Low-dose Group Research Articles

Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: which dose is more suitable?

Cisplatin is a widely used and potent cytotoxic chemotherapy agent, but its nephrotoxicity is a significant limiting side effect. Various premedication approaches have been implemented to preserve renal function, including magnesium (Mg) preloading. However, the optimal Mg dosage is still unknown. Our study aimed to assess the protective effects of different Mg doses as premedication in cisplatin-based chemoradiotherapy for patients with local/locally advanced cervical and head-neck cancers. This retrospective, multicenter study involved premedication with saline infusion containing potassium chloride and magnesium sulfate (MgSO4) for all patients before cisplatin treatment. Patients were divided into two groups: 12 mEq MgSO4 (low-dose Mg preload group, low-Mg) and 24 mEq MgSO4 (high-dose Mg preload group, high-Mg). Renal function was evaluated using serum creatinine (sCr, mg/dl) and estimated glomerular filtration rate (eGFR, ml/min). Acute kidney injury (AKI) was defined per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Renal outcomes and efficacy were compared between the groups. In the low-Mg group (n = 159), sCr levels were significantly higher compared to baseline, various weeks during treatment, and at the 1st, 3rd, 6th, and 12th months post-treatment (p < 0.001). In the high-Mg group (n = 128), no significant changes were observed during treatment and at 1st, 3rd, and 12th months post-treatment (p > 0.05). A significant reduction in mean sCr level from baseline to 6 months was noted in the high-Mg group (p < 0.001). eGFR values are generally correlated with sCr levels. AKI occurred in 21 (13.2%) and 22 (17.7%) patients in the low-Mg and high-Mg groups, respectively (p = 0.292). There was no difference in progression-free or overall survival between the groups. We clearly demonstrated that saline hydration with 24 mEql MgSO4 supplementation before cisplatin treatment has a better renal protective effect than 12 mEql MgSO4 without reducing efficacy, especially in patients with local/local advanced cervical and head-neck cancer receiving cisplatin with concurrent radiotherapy.

Mechanism of total saponins of Panax japonicus against liver injury induced by acetaminophen in mice based on ERK/NF-κB/COX-2 signaling pathway

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1β), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1β, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1β, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1β, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.

The Effect of Gestational PFOS Exposure on Metabolism in the F344 Rat

Perfluorooctanesulfonate (or PFOS) is a type of PFOA known as (per-and poly-fluorinated alkylated substance) which is a manufactured compound chemical made of a strong carbon-fluorine and sulfonic acid. Due to its hydrophobic and lipophobic properties, industries use it in food wrappers, fire-fighting foam, sweat-proof clothing, and household cleaning products. PFOS exposure is an endocrine disruptor that may induce Metabolic Syndrome (MetS), an association of disorders that increases the risk of significant health issues like heart disease, diabetes, and stroke. Gestational and lactational exposure to Perfluorooctanesulfonate (PFOS) in F344/Stm rats was hypothesized to induce metabolic dysfunction in both female and male offspring. Pregnant F344 rats were given a control diet or diet containing 15mg/kg or 30mg/kg of PFOS; measures of body weight and body composition through nuclear magnetic resonance (NMR) were performed, and tissue was measured at the euthanasia of the dams. Both female and male offspring exposed during pregnancy and lactation were subject to the same protocol with tissue collection at three ages. On both low and high doses of PFOS, the pregnant females showed a decreased body weight gain compared to the control group; males and females also showed decreased body weight at three weeks of age when weaned from the exposed female. At 16 weeks of age, the same patterns were not revealed. The results from NMR suggested a 21% decrease in fat percentage and a 23% decrease in fat for the high exposure in the dams. The offspring at three weeks old showed a reduction in fat mass, fat mass %, and fat-free % in both high and low-dose groups compared to the control group; on the other hand, at 16 weeks old, this trend is not shown. The results suggest that PFOS had a short-term metabolic effect on the offspring at the younger; however, at the adult age, they seem to recover their initial phenotypes. For future studies, it suggested the focus on underlying mechanisms responsible for the rodent's recovery. ASPIRE Program (R25HL168782) Medical College of Wisconsin. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the efficacy and mechanism of Bailing capsule to improve polycystic ovary syndrome in mice based on intestinal-derived LPS-TLR4 pathway

