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BMC Medicine Nov 2022The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five...
BACKGROUND
The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs.
METHODS
Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass.
RESULTS
The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols.
CONCLUSIONS
This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.
Topics: Humans; Pregnancy; Female; Pre-Eclampsia; Biological Products; Dietary Supplements; Vitamin D; Metformin
PubMed: 36329468
DOI: 10.1186/s12916-022-02582-z -
Clinical Drug Investigation Dec 2022BACKGROUND AND OBJECTIVE: Cancer patients are at elevated risk of cancer-associated thrombosis (CAT). Randomized controlled trials have found that direct oral...
UNLABELLED
BACKGROUND AND OBJECTIVE: Cancer patients are at elevated risk of cancer-associated thrombosis (CAT). Randomized controlled trials have found that direct oral anticoagulants (DOACs) are associated with fewer recurrent venous thromboembolism (VTE) events and an increased risk of bleeding than low molecular weight heparins (LMWHs) in CAT. With new clinical data available, this study aims to assess the comparative cost-effectiveness of DOACs and LMWHs over 6- and 60-month treatment durations from the US healthcare system and societal perspectives.
METHODS
A Markov model for cancer patients eligible to receive rivaroxaban, edoxaban, apixaban, enoxaparin, or dalteparin was used to conduct a cost-utility analysis. Clinical scenarios were analyzed based on 6- and 60-month time horizons from the US healthcare system and societal perspectives. The main outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost in US dollars per quality-adjusted life year (QALY). One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the results.
RESULTS
DOACs were cost-saving and clinically superior to LMWHs and were associated with a cost change ranging from - $9134.66 to - $15,281.92 and incremental effectiveness of 0.43-1.25 QALYs among four clinical scenarios. The most influential model inputs for ICER were the utility associated with LMWH use and probabilities of non-VTE and non-bleeding related death. Probabilistic sensitivity analyses were consistent with the results.
CONCLUSIONS
DOACs were found to dominate LMWHs, suggesting that DOACs may be a cost-effective alternative to LMWHs for CAT. This study can help inform decision-makers on the cost-effectiveness of anticoagulation strategies and help in the development of future practice recommendations for cancer patients.
Topics: Humans; Heparin, Low-Molecular-Weight; Cost-Benefit Analysis; Secondary Prevention; Anticoagulants; Venous Thromboembolism; Thrombosis; Hemorrhage; Neoplasms
PubMed: 36315349
DOI: 10.1007/s40261-022-01217-8 -
Experimental Hematology & Oncology Oct 2022Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of... (Review)
Review
Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of treatment, but can be challenging due to the high bleeding risk in some cancers and the high risk of recurrent venous thromboembolism (VTE) in patients with malignancies. Direct oral anticoagulants (DOACs) are well established as first-choice treatments for VTE in non-cancer patients, offering a more convenient and less invasive treatment option than low-molecular-weight heparin (LMWH). Asian patients have exhibited comparable efficacy and safety outcomes with other races in trials of DOACs for VTE in the general population. Although no specific data are available in Asian patients with CAT, results from randomized controlled trials of apixaban, edoxaban, or rivaroxaban versus the LMWH, dalteparin, indicate that DOACs are a reasonable alternative to LMWH for anticoagulation in Asian patients with CAT. This is further supported by analyses of real-world data in Asian populations demonstrating the efficacy and safety of DOACs in Asian patients with CAT. Apixaban, edoxaban, or rivaroxaban are recommended in the most recently updated international guidelines as first-line therapy for CAT in patients without gastrointestinal or genitourinary cancers and at low risk of bleeding. An increased risk of major gastrointestinal bleeding was evident with edoxaban or rivaroxaban, but not apixaban, versus dalteparin in the clinical trials, suggesting that apixaban could be a safe alternative to LMWH in patients with gastrointestinal malignancies. Determining the optimal anticoagulant therapy for patients with CAT requires careful consideration of bleeding risk, tumor type, renal function, drug-drug interactions, financial costs, and patients' needs and preferences.
