toxsci/kfu198
Farooqi IS, Yeo GSH, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O’Rahilly S (2000) Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106:271–279. https://doi.org/10.1172/JCI9397
Ferri N, Siegl P, Corsini A, Herrmann J, Lerman A, Benghozi R (2013) Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol Ther 138:470–484. https://doi.org/10.1016/j.pharmthera.2013.03.005
Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun J-H, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DE (2000) Possible role of valvular 5-HT2B receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 57:75–81
Frey N, Luedde M, Katus HA (2012) Mechanisms of disease: hypertrophic cardiomyopathy. Nat Rev Cardiol 9:91–100. https://doi.org/10.1038/nrcardio.2011.159
Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, Lesnikov AV, Gavva NR, Romanovsky AA (2011) Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 31:1721–1733. https://doi.org/10.1523/JNEUROSCI.4671-10.2011
Gavva NR (2008) Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV. TIPS 29:550–557. https://doi.org/10.1016/j.tips.2008.08.003
Gavva NR, Treanor JJS, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman NH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–210. https://doi.org/10.1016/j.pain.2008.01.024
Gomeza J, Shannon H, Kostenis E, Felder C, Zhang L, Brodkin J, Grinberg A, Sheng H, Wess J (1999) Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice. PNAS 96:1692–1697. https://doi.org/10.1073/pnas.96.4.1692
Graham DK, DeRyckere D, Davies KD, Earp HS (2014) The TAM family: phosphatidylserine-sensing receptor kinases gone awry in cancer. Nat Rev Cancer 14:769–785. https://doi.org/10.1038/nrc3847
Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, Henze M, Kawas R, Oslob JD, Rodriguez HM, Song Y, Wan W, Leinwand LA, Spudich JA, McDowel RS, Seidman JG, Seidman CE (2016) A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351:617–621. https://doi.org/10.1126/science.aad3456
Greenfield JR (2010) Melanocortin signalling and the regulation of blood pressure in human obesity. J Neuroendocrinol 23:186–193. https://doi.org/10.1111/j.1365-2826.2010.02088.x
Guo W, Li H, London B, Nerbonne JM (2000) Functional consequences of elimination of Ito,f and Ito,s. Early afterdepolarizations, atrioventricular block, and ventricular arrythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 α subunit. Circ Res 87:73–79. https://doi.org/10.1161/01.RES.87.1.73
Hall JE, Brands MW, Hildebrandt DA, Kuo J, Fitzgerald S (2000) Role of sympathetic nervous system and neuropeptides in obesity hypertension. Brazilian J Med Biol Res 33:605–618
Hamm G, Maglennon G, Williamson B, Macdonald R, Doherty A, Jones S, Harris J, Blades J, Harmer AR, Barton P, Rawlins PB, Smith P, Winter-Holt J, McMurray L, Johansson J, Fitzpatrick P, McCoull W, Coen M (2022) Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment. Arch Toxicol:96613–96624. https://doi.org/10.1007/s00204-021-03197-8
Huang X-P, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, Revankar C, Robers M, Doucette C, Roth BL (2009) Parallel functional activity profiling reveals valvulopathogens ate potent 5-hydroxytryptamine2B receptor agonists: implications for drug safety assessment. Mol Pharmacol 76:710–722. https://doi.org/10.1124/mol.109.058057
Hurwitz RL, Bunt-Milam AH, Chang ML, Beavo JA (1985) cGMP phosphodiesterase in rod and cone outer segments of the retina. J Biol Chem 260:568–573. https://doi.org/10.1016/S0021-9258(18)89770-8
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141. https://doi.org/10.1016/S0092-8674(00)81865-6
