scholarly journals Improved Up-and-Down Procedure for Acute Toxicity Measurement With Reliable LD50 Verified by Typical Toxic Alkaloids and Modified Karber Method

2021 ◽  
Author(s):  
Yan-Yu Zhang ◽  
Yu-Feng Huang ◽  
Jie Liang ◽  
Hua Zhou
Keyword(s):  
Acute Toxicity ◽  
Reliable Method ◽  
Experimental Period ◽  
Observation Time ◽  
Minor Amount ◽  
Berberine Hydrochloride ◽  
Toxic Alkaloids ◽  
Lethal Dosage ◽  
Sinomenine Hydrochloride

Abstract Background: Up-and-down procedure (UDP) was recommended to replace traditional acute toxicity methods. However, it was limited due to the long experimental period (20 - 42 days). To improve UDP, an improved UDP method (iUDP) was developed by shortening observation time between sequence dosages. The aim of this study was to test the reliability of iUDP to provide a reliable method for the acute toxicity measurement of valuable or minor amount compounds. Methods: Oral median lethal dosage (LD50) of nicotine, sinomenine hydrochloride and berberine hydrochloride were measured both by iUDP and modified Karber method (mKM). Results: LD50 of the three alkaloids measured by iUDP with 23 mice were 32.71 ± 7.46, 453.54 ± 104.59, 2954.93 ± 794.88 mg/kg, respectively. LD50 of the three alkaloids measured by mKM with 240 mice were 22.99 ± 3.01, 456.56 ± 53.38, 2825.53 ± 1212.92 mg/kg, respectively. The average time consumed by the two methods were 22 days and 14 days respectively. Total grams of the alkaloids used by the two methods were 0.0082 and 0.0673 (nicotine), 0.114 and 1.24 (sinomenine hydrochloride), 1.9 and 12.7 (berberine hydrochloride). Conclusion: iUDP could replace mKM to detect acute toxicity of substances with comparable and reliable result. And it was suitable for valuable or minor amount substances.

scholarly journals Improved up-and-down procedure for acute toxicity measurement with reliable LD50 verified by typical toxic alkaloids and modified Karber method

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Yan-Yu Zhang ◽  
Yu-Feng Huang ◽  
Jie Liang ◽  
Hua Zhou
Keyword(s):  
Acute Toxicity ◽  
Reliable Method ◽  
Lethal Dose ◽  
Experimental Period ◽  
Observation Time ◽  
Minor Amount ◽  
Berberine Hydrochloride ◽  
Median Lethal Dose ◽  
Toxic Alkaloids ◽  
Sinomenine Hydrochloride

Abstract Background Up-and-down procedure (UDP) was recommended to replace traditional acute toxicity methods. However, it was limited due to the long experimental period (20–42 days). To improve UDP, an improved UDP method (iUDP) was developed by shortening observation time between sequence dosages. The aim of this study was to test the reliability of iUDP to provide a reliable method for the acute toxicity measurement of valuable or minor amount compounds. Methods Oral median lethal dose (LD50) of nicotine, sinomenine hydrochloride and berberine hydrochloride were measured both by iUDP and modified Karber method (mKM). Results LD50 of the three alkaloids measured by iUDP with 23 mice were 32.71 ± 7.46, 453.54 ± 104.59, 2954.93 ± 794.88 mg/kg, respectively. LD50 of the three alkaloids measured by mKM with 240 mice were 22.99 ± 3.01, 456.56 ± 53.38, 2825.53 ± 1212.92 mg/kg, respectively. The average time consumed by the two methods were 22 days and 14 days respectively. Total grams of the alkaloids used by the two methods were 0.0082 and 0.0673 (nicotine), 0.114 and 1.24 (sinomenine hydrochloride), 1.9 and 12.7 (berberine hydrochloride). Conclusion iUDP could replace mKM to detect acute toxicity of substances with comparable and reliable result. And it is suitable for valuable or minor amount substances.

