Administration Of High Doses Research Articles

Long-term Administration of High-Dose Methylphenidate Impairs Spatial Memory and Induces Neurodegeneration in the Hippocampus

Background: Methylphenidate hydrochloride (MPH) is used as a first-line treatment for attention-deficit/hyperactivity disorder. Nonetheless, there are a few studies regarding the relationship between memory and hippocampal neuron changes following long-term MPH treatment. Objectives: This study aimed to investigate the effects of pathological changes on memory following long-term MPH treatment. Methods: Forty rats were randomly and equally divided into four groups based on dosages. Animals underwent 0.6, 2.5 (low doses), or 10 (high dose) mg/kg MPH or saline (control) per day for 28 days. The Morris water maze (MWM) test was conducted at two time points: Two hours and four weeks after initiating MPH administration. The two-hour test evaluated single dose effects of MPH on memory, while the four-week test assessed long-term administration of MPH effects on memory performance. Finally, the brains were removed and pathological alterations in the cornu ammonis (CA1) and dentate gyrus (DG) regions of the hippocampus were investigated. Results: Single-dose administration of 10 mg/kg MPH decreased the latency time in the MWM test, while long-term administration of MPH increased the latency time. Furthermore, histopathology results showed that MPH at doses of 2.5 mg/kg and 10 mg/kg significantly increased the percentage of neurodegeneration in both the CA1 and DG regions compared to controls. Conclusions: Our findings show that a high single dose of MPH improves memory in rats. However, long-term administration of high dose of MPH impaired memory; such impairment may be associated with the neurodegeneration in the pyramidal layer cell of the CA1 and the granular layer cell of the DG.

Unlocking the Microbial Potential of Intercalated Calcium-aluminum Layered Double Hydroxide-palmitic Acid

Introduction: An efficient and coherent drug delivery system is imperative in detouring a repetitive administration of high doses of the drug to achieve an effective therapeutic effect. This study, therefore, aims to synthesize the nanocomposite (CAPA) utilizing the layered double hydroxide as a drug carrier that can safeguard the medicine and improve its bioavailability while minimizing the adverse impact on the biological process. Method: The Calcium-aluminum Layered Double Hydroxide (CAL) was synthesized via the coprecipitation method followed by integrating palmitic acid (PA) drug into that host employing a similar approach. The successful intercalation was assessed utilizing X-ray diffraction (PXRD) analysis and Fourier transform infrared spectroscopy (FTIR). The characterization of the material was evaluated by using a thermogravimetric-derivative thermogravimetric analysis (TGA-DTG) and accelerated surface area and porosity (ASAP) analyzer. Result: The increment of basal spacing of CAPA (15.21Å) synthesized in this study implies the retainment of PA in the interlayer space of CAL. The FTIR spectra of CAPA, with the elimination of the nitrate ion peak at 1359.87 cm-1 and the appearance of carboxylate ion at 1643.17 cm-1, hint at the existence of PA in the host layer. The surface area of CAPA exhibited a value of 19.8 m2g-1, bigger than that of hosts, while its pore size is within the micropores range. Conclusion: The TGA analysis revealed that the thermal stability of PA was improved following the intercalation process due to the decomposition of the PA core that occurs at 260°C. The antimicrobial activity proposes that the synthesized CAPA can retain the drug's activity against S. aureus, emphasizing the ability of CAL as a potential drug delivery vehicle for PA.

A Review on Diabetes: Current and Future Perspectives

Diabetes Mellitus (DM) is a metabolic syndrome that gradually leads to chronic microvascular or macrovascular complications. There are 2 types of DM: Insulin-dependent diabetes, commonly called type I DM, is an organ-specific autoimmune disorder that destroys the body’s pancreatic β cells, causing insulin deficiency, and can be treated through insulin replacement therapy. Non-insulin-dependent diabetes mellitus, or type II DM, is caused by pancreatic cell dysfunction that affects a person’s ability to use insulin and can be treated with oral hypoglycaemics. Recent investigation confirms that combination therapy of metformin (biguanides), sodium-glucose co-transporter-2 (SGLT2) inhibitors, and Dipeptidyl Peptidase-4 (DPP-4) inhibitors not only reduces HbA1c glucose dependently but also provides better sustained glycaemic stability with good tolerability in comparison to monotherapy. Multi-particulate drug delivery provides targeted drug administration with high bioavailability and compressed dosage administration. In this review analysis, an effort has been made to explore the pathophysiology of type II DM and the importance of combination therapy using microspheres for the delivery of drugs for the management of type II DM.

