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IntroductionMajor depressive disorder (MDD) is the most prevalent mental illness. Antidepressants with rapid efficacy and acceptable tolerance have been investigated for many years. A preclinical study performed by our group revealed that the dysregulation of extracellular ATP is related to the pathophysiology of depression and that the medial prefrontal cortex-lateral habenula pathway is a potential cellular and neural circuit target for ATP involvement in depression-like behaviour. Moreover, through small-sample clinical trials, the group has preliminarily discovered the antidepressant effect of ATP. However, the antidepressant effects of and neural circuit mechanisms underlying ATP in depressed patients remain largely unexplored. This study pioneers the intravenous use of escitalopram in combination with oral escitalopram for the treatment of MDD, thus representing a new direction in antidepressant research.Methods and analysisThis clinical study is a single-centre, randomised, double-blind, placebo-controlled, superiority trial involving 120 MDD patients evenly divided into two groups. The experimental group will receive an intravenous injection of 10 mL ATP in 100 mL normal saline (NS) two times per day (BD) for 2 weeks, whereas the control group will receive 110 mL NS BD for 2 weeks. All of the participants will take 10 mg of oral escitalopram daily for 4 weeks, with flexible adjustment thereafter based on clinical response. Our primary outcome will be the change in the Hamilton Depression Rating Scale 24 (HAMD-24) score from baseline to 2 and 4 weeks. The secondary outcomes assessment (at 1, 2, 4, 12 and 24 weeks) will be done by the Montgomery-Asberg Depression Rating Scale, HAMD-24, Hamilton Anxiety Scale, Beck Depression Inventory, Snaith-Hamilton Pleasure Scale, Clinical Global Impression, Insomnia Severity Index, Columbia-Suicide Severity Rating Scale, Side Effect Rating Scale of Asberg, MRI, cognitive function and cytokine level analyses.Ethics and disseminationThe study protocol and all of the related materials were approved by the Institutional Ethics Committee of Nanfang Hospital, Southern Medical University (No. NFEC-2024-070, NFEC-2020-153, Guangzhou, China). Results will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberNCT06266715.

To evaluate the vasodilator effect of adenosine triphosphate (ATP) compared with adenosine in stress perfusion cardiac magnetic resonance (CMR) examinations. A total of thirty-three patients underwent clinically indicated stress/rest perfusion CMR examination following intravenous injection of a total dose of 0.2 mmol/kg of gadobutrol. Individuals were randomly assigned to ATP (160 mcg/kg/min) or adenosine (140 mcg/kg/min). The vasodilator effect of both drugs was analyzed by comparing differences in heart rate, symptoms during stress, and semiquantitative myocardial and splenic perfusion parameters, including time, time to peak, upslope, myocardial perfusion reserve index, tissue perfusion values, splenic and myocardial signal intensity ratios, and splenic-to-myocardial signal intensity ratios. No significant difference was found in heart rate variation between the stressors (26.1 ± 19.1 bpm for ATP vs. 21.7 ± 17.3 bpm for adenosine, p = 0.52). Patients receiving ATP referred less pronounced clinical symptoms. Semiquantitative myocardial perfusion parameters were comparable, and patients in the adenosine and ATP groups showed similar myocardial perfusion reserve index values (2.34 [1.62–2.73] vs 1.63 [1.29–2.10], p = 0.07). Splenic switch off was visually confirmed in all patients and estimated spleen to myocardium ratio was similar (0.92 [0.53–1.09] vs 0.81 [0.53–0.86] with ATP and adenosine, respectively, p = 0.12). Both ATP and adenosine are potent coronary vasodilators that can be safely employed in stress-CMR. Both stressor cause similar hyperemic response. Splenic switch-off can be used to assess stress adequacy in patients undergoing stress-CMR with either adenosine or ATP.

Background Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50–75% of patients have a treatment response but require 4–6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD. Methods This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items. Discussion In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation. Trial registration NCT03138681 . Registered on 3 May 2017. First patient: 4 May 2017.