scholarly journals Acute and Subchronic (28-day) Oral Toxicity Studies on the Film Formulation of k-Carrageenan and Konjac Glucomannan for Soft Capsule Application

2019 ◽  
Vol 87 (2) ◽  
pp. 9 ◽  
Author(s):  
Ni Sutrisni ◽  
Sundani Soewandhi ◽  
I Adnyana ◽  
Lucy Sasongko
Keyword(s):  
Acute Toxicity ◽  
Experimental Period ◽  
Konjac Glucomannan ◽  
Toxicity Study ◽  
Oral Toxicity ◽  
Subchronic Toxicity ◽  
Acute Toxicity Study ◽  
Relative Organ Weight ◽  
Film Formulation ◽  
Safe Dose

The aim of this study was to investigate the acute and subchronic toxicity of a film formulation that combines κ-Carrageenan and konjac glucomannan for soft capsule application. For the acute toxicity study, a dose of 2000 mg/kg body weight (bw) of the film suspension was administered orally to rats. The animals were observed for toxic symptoms and mortality daily for 14 days. In a subchronic toxicity study, the film suspension, at doses of 10, 30 and 75 mg/kg bw for 28 days, were orally administered to rats. After 28 days, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity study, neither signs of toxicity nor death among the rats were observed for up to 14 days of the experimental period. The results of the subchronic toxicity study show that there were no significant changes observed in the hematology and organ histology. Some alterations to the relative organ weight and blood biochemistry were observed, but they were considered to be temporary effects and not an indication of toxic effects. The overall findings of this study indicate that the film formulation of κ-Carrageenan and konjac glucomannan is non-toxic up to a dose of 75 mg/kg bw, which could be considered a safe dose for soft capsule application.

BACOPP-D - An Etoposide-Free Dose-Escalated Polychemotherapy Regimen in Advanced Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2317-2317
Author(s):  
Ralph Naumann ◽  
Katrin Wetzko ◽  
Annette Haenel ◽  
Kai Friedrichsen ◽  
Ernst Zschuppe ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Observation Time ◽  
Hypopharyngeal Carcinoma ◽  
High Dose ◽  
Who Grade ◽  
Fdg Uptake ◽  
Pet Scans ◽  
Grade Iii

Abstract Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin Lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide free as well as dose intensified BACOPP-D protocol. Methods: Since May 2000 a total of 115 patients with Hodgkin Lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results: Until now 97 patients (median age 35 years, range 17-65; 61 male, 36 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 728 cycles of BACOPP-D. CTC/WHO grade III/IV haematological toxicities per patient were observed as follows: leukopenia 93%, anemia 39%, and thrombocytopenia 33%. CTC grade III/IV non-haematological side effects included documented infection (4%) and lung toxicity (one patient). A total of 85 patients (88%) achieved complete remission, 9 patients (9%) achieved partial remission, three patients (3%) had progressive disease. At a median observation time of 39 months (0,9-77 months), five patients have relapsed, and nine deaths were documented (4 HL-specific and 3 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction). One patient developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic). The overall survival and freedom from treatment failure rates at 39 months were 91% and 85%, respectively. FDG-PET scans after BACOPP-D chemotherapy were performed in 68 of 97 patients. PET scans revealed no increased FDG uptake in 48/68 patients (71%), in 20 patients (29%) increased FDG uptake was detected. In the group of patients with increased FDG uptake, one patient developed progressive disease and four patients relapsed. In the group with PET-negative findings no patient relapsed. Diskussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic and metabolic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred until now.

