Preclinical 28-Day Inhalation Toxicity Assessment of S-Nitrosoglutathione in Beagle Dogs and Wistar Rats

2011 ◽  
Vol 30 (5) ◽  
pp. 466-477 ◽  
Author(s):  
Dorothy B. Colagiovanni ◽  
Daxa Borkhataria ◽  
Doug Looker ◽  
Detlef Schuler ◽  
Corinna Bachmann ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Therapeutic Agent ◽  
Recovery Period ◽  
Clinical Pathology ◽  
Toxicity Assessment ◽  
Clinical Development ◽  
Inhalation Toxicity ◽  
Toxicity Profile ◽  
Beagle Dogs ◽  
Related Compounds

To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period. Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds.

scholarly journals Toxicity Profile of Artesunate in Rats and Dogs

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.

A 90-Day Oral Gavage Toxicity Study of d-Methylphenidate and d, I-Methylphenidate in Beagle Dogs

2003 ◽  
Vol 22 (3) ◽  
pp. 215-226 ◽  
Author(s):  
Steve K. Teo ◽  
David I. Stirling ◽  
Steve D. Thomas ◽  
Mark G. Evans ◽  
Vikram D. Khetani
Keyword(s):  
Body Weight ◽  
Recovery Period ◽  
Clinical Pathology ◽  
Body Weight Loss ◽  
High Dose ◽  
Beagle Dogs ◽  
Weight Changes ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Therapeutic Doses

d-Methylphenidate ( d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d, l-methylphenidate ( d, l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d, l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d, l-MPH in d-MPH content. The 10-mg/kg d-MPH and d, l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d, l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d, l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day.

scholarly journals Cytoplasmic Vacuolation and Tapetal Changes Induced by a Novel Analgesic Agent in Beagle Dogs

2019 ◽  
Vol 47 (4) ◽  
pp. 494-503
Author(s):  
Kei Takahashi ◽  
Yasuhiro Morita ◽  
Shuji Udagawa ◽  
Seiki Yamakawa ◽  
Dai Watanabe ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Recovery Period ◽  
Dependent Manner ◽  
Beagle Dogs ◽  
Oral Toxicity ◽  
Drug Induced ◽  
Once Daily ◽  
Cytoplasmic Vacuolation ◽  
Light Microscopic Observation ◽  
Dose Dependent

Drug-induced unique cytoplasmic vacuolation was found in the subchronic oral toxicity study of 4-dimethylamino-1-{3-(1-methyl-1H-imidazole-2-yl)propanoyl}piperidine (DMIP), a potential therapeutic agent for neuropathic pain, in beagle dogs. In the first study, DMIP was administered at a dose of 250, 500, or 1,000 mg/kg/day once daily for 14 days. Discoloration of tapetum lucidum accompanied by tapetal swelling was observed at ≥250 mg/kg/day. The tapetal swelling was correlated to the light microscopic observation of cytoplasmic vacuolation in tapetal cells, and similar vacuolation was observed in several other tissues, including the coronary artery and aortal arch, in a dose-dependent manner. Immunohistochemistry for lysosomal-associated membrane protein 2 indicated that the vacuoles were enlarged lysosomes. However, the nature of these vacuoles was different from that of phospholipidosis because no lamellar bodies were observed. In the second study, DMIP was administered at a dose of 10, 50, or 250 mg/kg/day once daily for 14 days followed by a 14-day recovery period. Tapetal changes and systemic vacuolation were not observed at ≤50 mg/kg/day, and vacuolation observed at 250 mg/kg/day was reversible. A few reports have described the enlargement of lysosomes not attributable to phospholipid accumulation. Our findings provide further information about the toxicological implications of drug-induced lysosomal swelling.

Study on Medicinal Chemistry of K203 in Wistar Rats and Beagle Dogs

2013 ◽  
Vol 20 (16) ◽  
pp. 2137-2144 ◽  
Author(s):  
H. Kalasz ◽  
P. Szegi ◽  
G. Janoki ◽  
L. Balogh ◽  
Z. Postenyi ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Medicinal Chemistry ◽  
Beagle Dogs

Phytoconstituents in the Management of Covid-19: Demystifying the Fact

Drug Research ◽  
2022 ◽  
Author(s):  
Md. Abul Barkat ◽  
Pawan Kaushik ◽  
Harshita Abul Barkat ◽  
Mohammad Idreesh Khan ◽  
Hazrina Ab Hadi
Keyword(s):  
Therapeutic Agent ◽  
Clinical Development ◽  
World Health ◽  
Therapeutic Drug ◽  
Scientific Communities ◽  
Synthetic Drugs ◽  
Naturally Occurring ◽  
Deadly Disease ◽  
Novel Coronavirus ◽  
Health Organization

