Dr. Ron’s Research Review – November 30, 2011

This week’s research review: Adenosine (ATP)

Intravenous ATP infusions are beneficial for pain in cancer patients and can be safely administered in the home setting. (Beijer, Gielisse et al. 2007) (Beijer, van Rossum et al. 2007)  

Intravenous infusion of adenosine 5"-triphosphate (ATP) alleviated a disabling postherpetic neuralgia. (Hayashida, Fukuda et al. 2005)

Adenosine may have therapeutic potential as a prophylactic and acute neuroprotectant in stroke. (Williams-Karnesky and Stenzel-Poore 2009)

Vasodilatory responsiveness to adenosine triphosphate in ageing humans. (Kirby, Crecelius et al. 2010)

Extracellular adenosine 5'-triphosphate alters motility and improves the fertilizing capability of mouse sperm. (Rodriguez-Miranda, Buffone et al. 2008)

Dr. Ron


Articles

Vasodilatory responsiveness to adenosine triphosphate in ageing humans

            (Kirby, Crecelius et al. 2010) Download

Endothelium-dependent vasodilatation is reduced with advancing age in humans, as evidenced by blunted vasodilator responsiveness to acetylcholine (ACh). Circulating adenosine triphosphate (ATP) has been implicated in the control of skeletal muscle vascular tone during mismatches in oxygen delivery and demand (e.g. exercise) via binding to purinergic receptors (P2Y) on the endothelium evoking subsequent vasodilatation, and ageing is typically associated with reductions in muscle blood flow under such conditions. Therefore, we tested the hypothesis that ATP-mediated vasodilatation is impaired with age in healthy humans. We measured forearm blood flow (venous occlusion plethysmography) and calculated vascular conductance (FVC) responses to local intra-arterial infusions of ACh, ATP, and sodium nitroprusside (SNP) before and during ascorbic acid (AA) infusion in 13 young and 13 older adults. The peak increase in FVC to ACh was significantly impaired in older compared with young adults (262 +/- 71% vs. 618 +/- 97%; P < 0.05), and this difference was abolished during AA infusion (510 +/- 82% vs. 556 +/- 71%; not significant, NS). In contrast, peak FVC responses were not different between older and young adults to either ATP (675 +/- 105% vs. 734 +/- 126%) or SNP (1116 +/- 111% vs. 1138 +/- 148%) and AA infusion did not alter these responses in either age group (both NS). In another group of six young and six older adults, we determined whether vasodilator responses to adenosine and ATP were influenced by P1-receptor blockade via aminophylline. The peak FVC responses to adenosine were not different in young (350 +/- 65%) versus older adults (360 +/- 80%), and aminophylline blunted these responses by approximately 50% in both groups. The peak FVC responses to ATP were again not different in young and older adults, and aminophylline did not impact the vasodilatation in either group. Thus, in contrast to the observed impairments in ACh responses, the vasodilatory response to exogenous ATP is not reduced with age in healthy humans. Further, our data also indicate that adenosine mediated vasodilatation is not reduced with age, and that ATP-mediated vasodilatation is independent of P1-receptor stimulation in both young and older adults.


Intravenous infusion of adenosine 5"-triphosphate alleviated a disabling postherpetic neuralgia

            (Hayashida, Sato et al. 2004) Download

Analgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine

            (Hayashida, Fukuda et al. 2005) Download

PURPOSE: No study has been performed on the analgesic effect of adenosine 5'-triphosphate (ATP) on postherpetic neuralgia (PHN). We conducted an open-label trial of ATP in patients with PHN, and compared ATP with ketamine and lidocaine. METHODS: Twelve patients with PHN were studied. On separate days, ketamine (0.3 mg.kg(-1)), lidocaine (2 mg.kg(-1)), and ATP (100 microg.kg(-1).min(-1) or less for 120 min) were administrated intravenously. The intensity of spontaneous pain as well as tactile allodynia was assessed using a visual analog scale (VAS). When the VAS score for spontaneous pain was decreased by more than 50%, the patient was classified as a responder. RESULTS: Five, 6, and 6 patients responded to ketamine, lidocaine, and ATP, respectively. In 6 ATP responders, pain relief developed slowly and lasted for 9 (median) h (range: 3-72 h). All 5 ketamine responders and only 1 of 7 ketamine nonresponders responded to ATP (5/5 vs 1/7, P < 0.05, chi2 test) whereas 2 of 6 responders to lidocaine and 4 of 6 nonresponders to lidocaine responded to ATP (2/6 vs 4/6, P > 0.05). The ketamine responders responded to ATP more often than did the lidocaine responders (5/5 vs 2/6, P < 0.05). CONCLUSION: Intravenous ATP exerted slowly developing and long-lasting analgesic effects in half of patients with PHN. Patients with ketamine-responsive PHN were likely to respond to ATP.

