Discovery and Development of Veterinary Pharmaceuticals in Telemetered Animals

DISCOVERY AND DEVELOPMENT OF VETERINARY PHARMACEUTICALS IN TELEMETERED ANIMALS R. J. G. Zwijnenberg 2010 ISBN: 978‐90‐39354742 DISCOVERY AND DEVELOPMENT OF VETERINARY PHARMACEUTICALS IN TELEMETERED ANIMALS Ontdekking en ontwikkeling van veterinaire farmaceutische produkten in van telemeters voorziene dieren (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 14 december 2010 des middags te 2.30 uur door: Raphaёl Johannes Gerhardus Zwijnenberg geboren op 22 december 1961 te Winterswijk Promotor: Prof. dr. J. Kirpensteijn Colophon My parents own a house in Palma de Gandia, Valencia, Spain. It is a typically Spanish house with many terraces and retaining walls. All these retaining walls have been built by hand by my parents. As they were building the retaining walls in their garden, my parents lovingly named each one of these walls by a different name. E.g. the longest wall was called “la Langedocienne” after a piece of the French autoroute that is long and doesn’t seem to end. The one wall I tried to help construct my parents named the “klaagmuur” in Dutch. The translation in English means “the wall of complaints” as the Wailing Wall is called in Dutch. I must have complained a lot during construction, or at least my parents thought so. Also doing a PhD by publication, as is the custom in the Netherlands, is a long process of writing and re‐ writing articles, sign‐off procedures, satisfying both scientific and company standards and procedures. When submitting my fifth article for sign off, some people within the company were clearly showing signs of fatigue for being confronted again by a “nagging” and demanding author. Over the centuries the Wailing Wall has been a source of conflict but also a source of inspiration, a symbol of hope and freedom. Reaching my PhD I will regard as a personal freedom from a desire I had since I graduated as a veterinarian in 1987. I herewith would like to express my thanks to Guy Rosner (Tel Aviv, Israel) who as a personal friend and a great artist agreed to make this painting for the cover of my thesis. Raphael Zwijnenberg. Sydney, 1 November 2010. Contents Chapter 1 Introduction 1 Chapter 2 Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs when given as a pre‐anesthetic IV, IM or SQ and in combination with butorphanol 9 Chapter 3 Effects of perzinfotel and PLA‐ 695 on kinetic gait and subjective lameness scores in a sodium urate‐induced synovitis model in dogs 25 Chapter 4 Effects of perzinfotel, butorphanol and a butorphanol‐ perzinfotel combination on the minimum alveolar concentration of isoflurane in cats 39 Chapter 5 Evaluation of oscillometric and vascular‐access‐port derived arterial blood pressure measurement techniques in anesthetized cats: comparative performance versus implanted telemetry 55 Chapter 6 Evaluation of the potential for interaction between a metaflumizone‐amitraz combination and dexmedetomidine hydrochloride in dogs 69 Chapter 7 Discussion 79 Chapter 8 Conclusion 89 Samenvatting 91 Acknowledgements 93 Curriculum Vitae 95 List of publications 97 CHAPTER 1 Introduction CHAPTER 1 Pharmaceutical Drug Discovery Pharmaceutical drug discovery is the process by which drugs are discovered and/or designed and commonly takes place in scientific institutions and pharmaceutical companies. In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge1. This field of science is typified by great discoveries of novel actives through active research programs into specific classes of chemistry, endless screening of libraries of potential actives as well as (still) pure serendipity. Pharmaceutical drug discovery can also be disappointing, e.g. when promising actives fail safety and/or efficacy criteria. Despite significant advances in understanding of disease on a molecular and physiological level, drug discovery is still a lengthy, expensive and inefficient process with a relatively low rate of success2. It is estimated that the discovery and development of a human pharmaceutical takes on average 13 years at an average cost of US$1.8 billion dollars for each new molecular entity3. Discovery studies such as proof of concept, efficacy, safety, dose titration etc., are typically done in a limited number of animals (n=6‐8) per treatment group. The statistical power and the level of significance (P < 0.05) of effects observed are used as considerations to move projects into development. Ethical considerations are an important factor to limit the number of animals used in discovery studies. Typically, after establishing a satisfactory efficacy and safety profile (including toxicology), a marketing need, formulation, reasonable manufacturing costs etc., drugs can move into the process of drug development. 