Irwin CG, Bates JHT (2003) Measuring lung function in the mouse: the challenge of size. Respir Res 4. https://doi.org/10.1186/rr199
Jost N, Virag L, Comtoise P, Ordog B, Szuts V, Seprenyl G, Bitay M, Kohajda Z, Koncz N, Szel T, Magyar J, Kovacs M, Puskas LG, Lengyel C, Wettwer E, Ravens U, Nanasi PP, Papp JG, Varro S, Nattel S (2013) Ionic mechanism limiting cardiac repolarization reserve in humans compared to dogs. J Physiol 591:4189–4206. https://doi.org/10.1113/jphysiol.2013.261198
Kleinman RB, Shah RR, Morganroth J (2014) Replacing the thorough QT study: reflections of a baby in the bath water. Br J Clin Pharmacol 78(2):195–201. https://doi.org/10.1111/bcp.12296. PMID: 24286381; PMCID: PMC4137815
Klymiuk N, Seeliger F, Bohlooly-Y M, Blutke A, Rudmann DG, Wolf E (2015) Tailored pig models for preclinical efficacy and safety testing of targeted therapies. Toxicol Pathol 44:346–357. https://doi.org/10.1177/0192623315609688
Kozhevnikov DO, Yamamoto K, Robotis D, Restivo M, El-Sherif N (2002) Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmia. Circulation 105:1128–1134. https://doi.org/10.1161/hc0902.104711
Laties AM, Zrenner E (2002) Viagra (sildenafil citrate) and ophthalmology. Prog Retin Eye Res 21:485–506. https://doi.org/10.1016/S1350-9462(02)00013-7
Lee MA, Dae MW, Langberg JJ, Griffin JC, Chin M, Finkbeiner WE, O’Connell JW, Botvinick E, Scheinman MM, Rosenqvist M (1994) Effects of long-term ventricular apical pacing on left ventricular perfusion, innervation, function, and histology. J Am Coll Cardiol 24:225–232
Lees-Miller J, Guo J, Somers JR, Roach DE, Sheldon RS, Rancourt DE, Duff HJ (2003) Selective knockout of mouse ERG1 B potassium channel eliminates IKr in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia. Mol Cell Biol 23:1856–1862. https://doi.org/10.1128/MCB.23.6.1856-1862.2003
Leishman DJ, Beck TW, Dybdal N, Gallacher DJ, Guth BD, Holbrook M, Roche B, Wallis RM (2012) Best practice in the conduct of key nonclinical cardiovascular assessments in drug development: current recommendations from the safety pharmacology society. J Pharmacol Toxicol Methods 65:93–101. https://doi.org/10.1016/j.vascn.2011.08.006
Li Z, Mirams GR, Yoshinaga T, Ridder BJ, Han X, Chen JE, Stockbridge NL, Wisialowski TA, Damiano B, Severi S, Morissette P, Kowey PR, Holbrook M, Smith G, Rasmusson RL, Liu M, Song Z, Qu Z, Leishman DJ, Steidl-Nichols RB, Bueno-Orovio A, Zhou X, Passini E, Edwards AG, Morotti S, Ni H, Grandi E, Clancy CE, Vandenberg J, Hill A, Nakamura M, Singer T, Polonchuk L, Greiter-Wilke A, Wang K, Nave S, Fullerton A, Sobie EA, Paci M, Tshinanu FM, Strauss DG (2020) General principles for validation of proarrhythmia risk prediction models: an extension of the CiPA in silico strategy. Clin Pharmacol Ther 107:102–111. https://doi.org/10.1002/cpt.1647
Liu GX, Zhou J, Nattel S, Koren G (2004) Single-channel recordings of a rapid delayed rectifier current in adult mouse ventricular myocytes: basic properties and effects of divalent cations. J Physiol 556:401–413. https://doi.org/10.1113/jphysiol.2003.059303
Loen V, Voss MV, van der Heyden MAG (2021) The canine chronic atrioventricular block model in cardiovascular research. Br J Pharmacol 179:859–881. https://doi.org/10.1111/bph.15436
Lu HR, Remeysen P, De Clerk F (2000) Nonselective IKr blockers do not induce torsades de pointes in the anaesthetized rabbit during α1-adrenoceptor stimulation. J Cardiovasc Pharmacol 36:738–736
Lu HR, Remeysen P, Somers K, Saels A, De Clerck F (2003) Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model. https://doi.org/10.1046/j.1540-8167.2001.00538.x
