Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exercise-induced ischemia is generally attributed to an increase in myocardial demand in the presence of coronary stenosis limiting flow supply. An additional mechanism--the occurrence of coronary steal due to excessive endogenous adenosine release--has also been hypothesized. The effect of adenosine receptor blocking by aminophylline in effort ischemia was tested in 8 patients with stable effort-induced angina pectoris, reproducible positive exercise stress tests and angiographically assessed coronary artery disease. Following double-blind, randomized intravenous infusion of aminophylline (3 mg/kg over 3 minutes) or placebo (20 ml of saline over 3 minutes), the patients underwent upright bicycle exercise stress tests on 2 consecutive days. After aminophylline, there was an increase in work tolerance (aminophylline 7.5 +/- 1.8 minutes of exercise vs placebo 5.4 +/- 1.5 minutes; p less than 0.05). There was a parallel increase in the ischemic threshold, evaluated with the rate-pressure product (mm Hg X beats/min X 100(-2)) at 0.1 mV of ST-segment depression (221 +/- 35 vs 184 +/- 20; p less than 0.01). Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced ischemia, possibly through the prevention of myocardial flow maldistribution elicited by excessive adenosine release during effort.
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PMID:Exercise capacity after acute aminophylline administration in angina pectoris. 290 50

The effect of theophylline on the working capacity of patients with ischaemic heart disease was evaluated in a double-blind, randomized cross-over study. Eight patients, receiving no medication, with stable effort-provoked angina pectoris and typical exercise-induced ST depressions were studied. Following intravenous administration of theophylline or placebo, the patients did a supine leg exercise limited by intolerable chest pain. The workload was continuously increased by 10 W/min. Following theophylline treatment the workload at the onset of chest pain increased from 71 +/- 9 to 114 +/- 14 W (P less than 0.002). The ST depression was less pronounced following theophylline at submaximal exercise (-0.01 +/- 0.00 vs. -0.09 +/- 0.02 mV, P less than 0.005, at 70 W). The maximum tolerable workload increased from 129 +/- 15 after placebo infusion to 153 +/- 12 W after theophylline infusion P less than 0.01). It is speculated that this beneficial effect of the adenosine receptor antagonist theophylline may possibly be due to inhibition of a pathophysiological coronary steal induced by elevated levels of adenosine during ischaemia.
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PMID:Improved working capacity following theophylline infusion in patients with ischaemic heart disease. 319 60

Clinical characteristics: Angina pectoris represents a visceral pain caused by reversible myocardial ischemia. The majority of ischemic attacks are symptomless. When pain is manifested, it appears late during the ischemic event. The pain is complex in its quality and bears little relation to the region of myocardial ischemia. Pain shows a sensitive dependence on initial conditions suggesting a mechanism with deterministic chaotic dynamics for the association between myocardial ischemia and pain. Neurophysiological substrate: Ganglia are present within the heart, particularly in epicardial fat. The blood supply of intrinsic cardiac ganglia arises primarily from branches of the proximal coronary arteries. Both afferent and efferent neurons within the intrinsic cardiac nervous system exist, while the majority of neurons in that location may be local circuit neurons. Integration takes place not only in the intrinsic cardiac nervous system, but also in mediastinal, middle cervical, and stellate ganglia. Cardiac afferent receptors are also connected to cell bodies in dorsal root and nodose ganglia, as well as intrathoracic ganglia. Myocardial regions have no spatial representation in these ganglia. Adenosine, among a number of substances, can modulate the activity generated by cardiac afferent nerve endings and intrinsic cardiac neurons. Such effects appear to be exerted at A1 receptors. Adenosine as a pain messenger: During myocardial ischemia adenosine is released in large quantities into the interstitial space. The endothelium takes up the major amount of adenosine. Thus only small increments of adenosine are detected in the blood-stream. Given as an intravenous bolus to healthy volunteers or to patients with ischemic heart disease and angina pectoris, adenosine provokes angina pectorislike pain, which is similar to habitual angina pectoris with regard to quality and location. Pain is provoked in the absence of ECG signs of ischemia. Patients with asymptomatic myocardial ischemia are less sensitive to adenosine, whereas patients with Syndrome X are more sensitive with respect to adenosine-provoked pain. When adenosine is given intraarterially, including into the coronary arteries, pain is provoked in the corresponding vascular bed. Adenosine-provoked pain and ischemic pain are counteracted by previous administration of the adenosine receptor antagonist theophylline.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of pain in angina pectoris--a critical review of the adenosine hypothesis. 811 Jun 16