BACOPP-D - An Etoposide-Free Dose-Escalated Polychemotherapy Regimen In Advanced Hodgkin‘s Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1754-1754
Author(s):  
Ralph Naumann ◽  
Diana Kluge ◽  
Annette Haenel ◽  
Katrin Wetzko ◽  
Nadja Friedel ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Hodgkin’S Lymphoma ◽  
Conflicts Of Interest ◽  
Observation Time ◽  
Hodgkin's Lymphoma ◽  
Hypopharyngeal Carcinoma ◽  
Secondary Malignancy ◽  
High Dose ◽  
Advanced Hodgkin’S Lymphoma ◽  
Grade Iii

Abstract Abstract 1754 Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin‘s lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide-free as well as dose-intensified BACOPP-D protocol. Methods: From May 2000 until August 2008 a total of 139 untreated patients with Hodgkin‘s lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results: All patients (median age 34 years, range 16–65; 86 male, 53 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 1060 cycles of BACOPP-D. CTC grade III/IV haematological toxicities per patient were observed as follows: leukopenia 92%, anemia 40%, and thrombocytopenia 35%. CTC grade III/IV non-haematological side effects included documented infection (8%) and lung toxicity (one patient). Consolidation radiotherapy was given in 73 patients (52,5%). A total of 125 patients (89,9%) achieved complete remission, 9 patients (6,5%) achieved partial remission, five patients (3,6%) had progressive disease. At a median observation time of 46 months (5-109 months), 9 patients (6,5%) have relapsed, and 11 deaths were documented (4 HL-specific and 4 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction and 1 death due to secondary malignancy). Only two patients developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic; melanoma). The overall survival and progression free survival rates at 46 months were 89,7% and 85,9%, respectively. Discussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred so far. Disclosures: No relevant conflicts of interest to declare.

Acute Toxicity of Subcutaneously Administered Vitamin E Isomers Delta- and Gamma-Tocotrienol in Mice

2014 ◽  
Vol 33 (6) ◽  
pp. 450-458 ◽  
Author(s):  
Sibyl N. Swift ◽  
Roli L. Pessu ◽  
Kushal Chakraborty ◽  
Vilmar Villa ◽  
Eric Lombardini ◽  
...  
Keyword(s):  
Vitamin E ◽  
Acute Toxicity ◽  
Injection Site ◽  
Dose Range ◽  
Skin Irritation ◽  
Experimental Period ◽  
Toxicity Study ◽  
Histopathological Analysis ◽  
Toxic Dose ◽  
Gamma Tocotrienol

The toxicity of parenterally administered vitamin E isomers, delta-tocotrienol (DT3) and gamma-tocotrienol (GT3), was evaluated in male and female CD2F1 mice. In an acute toxicity study, a single dose of DT3 or GT3 was administered subcutaneously in a dose range of 200 to 800 mg/kg. A mild to moderately severe dermatitis was observed clinically and microscopically in animals at the injection site at doses above 200 mg/kg. The severity of the reaction was reduced when the drug concentration was lowered. Neither drug produced detectable toxic effects in any other tissue at the doses tested. Based on histopathological analysis for both DT3 and GT3, and macroscopic observations of inflammation at the injection site, a dose of 300 mg/kg was selected as the lowest toxic dose in a 30-day toxicity study performed in male mice. At this dose, a mild skin irritation occurred at the injection site that recovered completely by the end of the experimental period. At a dose of 300 mg/kg of DT3 or GT3, no adverse effects were observed in any tissues or organs.

scholarly journals Toxicity assessment of gelsenicine and the search for effective antidotes

2022 ◽  
Vol 41 ◽  
pp. 096032712110628
Author(s):  
Yu-Juan Li ◽  
Kun Yang ◽  
Xue-Ming Long ◽  
Gang Xiao ◽  
Si-Juan Huang ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Toxic Substance ◽  
Organ Damage ◽  
Toxicity Assessment ◽  
Toxicity Study ◽  
Female Rats ◽  
Male Rats ◽  
Acute Toxicity Study ◽  
Toxicity Mechanisms ◽  
Toxic Alkaloids