Ethnopharmacological relevancePolycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive dysfunction and metabolic abnormalities, particularly characterized by insulin resistance and chronic low-grade inflammation. Multiple clinical studies have clearly demonstrated the significant efficacy and safety of the combination of Bailing capsules (BL) in the treatment of PCOS, but its pharmacological effects and mechanisms still require further study. Aim of the studyTo evaluate the effect of BL on improving PCOS in mice and explore the mechanism. MethodsIn this study, Dehydroepiandrosterone (DHEA) injection was administered alone and in combination with a high-fat and high-sugar diet to induce PCOS-like mouse. They were randomly divided into five groups: normal group (N), PCOS group (P), Bailing capsule low-dose group (BL-L), Bailing capsule high-dose group (BL-H) and Metformin + Daine-35 group (M + D). Firstly, the effects of BL on ovarian lesions, serum hormone levels, HOMA-IR, intestinal barrier function, inflammation levels, along with the expression of IRS1, PI3K, AKT, TLR4, Myd88, NF-κB p65, TNF-α, IL-6, and Occludin of the ovary, liver and colon were investigated. Finally, the composition of the gut microbiome of fecal was tested. ResultsThe administration of BL significantly reduced body weight, improved hormone levels, improved IR, and attenuated pathological damage to ovarian tissues, up-regulated the expression of IRS1, PI3K, and AKT in liver. It also decreased serum LPS, TNF-α, and IL-6 levels, while downregulating the expression of Myd88, TLR4, and NF-κB p65. Additionally, BL improved intestinal barrier damage and upregulated the expression of Occludin. Interestingly, the abundance of norank_f__Muribaculacea and Lactobacillus was down-regulated, while the abundance of Akkermansia was significantly up-regulated. ConclusionThe results of the study showed that BL exerts a treatment PCOS effect, which may be related to the modulation of the gut microbiota, the improvement of insulin resistance and the intestinal-derived LPS-TLR4 inflammatory pathway. Our research will provide a theoretical basis for the clinical treatment of PCOS.

The impact of bacillus pumilus TS2 isolated from yaks on growth performance, gut microbial community, antioxidant activity, and cytokines related to immunity and inflammation in broilers.

Intensive poultry farming faces challenges like gut inflammation in the absence of antibiotics, resulting in reduced productivity, heightened susceptibility to enteric diseases, and other complications. Alternative strategies are needed to manage inflammation and maintain sustainable poultry production. Yaks living in high-altitude hypoxic environments have specialized gut microbes. However, yak probiotics remain largely uncharacterized. We previously isolated a strain of Bacillus pumilus (named TS2) from yaks and demonstrated its potential as a probiotic in vitro. Therefore, in this study, we evaluated the in vivo growth-promoting, antioxidant, immune, and anti-inflammatory effects of Bacillus pumilus isolated from yaks in broilers. We demonstrated the safety of TS2 isolated from yaks in broilers. Furthermore, we found that TS2 increased the average daily weight gain (ADWG) and reduced the feed conversion ratio (FCR). Supplementation with TS2 also improved the mucosal morphology, the ratio of villi to crypt cells, and enzyme activity. High-throughput sequencing showed that the abundance of Lactobacillus was higher in the TS2 treated broilers. Importantly, the serum level of malondialdehyde (MDA) was reduced and the levels of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity were increased in the low-dose TS2 group, while the inflammatory factors interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were downregulated compared with the control group. We demonstrated that TS2 supplementation can increase the overall growth performance and ameliorate the blood parameters related to inflammation and immunity in broilers.

The renoprotective activity of amikacin–gamma-amino butyric acid–chitosan nanoparticles: a comparative study

The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection. The AMK–GABA–CSNPs were prepared with the ionic gelation method, the morphology was studied using transmission electron microscopy (TEM), zetasizer and the Fourier transform-infrared spectroscopy (FT-IR) spectrum of the synthesized NPs was observed. The average size of AMK–GABA–CSNPs was 77.5 ± 16.5 nm. Zeta potential was + 38.94 ± 2.65 mV. AMK–GABA–CSNPs revealed significant in vitro antioxidant, anti-coagulation, non-hemolytic properties and good cell compatibility. To compare the effects of the unloaded AMK–GABA combination and AMK–GABA–CSNPs on the renal tissue, 42 healthy Sprague–Dawley rats were divided into seven groups. G1: normal control (NC), normal saline; G2: low-dose nephrotoxic group (LDN), AMK (20 mg/kg/day; i.p.); G3: unloaded AMK (20 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.); G4: AMK–GABA–CSNPs (20 mg/kg/day; i.p.); G5: high-dose nephrotoxic group (HDN), AMK (30 mg/kg/day; i.p.); G6: unloaded AMK (30 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.) and G7: AMK–GABA–CSNPs (30 mg/kg/day; i.p.). The results showed that AMK–GABA–CSNPs formulation is superior to unloaded AMK–GABA combination as it ameliorated kidney functions, oxidative stress and displayed a significant homeostatic role via suppression of inflammatory cytokines of Th1, Th2 and Th17 types. Hence, AMK–GABA–CSNPs could afford a potential nano-based therapeutic formula for the management of AMK-nephrotoxicity.

