The use of large number of animals for determination of median lethal dose LD 50 has been discouraged worldwide [ 20 ]. Hence, based on the principle of R3 Reduction, Refinement and Replacement , the number of animals for LD 50 determination has been reduced to 2—6 animals [ 6 ]. The inherent variability, lack of predictive validity and lack of reliability of experimental animal models and conflicting clinical reports on therapeutic indices, safety margins and lethal times of some psychostimulants, psychotomimetics and snake antivenoms have necessitated the need to revise the current therapeutic index and safety margin formulas.
Literatures from journals published by Elseviers, Springer, Springer Nature, Sage, Tailor and Francis, Wiley and other publishers were searched for reports on LD 50 of amphetamine, dextroamphetamine, lysergic acid diethylamide, potassium permanganate, Abrus precatorius and tetrahydroxycannonbinol in dog, rabbit, mouse, human and rat, respectively. The d-tubocurarine has been reported to counteract their effects to some levels.
However the reported LD 50 and ED 50 of some snake venoms and antivenoms were used for the study. The formulas used in determination of LD 50 for snake venom with effective dose fifty ED 50 divided by the denominator 3 as well as other related formulas, were incorporated into derived therapeutic index, lethal time and margin safety formulas [ 3 — 27 ].
The derivations are as follow:. Substitute for LD 50 in Eq. Remember Eq. So, integrate Eqs. But if D can kill one animal as shown in Eq. The formulas were used to calculate LD 50 , ED 50 , LT 50 , LD 1 , ED 99 , therapeutic index TI and safety of margin for all the reported antidotes for snake envenomation, Abrus precatorius , lysergic acid diethylamide, tetrahydroxycannabinol, amphetamine, methamphetamine, dextroamphetamine and potassium permanganate poisoning.
All the LT 50 in hour and minute should be converted to second. The LD 50 , ED 50 , LT 50 , LD 1 , ED 99 , dose of toxicants, therapeutic index and safety margin of amphetamine, dextroamphetamine, methamphetamine, lysergic acid diethylamide, tetrahydroxycannabinol, potassium permanganate and Abrus precatorius are presented in Table 1. Consroe et al. Side effects, adverse drug reactions, untoward effects, side toxicity and idiosyncratic effects associated with drugs may be due to normal dose, under dose or drug over dose [ 5 , 28 ].
The calculated therapeutic index of amphetamine 2. However, the previously established formula yielded very high therapeutic index for LSD The findings agree with the report indicating that the conventional formula for calculation of therapeutic index is not a truthful measure of safety of a drug in clinical setting [ 10 ].
The low therapeutic index of 0. Very low therapeutic index 0. The associated toxicity signs are rapid shallow respiration, diarrhea, gastroenteritis, liver and kidney damage and death. The low therapeutic index 0. This may be due to presence of toxic principle called abrin [ 29 ].
However, the relatively high therapeutic index of The therapeutic index for LSD using the conventional 15 and new formula 0. However d-tubocurarine can alleviate toxicity effects of amphetamine, dextroamphetamine, methamphetamine [ 26 ], Abrus precatorius [ 30 ], tetrahydroxycannabinol [ 31 ], potassium permanganate [ 32 ], and lysergic acid diethylamide [ 33 ].
The dose-toxicity response pattern in graded fashion may culminate in LD 50 and could be counteracted by therapeutic dose This explains individual variation of susceptibility to doses of toxicants as proven by low therapeutic index 0. The low to high therapeutic indices of all the snake antivenoms in the present study indicate that, treatments of snake envenomation is by toxin neutralization, using specific antidotes for specific snakes [ 8 ].
The obtaining of therapeutic index 0. Therefore one vial of the relevant antivenom is sufficient for the circulating venom, but recovery time may be delayed, because many clinical and laboratory effects are not reversed immediately [ 35 ].
Hence clinical trials of antivenoms are potentially more important and useful [ 36 ]. Pain score of more than two 2 requires additional antivenom and patient should be frequently assessed [ 37 ] for improvement. Therefore, there is need for clinicians and laboratory toxicologists to improve therapeutic knowledge of snake envenomation [ 38 ]. Cardio-respiratory distress, coagulopathy and swelling in the first hours of admission are poor prognostic signs associated with weak therapeutic response to snake envenomation [ 39 ].
Effective dose 99 7. Therefore, more purified and specific antivenoms are required to avoid post-treatment reactions [ 41 ], suggesting that polyvalent antivenom may be less effective against neurotoxic snake bite [ 42 ], translating to required 30 vials of antivenom [ 43 ].