Evaluating anti-inflammatory and anti-oxidative potentialities of the chloroform fraction of Asparagus racemosus roots against cisplatin induced acute kidney injury

Ethnopharmacological relevanceAcute kidney injury (AKI), a global public health concern that increases the risk of death, end-stage renal disease, and prolonged hospital admissions. As of this point, supportive measures like fluid resuscitation and replacement therapy for renal failure are the only treatments available for treating AKI. Asparagus racemosus (AR) also known as Shatavari, belongs to family Liliaceae and is considered exceptional in Ayurvedic medicine due to its versatility in treating and preventing a variety of illnesses. Aim of the studyThe purpose of this study is to determine the effectiveness of chloroform fraction of Asparagus racemosus (CFAR) against cisplatin (CP) induced AKI. Materials and methodsHPLC was used to analyse the presence of bioactive phytocompounds in CFAR using standard quercetin. Further LC-MS study indicated the existence of different bioacive compounds. Normal Rat Kidney (NRK-52E) cells were used to study the nephroprotective effect of CFAR. Cells were untreated, treated or cotreated with CP (20uM) and CFAR (5, 25, 50, 100, 200 and 400μg/ mL) for 24 h. After 24 h of treatment, cell viability assay and assay of apoptosis parameters were performed. The CFAR at the dose of 50mg, 100mg and 200/kg/day was administered orally for 15 days and acute kidney injury was induced in rats by intraperitoneal injection of CP (10mg/kg body weight) at the 10th day of experimentation. Biochemical studies were performed to evaluate kidney function; protein expression by western blot and mRNA expression of related gene were studied from the kidney tissues to evaluate the effects of CFAR. Histopathological analysis was done to investigate the structural abnormalities and fibrosis of renal tissues. ResultOur result reported that CFAR contain many bioactive phytomolecules having many pharmacological properties. Cell viability assay and assay of apoptosis reported that different doses of CFAR could reduced CP-induced cell death and cell apoptosis. The levels of kidney injury markers (BUN, sCr and eGFR), inflammatory markers (Interleukin-18, KIM-1, Cys-C, NF-kB and NGAL), and antioxidant markers (SOD, GSH, CAT, Nrf2 and Bcl2) and lipid peroxidation (MDA) were settled to a normal level by the oral administration of high doses (100 and 200mg/kg body weight) of CFAR after intraperitoneal injection of CP as suggested by biochemical, histopathological, protein and gene expression studies. ConclusionIn conclusion, CFAR at the high doses (100 and 200 mg/kg body weight) could able to protect the kidneys from CP induced oxidative stress and inflammation due to presence of bioactive phytomolecules that prevent the activation of oxidative stress induced signalling cascades leading to kidney damage.

Dose-Related Effects and Bleeding Risk of Ketorolac in Pediatric Tonsillectomy.

To investigate the safety and effectiveness of dose-related ketorolac administration in children who underwent tonsillectomy. Data sourced from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases, encompassing literature from their inception until June 2024. The perioperative administration of ketorolac in comparison with a control group was included in this analysis. The outcomes assessed were postoperative pain levels; utilization patterns of analgesic medication in terms of quantity and frequency; and the incidence rates of postoperative nausea, vomiting, and bleeding. Eighteen studies with 11,729 patients that investigated. The ketorolac treatment group with postoperative bleeding had a higher incidence of primary bleeding (significant bleeding and operative bleeding control) compared to the control group. However, ketorolac treatment did not affect the risk of secondary bleeding. Subgroup analysis showed that 0.9 to 1 mg/kg of ketorolac significantly increases primary operative control (odds ratio [OR] = 4.0700 [1.6352; 10.1302]; I2 = 0.0%) and primary significant bleeding (OR = 2.3200 [1.1322; 4.7538]; I2 = 0.0%). On the other hand, 0.5 mg/kg ketorolac did not show any influence on primary operative control. The administration of ketorolac (both 0.9-1 and 0.5 mg/kg) led to a significant decrease in postoperative pain (2-24 hours), nausea, and vomiting compared to the control group. Low-dose (0.5 mg/kg) ketorolac administration to children could significantly reduce the risk of primary significant bleeding and surgical hemostasis compared to high-dose administration (0.9-1.0 mg/kg). In addition, low-dose ketorolac administration could provide sufficient pain control and reduce postoperative nausea and vomiting.