OBJECTIVE: Sympathetic vasoconstriction is blunted in contracting human skeletal muscles (functional sympatholysis). In young subjects, infusion of adenosine and ATP increases blood flow, and the latter compound also attenuates α-adrenergic vasoconstriction. In patients with type 2 diabetes and age-matched healthy subjects, we tested 1) the sympatholytic capacity during one-legged exercise, 2) the vasodilatory capacity of adenosine and ATP, and 3) the ability to blunt α-adrenergic vasoconstriction during ATP infusion. RESEARCH DESIGN AND METHODS: In 10 control subjects and 10 patients with diabetes and normal endothelial function, determined by leg blood flow (LBF) response to acetylcholine infusion, we measured LBF and venous NA, with and without tyramine-induced sympathetic vasoconstriction, during adenosine-, ATP-, and exercise-induced hyperemia. RESULTS: LBF during acetylcholine did not differ significantly. LBF increased ninefold during exercise and during adenosine- and ATP-induced hyperemia. Infusion of tyramine during exercise did not reduce LBF in either the control or the patient group. During combined ATP and tyramine infusions, LBF decreased by 30% in both groups. Adenosine had no sympatholytic effect. CONCLUSIONS: In patients with type 2 diabetes and normal endothelial function, functional sympatholysis was intact during moderate exercise. The vasodilatory response for adenosine and ATP did not differ between the patients with diabetes and the control subjects; however, the vasodilatory effect of adenosine and ATP and the sympatholytic effect of ATP seem to decline with age.

Extracellular adenosine 5′-triphosphate (ATP) causes neurogenic bronchoconstriction, inflammation, and coughs, and may play a mechanistic role in obstructive airway diseases. The aims of this study were to determine the effects of inhaled ATP on airway function, and to compare these effects with those of adenosine 5′-monophosphate (AMP). Prospective, randomized, double-blind study. Clinical research laboratory of a postgraduate teaching hospital. The effects of inhaled equimolar doses of ATP and AMP on airway caliber, perception of dyspnea quantified by the Borg score, and other symptoms were determined in 10 nonsmokers (age 41 ± 3 years) and 10 patients with asthma (age 39 ± 3 years) [± SEM]. None of the healthy nonsmokers responded to ATP or AMP. All the patients with asthma responded to ATP, and 90% responded to AMP. The geometric mean of the provocative dose causing a 20% fall in FEV1 (PD20) of ATP was 48.7 μmol/mL and that of PD20 AMP was 113.5 μmol/mL in responsive asthmatics (p < 0.05). In asthmatic patients, the percentage change in FEV1 caused by ATP was greater than that caused by AMP (ΔFEV1 ATP = 29% vs ΔFEV1 AMP = 22%, p < 0.05). Borg score increased significantly in asthmatics after ATP (from 0.1 to 3.3, p < 0.01) and after AMP (from 0.2 to 2.5, p < 0.01). This increase was also greater after ATP than AMP in asthma (ΔBorg ATP = 3.2 vs ΔBorg AMP = 2.3, p < 0.05). ATP induced cough in 16 subjects (80%), while AMP induced cough in 8 subjects (40%) [p < 0.05]; in addition, more subjects had throat irritation after inhalation of ATP than AMP (p < 0.05). ATP is a more potent bronchoconstrictor and has greater effects on dyspnea and other symptoms than AMP in asthmatic patients. Therefore, ATP could potentially be used as a bronchoprovocator in the clinical setting.

Background Myocardial perfusion single-photon emission computed tomography (SPECT) imaging with stress is a useful examination for detecting coronary artery disease. Since the presence of artifacts is remaining challenges, we aimed to define the minimum intensity of low-grade exercise stress levels combined with drug stress to reduce undesired artifacts and their related factors. Methods We divided patients with suspicious coronary artery disease into 4 groups as follows: group A, adenosine triphosphate (ATP) for 6 min; group A + 25 W, ATP + 25 W exercise for 6 min; group A + 35 W, ATP + 35 W exercise for 6 min; group A + 45 W, ATP + 45 W exercise for 6 min) and enrolled only those whose summed stress scores were < 3. Undesired artifacts were evaluated on the basis of heart-to-liver activity ( H/L ) ratio and heart-to-10 pixels below the heart ( H /below the H ) ratio. Results The logarithmic values of H/L and H /below the H ratios were significantly higher in groups A + 35 W and A + 45 W than in group A ( p  < 0.05, each). In all the patients, the logarithmic values of H/L and H /below the H ratios positively correlated with the increment of rate pressure product (RPP, p  = 0.002 and p  = 0.005, respectively) after stress in the univariate analysis. The left ventricular end-diastolic volume (LVEDV) after stress ( p  = 0.002) negatively correlated with the logarithmic value of H /below the H ratio, but not H/L ratio. Although the increment of RPP was independently associated with the logarithmic values of both H/L ( p  = 0.001) and H /below the H ratios ( p  = 0.005), LVEDV was also independently associated with the logarithmic value of H /below the H ratio ( p  < 0.001) in multivariate regression analysis under adjusting with age and sex. Conclusion ATP plus ≥35 W exercise stress for 6 min was useful for reducing undesired artifacts after stress in myocardial perfusion SPECT. LVEDV after stress in addition to the increment of RPP was independently associated with the H /below the H ratio, but not the H/L ratio.

