Decreased Oral Toxicity with the Local Use of Allopurinol in Patients Who Received High Dose 5-Fluorouracil

In an 18-month oral toxicity study of soterenol hydrochloride, a stimulant of the β-adrenergic receptors, mesovarial leiomyomas were observed in three of 30 low-dose, six of 30 middle-dose and 10 of 30 high-dose rats. There was also an increase in the prevalence of ovarian cysts and of focal hyperplasia of smooth muscle in the mesovaria in the treated rats, especially in the high-dose group.

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Thirteen-Week Oral Toxicity Study of HVC1 in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/8104951 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Kyungjin Lee ◽

Ho-Young Choi

Keyword(s):

Hematological Parameters ◽

Clinical Signs ◽

Ethanol Extract ◽

New Drugs ◽

Control Group ◽

High Dose ◽

Sprague Dawley ◽

Weight Changes ◽

Oral Toxicity ◽

Blood Biochemical

Studies on the safety of herbal medicine are essential for the development of new drugs. The aim of this study was to evaluate the no-observed-adverse-effect-level (NOAEL) of HVC1 (Gamisamhwangsasim-tang, a 30% ethanol extract of a mixture of Pruni Cortex, Scutellariae Radix, Coptidis Rhizoma, and Rhei Rhizoma) and identify its target organs after oral administration to Sprague-Dawley (SD) rats repeatedly for 13 weeks. Three test groups were treated with HVC1 at a dose of either 500 (low-dose), 1,000 (middle-dose), or 2,000 (high-dose) mg/kg/day. Another group received high-dose HVC1 and was observed for 4 weeks following treatment to examine recovery from the effects of the extract. All treatment groups were compared to a vehicle control group. During the study, mortality, clinical signs, body weight changes, food consumption, abnormal lesions in the eye, urinary parameters, hematological parameters, blood coagulation time, blood biochemical parameters, changes in organ weight, gross findings, and histopathological changes were examined. No systemic toxicity related to HVC1 was observed in any group, and it was concluded that the NOAEL of HVC1 was 2,000 mg/kg/day. No target organ was identified.

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Toxicological Investigations of Aristolochia longa Root Extracts

Journal of Toxicology ◽

10.1155/2020/7643573 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Nasreddine El Omari ◽

Omar El Blidi ◽

Abdelhakim Bouyahya ◽

Karima Sayah ◽

Saad Bakrim ◽

...

Keyword(s):

Histopathological Examination ◽

Global Analysis ◽

Clinical Signs ◽

Experimental Period ◽

High Dose ◽

Herbaceous Plant ◽

Oral Toxicity ◽

Toxicity Potential ◽

Liver And Kidney

Aristolochia longa L. (Aristolochiaceae) is an herbaceous plant recognized in alternative medicine for its many therapeutic virtues. The aim of this study was to determine the pharmacotoxicological effects of this plant in order to ensure safe clinical use. The oral toxicity of the aqueous extract of A. longa roots was performed in vivo on Wistar rats at doses of 0.8, 1.25, 2, 2.5, and 5 g/kg/day for 21 days. Clinical signs were observed throughout the experimental period, followed by measurement of body weight change, while selected biochemical parameters, as well as relative organ weights and the histology of liver, kidney, and intestinal tissues, were evaluated after 6, 11, and 16 days and then at the end of 21 days of daily administration. At repeated doses for 21 days, the extract contributed to significant weight gain, in both control and treated rats. The global analysis of hepatic and renal biomarkers showed a significant increase between control and different doses of the extract, from the first to the third week of treatment, indicating the likely toxic effect of the extract on liver and kidney function. Organ toxicity was confirmed by histopathological examination, which revealed greater renal and hepatic parenchymal changes in animals treated with a high dose beyond the 16th day. At the end of the treatment, relatively small size of intestinal villi was also observed. It was concluded that ALAE has a low toxicity potential in nonprolonged oral administrations. However, at high chronic oral doses, A. longa appears to have significant toxicity on the organs tested.

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Subchronic Oral Toxicity Study of Decitabine in Combination With Tetrahydrouridine in CD-1 Mice

International Journal of Toxicology ◽

10.1177/1091581814524994 ◽

2014 ◽

Vol 33 (2) ◽

pp. 75-85 ◽

Cited By ~ 7

Author(s):

Pramod Terse ◽

Kory Engelke ◽

Kenneth Chan ◽

Yonghua Ling ◽

Douglas Sharpnack ◽

...

