Efficacy and safety of adenosine, rapid ventricular pacing and hypothermia in cerebral aneurysms clipping: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Cerebral aneurysms in complex anatomical locations and intraoperative rupture can be challenging. Many methods to reduce blood flow can facilitate its exclusion from the circulation. This study evaluated the safety and efficacy of using adenosine, rapid ventricular pacing, and hypothermia in cerebral aneurysm clipping. METHODS: Databases (PubMed, Embase, and Web of Science) were systematically searched for studies documenting the use of adenosine, rapid ventricular pacing, and hypothermia in cerebral aneurysm clipping and were included in this single-arm meta-analysis. The primary outcome was 30-day mortality. Secondary outcomes included neurological outcomes by mRs and GOS, and cardiac outcomes. We evaluated the risk of bias using ROBIN-I, a tool developed by the Cochrane Collaboration. OpenMetaAnalyst version 2.0 was used for statistical analysis and I2 measured data heterogeneity. Heterogeneity was defined as an I2 > 50%. RESULTS: Our systematic search yielded 10,100 results. After the removal of duplicates and exclusion by title and abstract, 64 studies were considered for full review, of which 29 were included. The overall risk of bias was moderate. The pooled proportions of the adenosine analysis for the different outcomes were: For the primary outcome: 11,9%; for perioperative arrhythmia: 0,19%; for postoperative arrhythmia: 0,56%; for myocardial infarction incidence: 0,01%; for follow-up good recovery (mRs 0-2): 88%; and for neurological deficit:14.1%. In the rapid ventricular pacing analysis, incidences were as follows: peri operative arrhythmia: 0,64%; postoperative arrhythmia: 0,3%; myocardial infarction: 0%. In the hypothermia analysis, the pooled proportion of 30-day mortality was 11,6%. The incidence of post-op neurological deficits was 35,4% and good recovery under neurological analysis by GOS was present in 69.2%. CONCLUSION: The use of the three methods is safe and the related complications were very low. Further studies are necessary, especially with comparative analysis, for extended knowledge.

Role of N6­methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review).

Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle­aged males between the ages of 45 and 60 years, and is the highest cause of cancer­associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N6­methyladenosine (m6A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m6A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m6A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m6A methylation modification in PCa. It is considered that the treatment of PCa with micro­molecular drugs that target the epigenetics of the m6A regulator to correct abnormal m6A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.

Ticagrelor downregulates the expression of proatherogenic and proinflammatory miR125-b compared to clopidogrel: A randomized, controlled trial.

BACKGROUND: Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES: We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS: After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS: Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS: Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy.

The N6-methyladenosine (m6A) RNA modification has gained significant prominence as a new layer of regulatory mechanism that governs gene expression. Over the past decade, various m6A regulators responsible for introducing, eliminating, and recognising RNA methylation have been identified. Notably, these m6A regulators often exhibit altered expression patterns in cancer, occasionally offering prognostic value. Nonetheless, the complex roles of these regulators in human cancer pathology remain enigmatic, with conflicting outcomes reported in different studies.In recent years, a multitude of inhibitors and activators targeting m6A regulators have been reported. Several of these compounds have demonstrated promising efficacy in both in vitro and in vivo cancer models. These findings collectively underscore the dynamic landscape of m6A regulation in cancer biology, revealing its potential as a therapeutic target and prognostic indicator.

Diagnosis and Management of Paroxysmal Supraventricular Tachycardia.

Importance: Paroxysmal supraventricular tachycardia (PSVT), defined as tachyarrhythmias that originate from or conduct through the atria or atrioventricular node with abrupt onset, affects 168 to 332 per 100 000 individuals. Untreated PSVT is associated with adverse outcomes including high symptom burden and tachycardia-mediated cardiomyopathy. Observations: Approximately 50% of patients with PSVT are aged 45 to 64 years and 67.5% are female. Most common symptoms include palpitations (86%), chest discomfort (47%), and dyspnea (38%). Patients may rarely develop tachycardia-mediated cardiomyopathy (1%) due to PSVT. Diagnosis is made on electrocardiogram during an arrhythmic event or using ambulatory monitoring. First-line acute therapy for hemodynamically stable patients includes vagal maneuvers such as the modified Valsalva maneuver (43% effective) and intravenous adenosine (91% effective). Emergent cardioversion is recommended for patients who are hemodynamically unstable. Catheter ablation is safe, highly effective, and recommended as first-line therapy to prevent recurrence of PSVT. Meta-analysis of observational studies shows single catheter ablation procedure success rates of 94.3% to 98.5%. Evidence is limited for the effectiveness of long-term pharmacotherapy to prevent PSVT. Nonetheless, guidelines recommend therapies including calcium channel blockers, ß-blockers, and antiarrhythmic agents as management options. Conclusion and Relevance: Paroxysmal SVT affects both adult and pediatric populations and is generally a benign condition. Catheter ablation is the most effective therapy to prevent recurrent PSVT. Pharmacotherapy is an important component of acute and long-term management of PSVT.