Background Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth ( G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. Objective This study aimed to analyse the toxicity characteristics of gelsenicine. Methods Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. Results In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. Conclusions Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine -related poisoning and its toxicity mechanisms.

scholarly journals Intra-Herb Interactions: Primary Metabolites in Coptidis Rhizoma Extract Improved the Pharmacokinetics of Oral Berberine Hydrochloride in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Zhao ◽  
Ting Zhou ◽  
Jing-Ze Lu ◽  
Dan Ye ◽  
Sheng Mu ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Malic Acid ◽  
Choline Chloride ◽  
Cell Monolayer ◽  
Weight Ratio ◽  
Plant Metabolites ◽  
Primary Metabolites ◽  
Berberine Hydrochloride ◽  
Natural Deep Eutectic Solvents ◽  
Coptidis Rhizoma

Primary plant metabolites can be used for artificial preparation of natural deep eutectic solvents (NADESs), which have strong dissolving capacity, good biocompatibility, and biodegradability. In this study, for the first time, we verified that NADESs were present in Coptidis Rhizoma extract and systematically investigated its effects and mechanisms on the pharmacokinetics of oral berberine hydrochloride (BBR), a co-existing bioactive constituent. First, three LC-MS/MS based methods were established and fully validated to determine the levels of 11 primary metabolites in Coptidis Rhizoma extract. According to the weight ratio of four major primary metabolites in the Coptidis Rhizoma extract, a stable “endogenous” NADES was prepared using the heating method by the addition of 350 μl of water to 1,307.8 mg of the mixture of malic acid (490.5 mg), glucose (280.6 mg), sucrose (517.7 mg), and choline chloride (19.0 mg). The prepared NADES showed significant acute toxicity in mice and cytotoxicity in MDCK-MDR1 cells. However, after being diluted 10 times or 100 times, the NADES had no significant acute toxicity or cytotoxicity, respectively. The dilutions of the NADES significantly increased the water solubility of BBR, reduced its efflux in gut sacs and MDCK-MDR1 cell monolayer, and improved its metabolic stability in intestinal S9. In addition, the NADES dilutions reversibly opened the tight junctions between the enterocytes in the gut sacs. Moreover, the NADES dilutions significantly improved the exposure levels of BBR in the portal vein and livers of mice that were administered oral BBR. Malic acid was identified as a major component in the NADES in terms of solubility, acute toxicity, cytotoxicity, and pharmacokinetic-improving effects on oral BBR. In conclusion, the primary metabolites of Coptidis Rhizoma extract could form “endogenous” NADES, and its dilutions improve the pharmacokinetics of oral BBR. This study demonstrates the synergistic interaction of the constituents of Coptidis Rhizoma extract and the potential use of the NADES dilutions in oral BBR delivery.

scholarly journals Antisnake Venom Activity ofHibiscus aethiopicusL. againstEchis ocellatusandNaja n. nigricollis

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
S. S. Hasson ◽  
A. A. Al-Jabri ◽  
T. A. Sallam ◽  
M. S. Al-Balushi ◽  
R. A. A. Mothana
Keyword(s):  
Acute Toxicity ◽  
Protective Effect ◽  
Snake Venom ◽  
Guinea Pigs ◽  
Muscle Cells ◽  
Endogenous Inhibitor ◽  
Abnormal Behaviour ◽  
Cytotoxic Effects ◽  
Neutralization Activity ◽  
Lethal Dosage

