Clopidogrel-Herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model

Background: Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. Objective: The current investigation was aimed to evaluate the effect of commonly used herbal products, including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum), on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. Methods: A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of the black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with the clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. Results: Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 µg/ml*h (p<0.05), 26.01 ±0.90 µg/ml*h (p>0.05) and 32.80 ±2.51 µg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 µg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 µg/ml versus 6.12 ±0.21 µg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% about clopidogrel therapeutic effect (p<0.05). The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. Conclusion: This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

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Prospects of Aloe vera and its Bioactive Compounds in Diabetes: Critical Review

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.15.4.54 ◽

2021 ◽

Author(s):

Mukesh Kumar Sharma ◽

Jagat Chauhan ◽

Mohan Kumar ◽

Chetan Kumar Joshi ◽

Sandeep Sharma ◽

...

Keyword(s):

Bioactive Compounds ◽

Aloe Vera ◽

Underlying Mechanism ◽

Biologically Active ◽

Effective Control ◽

Public Health Issue ◽

Herbal Products ◽

Daily Diet ◽

Significant Public Health ◽

Control Of Diabetes

Diabetes is a significant public health issue. The global diabetes epidemic has had a tremendous impact on India, and the disease burden has increased dramatically. Diabetes is quickly increasing in prevalence, especially in Indian cities, according to data. Therefore, an ideal drug is sought that has better safety and tolerability and the most effective control of diabetes. Many effective medications come from plant sources. Natural products like onion and garlic can effectively control diabetes. In this review, we should pay attention to Aloe vera and its bioactive compounds, that with the development of traditional medicine, Aloe vera can be used to treat various diseases. Some reports have questioned the safety and efficacy of Aloe vera or its compounds, especially at different doses, and some studies have shown no side effects. In this review we also focus on benefits on human health so that Aloe vera is part of the daily diet in many countries and appears to be non-toxic, it is necessary to investigate whether aloe vera dietary supplement can be a beneficial preventive or nutritional mitigation strategy to reduce the effects of diabetes. This review focuses on Aloe vera and its biologically active compounds that play a role in the treatment or prevention of this morbid disease: diabetes, including its underlying mechanism of blood sugar lowering properties, and herbal products that have been marketed for the treatment of diabetes or the therapeutic effect of diabetes.

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Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid

Thrombosis and Haemostasis ◽

10.1160/th05-08-0592 ◽

2006 ◽

Vol 95 (02) ◽

pp. 224-228 ◽

Cited By ~ 5

Author(s):

Markus Hinder ◽

Annke Frick ◽

Ronald Rosenburg ◽

Galina Hesse ◽

Marie-Laure Ozoux ◽

...

Keyword(s):

Drug Interaction ◽

Acetylsalicylic Acid ◽

Platelet Function ◽

Bleeding Time ◽

Factor Xa ◽

Pharmacokinetic Parameters ◽

Parameter Estimates ◽

Factor Xa Inhibitor ◽

Direct Factor ◽

Geometric Means

SummaryThe pharmacokinetics, pharmacodynamics and safety of the direct factor Xa inhibitor, otamixaban, with and without concomitant acetylsalicylic acid (ASA) were investigated in healthy volunteers. The study was a double-blind, placebo-controlled 3-way crossover study. Sixty-eight male volunteers in total were randomised to otamixaban, ASA, or otamixaban with ASA. ASA (300 mg once a day) was started2 days before and continued on the day of the otamixaban 6-hour IV infusion (0.3 and 0.5 mg/kg). Pharmacokinetic and pharmacodynamic parameters (coagulation markers, platelet function tests and skin bleeding time) were determined. Drug interaction was assessed by the ratios of geometric means and 90 confidence intervals (90% CI)of the parameter estimates.Pharmacokinetic parameters of otamixaban remain ed unchanged with ASA. Ratios of geometric means (90% CI) were for Ceoi 96.54 (91.21–102.19) and 95. 04 (90. 10–100. 24) and for AUC 98. 0 (93. 92–102. 25) and 95. 90 (92. 61–99. 31), for 0. 3 and 0. 5 mg/kg, respectively. No drug interaction was observed between otamixaban andASA on the coagulation and platelet function parameters. Neither otamixaban nor ASA had an effect on skin bleeding time; their co-administration led toa slight prolongation of skin bleeding time above the normal range without any clinically relevant bleeding. This study demonstrated that the desired effects of otamixaban and ASA, namely anticoagulation and platelet inhibition, respectively, are maintained during co-administration of both drugs.

