scholarly journals Pharmacokinetics and Toxicokinetics of Artemisinin-Hydroxychloroquine Sulfate Tablets in Rats and Dogs

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xiaobo Li ◽  
Jiaoting Hu ◽  
Yueming Yuan ◽  
Yunhan Wang ◽  
Zheng Yuan ◽  
...  
Keyword(s):  
Gender Difference ◽  
Oral Administration ◽  
Systemic Exposure ◽  
Female Rats ◽  
Sprague Dawley ◽  
Kinetics Parameters ◽  
Toxic Reaction ◽  
Liquid Chromatography Tandem Mass ◽  
Repeated Dosing ◽  
Drug Resistant Strains

Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but Cmax varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and Cmax of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.

scholarly journals Absorption, Distribution, Excretion, and Pharmacokinetics ofC-Pyronaridine Tetraphosphate in Male and Female Sprague-Dawley Rats

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Sang Hyun Park ◽  
Kannampalli Pradeep
Keyword(s):  
Clinical Trials ◽  
Small Intestine ◽  
Oral Administration ◽  
Female Rats ◽  
Sprague Dawley ◽  
Male And Female ◽  
Phase Ii Clinical Trials ◽  
Male And Female Rats ◽  
Sprague Dawley Rats ◽  
Peak Value

The main objective of this investigation was to determine the absorption, distribution, excretion, and pharmacokinetics of the antimalarial drug pyronaridine tetraphosphate (PNDP) in Sprague-Dawley rats. Following oral administration of a single dose (10 mg/Kg) ofC-PNDP, it was observed that the drug was readily absorbed from the small intestine within 1 hour following oral administration and was widely distributed in most of the tissues investigated as determined from the observed radioactivity in the tissues. The peak value of the drug in the blood was reached at around 8 hours postadministration, and radioactivity was detected in most of the tissues from 4 hours onwards.C-PNDP showed a poor permeability across the blood-brain barrier, and the absorption, distribution, and excretion ofC-PNDP were found to be gender-independent as both male and female rats showed a similar pattern of radioactivity. Excretion of the drug was predominantly through the urine with a peak excretion post 24 hours of administration. A small amount of the drug was also excreted in the feces and also in the breath. It was found that theCmax, AUC (0-inf), andTmaxvalues were similar to those observed in the Phase II clinical trials of pyronaridine/artesunate (Pyramax) conducted in Uganda.

scholarly journals Pharmacokinetics and Tolerability of Δ9-THC-Hemisuccinate in a Suppository Formulation as an Alternative to Capsules for the Systemic Delivery of Δ9-THC

2018 ◽  
Vol 1 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Mahmoud A. ElSohly ◽  
Waseem Gul ◽  
Larry A. Walker
Keyword(s):  
Oral Administration ◽  
Solid Phase ◽  
Extraction Procedure ◽  
Systemic Exposure ◽  
Rectal Administration ◽  
Systemic Delivery ◽  
Time Curve ◽  
Liquid Chromatography Tandem Mass ◽  
Total Systemic Exposure

The objectives of this study were: (1) to assess the safety, tolerability, and pharmacokinetics of ascending doses of Δ9-tetrahydrocannabinol-hemisuccinate (THC-HS) after rectal administration as suppositories in male volunteers; and (2) to compare the pharmacokinetics of oral administration of Δ9-tetrahydrocannabinol (Δ9-THC) with an equivalent amount of Δ9-THC delivered as THC-HS via the suppository formulation. In support of the pharmacokinetic evaluations, an analytical method was developed and validated for the determination of Δ9-THC and for its major circulating metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human plasma. Δ9-THC, 11-OH-THC, and THC-COOH were extracted from plasma using solid phase extraction and analyzed by liquid chromatography-tandem mass spectrometry. The limits of detection and quantitation for all 3 analytes were 0.25 and 0.5 ng/mL, respectively. The method was validated over the range of 0.5–25 ng/mL. This method was used to quantify Δ9-THC and any THC-HS as Δ9-THC due to the inclusion of a hydrolysis step as part of the extraction procedure. Therefore, Δ9-THC measured was the total THC (free Δ9-THC plus Δ9-THC derived from THC-HS). The assay was reproducible for the measurement of all 3 analytes, with a variability of 7.2, 13.7, and 8.3%, respectively, at the 1 ng/mL level. The method was then used to assess the pharmacokinetics of Δ9-THC and metabolites from the suppository dosage form in doses equivalent to 1.25, 2.5, 5, 10, and 20 mg Δ9-THC per suppository as THC-HS. Systemic exposure to Δ9-THC, administered as THC-HS suppository, increased broadly dose proportionally. Systemic exposure and Cmax (obs) estimates for 11-OH-THC and THC-COOH generally increased subproportionally. The pharmacokinetic profiles of Δ9-THC and metabolites were also compared after oral administration of 10 mg Δ9-THC (as dronabinol capsules) and after administration of 10 mg equivalents of Δ9-THC as THC-HS in suppository form. Total systemic exposure to Δ9-THC was considerably higher following rectal administration of THC-HS than after oral administration. The Δ9-THC area under the plasma concentration versus time curve (AUC(0–∞)) for THC-HS was 2.44-fold higher (90% confidence interval: 1.78, 3.35) than for the capsule administration.

