Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in in vitro and in vivo test systems

2021 ◽  
Vol 98 (5) ◽  
pp. 548-557
Author(s):  
E. A. Jain ◽  
D. Pleimes ◽  
A. A. Globenko
Keyword(s):  
Oral Administration ◽  
Chromosomal Aberrations ◽  
Ames Test ◽  
Chronic Toxicity ◽  
Micronucleus Test ◽  
Human Lymphocytes ◽  
Antiviral Drug ◽  
Systemic Exposure

Introduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxic properties in in vitro and in vivo models, as well as to study the toxicity of IPA following chronic oral administration to rats and dogs.Materials and methods. Mutagenic and genotoxic properties of IPA were assessed using the Ames test, the test of chromosomal aberrations in human lymphocytes, and the micronucleus test in rats. The chronic toxicity of IPA was studied in Sprague Dawley rats and beagle dogs of both sexes, to which IPA was administered orally at doses of 30-300 mg/kg/day for 26 and 39 weeks, respectively.Results and discussion. In the Ames test, the addition of IPA up to the maximum dose (5000 mcg/plate) did not result in the increase in the number of revertant colonies. At a concentration of up to 5000 mcg/ml, IPA did not cause chromosomal aberrations in human leukocytes. At doses doses ≤ 2000 mg/kg, IPA did not increase the amount of micronuclei in the bone marrow of rats. In chronic experiments, animals tolerated the administration of IPA well: the dose without an observed effect (NOEL) for rats and dogs was 300 mg/kg/day.Conclusion. IPA did not show mutagenic and genotoxic properties in standard in vitro and in vivo tests. With chronic oral administration to rats and dogs, NOEL IPA equal to 300 mg/kg/day provided a systemic exposure that was 8-10 and 41-65 times higher than that in humans, respectively. The results obtained allow us to consider the safety profile of the prolonged use in humans as favorable.

Changes in the hypothalamic contents of LHRH-I and -II and in pituitary responsiveness to synthetic chicken LHRH-I and -II during the progesterone-induced surge of LH in the laying hen

1990 ◽  
Vol 127 (3) ◽  
pp. 487-496 ◽  
Author(s):  
S. C. Wilson ◽  
R. A. Chairil ◽  
F. J. Cunningham ◽  
R. T. Gladwell
Keyword(s):  
Plasma Concentration ◽  
Pituitary Gland ◽  
Laying Hens ◽  
Plasma Concentrations ◽  
Posterior Hypothalamus ◽  
Anterior Hypothalamus ◽  
Significant Fall ◽  
Basal Plasma

ABSTRACT The contents of LHRH-I and -II in the anterior hypothalamus and posterior hypothalamus (including the mediobasal hypothalamus and median eminence) were measured at 90, 180 and 360 min after the i.m. injection of laying hens with progesterone. Whilst no changes were observed in the content of LHRH-I in the anterior hypothalamus, LHRH-I in the posterior hypothalamus tended to fall at 90 and 180 min after injection of progesterone in hens maintained on 16 h light:8 h darkness (16L:8D) and 8L:16D respectively. Pretreatment of laying hens with tamoxifen significantly increased the hypothalamic contents of LHRH-I and -II, raised the basal plasma concentration of LH and modified the LH response to progesterone injection. In hens in which tamoxifen prevented an increase in the plasma concentration of LH after progesterone injection, the content of LHRH-I in the posterior hypothalamus remained unchanged. In contrast, in hens in which progesterone stimulated a steep increase in LH within 90 min, there was a pronounced and significant fall in LHRH-I content of the posterior hypothalamus. No change in the hypothalamic content of LHRH-II was observed during the progesterone-induced surge of LH until plasma concentrations had attained maximal values or started to decline. Then, in hens maintained on 16L:8D, a significant fall in the content of LHRH-II in the anterior hypothalamus was found at both 180 and 360 min after injection with progesterone. Tests in vitro and in vivo of the responsiveness of the pituitary gland to synthetic LHRH-I and -II revealed no change at 90 min after injection of laying hens with progesterone, when plasma concentrations of LH were increasing, but a pronounced reduction when plasma LH concentrations were maximal or falling. These results suggest that LHRH-I mediates in the progesterone-induced increase in the plasma concentration of LH. Although the subsequent decline in plasma LH was associated with a reduced responsiveness of the pituitary gland to LHRH, a significant correlation between the contents of LHRH-I and -II in the anterior hypothalamus and a fall in the hypothalamic content of LHRH-II when plasma LH was maximal or declining allows the possibility of an involvement of this peptide in the neuroendocrine events preceding ovulation. Journal of Endocrinology (1990) 127, 487–496

scholarly journals Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

2020 ◽  
Author(s):  
Xi Yu ◽  
Liming Zhang ◽  
Liangqin Tong ◽  
Nana Zhang ◽  
Han Wang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Lipase Activity ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Viral Envelope ◽  
Global Public Health ◽  
Virucidal Activity ◽  
Extracellular Milieu

AbstractViruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

scholarly journals Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 782
Author(s):  
Ji-Min Kim ◽  
Seong-Wook Seo ◽  
Dong-Gyun Han ◽  
Hwayoung Yun ◽  
In-Soo Yoon
Keyword(s):  
Plasma Concentration ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Systemic Exposure ◽  
Concurrent Administration ◽  
Time Curve ◽  
Mixed Inhibition

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Inhibition of Prothrombinase and Not Soluble Factor Xa (fXa) Predicts Efficacy of fXa Inhibitors in an In Vivo Model of Deep Vein Thrombosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 902-902
Author(s):  
Suzanne Delaney ◽  
Ann Arfsten ◽  
Sherin Halfon ◽  
Gail Siu ◽  
John Malinowski ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Vein Thrombosis ◽  
Prothrombinase Complex ◽  
Antithrombotic Efficacy ◽  
Deep Vein

Abstract Factor Xa (fXa) inhibitors are being tested in the clinic for the prevention and treatment of deep vein thrombosis (DVT) following orthopedic surgery. The antithrombotic efficacy of these drug candidates has traditionally been established in animal models as it is not known whether fXa amidolytic activity, activated partial thromboplastin time (aPTT) or prothrombin time (PT) predict efficacious doses. The present study was designed to test the hypothesis that the potency of fXa inhibitors against fXa incorporated into the prothrombinase complex would predict in vivo antithrombotic efficacy. Eight fXa inhibitors from four structurally distinct chemical series with a range of activities against fXa were tested for their ability to inhibit the prothrombinase complex in human plasma. Thrombin generation and subsequent cleavage of a specific thrombin substrate was used as a measure of prothrombinase activity, inhibitory activity being defined by the concentration of inhibitor required to produce a 2-fold extension in the time to maximal thrombin production (2x lag). In vitro rabbit PTs were also determined. Inhibition in the rabbit DVT model was assessed as previously described (Thromb Haemost1994; 71:357) and related to plasma concentrations of drug. Agent fXa IC50 (nM) Prothrombinase 2x lag (μM) Plasma concentration in DVT (μM) Thrombosis inhibition (%) Rabbit PT 2x change (μM) PRT50034 0.5 0.18 0.06 94 7.0 PRT54681 1.3 0.22 1.14 37 2.7 PRT54676 0.7 0.24 1.65 47 1.7 PRT54004 0.4 0.25 1.04 47 1.0 PRT54456 0.8 0.34 3.39 41 1.5 PRT56848 4.4 0.92 5.2 11 4.7 PRT54955 3.5 1.35 4.6 19 8.8 PRT57106 8.2 1.66 9.2 0 64 All compounds inhibited soluble fXa by 50 % at concentrations less than 10 nM. However, the rank order of potencies for inhibition of soluble fXa differed from that required to inhibit the prothrombinase complex. There was also poor correlation between the 2x lag value for prothrombinase inhibition and the concentration required to achieve a 2x change in rabbit PT (r2 = 0.57). Neither the activities of fXa inhibition nor the change in rabbit PT predicted activity in the DVT model. In contrast, compounds could be broadly divided into 3 levels of efficacy for inhibition of in vivo thrombus growth depending on their potency in the in vitro prothrombinase assay. PRT50034 had the lowest 2x lag value of 0.18 μM and was the most potent inhibitor of in vivo thrombosis with 94 % inhibition at a plasma concentration of 65 nM. The second group of compounds, with 2x lag values in the prothrombinase assay ranging from 0.22 to 0.34 μM, inhibited in vivo thrombus formation by 37 to 47 % at plasma concentrations ranging from 1.04 to 3.39 μM. Compounds in the third category were the least potent prothrombinase inhibitors (2x lag values greater than 0.92 μM) and were unable to significantly inhibit in vivo thrombosis even at plasma concentrations of 9.2 μM. These data show that the 2x lag value obtained in the prothrombinase assay, and not inhibition of soluble fXa or extension of rabbit PT, is capable of predicting fXa inhibitor efficacy in the in vivo rabbit DVT model.