P084 Gout symptom improvements and patient outcomes with SEL-212 in gout refractory to conventional therapy: DISSOLVE I &amp; II phase 3, double-blind, placebo-controlled clinical trials

Abstract Background/Aims Serum uric acid (sUA) ≥6.8 mg/dL often leads to severe clinical manifestations in gout refractory to conventional therapy. Uricase-based therapies can be effective, although immunogenicity can reduce efficacy and increase infusion-reaction risk. SEL-212 is a novel, once-monthly treatment of sequential infusions of tolerogenic nanoparticles containing sirolimus (SEL-110) followed by a pegylated uricase (pegadricase, SEL-037). DISSOLVE I and II (DI and DII) evaluated the safety/efficacy of SEL-212 in adults with refractory gout. Here we report secondary and key safety endpoints. Methods DI (US) and DII (Global) were placebo-controlled, double-blind, randomised clinical trials that evaluated a combination of SEL-110 at either 0.15 mg/kg [high-dose] or 0.1 mg/kg [low-dose] with SEL-037 (0.2 mg/kg) in refractory gout. Six-month outcomes included sUA reduction, number of tender/swollen joints, tophus burden, health-related quality-of-life, and safety. Results 112 participants (96% male, 66% aged ≥50 years, DI) and 153 participants (97% male, 72% ≥50 years, DII) were dosed (Table 1). Mean age was 55 years, 57% (DI) and 67% (DII) had tophi at baseline, and time since gout diagnosis was 12.9 (DI) and 11.0 years (DII). Both SEL-212 doses significantly reduced mean sUA levels versus placebo over 6-months (5.2-5.6 mg/dL in DI and 3.3-4.5 mg/dL in DII, p &amp;lt; 0.001 for all), with marked reductions during the first-treatment period. In DII, tender joints declined significantly between baseline and six-months in the high- and low-dose groups (8.1 joints, p = 0.003; 9.2 joints, p &amp;lt; 0.001, respectively) versus placebo (4.4 joints). Swollen joints were also significantly reduced with high-dose SEL-212 (5.7 joints, p = 0.013) versus placebo (3.4 joints). There were significant improvements in SF-36 physical component score with both SEL-212 doses versus placebo (p ≤ 0.01), while HAQ-DI was significantly improved with low-dose versus placebo (p = 0.018) in DII. In DI non-statistically significant trends favouring SEL-212 across all secondary endpoints were observed. This may reflect the smaller sample size and milder baseline symptom burden of patients in DI versus DII. Infusion reactions occurred in 3.4% of the combined high-dose groups. Conclusion SEL-212 was well tolerated and provided significant reductions in mean sUA over time, improvement in SF-36 physical and HAQ-DI measures and reduced the number of tender/swollen joints. Disclosure H.S.B. Baraf: Corporate appointments; Sobi, Selecta BioScience, Grünenthal, Fresenius Kabi and Olatec. Member of speakers’ bureau; Horizon Pharmaceuticals. Grants/research support; Horizon Pharmaceuticals, Swedish Orphan Biovitrum. P. Khanna: Consultancies; Horizon, Sobi. Other; Investigator: Selecta Bioscience, Dyve Biosciences. A. Patel: Member of speakers’ bureau; Lexicon Pharmaceuticals. J. Sobierska: Other; Employee of Sobi. J. Christie: Shareholder/stock ownership; GSK Pharma. Other; Employee of Sobi. W. DeHaan: Shareholder/stock ownership; Selecta Biosciences. Other; Employee of Selecta Biosciences. R. Azeem: Shareholder/stock ownership; Selecta Biosciences. Other; Employee of Selecta Biosciences;. P.G. Traber: Shareholder/stock ownership; Selecta Biosciences. Other; Employee of Selecta Biosciences. A. Kivitz: Consultancies; AXDEV Group, Amgen, Pfizer, Janssen, Boehringer Ingelheim, AbbVie, Flexion, Gilead, Grünenthal, Orion, Regeneron, Sun Pharma Advance Research, and ECOR1. Shareholder/stock ownership; Pfizer, GSK, Gilead, Novartis, and Amgen. Member of speakers’ bureau; Merck &amp; Co, Eli Lilly, Novartis, Pfizer, Flexion, AbbVie, Amgen, Genentech, Regeneron, UCB, Horizon, and GSK.