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Persistence of Intraluminal Thrombus Makes Saccular Aneurysm More Biologically Active than Fusiform in an Experimental Rat Model

Journal of Vascular Research ◽

10.1159/000506159 ◽

2020 ◽

Vol 57 (3) ◽

pp. 164-176

Author(s):

Harry Etienne ◽

Clément Journé ◽

Aymeric Rouchaud ◽

Jean Senemaud ◽

Liliane Louedec ◽

...

Keyword(s):

Rat Model ◽

Biologically Active ◽

Saccular Aneurysm ◽

Intraluminal Thrombus ◽

Experimental Rat Model

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Higher bioavailability of isoflavones after a single ingestion of a soya-based supplement than a soya-based food in young healthy males

British Journal Of Nutrition ◽

10.1017/s0007114507803953 ◽

2008 ◽

Vol 99 (2) ◽

pp. 333-344 ◽

Cited By ~ 25

Author(s):

Sébastien Vergne ◽

Catherine Bennetau-Pelissero ◽

Valérie Lamothe ◽

Philippe Chantre ◽

Mylène Potier ◽

...

Keyword(s):

Healthy Volunteers ◽

Crossover Trial ◽

Human Subjects ◽

Biologically Active ◽

Pharmacokinetic Parameters ◽

Relative Importance ◽

Elisa Method ◽

Isoflavone Content ◽

Derivative Products ◽

Healthy Males

Soya isoflavones, genistein and daidzein, are the focus of numerous studies investigating their potential effects on health and results remain controversial. Bioavailability is clearly a crucial factor influencing their bioefficacy and could explain these discrepancies. This study aimed at assessing: (1) the isoflavone content of sixty-nine European soya-derivative products sold on the French market; (2) the bioavailability of isoflavones comparing supplement with food. Twelve healthy volunteers were recruited in a randomized two-way crossover trial and received 35 mg isoflavones equivalent aglycone either through supplements or through cheese, both containing different patterns of isoflavone conjugates and different daidzein:genistein ratios. A specific ELISA method was used to assess the plasma and urinary concentrations of isoflavones and thus the pharmacokinetic parameters, which were then normalized to mg of each isoflavone ingested. Results showed that the normalized Cmax of daidzein (P = 0·002) and similarly the normalized AUC0 → ∞andCmaxof genistein (P = 0·002) from soya-based capsules were higher than that from soya-based cheese. In conclusion, this work completes studies on isoflavone bioavailability and presents new data regarding isoflavone concentrations in soya-derivative products. Assuming that isoflavone conjugation patterns do not influence isoflavone bioavailability, this study shows that isoflavones contained in capsules are more bioavailable than those contained in soya-based cheese. Although the supplement is more bioavailable, the relative importance of this is difficult to interpret as there is little evidence that supplements are biologically active in human subjects to date and further studies will be necessary for this specific supplement to prove its efficacy.

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Exploratory Pharmacokinetics of Geniposide in Rat Model of Cerebral Ischemia Orally Administered with or without Baicalin and/or Berberine

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/349531 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Linmei Pan ◽

Wenzhe Wang ◽

Feiyan Shi ◽

Jing Zhou ◽

Meng Zhang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Rat Model ◽

Active Ingredient ◽

Pharmacokinetic Parameters ◽

Rat Serum ◽

Absorption Increase ◽

Classical Chinese

Huang-Lian-Jie-Du-Tang (HLJDT), a classical Chinese prescription, has been clinically employed to treat cerebral ischemia for thousands of years. Geniposide is the major active ingredient in HLJDT. The aim is to investigate the comparative evaluations on pharmacokinetics of geniposide in MCAO rats in pure geniposide, geniposide : berberine, and geniposide : berberine : baicalin. Obviously, the proportions of geniposide : berberine, geniposide : baicalin, and geniposide : berberine : baicalin were determined according to HLJDT. In our study, the cerebral ischemia model was reproduced by suture method in rats. The MCAO rats were randomly assigned to four therapy groups and orally administered with different prescription proportions of pure geniposide, geniposide : berberine, geniposide : baicalin, and geniposide : berberine : baicalin, respectively. The concentrations of geniposide in rat serum were determined using HPLC, and main pharmacokinetic parameters were investigated. The results indicated that the pharmacokinetics of geniposide in rat serum was nonlinear and there were significant differences between different groups. Berberine might hardly affect the absorption of geniposide, and baicalin could increase the absorption ability of geniposide. Meanwhile, berberine could decrease the absorption increase of baicalin on geniposide.