Keyword(s):

Bone Marrow ◽

Combination Therapy ◽

Food Consumption ◽

Blood Cells ◽

Recovery Period ◽

White Blood Cells ◽

Clinical Pathology ◽

High Dose ◽

Severe Toxicity ◽

Oral Toxicity

Decitabine (5-aza-2′-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.

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In vivo hepatotoxicity of chemically modified nanocellulose in rats

Human & Experimental Toxicology ◽

10.1177/0960327119881672 ◽

2019 ◽

Vol 39 (2) ◽

pp. 212-223 ◽

Cited By ~ 4

Author(s):

CA Otuechere ◽

A Adewuyi ◽

OL Adebayo ◽

IA Ebigwei

Keyword(s):

Body Weight ◽

Relative Weight ◽

High Dose ◽

Hydroxyl Groups ◽

Oral Toxicity ◽

Tissue Samples ◽

Liver Histopathology ◽

Biological Functionality ◽

Oxide Synthase

Chemical modification of cellulose is currently attracting attention as researchers attempt to take advantage of the abundance of hydroxyl groups on its surface to introduce extra biological functionality. However, the possible deleterious effect of exposure to functionalized nanocellulose (CSN) remains a concern. Therefore, this study aims to explore the potential mechanisms of hepatotoxicity of CSN modified with oxalate ester (NCD) in rats. A 7-day repeated oral toxicity study of NCD at the doses of 50 and 100 mg kg−1 body weight was conducted, and plasma and liver tissue samples were assayed using biochemical analysis, liver histopathology, and protein expression. NCD, at both doses, did not significantly ( p > 0.05) alter the relative weight of liver, alkaline phosphatase activity, and lipid peroxidation levels of the animals. However, NCD at the dose of 100 mg kg−1 body weight significantly elevated aspartate aminotransferase, alanine aminotransferase, and myeloperoxidase activities. NCD also enhanced the immunohistochemical expression of inducible nitric oxide synthase and Bcl-2-associated X protein in the liver of rats. Histological observations revealed necrosis and severe cellular infiltration at the high-dose treatment. Our study provides an experimental basis for the safe application of NCDs.

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Prospective Oral Mucositis Audit (POMA): Occurrence and Consequences of Severe Oral Mucositis in High Dose Melphalan and BEAM Conditioning.

Blood ◽

10.1182/blood.v108.11.46.46 ◽

2006 ◽

Vol 108 (11) ◽

pp. 46-46

Author(s):

Nicole N.A. Blijlevens ◽

Shaun McCann ◽

Pam Bacon ◽

Roisín Cinnéide ◽

Barry Quinn ◽

...

Keyword(s):

Length Of Stay ◽

Oral Mucositis ◽

Resource Use ◽

Well Being ◽

High Dose ◽

Routine Practice ◽

Cell Transplant ◽

Oral Toxicity ◽

Post Transplant ◽

High Dose Melphalan

Abstract Oral mucositis (OM) is an adverse effect of myeloablative regimens which seriously affects patient well-being and may increase risk of systemic infection and delay recovery. Trial-based reports of OM occurrence vary widely, with evidence of underreporting, and data on the incidence and impact of OM in routine practice are limited. Initiated by the European Group for Blood and Marrow Transplantation, this study observed pts. with multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) from 25 transplant centres across 13 European countries, receiving high dose melphalan or BEAM followed by autologous stem-cell transplant. Aims were to assess duration and incidence of severe (WHO oral toxicity scale Grade III–IV) OM and ulcerative (Grade II–IV) OM, medical resource use for OM prevention and treatment, and associations with infection and duration of hospitalisation. Prospective OM assessments were conducted daily from the start of conditioning until 30 days post transplant or hospital discharge. To achieve high and consistent quality of OM assessment, nurse assessors underwent a multimedia-assisted face-to-face training before study initiation. Of 197 evaluable pts., 110 (56%) had MM and 87 (44%) had NHL. Mean age at enrolment ± SD was 57 ± 8 years for MM and 50 ± 13 years for NHL. Women accounted for 36% of the MM sample and 51% of the NHL sample. In both sub-samples, 94% of pts. had ECOG status ≤ 1. The incidence of severe OM was 46% (95% CI 37–56%) for MM and 41% (95% CI 31–52%) for NHL. Severe OM episodes had a mean duration of 5.4 ± 3.3 days (95% CI 4.6–6.3 days) in MM and 5.3 ± 3.2 days (95% CI 4.3–6.4 days) in NHL. Ulcerative OM occurred in 67% (95% CI 58–76%) of MM pts. and 60% (95% CI 49–70%) of NHL pts., with a mean duration of 6.6 ± 4.4 days (95% CI 5.6–7.6 days) and 6.5 ± 3.8 days (95% CI 5.6–7.7 days), respectively. WHO scale results and indicators of specific OM symptoms showed very similar temporal patterns, reaching their maximum around day 12 after the start of conditioning in both groups. Clinically relevant associations with type of disease/conditioning or gender were not detected. A non-statistically significant trend hinted at an association of OM duration with age. The incidence of fever ≥ 38° C was 68% in pts. with severe OM vs. 47% in pts. without (univariate p = 0.004; odds ratio 2.4, 95% CI 1.3–4.4). Mean length of stay ± SD (truncated at 30 days post transplant) was 21.1 ± 4.0 days in pts. with severe OM vs. 19.9 ± 4.8 days in pts. without (univariate p = 0.023). Preliminary multivariate analysis adjusting for other potential predictors confirmed these effects. Based on a close collaboration of nurses and physicians, this study showed severe OM to be a substantial clinical problem in pts. receiving high dose melphalan or BEAM conditioning chemotherapy. Associations with fever occurrence and length of stay indicate potentially harmful clinical sequelae and relevant economic consequences. Associations with confirmed infection, and resource use for OM management, remain to be assessed.

