Low-dose Administration Research Articles

A model of alcoholic liver disease based on different hepatotoxics leading to liver cancer

The worst-case scenario related to alcoholic liver disease (ALD) arises after a long period of exposure to the harmful effect of alcohol consumption along with other hepatotoxics. ALD encompasses a broad spectrum of liver-associated disorders, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Based on the chronic administration of different hepatotoxics, including ethanol, sucrose, lipopolysaccharide, and low doses of diethylnitrosamine over a short period, here we aimed to develop a multiple hepatotoxic (MHT)-ALD model in the mouse that recapitulates the human ALD-associated disorders. We demonstrated that the MHT-ALD model induces ADH1A and NXN, an ethanol metabolizer and a redox-sensor enzyme, respectively; promotes steatosis associated with the induction of the lipid droplet forming FSP27, inflammation identified by the infiltration of hepatic neutrophils-positive to LY-6G marker, and the increase of MYD88 level, a protein involved in inflammatory response; and stimulates the early appearance of cellular senescence identified by the senescence markers SA-β-gal activity and p-H2A.XSer139. It also induces fibrosis associated with increased desmin, a marker of hepatic stellate cells whose activation leads to the deposition of collagen fibers, accompanied by cell death and compensatory proliferation revealed by increased CASP3-mediated apoptosis, and KI67- and PCNA-proliferation markers, respectively. It also induces histopathological traits of malignancy and the level of the HCC marker, GSTP1. In conclusion, we provide a useful model for exploring the chronological ALD-associated alterations and stages, and addressing therapeutic approaches.

Early intravenous hydrocortisone in sepsis: A randomized control trial (Protocol)

Background: The evidence of the appropriate timing of hydrocortisone is still weak and controversial. Observational studies showed a trend towards greater benefits when hydrocortisone was given earlier in the course of septic shock resuscitation. This study evaluates the effects of early intravenous low-dose hydrocortisone administered at the beginning of the onset of sepsis-induced hypotension compared with standard care. Methods: This study is a single-center, parallel-group, double-blinded, randomized control trial, conducted in a non-trauma emergency department. Adult patients with sepsis-induced hypotension will be included. Patients will be randomly assigned in a 1:1 ratio to receive early intravenous low-dose hydrocortisone or standard care. Blood inflammatory biomarkers at baseline will be collected. The primary outcome is 28-day mortality. Resuscitation-related secondary outcomes and safety outcomes will also be observed. Outcomes will be compared between groups. Subgroup analyses considering inflammatory biomarker levels will also be performed to evaluate the effect of early intravenous hydrocortisone, especially in patients with hyperinflammation. Hypothesis: We hypothesize that early intravenous low-dose hydrocortisone administration in patients with sepsis-induced hypotension would result in less mortality and improve resuscitation outcomes, especially in subgroup of patients with hyperinflammation. Ethics and dissemination: The study protocol was approved by the Siriraj Institutional Review Board with the certificate of approval number Si 917/2023. Trial registration: Clinicaltrial.gov NCT06217939

Knowledge, attitudes, and practices on antimicrobial use and antimicrobial resistance among poultry practitioner veterinarians.

