Pulmonary system evaluation

Inhalation of fibrous materials with evaluation of acute and chronic toxicity and carcinogenicity on the pulmonary system. 

Morimoto, K., Katsumata, H., Yabuta, T., et al. (2000). Gelatin microspheres as a pulmonary delivery system Evaluation of salmon calcitonin absorption. J. Pharm. Pharmacol., 52, 611-617. 

Tests of pulmonary function are useful tools for evaluating the potential for compounds to produce toxicity affecting the pulmonary system. Insults to the pulmonary system (i.e., due to drugs, biologies, toxins) can cause detectable dysfunction through multiple mechanisms. Manifestation of the response to insults will depend on the component(s) involved and the compensatory mecha-nism(s) initiated. The purpose of this chapter is to introduce the concepts of pulmonary testing as it is applied to the preclinical evaluation of pharmaceutical test articles. The topics will include the techniques and methods that have been developed for use in nonclinical (animal) subjects and the parameters that are routinely measured. 

Functional evaluations of cardiovascular and pulmonary systems could be incorporated into a non-human primate multi-dose toxicity study. If appropriate, potential reproductive toxicity can be evaluated in a non-human primate. 

Yamamoto A, Tanaka H, Okumura S, Shinsako K, Ito M, Yamashita M, Okada N, Fujita T, Muranishi S (2001) Evaluation of insulin permeability and effects of absorption enhancers on its permeability by an in vivo epithelial system using Xenopus pulmonary membrane. Biol Pharm Bull 385-389... 

Too often results are compromised by a poor experimental set-up of the studies and nontransparent data. Even essential information such as the relevant physicochemical characteristics of the drug in relation to the chosen aerosol system or the fraction that is deposited in the alveoli is often not provided. This makes it impossible to evaluate the impact of such studies. As a result, it is unclear until now to what extent and at what rate macromolecular drugs (> 20 kDa) can be absorbed by the lung. Moreover, the routes by which macromolecules pass through the different pulmonary membranes, especially the alveolar membrane, are unknown. Appropriate experiments and models that provide adequate answers to these questions are required in the coming years. 

Exposed individuals with evidence of central nervous system depression or seizures should be evaluated for the presence of some other underlying disorder. Diazepam or phenobarbital may be administered to alleviate seizures. Supplemental oxygen can also be administered. If pulmonary edema occurs, conventional therapy should be considered. Additional information regarding the treatment of individuals exposed to cresols may be obtained from Bronstein and Currance (1988), Haddad and Winchester (1990), and Stutz and Janusz (1988). 

The therapeutic efficacy of either systemic or local pulmonary delivery of the IFN-y gene was evaluated in a murine allergen-induced airway hyperresponsiveness (AHR) model (Dow et al. 1999) and it was found that a high efficiency of gene transfer could be achieved. Intratracheal administered cationic liposomes were prepared from a mixture of l,2-diacylglycero-3-ethylphosphocholine (EDMPC) and cholesterol. Intravenous injections were prepared from l,2-dioleyl-3-trimethylammo-ninm propane (DOTAP) and cholesterol and compared with pulmonary administered... 

The use of iloprost has been proposed in patients with systemic sclerosis, a disease that is often characterized by pulmonary hypertension and Raynaud s phenomenon. Three patients with systemic sclerosis who were treated with iloprost developed acute thrombotic events (3). In one case, intestinal infarction occurred 1 day after infusion of iloprost. In another patient the left kidney was not perfused 22 days after the last infusion of iloprost because of thrombosis of the left renal artery. The last patient, 9 months after the start of treatment with iloprost, and 5 days after the last infusion, had an anterolateral myocardial infarction. The authors commented that their observations did not allow them to conclude that there is a direct relation between infusion of iloprost and thrombotic events. However, they said that this possibility should be considered, and they suggested that risk factors for thromboembolism should be carefully evaluated in each patient with systemic sclerosis who is receiving iloprost. 

The above radiopharmaceuticals have been used to evaluate the pulmonary MAO system and for detecting lung injury at an early stage preceding clinical symptoms493,494. 

More broadly, timolol therapy should be considered with caution in patients with any significant sign, symptom, or history for which systemic beta-blockade would be medically imwise.This includes disorders of cardiovascular or respiratory origin (e g., asthma, chronic bronchitis, and emphysema) as well as many other conditions. Spirometric evaluation after institution of timolol therapy may help to identify patients in whom bronchospasm develops after commencement of therapy. In general, however, patients with asthma and other obstructive pulmonary diseases should avoid this drug. Sympathetic stimulation may be essential to support the circulation in individuals with diminished myocardial contractility, and its inhibition by P-adrenoceptor antagonists may precipitate more severe cardiac feilure. 

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