Favorable inhibitory effect of clodronate on hepatic steatosis in short bowel syndrome model rats

PurposeThis study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS).MethodsThe rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20 mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60 mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed.ResultsHepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups.ConclusionThe high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS.

NCMP-05. CLINICAL AND RADIOGRAPHIC IMPROVEMENT WITH REPLACEMENT OF FOLATE METABOLITES IN A PATIENT WITH INTRATHECAL METHOTREXATE-INDUCED MYELOPATHY

Abstract Methotrexate (MTX)-induced myelopathy is a rare but serious adverse effect of intrathecal (IT) MTX, which may mimic subacute combined degeneration (SCD). MTX disrupts the normal synthesis of methionine, which plays an important role in maintaining myelin sheath integrity, resulting in degeneration of the dorsal columns. This degeneration does not respond to classic treatment with vitamin B12 and folate supplementation, unlike SCD. Here, we describe a case of a 45-year-old woman with Philadelphia-positive B-cell acute lymphoblastic leukemia treated with hyperCVAD regimen with ponatinib, who after 14 doses of prophylactic IT MTX, developed progressive lower extremity weakness, paresthesias, gait instability, saddle anesthesia, and bowel/bladder dysfunction. Her neurologic exam was also notable for diffuse hyporeflexia. The onset of symptoms followed a diarrheal infection, and an initial MRI spine showed no evidence of abnormal enhancement. She was initially treated with intravenous immunoglobulins for presumed acute inflammatory demyelinating polyneuropathy. She then re-presented one week later with progressively worsening symptoms. A repeat MRI spine revealed a new longitudinally extensive T2 hyperintense signal within the dorsal columns from T7 to T12. CSF results were notable for mild pleocytosis and increased myelin basic protein; the latter of which is often seen in MTX-induced myelopathy. The patient received high-dose administration of key metabolites of the methyl-transfer pathway including S-adenosylmethionine (PO 400mg three times daily), folinate (IV 20mg four times daily), cyanocobalamin (PO 1000mcg once daily) and methionine (PO 5mg once daily) for 7 days. This treatment regimen resulted in both clinical and radiographic improvement. Subsequent MRI spine demonstrated complete resolution of the abnormal signal in the thoracic cord. This case highlights (1) the diagnostic complexity of IT MTX-induced myelopathy (2) the role response to treatment plays in uncovering this diagnosis, and (3) how the replacement of folate metabolites facilitates both radiographic and clinical improvement in IT MTX-induced myelopathy.

P-Coumaric Acid alleviates non-alcoholic fatty liver disease by promoting GLP-1 secretion via the GRP78-Ca2+ signaling axis