Mass spectrometry-based pseudotargeted metabolomics reveals metabolic variations in a2-induced gastric cancer cell.

Gastric cancer (GC) is one of the most malignant tumors with high morbidity and mortality in the world. Compound a2, a Jiyuan oridonin derivative, exhibited excellent anti-proliferative activity against GC cells. To investigate the gastric cellular response to a2 therapy as a novel drug candidate, we adopted a pseudotargeted metabolomics method to explore metabolic variation in a2-induced MGC-803 gastric cells using liquid chromatography tandem mass spectrometry combined with multivariate statistical analysis. The results showed that a2 treatment induced significant metabolic changes in the levels of aminoacyl-tRNA biosynthesis, alanine, aspartate and glutamate metabolism, pyrimidine metabolism, and tricarboxylic acid cycle, approximately 80% of the metabolites were down-regulated in the low-dose and high-dose groups including aspartate, tryptophan, sedoheptulose 7-phosphate, succinate, 2'-deoxyadenosine, uridine, cytidine, etc. which can provide evidence for a new therapy of GC.

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model.

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11h-1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials.

Low-dose IL-2 treatment confers anti-inflammatory effect against subarachnoid hemorrhage in mice

ObjectiveSubarachnoid hemorrhage (SAH) was a stroke with high occurrence and mortality. At the early stage, SAH patients have severe cerebral injury which is contributed by inflammation. In this study, we aimed to explore the anti-inflammation effect of low-dose IL-2 in SAH mice. MethodsThe 12-week-old C57BL/6J male mice were conducted with SAH surgery (Internal carotid artery puncture method). Different dose of IL-2 was injected intraperitoneally for 1 h, 1 day, and 2 days after SAH. Single-cell suspension and flow cytometry were used for the test of regulatory T (Treg) cells. Immunofluorescence staining was used to investigate the phenotypic polarization of microglia and inflammation response around neurons. Enzyme-Linked Immuno-sorbent Assay (ELISA) was applied to detect the level of pro-inflammatory factors. ResultsLow-dose IL-2 could enrich the Treg cells and drive the microglia polarizing to M2. The level of pro-inflammatory factors, IL-1α, IL-6, and TNF-α decreased in the low-dose IL-2 group. The inflammation response around neurons was attenuated. Low-dose IL-2 could increase the number of Treg cells, which could exert a neuroprotective effect against inflammation after SAH. ConclusionLow-dose IL-2 had the potential to be an effective clinical method to inhibit inflammation after SAH.

