Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats.
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ABSTRACT:
SUBMITTER: Shvartsur R
PROVIDER: S-EPMC8619680 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.
| S-EPMC7555481 | biostudies-literature
Project description:UnlabelledAntiplatelet agents are pivotal for prevention of coronary artery disease and cerebrovascular disease worldwide. Individual patient data meta-analysis indicates that low-dose aspirin causes a 10% risk reduction in pre-eclampsia for women at high individual risk. However, in the last 15 years it has emerged that a significant proportion of aspirin-treated individuals exhibit suboptimal platelet response, determined biochemically and clinically, termed 'aspirin non-responsiveness', 'aspirin resistance' and 'aspirin treatment failure'. More recently, investigation of aspirin responsiveness has begun in pregnant women. This review explores the history and clinical relevance of 'aspirin resistance' applied to high-risk obstetric populations.Tweetable abstractIs 'aspirin resistance' clinically relevant in high-risk obstetrics?
| S-EPMC5069612 | biostudies-literature
Project description:BackgroundThere are often disparities between current evidence and current practice. Decreasing the gap between desired practice outcomes and observed practice outcomes in the healthcare system is not always easy. Stopping previously recommended or variably recommended interventions may be even harder to achieve than increasing the use of a desired but under-performed activity. For over a decade, aspirin has been prescribed for primary prevention of cardiovascular disease and for patients with the coronary artery disease risk equivalents; yet, there is no substantial evidence of an appropriate risk-benefit ratio to support this practice. This paper describes the protocol of a randomized trial being conducted in six primary care practices in the Denver metropolitan area to examine the effectiveness of three interventional strategies to change physician behavior regarding prescription of low-dose aspirin.MethodsAll practices received academic detailing, one arm received clinician reminders to reconsider aspirin, a second arm received both clinician and patient messages to reconsider aspirin. The intervention will run for 15 to 18 months. Data collected at baseline and for outcomes from an electronic health record will be used to assess pre- and post-interventional prescribing, as well as to explore any inappropriate decrease in aspirin use by patients with known cardiovascular disease.DiscussionThis study was designed to investigate effective methods of changing physician behavior to decrease the use of aspirin for primary cardiovascular disease prevention. The results of this study will contribute to the small pool of knowledge currently available on the topic of ceasing previously supported practices.Trial registrationClinicalTrials.gov: NCT01247454.
| S-EPMC3141566 | biostudies-literature
Project description:To examine the association between cardioprotective use of low-dose aspirin and the risk of recurrent gout attacks among gout patients.We conducted an online case-crossover study of individuals with gout over 1 year. The following information was obtained during gout attacks: the onset dates, symptoms and signs, medications, and exposure to potential risk factors, including daily aspirin use and dosage, during the 2-day hazard period prior to the gout attacks. The same exposure information was also obtained over 2-day control periods.Of the 724 participants analysed, 40.5% took aspirin ?325 mg/day during either a hazard or a control period. Compared with no aspirin use, the adjusted OR of gout attacks increased by 81% (OR=1.81, 95% CI 1.30 to 2.51) for ?325 mg/day of aspirin use on two consecutive days. The corresponding ORs were stronger with lower doses (eg, OR=1.91 for ?100 mg, 95% CI 1.32 to 2.85). These associations persisted across subgroups by sex, age, body mass index categories and renal insufficiency status. Concomitant use of allopurinol nullified the detrimental effect of aspirin.Our findings suggest that the use of low-dose aspirin on two consecutive days is associated with an increased risk of recurrent gout attacks. Recommended serum urate monitoring with concomitant use and dose adjustment of a urate-lowering therapy among patients with gout may be especially important to help avoid the risk of gout attacks associated with low-dose aspirin.