Unlicensed antiviral products used for the at-home treatment of feline infectious peritonitis contain GS-441524 at significantly different amounts than advertised.

OBJECTIVE: To analyze the content of unlicensed GS-441524-like products being used as a largely successful at-home treatment for cats suspected to have FIP. The remdesivir content and pH were also measured. SAMPLE: 127 injectable and oral samples from 30 of the most popular brands of black market producers. METHODS: Unlicensed GS-441524-like products were procured through donations and tested for GS-441524 and remdesivir content by liquid chromatography with tandem mass spectrometry. A pH meter measured the pH of injectable samples. RESULTS: Of the 87 injectable formulations, 95% contained more (on average 39% more) GS-441524 than expected based on the producer's marketed concentrations. The average pH (1.30 pH) was well below the physiologic pH conditions recommended for SC injections. The oral formulations were more variable, with 43% containing more GS-441524 (on average 75% more) than expected and 58% containing less (on average 39% less) than the expected content. There was minimal variability in GS-441524 content between replicate samples in the injectables formulations (measured by coefficient of variation). One injectable and 2 oral samples additionally contained remdesivir. CLINICAL RELEVANCE: All unlicensed products used for the at-home treatment of FIP that we tested contain GS-441524. The injectables generally contain significantly more drug than advertised at a below-physiologic pH. Unlicensed oral products vary more widely in drug content and suffer from unconventional dosing and labeling. These data should highlight the need for regulation of these products and the development of legal pathways to procure GS-441524.

Adenosine metabolic signature in circulating CD4+ T cells predicts remission in rheumatoid arthritis.

OBJECTIVES: Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. METHODS: Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data). RESULTS: Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission: AMPD1 (p<0.001), ADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) CONCLUSIONS: Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease.

Combined modified Valsalva maneuver with adenosine supraventricular tachycardia: A comparative study.

BACKGROUND AND IMPORTANCE: Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia commonly seen in the emergency department. Both modified Valsalva maneuver (MVM) and intravenous adenosine are the first line treatment, of which the former has e lower success rate while the latter has a higher success rate but some risks and adverse effects. Given both of these reverse rhythms quickly, combining them may achieve a better effect. OBJECTIVE: The objective of this study is to evaluate the success rate and potential risk of combining the use of intravenous adenosine while patients were doing MVM as a treatment for paroxysmal supraventricular tachycardia(pSVT). DESIGN, SETTINGS AND PARTICIPANTS: We recruited patients with pSVT from 2017 to 2022, and randomly assigned them into 3 groups, MVM group, intravenous adenosine group, and combination therapy group, in which MVM was allowed to be performed twice, while intravenous adenosine was given in a titration manner to repeat three times, recorded the success rate and side effects in each group. MAIN RESULTS: The success rate of the MVM group, adenosine group, and combination group are 42.11%, 75.00 and 86.11%, respectively. The success rate of the adenosine group and combination group is significantly higher than the n MVSM group (p < 0.01, p < 0.001), while the success rate of the combination group is higher than the adenosine group, it has no significant difference (p = 0.340). In terms of safety, the longest RR durations (asystole period) are 1.61 s, 1.60s, and 2.27 s, there is a statistical difference among the three groups (p < 0.01) and between the adenosine and combination group (0.018). CONCLUSION: Therefore, we can conclude that combination therapy has a relatively high success rate and good safety profile, but the current study failed to show its superiority to adenosine.

Bridging the translational gap: adenosine as a modulator of neuropathic pain in preclinical models and humans.

