Corticosteroids

Summary

drug class: Corticosteroids

generic and trade names:
• Beclomethasone: Beconase®, Beclovent®, Vancenase®, Vanceril®   
• Betamethasone
• Budesonide: Pulmicort®, Rhinocort®
• Cortisone
• Dexamethasone: Decadron®, Decadron Phosphate Turbinaire®, Hexadrol®, etc.
• Dexamethasone/Tobramycin: Tobradex®
• Fludrocortisone
• Flunisolide: AeroBid®, Nasalide®
• Fluticasone: Cutivate®, Flonase®
• Hydrocortisone: Cortef®, Solu-Cortef®, Hytone®, etc.
• Methylprednisolone: Depo-Medrol®, Medrol®, Solu-Medrol®
• Mometasone: Elocon®      
• Prednisolone: Delta-Cortef®, Pediapred®, etc.
• Prednisone: Deltasone®, Orasone®, etc.
• Triamcinolone: Aristocort®, Azmacort®, Kenalog®, Nasacort®, etc.

type of drug: Glucocorticoid, steroidal anti-inflammatory; immunosuppressant. Corticosteroids are synthetic analogues of hormones secreted by the adrenal cortex, especially cortisol.

note: Hydrocortisone is the primary glucocorticoid secreted by the adrenal cortex. Hydrocortisone is now favored over cortisone since it is already pharmacologically active; cortisone must be converted to hydrocortisone in the liver.

application: Oral - systemic; inhalant; topical.

used to treat: Used for a wide range of conditions to symptomatically reduce swelling, redness, itching, and allergic reactions. The indicated conditions include: allergic rhinitis, ankylosing spondylitis, asthma, atopic dermatitis, autoimmune disorders, bursitis, Crohn's disease, congenital adrenal hyperplasia, contact dermatitis, dermatological disorders, drug hypersensitivity reactions, endocrine disorders, hypercalcemia associated with cancer, iritis and iridocyclitis, nonsuppurative thyroiditis; primary or secondary adrenocortical insufficiency, psoriatic and rheumatoid arthritis, tendinitis and non-specific tenosynovitis, and ulcerative colitis.

adverse drug effects: Fluid and electrolyte disturbances: sodium retention; fluid retention; congestive heart failure in susceptible patients; potassium loss; hypokalemic alkalosis; hypertension; hypocalcemia. Other common risks of long-term corticosteroid treatment include Cushing-like changes, decreased glucose tolerance and the usually benign steroid diabetes.

overview of interactions:
• nutrients affected by drug: Calcium and Vitamin D

• nutrient affected by drug: Magnesium

• nutrient affected by drug: Potassium

• nutrient affected by drug: Sodium

• nutrient affected by drug: Zinc

• nutrient affected by drug: Vitamin A

• nutrient affected by drug: Vitamin B6 (Pyridoxine)

• nutrient affected by drug: Vitamin C

• nutrient affected by drug: Vitamin D

• nutrient affected by drug: Vitamin K

• nutrient affecting drug toxicity: DHEA (Dehydroepiandrosterone)

• nutrient affecting drug performance: Flavonoids, Quercitin and/or Grapefruit Juice

• herb affecting drug performance: Aloe vera (Aloe)

• herb affecting drug performance and toxicity: Digitalis purpureaDigitalis, Foxglove)

• herb affecting drug performance: Ephedra sinica (Ephedra, Ma Huang)

• herb affecting drug performance: Glycyrrhiza glabra (Licorice)

• herbal formula affecting drug performance: Minor Bupleurum Decoction (Xiao Chai Hu Tang, Saiboku-To)

• substance affecting drug performance and toxicity: Alcohol

• nutrient affected by drug: Food

• nutrient affected by drug: Dietary Protein

Interactions

nutrients affected by drug: Calcium and Vitamin D

• mechanism: Steroidal anti-inflammatory drugs interferes with the body’s ability to activate vitamin D and thus cause greater risk of bone loss. Under active transport conditions, administration of cortisone produces a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. (Yeh JK, et al. Calcif Tissue Int 1984 Sep;36(5):608-614.) In a 1998 study Lems et al reported that low-dose (10 mg/day) prednisone (LDP) treatment led to a decrease in osteocalcin, P1CP and alkaline phosphatase and an increase in urinary excretion of calcium. They concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly.
(Lems WF, et al. Br J Rheumatol 1998 Jan;37(1):27-33; Pronsky, Z. 1991, 60.)

