Prediction of herb-drug interactions involving consumption of furanocoumarin-mixtures and cytochrome P450 1A2-mediated caffeine metabolism inhibition in humans

Mapping Intimacies ◽

10.21203/rs.3.rs-836915/v1 ◽

2021 ◽

Author(s):

Zeyad Ibrahim Alehaideb

Keyword(s):

Drug Interaction ◽

Concentration Addition ◽

Herbal Products ◽

Product Consumption ◽

Dose Concentration ◽

Caffeine Metabolism ◽

Inhibitor Drug ◽

Almost All

Abstract Herb-drug interaction (HDI) has become important due to the increasing popularity of natural product consumption worldwide. HDI is difficult to predict as botanical drugs usually contain complex phytochemical-mixtures which interact with drug metabolism. Currently, there is no pharmacological tool to predict HDI since almost all in vitro-in vivo-extrapolation (IVIVE) Drug-Drug Interaction (DDI) models deal with one inhibitor-drug and one victim-drug. The objectives were to modify IVIVE models of Mayhew et al. (2000) and Wang et al. (2004) for prediction of in vivo interaction between caffeine and furanocoumarin-containing herbs, and to confirm model prediction by comparing the predictive results with experimental data. The models were modified to predict in vivo herb-caffeine interaction using the same set of inhibition constants but different integrated dose/concentration of furanocoumarin mixtures in the liver. Different hepatic inlet inhibitor concentration ([I]H) surrogates were used for each furanocoumarin. In the Mayhew et al., the [I]H was predicted using the concentration-addition model for chemical-mixtures. In the Wang et al., the [I]H was calculated by adding individual furanocoumarins together. Once [I]H was determined, the models predicted an area-under-curve-ratio (AUCR) of each interaction. The results indicate that both models were able to predict the experimental AUCR of herbal products reasonably well.

Download Full-text

Effects of herbal products in vitro and in vivo

Planta Medica ◽

10.1055/s-0033-1352314 ◽

2013 ◽

Vol 79 (13) ◽

Author(s):

MJ Groot ◽

MG Pikkemaat ◽

WD Driessen van Lankveld

Keyword(s):

Herbal Products

Download Full-text

In vitro and In vivo Studies of Drug-Drug Interaction between Metformin and Cefepime

Pharmaceutica Analytica Acta ◽

10.4172/2153-2435.1000348 ◽

2015 ◽

Vol 06 (03) ◽

Cited By ~ 2

Author(s):

Shomita Ferdous Md Zakir Sultan

Keyword(s):

Drug Interaction ◽

In Vivo Studies ◽

Drug Drug Interaction

Download Full-text

In vitro and in vivo Drug-Drug Interaction of Losartan and Glimepiride in Rats and Its Possible Mechanism

Pharmacology ◽

10.1159/000377637 ◽

2015 ◽

Vol 95 (3-4) ◽

pp. 133-138 ◽

Cited By ~ 3

Author(s):

Sai-Zhen Chen ◽

Pei-Pei Pan ◽

Shuang-Hu Wang ◽

Jun Luo ◽

Guo-Xin Hu ◽

...

Keyword(s):

Drug Interaction ◽

Drug Drug Interaction

Download Full-text

METABOLISM OF RAM TESTICULAR SPERMATOZOA IN THE PRESENCE OF TESTOSTERONE AND RELATED STEROIDS

Acta Endocrinologica ◽

10.1530/acta.0.0650565 ◽

1970 ◽

Vol 65 (3) ◽

pp. 565-576 ◽

Cited By ~ 10

Author(s):

J. K. Voglmayr ◽

R. N. Murdoch ◽

I. G. White

Keyword(s):