Antimicrobial resistance (AMR) poses a serious global threat to human and animal health. In the context of antimicrobial usage (AMU) in livestock production, veterinarians are key stakeholders. However, there is a lack of comprehensive situational analysis regarding the current Knowledge, Attitudes, and Practices (KAP) among veterinarians concerning AMU and AMR in poultry production in Nepal. The primary objective of this study was to evaluate the situation of AMU and KAP regarding AMU and AMR of among poultry practitioner veterinarians in Nepal. A total of 327 respondents from 56 districts across seven provinces participated. Demographic information and AMU situation were collected and analyzed using descriptive statistics, and factors affecting KAP on AMU and AMR were performed using logistic regression analysis. Nearly half of veterinarians (49.2%) were from Bagmati, followed by Lumbini (16.5%) and Gandaki (8.9%) provinces. Most of the respondents (85.0%) identified themselves as male with a mean age of 31.9 ± 7.8 years, with a range of 24-74 years. A large proportion of veterinarians held a master's degree (43.8%). Regarding reasons for AMR, 51.1% of them attributed it to the irrational use of antimicrobials. Other identified reasons for AMR, including over-the-counter sales (27.8%), low-dose administration (12.3%), and low-quality antimicrobials (6.7%). Based on antibiotic prescription rates, most veterinarians (50.8%) prescribed antimicrobials at a rate of 20-40%, while 25.9% prescribed at a rate of less than 20.0 and 18.9% at a rate of 40-60%. Approximately 89.0% of veterinarians agreed that vaccination could reduce the use of antimicrobials in poultry, and 75.6% preferred narrow-spectrum antimicrobials than broad-spectrum antimicrobials. A combination of broad-spectrum antimicrobials such as colistin with amoxicillin, gentamicin, tylosin, and tetracycline was commonly used in poultry production. In logistic regression analysis, it was observed that veterinarians aged 45-60 years demonstrated significantly higher levels of knowledge concerning AMU and AMR (p = 0.02) compared to those in the 24-30 age group. This study indicates that the need for robust regulatory mechanisms in veterinary drug administration and increased awareness among veterinarians to address the AMR issue livestock production.

Trans men can achieve adequate muscular development through low-dose testosterone therapy: A long-term study on body composition changes.

Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT. To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose. Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5mg/wk) to a high-dose group(>62.5mg/wk). Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3mo, P=0.006, P<0.001; 6mo, P=0.015, P<0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia. Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass.

Clinical Efficacy and Safety of Low-Dose Pemafibrate in Patients With Severe Renal Impairment: A Retrospective Study.

The management of hypertriglyceridemia in patients with chronic kidney disease (CKD) is important. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator with less toxic effects on liver and kidney function than those of other fibrates, has recently been approved for the treatment of patients with an estimated glomerular filtration rate (eGFR) lower than 30mL/min/1.73 m2. However, the efficacy and safety of pemafibrate in patients with severe renal impairment have not yet been established. This single-center, retrospective observational study included 12 outpatients with CKD and hypertriglyceridemia, who were newly started on low-dose pemafibrate (0.1 mg/day) treatment between December 2021 and May 2023 and whose eGFRs were less than 30 mL/min/1.73 m2 at baseline. Blood samples were collected before and at 12 weeks after pemafibrate treatment. After 12 weeks of treatment, the serum triglyceride level was significantly decreased, whereas the high-density lipoprotein cholesterol level was significantly increased. The serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and uric acid levels were also significantly decreased, without worsening of the eGFR and serum creatinine levels. In the subgroup analysis, there were no significant differences in the changes in clinical parameters regardless of statin use and CKD stage at baseline. Low-dose pemafibrate administration in patients with severe renal impairment resulted in significant improvements in triglyceride, high-density lipoprotein cholesterol, and serum uric acid levels, and liver function, without adverse events.

Inflammatory Response Modulation by Low-Dose Anti-inflammatory Drugs Treatment in an In Vitro Osteoarthritis Cellular Model.

Low-dose-medicine is based on the administration of low doses of biological regulators to restore the immunologic balance altered in the disease. Cytokines are pivotal regulators of cellular and tissue functions and impaired crosstalk, due to an imbalance between specific cytokines, it is fundamental in acute inflammation and diseases correlated to low-grade chronic inflammation. Osteoarthritis is the most prevalent arthritic disease and a leading cause of disability. In the treatment of muscle- skeletal pathologies, the therapeutic integration of conventional medicine with homotoxicology, or low-dose-medicine appears to be beneficial. This study aims to get more insights into the role of inflammatory cytokines and chemokines during the development of osteoarthritis and to evaluate a possible blocking strategy using anti-inflammatory molecules, we resort to an in vitro experimental model using an established human chondrosarcoma cell line that underwent to a well known pro-inflammatory stimulus as bacterial lipopolysaccharide. We tested the production of inflammatory-related cytokines and chemokines, and the efficacy of low-dose (LD) administration of anti-inflammatory compounds, namely IL-10 and anti-IL-1, to block inflammatory cellular pathways. Following an inflammatory insult, chondrocytes upregulated the expression of several pro-inflammatory cyto-/chemokines and this induction could be counteracted by LD IL-10 and anti-IL-1. We reported that these effects could be ascribed to an interfering effect of LD drugs with the NF-κB signaling. Our results provided a good indication that LD drugs can be effective in inhibiting the inflammatory response in chondrocytes opening the way to new therapies for the treatment of diseases such as osteoarthritis.

Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting “no-threshold” concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies.

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

Dysphagia as a Missing Link Between Post-surgical- and Opioid-Related Pneumonia.

Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk. Eight healthy adult cats were evaluated to determine changes in airway protection status and for evidence of dysphagia in two experiments. (1) In four female cats, airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015mg/kg, IM, q8-12h; n = 5). (2) Using a cross-over design, four naive cats (2 male, 2 female) were treated with moderate-dose (0.02mg/kg) or high-dose (0.04mg/kg) buprenorphine (IM, q8-12h; n = 5). Airway protection was significantly affected in both experiments, but the most severe deficits occurred post-surgically as 75% of the animals exhibited silent aspiration. Oropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the postoperative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations.

Adjusting and validating a procedure for parenteral anaesthesia in neonatal mice.

For neonatal pups, parenteral anaesthesia is said to be not reliable as low doses induce no anaesthesia whereas high doses render high mortality rates. In this work we have adapted parenteral anaesthesia procedures approved for pups >7 days of age, to anaesthetize neonatal animals (postnatal days 3-4; P3-P4) for keeping them immobile for a long period. In our first experiment we analysed the behaviour of P3-P4 mouse pups for 70 min after intraperitoneal administration of low (37.5/3.75 mg/kg) or high (50/5) doses of a ketamine/xylazine anaesthetic mixture, both in the low range as compared with dosages employed in adults. Pups became immobile in ≈7 min and remained immobile for ≈45 min, irrespective of the age and dose of anaesthesia, younger pups (P3) being apparently more sensitive to the dosage. In the second experiment, we studied the response of P3 pups to mildly nociceptive stimulations, performed with a 4.0 g von Frey filament applied to the dorsal aspect of their paws. These stimuli elicited reaction in 100% of the cases in non-anaesthetized pups. The results indicate that the high dose significantly reduced responses as compared with the low dose of anaesthesia. With the low dose, <40% of the pups were unresponsive to nociceptive stimulation, whereas the high dose resulted in 50-60% of the animals not responding. Mortality was low irrespective of age or dose, suggesting that doses can be further increased if needed for invasive experimental procedures.

Secondary Prophylaxis of Venous Thromboembolism (VTE) with Low Dose Apixaban or Rivaroxaban: Results from a Patient Population with More than 2 Years of Median Follow-up.

Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up. The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months. The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC. Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.

Local Low-dose Anti-PD-L1 Antibodies Improve Antitumor Effects in Oral Squamous Cell Carcinoma.

Immune checkpoint inhibitors are highly effective for treating recurrent and metastatic head and neck cancers. However, they require systemic administration and are associated with immune-related adverse events (irAEs). Reducing therapeutic antibody doses to prevent irAEs is challenging. Mouse buccal mucosa squamous cell carcinoma cells (Sq-1979) were transplanted into the backs of mice to induce tumors. The antitumor efficacy and tumor immunohistological environment in tumor-bearing mice were compared after administering a standard dose of programmed death-ligand 1 (PD-L1) antibodies systemically (200 mg/body) or 1/10th of the standard dose (20 mg/body) directly to tumors. Mice received four doses of antibody administered in 3-day intervals. Tumor reduction rates and antitumor efficacies were evaluated 21 days after initiating treatment. CD8+T cell counts and PD-L1, PD-1, perforin, and granzyme B levels; CD25 and Foxp3 expression levels; and tumor Tregs were assessed in the resected subcutaneous tumors. The antitumor efficacies in the local low-dose and systemic standard-dose groups were compared with that of the control group. The efficacies of the two treatment groups were similar, and both treatment groups revealed significant antitumor effects compared to the control group. Perforin and granzyme B levels were higher in the local low-dose group (p<0.05). Local low-dose administration of anti-PD-L1 antibodies exhibits antitumor efficacy similar to systemic standard-dose administration suggesting that local low-dose administration is useful for treating oral squamous cell carcinoma.