• research: Studies on a wide range of corticosteroids have established the usefulness of calcium and vitamin D supplements in the treatment and the prevention of steroid-induced osteoporosis. In particular, the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover can usually be counteracted by the combined administration of supplemental doses of calcium and physiological doses of 25OHD3.
(Yeh JK, et al. Calcif Tissue Int 1984 Sep;36(5):608-614; O'Regan S, et al. Acta Paediatr Scand 1979 Jan;68(1):109-111; Trovato A et al. Am Family Phys 1991;44:1651-1658; Chesney RW et al. Lancet 1978;ii:1123-1125; Lund B, et al. Clin Endocrinol (Oxf) 1977 Dec;7 Suppl:177s-181s; Nuti R, et al. J Endocrinol Invest 1984 Oct;7(5):445-448.)

In one study individuals using low doses of prednisone as treatment for rheumatoid arthritis maintained their bone density when they also took daily supplement doses of 1,000 mg (1 gram) of elemental calcium and 500 IU of vitamin D.
(Buckley LM, et al. Ann Intern Med 1996;125:961-968.) 

In a more recent study with low-dose prednisone, Lems et al found parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%). The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.
(Lems WF, et al. Br J Rheumatol 1998 Jan;37(1):27-33.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should discuss the nutritional implications with their prescribing physician and/or a nutritionally trained healthcare professional. In particular, supplementation of vitamin D and calcium should be considered. Most research supports the benefit of taking daily supplemental doses of 1,000-1,500 mg (1-1.5 gram) of calcium and 500 IU of vitamin D. Individuals using corticosteroids for an extended period of time might consult with their prescribing physician about laboratory testing of levels of 1,25 dihydroxycholecalciferol, the activated form of vitamin D. If a deficiency is discovered, activated vitamin D can be obtained by prescription as "calcitriol."

The importance of mild-to-moderate exercise in the prevention of osteoporosis cannot be overemphasized. However, individuals with known or potential bone loss are advised to develop an exercise program under the supervision of a physician or other healthcare professional familiar with the increased risks of fracture associated with long-term use of steroids.

nutrient affected by drug: Magnesium

• mechanism: Corticosteroids can contribute to depletion of magnesium.
(Holt GA. 1998, 83; Pronsky, Z. 1991, 60.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with magnesium to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 300-400 mg of magnesium per day.

nutrient affected by drug: Potassium

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of potassium through the urine. Though widely observed, it remains unclear as to whether this is clinically significant. However, it is known that the mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration which might lead to water retention, weight gain, and increased risk of hypertension.
(Thelkeld DS, ed. Apr 1991; Pronsky, Z. 1991, 60.)

• nutritional support: Supplemental potassium may be necessary in some patients. However, increasing the daily consumption of fruit can be the most effective way to obtain the potassium supplementation needed to make up for depletion due to steroidal anti-inflammatory drugs. In fact, the levels of potassium available through fruit will usually exceed those found in most potassium supplements since they cannot legally exceed 99 mg each.

nutrient affected by drug: Sodium

• mechanism: Steroidal anti-inflammatory drugs typically cause increased sodium retention. The mineralocorticoid action of cortisol can cause a drop in serum potassium and an increase in serum sodium concentration which might lead to water retention, weight gain, and increased risk of hypertension. Individuals using corticosteroids should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to restrict dietary salt intake.

nutrient affected by drug: Zinc

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of zinc through the urine. Though widely observed, the clinical implications of this pattern remain unclear.
(Buist RA. Intl Clin Nutr Rev 1984;4(3):114.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with zinc to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 15-50 mg of zinc per day. Moderate amounts of zinc can usually be obtained through dietary sources but may be hampered as drug-induced malabsorption reduces assimilation.

