Methods for Route-To-Route Extrapolation of Dose

Results of acute toxicity studies for a variety of chemicals have indicated that, in most cases, although the inhalation route was more effective than the IG route, wide variations in toxicity occurred between these two routes. The major factors that may result in variations in toxicity between routes include: (1) differences in absorption efficiency; (2) differences in systemic effects; (3) occurrence of critical toxicological effects at the portal of entry; (4) first-pass effects resulting in inactivation or activation of the chemical agent before it reaches the target organ; and (5) variations in temporal patterns of target organ concentrations. Extrapolation to determine safe exposure levels during chronic exposure becomes less reliable, not only as information relating to these factors decreases, but also as the quality or length of exposure decreases in the available toxicologic studies. VDC is an example of one of a few chemicals for which both chronic inhalation and oral toxicity data are available, along with detailed pharmacokinetic information. On the basis of the pharmacokinetic data, differences in toxicity between the two routes did not appear to be very likely for this chemical. This conjecture was supported by the results of chronic toxicity studies. Finally, assuming sufficient data and pharmacokinetic parameters are available, this paper presents a useful and practical approach to route extrapolation.

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Bioactive Composition and Acute Oral Toxicity Studies on Persea Americana Seed Ethyl Acetate Fraction

Asian Journal of Research in Biochemistry ◽

10.9734/ajrb/2021/v8i430186 ◽

2021 ◽

pp. 10-17

Author(s):

E. S. Asiwe ◽

C. U. Igwe ◽

K. M. E. Iheanacho ◽

I. O. Onyeocha ◽

V. A. Onwuliri

Keyword(s):

Acute Toxicity ◽

Ethyl Acetate ◽

Ethyl Acetate Fraction ◽

Persea Americana ◽

Export Market ◽

Oral Toxicity ◽

Toxicological Effects ◽

Phytochemical Composition ◽

Toxicity Studies ◽

Flame Ionization

Aims: Persea americana (P. americana) dubbed ‘green gold’ is a highly sought after fruit today, with insatiable export market. Different parts of avocadoes have been consumed both for nutritional and health benefits across regions of the world. Therefore, this study investigates the bioactive composition of P. americana seed ethyl acetate fraction and acute toxicological effects. Place and duration of study: Department of Biochemistry, Federal University of Technology Owerri, Imo State, Nigeria; between May 2019 and October, 2019. Methodology: Quantitative phytochemical composition was assessed using gas chromatography fitted with flame ionization detector (GC-FID) and acute toxicity determined using standard method. Results: Result of quantitative phytochemical composition of P. americana seed fraction shows a rich presence of phytochemicals such as epicatechin, kaempferol, proanthocyanin, rutin, resveratrol, ribalinidine, naringin, spartein, quinine, flavan-3-ol, anthocyanin, lunamarin, sapogenin, flavonones, flavones. The quantitative phytochemical composition of P. americana seed shows that among other phytochemicals, the seed is relatively rich in anthocyanin, quinine, epicatechin, tannin and proanthocyanin with concentrations of 69.39 ± 8.33 µg/g, 22.16 ±1.77 µg/g, 21.88 ± 2.53 µg/g, 19.86 ± 1.19 µg/g and 10.98 ± 0.55 µg/g respectively. The acute toxicity studies on the seed reveal that the ethyl acetate fraction of P. americana seed did not elicit any lethal signs of morbidity and mortality at doses up to 5000mg/Kgb.wt. and are therefore considered generally safe. Conclusion: P. americana seed ethyl acetate fraction contains essential phytochemicals with useful phyto-medicinal and nutraceutical benefits. The implications of these findings are further discussed.

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Structured Data Entry for Reliable Acquisition of Pharmacokinetic Data

Methods of Information in Medicine ◽

10.1055/s-0038-1634673 ◽

1996 ◽

Vol 35 (03) ◽

pp. 261-264 ◽

Cited By ~ 3

Author(s):

T. Schromm ◽

T. Frankewitsch ◽

M. Giehl ◽

F. Keller ◽

D. Zellner

Keyword(s):

Text Processing ◽

Data Entry ◽

Processing System ◽

Database System ◽

Structured Data ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Probability Of Error ◽

Error Frequency ◽

Estimated Error

Abstract:A pharmacokinetic database was constructed that is as free of errors as possible. Pharmacokinetic parameters were derived from the literature using a text-processing system and a database system. A random data sample from each system was compared with the original literature. The estimated error frequencies using statistical methods differed significantly between the two systems. The estimated error frequency in the text-processing system was 7.2%, that in the database system 2.7%. Compared with the original values in the literature, the estimated probability of error for identical pharmacokinetic parameters recorded in both systems is 2.4% and is not significantly different from the error frequency in the database. Parallel data entry with a text-processing system and a database system is, therefore, not significantly better than structured data entry for reducing the error frequency.