PubMed: 36303259
DOI: 10.1186/s40164-022-00331-9 -
Proceedings of the National Academy of... Oct 2022The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell...
The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P-O bond cleavage; 3) four concomitant events: W1-PO formation, OH and proton cleavage, nucleophilic attack by the OH against P, and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.
Topics: Actins; Adenosine Diphosphate; Adenosine Triphosphate; Dalteparin; Hydrolysis; Myosins; Protons; Water
PubMed: 36252034
DOI: 10.1073/pnas.2122641119 -
Angiology Sep 2023Women with a history of venous thromboembolisms (VTEs) and/or thrombophilia are at increased risk of VTE during pregnancy. We analysed our cohort of such women who were...
Women with a history of venous thromboembolisms (VTEs) and/or thrombophilia are at increased risk of VTE during pregnancy. We analysed our cohort of such women who were treated with a prophylactic doses of dalteparin. 152 pregnant women with 179 pregnancies were classified into 3 groups: (1) previous VTE without thrombophilia (122 pregnancies); (2) previous VTE with thrombophilia (26 pregnancies) and (3) thrombophilia only (31 pregnancies). They were treated with prophylactic dalteparin in the prepartum and postpartum periods or only in the postpartum period. Occurrences of symptomatic VTE and bleeding episodes were followed, as well as dalteparin discontinuation and anti-Xa activity. Symptomatic deep vein thrombosis occurred in 4 women (2.2%) with 2 episodes in group 1 (in the postpartum period) and 2 episodes in group 2 (one in the prepartum and another in the postpartum period). Seven episodes (3.9%) of minor bleeding occurred. Dalteparin was not stopped in any women. Anti-Xa levels were within the prophylactic range. Our real-world data show a low incidence of thrombosis and minor bleeding in pregnant women treated with prophylactic dalteparin. The incidence of recurrent VTE was lower than that reported in women with similar risk, but without prophylactic anticoagulation.
Topics: Female; Humans; Pregnancy; Dalteparin; Venous Thromboembolism; Pregnant Women; Risk Factors; Venous Thrombosis; Heparin, Low-Molecular-Weight; Thrombophilia; Hemorrhage; Anticoagulants
PubMed: 36113126
DOI: 10.1177/00033197221126244 -
Analytical Chemistry Sep 2022In this work, the first version of "Glycomapping" software is developed for the analysis of the most common low-molecular-weight heparin (LMWH), enoxaparin. Using...
In this work, the first version of "Glycomapping" software is developed for the analysis of the most common low-molecular-weight heparin (LMWH), enoxaparin. Using ultrahigh-performance liquid chromatography-mass spectrometry, size exclusion chromatography is applied, and a virtual database of glycans in enoxaparin is established for the initial searching. With "Glycomapping", a complex chromatogram can be fitted, significantly improving resolution and confirming an accurate distribution range for each size of glycan within enoxaparin. In addition, randomly matched MS data can be corrected, with the constraint of the corresponding chromatographic retention time range, to remove most false positive data. The analytical stability of "Glycomapping" software was confirmed. Enoxaparin, prepared by different manufacturers and from different animal sources, was analyzed using "Glycomapping." Compared to raw data, data processed with "Glycomapping" are more robust and accurate. Another two LMWHs, nadroparin and dalteparin could also be analyzed with this software. This work lays a solid foundation for the automated analysis of heterogeneous mixtures of natural glycans, such as LMWHs and other complex oligosaccharides and polysaccharides.
Topics: Animals; Anticoagulants; Chromatography, Liquid; Dalteparin; Enoxaparin; Heparin; Heparin, Low-Molecular-Weight; Nadroparin; Software
PubMed: 36102213
DOI: 10.1021/acs.analchem.2c01579 -
Frontiers in Veterinary Science 2022Pulmonary thromboembolism (PTE) secondary to immune-mediated hemolytic anemia (IMHA) is rarely diagnosed in cats. In this report, a 3-year-old cat was referred to our...
