Establishing a physiologically based pharmacokinetic framework for aldehyde oxidase and dual aldehyde oxidase-CYP substrates.

Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug-metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO-mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO-CYP substrates.

Challenges and Opportunities for In Vitro-In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation.

Underestimation of aldehyde oxidase (AO)-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation of unbound hepatic intrinsic clearance (CL) and unbound hepatic intrinsic clearance by AO (CL) was assessed using a comprehensive literature database of in vitro (human cytosol/S9/hepatocytes) and in vivo (intravenous/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies).

Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (K  ~2 μM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure.

Lupus anticoagulant-hypoprothrombinemia syndrome in children: Three case reports and systematic review of the literature.

Objective: Children with lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) are characterized by prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT), lupus anticoagulant positivity and low prothrombin (factor II, FII) levels. Bleeding or thrombosis tendencies related to LAHPS in children can occur due to the development of anti-prothrombin antibodies that are usually linked to autoimmune or infectious diseases.

Methods: We report three pediatric cases of LAHPS and describe details on their clinical symptoms, laboratory characteristics, treatment.

Association between vitamin D level and pediatric inflammatory bowel disease: A systematic review and meta-analysis.

Background: Previous studies have reported that the incidence of pediatric inflammatory bowel disease (IBD) is related to vitamin D, but it is still unclear. This study intends to calculate the relationship between pediatric IBD and vitamin D.

Methods: A comprehensive literature search from inception to January 2023 was performed in the PubMed, EMBASE, Medline, Web of Science, and Google Scholar databases.

Recent Trends in Nano-Fertilizers for Sustainable Agriculture under Climate Change for Global Food Security.

Nano-fertilizers (NFs) significantly improve soil quality and plant growth performance and enhance crop production with quality fruits/grains. The management of macro-micronutrients is a big task globally, as it relies predominantly on synthetic chemical fertilizers which may not be environmentally friendly for human beings and may be expensive for farmers. NFs may enhance nutrient uptake and plant production by regulating the availability of fertilizers in the rhizosphere; extend stress resistance by improving nutritional capacity; and increase plant defense mechanisms.

Influence of Silicon on Biocontrol Strategies to Manage Biotic Stress for Crop Protection, Performance, and Improvement.

Silicon (Si) has never been acknowledged as a vital nutrient though it confers a crucial role in a variety of plants. Si may usually be expressed more clearly in Si-accumulating plants subjected to biotic stress. It safeguards several plant species from disease.

Investigation of Defensive Role of Silicon during Drought Stress Induced by Irrigation Capacity in Sugarcane: Physiological and Biochemical Characteristics.

Water stress may become one of the most inevitable factors in years to come regulating crop growth, development, and productivity globally. The application of eco-friendly stress mitigator may sustain physiological fitness of the plants as uptake and accumulation of silicon (Si) found to alleviate stress with plant performance. Our study focused on the mitigative effects of Si using calcium metasilicate (wollastonite powder, CaO·SiO) in sugarcane ( L.

Exploration of silicon functions to integrate with biotic stress tolerance and crop improvement.

In the era of climate change, due to increased incidences of a wide range of various environmental stresses, especially biotic and abiotic stresses around the globe, the performance of plants can be affected by these stresses. After oxygen, silicon (Si) is the second most abundant element in the earth's crust. It is not considered as an important element, but can be thought of as a multi-beneficial quasi-essential element for plants.

Modeling Pharmacokinetic Natural Product-Drug Interactions for Decision-Making: A NaPDI Center Recommended Approach.

The popularity of botanical and other purported medicinal natural products (NPs) continues to grow, especially among patients with chronic illnesses and patients managed on complex prescription drug regimens. With few exceptions, the risk of a given NP to precipitate a clinically significant pharmacokinetic NP-drug interaction (NPDI) remains understudied or unknown. Application of static or dynamic mathematical models to predict and/or simulate NPDIs can provide critical information about the potential clinical significance of these complex interactions.

Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions.

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH).

Paeonol ameliorates CFA-induced inflammatory pain by inhibiting HMGB1/TLR4/NF-κB p65 pathway.

The enhanced release of inflammatory cytokines mediated by high mobility group box1 (HMGB1) leads to pain sensation, and has been implicated in the etiology of inflammatory pain. Paeonol (PAE), a major active phenolic component in Cortex Moutan, provides neuroprotective efficacy via exerting anti-inflammatory effect. However, the role and mechanism of PAE in inflammatory pain remain to be fully clarified.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity.

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations.

Preparations from the leaves of the kratom plant () are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities.

