Animal Pharmacology

Comparative data involving the extractino of Tc-99m-tetrofosmin and Tl-201 in isolated rabbit hearts indicate that the myocardial uptake (extraction x coronary blood flow) of both imaging agents is similar and linearly proportional to coronary blood flow (Figure 2).11,12

As with all perfusion scintigraphic agents currently available, the proportionali- ty between Tc-99m-tetrofosmin uptake and blood flow rate does not hold at very low or high flow rates when true blood flow is either over-or under-estimated, respectively.⁶ However, in vitro studies revealed that Tc-99m-tetrofosmin uptake increased by 3-fold over a 2.7-fold flow range compared with a 2.5-fold range for TI- 201 (at maximum levels of extraction). Maximum extraction at a mean flow rate of 1.65ml/min/g was 0.36 for the former in rabbit heart, known to be a poor model for Tc-99m-tetrofosmin uptake. Despite low extraction relative to TI-201, these data suggest that the distribution of Tc-99m-tetrofosmin more closely reflects changes in human blood flow than TI-201.⁷

The correlation of Tc-99m-tetrofosmin uptake and coronary blood flow was also confirmed in another study that examined myocardial retention under condi- tions of ischemia and dobutamine stress in white pigs.¹³ All twelve animals received anesthesia and experimental occlusion of the left anterior descending coronary artery followed by Tc-99m-tetrofosmin injection. Seven of the pigs received dobutamine 5 minutes prior to occlusion. Myocardial blood flow was estimated using radiolabelled microspheres. A linear correlation between reten- tion and blood flow was observed in 11 of 12 animals.¹³ This proportionality was sustained in four of the dobutamine-treated pigs, even at a relatively high flow rates (ie, 1.6 to 1.8ml/min/g).⁷ These data suggest that Tc-99m-tetrofosmin injection, like TI-201, has characteristics necessary for the clinical measurement of myocardial blood flow and the clinical evaluation of CAD.

The effects of large doses of tetrofosmin on cardiac function were measured in other preclinical studies involving rats.⁷ At a dose of 7.5mg/kg (1050-fold higher than the maximum human dose (MHD); MHD for a 70-kg individual is the tetrofosmin content of approximately 1 vial of reconstituted MYOVIEW),^7,11 tetrofosmin caused early and transient increases in cardiac contractility and mean arterial pressure, while later changes included bradycardia, reduced cardiac output, and reflex vasoconstriction. These effects were minor and transient, whereas the same changes brought about by a 30mg/kg tetrofosmin dose (4200- fold MHD) were more marked and persistent. These and other data indicate that 30mg/kg tetrofosmin exerts indirect negative chronotropic, direct positive inotropic, and slight transient pressor effects, as well as motor activity depression.⁷

Neither dose caused arrhythmias during in vivo rat or guinea pig studies.⁷ Studies involving isolated rat and guinea pig hearts, however, revealed that 0.3 to 0.75mg/ ml tetrofosmin (>1560 MHD and higher doses than used in intact animals) gave rise to arrhythmias and dysrhythmias in guinea pig hearts only, an effect that lasted up to 20 to 30 minutes post-infusion. Other data generated from isolated guinea pig hearts concomitantly perfused with tetrofosmin and other cardiovascular agents suggest that tetrofosmin acts upon the myocardial cell membrane at a site close to the calcium entry site, perhaps via a calcium- mediated inhibition of rectifying potassium channels. Prolongation of the action potential in cardiac tissue is consistent with the observed pharmacological effects described above. Data obtained from isolated animal heart studies do not support a mechanism involving is-adrenergic or calcium channel receptors. Since the tetrofosmin doses necessary to produce any effects observed in these animal studies were in vast excess of those that would be used clinically, it is unlikely that MYOVIEW would exhibit any interactions with other therapeutic cardiovascular agents.⁷

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