The effects of repeated doses of xylazine-ketamine and medetomidineketamine anesthesia on DNA damage in the liver and kidney

Purpose: This study evaluated the DNA damage caused by repeated doses of xylazine-ketamine and medetomidine-ketamine anesthesia in the liver and kidneys. Methods: In this study, 60 rats were used. The rats were divided into group 1 (xylazine-ketamine), and group 2 (medetomidine-ketamine), and these anesthetic combinations were administered to the rats at repeated doses with 30-min intervals. The effects of these anesthetic agents on the tumor necrosis factor-alpha gene for DNA damage were investigated. Results: According to the gene expression results, it was observed that a single dose of xylazine-ketamine was 2.9-fold expressed, while first and second repeat doses did not show significant changes in expression levels. However, in the case of the third repetition, it was observed to be 3.8-fold overexpressed. In the case of medetomidine-ketamine administration, it was observed that a single-dose application resulted in a 1.04-fold expression, while the first and the third repeat doses showed a significant down expression. The samples from the second repeat dose administration group were found to have insignificant levels of expression. Conclusions: This study can contribute to understanding the safe anesthetic combination in research and operations in which xylazine-ketamine and medetomidine-ketamine combinations are used.

Vacunación contra SARS-CoV-2 y su relación con enfermedad y muerte por COVID-19 en Argentina / Vaccination against SARS-CoV-2 and its relationship with illness and death from COVID-19 in Argentina / Vacinação contra SARS-CoV-2 e sua relação com doença e morte por COVID-19 na Argentina

RESUMEN Objetivo. Conocer la efectividad de la vacunación contra SARS-CoV-2 para prevenir el desarrollo de enfermedad y muerte por COVID-19 en Córdoba, Argentina, en el periodo enero-junio de 2021. Métodos. Se llevó a cabo un estudio de cohorte retrospectivo en 1 139 458 residentes en la provincia de Córdoba. Se construyeron modelos de regresión logística múltiple que relacionaron la vacunación con la infección por SARS-CoV-2 o la muerte por COVID-19, considerando comorbilidades y factores de riesgo de enfermedades crónicas y ajustando por sexo y edad. Resultados. El haber recibido una o dos dosis de vacuna en la población general redujo el riesgo de enfermar un 98,8% y 99,3%, respectivamente; y de morir un 83% y 96,5%, respectivamente. En quienes contrajeron COVID-19, la probabilidad de morir se redujo en 57% y 80%, respectivamente. En cuanto a la probabilidad de muerte, el riesgo aumentó a medida que aumentaba la edad y con la pertenencia al sexo masculino o la presencia de obesidad, hipertensión arterial o diabetes mellitus. Conclusión. La vacunación es efectiva y protege contra la posibilidad de contraer COVID-19, desarrollar enfermedad grave o morir. Presentar obesidad, hipertensión arterial o diabetes mellitus, en orden decreciente, aumentan el riesgo de morir.

ABSTRACT Objective. To determine the effectiveness of vaccination against SARS-CoV-2 in preventing illness and death from COVID-19 in Córdoba, Argentina, during the period from January through June 2021. Methods. A retrospective cohort study was conducted among 1,139,458 residents of the province of Córdoba. Multiple logistic regression models were developed to describe the relationship between vaccination and the presence of SARS-CoV-2 or death from COVID-19, while taking account of comorbidities and chronic disease risk factors and adjusting for sex and age. Results. Among the general population, having received one or two doses of vaccine reduced the risk of illness by 98.8% and 99.3%, respectively, and the risk of dying by 83% and 96.5%, respectively. Among those who developed COVID-19, the probability of dying was reduced by 57% and 80%, respectively. Regarding probability of death, risk increased with age, with being male, and with obesity, arterial hypertension, and diabetes mellitus. Conclusion. Vaccination is effective and protects against the risk of getting COVID-19, developing severe disease, or dying. Having obesity, arterial hypertension, or diabetes mellitus, in descending order, increases the risk of death.