CROCuS, a Phase II Study Evaluating the Antiviral Activity, Clinical Outcomes, and Safety of Rilematovir in Children Aged ≥28 Days and ≤3 Years with Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children aged ≤5 years and adults aged ≥60 years worldwide. Despite this, RSV-specific therapeutic options are limited. Rilematovir is an investigational, orally administered inhibitor of RSV fusion protein-mediated viral entry. To establish the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir (low or high dose) in children aged ≥28days and ≤3years with RSV disease. CROCuS was a multicenter, international, double-blind, placebo-controlled, randomized, adaptive phase II study, wherein children aged ≥28 days and ≤3 years with confirmed RSV infection who were either hospitalized (Cohort 1) or treated as outpatients (Cohort 2) were randomized (1:1:1) to receive rilematovir (low or high dose) or placebo. Study treatment was administered daily as an oral suspension from days 1 to 7, with dosing based on weight and age groups. The primary objective was to establish antiviral activity of rilematovir by evaluating the area under the plasma concentration-time curve of RSV viral load in nasal secretions from baseline through day 5. Severity and duration of RSV signs and symptoms and the safety and tolerability of rilematovir were also assessed through day 28 (±3). In total, 246 patients were randomized, treated, and included in the safety analysis population (Cohort 1: 147; Cohort 2: 99). Of these, 231 were included in the intent-to-treat-infected analysis population (Cohort 1: 138; Cohort 2: 93). In both cohorts, demographics were generally similar across treatment groups. In both cohorts combined, the difference (95% confidence interval) in the mean area under the plasma concentration-time curve of RSV RNA viral load through day 5 was -1.25 (-2.672, 0.164) and -1.23 (-2.679, 0.227) log10 copies∙days/mL for the rilematovir low-dose group and the rilematovir high-dose group, respectively, when compared with placebo. The estimated Kaplan-Meier median (95% confidence interval) time to resolution of key RSV symptoms in the rilematovir low-dose, rilematovir high-dose, and placebo groups of Cohort 1 was 6.01 (4.24, 7.25), 5.82 (4.03, 8.18), and 7.05 (5.34, 8.97) days, respectively; in Cohort 2, estimates were 6.45 (4.81, 9.70), 6.26 (5.41, 7.84), and 5.85 (3.90, 8.27) days, respectively. A similar incidence of adverse events was reported in patients treated with rilematovir and placebo in Cohort 1 (rilematovir: 61.9%; placebo: 58.0%) and Cohort 2 (rilematovir: 50.8%; placebo: 47.1%), with most reported as grade 1 or 2 and none leading to study discontinuation. The study was terminated prematurely, as the sponsor made a non-safety-related strategic decision to discontinue rilematovir development prior to full recruitment of Cohort 2. Data from the combined cohort suggest that rilematovir has a small but favorable antiviral effect of indeterminate clinical relevance compared with placebo, as well as a favorable safety profile. Safe and effective therapeutic options for RSV in infants and young children remain an unmet need. EudraCT Number: 2016-003642-93; ClinicalTrials.gov Identifier: NCT03656510. First posted date: 4 September, 2018.

Evaluating the Effect of Maternal Opioid Maintenance Dose on the NOWS-COS Outcome Criteria: A Pilot Study.

This retrospective cohort study included 77 mother-infant dyads that delivered term pregnancies at a single tertiary care institution. The primary objective was to investigate whether maternal dose of opioid maintenance therapy during pregnancy affects infant outcomes. All infants had prenatal exposure to opioid maintenance therapies. Maternal dose was converted into morphine milligram equivalents (MMEs) and stratified into high- (MME >1000 mg) and low-dose groups (MME ≤1000 mg). Associations between infant outcomes and MME dosage were examined using Wilcoxon rank-sum and Fisher's Exact tests. Days to symptom control were significantly higher in the high MME group (5 days vs 2.8 days, P = .016). Rates of developmental delay at 24 months were higher in the high MME group (21.2% vs 4.5%, P = .0335). Maternal MME did not predict need for NOWS treatment. Higher MME-exposed infants should have optimized nonpharmacologic interventions for consolation and be increasingly observed for signs of developmental delay.

Behavioral toxicity and neurotoxic mechanisms of PLA-PBAT biodegradable microplastics in zebrafish

Escalation of ecological concern due to biodegradable plastics has attracted the attention of many contemporary researchers. This study searched to investigate the acute and sub-chronic toxicity of polylactic acid (PLA) and polybutyleneadipate-co-terephthalate (PLA-PBAT) bio-microplastics on 3-month-old zebrafish to elucidate their potential toxic mechanisms. Acute toxicity assessments revealed 96 h-LC50 value of 12.69 mg/L for PLA-PBAT. Sub-chronic exposure of over 21 days revealed deviations in critical behavioral patterns and physiological indicators. In treated groups, weight gain and specific growth rates were significantly lower than those obtained for the control group, such that high doses induced significant reductions in total organ coefficient (p < 0.05). A positive correlation was observed between zebrafish mortality and increased doses. Detailed behavioral evaluations revealed a dose-dependent decrease in the speed and range of swimming, along with modifications in shoaling behavior, anxiety-like responses, and avoidance behaviors. Brain tissues transcriptomic analyses revealed the molecular responses underlying sub-chronic exposure to PLA-PBAT. Totally 702 DEGs and 5 KEGG pathways were significantly identified in low-dose group, with the top 2 significant pathways being ribosome pathway and cytokine-cytokine receptor interaction pathway. Totally 650 DEGs and 5 KEGG pathways were significantly identified in medium-dose group, with the top 2 significant pathways being Herpes simplex virus 1 infection pathway and complement and coagulation cascades pathway. Totally 1778 DEGs and 16 KEGG pathways were significantly identified in high-dose group, with the top 2 significant pathways being metabolism of xenobiotics by cytochrome P450 and drug metabolism - cytochrome P450 pathway. Most significantly enriched pathways are associated with immune responses. The validation of key gene in cytokine-cytokine receptor interaction pathway also confirmed its high correlation with behavioral indicators. These results indicate that PLA-PBAT is likely to cause behavioral abnormalities in zebrafish by triggering immune dysregulation in the brain.

