Toxicity Profile of Artesunate in Rats and Dogs

Mapping Intimacies ◽

10.1101/2021.02.16.431559 ◽

2021 ◽

Author(s):

Johanna Susanne Lang

Keyword(s):

Clinical Pathology ◽

Toxicity Profile ◽

Beagle Dogs ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Respiratory Parameters ◽

Safety Parameters ◽

Repeated Administrations ◽

Single Intravenous Administration ◽

Intramuscular Artesunate

OBJECTIVES: The objectives of these studies were to investigate the toxicity, safety and toxicokinetics of single and multiple doses of artesunate for injection in rats and dogs. METHODS: Sprague-Dawley rats and Beagle dogs were treated intravenously or intramuscularly for 28 consecutive days with doses of up to 30 mg/kg artesunate, evaluating toxicity, kinetics, genotoxicity, and cardiovascular and central nervous safety parameters after single and 4-week repeated administrations. Furthermore, respiratory parameters were evaluated after a single intravenous administration in rats. RESULTS: Artesunate was well tolerated with no mortality and only minor effects on clinical pathology parameters. CONCLUSIONS: The results obtained in these studies support the safe use of intravenous and intramuscular artesunate in humans.

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Intraneuronal accumulations of lysosomes in the cerebellum of rats and dogs after dosing with MDL-832

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100161710 ◽

1990 ◽

Vol 48 (3) ◽

pp. 830-831

Author(s):

S.D. Barnard ◽

S.D. Warner

Keyword(s):

Brown Pigment ◽

Beagle Dogs ◽

Sprague Dawley ◽

Gelatin Capsules ◽

Pigment Granules ◽

Sprague Dawley Rats ◽

Hematoxylin And Eosin ◽

Dose Levels

1, 2, 9, 10-tetramethoxyaporphine phosphate (MDL-832) was once considered a potential human antitussive. MDL-832 was administered orally in the diets of Sprague-Dawley rats at dose levels of 0, 5, 10, 20, 40, 80 and 160 mg/kg/day for 3 and 6 months and in gelatin capsules to Beagle dogs at 0, 5, 10, 15, 30 and 60 mg/kg/day for 3, 6 and 12 months. Histopathologic examinations of hematoxylin and eosin-stained cerebellar sections revealed intracytoplasmic brown pigment accumulations in large fusiform neurons (presumably the motor type) of the pons. The pigment granules were found to be PAS-positive, non-acid fast, iron-free, Sudan B-positive and fuchsinophilic. Intraneuronal pigment accumulations were seen in rats after 3 months of treatment at 80 mg but not at 40 mg and after 6 months at 20 mg but not at 10 mg. For dogs the effect was observed after 3 months at 60 mg but not at 30 mg and after 12 months at 10 mg but not at 5 mg.

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Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal tract

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1986.251.3.g332 ◽

1986 ◽

Vol 251 (3) ◽

pp. G332-G340 ◽

Cited By ~ 2

Author(s):

J. A. Fix ◽

K. Engle ◽

P. A. Porter ◽

P. S. Leppert ◽

S. J. Selk ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Drug Absorption ◽

Structural Integrity ◽

Somatostatin Analogue ◽

Beagle Dogs ◽

Sprague Dawley ◽

Solid Dosage Forms ◽

Intestinal Tissue ◽

Solid Dosage ◽

Sprague Dawley Rats

Acylcarnitines were tested as potential absorption-enhancing agents for drugs that are poorly absorbed from the gastrointestinal tract. Urethan-anesthetized Sprague-Dawley rats and conscious Beagle dogs were used. Palmitoyl-DL-carnitine was the most effective acylcarnitine tested, although significant increases in drug absorption were observed with acylcarnitines containing C12 through C18 fatty acid chains. Palmitoyl-DL-carnitine afforded significant increases in the absorption of cefoxitin, gentamicin, cytarabine, somatostatin analogue, and alpha-methyldopa. The response to palmitoyl-DL-carnitine was concentration dependent and reversible within 60-120 min. Histological examination of the intestinal tissue revealed no apparent change in mucosal structural integrity at doses of palmitoyl-DL-carnitine that resulted in increased drug absorption. The acylcarnitines were effective in increasing drug absorption from the small intestine and the rectal compartment of both rats and dogs. The data also demonstrated effectiveness with aqueous and solid dosage forms (Witepsol H-15 suppositories). The data suggest that acylcarnitines may be effective and safe absorption-enhancing agents for a variety of drugs.