nutrient affected by drug: Vitamin A

• research: Steroidal anti-inflammatory drugs can contribute to depletion of vitamin A. In one study using adult male rats researchers found that the administration of large doses of corticosterone resulted in a rapid loss of vitamin A from the plasma, liver, adrenals and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. Further research showed that supplementation with vitamin A, in conjunction with the corticosterone, resulted in a reversal of the steroid-mediated depression of vitamin A levels in plasma and tissue.
(Atukorala TM, et al. Ann Nutr Metab 1981;25(4):234-238; Pronsky Z. 1991, 60.)

• nutritional support: Individuals considering the use of supplemental Vitamin A while using corticosteroids should consult with their prescribing physician and/or a nutritionally trained healthcare professional. Daily doses of up to 25,000 IU (7,500 mcg) of vitamin A are considered safe for men and postmenopausal women. However, women at risk of becoming pregnant should restrict their daily intake of vitamin A to less than 10,000 IU (3,000 mcg). On the other hand, daily doses of 25,000 IU (15 mg), or even as high as 100,000 IU (60 mg), are considered safe when beta-carotene is used as the supplemental source.
(Yamaguchi T. Shikwa Gakuho 1967 Nov;67(11):1329-1339; Corball M, et al. Ir J Med Sci 1985 Aug;154(8):306-310.)

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• mechanism: Corticosteroid drugs can contribute to depletion of vitamin B6.
(Pronsky, Z. 1991, 60; Holt GA. 1998, 83.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with vitamin B6 to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 25-50 mg of vitamin B6 per day.

nutrient affected by drug: Vitamin C

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of vitamin C through the urine. Though widely observed, the clinical implications of this pattern remain unclear.
(Buist RA. Intl Clin Nutr Rev 1984;4(3):114; Pronsky Z. 1991, 60.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with vitamin C to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 500-1500 mg of vitamin C per day. Vitamin C can be also given to promote wound healing as increased bruising and slower healing responses are characteristic of patients using anti-inflammatory steroidal drugs..

nutrient affected by drug: Vitamin D
see Calcium above

nutrient affected by drug: Vitamin K

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of vitamin K through the urine. Though widely observed, the clinical implications of this pattern remain unclear.
(Buist RA. Intl Clin Nutr Rev 1984;4(3):114; Pronsky Z. 1991, 60.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with vitamin K to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 65-80 mg of vitamin K per day, a level easily obtained by eating leafy green vegetables.

nutrient affecting drug toxicity: DHEA (Dehydroepiandrosterone)

• mechanism: The presence of exogenous corticosteroids from use of prednisone or related drugs can confuse the internal hormonal regulatory processes. If the pituitary senses that corticosteroid levels are higher than normal the regulatory feedback loops can send a signal to decrease the production of ACTH (adrenocortical stimulating hormone) and thus reduce the levels of several key hormones. As a consequence of these changes in hormonal balance, the internal stimulation to produce DHEA can often fall, androgen levels can rise, and the cascade of side effects, such as muscle wasting, ensue.

• nutritional support: Individuals using corticosteroids for extended periods should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential benefits of supplementing with DHEA to prevent muscle wasting without losing the antiinflammatory effect of prednisone. Laboratory tests can determine the degree to which DHEA has been adversely affected and suggest an appropriate level of supplementation, if needed.
(Gennari R, Alexander JW. Crit Care Med 1997 Jul;25(7):1207-1214.)

Note: See also below for information on the role of DHEA as a "digitalis like factor" (DLF).

nutrient affecting drug performance: Flavonoids, Quercitin and/or Grapefruit Juice

• interactions: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. Inhibition of cytochrome P-450 activity in the blood contributes to sustaining blood levels of corticosteroids. Moderate amounts of flavonoids, such as quercetin, can also be found in apples, onions and tea, with smaller amounts available in leafy green vegetables and beans.
(Schubert W, et al. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.)