To investigate the effects of the acute administration of aminophylline and nitroglycerin on effort ischemia, 20 patients with syndrome X underwent 3 bicycle exercise tests after sublingual nitroglycerin (0.3 mg) and after 90 minutes of oral administration of aminophylline (400 mg). Compared with the basal test, only aminophylline induced a significant increase in the time to ischemic threshold and to angina; these findings support the potential therapeutic role of this adenosine receptor blocking agents and suggest a possible role of "steal phenomenon" in the pathogenesis of effort angina in patients with syndrome X.
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PMID:Different effects of acute administration of aminophylline and nitroglycerin on exercise capacity in patients with syndrome X. 871 25

The phenomenon of ischaemic preconditioning, highlights a new and endogenous route to myocardial protection, which we believe could be exploited in our search for new therapeutic ways to protect the infarcting myocardium. Ischaemic preconditioning has been shown to be associated with both an early, or acute phase of protection lasting approximately 1-2 hours, as well as a delayed phase or "second window of protection" seen at least 24 hours following the initial sublethal ischaemic insult, and lasting up to 72 hours. We believe that both responses are triggered by similar receptor mediated events in addition to using the similar signalling pathways involving kinase cascades. However it is thought that the ultimate target or end-effector through which the protection is manifest may be different for the early vs. late effects. Some evidence exists that the end-effector involved in early preconditioning may be via the ATP-sensitive potassium channel (K(ATP)). With respect to the second window of protection, the cellular mechanisms underlying this are not fully understood at present, however we believe that they may be dependent upon a similar signalling transduction pathway with upregulation of cytoprotective proteins such as the heat stress proteins, and/or anti-oxidant proteins. Evidence demonstrating that preconditioning can occur in the human myocardium is also accumulating. In this respect cultured human ventricular myocytes as well as human atrial muscle have been shown to be preconditioned with brief episodes of simulated ischemia. These human preparations also respond to the known triggers and possible end-effectors of preconditioning, (e.g. adenosine receptor stimulation and K(ATP) channel opening) as well as being able to elicit their responses through the PKC signalling pathway. Further support for this phenomenon, in man, comes from PTCA studies demonstrating that this invasive procedure can put patients into a "preconditioned state"; this effect being associated with reduced ischaemic symptoms as well as the involvement of the adenosine receptor and K(ATP) channel. Of further interest is the observation that patients with a previous history of angina, prior to a MI, sustain smaller infarcts and have an improved survival. However the most direct evidence that preconditioning occurs in man comes from studies in patients undergoing coronary artery bypass surgery. The above evidence that preconditioning can occur in man makes it now possible to begin to design clinical studies investigating cardioprotective properties of drugs that can specifically mimic this phenomenon.
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PMID:Myocardial adaptation to ischaemia--the preconditioning phenomenon. 1032 17

A variety of experimental studies have confirmed that preconditioning the myocardium by brief periods of ischemia represents a powerful cardioprotective effect resulting in a reduction of infarct size. After 15 years of research in the experimental laboratory, some evidence shows the existence of preconditioning in human patients with coronary artery disease: repeated balloon inflations before coronary angioplasty induce preconditioning-like effects; moreover, some studies demonstrate better clinical outcome in patients with angina before acute myocardial infarction, resembling a preconditioning effect. So far, a few drugs have been identified as potential mediators of preconditioning, e.g., adenosine, adenosine receptor agonists, and adenosine triphosphate-sensitive potassium channel openers. Before coronary angioplasty and heart surgery, these preconditioning mimetics might be used to protect myocardial tissue by means of preconditioning. Further research is required before preconditioning mimetics could be used for therapy in patients with chronic myocardial ischemia. Possible antipreconditioning effects of several drugs, e.g., sulfonylurea drugs have to be considered in the treatment of patients with coronary artery disease.
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PMID:Clinical effects of ischemic preconditioning. 1044 15

This study examined whether the adenosine receptor antagonist theophylline prevents the warm-up phenomenon in patients with stable angina undergoing serial exercise tests. Our findings offer evidence that adenosine does not play a role in the warm-up phenomenon, and indirectly suggest that the warm-up phenomenon does not represent ischemic preconditioning in humans.
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PMID:Effect of theophylline on the warm-up phenomenon. 1056 67

