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

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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Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin

Human & Experimental Toxicology ◽

10.1177/0960327107073825 ◽

2007 ◽

Vol 26 (1) ◽

pp. 19-35 ◽

Cited By ~ 51

Author(s):

F Kratz ◽

G Ehling ◽

H-M Kauffmann ◽

C Unger

Keyword(s):

Phase I Study ◽

Albumin Binding ◽

Repeat Dose ◽

Beagle Dogs ◽

Sprague Dawley ◽

Repeat Dose Toxicity ◽

Toxicity Studies ◽

Sprague Dawley Rats ◽

Dose Levels ◽

Hydrazone Derivative

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models, and has been evaluated in a phase I study. In order to establish the toxicity profile of this prodrug, acute and repeat-dose toxicity studies were performed with DOXO-EMCH in CD1-mice, Sprague-Dawley rats and Beagle dogs. Although the objective of the acute toxicity studies was not the determination of LD50 values, the LD50 of DOXO-EMCH was >60mg/kg doxorubicin equivalents in both male and female mice (the LD50 of doxorubicin in CD-1 mice is ~12 mg/kg). In Sprague-Dawley rats, the LD50 was 23.4 and 45.9 mg/kg doxorubicin equivalents for males and females, respectively. For comparison, the LD50 of doxorubicin in Sprague-Dawley rats is ~10.5 mg/kg. The major clinical sign noted following intravenous administration of DOXOEMCH in mice and rats was a dose-dependent peripheral neuropathy which, in general, developed as a delayed toxicity 1-3 weeks after application. The observed neurotoxicity has been well documented for Sprague-Dawley rats treated with doxorubicin at a dose of 5 and 10 mg/kg. In Beagle dogs, LD10 was not reached for DOXO-EMCH at 4.5 mg/kg doxorubicin equivalents. A four-cycle intravenous study with DOXO-EMCH at dose levels of 4×2.5, 5.0 or 7.5 mg/kg doxorubicin equivalents in rats revealed approximately three-fold less side effects on the hemolymphoreticular system when compared to 4×2.5 mg/kg doxorubicin dose, whereas effects on the testes/oligospermia seem to be comparable between both drugs at equitoxic dose. A No Observable Adverse Effect Level (NOAEL) for DOXO-EMCH of 4×2.5 mg/kg doxorubicin equivalents was established in this study. This dose is equivalent to the maximum tolerated dose (MTD) of doxorubicin in rats. In a two-cycle study over a period of 6 weeks in Beagle dogs (intravenous administration of DOXO-EMCH at dose levels of 1.5, 3.0 or 4.5 mg/kg doxorubicin equivalents), dose-related systemic histamine-like reactions within the first 3 hours after injection were noted in all treated groups. Only transient and temporary effects on hematology, urinary function, as well as on histopathology in mid- and/or high-dose animals, were observed. The low dose of 2×1.5 mg/kg was considered to be the NOAEL in this study, which is equivalent to twice the MTD of doxorubicin in Beagle dogs. In summary, the toxicity studies with DOXO-EMCH in mice, rats or dogs have not identified any other special toxicity when compared to the toxicity data for doxorubicin. Preclinical tolerance of DOXO-EMCH was higher in mice, rats and dogs compared to doxorubicin. A dose of 20 mg/m2 doxorubicin equivalents was recommended as the starting dose for a phase I study with DOXO-EMCH.

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Androgen-mediated sex differences of cardiovascular responses in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1978.235.2.h242 ◽

1978 ◽

Vol 235 (2) ◽

pp. H242-H246 ◽

Cited By ~ 3

Author(s):

P. J. Baker ◽

E. R. Ramey ◽

P. W. Ramwell

Keyword(s):

Sex Differences ◽

Arachidonic Acid ◽

Rank Order ◽

Cardiovascular Responses ◽

Sprague Dawley ◽

Similar Treatment ◽

Depressor Response ◽

Sprague Dawley Rats ◽

Significant Change ◽

Dose Levels

Sex differences in the systemic depressor response to arachidonic acid (50 or 150 microgram/kg iv) were observed in intact and castrated anesthetized Sprague-Dawley rats. The rank order of responsiveness was: castrate males, castrate females, females, males; all four groups were significantly different (P less than 0.05) at the higher dose. Castrated males pretreated with testosterone (1 mg/kg sc) 5 or 7 days previously gave a response at the higher arachidonate dose levels that was of the same order as that obtained with intact males. Similar treatment of castrate males with androgen potentiated (P less than 0.05) the vasopressor action of norepinephrine (0.25 microgram/kg) on day 7 after the testosterone pretreatment. In contrast, treatment with depot estradiol (100 microgram/kg sc) in castrate males produced no significant change in the response to either of the vasoactive compounds on both days 5 and 7 after pretreatment. These data suggest that testosterone may be a significant factor in the development of sex differences in the cardiovascular systems of rats.