scholarly journals CITCO as an Adjuvant Facilitates CHOP-Based Lymphoma Treatment in hCAR-Transgenic Mice

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2520
Author(s):  
Ritika Kurian ◽  
William Hedrich ◽  
Bryan Mackowiak ◽  
Linhao Li ◽  
Hongbing Wang
Keyword(s):  
Transgenic Mice ◽  
Constitutive Androstane Receptor ◽  
Plasma Concentrations ◽  
Survival Rates ◽  
Pharmacokinetic Profile ◽  
In Vivo Studies ◽  
Chop Regimen ◽  
Transgenic Mouse Line

Non-Hodgkin’s lymphoma (NHL) is a malignant cancer originating in the lymphatic system with a 25–30% mortality rate. CHOP, consisting of cyclophosphamide (CPA), doxorubicin, vincristine, and prednisone, is a first-generation chemotherapy extensively used to treat NHL. However, poor survival rates among patients in advanced stages of NHL shows a need to improve this standard of care treatment. CPA, an integral component of CHOP, is a prodrug that requires CYP2B6-mediated bioactivation to 4-hydroxy-CPA (4-OH-CPA). The expression of CYP2B6 is transcriptionally regulated by the constitutive androstane receptor (CAR, NRi13). We have previously demonstrated that the induction of hepatic CYP2B6 by CITCO, a selective human CAR (hCAR) agonist, results in CHOP’s enhanced antineoplastic effects in vitro. Here, we investigate the in vivo potential of CITCO as an adjuvant of CPA-based NHL treatment in a hCAR-transgenic mouse line. Our results demonstrate that the addition of CITCO to the CHOP regimen leads to significant suppression of the growth of EL-4 xenografts in hCAR-transgenic mice accompanied by reduced expression of cyclin-D1, ki67, Pcna, and increased caspase 3 fragmentation in tumor tissues. CITCO robustly induced the expression of cyp2b10 (murine ortholog of CYP2B6) through hCAR activation and increased plasma concentrations of 4-OH-CPA. Comparing to intraperitoneal injection, oral gavage of CITCO results in optimal hepatic cyp2b10 induction. Our in vivo studies have collectively uncovered CITCO as an effective facilitator for CPA-based NHL treatment with a pharmacokinetic profile favoring oral administration, promoting CITCO as a promising adjuvant candidate for CPA-based regimens.

scholarly journals Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline Infectious Peritonitis (FIP)

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1000
Author(s):  
Jane Yu ◽  
Benjamin Kimble ◽  
Jacqueline M. Norris ◽  
Merran Govendir
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Feline Calicivirus ◽  
Potential Treatment ◽  
Feline Infectious Peritonitis ◽  
Feline Coronavirus

The pharmacokinetic profile of mefloquine was investigated as a preliminary study towards a potential treatment for feline coronavirus infections (such as feline infectious peritonitis) or feline calicivirus infections. Mefloquine was administered at 62.5 mg orally to seven clinically healthy cats twice weekly for four doses and mefloquine plasma concentrations over 336 h were measured using high pressure liquid chromatography (HPLC). The peak plasma concentration (Cmax) after a single oral dose of mefloquine was 2.71 ug/mL and time to reach Cmax (Tmax) was 15 h. The elimination half-life was 224 h. The plasma concentration reached a higher level at 4.06 ug/mL when mefloquine was administered with food. Adverse effects of dosing included vomiting following administration without food in some cats. Mild increases in serum symmetric dimethylarginine (SDMA), but not creatinine, concentrations were observed. Mefloquine may provide a safe effective treatment for feline coronavirus and feline calicivirus infections in cats.

scholarly journals Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry

2020 ◽  
pp. 1-9
Author(s):  
Tobias Kammerer ◽  
Philipp Groene ◽  
Sophia R. Sappel ◽  
Sven Peterss ◽  
Paula A. Sa ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Tranexamic Acid ◽  
Plasminogen Activator ◽  
Kidney Function ◽  
Plasma Concentrations ◽  
Dose Effect ◽  
Duration Of Action ◽  
Lysis Inhibition

