Coronary and systemic arterial physiology and immunohistochemical markers related to early coronary arterial lesions in beagle dogs given the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611.

We evaluated immunohistochemistry (von Willebrand Factor [vWF] or fibrinogen) and systemic and coronary arterial physiological parameters in beagle dogs to investigate early arterial lesions induced by the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611. Dogs given an oral dose of ZD6169 (experiment 1) were terminated 1 day later and showed arterial and myocardial lesions. Minimal arterial lesions exhibited few condensed medial smooth muscle cells only, with others showing segmental medial necrosis occasionally with medial/adventitial acute inflammation. Intercellular immunostaining was seen in ostensibly normal tissue, where no pathology was present in conventionally stained sections. vWF and fibrinogen are valuable tools for detecting disruption of arterial integrity. In experiment 2, 2 dogs were given a single high dose of ZD6169 or ZD1611 and BP/HR monitored by conventional measures or telemetry. Substantially reduced systolic/diastolic BP and increased HR occurred within 10 min of ZD6169 infusion: ZD1611 caused minor BP decrease and HR increase. In experiment 3, both drugs given to anaesthetized dogs induced markedly exaggerated systolic phasic forward and reverse flow in left descending and right coronary arteries. Diastolic coronary artery flows were unaffected with ZD1611 and increased slightly with ZD6169. In both coronary arteries, the ZD1611-induced increase in flows paralleled decreased resistance.

Effects of group housing on ECG assessment in conscious cynomolgus monkeys.

INTRODUCTION: Assessing the cardiovascular safety of new chemical or biological entities is important during pre-clinical development. Electrocardiogram (ECG) assessments in non-human primate (NHP) toxicology studies are often made using non-invasive telemetry systems. We investigated whether ECG recording was feasible during group housing of NHPs, rather than the usual single housed arrangement, and whether it would impact the data collected or affect the ability to detect drug-induced changes in QTc interval. METHODS: Following a period of acclimatisation to jackets, cynomolgus monkeys (3 males and 3 females) were housed in same sex groups of 3. Female monkeys were administered 4 doses of vehicle while male monkeys were administered vehicle, 15, 45, and 135mg/kg moxifloxacin. Each dose was administered on a separate dosing day. The same dosing protocol was repeated with the animals singly housed and the results from the two phases were compared including assessment of statistical power. RESULTS: Heart rate (HR) was significantly lower, and PR and QT intervals were significantly higher, at multiple time points when the animals were group housed compared with the singly housed phase. QRS duration and QTc interval were less affected. Moxifloxacin increased QT and QTc intervals but had no consistent effect on HR, QRS duration or PR interval under group housed or singly housed conditions. Power analysis suggested that group housing did not adversely affect the magnitude of detectable changes of ECG parameters. In general, detection of slightly smaller changes was achieved under conditions of group housing. DISCUSSION: The current study shows group housing to be technically possible during non-invasive ECG recording, resulting in lower resting heart rates and small improvements in sensitivity of detection of drug-induced effects. Given the psychological benefits of group housing for NHPs, it is a refinement that should be considered when conducting ECG assessments in NHP toxicology studies.

Effects of group housing on ECG assessment in conscious cynomolgus monkeys.

INTRODUCTION: Assessing the cardiovascular safety of new chemical or biological entities is important during pre-clinical development. Electrocardiogram (ECG) assessments in non-human primate (NHP) toxicology studies are often made using non-invasive telemetry systems. We investigated whether ECG recording was feasible during group housing of NHPs, rather than the usual single housed arrangement, and whether it would impact the data collected or affect the ability to detect drug-induced changes in QTc interval. METHODS: Following a period of acclimatisation to jackets, cynomolgus monkeys (3 males and 3 females) were housed in same sex groups of 3. Female monkeys were administered 4 doses of vehicle whilst male monkeys were administered vehicle, 15, 45 and 135mg/kg moxifloxacin. Each dose was administered on a separate dosing day. The same dosing protocol was repeated with the animals singly housed and the results from the two phases were compared including assessment of statistical power. RESULTS: Heart rate (HR) was significantly lower, and PR and QT interval significantly higher, at multiple time points when the animals were group housed compared with the singly housed phase. QRS duration and QTc interval were less affected. Moxifloxacin increased QT and QTc intervals but had no consistent effect on HR, QRS duration or PR interval under group housed or singly housed conditions. Power analysis suggested that group housing did not adversely affect the magnitude of detectable changes of ECG parameters. In general, detection of slightly smaller changes was achieved under conditions of group housing. DISCUSSION: The current study shows group housing to be technically possible during non-invasive ECG recording, resulting in lower resting heart rates and small improvements in sensitivity of detection of drug-induced effects. Given the psychological benefits of group housing for NHPs, it is a refinement that should be considered when conducting ECG assessments in NHP toxicology studies.

Non-invasive telemetric electrocardiogram assessment in conscious beagle dogs.

INTRODUCTION: The primary objective of this investigation was to evaluate the sensitivity of a non-invasive telemetry system for the detection of drug-induced electrocardiogram (ECG) changes in conscious, freely moving dogs. A secondary objective was to compare, in the same set of dogs, ECG data acquired by a non-invasive system with data acquired from a surgically implanted telemetry device (invasive system). METHODS: Continuous beat-to-beat Lead II ECG data were simultaneously acquired from 6 male dogs using a non-invasive and an invasive telemetry system for 1h pre-dose and 6h following a sham control dose or single oral doses of (+/-) sotalol (4, 8 or 16 mg/kg). ECG parameters of heart rate, RR, PQ, QRS, QT and QT corrected for heart rate according to Van de Water (QTcV) and by an individual linear regression formula (QTcR), were determined. RESULTS AND DISCUSSION: Statistically significant dose-dependent reduction of heart rate, and increases in PQ, QT and QTc (V and R) were detected at all dose levels of (+/-) sotalol, with partial recovery during the 6-hour monitoring period. Statistically significant correlations for heart rate, RR, PQ, QT and QTc (V and R) were found between the two systems. QRS duration did not correlate. However, the difference between the two systems was consistent over the range studied. Based on these findings, the non-invasive system is quantitatively comparable to invasive telemetry, and can be used successfully to acquire continuous ECG data on a beat-to-beat basis from conscious freely moving dogs for at least 6h post-dose.

Mouse transferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus.

Enveloped viruses enter cells by binding to their entry receptors and fusing with the membrane at the cell surface or after trafficking through acidic endosomal compartments. Species-specific virus tropism is usually determined by these entry receptors. Because mouse mammary tumor virus (MMTV) is unable to infect Chinese hamster cells, we used phenotypic screening of the T31 mouse/hamster radiation hybrid panel to map the MMTV cell entry receptor gene and subsequently found that it is transferrin receptor 1. MMTV-resistant human cells that expressed mouse transferrin receptor 1 became susceptible to MMTV infection, and treatment of mouse cells with a monoclonal antibody that down-regulated cell surface expression of the receptor blocked infection. MMTV, like vesicular stomatitis virus, depended on acid pH for infection. MMTV may use transferrin receptor 1, a membrane protein that is endocytosed via clathrin-coated pits and traffics through the acidic endosomes, to rapidly get to a compartment where acid pH triggers the conformational changes in envelope protein required for membrane fusion.