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90-Days Repeated Dose Oral Toxicity Study of Sharbat-e-Deenar (A Hepatoprotective Unani Herbal Formulation)

Traditional and Integrative Medicine ◽

10.18502/tim.v6i1.5924 ◽

2021 ◽

Author(s):

Gulam Mohammed Husain ◽

Tasleem Ahmad ◽

Syeda Hajra Fatima ◽

Ghazala Javed ◽

Munawwar Husain Kazmi ◽

...

Keyword(s):

Body Weight ◽

Liver Function ◽

Clinical Sign ◽

Equivalent Dose ◽

Toxicity Study ◽

Feed Consumption ◽

Repeated Dose ◽

High Dose ◽

Oral Toxicity ◽

Dose Oral

Sharbat-e-Deenar (SDR) is a compound Unani pharmacopoeial formulation recommended for the treatment of Waram-e-Kabid (hepatitis), Waram-e-Rahem (uterine inflammation/ Pelvic Inflammatory Diseases), Yarqan-e-Suddi (obstructive jaundice), and Istisqa (ascites). The current study was carried out to investigate repeated dose oral toxicity study of SDR for 90 days in Sprague dawley (SD) rats. SDR was orally administered (gavage) at the doses of 4, 10 and 20 mL/kg bw/day. A periodic observation was performed for mortality, morbidity and any clinical sign of toxicity. Changes in body weight and feed consumption were observed weekly throughout study duration. After the treatment duration of three months, animals were anaesthetized and blood samples were subjected to haematological investigation and serum was subjected to different biochemical estimation. Gross necropsy was performed and internal organs/ tissues were processed for histopathological investigation. Treatment with SDR showed no incidence of mortality and no clinical sign of systemic toxicity. Body weight showed pattern of weight gain except significance decrease at mid and high dose at 13th week of study duration. Feed consumption exhibited a significant decrease as compare to control. Haematology and biochemistry profile found normal except certain isolated changes which was considered toxicologically not significant as the values lies in the normal physiological range. There were no changes observed in the gross necropsy and relative organ weight data of control and SDR treated rats. It is reported that few of the animals showed changes in liver at mid (2.5 times of therapeutic equivalent dose) and high dose (5 times of therapeutic equivalent dose) in SDR treated animals that may be attributed to SDR treatment, however, associated liver function parameters like ALT, AST and ALP did not show any alteration of liver function. Based on the results of this study, it may be indicated that liver may be the target organ for toxicity if SDR is used above recommended therapeutic dose for longer duration.

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Role of Pediococcus Acidilactici J9 in Decreasing the Occurrence of Gastritis Caused by H.pylori Infection and Two-week Repeated-dose Oral Toxicity Study in Mice

10.21203/rs.3.rs-25937/v1 ◽

2020 ◽

Author(s):

Mijung Lee ◽

Jin-Young Chung ◽

Ka Yeun Kim ◽

Wooseok Im ◽

Manho Kim

Keyword(s):