RESUMO Objetivo. Conhecer a eficácia da vacinação contra SARS-CoV-2 para prevenir o desenvolvimento de doença e morte por COVID-19 em Córdoba, Argentina, no período de janeiro a junho de 2021. Métodos. Foi realizado um estudo de coorte retrospectivo em 1.139.458 residentes da província de Córdoba. Foram construídos modelos de regressão logística múltipla que relacionaram a vacinação à presença de SARS-CoV-2 ou morte por COVID-19, considerando comorbidades e fatores de risco para doenças crônicas e ajustando por sexo e idade. Resultados. Ter recebido uma ou duas doses da vacina na população geral reduziu o risco de adoecimento em 98,8% e 99,3%, respectivamente; e de morrer, em 83% e 96,5%, respectivamente. Naqueles que contraíram COVID-19, a probabilidade de morrer foi reduzida em 57% e 80%, respectivamente. Em relação à probabilidade de morte, o risco aumentou com o aumento da idade e para o sexo masculino, ou com a presença de obesidade, hipertensão arterial ou diabetes mellitus. Conclusão. A vacinação é efetiva e protege contra a possibilidade de contrair COVID-19, desenvolver doença grave ou morrer. A presença de obesidade, hipertensão arterial ou diabetes mellitus, em ordem decrescente, aumenta o risco de morte.

Toxicity study of oral administration of Shufeng Jiedu Capsule for 14 d in SD rats during peri-weaning period / 中草药

Objective To characterize the oral toxicity of Shufeng Jiedu Capsule (SFJD) in SD rats during peri-weaning period, and provide reference for the clinical application of SFJD in infants. Methods Ten-day-old healthy SD rats were exposed to 0 and 4 g/kg of SFJD once per day for 14 d via intra-gastric administration. Mortality, general physical signs, body weights, spontaneous motor activity, learning and memory functions, hematology (with T and B lymphocyte subgroups included), serum chemistry, serum testosterone, insulin-like growth factor, organ weights, as well as gross pathological findings were evaluated between the control and exposure group. Physical development indicators such as pinna unfolding, coat growth, incisor eruption, and eyes opening time, were also recorded. The body length and tail length of rats under anesthesia were detected. Results After SFJD administration, loose stools and orange colored urine were found in rats, and the color of the urine was related to the color of drugs. The body weight growth rates were decreased compared with the control group. Urine specific gravity was increased in rats. RBC and Ret concentrations were decreased in two of the 16 tested animals. Liver, spleen, and kidney ratios to body and brain weight were increased in rats; The weight of spleen was also increased compared with the control group. Conclusion It was well tolerated to peri-weaning rats after the ig administration of 4 g/kg SFJD. The concerns of diarrhea, mild body weight growth rate, as well as RBC and Ret decrease should be noted for long term and high dose usage in infants and toddlers.

Safety Evaluation of Methoxyflavones Mixture (Ⅱ) from Kempferia parviflora：28-day Repeated Dose Oral Toxicity Test / 日本補完代替医療学会誌

Kaempferia parviflora rhizome is used folk medicines for treatment of various symptoms in Thailand since anticent times.Several types of methoxyflavones has been identified in this plant and their physiological functions have been reported.We determined that six kinds of methoxyflavones (5,7,3',4'-tetramethoxyflavone, 3,5,7,3',4'-pentamethoxyflavone, 5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone, 3,5,7-trimethoxyflavone, 3,5,7,4'-tetramethoxyflavone) were included in the 80% ethanol extract of K. parviflora rhizome.The safety of six methoxyflavones mixture was evaluated with 28-day repeated oral dose toxicity test in mice.These results indicated no significant toxicity on body weight, blood analyses, organ weight, blood biochemical analyses.

Comparison of the repeated dose toxicity of doxorubicin liposome injection and doxorubicin injection in rats / 中国比较医学杂志

Objective To investigate the repeated dose toxicity of doxorubicin liposome injection and doxorubicin injection in rats. Methods Ninety SD rats ( body weight 180-220 g, male:female=1:1 ) were divided into 3 groups (30 rats in each group), and were administered intravenously with physiological saline, doxorubicin liposome injection (1 mg·kg-1 ) and doxorubicin injection ( 1 mg·kg-1 ) , respectively, once every three days for thirteen times. The body weight, blood biochemistry, hematology, organ coefficient and histopathology were analyzed for the overall toxicity assessment. Results The rats administered with doxorubicin liposome injection (1 mg/kg) showed hair loss and skin ulcer, significantly reduced growth of body weight, increased levels of urea nitrogen ( BUN ) , alanine aminotransferase ( ALT ) , blood platelet ( PLT ) , and kidney and heart coefficients, decreased thymus and testicular coefficients, myofibrillar rupture and lysis, and partial loss of cell nuclei, hyaline casts in the renal convoluted tubules, interstitial edema and loss of spermatogenic cells in the testicular tubules. Compared with the doxorubicin liposome injection group, similar abnormal changes were also observed in the doxorubicin injection group, but the hair loss and skin ulcer were milder and the heart and kidney toxicities were severer. Conclusions Compared with doxorubicin injection, the doxorubicin liposome injection causes milder heart and kidney toxicity but more serious skin toxicity.

