Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin

Purpose: Delineate the stereospecific pharmacokinetics and pharmacodynamics of the chiral flavonoids pinocembrin and pinostrobin. Objective: Characterize for the first time the stereoselective pharmacokinetics of two flavonoids, pinocembrin and pinostrobin and their bioactivity in several in vitro assays with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology. Methods: Chiral flavonoids were intravenously and orally administered to male Sprague-Dawley rats. Concentrations in serum and urine were characterized via stereospecific HPLC or LC/MS. Pure enantiomeric forms of each flavonoid were tested, where possible, to identify the stereospecific contribution to bioactivity in comparision to their racemates. Results: Short half-lives (0.2-6 h) in serum were observed, while a better estimation of half-life (3-26 h) and other pharmacokinetic parameters were observed using urinary data. The flavonoids are predominantly excreted via non-renal routes (fe values of 0.3-4.6 %), and undergo rapid and extensive phase II metabolism. Chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. Conclusion: The importance of understanding the stereospecific pharmacokinetics and pharmacodynamics of two chiral flavonoids were delineated.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Preclinical Study to Evaluate the Effect of Polyherbal Formulation on Metformin: Potential Herb-drug Interaction

The Natural Products Journal ◽

10.2174/2210315508666180507152031 ◽

2019 ◽

Vol 9 (1) ◽

pp. 69-76

Author(s):

Devendra Kumar ◽

Neerja Trivedi ◽

Rakesh Kumar Dixit

Keyword(s):

Diabetes Mellitus ◽

Preclinical Study ◽

Oral Route ◽

Diabetic Rats ◽

Pharmacokinetic Parameters ◽

Sprague Dawley ◽

Pharmacokinetics And Pharmacodynamics ◽

Polyherbal Formulation ◽

Sprague Dawley Rats ◽

Significant Difference

Objective: The aim of the present study was to examine the effect of a polyherbal formulation (PHF) on pharmacokinetics and pharmacodynamics of metformin in rats. Methods: The present study was conducted to determine the beneficial outcomes of PHF along with metformin by studying herb-drug interactions. PHF was prepared by five indigenous herbs, Those are being used traditionally as antidiabetic in India. PHF doses (100 mg/kg/day) were administered to Sprague-Dawley rats by an oral route of different groups for multiple weeks except for control. Metformin (100 mg/kg) was orally administered at 7th and 30th day to control and PHF pretreated rats for pharmacokinetics study while pharmacodynamics study was conducted in PHF treated and untreated diabetic rats. No more significant difference was found in the pharmacokinetic parameters in PHF treated at 7th day while a significant increase was found in AUC at the 30th day. Results: The hypoglycemic effect was observed with a combination of metformin and PHF, significantly more compared to control. Metformin decreased the blood glucose 1.51 fold at 7th day and 1.7 fold at 30th day respectively, compared to control. Conclusion: Thus, this finding indicates that PHF increased the AUC of metformin. It might increase bioavailability through drug-herb interaction thereby affecting the therapeutic effect. This formulation can be considered as an adjunct to metformin in the management of diabetes mellitus.

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Characterization of Highly Polar Dna Adducts Derived from Dibenz[A,H]Anthracene (DBA), 3,4-Dihydroxy-3,4-Dihydro-DBA, and 3,4,10,11-Tetrahydroxy-3,4,10,11-Tetrahydro-DBA

Toxicology and Industrial Health ◽

10.1177/074823379300900309 ◽

1993 ◽

Vol 9 (3) ◽

pp. 503-509 ◽

Cited By ~ 3

Author(s):

Juergen Fuchs ◽

Jiri Mlcoch ◽

Franz Oesch ◽

Karl Ludwig Platt

Keyword(s):

Dna Adducts ◽

Liver Microsomes ◽

Metabolic Activation ◽

Reversed Phase ◽

Reversed Phase Hplc ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Calf Thymus