scholarly journals Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 152 ◽  
Author(s):  
Tae Kim ◽  
Subindra Thapa ◽  
Da Lee ◽  
Seung Chung ◽  
Jun Lim ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Gastric Ulceration ◽  
Sprague Dawley ◽  
Food Effects ◽  
Concurrent Administration ◽  
Gastrointestinal Complications ◽  
Sprague Dawley Rats ◽  
Liquid Chromatography Tandem Mass ◽  
Lesion Index

This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated.

scholarly journals Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 354 ◽  
Author(s):  
Young-Guk Na ◽  
Jin-Ju Byeon ◽  
Hyun Wook Huh ◽  
Min-Ki Kim ◽  
Young G. Shin ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Oral Administration ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Male Rats ◽  
Combination Regimen ◽  
Sprague Dawley ◽  
Pharmacokinetic Properties ◽  
Pretreated Group ◽  
Few Data

Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.

scholarly journals Effects of Mad Honey on Some Biochemical Parameters in Rats

2016 ◽  
Vol 21 (4) ◽  
pp. 255-259 ◽  
Author(s):  
Huseyin Sahin ◽  
Oktay Yildiz ◽  
Sevgi Kolayli
Keyword(s):  
Creatine Kinase ◽  
Biochemical Parameters ◽  
Female Rats ◽  
Control Group ◽  
Honey Sample ◽  
Sprague Dawley ◽  
Mad Honey ◽  
Liquid Chromatography Tandem Mass ◽  
Experimental Animal Study ◽  
Control Group Group

The aims of this study were to determine grayanotoxin (GTX-III) toxin level in mad honey using liquid chromatography-tandem mass spectrometry and examine the dynamic changes of certain biochemical parameters in blood serum of rats that consumed mad honey. For the experimental animal study, 20 Sprague-Dawley female rats were divided into 5 groups of 4 rats each, with one group being the control group (Group 1) and the others being the experimental groups (Groups 2-5). Groups 2, 3, 4, and 5 were, respectively, given mad honey extract at doses of 0.3, 0.6, 1.2, and 2.4 mg/g body weight/day via oral gavage for 8 days. According to results, the quantity of GTX-III found in the honey sample as 39.949 ± 0.020 μg GTX-III/g honey, and the biochemical analysis of the tested parameters (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine kinase, and creatine kinase muscle and brain) showed a significant elevation with increasing concentration of honey. In conclusion, the use of increasing concentrations of Rhododendron honey was seen as a source of enzymatic symptoms.

scholarly journals Effects of Oral Administration of Manganese on the Kidneys and Urinary Bladder of Sprague-Dawley Rats

2003 ◽  
Vol 22 (3) ◽  
pp. 227-232 ◽  
Author(s):  
Tulasi Ponnapakkam ◽  
Marcus Iszard ◽  
Gerelyn Henry-Sam
Keyword(s):  
Urinary Bladder ◽  
Oral Administration ◽  
Kidney Tissue ◽  
Female Rats ◽  
Male Rats ◽  
Manganese Acetate ◽  
High Dose ◽  
Sprague Dawley ◽  
Sd Rats ◽  
Significant Difference

The purpose of this study was to investigate the effect of oral administration of manganese acetate on the kidneys and urinary bladder of Sprague-Dawley (SD) rats. Male and female SD rats (150 to 175 g), 6 weeks old, were administered varying doses of manganese acetate for 63 days by oral gavage. At the end of 63 days, 50% of the animals were sacrificed and kidney tissue was isolated and fixed for histopathological studies (study A). The remaining 50% were cross-mated and dosing ceased. Animals were sacrificed after 2 weeks (study B). Male treated animals were noted to have viscous, gritty urine in the urinary bladder, and the high-dose groups had urinary bladder stones (uroliths). Histopathologically, the most striking lesions were observed in the kidneys and prostate glands of male animals. Mild-to-moderate tubulointerstitial nephritis with tubular proteineous and glomerulosclerosis was observed in animals of all treatment groups. Urolithiasis in the urinary bladder was confirmed in 33% to 66% of treated animals. Female animals did not show a significant difference above controls in renal tissues. Results of this study suggest that male rats are more sensitive to the effects of high levels of manganese given orally than female rats and that the genitourinary structures represent target organs of toxicity.