Pulmonary thromboembolism (PTE) secondary to immune-mediated hemolytic anemia (IMHA) is rarely diagnosed in cats. In this report, a 3-year-old cat was referred to our private hospital with dyspnea, anorexia, and anemia. On the thoracic radiography, cardiac enlargement and pulmonary edema were noted. Echocardiography revealed right ventricular and right atrium enlargement with mild tricuspid regurgitation (tricuspid regurgitation velocity 3.28 m/s). A thrombus was recognized in the main pulmonary artery on the right parasternal short-axis view. Blood examination suggested regenerative anemia and autoagglutination. The findings suggested immune-mediated hemolytic anemia and PTE. Antithrombotic therapy (dalteparin) and immunosuppressive therapy (prednisolone) were administered under oxygen supplementation in the ICU cage. After treatment, regenerative anemia and right-heart failure were improved. During follow-up, the cat remained hemodynamically stable, and the owner reported no cardiac-related clinical signs. Further blood examination confirmed the anemia was improved. Prednisolone was discontinued on Day 56, and the cat continues in good health, administered only mycophenolate mofetil. The clinical outcome of PTE secondary to the IMHA throughout 100 days of periodical observation was reported.
PubMed: 36032299
DOI: 10.3389/fvets.2022.930210 -
Journal of Stroke and Cerebrovascular... Oct 2022Stroke is an independent risk factor for venous thromboembolism (VTE). Although the risk of VTE persists after hospital discharge, information on the utilization of...
BACKGROUND
Stroke is an independent risk factor for venous thromboembolism (VTE). Although the risk of VTE persists after hospital discharge, information on the utilization of anticoagulants among stroke patients after discharge remains limited.
OBJECTIVE
To evaluate changes in post-discharge thromboprophylaxis among stroke patients between 2006 and 2019.
METHODS
We conducted a retrospective repeated cross-sectional analysis using a commercial healthcare insurance database in the United States. We included patients aged ≥ 18 years with incident stroke diagnosis and assessed prophylactic use of anticoagulants in the 30 days following hospital discharge including low-molecular-weight heparin (enoxaparin ≤40 mg/day, dalteparin ≤5000 IU/day), unfractionated heparin ≤5000 IU/ twice daily or 3 times a day, apixaban 2.5 mg twice daily, and rivaroxaban 10 mg/day. Patients with atrial fibrillation, VTE, mechanical heart valves, cancer, antiphospholipid antibody syndrome, and users of therapeutic doses of anticoagulants were excluded. We used the Cochrane-Armitage test to assess changes in the use of anticoagulants across the study period.
RESULTS
There was a small increase in the overall use of post-discharge prophylactic anticoagulants among stroke patients between 2006 and 2019 from 0.5% to 1.9%. The use of heparin decreased from 0.5% in 2006 to 0.3% in 2019 (P-value for trend = 0.001). In contrast, the use of apixaban or rivaroxaban increased from 0.1% in 2013 to 1.6% in 2019 (P-value for trend < 0.001). Apixaban was more commonly used than rivaroxaban.
CONCLUSIONS
In this population-based study of stroke patients, we found that post-discharge anticoagulant use remains low through 2019. Prophylactic use of heparin or rivaroxaban was relatively low but the use of apixaban increased over the study period. Further research is needed to determine if these agents are safe and effective for VTE prevention in stroke patients.
Topics: Aftercare; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Dalteparin; Enoxaparin; Heparin; Heparin, Low-Molecular-Weight; Humans; Patient Discharge; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; United States; Venous Thromboembolism
PubMed: 35964533
DOI: 10.1016/j.jstrokecerebrovasdis.2022.106700 -
The Journal of Thoracic and... Dec 2022The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and... (Review)
Review
OBJECTIVE
The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and venous thromboembolism in patients undergoing early-stage lung cancer resection and the impact of change from short duration to extended thromboprophylaxis.