In individuals with obesity-related non-alcoholic fatty liver disease (NAFLD), endogenous Glucagon-like peptide-1 (GLP-1) secretion is compromised, and supplementation with GLP-1 receptor agonists has shown efficacy in ameliorating NAFLD. However, there is currently a scarcity of research focused on the direct promotion of endogenous GLP-1 secretion from L-cells by plant-derived phenolic acids. Hence, this study reveals that p-Coumaric Acid (p-CA), a widely occurring phenolic acid in the plant, holds potential as a therapeutic approach by stimulating the secretion of GLP-1 to improve glucose-lipid metabolism alterations and alleviate NAFLD symptoms. In diet-induced obese (DIO) mouse models, administration of high doses of p-CA led to a significant elevation in serum GLP-1 levels, as well as improvements in body weight gain, glucose level, insufficient insulin secretion, and biochemical abnormalities associated with NAFLD in mice fed with a high-fat diet. Moreover, the number of lipid droplets in the liver tissue of p-CA-treated mice was notably reduced, suggesting its effectiveness in mitigating liver fat accumulation and ameliorating NAFLD severity. Experimental evidence suggests that p-CA exerts its effects by influencing the transcriptional regulation of Glucose-regulated protein 78 kDa (GRP78) through interaction with Nucleophosmin 1 (NPM1), thereby downregulating GRP78 expression. This decrease in GRP78 expression subsequently leads to an increase in intracellular Calcium ions (Ca2+) concentration, which promotes the production and exocytosis of GLP-1-containing vesicles in L cells, consequently enhancing GLP-1 secretion. This research demonstrates the mechanistic role and therapeutic effects of p-CA in regulating GLP-1 secretion and its implications for improving NAFLD, underscoring the pharmacological significance of this natural compound as a dietary supplement.

Advances and Challenges in Microdystrophin gene therapy for Duchenne Muscular Dystrophy: progress and future directions

Duchenne muscular dystrophy (DMD) is a severe degenerative genetic muscle disease affecting mainly young boys, characterized by a significant alteration or absence of dystrophin expression. Significant strides have been made in comprehending and treating DMD, particularly with the recent approval of the first gene therapy using a recombinant adeno-associated vector (rAAV) to deliver a shortened form of dystrophin (microdystrophin). Nevertheless, major challenges remain in improving therapeutic outcomes. The use of rAAV vectors is hindered by major limitations, notably the risks of immunotoxicity and hepatotoxicity, linked to high-dose administration. Additionally, microdystrophin exhibits inherent functional limitations and immunological risks. This article examines these challenges and explores the avenues for enhancing gene therapy for DMD.

Is acetylsalicylic acid use in cats contraindicated or limited indicated?

Acetylsalic acid, (Aspirin®) is a nonsteroidal anti-inflammatory drug (NSAID) widely used in human and veterinary medicine, especially for its analgesic and antithrombotic effects, mainly in the prevention of cardiovascular complications and in the treatment of various diseases. Aspirin® can not be metabolized in cats because they do not have the enzyme glucuronyl transferase. For this reason, it has a long half-life and a narrow dose range. High dose administration in cats may cause serious toxicity in the liver. Acetylsalicylic acid is known to cause gastric ulcers associated with decreased prostaglandin levels. For these reasons, it is considered toxic to cats. But it also has antipyretic, analgesic, anti-inflammatory and antithrombotic properties. It is indicated for use alone or in combination with other antithrombotic drugs in the treatment and prophylaxis of thrombus formation resulting from cardiovascular diseases. This review aims to examine the indicated and contraindicated areas of use of Aspirin®, which is widely considered toxic in cats.

Risk factors of pediatric steroid-induced ocular hypertension.

Steroid-induced ocular hypertension (SIOH) is a significant ocular complication of pediatric steroid administration. In this study, we analyzed the risk factors associated with pediatric SIOH. We retrospectively collected data from 78 children under 20 years of age who received systemic steroids during hospitalization. The data included age, gender, primary disease, intraocular pressure (IOP) before and one month after administration, total monthly steroid dose adjusted for body weight (BW), and one-month changes in red blood cell, white blood cell, and platelet counts. A multivariate analysis was used to identify risk factors related to steroid responsiveness. Thirty patients (38.5%) were classified as steroid responders, and 48 as non-responders. The median IOP during the first month of steroid treatment was 24.0 mmHg (IQR; 23.0-28.3) for responders and 15.0 mmHg (IQR; 12.3-18.0) for non-responders. The Generalized Estimating Equations analysis revealed that younger age, male sex, primary disease, increase the amount of white blood cell (WBC) and total steroid dose per BW in one month were independently associated variables. The receiver operating characteristic analysis also revealed that the cutoff values for age, total monthly steroid dose, the increase amount of WBC were 11.0 years, 40.7mg/kg and 3.40 × 10²/µl respectively. High-dose steroid administration, especially in male, younger patients, necessitates careful monitoring for IOP changes during treatment. WBC count also needs to be monitored during IOP follow-ups. What is known Steroid-induced ocular hypertension (SIOH) is one of the essential complicationsduring steroid administration,but onlylimited analyses have been performed in children. What is new A comprehensive analysis of multiple factors was performed that are predicted to be associated with pediatric SIOH from previous literature. Younger age, male sex, primary disease, increase the amount of WBC, and highertotal monthly steroid dose were extracted as risk factors of SIOH. This study can contribute to the prediction of cases in which ophthalmologic examinations are particularly important during systemic steroid administration in children.