Aminophylline was known to decrease effort angina and ischaemia in patients with coronary artery disease and stable angina. This effect has been explained by the antagonization of the vasodilatation caused by adenosine and the prevention of the transmural myocardial maldistribution (steal phenomenon). In this study, treadmill exercise tests (with Bruce protocol) were performed in 14 patients (11 women, 3 men, mean age 51 +/- 9.9 years) diagnosed with syndrome X (typical anginal chest pain, abnormal stress test, normal coronary angiography) before (basal condition) and after the acute i.v. aminophylline infusion (total dosage 6 mg/kg within 15 minutes). It was shown that aminophylline lengthened the time before the occurrence of ischaemia in patients with syndrome X by increasing the ischaemia threshold in spite of the occurrence of tachycardia but it had no effect on the total exercise duration. Aminophylline infusion also exerted a beneficial effect on exercise-induced chest pain. It has been suggested that the role of the adenosine receptor could be important in the pathogenesis of syndrome X.
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PMID:The effect of aminophylline infusion on the exercise capacity in patients with syndrome X. 1067 89

Intense efforts of many pharmaceutical companies and academicians in the A(1) adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric enhancers. The A(1)AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human (h) A(1)AR subtype (hA(1) K (i) < 10 nM), > 200-fold selectivity over the hA(2A) subtype, and demonstrate renal protective effects in multiple animal models of disease and pharmacologic effects in human subjects. In the A(1)AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68-4986). The challenges associated with the development of any A(1)AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A(1)AR desensitization leading to tachyphylaxis. For the IV antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful IV dosing paradigms. The treatment of type II diabetes using A(1)AR agonists in the clinic has met with limited success due to cardiovascular side effects and a well-defined desensitization of full agonists in human trials (GR79236, ARA, and RPR 749). However, new partial A(1)AR agonists are in development, including CVT-3619 hA(1) AR K(i) = 55nM, hA(2A:hA2B:hA(3))1,000:20, CV Therapeutics), which have the potential to provide enhanced insulin sensitivity without cardiovascular side effects and tachyphylaxis. The nonnucleosidic A(1)AR agonist BAY 68-4986 (capadenoson) represents a novel approach to angina wherein both animal studies and early human studies are promising. T-62 is an A(1)AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. The challenges associated with developing A(1)AR antagonists, agonists, or allosteric enhancers for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying A(1)AR antagonists for the treatment of edema associated with congestive heart failure (CHF), A(1)AR agonists for the treatment of atrial arrhythmias, type II diabetes and angina, and A(1)AR allosteric enhancers for the treatment of neuropathic pain.
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PMID:A1 adenosine receptor antagonists, agonists, and allosteric enhancers. 1963 78

Adenosine is a neuromodulator that interacting with four receptors, A(1), A(2A), A(2B) and A(3), is involved in the regulation of several biological functions in different organs and tissues, including the central nervous system, the cardiovascular system and the airways; many pathophysiological states are associated with changes of adenosine levels. For these reasons pharmaceutical companies and academicians performed intense efforts to obtain agonists, antagonists and allosteric enhancers selective for each adenosine receptor subtypes as potential clinical candidates. In fact, therapeutic modulation of the adenosine system could offer the possibility of a "soft" treatment of different diseases, but, due to the ubiquitous distribution of adenosine and of its receptors, the challenge in therapy development depends from specificity for the different receptor subtypes. Some A(1) agonists and antagonists, very potent and selective, reached clinical trials for the treatment of different diseases. A(1) agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in pain management, while A(1) antagonists are in study as potassium-sparing diuretics with kidney-protecting properties and in chronic heart diseases. Several reviews, recently published and herein cited reported in detail the biological and clinical aspects of such molecules. This review focuses on the A(1) adenosine receptor (A(1)AR) ligands, both agonists and antagonists, appeared in the literature in the last few years, together with their potential therapeutic application, pointing the attention on their chemical structures and SAR (Structure Activity Relationship) and also reporting new findings on preclinical or clinical trials of some important A(1)AR ligands synthesized in the past.
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PMID:A1 receptors ligands: past, present and future trends. 2037 Jun 61


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