Inhaled prolonged therapy

Glucocorticoids are available in a wide range of preparations, so that they can be administered parenterally, orally, topically, or by inhalation. Obviously the oral route is preferred for prolonged therapy. However, parenteral administration is required in certain circumstances. Intramuscular injection of a water-soluble ester (phosphate or succinate) formed by esterification of the C21 steroid alcohol produces peak plasma steroid levels within 1 hour. Such preparations are useful in emergencies. By contrast, acetate and tertiary butylacetate esters must be injected locally as suspensions and are slowly absorbed from the injection site, which prolongs their effectiveness to approximately 8 hours. 

Elaborate precautions must be taken to prevent the entrance of Pu iato the worker s body by ingestion, inhalation, or entry through the skin, because all common Pu isotopes except for Pu ate a-emitters. Pu is a P-emitter, but it decays to Am, which emits both (X- and y-rays. Acute intake of Pu, from ingestion or a wound, thus mandates prompt and aggressive medical intervention to remove as much Pu as possible before it deposits in the body. Subcutaneous deposition of plutonium from a puncture wound has been effectively controlled by prompt surgical excision followed by prolonged intravenous chelation therapy with diethylenetriaminepentaacetate (Ca " —DTPA) (171). 

Asthma is a chronic inflammatory disease. Therefore steroids represent the most important and most frequently used medication. Already after the fust treatment, steroids reduce cellular infiltration, inflammation, and the LAR, whereas changes in the EAR require prolonged treatment to lower the existent IgE levels. The mechanisms of steroid actions are complex and only incompletely understood. Besides their general antiinflammatory properties (see chapter glucocorticoids), the reduction of IL-4 and IL-5 production from T-lymphocytes is particularly important for asthma therapy. The introduction of inhaled steroids, which have dramatically limited side effects of steroids, is considered one of the most important advancements in asthma therapy. Inhaled steroids (beclomethasone, budesonide, fluticasone, triamcinolone, momethasone) are used in mild, moderate, and partially also in severe asthma oral steroids are used only in severe asthma and the treatment of status asthmaticus. Minor side effects of most inhaled steroids are hoarseness and candidasis, which are avoided by the prodrug steroid ciclesonide. 

One of the unique aspects of the IPEC approach is that not all tests are required. Some of the tests are conditional upon findings in other test procedures. Specific attention is paid to the route of exposure as well as to tests that might be required as potential exposure duration is increased. Emphasis is placed on the fact that the route of exposure for the test animals should be the same as the route of exposure anticipated in humans. Strict attention is paid to the type of exposure. For example, a protocol for study of a product intended for inhalation therapy that results in prolonged exposure of up to several hours per day will differ from that used to evaluate a material that would be used in a product resulting in exposure to several metered doses each day. Some tests may have to be conducted using a route of exposure different from the intended use route. This may be due to the nature of the test animal (e.g., reproductive tests in rabbits may require that the dosage route be other than inhalation, if inhalation is to be the route of use of the formulation containing the excipient). 

The earliest major clinical application of (2) was the report in 1900 (69) of the utility of injected adrenal extracts in treating asthma attacks, followed in 1903 by a report (70)of the use of purified (2) for the same purpose. Injected epinephrine rapidly became the standard therapy for treatment of acute asthma attacks. A nasal spray containing epinephrine was available by 1911 and administration through an inhaler was reported in 1929. Also, early in the 1900s Hoechst employed the vasoconstrictor properties of epinephrine to prolong the duration of action of their newly developed local anesthetic procaine (63). 

The concentrations of the drug at the desired sites and at the sites of toxicity within the respiratory tract will depend on the balance of the drug supply and clearance rates at these sites [37]. We may speculate that this is one of the reasons for the higher doses required for the delivery of topical medications by nebulizers (typically over 10-25 min) vs. metered-dose inhalers or dry powder inhalers that deliver the medication in one or two breaths. There is little doubt that prolonged inhalation reduces the patient s enthusiasm for the therapy. It is therefore appropriate to evaluate nebulizers in terms of their useful output, that is, the dose of the therapeutic or diagnostic agent delivered in the desired aerodynamic size range per unit time [145]. 

Clinical complications related to the use of nebulizers have been observed. Facial dermatitis with superimposed bacterial infections have been described and are caused by the prolonged use of a face mask [145]. Contamination of the small-volume nebulizers has been linked with oropharyngeal colonization [146,147]. In one report, infections were seen four times more frequently in patients receiving inhalation therapy for respiratory diseases than in those who are not. At least one example of death resulting from contamination has been reported. 

Resistant Pseudomonas species have been reported with prolonged use or repetitive courses of inhaled tobramycin. After three months of treatment with aerosolized tobramycin 600 mg three times daily, the percentage of patients growing a pseudomonal isolate with a tobramycin MIC of 8 or more increased from 29% to 73% [32]. In studies with the commercially available product where cyclic therapy was administered, the tobramycin MIC = 16 against Pseudomonas aeruginosa was higher in the treatment group compared to placebo (23% vs. 8%) [36]. 

The replacement of systemic corticosteroid therapy and its attendant side effects in asthmatic and allergy patients with locally acting corticosteroids by way of aerosol inhalation devices is a gratifying success story. Even though dexamethasone phosphate was initially used for brief periods, the development of systemic effects such as adrenal suppression offered no advantage over oral therapy. Beclomethasone diproprionate showed itself to be hundreds of times more potent, and it produced no systemic symptoms even even on prolonged use with 400 pg daily doses. Some systemic symptoms developed at three to four times higher doses. 

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