Two highly polar DNA adducts were found after metabolic activation of 3,4,10,11-tetrahydroxy-3,4,10,11-tetrahydrodibenz[ a,h]anthracene(DBA-3,4;10, 11-bisdiol) by liver microsomes isolated from male Sprague-Dawley rats pretreated with Aroclor 1254 in presence of calf thymus DNA. These DNA adducts could be assigned to the metabolites of dibenz[ a,h]anthracene (DBA), of 3R,4R,10R,11R-tetrahydroxy-3,4,10,11-tetrahydro-DBA and of 3R,4R,10S,US-tetrahydroxy-3,4,10,11-tetrahydro-DBA. DNA adducts derived from metabolites of 3S,4S,10S,11S-tetrahydroxy-3,4,10,11-tetrahydro-DBA were not found. These highly polar adducts also could be detected by reversed phase HPLC after incubation of dibenz[ a,h]anthracene, 3R,4R-dihydroxy-3,4-dihydro-DBA ((-)-DBA-3,4-diol) and 3S,4S- dihydroxy-3,4-dihydro-DBA ((+)-DBA-3,4-diol) with DNA in presence of the activating system. After incubation of 14C labelled DBA DNA adducts derived from DBA-3,4;10,11-bisdiol were found in a fraction of 38% and bay region 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydro-DBA-DNA adducts at a level of 25%. DBA-3,4; 10,11-bisdiol exhibited a higher DNA binding yield (38 × 12 pmollmg DNA) than (-)-DBA-3,4-diol (23 × 6 pmol/mg DNA), the most mutagenic 3,4-diol enantiomer. For (+)-DBA-3,4-diol the highly polar DNA adducts derived from DBA-3,4;10,11-bisdiol were by far the most predotmnant adducts in vitro.

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Bioactive Markers Based Pharmacokinetic Evaluation of Extracts of a Traditional Medicinal Plant,Piper sarmentosum

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep143 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Khalid Hussain ◽

Zhari Ismail ◽

Amirin Sadikun ◽

Pazillah Ibrahim

Keyword(s):

Oral Bioavailability ◽

High Performance ◽

Ethanol Extract ◽

Intestinal Wall ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Human Pharmacokinetics ◽

Sprague Dawley ◽

Sprague Dawley Rats

In vitroassays are economical and easy to perform but to establish relevance of their results to real clinical outcome in animals or human, pharmacokinetics is prerequisite. Despite variousin vitropharmacological activities of extracts ofPiper sarmentosum, there is no report of pharmacokinetics. Therefore, the present study aimed to evaluate ethanol extract of fruit of the plant in dose of 500 mg kg−1orally for pharmacokinetics. Sprague-Dawley rats were randomly divided into groups 1, 2, and 3 (eachn= 6) to study absorption, distribution and excretion, respectively. High performance liquid chromatography (HPLC) with ultraviolet detection was applied to quantify pellitorine, sarmentine and sarmentosine in plasma, tissues, feces and urine to calculate pharmacokinetic parameters. Pellitorine exhibited maximum plasma concentration (Cmax) 34.77 ng mL−1± 1.040, time to achieveCmax(Tmax) 8 h, mean resident time (MRT) 26.00 ± 0.149 h and half life (t1/2) 18.64 ± 1.65 h. Sarmentine showedCmax191.50 ± 12.69 ng mL−1,Tmax6 h, MRT 11.12 ± 0.44 h andt1/210.30 ± 1.98 h. Sarmentosine exhibited zero oral bioavailability because it was neither detected in plasma nor in tissues, and in urine. Pellitorine was found to be distributed in intestinal wall, liver, lungs, kidney, and heart, whereas sarmentine was found only in intestinal wall and heart. The cumulative excretion of pellitorine, sarmentine and sarmentosine in feces in 72 h was 0.0773, 0.976, and 0.438 μg, respectively. This study shows that pellitorine and sarmentine have good oral bioavailability while sarmentosine is not absorbed from the gastrointestinal tract.

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Evaluation of Iron Nutritional Quality of Two Amaranth Species sing Hemoglobin Repletion in Rats

HortScience ◽

10.21273/hortsci.30.4.811a ◽

1995 ◽

Vol 30 (4) ◽

pp. 811A-811

Author(s):

Anusuya Rangarajan ◽

Wanda Chenoweth ◽

John F. Kelly ◽

Karen Agee

Keyword(s):

