Hendrik J. Agteresch

Adenosine triphosphate. Established and potential clinical applications

Adenosine 5′-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5′-triphosphate.

Randomized clinical trial of adenosine 5'-triphosphate on tumor growth and survival in advanced lung cancer patients.

We recently reported that regular infusions of adenosine 5′-triphosphate (ATP) inhibited loss of body weight and quality of life in patients with non-small cell lung cancer (NSCLC). In the present paper we investigated whether ATP affects tumor growth and survival in the same group of patients. Fifty-eight NSCLC patients (stage IIIB or IV) were randomly assigned to receive either 10 i.v. 30-h ATP infusions every 2–4 weeks over a 24-week period (n = 28) or no ATP (control patients, n = 30). ATP was given for a median of 6.5 infusions. Differences in time to progression and survival between patients in both groups were tested by means of the log-rank test and Cox regression analysis. Forty-nine patients were evaluable for tumor response. None of the evaluable patients showed a complete or partial response. Median time to progression was 3.9 months [95% confidence interval (CI) = 2.3–5.5] in the ATP group compared to 3.0 months (95% CI = 2.4–3.7) in the control group (p = 0.71). Median survival was 5.6 months (95% CI = 1.1–10.1) for the ATP group and 4.7 months (95% CI = 2.6–6.8) for the control group (p = 0.68). ATP treatment was associated with a significant increase in survival in the subgroup of weight-losing patients with stage IIIB NSCLC: in this subgroup, median survival was 9.3 months (95% CI = 2.1–16.5) for ATP-treated patients versus 3.5 months (95% CI = 2.3–4.7) for control patients (between-group difference: p = 0.009). No significant effect of ATP was observed for weight-losing patients with stage IV NSCLC or for weight-stable NSCLC patients. Although ATP as a single therapy does not lead to tumor regression or increased survival in patients with advanced lung cancer, it may prolong survival in weight-losing patients with stage IIIB lung cancer. The latter finding is intriguing, but requires confirmation in larger clinical trials.

The effect of nitric oxide donors on haemodynamics and blood flow distribution in the porcine carotid circulation

1 The role of nitric (NO) in the regulation of capillary and arteriovenous anastomotic blood flow was evaluated in the carotid circulation of the pig. For this purpose, the effect of intracarotid (i.c.) infusions of saline and two NO donors, nitroprusside sodium (NPR) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in concentrations of 3–100 μg min−1 was studied on systemic haemodynamics and carotid blood flow and its distribution in anaesthetized pigs with low arteriovenous anastomotic blood flow, by use of the radioactive microsphere method.

Beneficial Effects of Adenosine Triphosphate on Nutritional Status in Advanced Lung Cancer Patients: A Randomized Clinical Trial

Background: In a randomized clinical trial in patients with advanced non–small-cell lung cancer (NSCLC), infusion with adenosine 5′-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expendi- ture as secondary outcome measures in the same patients are reported. Methods: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 IV, 30-hour ATP infusions every 2 to 4 weeks, or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expendi- ture (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance. Results: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas p...