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Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.103.063610 ◽

2004 ◽

Vol 309 (2) ◽

pp. 498-505 ◽

Cited By ~ 23

Author(s):

Jean-Michel Dogné ◽

Julien Hanson ◽

Xavier de Leval ◽

Philippe Kolh ◽

Vincent Tchana-Sato ◽

...

Keyword(s):

Receptor Antagonist ◽

Rat Model ◽

Arterial Thrombosis ◽

Bleeding Time ◽

Thromboxane A2 ◽

Pharmacological Characterization ◽

Thromboxane A2 Receptor ◽

Thromboxane Synthase Inhibitor ◽

Synthase Inhibitor

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Enteral intestinal alkaline phosphatase reduces biologically active LPS and TLR4 expression in the rat model of necrotizing enterocolitis

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2013.07.181 ◽

2013 ◽

Vol 217 (3) ◽

pp. S82 ◽

Cited By ~ 1

Author(s):

Nathan P. Heinzerling ◽

David M. Gourlay ◽

Scott R. Welak ◽

Jennifer L. Liedel ◽

Katherine Fredrich ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Necrotizing Enterocolitis ◽

Rat Model ◽

Biologically Active ◽

Tlr4 Expression ◽

Intestinal Alkaline Phosphatase

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Neutralization Of Hemorrhage Induced By Direct Factor Xa and Thrombin Inhibitors In a Rat Model

Blood ◽

10.1182/blood.v122.21.3644.3644 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3644-3644 ◽

Cited By ~ 1

Author(s):

Walter Jeske ◽

Vicki Escalante ◽

Brian McGuire ◽

Jeanine M. Walenga ◽

Jawed Fareed ◽

...

Keyword(s):

Rat Model ◽

Bleeding Time ◽

Factor Xa ◽

New Drugs ◽

Thrombin Inhibitors ◽

Medical Emergency ◽

Individual Treatment ◽

Direct Factor ◽

Major Hemorrhage ◽

Prolonged Bleeding

Abstract Introduction Direct factor Xa and thrombin inhibitors (apixaban, Bristol-Myers Squibb, Princeton, NJ; rivaroxaban, Bayer Healthcare, Leverkusen, Germany; dabigatran, Boehringer Ingelheim, Ridgefield, CT) have shown favorable efficacy profiles in comparison to standard therapy in a variety of clinical conditions including the prevention of stroke in patients with non-valvular atrial fibrillation. Although clinical trials have shown that the safety of these new drugs in terms of the incidence of major hemorrhage is similar or better than with conventional therapies, there remains concern over the ability to reverse their anticoagulant effects in cases of overdose or medical emergency. Prothrombin complex concentrates (PCCs) have been used to reverse the effect of warfarin and in cases of significant bleeding in patients with coagulopathy. PCCs may be useful in modulating hemorrhage caused by the new oral anticoagulant drugs. This study tested the ability of three PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat model. Methods Following anesthesia with an IM injection of ketamine and xylazine, male Sprague-Dawley rats were anticoagulated by an IV injection of apixaban (100 or 300 µg/kg), rivaroxaban (100 or 300 µg/kg) or dabigatran (50 or 100 µg/kg). After 5 minutes, rats were treated with vehicle, a 3-factor PCC (Profilnine, Grifols Biologicals, Los Angeles, CA), a 4-factor PCC (Beriplex, CSL Behring, Marburg, Germany) or an activated 4-factor PCC (FEIBA, Baxter, Deerfield, IL). Five minutes after PCC administration, a standardized tail snip was performed and the time for bleeding to stop was measured. Upon cessation of bleeding, a blood sample was collected by cardiac puncture and the rat was humanely euthanized. Platelet poor plasma was prepared from the blood samples and was analyzed using PT, aPTT and PiCT assays. Results for individual treatment groups were compared using one-way ANOVA (SigmaPlot 12, Systat, San Jose, CA). Results While at a dose of 100 µg/kg, apixaban did not increase the bleeding time vs. saline (6.25 ± 0.8 vs. 6.0 ± 1.7 min), a dose of 300 µg/kg apixaban significantly prolonged the bleeding time (17.1 ± 5.6; p=0.024). Administration of Beriplex at doses up to 10 U/kg did not shorten the bleeding time. 10 U/kg Profilnine shortened bleeding time, but not completely to baseline (9.8 ± 4.2 min). The administration of FEIBA dose-dependently prolonged bleeding beyond that seen with apixaban alone (22.6 ± 11.4 and 37.5 ± 5.2 min for doses of 5 and 10 U/kg, respectively; p<0.001 apixaban + 10 U/kg FEIBA vs. apixaban alone). Doses of 100 and 300 µg/kg rivaroxaban prolonged bleeding time (20.8 ± 2.5, p=0.002 vs. saline; 25.0 ± 10.0 min, p<0.001 vs. saline, respectively). While 10 U/kg Beriplex or Profilnine shortened the bleeding time, Profilnine was more effective (9.7 ± 3.2 min; p=0.508 vs. saline). FEIBA at a dose of 5 U/kg did not reverse rivaroxaban-induced bleeding. Dabigatran caused a dose-dependent increase in bleeding time which could be prevented by the administration of Beriplex or Profilnine (10 U/kg). As with apixaban, the administration of FEIBA enhanced the bleeding seen with dabigatran (50.3 ± 8.3 vs. 15.9 ± 1.2 min; p<0.001). As it was hypothesized that the increased bleeding observed following FEIBA administration may be due to a Protein C mediated facilitation of fibrinolysis, additional groups of rats were anticoagulated with apixaban or rivaroxaban and then treated with FEIBA + 10 mg/kg epsilon aminocaproic acid. In these rats, the bleeding times were comparable to those in non-anticoagulated rats (6.7 ± 5.0 min with apixaban; 7.7 ± 6.4 min with rivaroxaban). Discussion PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors. Owing to their different compositions, each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor with a PCC may enhance the effectiveness of hemorrhage reversal. Disclosures: Jeske: Bristol-Myers Squibb: Research Funding.