Aerobic Glycolysis ◽

Rete Testis ◽

Glycolytic Metabolism ◽

Anaerobic Conditions ◽

Aerobic Conditions ◽

Testicular Spermatozoa ◽

Almost All ◽

Oxidation Of Glucose

ABSTRACT The effects of testosterone* and related steroids on the oxidative and glycolytic metabolism of freshly collected ram testicular spermatozoa and of spermatozoa stored under air in rete testis fluid for 3 days at 3°C have been studied. When freshly collected testicular spermatozoa were incubated with glucose under aerobic conditions only a small proportion of the utilized glucose could be accounted for as lactate. The addition of a number of steroids, including testosterone, androstanedione, 5β-androstanedione, androsterone, epiandrosterone and 5β-androsterone, greatly increased aerobic glycolysis, the oxidation of the substrate and the proportion of the utilized substrate converted to lactic acid. After 3 days storage at 3°C, testicular spermatozoa respired at a greater rate than spermatozoa freshly collected from the testes. Although the stimulating effect of steroids on aerobic glycolysis increased after storage, they depressed rather than stimulated the oxidation of glucose by stored testicular spermatozoa. With the exception of androstanedione, which slightly stimulated glycolysis, storage of testicular spermatozoa for 3 days in the presence of steroids did not significantly influence their subsequent metabolism when washed free of the steroids. Both freshly collected and stored ram testicular spermatozoa displayed a marked Pasteur effect, and utilized more glucose and produced more lactate under anaerobic than under aerobic conditions. In the absence of oxygen the steroids did not stimulate glycolysis to any extent. However, epiandrosterone depressed the glycolysis of freshly collected spermatozoa under anaerobic conditions and after storage, 5β-androsterone had a similar effect. Androstanedione, 5β-androstanedione, epiandrosterone and 5β-androsterone were the most effective steroids in altering the metabolism of testicular spermatozoa and, under almost all conditions of incubation, depressed the synthesis of amino acids from glucose. The results suggest that the effects of testosterone and related steroids in vitro may depend on the age of the spermatozoa after their release from the Sertoli cells; the steroid effects may have important consequences in vivo in relation to sperm maturation.

Download Full-text

Medicinal Plants Used for the Traditional Management of Diabetes in the Eastern Cape, South Africa: Pharmacology and Toxicology

Molecules ◽

10.3390/molecules23112759 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2759 ◽

Cited By ~ 8

Author(s):

Samuel Odeyemi ◽

Graeme Bradley

Keyword(s):

South Africa ◽

Medicinal Plants ◽

Scientific Evidence ◽

Traditional Healers ◽

Bioactive Molecules ◽

Eastern Cape ◽

Insulin Mimetic ◽

Almost All

The use of medicinal plants for the management of diabetes mellitus is on the rise in the developing countries, including South Africa. There is increasing scientific evidence that supports the claims by the traditional healers. In this review, we compare the families of previously reported anti-diabetic plants in the Eastern Cape by rating the anti-diabetic activity, mode of action and also highlight their therapeutic potentials based on the available evidence on their pharmacology and toxicity. Forty-five plants mentioned in ethnobotanical surveys were subjected to a comprehensive literature search in the available electronic databases such as PubMed, ScienceDirect, Google Scholar and Elsevier, by using “plant name” and “family” as the keywords for the primary searches to determine the plants that have been scientifically investigated for anti-diabetic activity. The search returned 25 families with Asteraceae highly reported, followed by Asphodelaceae and Alliaceae. Most of the plants have been studied for their anti-diabetic potentials in vivo and/or in vitro, with most of the plants having a higher percentage of insulin release and inhibition against carbohydrate digesting enzymes as compared with insulin mimetic and peripheral glucose uptake. Almost all the investigated plants also inhibit oxidative stress as part of their hypoglycemic activity with less toxicity. However, the isolation of their bioactive molecules is still lacking. This review provides a resource to enable thorough assessments of the therapeutic profiles of available medicinal plants used for the management of diabetes in the Eastern Cape, South Africa. Further studies such as the identification of the active ingredients of potent plants still need to be carried out; this may lead to new molecules in drug discovery and development.

Download Full-text

Cycle initiation and colony formation in culture by murine marrow cells with long-term reconstituting potential in vivo

Blood ◽

10.1182/blood.v88.11.4149.4149 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4149-4158 ◽

Cited By ~ 3

Author(s):

M Trevisan ◽

XQ Yan ◽

NN Iscove

Keyword(s):

Colony Formation ◽

Interleukin 1 ◽

Methyl Cellulose ◽

Culture Conditions ◽

Liquid Suspension ◽

Almost All ◽

Marrow Cells

Abstract This investigation was directed at separating long-term reconstituting (LTR) stem cells in normal murine marrow from hematopoietic precursors detectable in short-term assays in vitro and in vivo, and then at determining whether purified LTR cells could themselves form colonies in culture. To do so, it was first necessary to identify culture conditions that would induce their growth while preserving their long- term reconstituting capacity. Marrow was cultured with various cytokines in liquid suspension for 4 days, after which the surviving LTR activity was quantitated in a competitive in vivo assay. Activity was preserved near input levels with combined murine c-kit ligand (KL), interleukin-1 (IL-1), IL-6, and IL-11. When the cultures also included tritiated or unlabeled thymidine, LTR potential was eliminated, indicating that essentially all LTR cells were induced into cell cycle with these cytokines. To purify them, marrow was sorted on the basis of Ly6A expression and Rhodamine 123 retention. The Ly6AhiRh123ls fraction contained 85% of total recovered LTR activity but only 1% of the recovered cells measured by multilineage colony formation in spleens or in vitro. This fraction was cultured in methyl cellulose with KL, IL-1, IL-6, and IL-11 for 4 to 6 days, after which colonies were isolated and injected into mice. High levels of permanent reconstitution were achievable in sublethally irradiated W41/W41 mice after the injection of a single reconstituting unit, and limiting dilution analysis estimated the frequency of multilineage LTR at 1 in 11,200 unpurified adult marrow cells. In either lethally irradiated normal or sublethally irradiated W41/W41 mice, 1-year lymphomyeloid reconstitutions were obtained from 1 in 65 to 84 colonies of 2 to 16 dispersed cells, but not from larger colonies or those with clumped cells. The results establish that resting marrow LTR cells can be separated from almost all of the more advanced clonogenic cells that are still pluripotential, can be induced to cycle in culture by defined cytokines with preservation of their reconstituting potential, and can be manipulated and assayed efficiently at single-cell and colony levels.