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its absence or inhibition increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. This mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, which can lead to water retention, weight gain, and an increased risk of hypertension. Dietary flavonoids, such as found in grapefruit juice, can inhibit this enzyme and at high doses may cause an apparent mineralocorticoid effect.
(Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71.)

herb affecting drug performance: Aloe vera (Aloe)

• research: In animal studies of chemically induced skin inflammation, a combination of hydrocortisone and topical Aloe vera demonstrated increased anti-inflammatory effect and reduced the drug's suppression of wound healing.
(Davis RH, et al. J Am Podiatric Med Assoc 1991;81:1-9; Davis RH, et al. J Am Podiatr Med Assoc 1994 Dec;84(12):614-621.)

herb affecting drug performance and toxicity: Digitalis purpurea (Digitalis, Foxglove)

• research: Digitalis spp. contain cardiac glycosides, upon which pharmaceutical digoxin was modeled and carrying the same actions and toxicities. Many researchers have investigated the occurrences and actions of so-called "digitalis like factors" (DLF) which occur naturally in the body. These substances are known to increase the risk of side effects during corticosteroid therapy. In fact, researchers have found that cortisol and DHEAS themselves can act as immunoreactive plasma digitalis like factors in healthy subjects.
(Threlkeld DS, ed. Apr 1991; Sandre C, et al. Ther Drug Monit 1995 Feb;17(1):19-24; Vasdev S, et al. Clin Nephrol 1987 Apr;27(4):169-174.)

herb affecting drug performance: Ephedra sinica (Ephedra, Ma Huang)

• mechanism: Research on the drug ephedrine, also a component of the herb Ephedra sinica, has been found to accelerate the metabolism of both glucocorticoids and corticosteroids, thereby decreasing their biological activity. In particular, ephedrine increases the clearance of, and thereby decreases the activity of, dexamethasone.
(Brooks SM, et al. J Clin Pharmacol 1977 May-Jun;17(5-6):308-318; Jubiz W, Meikle AW. Drugs 1979 Aug;18(2):113-121.)

• research: Brooks et al found that after treatment with ephedrine there was a 36% mean decrease in plasma dexamethasone half-life, and a 42% mean increase in metabolic clearance rate. Brooks et al concluded that caution is necessary when prescribing ephedrine for asthmatics requiring long-term therapy with dexamethasone and probably other corticosteroids. This research has tilted prescribing practices of bronchodilators for asthmatics away from ephedrine and toward theophylline.
(Brooks SM, et al. J Clin Pharmacol 1977 May-Jun;17(5-6):308-318.)

• herbal concerns: There is no significant evidence as to whether these findings have significant relevance to the use of ephedra. However, pending conclusive research it would appear judicious for individuals using steroidal anti-inflammatory drugs, especially dexamethasone, to avoid both ephedra and ephedrine-containing products.

herb affecting drug performance: Glycyrrhiza glabra (Licorice)

• mechanism: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-DH) oxidizes cortisol to inactive cortisone. Some kinds of licorice contain glycyrrhetic acid which inhibits the action of 11 beta-DH (e.g. in the kidney). Thus, licorice consumption can induce a mineralocorticoid excess state, most likely due to an acquired inhibition of this key enzyme, decreased transformation of cortisol into cortisone, and resultant increased cortisol levels at the mineralocorticoid receptor. In states of 11 beta-DH deficiency such as the syndrome of apparent mineralocorticoid excess (AME) and licorice ingestion, cortisol acts as a potent mineralocorticoid. Furthermore, this increased mineralocorticoid action of cortisol can cause a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, and lead to water retention, weight gain, and increased risk of hypertension.