Nutritional Quality ◽

In Vitro Assay ◽

Total Iron ◽

In Vitro Assays ◽

Sprague Dawley ◽

Vitro Assay ◽

Sprague Dawley Rats ◽

Amaranth Species

Studies have been underway to evaluate the genetic variation in iron nutritional quality of the green leafy vegetable Amaranthus. Initial screening of 35 lines of amaranth from 12 species indicated wide variation in total iron, and small, but significant, differences in bioavailable iron, as determined by an in vitro assay. To verify if the differences in bioavailable iron detected by the in vitro assay were biologically significant, two lines of amaranth, A. tricolor Ames 5113 and A. hypochondriacus Ames 2171, were evaluated using a hemoglobin repletion assay in rats. Weanling Sprague-Dawley rats were made anemic by feeding an ironfree casein-based diet for 4 weeks. The anemic animals were fed treatment diets in which all Fe was provided by the amaranth lines. Hemoglobin levels were measured at the start and end of the treatment period to determine bioavailability. Although A. tricolor contained a higher concentration of total iron (670 ppm), the bioavailability of this iron to rats was lower than from the A. hypochondnacus line (total Fe = 210 ppm). Similar amounts of either amaranth line added to the diet produced similar changes in hemoglobin, although total iron concentrations were significantly different, confirming results observed with in vitro assays.

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Functional Characterization of the mazEF Toxin-Antitoxin System in the Pathogenic Bacterium Agrobacterium tumefaciens

Microorganisms ◽

10.3390/microorganisms9051107 ◽

2021 ◽

Vol 9 (5) ◽

pp. 1107

Author(s):

Wonho Choi ◽

Yoshihiro Yamaguchi ◽

Ji-Young Park ◽

Sang-Hyun Park ◽

Hyeok-Won Lee ◽

...

Keyword(s):

Agrobacterium Tumefaciens ◽

Physiological Function ◽

Functional Characterization ◽

Site Directed Mutagenesis ◽

In Vitro Assays ◽

Cell Growth Inhibition ◽

The Right

Agrobacterium tumefaciens is a pathogen of various plants which transfers its own DNA (T-DNA) to the host plants. It is used for producing genetically modified plants with this ability. To control T-DNA transfer to the right place, toxin-antitoxin (TA) systems of A. tumefaciens were used to control the target site of transfer without any unintentional targeting. Here, we describe a toxin-antitoxin system, Atu0939 (mazE-at) and Atu0940 (mazF-at), in the chromosome of Agrobacterium tumefaciens. The toxin in the TA system has 33.3% identity and 45.5% similarity with MazF in Escherichia coli. The expression of MazF-at caused cell growth inhibition, while cells with MazF-at co-expressed with MazE-at grew normally. In vivo and in vitro assays revealed that MazF-at inhibited protein synthesis by decreasing the cellular mRNA stability. Moreover, the catalytic residue of MazF-at was determined to be the 24th glutamic acid using site-directed mutagenesis. From the results, we concluded that MazF-at is a type II toxin-antitoxin system and a ribosome-independent endoribonuclease. Here, we characterized a TA system in A. tumefaciens whose understanding might help to find its physiological function and to develop further applications.

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Potential use of molecular and structural characterization of the gut bacterial community for postmortem interval estimation in Sprague Dawley rats

Scientific Reports ◽

10.1038/s41598-020-80633-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Huan Li ◽

Siruo Zhang ◽

Ruina Liu ◽

Lu Yuan ◽

Di Wu ◽

...

Keyword(s):

High Throughput Sequencing ◽

Interval Estimation ◽

The Body ◽

Taxon Richness ◽

Time Since Death ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Level Data ◽

Species Taxon

AbstractOnce the body dies, the indigenous microbes of the host begin to break down the body from the inside and play a key role thereafter. This study aimed to investigate the probable shift in the composition of the rectal microbiota at different time intervals up to 15 days after death and to explore bacterial taxa important for estimating the time since death. At the phylum level, Proteobacteria and Firmicutes showed major shifts when checked at 11 different intervals and emerged at most of the postmortem intervals. At the species level, Enterococcus faecalis and Proteus mirabilis showed a downward and upward trend, respectively, after day 5 postmortem. The phylum-, family-, genus-, and species-taxon richness decreased initially and then increased considerably. The turning point occurred on day 9, when the genus, rather than the phylum, family, or species, provided the most information for estimating the time since death. We constructed a prediction model using genus-level data from high-throughput sequencing, and seven bacterial taxa, namely, Enterococcus, Proteus, Lactobacillus, unidentified Clostridiales, Vagococcus, unidentified Corynebacteriaceae, and unidentified Enterobacteriaceae, were included in this model. The abovementioned bacteria showed potential for estimating the shortest time since death.

