THE IMPACT OF INCOMPLETE ACUTE TOXICITY STUDY IN EXPERIMENTAL PHARMACOLOGY: THE BASIC TECHNIQUE IN THE DEVELOPMENT OF UNKNOWN PRODUCTS INTO PHARMACEUTICAL ONE

Yilkal Belay

School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda

Abstract

Testing for acute toxicity is the basic technique in experimental pharmacology in which test substances and product types are routinely investigated as a regulatory requirement in order to ensure public health safety. There are a wide range of substances with different nature of toxicity in which the onset of its toxic effect in the organism has also different time limit. The pharmaco-toxicological property of ethanol and ether crude extracts from the dried seeds of Aristolochia elegans. Mast at different concentrations were therefore bioassayed on 45 Balb c mice for a maximum period of 10 days for each dose administered orally. There was no signs and symptoms of adverse effect observed in the laboratory mice which was given a single dose of both crude extracts at 1000-5000mg/kg for the first 3-4 days. However, the appetite of these mice was gradually depressed and they eventually died within 4-9 days after the dose was given orally. All treated mice died as if they were sleeping peacefully without any painful movement against the death. The length of time at which lethal effect was observed on sampled mice was dose related and its adverse effect becomes manifested within a short period of time when large amounts were administered. The effect of these crude extracts also remained after a long period of time when small amounts were administered in the same route. The physio-pathological development of test extracts on Balb c mice were similar to that of adrenocortical steroids (endocrine drugs) which causes permissive side effects on humans. The effects of both crude extracts on visceral organs were also investigated by histopathologic examination. All the sections from the kidney of the mice revealed marked degeneration and necrosis of tubular epithelial cells. Hyaline casts were observed in the lumen of the tubules. Focal parenchymal hemorrhages were also observed. The lesions were all similar with minor variations in their severity. Section from the liver showed mild to moderate hepathocellular degeneration and vacuolar to fatty degeneration with hepathocellular necrosis of individual cells. In general, the liver damage was less severe than the kidney damage. Hemorrhages in the stomach were seen in four out of ten mice. The dose had never limited the lethal effect of test extracts but the length of time at which its effect was observed in the exposed Balb c Mice. This means that the undesired effect of test substances were rather dependant on toxic reaction rate in the biology of Bulb c Mice which ultimately determined the toxic severity of test extracts. The toxic severity (s) is the toxic reaction rate (r) of test substance per administered dose (d) and multiplied by 100 which is expressed in percentage . The toxic severity of 1 - 3 ^g and 4 - 5 ^g of test extracts was (0.0002+ and 0.0003+) %/sec respectively. The toxic reaction rate (r) of test substance is the administered dose (d) over the period of time (t) up to which undesired effect was observed minus the immunological changes due to toxic counter response . The toxic reaction rate 'r' was (0.0145+, 0.0116+, 0.0069+, 0.0039+, and 0.0017+) ^mg/sec for the administered doses (5, 4, 3, 2 and 1) ^g respectively. The extra result of r was because of the dual effect, toxicity and immune depressant, of test extracts in which quantitative data for immunological changes had never been recorded. If toxic reaction rate (r) was ≤ 0, test extract would have been safe for life. But since it was > o, it has eventually caused death to Balb c Mice and it could cause disability or death at some stage in the life span of another organism with similar immunological fate. The lecture will also discuss acute toxicity study as the basic primary technique for comprehensive pharmacological characterization of test substances from its effect developed in the biology of an organism. An effort will also be made in the next study to investigate these pharmacologically active substances whether it could reverse carcinogenesis as it did degeneration of somatic cells which is likely to have pharmaceutical importance to develop chemotherapy for localized tumor treatment.

Keywords: Acute toxicity tests, Histopathologic examination, toxic reaction rate, toxic severity.

REFERENCE

www.atmph.org/text.asp?2011/4/1/33/80534