Lu HR, Van Ammel K, Vlaminckx E, De Clerk F (2004) QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement. J Cardiovasc Electrophysiol 12:538–545. https://doi.org/10.1016/j.vascn.2003.10.003
Mak IWY, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6:114–118
Maron BJ (2002) Hypertrophic cardiomyopathy: a systematic review. Clin Cardiol 287:1308–1320. https://doi.org/10.1001/jama.287.10.1308
Maron BJ, Maron MS (2013) Hypertrophic cardiomyopathy. Lancet 381:242–255. https://doi.org/10.1016/S0140-6736(12)60397-3
Martic-Kehl MI, Schibli R, Schubiger A (2012) Can animal data predict human outcome? Problems and pitfalls of translational animal research. Eur J Nucl Med Mol Imaging 39:1492–1496. https://doi.org/10.1007/s00259-012-2175-z
Martin M, Matifas A, Maldonado R, Kieffer BL (2003) Acute antinociceptive responses in single and combinatorial opioid receptor knockout mice: distinct mu, delta and kappa tones. Eur J Neurosci 17:701–708. https://doi.org/10.1046/j.1460-9568.2003.02482.x
Mead AN, Amouzadeh AR, Chapman K, Ewart L, Giarola A, Jackson SJ, Jarvis P, Jordaan P, Redfern W, Traebert M, Valentin J-P, Vargas HM (2016) Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials. Regul Toxicol Pharmacol 80:348–357. https://doi.org/10.1016/j.yrtph.2016.05.002
Morgan P, Van der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SDA (2012) Can the flow if medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today 17:419–424. https://doi.org/10.1016/j.drudis.2011.12.020
Morgan SJ, Couch J, Guzzie-Peck P, Keller DA, Kemper R, Otieno MA, Schulingkamp J, Jones T (2017) Regulatory forum opinion piece: use and utility of animal models of disease for nonclinical safety assessment: a pharmaceutical industry survey. Toxicol Pathol 45:372–380. https://doi.org/10.1177/0192623317701004
Nag S, Trivedi DV, Sarkar SS, Adhikari AS, Sunitha MS, Sutton S, Ruppel KM, Spudich JA (2017) The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Nat Struct Mol Biol 24:525–533. https://doi.org/10.1038/nsmb.3408
Nalivaiko E, de Pasuale CG, Blessing WW (2003) Ventricular arrhythmias triggered by altering stimuli in conscious rabbits pre-treated with dofetilide. Basic Res Cardiol 99:142–151. https://doi.org/10.1007/s00395-003-0448-1
Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hedge SM, Solomon S, Sehnert A, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D (2020) Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 396:759–769. https://doi.org/10.1016/S0140-6736(20)31792-X
Paglialunga S, Morimoto BH, Clark M, Friedrichs GS (2019) Translatability of the S7A core battery respiratory safety pharmacology studies: preclinical respiratory and related clinical adverse events. J Pharmacol Toxicol Methods 99:106596. https://doi.org/10.1016/j.vascn.2019.106596
Parkinson J, Chain ASY, van der Graaf PH, Visser SAG (2014) Pharmacometrics in Cardiovascular Safety. In: Schmidt, S., Derendorf, H. (eds) Applied Pharmacometrics. AAPS Advances in the Pharmaceutical Sciences Series, vol 14. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1304-6_7
Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Khan KS (2007) Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334:197. https://doi.org/10.1136/bmj.39048.407928.BE
Pound P, Ritskes-Hoitinga M (2018) Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. J Transl Med 16:304. https://doi.org/10.1186/s12967-018-1678-1
Redfern W, Valentin J-P (2017) Prevalence, frequency and impact of safety related issues throughout the pharmaceutical life cycle. The Toxicologist 156