Purinergic receptors are important for the regulation of inflammation, muscle contraction, neurotransmission and nociception. Extracellular ATP and its metabolites are the main ligands for these receptors. Occasional reports on beneficial results of ATP administration in human and animal studies have suggested the bioavailability of oral ATP supplements. We investigated whether prolonged daily intake of oral ATP is indeed bioavailable. Thirty-two healthy subjects were randomised to receive 0, 250, 1250 or 5000 mg ATP per d for 28 d by means of enteric-coated pellets. In addition, on days 0 and 28, all thirty-two subjects received 5000 mg ATP to determine whether prolonged administration would induce adaptations in the bioavailability of ATP. ATP supplementation for 4 weeks did not lead to changes in blood or plasma ATP concentrations. Of all ATP metabolites, only plasma uric acid levels increased significantly after the administration of 5000 mg of ATP. Prolonged administration of ATP was safe as evidenced from liver and kidney parameters. We conclude that oral administration of ATP only resulted in increased uric acid concentrations. On the basis of these findings, we seriously question the claimed efficacy of oral ATP at dosages even lower than that used in the present study.

Purpose Adenosine triphosphate (ATP) frequently triggers atrial fibrillation (AF), but the clinical significance of this phenomenon is unknown. The purpose of this study was to reveal the relevance between spontaneous AF and ATP-induced AF. Methods In 81 AF patients undergoing pulmonary vein isolation (PVI), we injected 20 mg of ATP before PVI, and recorded triggering sites of the AF induced. We also injected 20 mg of ATP in 44 patients receiving ablation for atrioventricular reciprocating tachycardia (AVRT). Results ATP provoked AF in 24 (29.6 %) of the 81 PVI patients and atrial ectopic beats in a further 48 (59.3 %). The trigger site of the AF was in the PV and the right atrium in 22 (91.7 %) and 2 patients, respectively. In 14 of those 24 patients, spontaneous AF arose from the same triggering site as the ATP-induced AF. In the 48 patients with ATP-provoked ectopic beats, spontaneous AF arose from the same site in 13. Conversely, among the 34 patients demonstrating spontaneous AF initiation, AF or ectopic beats were provoked by ATP from the same site in 14 (41.2 %) and 13 patients (38.2 %), respectively. ATP provoked AF in only 2 (4.5 %) of the AVRT patients. In summary, ATP provoked AF or atrial ectopic beats in 88.9 % of PVI patients, 36.1 % of whose triggering sites matched that of the spontaneous AF, while 79.4 % of spontaneous AF trigger sites matched ATP-provoked AF or ectopic beat sites. Conclusions ATP-induced AF was strongly associated with clinical AF, and ATP is useful for identifying arrhythmogenic sites.

Purpose Dormant conduction (DC) induced by intravenous adenosine triphosphate (ATP) after pulmonary vein (PV) isolation (PVI) could predict subsequent PV reconnection (RC) sites. This study aimed to investigate the relationship between the DC and RC sites during the long-term follow-up. Methods Ninety-one consecutive patients (62 males; mean age, 62 ± 11 years) with symptomatic persistent ( n  = 18) or paroxysmal ( n  = 73) atrial fibrillation (AF) who underwent PVI were included in this study. After a successful PVI, we administered ATP to reveal the DC sites. In total, DC sites were observed in 46 (51 %) patients, and all were left un-ablated after marking or tagging all of them using fluoroscopic images and a three-dimensional (3D) mapping system. After the follow-up period (14.8 ± 3.6 months), AF recurred in 29 (32 %) patients, all of whom had a DC in the initial ablation session, and underwent redo sessions. We divided the DC sites into three groups; in group A, the RC sites differed from the DC sites, in group B, the RC sites were identical to the DC sites, and in group C, the RC sites involved both DC and other sites. Results As a result, 20 (69 %), 3 (11.5 %), and 6 (19.5 %) patients belonged to groups A, B, and C, respectively. Statistical analyses comparing the agreement between DC and the RC sites yielded a weak relationship. Conclusions DC sites implying RC sites had a weak agreement, and other options to predict RC sites will be required to improve the clinical benefit of CA of AF.

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.