title: A non-human primate model for investigating drug-induced risk of orthostatic hypotension and sympathetic dysfunction: Preclinical correlate to a clinical test.
abstract: BACKGROUND
  Drug induced orthostatic hypotension (OH) is an important clinical concern and can be an unexpected hurdle during drug development. OH is defined as an abnormal decrease in blood pressure (BP) triggered by a rapid postural change. The sympathetic nervous system is critical for controlling normal cardiovascular function and compensatory responses to changes in posture. Thus, OH can also serve as a surrogate indicator of sympathetic dysfunction. However, preclinical conscious models for investigating risk of OH and/or sympathetic dysfunction are lacking. Herein, we describe a conscious nonhuman primate (NHP) model which mimics the widely used clinical tilt table test for OH.
  
  
  METHODS
  Male, Cynomolgus NHPs (n = 7-8) implanted with radio-telemetry transmitters were placed in modified tilt chairs in a supine position. Subsequently, a 90° head up tilt was performed for 3 min followed by return to the supine position. BP and heart rate were continuously monitored. Test compounds were administered either intravenously or via oral gavage in a crossover design, with blood samples collected at the end of the each tilt to assess total drug concentrations.
  
  
  RESULTS
  Tilt responses were assessed following treatment with positive control compounds that cause sympathetic dysfunction; hexamethonium (ganglionic blocker) and prazosin (alpha-1 adrenergic receptor antagonist). Both compounds induced marked OH as evidenced by robust and sustained BP reduction in response to a head up tilt (decrease of 25-35 mmHg for hexamethonium, decrease of 21-44 mmHg for prazosin). OH incidence rates increased in a dose-dependent manner. OH incidences following treatment with minoxidil (vasodilator) were markedly lower to those observed with hexamethonium and prazosin indicating the role of sympathetic dysfunction in causing OH.
  
  
  CONCLUSIONS
  These data demonstrate that the NHP tilt test is a valuable model for investigating OH risk. This model fills an important preclinical gap for assessing such a safety concern and can be applied to programs where a sympathetic deficit and/or OH are anticipated or clinically observed.
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA. Electronic address: Siddhartha.Bhatt@pfizer.com.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Foote
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Butler
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Steidl-Nichols
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001795:Blood Pressure Determination / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018738:Hexamethonium / Q000633:toxicity; D007024:Hypotension, Orthostatic / Q000139:chemically induced* / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D011224:Prazosin / Q000633:toxicity; D012307:Risk Factors; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology*; D018667:Tilt-Table Test / Q000379:methods
chemical_list: D000959:Antihypertensive Agents; D018738:Hexamethonium; D011224:Prazosin
keywords: Cardiovascular; Hexamethonium; Minoxidil; Postural hypotension; Prazosin; Tilt test