Aerosolized dosing

Chlordane is readily absorbed by warm-blooded animals through skin, diet, and inhalation. It is quickly distributed in the body and tends to concentrate in liver and fat (WHO 1984). Up to 75% of a single oral dose of chlordane administered to rats and mice was absorbed in the gut, and up to 76% of an aerosol dose was absorbed in the respiratory tract (Nomeir and Hajjar 1987). Rabbits absorbed 33% in the gut following oral administration (USEPA 1988). Chlordane residues in mammals were usually not measurable 4 to 8 weeks after cessation of exposure (Ingle 1965). Chlordane persistence in human serum and whole body was estimated at 88 days and 21 days, respectively this compares to a Tb 1/2 of about 23 days in rats fed chlordane for 56 days (USEPA 1980). 

Caution The T-2 mycotoxins are the only potential biological warfare agents that can harm and be absorbed through intact skin. Aerosol doses of T-2 toxins may be ten times more potent than parenteral doses. 

Tronde A, Baran G, Eirefelt S, Lennernas H, Bengtsson UH (2002) Miniaturized nebubzation catheters a new approach for delivery of defined aerosol doses to the rat lung. J Aerosol Med 15 289-296. 

Note that, to call attention to an important source of variability in the onset time, we used the term dose onset factor (Donset). As stated, it represents the decrease in Tonso, (the time at which NF performance first falls below 25% of baseline) when the incapacitating dose (IDso) is doubled. In the case of BZ, for example, doubling the absorbed dose shortens the Tonso from four hours to less than an hour. Doubling it again presumably shortens it to just a few minutes. This would be an important concept for military plarmers to consider. Our data were insufficient to measure the Domet precisely because we preferred not to administer double doses to volunteers, hr the few cases in which actual aerosol doses were considerably higher than the intended value, however, the dramatically earlier onset of incapacitation allowed an educated guess of the Donset. 

Aerosol dose-response 31 Jun-Dec 1962 aerosol broad range IQso estimated... 

Discussion Dosage accuracy and documentation of response intensity were satisfactory in only two subjects in the preceding series. One of them had reacted more severely than expected to an estimated inhalation dose equivalent to 6.0 mcg/kg ) administered in a wind tunnel. Details of the results are not known, but the examiners concluded that this individual had not over-reacted to the previously administered aerosol dose, since his previous response to BZ by the oral route had been within the expected range of intensity. They concluded that excessively deep inhalation in the grenade/wind tunnel was responsible for the apparent over-reaction. 

In order to estimate the relative effectiveness of the inhalation route, regression lines were drawn through dose-response values for both the oral route and the inhalation route, and the ratio of the dose values at which the two regression lines crossed the 20% performance line (an arbitrary choice) was calculated (Fig. 98). The ratio of the two slopes indicates that 3.75 times as large an aerosol dose would be needed to equal the effect of LSD given by the oral route, i.e., relative effectiveness equals 28%. 

Aerosol - Doses administered to mice between 35 and 150 mg/kg/day resulted in significant seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology. Partial recovery of sperm production was apparent 3 to 6 months following dose cessation. Testicular lesions (tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day was shown. 

Repeated JP-S Mouse IDO. 250,500,1,000, 2,500 mg/m, 1 hr/d for7d, inhalation (aerosolized) Dose-related decrease in spleen and thymus organ weights and decrease in total viable cells from those organs. At 100 and 250 mg/m1, loss of total cell numbers in the lymph nodes and peripheral blood, but an increase in bone marrow lota) cell numbers at 500 and 1,000 ing/m , increase in total cell numbers in lymph nodes and peripheral blood cell numbers, but a decrease in bone marrow cell numbers. Dose-related decrease in immune function observed in animals exposed to JP-8 and then treated with Concovalin-A D.T. Harris el al. 1997... 

Aerosol. Doses used ranged from 5.3 to 17.1 pg/kg In eight subjects. Understanding of the clinical manifestations was confounded by the use of antidotes at various times after exposure to Che drug. The time course was as follows ... 

Duration of aerosol dose generation should occupy a substantial part of a slow inhalation cycle. A generation time of greater than 1 s will permit the patient to better coordinate aerosol delivery effectively during inhalation. 

Laube, B.L. In vivo measurements of aerosol dose and distribution chnical relevance. J. Aerosol. Med. 1996, 9 (Suppl. 1), S77-S91. 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

Similar results were obtained for measurements of the concentrations of metabolites of phenanthrene, fluoranthene, pyrene, chrysene and benzo[a]pyrene in urine of female Wistar rats exposed to coal tar pitch aerosols (dose and duration not stated) (Grimmer et al. 1997). The urinary metabolite profile for each individual rat did not show significant variation during the course of the experiment, but there was a significant difference between individuals for both the absolute amounts of metabolites excreted and also for the ratio of metabolites produced. 

A number of pharmaceutical companies are developing INH dehvery systems using both liquid and dry-powder insulin formulations [34,35]. Table 4 briefly indicates those arrived at in phase HI studies. A few companies have developed systems based on hquid formulations, which utilize relatively complex pressurized metred-dose devices or nebuUzation systems to generate appropriately sized aerosolized doses, hi the AERx system inhalation flow rate, inhaled volume and duration are patient-controlled... 

The 2-hydroxyethylthio observation was pursued with the synthesis of many related compounds, a few of which are included in Table VII (69). However, the effect of this substituent proved to be quite structure specific. Thus, homologation of the chain (see entry 14), replacement of sulfur with oxygen (U), and replacement of hydroxy with sulfhydryl (1 ) or with methyl were ineffective. On clinical investigation, 1-11-deoxy-lla-(2-hydroxyethylthio)-PGE2 methyl ester (I) at aerosol doses as high as 800 ijg in asthmatic patients failed to produce a consistent bronchodilation (69). 

Chlordane is readily absorbed by warmblooded animals through skin, diet, and inhalation. It is quickly distributed in the body and tends to concentrate in liver and fat. Up to 75% of a single oral dose of chlordane administered to rats and mice was absorbed in the gut, and up to 76% of an aerosol dose was absorbed in the respiratory tract rabbits absorbed 33% in the gut following oral admiiustration. 

In the United States, federal regulation of aerosol doses varies with devices. The metered-dose inhaler (MDI) utilizes a metering valve that is highly regulated and functionally precise. Nebulizers as drug delivery systems are essentially unregulated. 

The Circulaire nebulizer system increases the rate and total aerosol dose delivered to the patient compared to the traditional constant-output nebulizer alone, and this has savings in treatment time as well as potentially reducing costs (12). Further, aerosol wasted to the environment is minimized, which, in turn, minimizes occupational exposures to drug aerosol (13,14). As with the Halolite system, the Circulaire is cumbersome and complicated to clean. 

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