Functional assessment of myocardium, in particular the evaluation of the myocardium's oxygen status, is important in guiding therapeutic decisions in the care of patients with cardiac ischemia. In current clinical practice, myocardial ischemia status is most often assessed using non-invasive nuclear perfusion imaging methodologies, such as planar scintigraphy or single photon emission computed tomography (SPECT), with thallium and technetium as the most frequently used isotopes. More recently, positron emission tomography (PET) with rubidium-82 has been gaining recognition as providing improved images with less radiation. Semi-invasive transesophageal doppler echography is also useful to study the motion of ventricular walls, and non-invasive transthoracic doppler echocardiography is an easy and non-invasive methodology for measurement of coronary flow reserve.
These functional tests typically require that the patient's heart be “stressed”, either through controlled exercise or by pharmacologic means, and are thus generically and colloquially known as “stress tests”. Pharmacological stressors for functional assessment of myocardium act through coronary vasodilation: by dilating normal vessels to a greater extent than diseased vessels, these agents establish a shunt, or “myocardial steal”, that produces differential increases in blood flow in healthy vs. diseased arteries in patients with coronary artery disease, optimizing the discriminatory imaging of cardiac muscle areas in need of oxygen supply.
Adenosine and dipyridamole are coronary vasodilators, each of which is approved for individual use as a pharmacologic stressor for stress testing. Adenosine acts directly by stimulating adenosine purinergic P1 receptors on the arterial wall. Dipyridamole is believed to work indirectly by blocking reuptake of adenosine at the cellular level, leading to an increase in endogenous adenosine concentration in the blood. Dipyridamole produces similar near-maximal coronary hyperemia to that produced by exogenous adenosine, but less quickly.
To ensure near-maximal coronary vasodilation, and to provide sufficient time for the acquisition of cardiac images, adenosine is infused for 6 minutes at a dosage rate of 140 μg/kg patient body weight/min; dipyridamole is infused for 4 minutes at 140 μg/kg patient body weight/min. Thus, the total recommended dose of adenosine is 0.84 mg/kg, and the total recommended dose for dipyridamole is 0.56 mg/kg at the minimum and 0.80 mg/kg on average in a 4 minute infusion. If vasodilation is insufficient, the total dose of dipyridamole can be increased up to 0.95 mg/kg, administered over a 6 minute infusion.
Although infused for only a few minutes, compounds that stimulate adenosine receptors are accompanied by numerous uncomfortable adverse effects. With adenosine, the most frequently reported are flushing (44%), chest pain or chest discomfort (40%), dyspnea (28%), headache (18%), throat or neck or jaw discomfort (15%), and gastrointestinal discomfort (13%); other side effects are less frequent.
The adverse effects of adenosine are dose-dependent. Symptoms such as heat sensation, flushed face, dyspnea and chest pain increase as adenosine dosage is increased from 60 to 140 μg/kg/min, in a six minute infusion. Chest pain typically appears at doses of 90 μg/kg/min, and becomes frequent at 120 μg/kg/min. At a dosage of 70 μg/kg/min or less, it has been noted that adenosine adverse reactions are very few and of mild intensity. However, when administered by intravenous perfusion at 70 μg/kg/min or less, or even at 90-120 μg/kg/min, adenosine shows reduced efficacy, and is not recommended for stress testing at such reduced dosages.
The side effect profile of dipyridamole is similar, but with adverse events occurring less often. However, dipyridamole side effects last longer, are more difficult to manage, and thus more frequently require the administration of intravenous aminophylline as an antidote.
Because dipyridamole is understood to act by increasing endogenous adenosine, use of both adenosine and dipyridamole at full intravenous dosage is contraindicated. Analogously, oral intake of dipyridamole prior to an adenosine pharmacologic stress testing is generally avoided.
In an effort to reduce side effects at maximally effective agonist doses, adenosinergic agents are being developed that are selective for the A2a receptor subtype. See, e.g., U.S. Pat. Nos. 6,531,457; 6,448,235; 6,322,771; and 5,877,180. Specific compounds in development include regadenoson, binodenoson and apadenoson (BMS068645). However, despite their receptor selectivity, only modest reductions in side effects have been observed with these compounds. In addition, the compounds have a longer duration of action than adenosine; accordingly, the side effects, e.g., flushing, headache, and dyspnea, are longer lasting. Thus, although more specific than adenosine, these agents may be more likely to trigger prolonged side effects, and to require administration of pharmacologic antidotes, than is adenosine itself, whose side effects rapidly dissipate once administration is stopped. Moreover, none of these selective agents has yet been approved for clinical use.
There thus exists a continuing need in the art for injectable agents that can be used for pharmacologic stress testing that have the rapid onset and short half-life of adenosine, and thus can be managed clinically in the same manner as adenosine, and that provide maximal efficacy with reduced side effects.
USPTO Backgrounds
USPTO Backgrounds