Reserpine-induced rat model for depression: Behavioral, physiological and PET-based dopamine receptor availability validation

BackgroundReserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT2) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes. MethodsExperiment 1. Following baseline behavior testing sensitive to depression-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D2/3 receptor PET scanning with [18F]DMFP following each Phase. The binding potential (BPND) of [18F]DMFP was quantified by kinetic analysis as a marker of striatal D2/3R availability. Weight and welfare were monitored throughout the study. ResultsSignificant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in D2R mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [18F]DMFP BPND (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls. ConclusionsThe longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity.

Repair effect of different doses of human umbilical cord mesenchymal stem cells on white matter injury in neonatal rats

To compare the repair effects of different doses of human umbilical cord mesenchymal stem cells (hUC-MSCs) on white matter injury (WMI) in neonatal rats. Two-day-old Sprague-Dawley neonatal rats were randomly divided into five groups: sham operation group, WMI group, and hUC-MSCs groups (low dose, medium dose, and high dose), with 24 rats in each group. Twenty-four hours after successful establishment of the neonatal rat white matter injury model, the WMI group was injected with sterile PBS via the lateral ventricle, while the hUC-MSCs groups received injections of hUC-MSCs at different doses. At 14 and 21 days post-modeling, hematoxylin and eosin staining was used to observe pathological changes in the tissues around the lateral ventricles. Real-time quantitative polymerase chain reaction was used to detect the quantitative expression of myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) mRNA in the brain tissue. Immunohistochemistry was employed to observe the expression levels of GFAP and neuron-specific nuclear protein (NeuN) in the tissues around the lateral ventricles. TUNEL staining was used to observe cell apoptosis in the tissues around the lateral ventricles. At 21 days post-modeling, the Morris water maze test was used to observe the spatial learning and memory capabilities of the neonatal rats. At 14 and 21 days post-modeling, numerous cells with nuclear shrinkage and rupture, as well as disordered arrangement of nerve fibers, were observed in the tissues around the lateral ventricles of the WMI group and the low dose group. Compared with the WMI group, the medium and high dose groups showed alleviated pathological changes; the arrangement of nerve fibers in the medium dose group was relatively more orderly compared with the high dose group. Compared with the WMI group, there was no significant difference in the expression levels of MBP and GFAP mRNA in the low dose group (P>0.05), while the expression levels of MBP mRNA increased and GFAP mRNA decreased in the medium and high dose groups. The expression level of MBP mRNA in the medium dose group was higher than that in the high dose group, and the expression level of GFAP mRNA in the medium dose group was lower than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the protein expression of GFAP and NeuN in the low dose group (P>0.05), while the expression of NeuN protein increased and GFAP protein decreased in the medium and high dose groups. The expression of NeuN protein in the medium dose group was higher than that in the high dose group, and the expression of GFAP protein in the medium dose group was lower than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the number of apoptotic cells in the low dose group (P>0.05), while the number of apoptotic cells in the medium and high dose groups was less than that in the WMI group, and the number of apoptotic cells in the medium dose group was less than that in the high dose group (P<0.05). Compared with the WMI group, there was no significant difference in the escape latency time in the low dose group (P>0.05); starting from the third day of the latency period, the escape latency time in the medium dose group was less than that in the WMI group (P<0.05). The medium and high dose groups crossed the platform more times than the WMI group (P<0.05). Low dose hUC-MSCs may yield unsatisfactory repair effects on WMI in neonatal rats, while medium and high doses of hUC-MSCs have significant repair effects, with the medium dose demonstrating superior efficacy.