OBJECTIVES: This review aims to analyse the published data on preclinical and human experimental and clinical adenosine modulation for pain management. We summarise the translatability of the adenosine pathway for further drug development and aim to reveal subgroups of pain patients that could benefit from targeting the pathway. CONTENT: Chronic pain patients suffer from inadequate treatment options and drug development is generally impaired by the low translatability of preclinical pain models. Therefore, validating the predictability of drug targets is of high importance. Modulation of the endogenous neurotransmitter adenosine gained significant traction in the early 2000s but the drug development efforts were later abandoned. With the emergence of new drug modalities, there is a renewed interest in adenosine modulation in pain management. In both preclinical, human experimental and clinical research, enhancing adenosine signalling through the adenosine receptors, has shown therapeutic promise. A special focus has been on the A1 and A3 receptors both of which have shown great promise and predictive validity in neuropathic pain conditions. SUMMARY: Adenosine modulation shows predictive validity across preclinical, human experimental and clinical investigations. The most compelling evidence is in the field of neuropathic pain, where adenosine has been found to alleviate hyperexcitability and has the potential to be disease-modifying. OUTLOOK: Adenosine modulation show therapeutic potential in neuropathic pain if selective and safe drugs can be developed. New drug modalities such as RNA therapeutics and cell therapies may provide new options.

Lung Protection After Severe Thermal Burns With Adenosine, Lidocaine, and Magnesium (ALM) Resuscitation and Importance of Shams in a Rat Model.

The management of severe burns remains a complex challenge. Adenosine, lidocaine, and magnesium (ALM) resuscitation therapy has been shown to protect against hemorrhagic shock and traumatic injury. The aim of the present study was to investigate the early protective effects of small-volume ALM fluid resuscitation in a rat model of 30% total body surface area (TBSA) thermal injury. Male Sprague-Dawley rats (320-340 g; n = 25) were randomly assigned to: 1) Sham (surgical instrumentation and saline infusion, without burn, n = 5), 2) Saline resuscitation group (n = 10), or 3) ALM resuscitation group (n = 10). Treatments were initiated 15-min after burn trauma, including 0.7 mL/kg 3% NaCl ± ALM bolus and 0.25-0.5 mL/kg/h 0.9% NaCl ± ALM drip, with animals monitored to 8.25-hr post-burn. Hemodynamics, cardiac function, blood chemistry, hematology, endothelial injury markers and histopathology were assessed. Survival was 100% for Shams and 90% for both ALM and Saline groups. Shams underwent significant physiological, immune and hematological changes over time as a result of surgical traums. ALM significantly reduced malondialdehyde levels in the lungs compared to Saline (P = .023), and showed minimal alveolar destruction and inflammatory cell infiltration (P < .001). ALM also improved cardiac function and oxygen delivery (21%, P = .418 vs Saline), reduced gut injury (P < .001 vs Saline), and increased plasma adiponectin (P < .001 vs baseline). Circulating levels of the acute phase protein alpha 1-acid glycoprotein (AGP) increased 1.6-times (P < .001), which may have impacted ALM's therapeutic efficacy. We conclude that small-volume ALM therapy significantly reduced lung oxidative stress and preserved alveolar integrity following severe burn trauma. Further studies are required to assess higher ALM doses with longer monitoring periods.

Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review).

RNA methylation modifications are closely linked to tumor development, migration, invasion and responses to various therapies. Recent studies have shown notable advancements regarding the roles of RNA methylation in tumor immunotherapy, the tumor microenvironment and metabolic reprogramming. However, research on the association between tumor chemoresistance and N6­methyladenosine (m6A) methyltransferases in specific cancer types is still scarce. Colorectal cancer (CRC) is among the most common gastrointestinal cancers worldwide. Conventional chemotherapy remains the predominant treatment modality for CRC and chemotherapy resistance is the primary cause of treatment failure. The expression levels of m6A methyltransferases, including methyltransferase­like 3 (METTL3), METTL14 and METTL16, in CRC tissue samples are associated with patients' clinical outcomes and chemotherapy efficacy. Natural pharmaceutical ingredients, such as quercetin, have the potential to act as METTL3 inhibitors to combat chemotherapy resistance in patients with CRC. The present review discussed the various roles of different types of key RNA methylation enzymes in the development of CRC, focusing on the mechanisms associated with chemotherapy resistance. The progress in the development of certain inhibitors is also listed. The potential of using natural remedies to develop antitumor medications that target m6A methylation is also outlined.

Management of acute supraventricular tachycardia in children.

QUESTION: Recently, a 3-year-old patient in my practice urgently needed to go to the emergency department. The patient was found to have supraventricular tachycardia (SVT) and needed immediate treatment with adenosine. What evidence is currently available for management of SVT in children? ANSWER: Supraventricular tachycardia is a common cardiac condition in the pediatric population that manifests as a narrow QRS complex tachycardia on electrocardiography. Symptoms may range from palpitations, poor feeding, and irritability to more substantial hemodynamic instability. Patients who are hemodynamically stable can benefit from interventions such as vagal maneuvers, which can be done in the office. Such maneuvers include the Valsalva maneuver, stimulation of the diving reflex (for infants), and unilateral carotid sinus massage. Other children may need pharmacologic therapies to restore normal heart rhythm, which usually consists of a rapid intravenous injection of adenosine under monitoring. For patients who are hemodynamically unstable, emergency cardioversion may be needed.