Redfern WS, Wakefield ID, Prior H, Pollard CE, Hammond TG, Valentin J-P (2002) Safety pharmacology – a progressive approach. Fundam Clin Pharmacol 16:161–173. https://doi.org/10.1046/j.1472-8206.2002.00098.x
Rinne P, Harjunpaa J, Scheinin M, Savontaus E (2008) Blood pressure regulation and cardiac autonomic control in mice overexpressing α- and γ-melanocyte stimulating hormone. Peptides 29:1943–1952. https://doi.org/10.1016/j.peptides.2008.06.012
Rogers DC, Fisher FMC, Brown SDM, Peters J, Hunter AJ, Martin JE (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8:711–713. https://doi.org/10.1007/s003359900551
Romberg R, Sarton E, Teppema L, Matthes HWD, Kieffer BL, Dahan A (2003) Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ-opioid receptor deficient mice. Br J Anaesth 91:862–870. https://doi.org/10.1093/bja/aeg279
Roy S, Liu H-C, Loh HH (1998) μ opioid receptor-knockout mice: the role if μ-opioid receptor in gastrointestinal transit. Mol Brain Res 56:281–283. https://doi.org/10.1016/S0169-328X(98)00051-5
Sibille M, Deigat N, Janin A, Kirkesseli S, Durand DV (1998) Adverse events in phase-I studies: a report in 1015 healthy volunteers. Eur J Clin Pharmacol 54:13–20. https://doi.org/10.1007/s002280050413
Singh BN, Vaughan Williams EM (1970) A third class of anti-arrhythmic action. Effects on atrial and ventricular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474. Br J Pharmacol 39:675–687. https://doi.org/10.1111/j.1476-5381.1970.tb09893.x
Smith R, Prosser WA, Donahue DJ, Morgan ME, Anderson CM, Shanahan WR (2008) Lorcaserin (APD356), a selective 5-HT2c agonist, reduces body weight in obese men and women. Obesity 17, 494–503. Obesity 17:494–503. https://doi.org/10.1038/oby.2008.537
Sparrow AJ, Watkins H, Daniels MJ, Redwood C, Robinson P (2020) Mavacamten rescues increased myofilament calcium sensitivity and dysregulation of Ca2+ flux caused by thin filament hypertrophic cardiomyopathy mutations. Am J Physiol Heart Circ Physiol 318:H715–H722. https://doi.org/10.1152/ajpheart.00023.2020
Starzl TE, Gaertner RA (1955) Chronic heart block in dogs. A method for producing experimental heart failure. Circulation XII:259–270
Stengel PW, Gomeza J, Wess J, Cohen ML (2000) M2 and M4 receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro. J Pharmacol Exp Ther 292:877–885
Stengel PW, Yamada M, Wess J, Cohen ML (2002) M3-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea. Am J Physiol Regul Comp Physiol 282:R1443–R1449. https://doi.org/10.1152/ajpregu.00486.2001
Sugiyama A (2009) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br J Pharmacol 154:1528–1537. https://doi.org/10.1038/bjp.2008.240
Szolcsanyi J (2015) Effect of capsaicin on thermoregulation: an update with new aspects. Temperature 2:277–296. https://doi.org/10.1080/23328940.2015.1048928
Thomsen MB, Volders PGA, Stengl M, Spaatjens RLHMG, Beekman JDM, Bischoff U, Kall MA, Frederiksen K, Matz J, Vos MA (2003) Electrophysiological safety of sertindole in dogs with normal and remodelled hearts. J Pharmacol Ther 307:776–784. https://doi.org/10.1124/jpet.103.052753
Thomsen MB, Beekman JDM, Attevelt NJM, Takahara A, Sugiyama A, Chiba K, Vos MA (2009) No proarrhythmic properties of the antibiotics moxifloxacin or azithromycin in anaesthetized dogs with chronic-AV block. Br J Pharmacol 149:1039–1048. https://doi.org/10.1038/sj.bjp.0706900
Tsang AH, Gouras P, Yamashita CK, Kjeldbye H, Fisher J, Farber DB, Gofft SP (1996) Retinal degeneration in mice lacking the γ subunit of the rod cGMP phosphodiesterase. Science 272:1026–1029. https://doi.org/10.1126/science.272.5264.1026
Unger EF (2007) All is not well in the world of translational research. J Am Coll Cardiol 50:38–740