Low-dose GBCA administration for brain tumour dynamic contrast enhanced MRI: a feasibility study

A key limitation of current dynamic contrast enhanced (DCE) MRI techniques is the requirement for full-dose gadolinium-based contrast agent (GBCA) administration. The purpose of this feasibility study was to develop and assess a new low GBCA dose protocol for deriving high-spatial resolution kinetic parameters from brain DCE-MRI. Nineteen patients with intracranial skull base tumours were prospectively imaged at 1.5 T using a single-injection, fixed-volume low GBCA dose, dual temporal resolution interleaved DCE-MRI acquisition. The accuracy of kinetic parameters (ve, Ktrans, vp) derived using this new low GBCA dose technique was evaluated through both Monte-Carlo simulations (mean percent deviation, PD, of measured from true values) and an in vivo study incorporating comparison with a conventional full-dose GBCA protocol and correlation with histopathological data. The mean PD of data from the interleaved high-temporal-high-spatial resolution approach outperformed use of high-spatial, low temporal resolution datasets alone (p < 0.0001, t-test). Kinetic parameters derived using the low-dose interleaved protocol correlated significantly with parameters derived from a full-dose acquisition (p < 0.001) and demonstrated a significant association with tissue markers of microvessel density (p < 0.05). Our results suggest accurate high-spatial resolution kinetic parameter mapping is feasible with significantly reduced GBCA dose.

Targeting nuclear receptor corepressors for reversible male contraception

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

The safety and efficacy of intra-arterial low-dose tirofiban administration during endovascular therapy in patients with large ischemic core volume

This study aimed to evaluate the safety and efficacy of intra-arterial (IA) administration of low- dose tirofiban during endovascular therapy in patients with large ischemic core volumes on initial brain CT. Patients were divided into two groups based on the use of IA tirofiban. We identified 87 patients (16 and 71 patients in the tirofiban and no-tirofiban groups, respectively) with acute ischemic stroke due to intracranial artery occlusion who underwent endovascular therapy with a low Alberta Stroke Program Early CT scores (2–5). Multivariate logistic regression analysis revealed no association between IA tirofiban administration and serious postprocedural hemorrhagic complications (adjusted odds ratio (aOR), 0.720; 95% confidence interval (CI) 0.099–5.219; p = 0.960), any radiologic hemorrhage (aOR 0.076; 95% CI 0.003–2.323; p = 0.139), or 3-month mortality (aOR, 0.087; 95% CI 0.005–1.501; p = 0.093). However, IA tirofiban was associated with a lower 90-day mRS score (aOR, 0.197; 95% CI 0.015–1.306; p = 0.017) and change of NIHSS compared with baseline (aOR, 0.698; 95% CI 0.531–0.917; p = 0.010). IA tirofiban administration during endovascular therapy in patients with large ischemic core volumes may be effective and safe.

Safety and Efficacy of Low-Dose Eptifibatide for Tandem Occlusions in Acute Ischemic Stroke.

The optimal treatment strategy for ischemic stroke in patients presenting with tandem occlusions of the internal carotid artery remains controversial. Several studies have demonstrated better clinical outcomes after eptifibatide, which is a short half-life antiplatelet agent. This retrospective analysis focused on the safety and efficacy of low-dose eptifibatide administration in stroke patients with tandem lesions. We evaluated the results of endovascular treatment in 148 stroke patients with tandem lesions. Patients in whom balloon angioplasty alone resulted in satisfactory cerebral flow did not receive eptifibatide (33 patients); others received this drug together with stent implantation (115 patients). Eptifibatide was given as an intravenous bolus of 180 μg/kg and then in a modified low dose of 1 μg/kg/min for 24 hours. There were no statistically significant differences between both groups regarding 30-day mortality, frequency of thrombotic events, or hemorrhagic complications. An analysis of clinical status at 30-day follow-up revealed that the administration of eptifibatide was associated with a statistically significant better outcome: a higher rate of either no neurological symptoms or only mild symptoms (4 NIHSS points maximally). The administration of eptifibatide in stroke patients presenting with tandem lesions is relatively safe. Moreover, treatment with this drug can improve clinical outcomes in these challenging patients.