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Poly(d,l-Lactide-Coglycolide) Particles Containing Gentamicin: Pharmacokinetics and Pharmacodynamics in Brucella melitensis- Infected Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00809-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1185-1190 ◽

Cited By ~ 46

Author(s):

M. C. Lecaroz ◽

M. J. Blanco-Prieto ◽

M. A. Campanero ◽

H. Salman ◽

C. Gamazo

Keyword(s):

Drug Delivery Systems ◽

Brucella Melitensis ◽

Free Drug ◽

Intravenous Dose ◽

Pharmacokinetic Parameters ◽

Single Intravenous Dose ◽

Pharmacokinetics And Pharmacodynamics ◽

Phagocytic Cells ◽

Target Organs ◽

Parameter Values

ABSTRACT Drug delivery systems containing gentamicin were studied as a treatment against experimental brucellosis in mice. Micro- and nanoparticles prepared by using poly(d,l-lactide-coglycolide) (PLGA) 502H and microparticles made of PLGA 75:25H were successfully delivered to the liver and the spleen, the target organs for Brucella melitensis. Both polymers have the same molecular weight but have different lactic acid/glycolic acid ratios. Microparticles of PLGA 502H and 75:25H released their contents in a sustained manner, in contrast to PLGA 502H nanoparticles, which were degraded almost completely during the first week postadministration. The values of the pharmacokinetic parameters after administration of a single intravenous dose of 1.5 mg/kg of body weight of loaded gentamicin revealed higher areas under the curve (AUCs) for the liver and the spleen and increased mean retention times (MRTs) compared to those for the free drug, indicating the successful uptake by phagocytic cells in both organs and the controlled release of the antibiotic. Both gentamicin-loaded PLGA 502H and 75:25H microparticles presented similar pharmacokinetic parameter values for the liver, but those made of PLGA 75:25 H were more effective in targeting the antibiotic to the spleen (higher AUCs and MRTs). The administration of three doses of 1.5 mg/kg significantly reduced the load associated with the splenic B. melitensis infection. Thus, the formulation made with the 75:25H polymer was more effective than that made with 502H microspheres (1.45-log and 0.45-log reductions, respectively, at 3 weeks posttreatment). Therefore, both, pharmacokinetic and pharmacodynamic parameters showed the suitability of 75:25H microspheres to reduce the infection of experimentally infected mice with B. melitensis.

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