Intranasal administration of recombinant human BDNF as a potential therapy for some primary headaches

BackgroundIn addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors.MethodsIn a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration.ResultsBoth doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP.ConclusionsThe findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine.

EFFECTIVENESS OF ROSELLA AS AN ANTI-INFLAMMATORY

Rosella flower (Hibiscus sabdariffa L.) can be used in the health sector. Rosella petal extract contains flavonoids such as gossypetin, hibiscetin, sabdaretine, alkaloids, and saponins. Rosella has properties such as an antiseptic, diuretic, anti-inflammatory, antibacterial, antioxidant, and can increase endurance. This paper discusses the anti-inflammatory effect of the rosella plant. The purpose of this article is to describe the effectiveness of rosella plant as an anti-inflammatory. This article collects research results from journals, textbooks, and websites accessed through the National Library of Medicine and Google scholar databases as a method. The reference source inclusion criteria are published in 2012-2022 with topics that are in line with the effectiveness of rosella as an anti-inflammatory. The reference source exclusion criteria were literature published before 2012. A total of 25 references were found, 15 references were selected, and 10 references were excluded. The studies have shown that the content of rosella flower extract is able to inhibit the cyclooxygenase enzyme thereby inhibiting the synthesis of inflammatory mediators, namely leukotrienes and prostaglandins and reducing the number of neutrophils so that it can accelerate the wound healing process, however administration of high doses of rosella extract is less effective as an anti-inflammatory because the levels of flavonoids decreased activity at high extract concentrations.

Corticosteroid-induced bradycardia following high-dose methylprednisolone administration: a case report

Introduction: Besides their wide use in the clinical field due to their anti-inflammatory and immune-modulating effect, corticosteroids still have a lot of adverse effects. The most common adverse effects are hyperglycemia, hypertension, osteoporosis, psychosis, immunosuppression, weight gain, and hyperlipidemia. Another important side effect is cardiac arrhythmias. Case presentation: We report a case of a 43-year-old woman with multiple sclerosis who developed symptomatic bradycardia after 3 days of treatment with a high dose of methylprednisolone. The patient received a dose of atropine and her bradycardia resolved after 36 h of stopping methylprednisolone. Discussion: While tachyarrhythmias are more common, bradyarrhythmias such as bradycardia and premature atrial or ventricular contraction are rare but crucial to be considered. Conclusion: Corticosteroid-induced bradycardia is usually in sinus rhythm and has an unknown etiology, possibly occurring at high and low doses. The majority of cases in the literature were asymptomatic and resolved spontaneously.

Investigating the Effect of High-Dose Vitamin D3 Administration on Inflammatory Biomarkers in Patients with Moderate to Severe Traumatic Brain Injury: A Randomized Clinical Trial.