Repeated dose toxicity of Tangwang Mingmu granules in Sprague-Dawley rats / 军事医学

Objective To observe toxic symptoms and signs , toxic damage extents and reversibility in rats after oral administration of Tangwang Mingmu granules .Methods Four dose groups with 40 rats in each group were designed in this study, including control group fed with distilled water and three groups at different dosages of the test drug .Tangwang Mingmu granules were orally administered to SD rats at the dosage of 8.4, 4.2 and 2.1 g/kg for 3 weeks and 14.0, 8.4 and 4.2 g/kg for 23 weeks, for 26 consecutive weeks .The general state of the rats was observed every day , while body mass and food consumption were calculated once a week .Halfway through and at the end of the administration (13 and 26 weeks) and after four weeks of recovery, parameters of body mass, hematology, hematological biochemistry, organ/body mass ratio and histopathology were measured .Results Compared with the control group at the same time-point, body mass of male rats in the other three groups was slightly reduced .Food consumption in high and medium dose groups was reduced (P<0.05), MCHC, ALT, TBIL and Na +in high dose group were decreased (P<0.05), TP, ALB and D-BIL were increased (P<0.05), the mean body mass and relative organ weight of thymus in medium dose male rats were decreased (P<0.05), relative organ weight of the liver and kidney in high dose male rats was increased (P<0.05), and focal chronic inflammation to different extent was observed in the liver , kidney and prostate gland .No dose-effect relationship was found in these perturbations that were all within the normal range of animals .No significant drug-related pathological changes were found.Conclusion The NOAEL of Tangwang Mingmu granules is considered to be 14.0 g/kg body mass/day (equal to 50 times the proposed clinical adult dosage ) for the 26-week repeated dose oral toxicity study in male andfemale rats.

A study on the effect of repeated -dose toxicity on rats exposed to dichloromethane by dermal route for 28 days / 预防医学

Objective To learn the toxic effects on rats repeatedly exposed to dichloromethane by dermal route at the same dose for 28 days.Methods Seventy two Sprague Dawley rats were divided into six groups:a solvent control group (oliver oil),four exposure groups (0.75,1.5,3.0 and 6.0 g/kg·BW)and a recovery group.Each group included six female and six male rats.The exposure groups were dermal exposed to DCM at 1.5,3.0 and 6.0 g/kg·BW,6 hours/day,5 days/week for four weeks.The recovery group was dermal exposed to 6.0 g/kg BW of DCMduring the same period then recovered for 2 weeks.Clinical signs including body weight and food consumption of each group were observed.After rats were sacrificed,the hematological and serum biochemical parameters were determined.Histopathological examination was performed on selected tissues for all animals.Results The male rats in test groups including four exposure groups and a recovery group,showed decreased body weight gain.Neutrophilia and lymphocytopenia were determined in females of 3.0 and 6.0 g/kg BW groups and males of 1.5,3.0 and 6.0 g/kg BW groups by blood routine test (P <0.05).The mean levels of serum ALT and AST significantly increased in males of 3.0 and 6.0 g/kg BW groups (P <0.05).Only the mean level of serum TG in males of 6.0 g/kg BW group decreased (P <0.05).No significant differences of these indexes were shown in female rats of all exposure groups compared to control group.The exposure -related significant increases on the incidences of epidermis and dermis lesion,hepatocellular degeneration and necrosis were observed in test groups compared to the control group.The rats of recovery group were exhibited normal percentages of lymphocytes and neutrophils,levels of ALT,AST and TG. The skin and hepatocellular lesion were improved to some extent, but not recovered exactly.Conclusion In a 4 -week repeated -dose toxic study,DCM induce dose -related effects in rats involving skin lesion and liver injury with adverse changes in body weight gain of male rats,part parameters of hematology and serum biochemistry .

Safety Evaluation of Methoxyflavones Mixture (Ⅰ)from <i>Kempferia parviflora</i>; 28-day Repeated Dose Oral Toxicity Test and Mouse Micronucleus Test / 日本補完代替医療学会誌

Kaempferia parviflora rhizome is used in traditional folk medicines for the treatments of various symptoms in Thailand since ancient times. Several types of methoxyflavones were identified from that plant and the functions of some of those were reported. We determined that five kinds of methoxyflavones (5-hydroxy-3,7,3’,4’-tetramethoxyflavone, 5-hydroxy-7-methoxyflavone, 5-hydroxy-3,7-dimethoxyflavone, 5-hydroxy-3,7,4’-trimethoxyflavone, 5-hydroxy-7,4’-dimethoxyflavone) were included the following treatments of K. parviflora rhizome. The 80 %ethanol extract of that were adsorbed resin, removed 70 % ethanol elution and the rest adsorbed materials were eluted with 99.5 % ethanol. The safety of that five methoxyflavones mixture was evaluated. We performed a 28-day repeated dose of oral toxicity test and a mouse micronucleus test. The former results showed no significant toxicity on body weight, blood analyses, organ weight, blood biochemical analyses. The latter results showed negative, believed that the sample has no mutagenicity for living bodies.

