Hepatic Effects in Beagle Dogs Administered Atorvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, for 2 Years

Walsh, Kathleen M.; Rothwell, Charles E.

doi:10.1177/019262339902700402

Cited by 14 publications

(6 citation statements)

References 25 publications

(44 reference statements)

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“…Several statins are used on canine in fundamental or clinical research with few side effects. 45,46,[94][95][96] However, the concentrations used in this in vitro study might not be attainable in vivo, but statins may nonetheless be of therapeutic benefit in CMT patients at lower concentrations. For instance, anti-cancer properties of statins are well established in humans, even when used at doses/concentrations designed for lipid lowering, which are far below the concentrations used in the context of this study.…”

Section: Discussionmentioning

confidence: 99%

“…These findings therefore establish the potential of statins for the treatment of inoperable mammary gland cancer in dogs. Several statins are used on canine in fundamental or clinical research with few side effects 45,46,94–96 . However, the concentrations used in this in vitro study might not be attainable in vivo, but statins may nonetheless be of therapeutic benefit in CMT patients at lower concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Statins downregulateYAPandTAZand exert anti‐cancer effects in canine mammary tumour cells

Vigneau

Rico

Boerboom

et al. 2021

Vet Comparative Oncology

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Canine mammary tumours (CMTs) are the most common neoplasms in intact bitches, and few chemotherapeutic options are available for highly invasive and metastatic tumours. Recent studies have shown the potential involvement of dysregulated Hippo signalling in CMT development and progression. Statins can activate the Hippo pathway by blocking protein geranylgeranylation (GGylation), resulting in decreased expression and activity of the transcriptional co‐activators YAP and TAZ. In this study, we therefore sought to determine if statins could exert anti‐cancer effects in CMT cells. Our results demonstrate that Atorvastatin and Fluvastatin are cytotoxic to two CMT cell lines (CMT9 and CMT47), with ED50 values ranging from 0.95 to 23.5 μM. Both statins acted to increase apoptosis and promote cell cycle arrest. Both statins also decreased YAP and TAZ expression and reduced the mRNA levels of key Hippo transcriptional target genes known to be involved in breast cancer progression and chemoresistance (CYR61, CTGF and RHAMM). Moreover, both statins effectively inhibited cell migration and anchorage independent growth, but did not influence matrix invasion. Taken together, our results demonstrate for the first time that statins act upon the Hippo pathway in CMT cells to counteract several molecular and cellular hallmarks of cancer. These findings suggest that targeting the Hippo pathway with statins represents a novel and promising approach for the treatment canine mammary gland cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Statins downregulateYAPandTAZand exert anti‐cancer effects in canine mammary tumour cells

Vigneau

Rico

Boerboom

et al. 2021

Vet Comparative Oncology

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“…Lipofuscin, a protein, accumulates within cells as a result of metabolic overload. This process is completely reversible and the pigment completely disappears with cessation of the metabolic overload (i.e., stop dosing) even after 1 full year of testing (Walsh and Rothwell 1999).…”

Section: Evaluation Of General Toxicitymentioning

confidence: 99%

Oral (Gavage) Two-Generation (One Litter Per Generation) Reproduction Study of Pentachlorophenol (Penta) in Rats

Bernard

Hoberman

Brown³

et al. 2002

Int J Toxicol

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The potential for pentachlorophenol (penta) to induce general and reproductive/developmental toxicity was evaluated in Crl Sprague-Dawley rats, employing a two-generation reproduction toxicity study. Penta was administered by gavage at doses of 0, 10, 30, and 60 mg/kg/day. In both generations, the parental animals (30/sex/group) were intubated daily for 10 weeks before cohabitation and continuing through cohabitation, gestation, and lactation periods. Intubation of the F1 generation was begun 28 days postpartum. Animals were evaluated daily for mortality and general toxicity (clinical observations, body weights and gains, feed consumption). Organ weights were recorded and histopathological evaluations were made. Specific indices of reproductive function evaluated included estrous cycles, mating and fertility, parturition, lactation, viability, and growth and development of offspring, including sexual maturation, sperm parameters, and numbers of ovarian primordial follicles. All deaths in the parental rats were unrelated to penta. Expected metabolic effects of penta, sporadic increased liver weights associated with hepatocellular centrilobular hypertrophy and vacuolation and lipofuscin pigmentation, were evident in the 10-, 30-, and 60-mg/kg/day dose group P1 and F1 animals. Toxicity, in the form of liver pathology (single cell necrosis), reduced body weights and associated reductions in organ weights, and reduced feed consumption were noted in both generations at the 30- and 60-mg/kg/day doses. Developmental toxicity associated with these doses included reduced pup weights and viability. The 60-mg/kg/day dose also resulted in delayed sexual maturation, decreased spermatid counts, small prostates and testes, decreased implantations, reduced fertility, and increased resorptions of embryos. Based on these results, it was concluded that 30 mg/kg/day is the lowest-observable-adverse-effect level (LOAEL) and 10 mg/kg/day is the no-observable-adverse-effect level (NOAEL) for both reproductive and general toxicity. These findings are consistent with results from previously conducted studies wherein reproductive/developmental toxicity was observed only at doses that also induced general toxicity. It differs from previous findings in that the NOAEL for general toxicity is two to three times higher for the more pure product than for products produced and tested previously. In addition, the results did not indicate bioaccumulation of penta. Thus, penta did not selectively affect reproduction or development of the offspring of rats at a dose of 10 mg/kg/day, a dose that is 7000 to 20,000 times higher than human exposure.

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“…Additionally, it prevents plaque and protects against strokes through anti-inflammatory and other mechanisms. (1). HMG-CoA reeducation is competitively inhibited by atorvastatin.…”

Section: Introductionmentioning

confidence: 99%

The effect of atorvastatin therapy on skeletal muscle function in hyperlipidemia patients in khartoum

Ali¹,

Mohamed²,

Ali³

et al. 2022

Int. J. Biol. Pharm. Sci. Arch.

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Background: Atorvastatin is a lipid-lowering medication that causes skeletal muscle side effects by altering serum levels of skeletal muscle biomarkers. The aim of this study is to assess the effect of atorvastatin on muscle function and biomarker serum levels of CK, LDH, AST, Myoglobin, and Troponin I in Sudanese patients. Method: The total study group of hindered participants, including 60 case group (under Atorvastatin treatment) and 40 healthy as a control group, was matched with age and sex for the case group. The serum CK, LDH, myoglobin, and lipid profiles in the study groups were estimated by automated chemistry analyzers in this study. Result: Muscle pain was reported in case studies (55 = 91%). There was a significant increase in CK, LDH, and myoglobin among case studies when compared to the control group. The dose of drug showed no significant difference among the studied parameters. No correlation was found between CK and LDH with the duration of drug administration. Conclusion: Atorvastatin medication causes skeletal muscle pain among case study and increase muscle biomarkers such as CK, LDH, and myoglobin levels.

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Hepatic Effects in Beagle Dogs Administered Atorvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, for 2 Years

Abstract: The chronic toxicity of atorvastatin (AT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was evaluated in beagle dogs. Dogs were treated with 0, 10, 40, or 120 mg/kg of AT daily. Treatment

Cited by 14 publications

References 25 publications

Statins downregulateYAPandTAZand exert anti‐cancer effects in canine mammary tumour cells

Statins downregulateYAPandTAZand exert anti‐cancer effects in canine mammary tumour cells

Oral (Gavage) Two-Generation (One Litter Per Generation) Reproduction Study of Pentachlorophenol (Penta) in Rats

The effect of atorvastatin therapy on skeletal muscle function in hyperlipidemia patients in khartoum

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