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Lack of Oncogenicity of Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medication, in Sprague-Dawley Rats

International Journal of Toxicology ◽

10.1080/109158101753253036 ◽

2001 ◽

Vol 20 (5) ◽

pp. 297-305 ◽

Cited By ~ 9

Author(s):

Tomoo Kuge ◽

Takashi Shibata ◽

Michael S. Willett ◽

Patricia Turck ◽

Karl A. Traul

Keyword(s):

Body Weight ◽

Dose Level ◽

Active Ingredient ◽

Clinical Signs ◽

Clinical Pathology ◽

Maximum Tolerated Dose ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Wood Creosote

Seirogan, an herbal medicine containing wood creosote (tablets, 10.0% w/w), has been developed and marketed for almost a century in various countries for the control of acute diarrhea and treatment of associated symptoms, such as abdominal cramping. Wood creosote (CAS no. 8021–39–4) is a mixture of simple phenolic compounds, including guaiacol and creosol and related compounds, and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. In the current study, the oncogenic potential of wood creosote was assessed in a 96/103-week oral gavage study in Sprague-Dawley rats. Groups of 60 rats/sex received wood creosote at dose levels of 20, 50, or 200 mg/kg body weight [bw]/day. An additional group of rats received the vehicle, 0.5% carboxymethylcellulose in deionized, distilled water, at the same dose volume as the treatment groups (10 ml/kg) and served as the controls. Treatment-related decreases in survival, body weight, and food consumption, as well as increased incidences of clinical signs that included rales, decreased activity, and salivation, were noted at 200 mg/kg bw/day when compared with the control group. There was an increased incidence of reddened and edematous lungs in rats from the 200 mg/kg bw/day group that died during the study. The lung findings were suggestive of test article aspiration during dose administration or agonal aspiration preceding and possibly resulting in death, especially because these observations were not seen in animals that survived to scheduled sacrifice. Additionally, phenols are generally recognized as having corrosive properties. There were no changes in clinical pathology and no increases in neoplastic or non-neoplastic lesions, excluding the lung findings, related to treatment with wood creosote at any dose level. Although the results of this study indicate that the maximum tolerated dose of wood creosote was met or exceeded at 200 mg/kg bw/day, there was no evidence of oncogenicity at any dose level. The lack of any evidence of oncogenicity supports the safety profile of the active ingredient in Seirogan, wood creosote.

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Comparative Toxicology Studies in Sprague-Dawley Rats, Rhesus Monkeys, and New Zealand White Rabbits to Determine a No Observed Adverse Effect Level for 1,1′-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] Dimethanesulfonate

International Journal of Toxicology ◽

10.1177/1091581813487564 ◽

2013 ◽

Vol 32 (4_suppl) ◽

pp. 59S-74S ◽

Cited By ~ 2

Author(s):

Merrill R. Osheroff ◽

Dean J. Kobs ◽

Matthew Buccellato ◽

Claire R. Croutch ◽

Laura E. Elcock ◽

...

Keyword(s):

Adverse Effect ◽

New Zealand ◽

Rhesus Monkeys ◽

Clinical Pathology ◽

Intramuscular Administration ◽

Sprague Dawley ◽

Single Dose Study ◽

Sprague Dawley Rats ◽

Adverse Effect Level ◽

Effect Level

Studies were conducted in Sprague-Dawley rats, New Zealand White (NZW) rabbits, and rhesus monkeys to characterize the toxicity of 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) following intramuscular administration. Rats received MMB4 DMS once daily for 7 days at 100, 200, 400, and 800 mg/kg/d; rabbits received a range of dose levels in 3 separate 7-day studies from 3 to 800 mg/kg/d and in a single-dose study from 50 to 200 mg/kg; and monkeys received MMB4 DMS at 150 to 600 mg/kg/d. Mortality was noted in rats and rabbits administered ≥200 mg/kg. All monkeys survived until scheduled termination. Adverse clinical observations were noted in the rats at ≥400 mg/kg/d and in rabbits administered ≥200 mg/kg; no adverse findings were noted in the monkeys. Clinical pathology changes were noted in the rabbit related to cardiac and renal function. In the rabbit and monkey, elevations in myoglobin, alanine aminotransferase/aspartate aminotransferase, platelets, creatine kinase, and coagulation factors were related to local inflammation at the intramuscular administration site. Light microscopic examination at the injection sites revealed acute skeletal muscle necrosis in vehicle control and treated groups. Target tissues in the rabbit studies were identified as kidney, heart, and lungs at ≥100 mg/kg/d. All changes noted in all the species demonstrated partial to complete recovery comparable to control values or to a clinically irrelevant level of effect. The NZW rabbit was the most sensitive species, and the no observed adverse effect level (NOAEL) was determined as 50 mg/kg/d; the NOAEL in the rat was 100 mg/kg/d; and the NOAEL in rhesus monkeys was >600 mg/kg/d.