Basal Lamina Formation in DMBA Induced Mammary Carcinoma

1977 ◽  
Vol 35 ◽  
pp. 534-535
Author(s):  
I. Russo ◽  
J. Saby ◽  
J. Russo
Keyword(s):  
Mammary Carcinoma ◽  
Virgin Female ◽  
Mammary Glands ◽  
Sesame Oil ◽  
Female Rats ◽  
Ultrastructural Changes ◽  
Post Inoculation ◽  
Intermediate Type ◽  
Sprague Dawley ◽  
Intercellular Spaces

It has been previously demonstrated that DMBA-induced rat mammary carcinoma originates in the terminal end bud (TEB) of the mammary gland by proliferation of intermediate type cells (1). The earliest lesion identified is the intraductal proliferation (IDP), which gives rise to intraductal carcinomas. These evolve to cribriform, papillary and comedo types (2). In the present work, we report the ultrastructural changes that take place in the IDP for the formation of a cribriform pattern.Fifty-five-day-old Sprague Dawley virgin female rats were inoculated intra- gastrically with 20 mg 7,12-dimethylbenz(a)anthracene (DMBA) in 1 ml sesame oil. Non-inoculated, age-matched females were used as controls. Mammary glands from both control and experimental rats were removed weekly from the time of inoculation until 86 days post-inoculation. The glands were fixed and processed for electron microscopy (2).The first change observed in IDP's was the widening of intercellular spaces and the secretion of an electron dense material into these spaces (Fig. 1).

Ultrastructural Changes in the Mammary Epithelial Cell Population During Neoplastic Development Induced by A Chemical Carcinogen.

1976 ◽  
Vol 34 ◽  
pp. 250-251 ◽  
Author(s):  
J. Russo ◽  
W. Isenberg ◽  
M. Ireland ◽  
I.H. Russo
Keyword(s):  
Mammary Gland ◽  
Cell Population ◽  
Virgin Female ◽  
Histological Change ◽  
Mammary Epithelial ◽  
Female Rats ◽  
Ultrastructural Changes ◽  
Post Inoculation ◽  
Chemical Carcinogen ◽  
Sprague Dawley

The induction of rat mammary carcinoma by the chemical carcinogen DMBA is used as a model for the study of the human disease (1). We previously described the histochemical changes that occur in the mammary gland of DMBA treated animals before the earliest manifested histological change, the intraductal proliferation (IDP), was observed (2). In the present work, we demonstrate that a change in the stable cell population found in the resting mammary gland occurs after carcinogen administration.Fifty-five day old Sprague-Dawley virgin female rats were inoculated intragastrically with 20mg of 7,12-dimethylbenz(a)anthracene (DMBA) in 1ml sesame oil. Non-inoculated, age-matched females were used as controls. Mammary glands from control and inoculated rats were removed weekly from the time of inoculation until 60 days post-inoculation. For electron microscopy, the glands were immersed in Karnovsky's fixative, post-fixed in 1% OsO4, dehydrated, and embedded in an Epon-Araldite mixture. Thick (lμ) sections were stained with 1% toluidine blue and were used for selecting areas for ultrastructural study.

Comparison of streptozotocin-induced diabetes at different moments of the life of female rats for translational studies

2021 ◽  
pp. 002367722110018
Author(s):  
Yuri K Sinzato ◽  
Eduardo Klöppel ◽  
Carolina A Miranda ◽  
Verônyca G Paula ◽  
Larissa F Alves ◽  
...  
Keyword(s):  
Adult Life ◽  
Tolerance Test ◽  
Full Term ◽  
Female Rats ◽  
Lower Percentage ◽  
Control Group ◽  
Oral Glucose ◽  
Postnatal Life ◽  
Sprague Dawley ◽  
Term Pregnancy

Animal models are widely used for studying diabetes in translational research. However, methods for induction of diabetes are conflicting with regards to their efficacy, reproducibility and cost. A comparison of outcomes between the diabetic models is still unknown, especially full-term pregnancy.To understand the comparison, we analyzed the streptozotocin (STZ)-induced diabetes at three life-different moments during the neonatal period in Sprague–Dawley female rats: at the first (D1), second (D2) and fifth (D5) day of postnatal life. At adulthood (90 days; D90), the animals were submitted to an oral glucose tolerance test (OGTT) for diabetic status confirmation. The diabetic and control rats were mated and sacrificed at full-term pregnancy for different analyses. Group D1 presented a higher mortality percentage after STZ administration than groups D2 and D5. All diabetic groups presented higher blood glucose levels as compared to those of the control group, while group D5 had higher levels of glycemia compared with other groups during OGTT. The diabetic groups showed impaired reproductive outcomes compared with the control group. Group D1 had lower percentages of mated rats and D5 showed a lower percentage of a full-term pregnancy. Besides that, these two groups also showed the highest percentages of inadequate fetal weight. In summary, although all groups fulfill the diagnosis criteria for diabetes in adult life, in our investigation diabetes induced on D5 presents lower costs and higher efficacy and reproducibility for studies involving diabetes-complicated pregnancy.

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