AbstractThe 2019-nCoV (COVID-19; novel coronavirus disease-2019) outbreak is caused by the coronavirus, and its continued spread is responsible for increasing deaths, social and economic burden. COVID-19 created a chaotic situation worldwide and claimed the lives of over 5,027,183 and 248,467,363 confirmed cases have been reported so far as per the data published by WHO (World Health Organization) till 5th November 2021. Scientific communities all over the world are toiling to find a suitable therapeutic drug for this deadly disease. Although till date no promising drug has been discovered for this COVID-19. However, as per the WHO, over 102 COVID-19 vaccines are in clinical development and 185 in pre-clinical development. Naturally occurring phytoconstituents possess considerable chemical richness in the form of anti-viral and anti-parasitic potential and have been extensively exploited for the same globally. Still, phytomedicine-based therapies are considered as the best available treatment option to minimize and treat the symptoms of COVID-19 because of the least possible side effects compared to synthetic drugs recommended by the physicians/clinicians. In this review, the use of plant chemicals as a possible therapeutic agent for severe acute respiratory syndrome coronavirus 2 (SARS CoV2) is highlighted with their proposed mechanism of action, which will prove fruitful and effective in finding a cure for this deadly disease.

scholarly journals Influence of estrous stages on electrocardiography, clinical pathology and ovarian weight of experimental beagle dogs: a retrospective analysis

2019 ◽  
Vol 12 (3) ◽  
pp. 149-156 ◽  
Author(s):  
Chitrang Shah ◽  
Laxit Bhatt ◽  
B.V. Ravichandra ◽  
Viren Kothule ◽  
Shekhar Kadam ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Estrous Cycle ◽  
Clinical Pathology ◽  
Mammary Glands ◽  
Beagle Dogs ◽  
Ovarian Weight ◽  
Qt Intervals ◽  
Pr Interval ◽  
Reproductive Life ◽  
Erroneous Interpretation

Abstract Estrous cycle is a repetitive phenomenon occurring during the reproductive life of a female dog. The duration of the canine estrous cycle is considerably longer than one in the most of the other animals and is broadly grouped into follicular phase (proestrus and estrus), luteal phase (diestrus) and non-seasonal anestrus. Dogs in the same stage of cycle can be inadvertently assigned to same group during routine safety and metabolic studies leading to possible erroneous interpretation of test-item related effects. This retrospective analysis was conducted by analyzing data of 86 female beagle dogs from control/placebo treated groups to correlate any possible effect of estrous stages with electrocardiography, clinical pathology and ovarian weight. Different estrous cycle stages of beagles were confirmed histologically by evaluating ovary, uterus, vagina and mammary glands. The incidence of beagles in diestrus was the highest, followed by anestrus, proestrus and estrus. No significant effect was noticed on heart rate, P–A, P–D, RR, QRS and QT intervals across different stages of estrous cycle. However, significantly higher PQ (PR) interval in dogs in proestrus stage was observed compared to dogs in anestrus and estrus. Marginally higher WBCs, neutrophils, lymphocytes, RBCs, hemoglobin, AST and lower hematocrit, lipid profile (total cholesterol, HDL, LDL, triglycerides), ALP level was evident in estrous period. Relative ovary weight was significantly higher in dogs in diestrus stage. Considering these results, one may need to exercise caution while interpreting experimental data from female beagle dogs.

Short term inhalation toxicity of a liquid aerosol of CdS/Cd(OH)2 core shell quantum dots in male Wistar rats

2012 ◽  
Vol 208 (2) ◽  
pp. 115-124 ◽  
Author(s):  
L. Ma-Hock ◽  
S. Brill ◽  
W. Wohlleben ◽  
P.M.A. Farias ◽  
C.R. Chaves ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Wistar Rats ◽  
Core Shell ◽  
Inhalation Toxicity ◽  
Short Term ◽  
Male Wistar Rats

Picking the Optimal Target for Antibody-Drug Conjugates

2013 ◽  
pp. e103-e107
Author(s):  
Rohan Mathur ◽  
George J. Weiner
Keyword(s):  
Critical Parameter ◽  
Therapeutic Agent ◽  
Therapeutic Window ◽  
Chemotherapeutic Drugs ◽  
Toxicity Profile ◽  
Cytotoxic Potential ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Optimal Target ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) combine the cytotoxic potential of chemotherapeutic drugs with the specificity of monoclonal antibodies (mAbs). After many years of unfulfilled promise, the field of ADCs is experiencing resurgence as more is learned about each of the components of an ADC and how these components need to be combined to produce a successful therapeutic agent. Choosing an appropriate target for ADCs is a critical parameter that effects the efficacy, therapeutic window, and toxicity profile of ADCs. This review will focus on the concepts underlying the choice of the target, review specific current ADCs and their targets, and look to the future of ADCs.

scholarly journals Comprehensive Subchronic Inhalation Toxicity Assessment of an Indoor School Air Mixture of PCBs

2020 ◽  
Vol 54 (24) ◽  
pp. 15976-15985
Author(s):  
Hui Wang ◽  
Andrea Adamcakova-Dodd ◽  
Susanne Flor ◽  
Laura Gosse ◽  
Violet E. Klenov ◽  
...  
Keyword(s):  
Toxicity Assessment ◽  
Inhalation Toxicity
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