Extracellular adenosine 5'-triphosphate alters motility and improves the fertilizing capability of mouse sperm

            (Rodriguez-Miranda, Buffone et al. 2008) Download

Extracellular adenosine 5'-triphosphate (ATPe) treatment of human sperm has been implicated in improving in vitro fertilization (IVF) results. We used the mouse model to investigate mechanisms of action of ATPe on sperm. ATPe treatment significantly enhanced IVF success as indicated by both rate of pronuclear formation and percentage cleavage to the 2-cell stage. However, ATPe did not increase the percentage of sperm undergoing spontaneous acrosomal exocytosis nor change the pattern of protein tyrosine phosphorylation normally observed in capacitated sperm. ATPe altered sperm motility parameters; in particular, both noncapacitated and capacitated sperm swam faster and straighter. The percentage of hyperactivated sperm did not increase in capacitated ATPe-treated sperm compared to control sperm. ATPe induced a rapid increase in the level of intracellular calcium that was inhibited by two distinct P2 purinergic receptor inhibitors, confirming that these receptors have an ionotropic role in sperm function. The observed motility changes likely explain, in part, the improved fertilizing capability when ATPe-treated sperm were used in IVF procedures and suggest a mechanism by which ATPe treatment may be beneficial for artificial reproductive techniques.

Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients

            (Beijer, Gielisse et al. 2007) Download

The aim of the study was to investigate the safety of adenosine 5'-triphosphate (ATP) administration at home in pre-terminal cancer patients. Included were patients with cancer for whom medical treatment options were restricted to supportive care, who had a life expectancy of less than 6 months, a World Health Organization performance status 1 or 2, and suffered from at least one of the following complaints: fatigue, anorexia or weight loss >5% over the previous 6 months. Side effects were registered systematically on a standard form according to the National Cancer Institute (NCI) Common Toxicity Criteria. Fifty-one patients received a total of 266 intravenous ATP infusions. Of these, 11 infusions (4%) were given at the lowest dose of 20 microg kg(-1) min(-1), 85 infusions (32%) at 25-40 microg kg(-1) min(-1), and 170 (64%) at the highest dose of 45-50 microg kg(-1) min(-1) ATP. The majority of ATP infusions (63%) were without side effects. Dyspnea was the most common side effect (14% of infusions), followed by chest discomfort (12%) and the urge to take a deep breath (11%). No symptoms of cardiac ischemia occurred in any of the infusions. All side effects were transient and resolved within minutes after lowering the ATP infusion rate. Side effects were most frequent in the presence of cardiac disorders. We conclude that ATP at a maximum dose of 50 microg kg(-1) min(-1) can be safely administered in the home setting in patients with pre-terminal cancer.

Application of adenosine 5'-triphosphate (ATP) infusions in palliative home care: design of a randomized clinical trial

            (Beijer, van Rossum et al. 2007) Download

BACKGROUND: Palliative care in cancer aims at alleviating the suffering of patients. A previous study in patients with advanced non-small-cell lung cancer showed that adenosine 5'-triphosphate (ATP) infusions had a favourable effect on fatigue, appetite, body weight, muscle strength, functional status and quality of life. The present study was designed 1. To evaluate whether ATP has favourable effects in terminally ill cancer patients, 2. To evaluate whether ATP infusions may reduce family caregiver burden and reduce the use of professional health care services, and 3. To test the feasibility of application of ATP infusions in a home care setting. METHODS/DESIGN: The study can be characterized as an open-labelled randomized controlled trial with two parallel groups. The intervention group received usual palliative care, two visits by an experienced dietician for advice, and regular ATP infusions over a period of 8 weeks. The control group received palliative care as usual and dietetic advice, but no ATP. This paper gives a description of the study design, selection of patients, interventions and outcome measures. DISCUSSION: From April 2002 through October 2006, a total of 100 patients have been randomized. Follow-up of patients will be completed in December 2006. At the time of writing, five patients are still in follow up. Of the 95 patients who have completed the study, 69 (73%) have completed four weeks of follow-up, and 53 (56%) have completed the full eight-week study period. The first results are expected in 2007.

Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant

            (Williams-Karnesky and Stenzel-Poore 2009) Download

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.


References

Beijer, S., E. A. Gielisse, et al. (2007). "Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients." Invest New Drugs 25(6): 571-9.

Beijer, S., E. van Rossum, et al. (2007). "Application of adenosine 5'-triphosphate (ATP) infusions in palliative home care: design of a randomized clinical trial." BMC Public Health 7: 4.

Hayashida, M., K. Fukuda, et al. (2005). "Analgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine." J Anesth 19(1): 31-5.

Hayashida, M., K. Sato, et al. (2004). "Intravenous infusion of adenosine 5"-triphosphate alleviated a disabling postherpetic neuralgia." J Anesth 18(1): 36-8.

Kirby, B. S., A. R. Crecelius, et al. (2010). "Vasodilatory responsiveness to adenosine triphosphate in ageing humans." J Physiol 588(Pt 20): 4017-27.

Rodriguez-Miranda, E., M. G. Buffone, et al. (2008). "Extracellular adenosine 5'-triphosphate alters motility and improves the fertilizing capability of mouse sperm." Biol Reprod 79(1): 164-71.

Williams-Karnesky, R. L. and M. P. Stenzel-Poore (2009). "Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant." Curr Neuropharmacol 7(3): 217-27.