Dexamethasone indications

Use in diagnosis dexamethasone suppression test. Dexamethasone acts on the h5q othalamus (like hydrocortisone), to reduce output of corticotropin releasing hormone (CRH), but it does not interfere with measurement of corticosteroids in blood or urine. Normal suppression of cortisol production after administering dexamethasone indicates that the hypothalamic/pituitary/adrenal axis is intact. Failure of suppression implies pathological hypersecretion of ACTH by the pituitary or of cortisol by the adrenal. Dexamethasone is used because its action is prolonged (24 h). There are several ways of carrying out the test. 

The importance of cross-talk in GR actions is indicated by the construction of a GR dimerisation-deficient mutant mouse in which GR is unable to dimerise and therefore bind to DNA, thus separating the DNA-binding (transactivation) and inflammatory gene repression (transrepression) activities of glucocorticoids. In these animals dexamethasone was able to inhibit AP-1- and NF-kB-mediated gene transcription,... 

There is concern regarding administration of dexamethasone to patients with pneumococcal meningitis caused by penicillin- or cephalosporin-resistant strains, for which vancomycin would be required. Animal models indicate that concurrent steroid use reduces vancomycin penetration into the CSF by 42% to 77% and delays CSF sterilization due to reduction in the inflammatory response.23 Treatment failures have been reported in adults with resistant pneumococcal meningitis who were treated with dexamethasone, but the risk-benefit of using dexamethasone in these patients cannot be defined at this time. Animal models indicate a benefit of adding rifampin in patients with resistant pneumococcal meningitis whenever dexamethasone is used.21,23... 

Determine if adjunctive dexamethasone therapy is indicated if so, start steroid therapy 15 to 20 minutes before the first dose of antimicrobial therapy. 

Dexamethasone therapy may reduce antibiotic penetration, so antimicrobial drug dosing may have to be increased (especially vancomycin) to achieve adequate CSF levels. Serum levels of vancomycin should be measured and doses titrated to ensure adequate CNS concentrations. Evaluate whether intraventricular or intrathecal antibiotics are indicated. 

There are certain histologic subtypes of diffuse, aggressive NHL that respond less well to treatment with conventional regimens such as CHOP. Burkitt s lymphoma, lymphoblastic lymphoma, mantel cell lymphoma, and primary CNS lymphoma are examples of disease that benefit from more intensive therapy. Regimens such as hyper-CVAD, which alternate cycles of hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone with high-dose cytarabine and methotrexate, often are substituted for CHOP. Intrathecal therapy with methotrexate is indicated with documented CNS infiltration of tumor or involvement of the sinuses. The recent appreciation of the etiology of Helicobacter pylori in the etiology of peptic ulcer disease and the association between colonization and mucosal-associated lymphoma (MALT) has spurred... 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

One class of agents which inhibits LT production in stimulated cell systems, but probably not by direct 5-LO inhibition, is the anti-inflammatory corticosteroids, represented by dexamethasone (10) [30-34]. The well-known inhibition of PG production seen with eorticosteroids is not due to direct CO inhibition, but has been attributed to the inhibition of arachidon-ic acid mobilization by phospholipase A2, caused by enhanced biosynthesis of one or more proteins called lipocortins [35] (although this hypothesis is now being seriously questioned [36]). More recent evidence indicates the possibility of down-regulation of CO enzyme levels [37-39] similar mechanisms involving altered gene regulation could be involved in the observed effects on LT production as well. 

Fig. 8. Time lapse images of two MMTV arrays visualized with GFP-GR. Time in minutes after addition of 100 nM dexamethasone is indicated. Some arrays become very extended (3-10 pm, B), whereas some cells exhibit a less extended array (< 3 pm, A) (from Ref [68]). Scale bar 1 pm.

Sofradex contains dexamethasone, framycetin and gramicidin and is indicated in otitis externa. Canesten contains clotrimazole and is indicated for fungal infections and may be used in otitis externa where a fungal infection is suspected. Nasonex contains mometasone, a corticosteroid, and is used in nasal allergy. 

Dexamethasone and betamethasone are corticosteroids available for topical application in eye products. Docusate sodium is indicated for ear wax removal. 

The first-line agents in the treatment of rheumatoid arthritis are non-steroidal anti-inflammatory drugs such as diclofenac. Diclofenac and indometacin, another NSAID, tend to have similar activity hov/ever, indometacin has a higher incidence of side-effects and therefore diclofenac is more appropriate for initial treatment. Sodium aurothiomalate is classified as a disease-modifying antirheumatic drug and is used as a second-line treatment in rheumatoid arthritis, but has been superseded by methotrexate, administered v/eekly. Paracetamol is often indicated in the management of osteoarthritis. Local intra-articular injections of dexamethasone may be administered for the relief of soft-tissue inflammatory conditions. 

Dexamethasone is used for the same indications as all corticosteroids however, it exhibits a significantly more powerful anti-inflammatory and anti-allergic action. 

Betamethasone is hardly ever used orally. It has a long duration of activity and can therefore also be used for alternate-day therapy. The parenteral formulation is also the sodium phosphate salt which when given IV or IM has a rapid onset of action. There are many similarities with dexamethasone such as their metabolic pathways and the indications for which both steroids are used, like the prevention of neonatal RDS and reduction of raised intracranial pressure. Combinations of betamethasone acetate and sodium phosphate have, when used for intra-articular and intra-lesional injections, the dual advantage of a rapid onset of action together with the long duration of action of a depot preparation. 

Fig. 1. Outline of treatment strategy applied in the ALL-Berlin-Frankfurt-Munster (BFM) 95 study (1995-2000). Patients were assigned to standard-risk (SR), intermediate-risk (MR) and high-risk (HR) subgroups. Elements containing 6-mercaptopurine (6-MP) or 6-thioguanine (6-TG) are indicated in grey. Abbreviations PRED-GR, prednisone good response PRED-PR, prednisone poor response DEXA, dexamethasone VCR, vincristine DNR, daunorubicin HD-MTX, high-dose methotrexate LD-ARA-C, low-dose cytarabine SCT, stem cell transplantation.

Residue depletion studies indicated that different formulations led to different dexamethasone depletion rates. Studies in cattle and pigs indicated that dexa-methasone residues were quickly eliminated from muscle and milk of cows. Residues did not occur in the free form in fat, whereas the depletion rate in liver was the slowest. Following intramuscular administration of 60 g/kg bw to cows, mean dexamethasone levels in milk declined from 8.4 ppb at the first milking after treatment to below 1 ppb at the sixth milking after treatment (52). 

A good initial approach is to study the behavior of known synthetic precursors, drug analogs or degradates. In our previous example, dexamethasone acetate, one can readily purchase compounds such as cortisone, cortisone acetate, dexamethasone alcohol, dexamethasone-17-keto analog, prednisolone alcohol, and so on. Their chromatographic responses, relative to the compound of interest, will indicate which structural modifications are detec-... 

An apparent association between severe retinopathy of prematurity and dexamethasone therapy has been shown in a retrospective study (SEDA-20, 372 76). Infants treated with dexamethasone required longer periods of mechanical ventilation (44 versus 26 days), had a longer duration of supplemental oxygen (57 versus 29 days), had a higher incidence of patent ductus arteriosus (28/38 versus 18/52), and required surfactant therapy more often for respiratory distress syndrome (17/38 versus 11/52). Prospective, randomized, controlled studies are needed to correct for differences in severity of cardiorespiratory disease. Until such studies are available, careful consideration must be given to indications, dosage, time of initiation, and duration of treatment with dexamethasone in infants of extremely low birthweight. 

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