Antidepressant Effect of Paeoniflorin Is Through Inhibiting Pyroptosis CASP-11/GSDMD Pathway.

Nod-like receptor protein 3 (NLRP3)-associated neuroinflammation mediated by activated microglia is involved in the pathogenesis of depression. The role of the pore-forming protein gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome mediating inflammatory programmed cell death, in depression has not been well defined. Here, we provide evidence that paeoniflorin (PF), a monoterpene glycoside compound derived from Paeonia lactiflora, ameliorated reserpine-induced mouse depression-like behaviors, characterized as increased mobility time in tail suspension test and forced swimming test, as well as the abnormal alteration of synaptic plasticity in the depressive hippocampus.

Echinacoside protects dopaminergic neurons by inhibiting NLRP3/Caspase-1/IL-1β signaling pathway in MPTP-induced Parkinson's disease model.

Persistent microglia-mediated neuroinflammation contributes to the progressive loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Recently, NOD-like receptor protein 3 (NLRP3) inflammasome-mediated neuroinflammation is considered to influence the pathogenesis of PD profoundly. Promoting DA neuron survival and/or inhibiting neuroinflammation may offer neuroprotection for PD.

Effects of banana powder (Musa acuminata Colla) on the composition of human fecal microbiota and metabolic output using in vitro fermentation.

Bananas are rich in indigestible carbohydrates and are considered potential whole-fruit prebiotics. To investigate banana-induced changes in the composition of the human gut microbiota and the production of short chain fatty acids (SCFAs), ripe banana (Musa acuminata Colla, Degrees Brix: 22.6 ± 0.

Muscular Tissue Oxygen Saturation and Posthysterectomy Nausea and Vomiting: The iMODIPONV Randomized Controlled Trial.

Background: Suboptimal tissue perfusion and oxygenation during surgery may be responsible for postoperative nausea and vomiting in some patients. This trial tested the hypothesis that muscular tissue oxygen saturation-guided intraoperative care reduces postoperative nausea and vomiting.

Methods: This multicenter, pragmatic, patient- and assessor-blinded randomized controlled (1:1 ratio) trial was conducted from September 2018 to June 2019 at six teaching hospitals in four different cities in China.

Modulation of Major Human Liver Microsomal Cytochromes P450 by Component Alkaloids of Goldenseal: Time-Dependent Inhibition and Allosteric Effects.

Botanical and other natural products (NPs) are often coconsumed with prescription medications, presenting a risk for cytochrome P450 (P450)-mediated NP-drug interactions. The NP goldenseal () has exhibited antimicrobial activities in vitro attributed to isoquinoline alkaloids contained in the plant, primarily berberine, (-)--hydrastine, and to a lesser extent, hydrastinine. These alkaloids contain methylenedioxyphenyl rings, structural alerts with potential to inactivate P450s through formation of metabolic intermediate complexes.

Efficacy of amisulpride on postoperative nausea and vomiting: a systematic review and meta-analysis.

Aim And Background: Postoperative nausea and vomiting (PONV) remains a significant clinical problem for surgical patients. Amisulpride is a well-studied DD antagonist that has the potential to be used for preventing and treating PONV. Our aim was to assess the efficacy and safety of amisulpride for prevention and treatment of PONV through a systematic review and meta-analysis.

Anxiolytic effects of polydatin through the blockade of neuroinflammation in a chronic pain mouse model.

Background: Chronic pain is frequently comorbid with anxiety disorder, thereby complicating its treatment. Polydatin, a component from the root of , has shown neuroprotection in the central nervous system. However, its effects on pain and anxiety processing have been rarely investigated.

genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial.

Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA.

A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model.

Patients with nonalcoholic steatohepatitis (NASH) exhibit altered hepatic protein expression of metabolizing enzymes and transporters and altered xenobiotic pharmacokinetics. The botanical natural product silymarin, which has been investigated as a treatment of NASH, contains flavonolignans that inhibit organic anion-transporting polypeptide (OATP) transporter function. The purpose of this study was to assess the individual and combined effects of NASH and silymarin on the disposition of the model OATP substrate pitavastatin.

Indinavir Increases Midazolam -Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In Vitro to In Vivo Approach.

Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hydroxylation, shifted to -glucuronidation in the presence of the CYP3A inhibitor ketoconazole, which may lead to an overprediction of the magnitude of a xenobiotic-midazolam interaction. Because ketoconazole is no longer recommended as a clinical CYP3A inhibitor, indinavir was selected as an alternate CYP3A inhibitor to evaluate the contribution of the -glucuronidation pathway to midazolam metabolism.