EFEKTIFITAS PEMBERIAN ASPIRIN DOSIS RENDAH UNTUK MENCEGAH PREEKLAMSIA DI RSPAL DR. RAMELAN SURABAYA

Background: Preeclampsia is a multisystem disorder in pregnancy. In developing countries, cases of preeclampsia are 7 times higher than in developed countries with a prevalence of 1.8%−18%. First-trimester screening needs to be done in detecting preeclampsia in every pregnant woman and preeclampsia prevention strategies with aspirin have proven effective in previous studies.&#x0D; Research Objectives: To determine the effectiveness of low-dose aspirin administration to prevent preeclampsia at dr. Ramelan for the period 13 June 2019 – 30 September 2021.&#x0D; Research Methods: The research design used in this study was descriptive using a retrospective cohort study. Researchers used secondary data in the form of patient medical records with a total sample of 118 patients.&#x0D; Results: From a total sample of 118 people, 30.5% had preeclampsia and 66.1% of patients who were given low-dose aspirin.&#x0D; Conclusion: Pregnant women who experienced preeclampsia after being given low-dose aspirin were recorded in 31 of 78 patients (39.7%) and pregnant women who experienced preeclampsia when not given low-dose aspirin were recorded in 5 of 40 patients (12.5%).&#x0D;

A Short Post-Reattachment Ultrasensitive Window of Time in Human Cancer Cells as Therapeutic Target of Prolonged Low-Dose Administration of Specific Compounds.

Prolonged low-dose administration (PLDA) of several FDA-approved drugs for noncancer conditions or dietary compounds is associated with a lower incidence of specific types of cancers and with the lower formation of metastasis. However, the underlying mechanism is unknown; there is a discrepancy between the concentration of drugs needed to kill cancer cells in vitro and the actual serum levels (10 and >1000 times lower) found in patients. In this study, we evaluated the hypothesis that clonogenicity may be the target of PLDA. We compared the effect of nigericin (NIG) and menadione (MEN) on the human A549 and H460 lung and MCF-7 and MDA-MB-231 breast cancer cell lines using routine MTT and colony forming assays (CFA). The ability of both NIG and MEN to eliminate 100% of cancer cells was at least 2-10 times more potent in CFA compared to MTT assays. Our results revealed the existence of a short post-reattachment window of time when cancer cells growing at low density are more sensitive to PLDA of specific drugs likely by targeting clonogenic rather than proliferation pathways. This short ultrasensitive window of time (SUSWoT) was cell- and drug-type specific: the SUSWoT for NIG was present in H460, A549, and MDA-MB-231 cells but not evident in MCF-7 cells. Conversely, a similar SUSWoT for MEN was present in MCF-7, MDA-MD-231, and A549 cells but not evident in H460 cells. Our findings partially explain the decreased incidence of specific types of cancer by PLDA of FDA-approved drugs (or dietary compounds) for noncancer conditions.

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use

BackgroundMethotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment.MethodsWe used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA.ResultsAfter identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs.ConclusionsStudies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

Potential therapeutic target for polysaccharide inhibition of colon cancer progression.

In recent years, colon cancer has become one of the most common malignant tumors worldwide, posing a great threat to human health. Studies have shown that natural polysaccharides have rich biological activities and medicinal value, such as anti-inflammatory, anti-cancer, anti-oxidation, and immune-enhancing effects, especially with potential anti-colon cancer mechanisms. Natural polysaccharides can not only protect and enhance the homeostasis of the intestinal environment but also exert a direct inhibition effect on cancer cells, making it a promising strategy for treating colon cancer. Preliminary clinical experiments have demonstrated that oral administration of low and high doses of citrus pectin polysaccharides can reduce tumor volume in mice by 38% (p < 0.02) and 70% (p < 0.001), respectively. These results are encouraging. However, there are relatively few clinical studies on the effectiveness of polysaccharide therapy for colon cancer, and ensuring the effective bioavailability of polysaccharides in the body remains a challenge. In this article, we elucidate the impact of the physicochemical factors of polysaccharides on their anticancer effects and then reveal the anti-tumor effects and mechanisms of natural polysaccharides on colon cancer. Finally, we emphasize the challenges of using polysaccharides in the treatment of colon cancer and discuss future applications.