Life-time inhalation studies

Here again we have the problem of extrapolation but at least from a whole animal. In the whole animal, as in man, the multiple processes of metabolic activation and inactivation, and cellular interactions can occur and result in observable disease which is not the case in isolated cells. Therefore, why have we not been very successful in these types of studies Firstly, only a few life-time inhalation studies have been completed. Secondly, there has been only a limited success in developing animal models for human diseases, pulmonary and otherwise. We are interested in those diseases which are most likely to be associated with the inhalation of incompletely combusted plant and/or animal material. These diseases include lung cancer, emphysema, chronic bronchitis and cardiovascular disease. 

The half-life of 2-hexanone and its metabolites in blood plasma has not been established however, elimination from the body does appear to occur in less than 24 hours following both inhalation and ingestion exposures (DiVincenzo et al. 1977, 1978). 2-Hexanone is not known to accumulate over time in any tissues in the body (see section 2.3.4). While elimination enhancement through stimulation of metabolism of 2-hexanone may reduce some forms of toxicity, if used within the short time that 2-hexanone is retained in the body, there is the risk that these same metabolic reactions may form reactive metabolites such as 2,5-hexanedione. Furthermore, concurrent exposures to other substances may also occur for which stimulation of these same metabolic pathways is contraindicated. Therefore, the benefit of stimulating specific metabolic pathways to enhance 2-hexanone elimination is unclear and should be studied further. 

CS is rapidly absorbed and distributed throughout the body after inhalation exposure. Pharmacokinetic studies show that CS is removed from circulation quickly with first-order kinetics, following inhalation exposure. CS half-life is just under 30 s (Olajos, 2004). Short half-lives in the circulatory system are also demonstrated for the major CS metabolites (2-chlorobenzyl malononitrile and 2-chlorobenzaldehyde) (Leadbeater, 1973). Currently, it is thought that significant amounts of CS, near the tolerable concentration around 10 mg/m, would not be absorbed following CS inhalation. The absorption of CS from the digestive tract in cases of exposure by ingestion is unknown at this time. Systemic toxicity... 

Pharmacokinetics After Oral and Intravenous Administration. For proper characterization of an inhalation drug, information on the systemic pharmacokinetic properties needs to be provided. One of the major challenges for such studies is to provide a suitable formulation for injection, especially because new drug candidates are often very lipophilic. The resulting parameters of such studies (systemic clearance, volume of distribution, half-life, mean residence time) can then easily be extracted from concentration-time profiles after IV administration and subsequent standard pharmacokinetic analysis by noncompartmental approaches. In addition, a detailed compartmental analysis based on concentration-time profiles will be useful in evaluating the systemic distribution processes in sufficient detail. This will be especially important if deconvolution procedures (see later) are included for the assessment of the pulmonary absorption profiles. 

The carcinogenicity of inhaled NDMA has been evaluated in two studies. Twice weekly 30-minute exposures to 50 or 100 ppm NDMA vapor for life produced malignant nasal cavity tumors in rats (Druckrey et al. 1967). The incidence of tumors was 67% in each group, and the time to induce tumors in 50% of the rats was 400 days. Group sizes were small (12 and 6 animals at 50 and 100 ppm, respectively), control data were not reported, and additional information regarding longevity was not provided. The 50 ppm concentration is included in Table 2-1 and Figure 2-1 as an effect level for cancer (cancer effect level, CEL) in rats due to intermittent inhalation exposure of chronic duration. 

Recombinant human DNase has been approved for use in CR When given by inhalation (2.5 mg once or twice daily), recombinant human (rh) DNase reduces the viscosity of CF sputum and leads to statistically significant, though modest, improvement in pulmonary function. More important, the regular use of rhDNase may help to decrease the incidence of (or lengthen the time between) respiratory exacerbations and thereby improve quality of life and indirectly decrease the overall costs of care in patients with mild to moderate disease. Should these outcomes be borne out in additional long-term studies, especially before the onset of clinical symptoms, this therapy may be justified as a way to prevent or delay the progression of pulmonary disease. 

Krypton-8Im is inhaled during studies to measure lung ventilation. Its half-life is only 13 seconds. How much time has passed before a sample of krypton-8Im with an original activity of 260 decays per minute has decreased to an activity of 8 decays per minute ... 

At that time we considered our stock data on anti-asthmatic compounds from experimental asthma studies in humans. Thus, we knew that mono- and bischromones were highly active by inhalation, but that none of the compounds which we had prepared up to that time were orally effective. This lack of oral activity was, we decided, due to the high polarity and low lipophilic character of the chromone derivatives that we had prepared up to that time. For example, cromolyn had a pKa of about 1.5 and an octanol/water (pH 7.4 aqueous buffer) log D value of about -3.5. Such a compound would be expected to have a very poor absorption profile. This was reflected in its short plasma half-life following intravenous administration and the fact that its plasma levels following oral administration in a number of species were extremely low ( ). 

---