Browsing by Subject "Adenosine"
Results Per Page
Sort Options
Item Open Access Activity of Galidesivir in a Hamster Model of SARS-CoV-2.(Viruses, 2021-12-21) Taylor, Ray; Bowen, Richard; Demarest, James F; DeSpirito, Michael; Hartwig, Airn; Bielefeldt-Ohmann, Helle; Walling, Dennis M; Mathis, Amanda; Babu, Yarlagadda SCoronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.Item Embargo Adenosine Delivery to Mitigate Bone Disorders(2023) Newman, HunterBone is a dynamic tissue which continuously undergoes remodeling primarily through osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balance is vital in maintaining both bone homeostasis and bone regeneration. With the increase in the global elderly population, the two most prominent bone disorders of fracture and osteoporosis pose a tremendous burden to the healthcare system. While these bone disorders are increasing in prevalence, treatment options remain stagnant, demonstrating the unmet need for new clinical solutions. Strategies that induce innate repair yet eliminate the need for expensive cellular or recombinant protein-based therapies are appealing. Adenosine, a naturally occurring nucleoside, has emerged as a part of key metabolic pathway that regulates bone tissue formation, function, and homeostasis. In this dissertation, I investigate the therapeutic potential of adenosine delivery to mitigate bone disorders. Despite the regenerative capacity of bone, age-associated changes result in injuries that suffer delayed healing. Therapeutic interventions that circumvent the age-associated impairments in bone tissue and promote healing are attractive options for geriatric fracture repair. Herein, I examined the changes in extracellular adenosine signaling with aging and the potential of local delivery of adenosine to promote fracture healing in aged mice. My results showed a concomitant reduction of CD73 expression in the bone and marrow of aged mice. Local delivery of adenosine using injectable microgel building blocks and drug carriers yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study provides new understandings of age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of local delivery of adenosine at the fracture site to circumvent the impaired healing capacity of aged fractures. Given the multi-functionality of adenosine signaling, it is possible that extracellular adenosine delivery influences various phases of bone healing. Towards this, I examined the potential immunomodulatory effect of adenosine delivery on both the local and systemic immune system for fracture repair. My results indicated that the immune cell populations of neutrophils and macrophages did not change with adenosine treatment in the fractured callus at either 3-, 7-, or 14-days post fracture. Additionally in the peripheral blood, CD8+ and CD4+ T cell populations did not change at any of the timepoints following adenosine treatment. This study provides potential insight into the role of exogenous adenosine in the inflammatory stage of fracture healing in young animals. Aging not only poses a risk for delayed fracture healing, but also for the development of osteoporosis. Osteoporosis results in bone fragility and subsequently a higher risk for fracture incidence. This disease is characterized by an imbalance in the coupled bone remodeling process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, I developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers the osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier was further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in an ovariectomized mice model of osteoporosis and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules, such as adenosine, that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis. Overall, this dissertation offers novel findings regarding adenosine as a therapeutic to treat both fractures and osteoporosis. These findings, along with the biomaterial delivery systems developed, further advance the potential of using adenosine as a therapeutic molecule to treat bone disorders.