The objective of the study is to investigate whether theHibiscus aethiopicusL. plant has neutralization activity against venoms of two clinically important snakes. TheH. aethiopicuswas dried and extracted with water. Different assays were performed to evaluate the plant's acute toxicity and its anti-snake venom activities. The results showed thatH. aethiopicusextract alone had no effect on the viability of C2C12muscle cells, but significantly (P<.05) protected muscle cells against the toxic effects ofE. ocellatusvenom at 55, 150, and 300 μg/mL. The maximum protective effect of the extract was exhibited at 75 μg/mL. The extract significantly (P<.001) inhibited the cytotoxic effects ofE. ocellatusvenom at 300 μg/mL. All rabbits (n=10) and guinea pigs (n=10) were alive after the two weeks of given the lethal dosage 16 g/Kg of theH. aethiopicusextract herbal solution. No abnormal behaviour was observed of both groups of animals. All guinea pigs (n=3) treated with venoms alone (5 mg/kg) died. However, all guinea pigs (n=21) treated with venom (5 mg/kg) and the extract (400 to 1000 mg/kg) survived. Guinea pigs (n=3) treated withNaja n. nigricollisvenom alone (2.5 mg/kg) and guinea pigs (n=21) venom with the extract (400 to 1000 mg/kg) died. TheH. aethiopicuscompletely (100%) blocked the haemorrhagic activity ofE. ocellatusin the egg embryo at 3.3 mg/mL of extract. These findings suggest thatH. aethiopicusmay contain an endogenous inhibitor of venom-induced haemorrhage.

Quantitative Diameter Measurements of Chromatin and TMV Fibers in the Freeze-Dried State

1988 ◽  
Vol 46 ◽  
pp. 170-171
Author(s):  
B. D. Athey ◽  
A. L. Stout ◽  
M. F. Smith ◽  
J. P. Langmore
Keyword(s):  
Reliable Method ◽  
Fiber Diameter ◽  
Quantitative Agreement ◽  
One Dimension ◽  
Fiber Axis ◽  
Two Dimensional ◽  
Fiber Density ◽  
Variable Diameter ◽  
Freeze Dried ◽  
Expected Values

Although there is general agreement that Inactive chromosome fibers consist of helically packed nucleosomes, the pattern of packing is still undetermined. Only one of the proposed models, the crossed-linker model, predicts a variable diameter dependent on the length of DNA between nucleosomes. Measurements of the fiber diameter of negatively-stained and frozen- hydrated- chromatin from Thyone sperm (87bp linker) and Necturus erythrocytes (48bp linker) have been previously reported from this laboratory. We now introduce a more reliable method of measuring the diameters of electron images of fibrous objects. The procedure uses a modified version of the computer program TOTAL, which takes a two-dimensional projection of the fiber density (represented by the micrograph itself) and projects it down the fiber axis onto one dimension. We illustrate this method using high contrast, in-focus STEM images of TMV and chromatin from Thyone and Necturus. The measured diameters are in quantitative agreement with the expected values for the crossed-linker model for chromatin structure

Detection of viruses by electron microscopy: Increased sensitivity by direct micro-ultracentrifugation of samples

1987 ◽  
Vol 45 ◽  
pp. 908-909
Author(s):  
Alain R. Trudel ◽  
M. Trudel
Keyword(s):  
Electron Microscopy ◽  
Fold Increase ◽  
Observation Time ◽  
Clinical Samples ◽  
Maximum Speed ◽  
Viral Particles ◽  
Structural Details ◽  
Latex Spheres ◽  
Increased Sensitivity ◽  
Size Of Particles

AirfugeR (Beckman) direct ultracentrifugation of viral samples on electron microscopy grids offers a rapid way to concentrate viral particles or subunits and facilitate their detection and study. Using the A-100 fixed angle rotor (30°) with a K factor of 19 at maximum speed (95 000 rpm), samples up to 240 μl can be prepared for electron microscopy observation in a few minutes: observation time is decreased and structural details are highlighted. Using latex spheres to calculate the increase in sensitivity compared to the inverted drop procedure, we obtained a 10 to 40 fold increase in sensitivity depending on the size of particles. This technique also permits quantification of viral particles in samples if an aliquot is mixed with latex spheres of known concentration.Direct ultracentrifugation for electron microscopy can be performed on laboratory samples such as gradient or column fractions, infected cell supernatant, or on clinical samples such as urine, tears, cephalo-rachidian liquid, etc..

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