A comparison of different dosing regimen of intravenous paracetamol for hemodynamically significant patent ductus arteriosus closure in premature neonates

To compare the efficacy of low vs conventional dose intravenous paracetamol in early closure of haemodynamically significant patent ductus arteriosus within 7 days of life. Preterm infants (<32 weeks of gestation) having echocardiographic evidence of hsPDA were given low dose (15 mg/kg initially followed by 7.5 mg/kg every 6 hourly) vs conventional dose (15 mg/kg every 6 hourly) for 5-7 days. In total, 56 infants (28 in each group) were enrolled. Ductal closure was achieved in 96% infants in the low-dose group and 100% infants in the conventional group (P = 1.00). Secondary outcomes, including ductal reopening and need for the second course of medical treatment (21% vs 3.5%, P = 0.1), median duration of hospital stay [30 (15, 43.5) vs 27 (18.5,45), P = 0.64], cumulative oxygen requirement [17.5 (7, 25) vs 14 (8.5, 25), P = 0.89], mortality (10.7% vs 25%, P = 0.29) and other morbidities, were comparable in both the groups. Median paracetamol levels were comparable in both the groups [53.4 μg/L (47, 2,70) vs 62.5 (55.6, 81.2), P = 0.67]. Low-dose paracetamol was non-inferior to conventional dose paracetamol for early ductal closure in preterm infants.

Effectiveness of Intravenous Low-Dose Ketamine Versus Morphine for Procedural Burn Pain Management During Dressing Changes: A Randomized Clinical Trial

Background: There is limited literature on using low-dose intravenous ketamine as a single agent for procedural burn pain management during adult dressing changes. Aims &amp; Objectives: To determine the effectiveness of low-dose ketamine compared to morphine as a single analgesic agent in procedural burn pain management during dressing changes. Materials &amp; Methods: We performed an institutional review board-approved, randomized, prospective, double-blinded, controlled, non-inferiority trial. All adult patients 18 years and above scheduled for dressing change were screened. Patients who consented were randomized to receive low-dose ketamine infusion at 0.2mg/kg/hr. In the treatment group, morphine infusion at 0.1mg/kg/hr. In the control group. The primary endpoint was pain intensity, measured using a visual analog scale. Data were analyzed on an intention-to-treat (ITT) approach. Secondary endpoints included rescue analgesia requirements and the occurrence of adverse effects in both groups. Results: 82 patients were enrolled (ketamine 41 vs. morphine 41). We compared VAS scores at 5-minute intervals during the dressing changes. Overall, pain scores are similar in both groups (p-value=0.595). The pain control was homogenous. However, the morphine group required more rescue analgesia throughout the dressing changes than the low-dose ketamine group (p=0.013 at T15, p&lt;0.001 at T20, and p&lt;0.001 at T30). The occurrence of side effects was similar in both groups. Conclusion: This study suggests that low-dose ketamine provides as effective and more predictable procedural analgesia as morphine during dressing procedures for adult burn patients.

Effects of Lactobacillus salivarius ssp. salicinius SA-03 Supplementation on Reversing Phthalate-Induced Asthma in Mice.

Probiotics may protect against asthma. We want to investigate whether probiotics can reverse the adverse effects of phthalate exposure on asthma. We selected the female offspring of BALB/c mice, born from pregnant female mice fed with diethylhexyl phthalate (DEHP). They were continuously administrated DEHP and Lactobacillus salivarius ssp. salicinius SA-03 when they were 5 weeks old, and ovalbumin (OVA) for asthma induction started at 6 weeks for 32 days. The mice were divided into four groups (n = 6/group): 1. control group (C), 2. OVA/DEHP group (OD), 3. OVA/DEHP/probiotics low-dose group (ODP-1X), and OVA/DEHP/probiotics high-dose group (ODP-5X). We found that the administration of probiotics significantly reduced the asthma severity of the mice, as well as serum IgE and IL-5. In the ODP-5X group, the proportion of CD4+ cells in the lung was reduced, whereas IL-10 in serum and CD8+ cells in BALF were increased. In histopathology, the ODP group showed reduced infiltration of inflammatory cells, bronchial epithelial cell hyperplasia, and tracheal mucus secretion. These results might indicate that high-dose probiotics may affect anti-inflammatory cytokines and reduce asthma-relative indicators. The above results may provide evidence that high-dose probiotics supplementation might play a modulating role in DEHP causes of allergic asthma in the pediatric animal model.

Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). To explore the role of HTG in the pathogenesis of AP. Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate andhigh-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1β, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.

Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8mg cyproheptadine and 5mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. The primary outcome was TAC change from baseline to month 3. A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6g/day, P = 0.016, Cohen's d = -0.44; -18.4g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.