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Pharmacological comparison of four biopolymeric natural gums as hemostatic agents for management of bleeding wounds: preliminary in vitro and in vivo results

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00237-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Himanshu Kushwah ◽

Nidhi Sandal ◽

Meenakshi Chauhan ◽

Gaurav Mittal

Keyword(s):

Xanthan Gum ◽

Guar Gum ◽

Human Lymphocytes ◽

Sprague Dawley ◽

Gum Tragacanth ◽

Civilian Trauma ◽

Sprague Dawley Rats ◽

Cytotoxicity Studies

Abstract Background Uncontrolled bleeding is one of the primary reasons for preventable death in both civilian trauma and military battle field. This study evaluates in vitro and in vivo hemostatic potential of four biopolymeric natural gums, namely, gum tragacanth, guar gum, xanthan gum, and gum acacia. In vitro evaluation of whole blood clotting time and erythrocyte agglutination assay were carried out. In vitro cytotoxicity studies with respect to each gum were done in human lymphocytes to ascertain percent cell viability. In vivo hemostatic potential of each gum (as sponge dressing and powder form) was evaluated in Sprague Dawley rats using tail bleeding assay and compared with commercially available hemostatic sponge. Other important parameters like (a) time taken for complete hemostasis, (b) amount of blood absorbed, (c) adherence strength of developed hemostatic dressing(s), (d) incidence of re-bleeding, and (e) survival of animals were also studied. Results Of the four test gums studied, xanthan gum (@3mg/ml of blood) and gum tragacanth (@35mg/ml of blood) were able to clot blood in least time (58.75±6.408 s and 59.00±2.082 s, respectively) and exhibited very good hemostatic potential in vitro. Except for xanthan gum, all other test gums did not exhibit any significant cytotoxicity at different time points till 24 h. In rat tail bleeding experiments, gum tragacanth sponge dressing and powder achieved hemostasis in least time (156.2±12.86 s and 76±12.55 s, respectively) and much earlier than commercially available product (333.3±38.84 s; p˂0.01). Conclusion Results indicate potential of gum tragacanth to be developed into a suitable hemostatic product.

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Bioavailability in Vivo of Benzo[a]Pyrene Adsorbed to Diesel Particulate

Toxicology and Industrial Health ◽

10.1177/074823379100700302 ◽

1991 ◽

Vol 7 (3) ◽

pp. 125-139 ◽

Cited By ~ 6

Author(s):

David R. Bevan ◽

David M. Ruggio

Keyword(s):

Health Risks ◽

Quantitative Description ◽

Intratracheal Instillation ◽

Direct Analysis ◽

Sprague Dawley ◽

Reasonable Estimate ◽

Diesel Particulate ◽

Sprague Dawley Rats

To evaluate health risks associated with exposure to particulates in the environment, it is necessary to quantify the bioavailability of carcinogens associated with the particulates. Direct analysis of bioavailability in vivo is most readily accomplished by adsorbing a radiolabeled form of the carcinogen to the particulate. A sam ple of native diesel particulate collected from an Oldsmobile die sel engine that contained 1.03 μ g benzo[ a] pyrene ( BaP)/ g particulate was supplemented with exogenous [ 3 H]- BaP to pro duce a particulate containing 2.62 μ g BaP/g. To insure that elu tion of BaP from native and [3 H] -BaP-supplemented particulate was similar, in vitro analyses were performed. When using phos pholipid vesicles composed of dimyristoylphosphatidylcholine (DMPC), 1.52% of total BaP was eluted from native particulate into the vesicles in 18 hrs; from [ 3 H] -BaP supplemented particu late, 1.68% was eluted. Using toluene as eluent, 2.55% was eluted from native particulate, and 8.25% from supplemented particulate, in 6 hrs. Supplemented particulate was then instilled intratracheally into male Sprague-Dawley rats and distribution of radioactivity was analyzed at selected times over 3 days. About 50% of radioactivity remained in lungs at 3 days following instil lation, with 30% being excreted into feces and the remainder dis tributed throughout the organs of the rats. To estimate the amount of radioactivity that entered feces through swallowing of a portion of the instilled dose, [3 H] -BaP-supplemented particu late was instilled intratracheally into rats that had a cannula sur gically implanted in the bile duct. Rate of elimination of radio activity into bile was monitored; 10.6% of radioactivity was re covered in 6 hr, an amount slightly lower than the 12.8% ex creted in 6 hrs into feces of animals with intact bile ducts. Our studies provide a quantitative description of the distribution of BaP and its metabolites following intratracheal instillation of diesel particulate. Because rates of elution of BaP in vitro are similar for native diesel particulate and particulate with supple mental [ 3H] -BaP, our results provide a reasonable estimate of the bioavailability in vivo of BaP associated with diesel particu late.