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Mechanism of Erythropoietin Production by Cobaltous Chloride

Blood ◽

10.1182/blood.v44.3.339.339 ◽

1974 ◽

Vol 44 (3) ◽

pp. 339-346 ◽

Cited By ~ 6

Author(s):

Marilyn E. Miller ◽

Donald Howard ◽

Frederick Stohlman ◽

Patricia Flanagan

Keyword(s):

Respiratory Alkalosis ◽

Sprague Dawley ◽

Acid Base Balance ◽

Acid Base ◽

Erythropoietin Production ◽

Sprague Dawley Rats ◽

Base Balance ◽

Subsequent Effect ◽

Significant Measure ◽

Dose Levels

Abstract Normal and nephrectomized Sprague-Dawley rats were treated with CoCl2 at three dose levels, 10, 20, and 25 µm/ 100 g body weight. The effects of this drug on acid-base balance were related to the production of erythropoietin. Within 6 hr after the administration of CoCl2 to normal rats, a dose-related respiratory alkalosis occurred associated with an increase in the affinity of hemoglobin for oxygen. This was followed by an increase in the production of erythropoietin. Nephrectomy altered the acid-base balance of the animal such that a profound acidosis occurred after the administration of CoCl2 with an associated decrease in the affinity of hemoglobin for oxygen. Erythropoietin could not be detected in these nephrectomized rats given CoCl2. These findings demonstrate that the production of erythropoietin after the administration of CoCl2 is related in significant measure to changes in acid-base balance with its subsequent effect on the affinity of hemoglobin for oxygen.

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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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Association between Chronic Acetaminophen Exposure and Allergic Rhinitis in a Rat Model

Allergy & Rhinology ◽

10.2500/ar.2015.6.0131 ◽

2015 ◽

Vol 6 (3) ◽

pp. ar.2015.6.0131 ◽

Cited By ~ 1

Author(s):

Nadieska Caballero ◽

Kevin C. Welch ◽

Patrick S. Carpenter ◽

Swati Mehrotra ◽

Tom F. O'Connell ◽

...

Keyword(s):

Allergic Rhinitis ◽

Mast Cells ◽

Rat Model ◽

Group Versus ◽

Inferior Turbinate ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Increased Risk ◽

Hematoxylin And Eosin

Background Several population studies demonstrated an increased risk of allergic rhinitis in patients exposed to acetaminophen. However, no histologic studies have been conducted to assess the relationship between acetaminophen exposure and allergic rhinitis. Objective In this study, we investigated the association between chronic acetaminophen exposure and the development of allergic rhinitis in a rat model. Methods Ten female Sprague-Dawley rats were randomly assigned to either a control (n = 5) or an acetaminophen group (n = 5). The acetaminophen group received 200 mg/kg/day of acetaminophen suspended in yogurt via oral gavage for 120 days. The control group received only the yogurt vehicle. Allergic behavioral responses, including nose rub, eye rub, ear scratching, and neck and/or face scratching, were quantified. The rats were killed, and the noses were harvested. The portion of the nose, including the nasal septum and the inferior turbinates, was embedded in paraffin, sectioned, and stained with hematoxylin and eosin to quantify the inflammatory infiltrate. Results The average number of allergic responses per animal was 13.2 in the acetaminophen group versus 6.2 in the control group (p = 0.032). All the rats in the acetaminophen group (100%) had mast cells infiltrating the lamina propria of the inferior turbinate, whereas mast cells were detected in only 40% of the animals in the control group. The average number of mast cells per animal in the acetaminophen group was 134 versus 21 in the control group (p = 0.048). Conclusions Our study was the first to demonstrate a histologic association between chronic exposure to acetaminophen and rhinitis. Further research to elucidate the mechanism that underlies these findings is necessary.

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Comparative carcinogenicity of ring-halogenated 3-methyl-1-phenyltriazenes and their 3,3-dimethyl analogs at equimolar dose levels in male Sprague-Dawley rats

Journal of Cancer Research and Clinical Oncology ◽

10.1007/bf00400750 ◽

1986 ◽

Vol 111 (2) ◽

pp. 129-132 ◽

Cited By ~ 1

Author(s):

Martin R. Berger ◽

George F. Kolar

Keyword(s):

Sprague Dawley ◽

Equimolar Dose ◽

Sprague Dawley Rats ◽

Dose Levels

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EFFECT OF THE WATER EXTRACT OF THE FOUR O’CLOCK HERB (MIRABILIS JALAPA L.) ON THE HEALING OF OPEN WOUNDS IN RATS

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018.v10s1.33 ◽

2018 ◽

Vol 10 (1) ◽

pp. 155

Author(s):

Puspita Puspasari ◽

Fadlina Chany Saputri

Keyword(s):

Wound Healing ◽

Water Extract ◽

Optimal Dose ◽

Positive Control ◽

Negative Control ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Mirabilis Jalapa ◽