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Acute and subacute toxicity assessment of Madhulai Manappagu (Siddha herbal syrup formulation) in animal model

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2020-0327 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Meenakshi Sundaram Malayappan ◽

Gayathri Natarajan ◽

Logamanian Mockaiyathevar ◽

Meenakumari Ramasamy

Keyword(s):

Body Weight ◽

Acute Toxicity ◽

Oral Route ◽

Toxicity Assessment ◽

Toxicity Study ◽

Female Rats ◽

Albino Rats ◽

Oral Toxicity ◽

Gross Pathology ◽

Toxicity Studies

Abstract Objectives Madhulai Manappagu – a well-known sastric and widely prescribed Siddha herbal syrup formulation indicated for treating Veluppu Noi (Anaemia especially Iron deficiency Anaemia) has been in day today practice in Tamil Nadu for a quite longer decades. The syrup is a herbal preparation which has a sweet pleasant odour and a palatable taste, contain the juice of pomegranate (Punica granatum L.) as the main ingredient. Though the formulation is a fruit juice, the safety profile of the syrup is not established and is being marketed without toxicological evaluation. The study is aimed at ascertaining the acute and sub-acute toxicity assessment of Madhulai Manappagu in Wistar Albino rats. Methods The acute and sub-acute (28day repeated oral) toxicity studies were performed as per the guidelines mentioned in the Organization for Economic Cooperation and Development (OECD) 423 (adopted on December 2001) and TG 407 (adopted on October 2008) with slight modifications respectively. For acute toxicity study, three female rats were randomly selected as control; three female rats were randomly selected and were administered a single dose of 5,000 mg/kg body weight per oral route. For sub-acute (28day repeated oral) toxicity studies, three doses of test drug MM of 500 mg/kg/day (low dose), 750 mg/kg/day (intermittent dose) and 1,000 mg/kg/day (high dose) were selected for administration. Both sexes of Wistar Albino rats were randomized into four groups of 10 animals each (five males, five females). Group I was kept as control group. Group II, III and IV served as low, intermittent and high doses of MM respectively. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In the acute toxicity study, rats showed no toxicological signs on behavior, gross pathology and body weight of rats when treated with a single dose of 5,000 mg/kg body weight per oral route. In the subacute (28 days repeated oral) toxicity study, rats have showed no significant changes on behavior, gross pathology, body weight, and hematological and biochemical parameters when treated with Madhulai Manappagu in three different doses. Conclusions The toxicity studies which include both acute and 28 days repeated (subacute) oral toxicity studies, revealed no observed adverse effect level (NOAEL) of Madhulai Manappagu in animals. Thus the safety of the drug in human usage was ensured.

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Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽

10.3390/biom11060909 ◽

2021 ◽

Vol 11 (6) ◽

pp. 909

Author(s):

Yurii A. Zolotarev ◽

Vladimir A. Mitkevich ◽

Stanislav I. Shram ◽

Alexei A. Adzhubei ◽

Anna P. Tolstova ◽

...

Keyword(s):

Molecular Modeling ◽

Mouse Model ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Laboratory Animals ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Bolus Administration ◽

Blood Brain ◽

The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation

Food and Chemical Toxicology ◽

10.1016/j.fct.2006.08.011 ◽

2007 ◽

Vol 45 (2) ◽

pp. 315-321 ◽

Cited By ~ 12

Author(s):

A.G. Schauss ◽

D.J. Merkel ◽

S.M. Glaza ◽

S.R. Sorenson

Keyword(s):

Oral Toxicity ◽

Toxicity Studies

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Relationship between Clinical and Biologic Variables and Chloramphenicol Pharmacokinetic Parameters in Pediatric Patients with Sepsis

Annals of Pharmacotherapy ◽

10.1345/aph.19050 ◽

2000 ◽

Vol 34 (3) ◽

pp. 393-397 ◽

Cited By ~ 6

Author(s):

Gustavo Lugo Goytia ◽

Ismael Lares-Asseff ◽

María Gabriela Pérez Guillé ◽

Adrián Guillé Pérez ◽

Cynthia Larios Mejía

Keyword(s):

Population Model ◽

Pediatric Patients ◽

Care Center ◽

Tertiary Care ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Study Group ◽

Validation Group ◽

Wbc Count ◽

Biologic Factors

OBJECTIVE: To evaluate the influence of several clinical and biologic factors on the disposition kinetics of oral chloramphenicol in pediatric patients and to determine the usefulness of this information to predict chloramphenicol serum concentrations. STUDY DESIGN: The clinical, biologic, and pharmacokinetic data of 30 consecutive pediatric patients diagnosed with sepsis and admitted to a tertiary care center were analyzed retrospectively. The patients were randomly assigned to a study group and a validation group. The model was developed by a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection by stepwise multiple linear regression. The model was tested in the study group and compared with a general population model using a prediction error analysis. RESULTS: Regression analysis revealed that weight, albumin, and white blood cell (WBC) count were the most important determinants for chloramphenicol distribution volume, whereas age, WBC count, and serum creatinine were the most important determinants for chloramphenicol clearance. The performance of the constructed population model improved significantly in terms of both bias and precision compared with the general model when tested in the validation group. CONCLUSIONS: Clinical and biologic factors may significantly influence chloramphenicol's disposition in pediatric patients with sepsis and therefore should be considered in programming dosage regimens.

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