Dose Group ◽

Clinical Signs ◽

Dosage Level ◽

Repeated Dose ◽

High Dose ◽

Pediococcus Acidilactici ◽

Oral Toxicity ◽

Gastric Cancer Cells ◽

Male And Female ◽

Female Mice

Abstract BACKGROUND Helicobacter pylori (H. pylori) is an important pathogen that causes chronic gastritis and peptic ulcer, and is related to the development of gastric carcinoma. Several chemicals, including antibiotics, have been used to eradicate H.pylori. However, more studies are yet requred to accomplish a sufficient therapy. Pediococcus acidilactici J9 were studied for inhibition of binding of H.pylori binding to human gastric cell lines. This study was performed in order to investigate the repeated-dose toxicity of Pediococcus acidilactici J9 in male and female mice.RESULTS C57BL/6 male and female Mus musculus were divided into four groups (n = 10 in each group). Pediococcus acidilactici J9 was administered daily by oral injection of vehicle control at dosage levels to a low-dose group (500 mg/kg/day), middle-dose group (1000 mg/kg/day), and high-dose group (2000 mg/kg/day) for two weeks. After 14 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathology exam. There were no bacterial-related deaths or abnormal clinical signs in either gender of mouse. The data was observed during the period in terms of body weight, food, intake, and water consumption. Also, no alterations in organ weights upon administration of Pediococcus acidilactici J9 alone were observed.CONCLUSIONS These results suggest that the oral application of Pediococcus acidilactici J9, up to a dosage level of 2,000 mg/kg/day, causes no adverse effects in both male and female mice. Pediococcus acidilactici J9 inhibits the adhesion of H.pylori to AGS gastric cancer cells. When used as probiotics, Pediococcus acidilactici J9 may help decrease the occurrence of gastritis and reduce the risk of H.pylori infection with promising safety issues.

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Acute and 30-day oral toxicity studies of a novel coccidiostat – ethanamizuril

Toxicology Research ◽

10.1039/c9tx00073a ◽

2019 ◽

Vol 8 (5) ◽

pp. 686-695 ◽

Cited By ~ 5

Author(s):

Wenlong Xiao ◽

Xiaoyang Wang ◽

Chunmei Wang ◽

Mi Wang ◽

Chenzhong Fei ◽

...

Keyword(s):

Clinical Signs ◽

Female Rats ◽

Male Rats ◽

Wall Thickening ◽

High Dose ◽

Alveolar Wall ◽

Oral Toxicity ◽

Male And Female Rats ◽

Adverse Effect Level ◽

Ld50 Value

Abstract Ethanamizuril is a novel triazine compound that exhibits remarkable anticoccidial activity. Owing to its pharmacological properties, this study was conducted to evaluate the acute and 30-day oral toxicity of ethanamizuril. In the acute study, ethanamizuril was administered once by oral gavage to mice and rats. The calculated LD50 values for mice and rats were 5776 and 4743 mg per kg b.w, respectively, but the LD50 value for male rats was higher than that of female rats. In the subchronic study, male and female rats were fed with diets supplemented with 0, 20, 60 or 120 mg kg−1 ethanamizuril for 30 days. Treatment related clinical signs of alopecia on the back and neck of the animals were observed in the 60 and 120 mg kg−1 dose groups from the third week of treatment. Significant differences in haematological and biochemical parameters as well as organ-to-body weight ratios were detected between the 60 and 120 mg kg−1 groups. Histopathological observations revealed that 60 and 120 mg kg−1 ethanamizuril could induce focal hepatocellular necrosis and split phase. Slight renal tubule protein casts in the kidneys and alveolar wall thickening in the lungs were also observed in the high dose groups of both genders. The dietary no-observed-adverse-effect level (NOAEL) of ethanamizuril for 30 days was 20 mg kg−1 feed.

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Final Report on the Safety Assessment of Hydroxybenzomorpholine

Journal of the American College of Toxicology ◽

10.3109/10915819109078630 ◽

1991 ◽

Vol 10 (1) ◽

pp. 205-213 ◽

Cited By ~ 1

Keyword(s):

Safety Assessment ◽

Micronucleus Test ◽

Coal Tar ◽

Skin Irritation ◽

High Dose ◽

Final Report ◽

Oral Toxicity ◽

Hair Dyes ◽

Hair Dye ◽

Rabbit Eye

Hydroxybenzomorpholine (HBM) is a heterocyclic compound that is used in cosmetics as a coupler in coal tar hair dyes. No deaths were reported in a subchronic oral toxicity study in rats. Some degenerative changes in the cortical tubules of the kidneys were observed in the mid and high-dose groups. HBM was considered to be practically nonirritating to the rabbit eye and produced only slight skin irritation. HBM was neither a sensitizer nor a photoallergen. HBM was not mutagenic in either the Ames assay or in the mouse micronucleus test. On the basis of the data included in the report, Hydroxybenzomorpholine is considered to be safe as a hair dye ingredient at the current concentrations of use.

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