Traumatic brain injury (TBI) is one of the most common neurological disorders worldwide. We aimed to investigate the efficacy of high-dose vitamin D3 on inflammatory biomarkers in patients with moderate to severe TBI. Thirty-five moderate to severe TBI patients were randomly assigned to intervention and control groups. Patients in the intervention group received a single intramuscular (IM) dose of 300,000 IU vitamin D. The primary endpoints were interleukin levels (IL-1β and IL-6), and the secondary endpoints were changes in neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), Glasgow Coma scale (GCS), and Glasgow Outcome Scale-Extended (GOS-E) scores compared between intervention and control arms of the study. The linear Generalized Estimating Equations were used for trend analysis and evaluating the association of independent factors to each outcome. The results revealed a significant decrease in IL-1β levels (-2.71±3.02, in the intervention group: P=0.001 vs. -0.14±3.70, in the control group: P=0.876) and IL-6 (-88.05±148.45, in the intervention group: P=0.0001 vs. -35.54±175.79, in the control groupL P=0.325) 3 days after the intervention. The improvement in the GCS score (P=0.001), reduction in NLR (P=0.001) and PLR (P=0.002), and improvement in the GOS-E score (P=0.039) was found to be greater in the vitamin D3 arm of the study than the control group. Administration of high-dose vitamin D3 in the acute phase of TBI could be effective in lowering the inflammatory markers and improving the level of consciousness and long-term performance outcomes.Trial Registration Number: IRCT20180522039777N2.

Effect of the combination of Lithospermum erythrorhizon and Lonicera japonica on dexamethasone-induced muscle atrophy in mice

AbstractSkeletal muscle atrophy occurs in several pathological conditions. Among other reasons, high-dose or long-term administration of glucocorticoids increases circulating glucocorticoid levels and causes muscle atrophy. The purpose of this study was to investigate whether Lithospermum erythrorhizon and Lonicera japonica complex extract (LELJ) has a beneficial effect on dexamethasone (Dexa)-induced muscle atrophy. In Dexa-induced myotube atrophy, treatment with LELJ increased myotube diameter, decreased the expression of muscle atrophy markers, and increased the expression of myosin heavy chain (MHC) isoforms. Supplementation with LELJ improved muscle function and performance in mice with Dexa-induced muscle atrophy as demonstrated by grip strength and running tests. Additionally, it increased skeletal muscle mass, size, and expression of MHC isoforms and protein synthesis-related markers. Furthermore, it reduced the upregulated protein levels of skeletal muscle atrophy markers in Dexa-treated mice. Supplementation with LELJ reversed Dexa-induced translocation of the glucocorticoid receptor and forkhead box O3 from the cytosol to the nucleus in skeletal muscles. LELJ also ameliorated age-related muscle loss by extending lifespan and increasing locomotor capacity in Caenorhabditis elegans. We identified loganin and lithospermic acid as bioactive compounds of LELJ and found that treatment with these agents increased myotube diameter, MHC isoform, and puromycin protein levels, and decreased atrophy markers in Dexa-treated myotubes. The current findings underscore how LELJ can prevent Dexa-induced skeletal muscle atrophy, attributing the effects to loganin and lithospermic acid.

The impact of freeze-dried Baiyedancong-Oolong tea aqueous extract containing bioactive compounds on the activities of CYP450 enzymes, the transport capabilities of P-gp and OATs, and transcription levels in mice.

In this study, (-)-epigallocatechin gallate (EGCG) and caffeine extracted from freeze-dried autumn Baiyedancong Oolong tea (FBOT) were orally administered to mice for 7 consecutive days to explore the effects of BOT and its bioactive compounds on the activities and transcription levels of CYP450 enzymes, intestinal effluence transporter P-gp, and renal ingestion Organic Anion Transporters (OATs). Concurrently, EGCG and caffeine enhanced the activities of CYP3A, CYP2E1, and CYP2C37 in the liver of mice, while impairing the transport capabilities of P-gp and OATs. Reduced levels of MDR1 encoding P-gp transcription in the small intestine and renal OAT1 and OAT3 revealed that transcription was involved in the regulation of CYP450, P-gp, and OATs. The reduced transcription level of liver CYP2E1 suggested that CYP2E1 activity may have been elevated due to alternative mechanisms, but not through transcription. The absorption, metabolism, and excretion of drugs may be influenced by the daily consumption or high-dose administration of BOT and its related products, in which EGCG and caffeine may make great contributions.

