Intratracheal administration

Narayan S, Bajpai A, Tyagi SR, et al. 1985b. Effect of intratracheal administration of DDT and endosulfan on cytochrome P-450 and glutathione-s-transferase in lung and liver of rats. Bull Environ Contam Toxicol 34 55-62. 

In vivo, SWNTs individually dispersed by Pluronic F108NF were demonstrated to be nontoxic after intratracheal administration to mice, whereas aggregated SWNTs caused granuloma-like structures with mild fibrosis in the lungs of the treated animals [39]. 

In summary, intratracheal instillation of CNTs has shown that their potential in eliciting adverse pulmonary effects is influenced by exposure time, CNT dose, CNT biopersistence, surface defects, and metal contamination [71, 72]. Despite the use of surfactants, all studies showed that intratracheal instillation caused major difficulties due to the agglomerative nature of CNTs in a biological environment. More realistic exposure methods, namely inhalation rather than intratracheal administration, are therefore needed for determining the pulmonary toxicity [59, 65, 73]. Several investigations have been performed by using administration different from intra-... 

English, J.C., Parker, R.D.R., R.P. Sharma, and S.G. Oberg. 1981. Toxicokinetics of nickel in rats after intratracheal administration of a soluble and insoluble form. Amer. Indus. Hygiene Assoc. Jour. 42 486-492. 

Hughes MF, Hall LL. 1995. Disposition of phenol in rat after oral, dermal, intravenous, and intratracheal administration. Xenobiotica 25 873-883. 

Sporadic clinical reports, without the support of data from controlled studies, repeatedly indicate the effectiveness of intratracheal administration of parenteral antimicrobial preparations in the treatment of tracheobronchitis and pneumonia in cattle. The expectation when using this route of administration is that a greater therapeutic effect will be achieved when the drug is placed as close to the infection site as possible, rather than relying on the systemic circulation for drug delivery. 

Intratracheal administration of 5-15 mg AAF one to two times per week for 17 months in hamsters (total dose 1100 mg) caused bladder tumors in 10 of 23 animals all mmors were transitional cell carcinomas with or without focal squamous cell carcinomas. ... 

Animal experiments with alumina have shown that the type of reaction in lung tissue is dependent on the form of alumina and its particle size, the species of animal used, and the route of administration. For example, intratracheal administration into rats of y-alumina of 2- j, average size caused only a mild fibrous reaction of loose reticulin. ° However, intratracheal administration of y-alumina of 0.02- to... 

U size into rats produced reticulin nodules that later developed into areas of dense collagenous fibrosis." The latter alumina by the same route in mice and guinea pigs caused development of a reticulin network with occasional collagen, whereas in rabbits only a slight reticulin network was observed. Intratracheal administration of another form of alumina in rats, corundum of particle size less than Ip, caused the development of compact nodules of reticulin. 

Indium arsenide and indium phosphide caused testicular damage in hamsters after repeated intratracheal administration. Both materials decreased reproductive organ weight and caudal sperm count and caused severe histopathologic changes in the testes."... 

Intratracheal administration to guinea pigs of 100 mg of tantalum oxide produced transient bronchitis, interstitial pneumonitis, and hyperemia, but it was not flbrogenic. There were some slight residual sequelae in the form of focal hypertrophic emphysema and organizing pneumonitis around metallic deposits, and there was slight epithelial hyperplasia in the... 

No effects in humans have been reported. Intratracheal administration of 50 mg of yttrium oxide in rats caused granulomatous nodules to develop in the lungs by 8 months. Nodules in the peribronchial tissue compressed and deformed several bronchi the surrounding lung areas were emphysematous, the interalveolar walls were thin and sclerotic, and the alveolar cavities dilated. Intraperitoneal injection... 

Preussmarm, R., Spiegelhalder, B., Eisenbrand, G, Wrirtele, G Hofmarm, I. (1981) Urinary excretion of V-nitrosodiethanolamine in rats following its epicutaneous and intratracheal administration and its formation in vivo following skin application of diethanolamine. Cancer Lett., 13, 227-231... 

Pour, P. Wallcave, L. (1981) The carcinogenicity of A -nitrosodiethanolamine, an environmental pollntant, in Syrian hamsters. Cancer Lett, 14, 23-27 Preussmann, R., Wiirtele, G, Eisenbrand, G Spiegelhalder, B. (1978) Urinary excretion of A -nitrosodiethanolamine administered orally to rats. Cancer Lett, 4, 207-209 Preussmann, R., Spiegelhalder, B., Eisenbrand, G, Wiirtele, G Hofmann, I. (1981) Urinary excretion of A -nitrosodiethanolamine in rats following its epicutaneous and intratracheal administration and its formation in vivo following skin application of diethanolamine. Cancer Lett, 13, 227-231... 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

Even when the appropriate inhaler is chosen, the influence of the disease state cannot be ignored. Disease states can influence the dimension and properties of the airways and hence the disposition of any inhaled drug. Thus, great care must be taken when extrapolating the findings based on intratracheal administration to different animal species in order to predict deposition profiles after inhalation of aerosol formulations by patients suffering from airway disease. DPIs are not appropriate in many diseases when the ability to have sufficient airflow is hindered. Since many diseases that we would like to treat via pulmonary administration of biomolecules cause a decrease in airflow, we must be careful in the decision of which type of inhalation mechanism to choose. 

Machida, M., Hayashi, M., and Awazu, S. (1996). Pulmonary absorption of recombinant human granulocyte colony- stimulating factor (rhG-CSF) after intratracheal administration to rats. Biologic. Pharmaceut. Bull., 19, 259-262. 

The advantages of administration by intramuscular injection are that the muscle can act as a depot, and the rate of disappearance of drug from the site of injection can be calculated. Inhalational, intranasal, and intratracheal administration are normally reserved for vapors and aerosols including anesthetics. Absorption is facilitated by small-sized particles, high lipid solubility, sufficient pulmonary blood flow, and a large absorptive surface area, as it is present in healthy lungs. Administration by these routes can be very rapid when several of the factors favoring increased absorption are combined. 

Studies of the carcinogenicity of chloroprene by the oral route or inhalation, intratracheal administration, subcutaneous or intramuscular injection or skin application were reviewed by lARC (1979) and found inadequate for evaluation. These studies are not considered further. 

Genotoxic Effects and Carcinogenicity. Tests for damages of the DNA [3.117] and cell transformation caused by crystalline cadmium sulfide were positive [3.118]. Cadmium sulfide also proved to be carcinogenic by intraperitoneal and after intratracheal administration [3.119]. The significance of such animal studies is being controversially discussed by toxicologists. 

The effect of intratracheal administration of 1-ethoxysilatrane and l-(chloro-methyl)silatrane on experimental silicosis has been studied"). Far from inhibiting silicosis, the former compound even stimulates it. l-(Chloromethyl)silatrane has proved to be a more fibrogenous compound than crystabolite, which is considered to be one of the most fibrogenic varieties of silica. 

Intratracheal administration of l-(chloromethyl)silatrane into the lungs increases its weight due to fibrogenesis of the connective tissue, growth of lymph nodes and an increase in the lipid and collagen contents of the lungs. 

Figure 3 Lung and liver glucocorticoid receptor occupancy after intratracheal administration of 100 Xg/kg triamcinolone acetonide phosphate solution (TAP, A), liposomal preparation of triamcinolone acetonide (B) and intratracheal administration of 200 nm TAP liposomes (C, intermediate release liposomes) and 800 nm TAP liposomes (D, slow release liposomes). Data taken from Ref. 69.

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