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A 90-Day Oral (Dietary) Toxicity Study of Rebaudioside A in Sprague-Dawley Rats

International Journal of Toxicology ◽

10.1080/10915810701876752 ◽

2008 ◽

Vol 27 (1) ◽

pp. 65-80 ◽

Cited By ~ 28

Author(s):

Andrey I Nikiforov ◽

Alex K Eapen

Keyword(s):

Clinical Pathology ◽

Stevia Rebaudiana ◽

Rebaudioside A ◽

Sprague Dawley ◽

Small Magnitude ◽

Stevia Rebaudiana Bertoni ◽

Sprague Dawley Rats ◽

The Difference ◽

High Concentrations ◽

And Behavior

Rebaudioside A is one of several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) stevia that has been identified as a potential sweetener. The present study (initiated in April 2006 and completed in October 2006) evaluated the safety of this sweetener when administered as a dietary admix at target exposure levels of 500, 1000, and 2000 mg/kg/day to Sprague-Dawley rats for 90 days. There were no treatment-related effects on the general condition and behavior of the animals as determined by clinical observations, functional observational battery, and locomotor activity assessments. Evaluation of clinical pathology parameters revealed no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Lower mean body weight gains were noted in males in the 2000 mg/kg/day group throughout the study, which was considered to be test article related; however, given the small magnitude of the difference as compared to controls, this effect was not considered to be adverse. Results of this study clearly demonstrate that dietary administration of high concentrations of rebaudioside A for 90 consecutive days to Sprague-Dawley rats was not associated with any signs of toxicity.

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Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs

Toxicology ◽

10.1016/j.tox.2011.05.015 ◽

2011 ◽

Vol 287 (1-3) ◽

pp. 76-90 ◽

Cited By ~ 37

Author(s):

Michael S. Werley ◽

Paddy McDonald ◽

Patrick Lilly ◽

Daniel Kirkpatrick ◽

Jeffrey Wallery ◽

...

Keyword(s):

Propylene Glycol ◽

Beagle Dogs ◽

Sprague Dawley ◽

Clinical Safety ◽

Sprague Dawley Rats

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Preclinical Toxicity Evaluation of Tepoxalin, a Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase, in Sprague—Dawley Rats and Beagle Dogs

Toxicological Sciences ◽

10.1093/toxsci/33.1.38 ◽

1996 ◽

Vol 33 (1) ◽

pp. 38-48

Author(s):

E. V. KNIGHT ◽

J. P. KIMBALL ◽

C. M. KEENAN ◽

I. L. SMITH ◽

F. A. WONG ◽

...

Keyword(s):

Beagle Dogs ◽

Sprague Dawley ◽

Toxicity Evaluation ◽

Dual Inhibitor ◽

Sprague Dawley Rats

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Subchronic toxicity of lyophilized apoaequorin protein powder in Sprague-Dawley rats

Toxicology Research and Application ◽

10.1177/2397847318756905 ◽

2018 ◽

Vol 2 ◽

pp. 239784731875690

Author(s):

Mark R. Bauter ◽

Odete Mendes

Keyword(s):

Active Ingredient ◽

Calcium Binding ◽

Clinical Pathology ◽

Female Rats ◽

Test Substance ◽

Sprague Dawley ◽

Oral Gavage ◽

Male And Female Rats ◽

Sprague Dawley Rats ◽

Dose Levels

Apoaequorin is a bioluminescent calcium-binding apoprotein endogenous to the Aequorea species of jellyfish and is commercially available in a dietary supplement in support of brain and cognitive health. Results from a previous 90-day subchronic oral gavage study established the no-observed-adverse-effect-level (NOAEL) of lyophilized apoaequorin protein powder (LAPP) at 666.7 mg/kg/day. The current 90-day oral gavage study in Sprague-Dawley rats administered dose levels of 1000, 2000, and 4000 mg/kg/day of test substance as received. These doses are expressed as milligram of supplement with the amounts of apoaequorin based on the analysis of the percentage of active ingredient. The corresponding amounts of apoaequorin protein are 603, 1206, and 2412 mg/kg/day. These dose levels target approximately 4221, 8442, and 16,844 times more than the expected human oral intake. There were no mortalities, clinical observations, ophthalmological, clinical pathology, or histopathological changes attributable to LAPP administration. Changes in mean body weight and feed efficiency, without other correlating clinical or pathological or other toxicologically relevant findings, were considered to be of little toxicological significance. Therefore, the NOAEL for LAPP administered orally up to 90 days was 4000 mg/kg/day (2412 mg/kg/day based on 603 mg/g or 60.3% active ingredient, apoaequorin protein), the highest dose tested in male and female rats.

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