Toxicity of Danshen injection in Beagle's dogs by repeated iv injection / 中草药·英文版

Objective: To re-evaluate the potential toxicity of Danshen Injection (DI) in Beagle's dogs by repeated iv injection. Methods: DI was iv given to the dogs at the doses of 0, 1.6, 5.4, and 16.0 g/(kg·d) (4 per sex per group) for 13 weeks. During the test period, the clinical signs, mortality, body weights, food consumption, rectal temperature, ophthalmoscopy, electrocardiography, urinalysis, hematology, serum biochemistry, organ weights, gross findings, and histopathology were examined. Results: Dogs iv given with DI at the doses of 0, 1.6, 5.4, and 16.0 g/(kg·d) for 13 weeks had no drug-related changes in mortality, body weight, food consumption, temperature, electrocardiography, ophthalmoscopy, urinalysis parameters, and organ weights. The hematological parameter data showed a significant decrease in red blood cells and hemoglobin concentration in the high-dose group and a significant increase in activated partial thromboplastin time suggesting an effect on haemopoiesis. For biochemical parameters, a significant decrease in glucose and a significant increase in total bilirubin were observed in the high-dose group, and the latter was considered to be toxicologically insignificant as lack of histopathological correlate. However, the histopathological examinations of the injection site showed that DI could cause dose-dependent focal inflammation. Conclusion: That the iv injection with DI into dogs at 16 g/(kg·d) for 13 weeks could cause the decreases in red blood cell parameters and glucose, as well as the lesions of the injection site. The no observed adverse effect level is 5.4 g/(kg·d), which suggests that safe clinical dosing be possible. © 2013 Tianjin Press of Chinese Herbal Medicines.

Evaluation of General Toxicity and Genotoxicity of the Silkworm Extract Powder

The silkworm extract powder contain 1-deoxynojirimycin (DNJ), a potent alpha-glycosidase inhibitor, has therapeutic potency against diabetes mellitus. Therefore, natural products containing DNJ from mulberry leaves and silkworm are consumed as health functional food. The present study was performed to evaluate the safety of the silkworm extract powder, a health food which containing the DNJ. The repeated toxicity studies and gentic toxicity studies of the silkworm extract powder were performed to obtain the data for new functional food approval in MFDS. The safety was evaluated by a single-dose oral toxicity study and a 90 day repeated-dose oral toxicity study in Sprague-Dawley rats. The silkworm extract powder was also evaluated for its mutagenic potential in a battery of genetic toxicity test: in vitro bacterial reverse mutation assay, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay. The results of the genetic toxicology assays were negative in all of the assays. The approximate lethal dose in single oral dose toxicity study was considered to be higher than 5000 mg/kg in rats. In the 90 day study, the dose levels were wet at 0, 500, 1000, 2000 mg/kg/day, and 10 animals/sex/dose were treated with oral gavage. The parameters that were monitored were clinical signs, body weights, food and water consumptions, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weights, and histopathological examination. No adverse effects were observed after the 90 day administration of the silkworm extract powder. The No-Observed-Adverse-Effect-Level (NOAEL) of silkworm extract powder in the 90 day study was 2000 mg/kg/day in both sexes, and no target organ was identified.

Acute Oral or Dermal and Repeated Dose 90-Day Oral Toxicity of Tetrasodium Pyrophosphate in Spraque Dawley (SD) Rats

OBJECTIVES: Tetrasodium pyrophosphate (TSP) is used in processed meat products, as an emulsifier in cheese, and as a color preservative in soybean paste. However, little is known about its toxicity. This study was conducted to investigate the potential acute and repeated dose toxicity of TSP in Spraque Dawley (SD) rats. METHODS: In the acute study, animals were administered with oral or dermal doses of 2,000 mg/kg TSP. In the repeated dose study, animals were administered doses of 0, 250, 500, and 1,000 mg/kg by oral gavage five times a week for 90 days. RESULTS: In acute toxicity studies, no dead animals or abnormal necropsy findings were found in the control or treated group. In the repeated dose toxicity study, there were no significant changes in body weight in the 1,000 mg/kg treatment group, or food consumption, urinalysis, and hematology in any group. With regards serum biochemistry, the levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses of 500 and 1,000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. With regards histopathological findings, cortical tubular basophilia of the kidney increased at the dose of 1,000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500, and 1,000 mg/kg. CONCLUSIONS: Based on the results, TSP is unclassified according to the Globally Harmonization System, with an LD50 value of over 2,000 mg/kg. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) were 250 and 500 mg/kg /day respectively and the target organ appears to be the kidney.