Paraspecific neutralization of snake venom by antivenom could induce coagulopathy in the affected patients [ 44 ]. Efficient, safety and thermal stability have been reported for freeze-dried trivalent antivenom for snake bites in larger phase III trial [ 45 ]. Neither antivenom nor time of its administration affects venom-induced coagulopathy [ 35 ].
Low dose of 20— ml reduced the hospital stay as compared to 40— ml dose, suggesting that the lower the dose of snake antivenom the more effective the antivenom. Fatality rates of Hence, the number of animals for similar study can be reduced [ 5 ].
The LT 50 0. The newly derived formulas yielded low and safer values for therapeutic indices and standard safety margins of drugs, toxicants, venoms, antivenom and other xenobiotics. But the safety of therapeutic agent is dependent on dose, lethal time, body weight, frequency and time of administration and safety factor of the drug.
The calculations were based on the findings from experiments conducted in various laboratories across the globe. All the lethal times have to be converted to seconds. The derived formulas were applied on different species of toxic animals and plants.
SAS designed and carried out the study, analyzed the data, wrote and proof read the manuscript. The author read and approved the final manuscript. All data generated or analyzed during this study are included in this published article. Not applicable, because neither animals nor humans were used for the study; the data were generated from earlier few data established in clinics and laboratories. Publisher's Note.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology Information , U. BMC Res Notes. Published online Jun Saganuwan Alhaji Saganuwan. Author information Article notes Copyright and License information Disclaimer.
Saganuwan Alhaji Saganuwan, Email: moc. Corresponding author. As a convenient abbreviation I would suggest for this the symbol LD 50".
To offer a suitable sacrifice for the gods of pharmacology, Trevan generated his LD 50 graph by using data from laboratory mice who were injected with lethal doses of cocaine. Obviously, as with everything, there are some problems with the usefulness of LD 50 as a means of comparing drugs. For example:. The literature seems to use the terms "therapeutic index" and "therapeutic ratio" in a way which might suggest that they are synonymous, even though there is an SAQ in the local anaesthetic primary exam which asked the candidates to interpret each term separately.
Fortunately, CICM examiners have not yet plagiarised this question. In Katzung, the therapeutic index is defined as. The official IUPC documents don't seem to have any sort of gospel answer, and every piece of literature seems to have some arbitrary way of defining this concept.
These pharmacologists' authority as experts Wiley gave them a chapter from their Encyclopedia of Clinical T rials suggests that one should at least be vaguely aware of how they define this concept:.
All of these variants are probably valid on some level, but the exam-going CICM trainee would probably be better off treating Katzung as the definitive official source for this sort of thing. As such, the von Zastrow definition is used for the purposes of the diagrams here. For real-life bedside clinical purposes, this therapeutic index concept leaves much to be desired.
In contrast, Birkett called this a therapeutic range , and describes it using an example rather than offering any exam-worthy definition. The therapeutic range, he says, is the range of drug concentrations " which gives a therapeutic effect The concept of the "therapeutic window" is perhaps more reasonable and flexible than the therapeutic index.
Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins. Neumann, E. Native albumin for targeted drug delivery.
Public Health Advisory — Pergolide marketed as Permax. Kvernmo, T. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Thalamas, C. Pergolide: multiple-dose pharmacokinetics in patients with mild to moderate Parkinson disease. Mano, Y. Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2.
Drug Dispos. Clozel, M. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist.
Dawson, S. In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. International Transporter Consortium. Membrane transporters in drug development. Company: G. Application No. Dajani, E. Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man. PubMed Google Scholar. Download references. The authors would like to thank B. Schmouder, L.
Urban, P. Bouchard, P. Hoffmann, P. Heining and V. Jarugula for their valuable input and in-depth interdisciplinary discussions on this topic. Patrick Y. Muller and Mark N. You can also search for this author in PubMed Google Scholar. Correspondence to Patrick Y. Reprints and Permissions. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 11, — Download citation.
Published : 31 August Issue Date : October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Nature Reviews Chemistry Scientific Reports International Journal of Peptide Research and Therapeutics Parasitology Research In Silico Pharmacology Advanced search.
Skip to main content Thank you for visiting nature. Abstract A key part of drug discovery and development is the characterization and optimization of the safety and efficacy of drug candidates to identify those that have an appropriately balanced safety—efficacy profile for a given indication.
Access through your institution. Buy or subscribe. Rent or Buy article Get time limited or full article access on ReadCube.
0コメント