Hematoxylin And Eosin ◽

Iodine Dose

Objective: This study aimed to analyze the effect on wound healing following treatment with a water extract of Mirabilis jalapa L. by investigatingwound contraction and the associated histopathological changes in rat skin.Methods: Male Sprague-Dawley rats were divided into five groups, namely negative control, positive control (povidone-iodine), dose 1, dose 2, anddose 3. A 20-×10-mm rectangular wound area was created for the test. In dose 1, 2, and 3 groups, the corresponding dose variation of a 0.5-mLM. jalapa L. water extract (dose 1: 5% v/v, ≈243.1 mg/kg body weight BW; dose 2: 10% v/v, ≈486.2 mg/kg BW; and dose 3: 20% v/v, ≈972.4 mg/kg BW)was topically applied for 14 days on open wounds of rats. Widespread wound contractions were measured on days 1, 3, 5, 7, 9, 11, and 13, andhistopathological changes in the skin were observed on day 15 using hematoxylin and eosin staining.Results: The M. jalapa L. water extract accelerated wound healing. The optimal dose was found to be 20% v/v (≈972.4 mg/kg BW).Conclusion: M. jalapa L. extracts are potential healing agents for open wounds.

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Repeated-Dose and Subchronic Toxicity Studies of 2,2,2-Trichloroethanol in Sprague-Dawley Rats

Journal of the American College of Toxicology ◽

10.3109/10915819109078632 ◽

1991 ◽

Vol 10 (2) ◽

pp. 223-232

Author(s):

J. Peter Bercz ◽

Merrel Robinson ◽

Lucille M. Garner ◽

Norbert P. Page ◽

Greg R. Olson

Keyword(s):

Toxic Effect ◽

Clinical Symptoms ◽

Clinical Chemistry ◽

Lactic Dehydrogenase ◽

Target Organ ◽

Male Rats ◽

High Dose ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Dose Levels

Male and female Sprague-Dawley rats were administered 2,2,2-trichloroethanol (TCE) by gavage for 14 or 90 consecutive days. The gavage solution consisted of TCE dissolved in distilled water, containing 10% Emulphor. Doses of 37.5, 75, 150, and 300 mg/kg/day in the 14-day study and 40, 80, 160, and 320 mg/kg/day for the 90-day study were employed. Evaluation of clinical symptoms, clinical chemistry, and pathology examinations did not reveal a specific toxic effect or identify a target organ. In male rats an increase of red blood cells (RBCs) and hematocrit (Hct) in both 14- and 90-day studies, as well as increased hemoglobin (Hgb) in the 90-day study was observed at the highest dose level. In the high-dose females only increase of Hgb was seen in the 14-day study. These hematopoietic indices were not accompanied by commensurate changes in reticulocytes, mean corpuscular volumes or spleen weights. Serum lactic dehydrogenase (LDH) levels were increased in males at the two highest dose levels of both studies. Other changes in chemistries were sporadic in nature and did not appear to be dose related. Collectively, there was no basis to identify a target organ. The RBC and LDH levels did not correlate with other biochemical or pathology results and did not support the hypothesis that they represent a specific toxic effect. Based on the lack of detectable toxicity of TCE at the highest doses tested in rats, the following lowest observed adverse effect levels (LOAEL) were assigned for this chemical: in the 14-day exposure, 300 mg/kg/day for both sexes; in the 90-day protocol, 320 mg/kg/day for female; and 160 mg/kg/day for male rats.

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Subacute Intramuscular Toxicity of the Acetylcholinesterase Reactivating Agent HI-6 in Rats and Dogs

Journal of the American College of Toxicology ◽

10.3109/10915819309140638 ◽

1993 ◽

Vol 12 (2) ◽

pp. 185-193 ◽

Cited By ~ 2

Author(s):

Barry S. Levine ◽

Michael J. Tomlinson

Keyword(s):

Injection Site ◽

Creatine Kinase Activity ◽

High Dose ◽

Sprague Dawley ◽

Hi 6 ◽

Sprague Dawley Rats ◽

High Doses ◽

Hematology Parameters ◽

Dose Levels ◽

Dose Injection

Studies herein describe the toxicity of HI-6 in Sprague-Dawley rats and Beagle dogs following i.m. injection for 14 days. Dose levels were 0, 50, 150, and 450 mg/kg/day for 10 rats/sex/dose and 0, 35, 70, and 140 mg/kg/day for 4 dogs/sex/dose. Three rats at the high dose, 2 males and 1 female, died prior to scheduled sacrifice. Reduced weight gain, decreased activity, tremors, hunched posture, and poor grooming were seen in high dose survivors. Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities at the mid and high doses suggested hepatotoxicity, although liver weights and histology were normal. Hematology parameters were unaffected except for slight, dose-related increases of platelets in both sexes. Injection site inflammation was seen; however, serum creatine kinase activity was not altered. In dogs, slight weight loss, vomiting, salivation, and diarrhea occurred at the high dose, but no deaths were observed at any of the doses. As with rats, dose-related increases in ALT and AST activities occurred at the mid and high doses, and were, in this case, accompanied at the high dose by hepatomegaly and hepatocellular vacuolization. Cardiotoxicity was evidenced by increased relative heart weights and subtle ECG changes, the latter of which occurred almost exclusively at the highest dose. Injection site inflammation, which was accompanied by dose-related elevations in serum CK-MM2 activity, was also observed.

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