1.2 Pharmaceutical Drug Development Pharmaceutical drug development is often an interaction between a pharmaceutical company and a regulatory body to identify the necessary trials to compose a dossier that would be acceptable for approval. In the veterinary field, these would typically include field trials in client owned animals as well as residue and environmental studies (especially in case of production animals). Due to more rigorous regulation the number of truly new medicines approved by the United States Food and Drug Administration (FDA) between 2003 and 2008 has decreased by 50% compared to the previous 5 years4. 2 INTRODUCTION 1.3 Perzinfotel, the drug In the Wyeth Central Nervous System (CNS) facility in Princeton, New Jersey (NJ), a novel potent N‐methyl‐D‐aspartate (NMDA) antagonist (EAA‐090, later named perzinfotel) was designed and synthesized for pharmaceutical research5. It was thought that perzinfotel, being a unique NMDA antagonist with a favourable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Later research confirmed that both perzinfotel and another NMDA antagonist (EAB‐318) protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate‐ and NMDA‐induced neurotoxicity. Both antagonists preferentially blocked NMDA‐elicited currents mediated by N‐methyl‐d‐aspartate receptor (NR)1 splice variants containing the N‐terminal insertion. They also favoured NR2A‐versus NR2B‐ or NR2C‐ containing NMDA receptors, with perzinfotel showing the greatest selectivity. Perzinfotel was 10 times more potent at blocking NR2A‐versus NR2B‐ or NR2C‐containing NMDA receptors6. NMDA receptors (NMDAR’s) are glutamate receptors that control synaptic plasticity and memory function and are located in the hippocampus and the cortex. The NMDAR is a heterotetramer consisting of two obligatory NR1 subunits and two of four possible NR2 subunits: NR2A, NR2B, NR2C, and NR2D. The NR2 subunits in the adult hippocampus and cortex are usually NR2A and NR2B subunits7. NR2A and NR2B have different roles in mediating cell death and cell survival. This was observed in an in vivo rat model of focal ischemic stroke. It was found that blocking NR2B‐mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and within 4.5 hours (h) after stroke. In great contrast, activation of NR2A‐mediated cell survival with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischaemic brain damage even when delivered 4.5 h after stroke onset. Hence perzinfotel, with a greater selectivity for the NR2A subunit, was considered as a potential drug candidate against stroke. Some NMDA antagonists like methadone and ketamine have analgesic effects. A study in rats showed that perzinfotel lacked antinociceptive effects but dose‐ and time‐dependently (10‐100 mg/kg) blocked prostaglandin E(2) (PGE(2))‐ and capsaicin‐induced thermal hypersensitivity in a warm‐water tail‐withdrawal assay in rats8. Perzinfotel was also considered for neuropathic pain in humans. Compared to current drugs on the market perzinfotel did not outperform. Because other Wyeth drugs were also considered for stroke, perzinfotel was offered for consideration to the Animal Health Division of Wyeth, Fort Dodge Animal Health, in 2006. 1.4 The veterinary discovery process of perzinfotel in canines After Fort Dodge Animal Health was given the opportunity to assess perzinfotel for veterinary use, an initial study was done in beagles to look at the clinical effects of perzinfotel with dosages ranging between 10‐60 mg/kg9. Perzinfotel, given at a dose of ≥30 mg/kg produced 3 CHAPTER 1 increasing muscular rigidity. This rigidity was transient and all dogs recovered uneventfully. All doses of perzinfotel resulted in pupil dilatation. Also the pupil dilation was a temporary side‐ effect from which all dogs recovered within 2‐8 hours. These observed side effects, however mild in nature, are the reason that in subsequent studies only doses up to 30 mg/kg were used. Perzinfotel alone did not produce anaesthesia at the studied doses. Although veterinary anaesthesia has become safer over the years through safer anaesthetics,

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