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Characterization of Postharvest Fungicide-Resistant Botrytis cinerea Isolates From Commercially Stored Apple Fruit

Phytopathology ◽

10.1094/phyto-07-16-0250-r ◽

2017 ◽

Vol 107 (3) ◽

pp. 362-368 ◽

Cited By ~ 16

Author(s):

Wayne M. Jurick ◽

Otilia Macarisin ◽

Verneta L. Gaskins ◽

Eunhee Park ◽

Jiujiang Yu ◽

...

Keyword(s):

Botrytis Cinerea ◽

Gray Mold ◽

Apple Fruit ◽

Sublethal Dose ◽

Long Term Storage ◽

Pose Control ◽

First Time

Botrytis cinerea causes gray mold and is an economically important postharvest pathogen of fruit, vegetables, and ornamentals. Fludioxonil-sensitive B. cinerea isolates were collected in 2011 and 2013 from commercial storage in Pennsylvania. Eight isolates had values for effective concentrations for inhibiting 50% of mycelial growth of 0.0004 to 0.0038 μg/ml for fludioxonil and were dual resistant to pyrimethanil and thiabendazole. Resistance was generated in vitro, following exposure to a sublethal dose of fludioxonil, in seven of eight dual-resistant B. cinerea isolates. Three vigorously growing B. cinerea isolates with multiresistance to postharvest fungicides were further characterized and found to be osmosensitive and retained resistance in the absence of selection pressure. A representative multiresistant B. cinerea strain caused decay on apple fruit treated with postharvest fungicides, which confirmed the in vitro results. The R632I mutation in the Mrr1 gene, associated with fludioxonil resistance in B. cinerea, was not detected in multipostharvest fungicide-resistant B. cinerea isolates, suggesting that the fungus may be using additional mechanisms to mediate resistance. Results from this study show for the first time that B. cinerea with dual resistance to pyrimethanil and thiabendazole can also rapidly develop resistance to fludioxonil, which may pose control challenges in the packinghouse environment and during long-term storage.

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Safety Assessment of a Hydroethanolic Extract of Caralluma fimbriata

International Journal of Toxicology ◽

10.1177/1091581813492827 ◽

2013 ◽

Vol 32 (5) ◽

pp. 385-394 ◽

Cited By ~ 3

Author(s):

Antoinette Y. Odendaal ◽

Narendra S. Deshmukh ◽

Tennille K. Marx ◽

Alexander G. Schauss ◽

John R. Endres ◽

...

Keyword(s):

Developmental Toxicity ◽

Toxicity Study ◽

Developmental Study ◽

Sprague Dawley ◽

Oral Toxicity ◽

Toxicological Assessment ◽

Sprague Dawley Rats ◽

Chromosomal Aberration Test ◽

Hydroethanolic Extract

This toxicological assessment evaluated the safety of a hydroethanolic extract prepared from Caralluma fimbriata (CFE), a dietary supplement marketed worldwide as an appetite suppressant. Studies included 2 in vitro genotoxicity assays, a repeated dose oral toxicity study, and a developmental study in rats. No evidence of in vitro mutagenicity or clastogenicity surfaced in the in vitro studies at concentrations up to 5000 μg of extract/plate (Ames test) or 5000 μg of extract/mL (chromosomal aberration test). No deaths or treatment-related toxicity were seen in the 6-month chronic oral toxicity study in Sprague-Dawley rats conducted at 3 doses (100, 300, and 1000 mg/kg body weight (bw)/d). The no observed effect level for CFE in this study was considered to be 1000 mg/kg bw/d. A prenatal developmental toxicity study conducted at 3 doses (250, 500, and 1000 mg/kg bw/d) in female Sprague-Dawley rats resulted in no treatment-related external, visceral, or skeletal fetal abnormalities, and no treatment-related maternal or pregnancy alterations were seen at and up to the maximum dose tested. CFE was not associated with any toxicity or adverse events.

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