Download Full-text

DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIES POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.058 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii288-iii288

Author(s):

Dannielle Upton ◽

Santosh Valvi ◽

Jie Liu ◽

Nicole Yeung ◽

Sandra George ◽

...

Keyword(s):

High Throughput ◽

Apoptotic Cell ◽

Safety Data ◽

Biologically Active ◽

Orthotopic Model ◽

High Throughput Drug Screening ◽

Diffuse Intrinsic Pontine Gliomas ◽

Almost All

Abstract DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.

Download Full-text

Postprandial transfer of colostral extracellular vesicles and their protein and miRNA cargo in neonatal calves

10.21203/rs.2.10032/v1 ◽

2019 ◽

Author(s):

Benedikt Kirchner ◽

Dominik Buschmann ◽

Vijay Paul ◽

Michael W. Pfaffl

Keyword(s):

Extracellular Vesicles ◽

Expression Profiles ◽

Bovine Milk ◽

Cell Types ◽

Specific Protein ◽

In Vivo Experiments ◽

Neonatal Calves ◽

Almost All

Abstract Background Extracellular vesicles (EVs) such as exosomes are key regulators of intercellular communication that can be found in almost all bio fluids. Although studies in the last decade have made great headway in discerning the role of EVs in many physiological and pathophysiological processes, the bioavailability and impact of dietary EVs and their cargo still remain to be elucidated. Due to its widespread consumption and high content of EV-associated microRNAs and proteins, a major focus in this field has been set on EVs in bovine milk and colostrum. Despite promising in vitro studies in recent years that show high resiliency of milk EVs to degradation and uptake of milk EV cargo in a variety of intestinal and blood cell types, in vivo experiments continue to be inconclusive and sometimes outright contradictive. Results To resolve this discrepancy, we assessed the potential postprandial transfer of colostral EVs to the circulation of newborn calves by analysing colostrum-specific protein and miRNAs, including specific isoforms (isomiRs) in cells, EV isolations and unfractionated samples from blood and colostrum. Our findings reveal distinct populations of EVs in colostrum and blood from cows that can be clearly separated by density, particle concentration and protein content (BTN1A1, MFGE8). Postprandial blood samples of calves show a time-dependent increase in EVs that share morphological and protein characteristics of colostral EVs. Analysis of miRNA expression profiles by Next-Generation Sequencing gave a different picture however. Although significant postprandial expression changes could only be detected for calf EV samples, expression profiles show very limited overlap with highly expressed miRNAs in colostral EVs or colostrum in general. Conclusions Taken together our results indicate a selective uptake of membrane-associated protein cargo but not luminal miRNAs from colostral EVs into the circulation of neonatal calves.

Download Full-text

METHODOLOGICAL FOUNDATIONS FOR SUBSTANTIATING SAFE LEVELS OF EXPOSURE TO ARTIFICIAL NANOMATERIALS (FOR EXAMPLE, CARBON NANOTUBES)

10.31089/978-5-6042929-2-1-2021-1-506-509 ◽

2021 ◽

Author(s):

G.A. Timerbulatova ◽

◽

Keyword(s):

Carbon Nanotubes ◽

Harmful Effect ◽

Exposure Level ◽

In Vivo Experiments ◽

World Markets ◽

Dose Concentration ◽

Exposure Levels ◽

Planning Of Experiments

Abstract: The unique physicochemical properties of carbon nanotubes allow them to be used in many fields. The global nanomaterials market is growing every year. An important step in introducing products to the domestic and world markets is to determine the safe exposure levels of CNTs. Establishing a corporate standard can serve as a preliminary stage before the approval of a state hygiene standard. Justification of the corporate standard is carried out in in vitro and in vivo experiments. The planning of experiments should be carried out taking into account the target organ under the influence of CNT - the respiratory system. The recommended dose / concentration range for experiments should include doses / concentrations derived from calculated and literature data. A necessary step is to obtain homogeneous dispersions in which CNTs become bioavailable for biological systems. During in vitro and in vivo experiments, the exposure level is determined at which no harmful effect is observed and / or the lowest level of exposure at which there is a harmful effect on the cell culture / respiratory tract of animals.

Download Full-text