Unno T, Matsuyama H, Sakamoto T, Uchiyama M, Izumi Y, Okamoto H, Yamada M, Wess J, Komori S (2009) M2 and M3 muscarinic receptor-mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice. Br J Pharmacol 146:98–108. https://doi.org/10.1038/sj.bjp.0706300
Valentin J-P, Hammon T (2008) Safety and secondary pharmacology: successes, threats, challenges, and opportunities. J Pharmacol Toxicol Methods 58:77–87. https://doi.org/10.1016/j.vascn.2008.05.007
Van Dam D, De Deyn PP (2012) Animal models in the drug discovery pipeline for Alzheimer’s disease. Br J Pharmacol 164:1285–1300. https://doi.org/10.1111/j.1476-5381.2011.01299.x
Van der Worp H, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, Macleaod MR (2010) Can animal models of disease reliably inform human studies? PLoS Med 7(3):e1000245. https://doi.org/10.1371/journal.pmed.1000245
Van Meer BJ, Tertoolen LGJ, Mummery CL (2016) Concise review: measuring physiological responses of human pluripotent stem cell derived cardiomyocytes to drugs and disease. Stem Cells 34:2008–2015. https://doi.org/10.1002/stem.2403
Varkevisser R, van der Heyden MAG, Tieland RG, Beekman JDM, Vos MA (2013) Vernakalant is devoid of proarrhythmic effects in the complete AV block dog model. Eur J Pharmacol 720:49–54. https://doi.org/10.1016/j.ejphar.2013.10.054
Varkevisser R, Vos MA, Beekman JD, Tieland RG, van der Heyden (2014) AV-block and conduction slowing prevail over TdP arrhythmias in the methoxamine-sensitized pro-arrhythmic rabbit model. J Cardiovasc Electrophysiol. https://doi.org/10.1111/jce.12533
Verduyn SC, Ramakers C, Snoep G, Leunissen JD, Wellens HLL, Vos MA (2001) Time course of structural adaptations in chronic AV block dogs: evidence for differential ventricular remodeling. Am J Physiol Heart Circ Physiol 280:H2882–H2890. https://doi.org/10.1152/ajpheart.2001.280.6.H2882
Vitek MP, Araujo JA, Fossel M, Greenberg BD, Howell GR, Rizzo SJS, Seyfried NT, Tenner AJ, Territo PR, Windisch M, Bain LJ, Ross A, Carrillo MC, Lamb BT, Edelmayer RM (2021) Translational animal models of Alzheimer’s disease: an Alzheimer’s association business consortium think tank. Alzheimers Dement 6:e12114. https://doi.org/10.1002/trc2.12114
Voss MA, de Groot SHM, Verduyn SC, van der Zande J, Leunissen HDM, Cleutjens JPM, van Bilsen M, Daemen MJA, Schreuder JJ, Allessie MA, Wellens HJJ (1998) Enhanced susceptibility for acquired torsade de pointes arrhythmia in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation 98:1125–1135. https://doi.org/10.1161/01.CIR.98.11.1125
Wallis RM (1999) The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. Folia Pharmacol Jpn 114:2–26. https://doi.org/10.1254/fpj.114.supplement_22
Wallis RM, Napier CM (1999) Muscarinic antagonists in development for disorders of smooth muscle function. Life Sci 64:395–401. https://doi.org/10.1016/S0024-3205(98)00585-2
Wallis RM, Leishman D, Pullman L, Graepel P, Heywood R (1998) Effects of sildenafil on retinal histopathology and electroretinogram (ERG) in dogs. Ophthalmic Res 30:S68
Wu SS, Fernando K, Allerton C, Jansen KU, Vincent MS, Dolsten M (2021) Reviving an R&D pipeline: a step change in the phase II success rate. Drug Discov Today 26:308–314. https://doi.org/10.1016/j.drudis.2020.10.019
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Wallis, R.M. (2022). Disease Models in Safety Pharmacology. In: Hock, F.J., Gralinski, M.R., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_88-1
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DOI: https://doi.org/10.1007/978-3-030-73317-9_88-1
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