Administration route reproducibility

Signs of disulfoton toxicity, such as muscle tremors, fasciculations, lacrimation, and salivation, in animals are generally observed after a few daily doses, but begin to diminish in severity as exposure to dislllfoton continues (Bombinski and DuBois 1958). This phenomenon is known as tolerance. Tolerance appears to be a reproducible phenomenon that does not depend on the organophosphate insecticide used, the route of administration, or the animal species (Costa et al. 1982b). Several possible mechanisms have been proposed /explain this phenomenon. 

With regard to the systemic administration of smaller proteins (<20 kDa), the development of insulin for inhalation has shown that the pulmonary route is a feasible route of administration. However, advanced inhalation devices and formulations were required to obtain a reproducible lung deposition. It will be especially necessary to deal with the problems that occur when drugs with a small therapeutic window are administered. To enable widespread use of the lung as port of entry for these small proteins, future developments should be directed towards more simple inhalation devices which still give a high and reproducible lung deposition. The formulations that will be required for these proteins are likely to be much more complex and advanced than those that are currently used. Examples are formu-... 

Regardless of the chemical tested and whether the test is for acute or chronic toxicity, all in vivo testing requires the reproducible administration of a known dose of the chemical under test, applied in a reproducible manner, that is generally related to the expected route of humans exposure. The nature and degree of the toxic effect can be... 

The vagina is a possible site for the systemic administration of various drugs. However, the low and erratic bioavailability of biopharmaceuticals via this route necessitates the use of absorption enhancers. Until safe, non-toxic absorption enhancers can be found, the route is of limited potential. A further major limitation of this route is the lack of reproducibility resulting from cyclic changes in the reproductive system. Finally, no matter what degree of optimization can be achieved via this route, it can only ever benefit approximately 50% of the population ... 

FIGURE 15 (a) Nasal administration of 100 U of (A) enoxaparin, (B) dalteparin, or (C) UFH formulated with ( ) and without (O) 0.25% tetradecylmaltoside. Data represent mean + SEM, n = 3. Asterisks indicate results that are significantly different from those obtained with the drug formulated with saline, P < 0.05. (b) Administration of 100U of enoxaparin via the subcutaneous (A), intravenous ( ), and nasal (O) routes. Nasal administration was performed with a formulation that included 0.25% TDM. Data represent mean SEM, n = 3. (Reproduced from ref. 83 with permission of John Wiley Sons.)... 

Reproduced from S. J. Farr et al., in Routes of Drug Administration (ed. A. T. Florence and E.G. Salole), Wright, London, 1990. 

As our primary test model we initially decided that we had to stay with the rat PCA screen. However, since we were now interested in orally effective compounds we studied the activity of the chromones following their administration either directly into the stomach or into the intestine of the animals, the latter following anaesthetisation and laparotomy. Experience showed that the results obtained on intra-duodenal dosing were much more reproducible than those obtained by straight oral dosing and so for a number of years we have used this route of drug administration to determine the likely oral activity of our compounds. 

To achieve the desired therapeutic effect of an active substance, an adequate administration form in relation to the chosen route of administration must be used. The current pharmaceutical-teclmological knowledge offers possibilities to achieve optimal absorption of an active substance. Optimal in this cOTitext means reliable, with a reproducible fraction absorbed and, if necessary, with a desired control of the release profile. Already small variations in excipients may significantly influence the pharmaceutical and biological availability and hence the therapeutic and adverse effects of a medicine. This applies to systemic as well as local administration. Furthermore, it is to be realised that the equivalence of these aspects may be of paramount importance for generic substitution. 

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