Adenosine in cancer immunotherapy: Taking off on a new plane.

As a new pillar of cancer therapy, tumor immunotherapy has brought irreplaceable durable responses in tumors. Considering its low response rate, additional immune regulatory mechanisms will be critical for the development of next-generation immune therapeutics. As a key regulatory mechanism, adenosine (ADO) protects tissues from excessive immune responses, but as a metabolite highly concentrated in tumor microenvironments, extracellular adenosine acts on adenosine receptors (mainly A2A receptors) expressed on MDSCs, Tregs, NK cells, effector T cells, DCs, and macrophages to promote tumor cell escape from immune surveillance by inhibiting the immune response. Amounting preclinical studies have demonstrated the adenosine pathway as a novel checkpoint for immunotherapy. Large number of adenosine pathway targeting clinical trials are now underway, including antibodies against CD39 and CD73 as well as A2A receptor inhibitors. There has been evidence of antitumor efficacy of these inhibitors in early clinical trials among a variety of tumors such as breast cancer, prostate cancer, non-small cell lung cancer, etc. As more clinical trial results are published, the combination of blockade of this pathway with immune checkpoint inhibitors, targeted drugs, traditional chemotherapy medications, radiotherapy and endocrine therapy will provide cancer patients with better clinical outcomes. We would elaborate on the role of CD39-CD73-A2AR pathway in the contribution of tumor microenvironment and the targeting of the adenosinergic pathway for cancer therapy in the review.

Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing.

Bone injuries such as fractures are one major cause of morbidities worldwide. A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects. Herein, we tested the hypothesis that the purine molecule, adenosine, can simultaneously alleviate pain and promote healing in a mouse model of tibial fracture by targeting distinctive adenosine receptor subtypes in different cell populations. To achieve this, a biomaterial-assisted delivery of adenosine is utilized to localize and prolong its therapeutic effect at the injury site. The results demonstrate that local delivery of adenosine inhibited the nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigated pain as demonstrated by weight bearing and open field movement tests. Concurrently, local delivery of adenosine at the fracture site promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) resulting in improved bone healing as shown by histological analyses and microCT imaging. This study demonstrates the dual role of adenosine and its material-assisted local delivery as a feasible therapeutic approach to treat bone trauma and associated pain.

The diagnostic and therapeutic challenge of atrial flutter in children: a case report.

BACKGROUND: Palpitations represent a common cause for consultation in the pediatric Emergency Department (ED). Unlike adults, palpitations in children are less frequently dependent from the heart, recognizing other causes. CASE PRESENTATION: A 11-year-old male came to our pediatric ED for epigastric pain, vomiting and palpitations. During the previous 6 month the patient was affected by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus). Electrocardiogram (ECG) revealed supraventricular tachycardia. Therefore, adenosine was administered unsuccessfully. The administration of adenosine, however, allowed us to make diagnosis of atypical atrial flutter. Multiple attempts at both electrical cardioversion, transesophageal atrial overdrive, and drug monotherapy were unsuccessful in our patient. Consequently, a triple therapy with amiodarone, flecainide, and beta-blocker was gradually designed to control the arrhythmic pattern with the restoration of a left upper atrial rhythm. There was not any evidence of sinus rhythm in the patient clinical history. CONCLUSIONS: The present study underlines the rarity of this type of dysrhythmia in childhood and the difficulties in diagnosis and management, above all in a patient who has never showed sinus rhythm. Raising awareness of all available treatment options is essential for a better management of dysrhythmia in children.

Adenosine Receptors as Potential Therapeutic Analgesic Targets.

Pain represents an international burden and a major socio-economic public health problem. New findings, detailed in this review, suggest that adenosine plays a significant role in neuropathic and inflammatory pain, by acting on its metabotropic adenosine receptors (A1AR, A2AAR, A2BAR, A3AR). Adenosine receptor ligands have a practical translational potential based on the favorable efficacy and safety profiles that emerged from clinical research on various agonists and antagonists for different pathologies. The present review collects the latest studies on selected adenosine receptor ligands in different pain models. Here, we also covered the many hypothesized pathways and the role of newly synthesized allosteric adenosine receptor modulators. This review aims to present a summary of recent research on adenosine receptors as prospective therapeutic targets for a range of pain-related disorders.