Ameliorative effects of Trichosanthes kirilowii Maxim. seed oil on hyperlipidemia rats associated with the regulation of gut microbiology and metabolomics

The mechanisms underlying the ameliorative effects of polyunsaturated fatty acids (PUFAs) on metabolic disorders induced by a high-fat diet (HFD) remain poorly unclear. In this study, we investigated the anti-hyperlipidemic effects of Trichosanthes kirilowii Maxim. (T. kirilowii) seed oil rich in conjugated linolenic acid in HFD-induced hyperlipidemic rats, by the gut microbiome, cecum bile acids (BAs), and serum metabolomics. The results showed that T. kirilowii seed oil improved dyslipidemia, hepatic steatosis, oxidative stress, and inflammatory responses in HFD-induced rats. Meanwhile, T. kirilowii seed oil inhibited sterol regulatory element-binding protein 1c (SREBP-1c) mediated fatty acid synthesis and upregulated cholesterol 7-alpha hydroxylase (CYP7A1) mediated hepatic cholesterol metabolism to exert hypolipidemic effects. The administration of high dose T. kirilowii seed oil (THD) improved gut microbiota dysbiosis, increased the relative abundance of beneficial bacteria Romboutsia and unidentified_Oscillospiraceae, and decreased the relative abundance of Christensenellaceae_R-7 group, Phascolarctobacterium, and Bacteroides in HFD-induced rats. T. kirilowii seed oil reduced the accumulation of cecum primary BAs in HFD-induced rats. In addition, THD reversed the HFD-induced changes in 24 serum metabolites including leucine, isoleucine, acetylcarnitine, and glucose. Metabolic pathway enrichment analysis of the differential metabolites revealed that valine, leucine and isoleucine metabolism, butanoate metabolism, citrate cycle, and glycolysis were potential metabolic pathways involved in the anti-hyperlipidemic effects of T. kirilowii seed oil. In conclusion, this study found that dietary T. kirilowii seed oil alleviated gut microbiota dysbiosis and improved metabolic disorders in hyperlipidemic rats. This provides new insights into the anti-hyperlipidemic mechanism by which other families of PUFAs are derived from different plants.

Early intravenous high-dose vitamin C in postcardiac arrest shock (VICEPAC): study protocol for a randomised, single-blind, open-label, multicentre, controlled trial

IntroductionThe high incidence of morbidity and mortality associated with the post-cardiac arrest (CA) period highlights the need for novel therapeutic interventions to improve the outcome of out-of-hospital cardiac arrest (OHCA)...

Optimizing rosemary oil nanoemulsion loaded with nelfinavir and epigallocatechin gallate: A Design Expert® endorsed approach for enhanced neuroAIDS management

This study focuses on optimizing the delivery of Nelfinavir (NFV), a vital protease inhibitor in antiretroviral therapy, and Epigallocatechin gallate (EGCG), a potent adjunctive anti- human immunodeficiency virus (anti-HIV) agent found in green tea. The challenge lies in NFV's low intrinsic dissolution rate, significant p-gp efflux, and high hepatic metabolism, necessitating frequent and high-dose administration. Our objective was to develop a nanoemulsion loaded with NFV and EGCG to enhance oral delivery, expediting antiretroviral effects for NeuroAIDS treatment. After meticulous excipient screening, we selected Tween 40 as the surfactant and polyethylene glycol 400 (PEG 400) as the co-surfactant. Employing a Quality by Design (QbD) approach with statistical multivariate methods, we optimized the nanoemulsion that exhibited a droplet size of 83.21 nm, polydispersity index (PDI) of 2.289, transmittance of 95.20 %, zeta potential of 1.495 mV, pH of 6.95, refractive index of 1.40, viscosity of 24.00 ± 0.42 mPas, and conductivity of 0.162 μS/cm. Pharmacokinetic studies demonstrated superior in vivo absorption of the optimized nanoemulsion compared to NFV and EGCG suspension. The optimized nanoemulsion showcased higher Cmax of NFV (9.75 ± 1.23 μg/mL) and EGCG (27.7 ± 1.22 μg/mL) in the brain, along with NFV (26.44 ± 1.44 μg/mL) and EGCG (313.20 ± 5.53 μg/mL) in the plasma. This study advocates for the potential of NFV and EGCG-loaded nanoemulsion in combination antiretroviral therapy (cART) for effective NeuroAIDS management.