| S-EPMC3902644 | biostudies-literature
Project description: Not available
| S-EPMC5863118 | biostudies-literature
Project description:Reproductive sterilization via surgical gonadectomy is strongly advocated to help manage animal populations, especially domesticated pets, and to prevent reproductive diseases. The present study explored the feasibility of using a single-injection method for inducing sterility in female animals as an alternative to surgical sterilization. The idea was based upon our recent finding that repetitive daily injection of estrogen into neonatal rats disrupted hypothalamic expression of Kisspeptin, the neuropeptide that triggers and regulates pulsatile secretion of GnRH in the hypothalamus. In this study, neonatal female rats were dosed with estradiol benzoate (EB) by daily injection for 11 days or subcutaneously implanted with an EB-containing Silastic capsule designed to release EB over a 2- to 3-week period. Rats treated by either method did not exhibit estrous cyclicity, were anovulatory, and became infertile. The EB-treated rats had fewer Kisspeptin neurons in their hypothalami, but their GnRH-LH axis retained responsiveness to Kisspeptin stimulation. To simplify usage, an injectable EB carrier was developed in the forms of biodegradable microspheres or pellets with pharmacokinetics comparable to the EB-containing Silastic capsule. A single injection of EB microspheres (300 µg EB) to neonatal rats made them sterile and female beagles implanted with an EB pellet at a neonatal age had lower KISS expression in their hypothalami. No concerning health impact other than infertility was observed in animals that received EB treatment at a neonatal age. Taken together, this study shows that neonatal EB administration could be developed as a non-surgical animal sterilization method.
2023-06-21 | GSE221002 | GEO
Project description:Molecular breast imaging (MBI) is a nuclear medicine technology that uses dual-head cadmium zinc telluride (CZT) gamma cameras to image functional uptake of a radiotracer, Tc-99m sestamibi, in the breast. An important factor in adoption of MBI in the screening setting is reduction of the necessary administered dose of Tc-99m sestamibi from the typically used dose of 740 MBq to approximately 148 MBq, such that MBI's whole-body effective dose is comparable to that of screening mammography. Methods that increase MBI count sensitivity may allow a proportional reduction in the necessary administered dose. Our objective was to evaluate the impact of two count sensitivity improvement methods on image quality by evaluating count sensitivity, spatial resolution, and lesion contrast in phantom simulations.Two dual-head CZT-based MBI systems were studied: LumaGem and Discovery NM 750b. Two count sensitivity improvement methods were implemented: registered collimators optimized for dedicated breast imaging and widened energy acceptance window optimized for use with CZT. System sensitivity, spatial resolution, and tumor contrast-to-noise ratio (CNR) were measured comparing standard collimation and energy window setting [126-154 keV (+10%, -10%)] with optimal collimation and a wide energy window [110-154 keV (+10%, -21%)].Compared to the standard collimator designs and energy windows for these two systems, use of registered optimized collimation and wide energy window increased system sensitivity by a factor of 2.8-3.6. Spatial resolution decreased slightly for both systems with new collimation. At 3 cm from the collimator face, LumaGem's spatial resolution was 4.8 and 5.6 mm with standard and optimized collimation; Discovery NM 750b's spatial resolution was 4.4 and 4.6 mm with standard and optimized collimation, respectively. For both systems, at tumor depths of 1 and 3 cm, use of optimized collimation and wide energy window significantly improved CNR compared to standard settings for tumors 8.0 and 9.2 mm in diameter. At the closer depth of 1 cm, optimized collimation and wide energy window also significantly improved CNR for 5.9 mm tumors on Discovery NM 750b.Registered optimized collimation and wide energy window yield a substantial gain in count sensitivity and measurable gain in CNR, with some loss in spatial resolution compared to the standard collimator designs and energy windows used on these two systems. At low-count densities calculated to represent doses of 148 MBq, this tradeoff results in adequate count density and lesion contrast for detection of lesions ≥8 mm in the middle of a typical breast (3 cm deep) and lesions ≥6 mm close to the collimator (1 cm deep).