<b><i>Introduction:</i></b> Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called “fibrinolytic shutdown”) correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). <b><i>Materials and Methods:</i></b> Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25–75th percentile). <b><i>Results:</i></b> In vivo TXA plasma concentration correlated with LT (<i>r</i> = 0.55; <i>p</i> &#x3c; 0.0001) and ML (<i>r</i> = 0.62; <i>p</i> &#x3c; 0.0001) at all time points. Lysis was inhibited up to 96 h (LT<sub>TPA-test</sub>: baseline: 398 s [229–421 s] vs. at 96 h: 886 s [626–2,175 s]; <i>p</i> = 0.0013). After 24 h, some patients (<i>n</i> = 8) had normalized lysis, but others (<i>n</i> = 17) had strong lysis inhibition (ML &#x3c;30%; <i>p</i> &#x3c; 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42–2.02] vs. 1.28 [1.01–1.52] mg/L; <i>p</i> = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89–13.45] vs.1.41 [1.30–2.34] µg/mL; <i>p</i> &#x3c; 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. <b><i>Conclusions:</i></b> Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

scholarly journals Bioavailability and pharmacokinetics of cefotaxime in Muscovy ducks

2016 ◽  
Vol 4 (1) ◽  
pp. 93 ◽  
Author(s):  
Mohamed Aboubakr
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Mean Values ◽  
Elimination Half ◽  
Maximal Plasma ◽  
The Mean ◽  
Muscovy Ducks

The pharmacokinetic profile of cefotaxime following a single intravenous (IV) and intramuscular (IM) injection was studied in Muscovy ducks. Cefotaxime was given at a dose rate of 25 mg/kg b.wt. for both routes. After IV injection, the plasma levels of cefotaxime estimated at 0.08 h was 70.87 μg/ml, which declined gradually and cefotaxime was detected up to 10 h (0.59 μg/ml). The mean values of CL, Vdss and t1/2β of cefotaxime in muscovy ducks were 0.22 l/kg/h, 0.51 l/kg and 1.81 h, respectively. After IM injection, maximum plasma concentration (Cmax) was (14.72 μg/ml), time of maximal plasma concentration (tmax) was (2.3 h) and elimination half-life (t1/2el)was (1.77 h). Bioavailability following IM injection was 79.61%, and in vitro protein binding percent was 31.48%. A recommended IM dosage for cefotaxime in muscovy ducks would be 30 mg/kg b.wt., repeated at 12 h intervals will provide a therapeutic plasma concentrations exceeding the MIC≤0.5 µg/ml for most susceptible pathogens in ducks.

Comparison of Specific Antibody, D-Phe-Pro-Arg-CH2Cl and Aprotinin for Prevention of In Vitro Effects of Recombinant Tissue-Type Plasminogen Activator on Haemostasis Parameters

1987 ◽  
Vol 58 (03) ◽  
pp. 921-926 ◽  
Author(s):  
E Seifried ◽  
P Tanswell
Keyword(s):  
Specific Antibody ◽  
Plasma Concentrations ◽  
Fibrinolytic Therapy ◽  
Tissue Type ◽  
Control Value ◽  
Type Plasminogen Activator ◽  
In Vitro Effects ◽  
Fibrinolytic Parameters

SummaryIn vitro, concentration-dependent effects of rt-PA on a range of coagulation and fibrinolytic assays in thawed plasma samples were investigated. In absence of a fibrinolytic inhibitor, 2 μg rt-PA/ml blood (3.4 μg/ml plasma) caused prolongation of clotting time assays and decreases of plasminogen (to 44% of the control value), fibrinogen (to 27%), α2-antiplasmin (to 5%), FV (to 67%), FVIII (to 41%) and FXIII (to 16%).Of three inhibitors tested, a specific polyclonal anti-rt-PA antibody prevented interferences in all fibrinolytic and most clotting assays. D-Phe-Pro-Arg-CH2Cl (PPACK) enabled correct assays of fibrinogen and fibrinolytic parameters but interfered with coagulometric assays dependent on endogenous thrombin generation. Aprotinin was suitable only for a restricted range of both assay types.Most in vitro effects were observed only with rt-PA plasma concentrations in excess of therapeutic values. Nevertheless it is concluded that for clinical application, collection of blood samples on either specific antibody or PPACK is essential for a correct assessment of in vivo effects of rt-PA on the haemostatic system in patients undergoing fibrinolytic therapy.

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