Soft corticosteroid

Because all inhaled corticosteroids are equally effective if given in equipotent doses, product selection should be individualized based on the available dosage form, delivery device, and patient preference. In infants, administration may require the use of a nebulizer or spacer/holding chamber with a facemask. Caregivers should use a soft, damp cloth to wipe the face of infants receiving an inhaled corticosteroid via a facemask to prevent topical candidiasis.18... 

Recent results suggest a promising application of soft drugs in the field of topical corticosteroids (e.g., loteprednol etabonate [142]) and calcium antagonists (e.g., clevipidine [143]). 

N. Bodor, T. Loftsson, W. M. Wu, Metabolism, Distribution, and Transdermal Permeation of a Soft Corticosteroid, Loteprednol Etabonate , Pharm. Res. 1992, 9, 1275-1278 N. Bodor, W. M. Wu, T. Murakami, S. Engel, Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats , Pharm. Res. 1995, 72, 875-879. 

Figure 2 Design and metabolism of soft corticosteroids (1) based on the inactive metabolite approach. The acid metabolites (2, 3) are inactive, but suitable substitution at the 17a-hydroxy and 17(5-carboxy functions (R h R2) can restore corticosteroid activity and also allow facile one-step deactivation. Loteprednol etabonate (4), a soft steroid, is an active anti-inflammatory compound that lacks the IOP-elevating side effect of the other steroids used ophthalmically.

M. Alberth, W.-M. Wu, D. Winwood, and N. Bodor, Lipophilicity, solubility and permeability of loteprednol etabonate a novel, soft anti-inflammatory corticosteroid, J. Biopharm. Sci. 2 115 (1991). 

N. Bodor, T. Loftsson, and W.-M. Wu, Metabolism, distribution, and transdermal permeability of a soft corticosteroid, loteprednol etabonate, Pharm. Res. 9 1275 (1992). 

N. Bodor, The application of soft drug approaches to the design of safer corticosteroids, Topical Corticosteroid Therapy A Novel Approach to Safer Drugs (E. Christophers, A. M. Kligman, E. Schopf, and R. B. Stoughton, eds.) Raven Press Ltd, New York, 1988, p. 13. 

N. Bodor, Design of novel soft corticosteroids, Topical Glucocorticoids with Increased Benefit-Risk Ratio, Vol. 21 (H. Korting, ed.) Karger AG, Basel, 1993,... 

For parenteral administration in intensive therapy or in emergendes, the sodium phosphate ester may be given intravenously by injection or infusion, or intramuscularly by injection. Dexamethasone sodium phosphate is also used in the treatment of cerebral edema caused by malignancy. The sodium phosphate ester is given by intra-articular, intra-lesional or soft tissue injection. Dexamethasone acetate may be given by intramuscular injection in conditions where corticosteroid treatment is indicated, but a prompt response of short duration is not required. 

Pitcairn, G, Reader, S., Pavia, D., and Newman, S. (2005), Deposition of corticosteroid aerosol in the human lung by respimat soft mist inhaler compared to deposition by metered dose inhaler or by turbuhaler dry powder inhaler, J. Aerosol Med., 18, 264-272. 

Bodor, N. Murakami, T. Wu, W.M. Soft drugs 18. Oral and rectal delivery of loteprednol etabonate, a novel soft corticosteroid, in rats—for safer treatment of gastrointestinal inflammation. Pharm. Res. 1995, 12 (6), 869-874. 

Corticosteroids can be used in various ways. They are valuable in controlling symptoms before the onset of action of DMARDs. A burst of corticosteroids can be used in acute flares. Continuous low doses may be adjuncts when DMARDs do not provide adequate disease control. Corticosteroids may be injected into joints and soft tissues to control local inflammation. Steroids seldom should be used as monotherapy. There are data to suggest they have disease-modifying activity however, it is preferable to avoid chronic use when possible to avoid long-term complications. NSAlDs and DMARDs have steroid-sparing properties that permit reductions of steroid doses. 

Corticosteroids Oral, IV, IM, lA, and soft-tissue injections variable Glucose blood pressure every 3-6 months Same as initial... 

Corticosteroids also may be delivered by injection. The intramuscular route is preferable in patients with compliance problems, since a depot effect is achieved. Depot forms of corticosteroids include triamcinolone acetonide, triamcinolone hexacetonide, and methylprednisolone acetate. This provides the patient with 2 to 8 weeks of symptomatic control. The depot effect provides a physiologic taper, avoiding withdrawal reaction associated with hypothalamic-pituitary axis suppression. It should be noted that the onset of effect via this route may be delayed by several days. Intravenous corticosteroids may be used to provide the patient with large amounts of drug during a steroid burst to control severe symptoms. Intra-articular injections of depot forms of corticosteroids can be useful in treating synovitis and pain when a small number of joints are affected. The onset and duration of symptomatic relief are similar to those of intramuscular injection. The intra-articular route often is preferred because it is associated with the fewest number of systemic adverse effects. If efficacious, intra-articular injections may be repeated every 3 months. No one joint should be injected more than two to three times per year because of the risk of accelerated joint destruction and atrophy of tendons. Soft tissues such as tendons and bursae also may be injected. This may help control the pain and inflammation associated... 

Figure 35.9. Illustration of the difference between soft (SD) and traditional (D) drugs for inhaled corticosteroids. For soft drugs, the designed-in metabolism rapidly deactivates any fraction that reaches the systemic circulation hence, the local effect is accompanied by no or just minimal side effect.

Currently, it is the only corticosteroid approved by the FDA for use in all inflammatory and allergy-related ophthalmic disorders, including inflammation after cataract surgery, uveitis, allergic conjunctivitis, and giant papillary conjunctivitis. Loteprednol etabonate resulted from a classic inactive metabolite-based soft drug approach (103-114). 

Hydrocortisone (24) (Ri, R, R Xj, X, = H, no A Fig. 15.10) undergoes a variety of oxidative and reductive metabolic conversions (115). Oxidation of its dihydroxyacetone side-chain leads to formation of cortienic acid (25) through a 21-aldehyde (21-dehydrocortisol) and a 21 -acid (cortisolicacid). Cortienic acid is an ideal lead for the inactive metabolite approach because it lacks corticosteroid activity and is a major metabolite excreted in human urine. To obtain active compounds,the important pharmacophores found in the 17a and 17P side-chains had to be restored. Suitable isosteric/isoelectronic substitution of the a-hydroxy and /3-carboxy substituents with esters or other types of functions should restore the original corticosteroid activity and also incorporate hydrolytic features to help avoid accumulation of toxic levels. More than 120 of such soft steroids (24) that resulted from modifications of the 17/3-carboxyl function and the 17o -hydroxy function together with other... 

Figure 15.11. Overlapping pharmacophore stmc-tuires of corticosteroids, (a) Clobetasol propionate (in gray) and the soft corticosteroid loteprednol eta-bcnate (26) (in black). The view is from the a side, from slightly below the steroid ring system, (b) Loteprednol etabonate (in black) and a 17a-dichlo-roester soft steroid (in gray). This view is from the j8 side, from above the steroid ring system. See color insert.

Simple alkyl esters also proved virtually inactive. Consequently, the 17/3-chloromethyl ester was held constant and 17a-carbonates with different substituents on the steroid skeleton were varied for further investigation. Loteprednol etabonate, and some of the other soft steroids, provided a significant improvement of the therapeutic index determined as the ratio between the anti-inflammatory activity and the thymus involution activity (114, 117,118). Furthermore, binding studies using rat lung cytosolic corticosteroid receptors showed that some of the compounds approach and even exceed the binding affinity of the most potent corticosteroids known. 

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