| S-EPMC3376156 | biostudies-other
Project description:Molecular breast imaging (MBI) has shown promise as an adjunct screening technique to mammography for women with dense breasts. The demonstration of reliable lesion detection with MBI performed at low administered doses of Tc-99 m sestamibi, comparable in effective radiation dose to screening mammography, is essential to adoption of MBI for screening. The concept of performing low-dose MBI with dual-head cadmium zinc telluride (CZT) gamma cameras has been investigated in phantoms in Part I. In this work, the objectives were to evaluate the impact of the count sensitivity improvement methods on image quality in patient MBI exams and to determine if adequate lesion detection could be achieved at reduced doses.Following the implementation of two count sensitivity improvement methods, registered collimation optimized for near-field imaging and energy acceptance window optimized for CZT, MBI exams were performed in the course of clinical care. Clinical image count density (counts/cm(2)) was compared between standard MBI [740 MBq (20 mCi) Tc-99 m sestamibi, standard collimation, standard energy window] and low-dose MBI [296 MBq (8 mCi) Tc-99 m sestamibi, optimized collimation, wide energy window] in a cohort of 50 patients who had both types of MBI exams performed. Lesion detection at low doses was evaluated in a separate cohort of 32 patients, in which low-dose MBI was performed following 296 MBq injection and acquired in dynamic mode, allowing the generation of images acquired for 2.5, 5, 7.5, and 10 min/breast view with proportionately reduced count densities. Diagnostic accuracy at each count density level was compared and kappa statistic was used to assess intrareader agreement between 10 min acquisitions and those at shorter acquisition durations.In patient studies, low-dose MBI performed with 296 MBq Tc-99 m sestamibi and new optimal collimation/wide energy window resulted in an average relative gain in count density of 4.2 ± 1.3 compared to standard MBI performed with 740 MBq. Interpretation of low-dose 296 MBq images with count densities corresponding to acquisitions of 2.5, 5, 7.5, and 10 min/view and median lesion size of 1.4 cm resulted in similar diagnostic accuracy across count densities and substantial to near-perfect intrareader agreement between full 10 min-views and lower count density views.Review of patient studies showed that registered optimized collimation and wide energy window resulted in a substantial gain in count sensitivity as previously indicated by phantom results. This proof of concept work indicates that MBI performed at administered doses of 296 MBq Tc-99 m sestamibi with the applied count sensitivity improvements permits the detection of small breast lesions in patients. Findings suggest that further reductions in acquisition duration or administered dose may be achievable.
| S-EPMC3376157 | biostudies-other
Project description:BackgroundDue to the shortage of donor hearts, the criteria for acceptance have been considerably expanded. Hearts with regional or global left ventricular dysfunction are excluded from donation, but stress echo might be useful to identify patients with reversible wall motion abnormalities, potentially eligible for donation.MethodsSix marginal candidate donors (mean age, 40 ± 13 years; three men) were enrolled. Resting echocardiography showed in all subjects a LV ejection fraction ? 45% (mean 51 ± 5%), but multiple risk factors were present. All donors had either global or discrete wall motion abnormalities: Wall Motion Score Index (WMSI) rest = 1.33 ± 0.25. Stress echocardiography was performed with the dipyridamole high dose of 0.84 mg/kg given over 6 min.ResultsThe stress echo results were abnormal in three donors (WMSI rest = 1.51 ± 0.19 vs peak = 1.41 ± 0.30). These hearts were excluded from donation and cardiac pathology verification was available in two cases of confirmed LV myocardial fibrosis and/or severe coronary stenosis. The remaining three hearts improved during stress (WMSI rest = 1.15 ± 0.13 vs peak = 1.04 ± 0.06) and were transplanted uneventfully. Recipients (three males, mean age 53 ± 4 years) underwent post-TX coronary angiography, IVUS and endomyocardial biopsies. No recipient had primary graft failure, and all showed normal coronary angiography and normal LV function (EF = 57 ± 6%; WMSI = 1 ± 0) at 1-month post-TX. The recipients were alive at 12-month median follow-up.ConclusionsDipyridamole stress echo performed in brain-dead potential donors with LV resting global or discrete wall motion abnormalities identifies hearts with severe morphologic abnormalities excluded from donation (with fixed response during stress echo) from hearts eligible for donation, showing improvement in regional wall motion during stress (viability response) and normal function and coronary anatomy following transplantation.
| S-EPMC3735394 | biostudies-literature
Project description:5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR's pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.
| S-EPMC6898594 | biostudies-literature