Item Open Access Adenosine-induced flow arrest to facilitate intracranial aneurysm clip ligation: dose-response data and safety profile.(Anesth Analg, 2010-05-01) Bebawy, John F; Gupta, Dhanesh K; Bendok, Bernard R; Hemmer, Laura B; Zeeni, Carine; Avram, Michael J; Batjer, H Hunt; Koht, AntounBACKGROUND: Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients. METHODS: This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period. RESULTS: A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes. CONCLUSIONS: For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.Item Open Access An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral.(Antiviral research, 2021-09-20) Julander, Justin G; Demarest, James F; Taylor, Ray; Gowen, Brian B; Walling, Dennis M; Mathis, Amanda; Babu, YSGalidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.Item Open Access Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.(Science translational medicine, 2022-06) Mao, Chengqiong; Yeh, Stacy; Fu, Juan; Porosnicu, Mercedes; Thomas, Alexandra; Kucera, Gregory L; Votanopoulos, Konstantinos I; Tian, Shaomin; Ming, XinTumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.Item Open Access Lifetime cost-effectiveness analysis of ticagrelor in patients with acute coronary syndromes based on the PLATO trial: a Singapore healthcare perspective.(Singapore medical journal, 2013-03) Chin, Chee Tang; Mellstrom, Carl; Chua, Terrance Siang Jin; Matchar, David BruceIntroduction
Ticagrelor is a novel antiplatelet drug developed to reduce atherothrombosis. The PLATO trial compared ticagrelor and aspirin to clopidogrel and aspirin in patients with acute coronary syndromes (ACS). Ticagrelor was found to be superior in the primary composite endpoint of cardiovascular death, myocardial infarction or stroke, without increasing major bleeding events. The current study estimates the lifetime cost-effectiveness of ticagrelor relative to generic clopidogrel from a Singapore public healthcare perspective.Methods
This study used a two-part cost-effectiveness model. The first part was a 12-month decision tree (using PLATO trial data) to estimate the rates of major cardiovascular events, healthcare costs and health-related quality of life. The second part was a Markov model estimating lifetime quality-adjusted survival and costs conditional on events during the initial 12 months. Daily drug costs applied were SGD 1.05 (generic clopidogrel) and SGD 6.00 (ticagrelor). Cost per quality-adjusted life years (QALY) was estimated from a Singapore public healthcare perspective using life tables and short-term costs from Singapore, and long-term costs from South Korea. Deterministic and probabilistic sensitivity analyses were performed.Results
Ticagrelor was associated with a lifetime QALY gain of 0.13, primarily driven by lower mortality. The resulting incremental cost per QALY gained was SGD 10,136.00. Probabilistic sensitivity analysis indicated that ticagrelor had a > 99% probability of being cost-effective, given the lower recommended WHO willingness-to-pay threshold of one GDP/capita per QALY.Conclusion
Based on PLATO trial data, one-year treatment with ticagrelor versus generic clopidogrel in patients with ACS, relative to WHO reference standards, is cost-effective from a Singapore public healthcare perspective.Item Open Access Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing.(Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-12) Shih, Yu-Ru V; Kingsley, David; Newman, Hunter; Hoque, Jiaul; Gupta, Ankita; Lascelles, B Duncan X; Varghese, ShyniBone 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.Item Open Access Myocardial Function in Premenopausal Women Treated With Ovarian Function Suppression and an Aromatase Inhibitor.(JNCI cancer spectrum, 2021-08) Jordan, Jennifer H; D'Agostino, Ralph B; Ansley, Katherine; Douglas, Emily; Melin, Susan; Sorscher, Steven; Vasu, Sujethra; Park, Sung; Kotak, Anuj; Romitti, Paul A; O'Connell, Nathanial S; Hundley, William G; Thomas, AlexandraPremenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (-1.3%, 95% confidence interval [CI] = -3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = -1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = -4.7%, 95% CI = -7.3% to -2.1%, Pdifference = .002). Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.Item Open Access Novel antiplatelet agent ticagrelor in the management of acute coronary syndrome.(Journal of interventional cardiology, 2011-06) Ramaraj, Radhakrishnan; Movahed, Mohammad Reza; Hashemzadeh, MehrnooshCurrent clinical guidelines recommend dual antiplatelet agents namely aspirin and clopidogrel for the treatment of patients suffering from acute coronary syndrome (ACS). But the efficacy of clopidogrel is variable as it is a pro-drug, which has to be metabolized to become an active drug thus exhibiting variable platelet inhibition, increases risk of bleeding, stent thrombosis, and ischemia. To overcome this limitation, prasugrel was developed with increased antiplatelet activity thereby reducing the risk of myocardial ischemia and stent thrombosis. This action of prasugrel was associated with an increased risk of major bleeding. Finally, a novel reversible and direct-acting oral adenosine diphosphate (ADP) receptor antagonist, ticagrelor was developed that showed consistent and increased P2Y12 inhibition with similar incidence of bleeding but greater reduction in cardiac events compared to clopidogrel. The focus of this article is to review ticagrelor as a new class of P2Y12 inhibitor.Item Open Access Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial.(European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 2018-01) Norgren, Lars; Patel, Manesh R; Hiatt, William R; Wojdyla, Daniel M; Fowkes, F Gerry R; Baumgartner, Iris; Mahaffey, Kenneth W; Berger, Jeffrey S; Jones, W Schuyler; Katona, Brian G; Held, Peter; Blomster, Juuso I; Rockhold, Frank W; Björck, Martin; EUCLID Steering Committee and InvestigatorsOBJECTIVES:Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established. DESIGN, MATERIALS, METHODS:The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss. RESULTS:In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI. CONCLUSIONS:Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.