Single- and repeated-dose toxicities of aloe fermentation products in rats / 한국실험동물학회지

In this study, aloe fermentation products were derived from mycelia from 3 mushrooms: Ganoderma lucidum (AG), Hericium erinaceum (AH), and Phellinus linteus (AP). Levels of aloin A and B increased with fermentation time. The highest levels were measured on the fifth day of fermentation. beta-Glucan levels decreased with fermentation time. The safety of aloe fermentation products were examined in male and female Sprague-Dawley rats. Rats were orally administered the three aloe fermentation products at dose levels of 1, 2 or 5 g/kg for single-dose toxicity test and 0.5, 1, or 2 g/kg for repeated-dose toxicity test. There were no significant differences in body weight gain between vehicle control and AG-, AH- or AP-treated rats. Also, significant changes in daily feed intake and water consumption were not observed. In hematological analysis, none of the parameters were affected by aloe fermentation products with mushroom mycelia. This suggests that there are no negative effects on homeostasis and immunity. In blood biochemistry analysis, none of the markers were affected by feeding rats with AG, AH or AP. Similarly, there were no significant effects on markers for liver, kidney, skeletal and heart muscle functions. No remarkable lesions were observed in these organs at histopathology. Since there were no adverse effects of AG, AH and AP in single- or repeated-dose toxicity tests, even at higher doses than normal, we conclude that the aloe fermentation products with mushroom mycelia possess long-term safety and could be candidates as multifunctional nutrients for the improvement of intestinal function and immunity.

Determining NOEL/NOAEL in Repeated-dose Toxicity Studies, When the Low Dose Group Shows Significant Difference in Quantitative Data / 한국실험동물학회지

In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.

Determining NOEL/NOAEL in Repeated-dose Toxicity Studies, When the Low Dose Group Shows Significant Difference in Quantitative Data / 한국실험동물학회지

In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.

Ensayo de toxicidad a dosis repetidas durante 28 días del extracto acuoso de Cecropia peltata L. (yagruma) en ratas Cenp: SPRD / Toxicity assay at repeated doses of Cecropia peltata L. (yagruma) aqueous extract in Cenp: SPRD rats during 28 days

El extracto acuoso de Cecropia peltata es elaborado a partir de la planta denominada comúnmente yagruma o guarumo en Cuba. Este se emplea en la elaboración de tabletas con acción broncodilatadora. A la planta se le atribuyen propiedades antiasmáticas, antiblenorrágicas, analgésicas y cicatrizantes por solo citar algunas. El ensayo se realizó para evaluar las características tóxicas del extracto acuoso y sus efectos tóxicos en ratas. Se administró por vía oral, una dosis de 1000 mg de sólidos totales/kg de peso corporal durante 28 días. Los animales se observaron diariamente para detectar signos de toxicidad. Al finalizar el tratamiento se realizaron exámenes de hematología, de química sanguínea y la necropsia, para hacer el examen anatomopatológico e histopatológico correspondiente. Se pudo concluir que no se afectaron los indicadores hematológicos y de química sanguínea por causa del extracto ensayado. Tampoco hubo afectaciones en el peso corporal y el consumo de alimento. Los resultados obtenidos con el análisis histopatológico corroboraron todo lo antes expuesto.

The aqueous extract of Cecropia peltata is made from a plant commonly called yagruma or guarumo in Cuba. This extract is used in the manufacture of tablets with bronchodilator action. This plant has antiasthmatic, antiblennorrheal, analgesic, and healing effects, among others. The assay was carried out to assess the toxic features of this aqueous extract and its toxic effects in rats. An oral dose of 1000 mg of total solids/kg of body weight was administered for 28 days. The animals were daily observed to detect signs of toxicity. At the end of the treatment hematology and blood chemistry tests were done and necropsy was performed to make the corresponding anatomopathological and histopathological examination. No affectations were reported in body weight and food consumption. The results attained by the histopathological examination confirmed all the above.