METHODS
We reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer following a change in protocol from inpatient-only to extended thromboprophylaxis to 28 days. Propensity-score matching of control (routine inpatient pharmacologic thromboprophylaxis) and treatment group (extended pharmacologic thromboprophylaxis) was performed. Adjustment for covariates based on the Caprini risk assessment model was undertaken. Thromboembolic outcomes were compared between the 2 groups.
RESULTS
Seven hundred fifty consecutive patients underwent resection of primary lung cancer at Oxford University Hospitals NHS Foundation Trust between January 2013 and December 2018. Six hundred patients were included for analysis and propensity-score matching resulted in 253 matched pairs. Extended prophylaxis was associated with a significant reduction in pulmonary emboli (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01). One patient (0.4%) developed a bleeding complication within the treatment cohort. Multivariable logistic regression model demonstrated that extended thromboprophylaxis was independently associated with a reduction in postoperative pulmonary emboli.
CONCLUSIONS
Patients undergoing lung cancer resection surgery are at moderate-to-high risk of postoperative thromboembolic disease. Extended dalteparin for 28 days is safe and is associated with reduced incidence of pulmonary embolus in patients undergoing resection of early-stage primary lung cancer.
Topics: Humans; Venous Thromboembolism; Anticoagulants; Drug Administration Schedule; Pulmonary Embolism; Postoperative Complications; Lung Neoplasms
PubMed: 35953309
DOI: 10.1016/j.jtcvs.2022.06.016 -
Zeitschrift Fur Gastroenterologie Apr 2023The increased risk of thrombosis and bleeding with an active tumor disease is known as the so-called "thrombo-hemorrhagic syndrome", which places high demands on...
The increased risk of thrombosis and bleeding with an active tumor disease is known as the so-called "thrombo-hemorrhagic syndrome", which places high demands on anticoagulation. There are currently 4 randomized, prospective studies on the use of new, non-vitamin K dependent oral anticoagulants (NOAC) for the treatment of venous thromboembolism (VTE) that have occurred in oncology. The FXa inhibitors rivaroxaban, edoxaban and twice apixaban were each used in individual studies versus the standard therapeutic agent dalteparin. Since there is no direct head-to-head comparison of the FXa inhibitors mentioned within a study, the largest study - always compared to dalteparin - was evaluated for each NOAC. The studies were analyzed with regard to their effectiveness, safety, fatal bleeding rates, the risk of gastrointestinal bleeding (GIB) and other differences using descriptive statistics. With dalteparin, the mean VTE recurrence rate was approximately 9% over a 6-month treatment period. All three FXa inhibitors were not inferior to dalteparin in terms of potency. The VTE recurrence rate was - 2.3% lower in edoxaban and apixaban-treated patients and - 5.0% in rivaroxaban-treated patients. In terms of safety, there was an increased rate of severe bleeding (both + 2.4%) for rivaroxaban and edoxaban compared to dalteparin; in particular, the number of GIBs was significantly increased. In contrast, the number of severe bleeding was not increased for apixaban, as was the case for various bleeding types including GIB. In the Apixaban study, the overall rate of severe GIB, which accounted for about 50% of all severe bleeding, and that of clinically relevant non-severe bleeding, were the lowest. The FXa inhibitors are not inferior to the standard therapy with dalteparin in the VTE recurrence rate in oncological patients. The GIB rate appears to be an important predictive factor for the safety of this group of substances, so that tumor location, gastrointestinal risk factors and other individual criteria should be given greater consideration in future therapy decisions for or against an FXa inhibitor.
Topics: Humans; Anticoagulants; Dalteparin; Factor Xa Inhibitors; Rivaroxaban; Venous Thromboembolism; Prospective Studies; Gastrointestinal Hemorrhage; Neoplasms
PubMed: 35878607
DOI: 10.1055/a-1886-4591