• research: In a 1979 in vitro study using rat livers Tamura et al found that two key components of licorice, glycyrrhetinic acid and glycyrrhizin, significantly suppressed the action of 5 beta-reduction. They further noted that 5 beta-reductase plays an important role in the regulation of cortisol and aldosterone metabolism in humans. In conclusion they "presumed" that the suppression of 5 beta-reductase activity by glycyrrhetinic acid or glycyrrhizin administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol resulting in the synergism of these steroids and glycyrrhetinic acid or glycyrrhizin. The simultaneous use of licorice, in concentrated or very large amounts for extended periods of time, could thus conceivably result in unintentionally high levels of circulating corticosteroids and increased incidence of drug-related side effects. In a single dose study involving six healthy men Chen et al found that the intravenous administration of a concentrated licorice extract, glycyrrhizin, together with prednisolone resulted in prolonged duration of action by the prednisolone in comparison to that in other subjects administered an equivalent dose of prednisolone without the glycyrrhizin. While such synergism could have beneficial uses, the authors cautioned that the enhanced activity of the prednisolone could result in increased side effects from the drug. Regardless, these findings may have only minimal relevance to the action of licorice used as an herb by the general public or as prescribed by trained medical herbalists of Western or Oriental traditions. Likewise, the practice of administering intravenous glycyrrhizin is relatively rare as it can only be administered legally by physicians in the United States and very few of them have the inclination or training to provide such treatments.
(Tamura Y, et al. Arzneimittelforschung 1979;29(4):647-64; Chen MF, et al. Endocrinol Jpn 1990 Jun;37(3):331-341; Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71; Pratesi C, et al. J Hypertens Suppl 1991 Dec;9(6):S274-275; Nanahoshi M. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319.)

• herbal synergy: One animal study by Kumagai et al found that glycyrrhizin can reduce or prevent the immunosuppressive actions of cortisone. Since endogenous cortisone is the natural hormone most similar to prednisone there is a possibility that these findings might extend to an interaction between glycyrrhizin and prednisone. Likewise, only through further research can the possibility that these animal-based findings hold true for humans can be confirmed.
(Kumagai A, et al. Endocrinol Jpn 1967;14:39-42.)

• herbal synergy: Some initial research has indicated a potential use of licorice compounds as having a potential role in enhancing the therapeutic efficacy of corticosteroids, thereby enabling the use of smaller doses. In tests on human skin samples and mice, Teelucksingh et al concluded that glycyrrhetinic acid was able to potentiate the action of hydrocortisone. Pending confirmatory findings the use of such combination therapy remains speculative.
(Teelucksingh S, et al. Lancet 1990 May 5;335(8697):1060-1063.)

• herbal concerns: The research cited above has focussed on concentrated extracts and intravenous forms of licorice. Common "licorice" candy usually contains no actual Glycyrrhiza, other than perhaps a minute amount as flavoring. No solid conclusions can be drawn as to how much these findings relate to the use of licorice in the forms commonly used by practitioners of Western and Chinese herbal medicine. A product known as DGL (Deglycyrrhizinated Licorice) is available which retains the anti inflammatory and anti-ulcer actions of whole licorice root without pseudo-aldosterone side effects. Individuals using steroidal anti-inflammatory drugs should consult with their prescribing physician and/or a qualified practitioner of herbal medicine about the potential risks involved in using any form of licorice.

herbal formula affecting drug performance: Minor Bupleurum Decoction (Xiao Chai Hu Tang, Saiboku-To)

• research: Five herbs contained in the traditional Oriental herbal formula Saiboku-To (also known as Xiao Chai Hu Tang or Minor Bupleurum Decoction) have been identified as exerting inhibitory effects on prednisolone metabolism through inhibition of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). Perillae frutescens, Zizyphus vulgaris, Magnolia officinalis and Scutellaria baicalensis were also found to contain unknown 11 beta-HSD inhibitors. Glycyrrhiza glabra contains well known 11 beta-HSD inhibitors, glycyrrhizin and glycyrrhetinic acid.
(Homma M, et al. J Pharm Pharmacol 1994 Apr;46(4):305-309.)

• herbal concerns: The use of herbs which inhibit the action of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) could result in unintentionally high levels of prednisolone or related drugs. This could prolong the drug's activity and possibly increase its side effects. Individuals using steroidal anti-inflammatory drugs should consult with their prescribing physician and/or a qualified practitioner of herbal medicine about the potential risks involved in using this herbal formula or others containing its suspect constituents.

substance affecting drug performance and toxicity: Alcohol

• adverse interaction: Corticosteriods and alcohol are both well known for their tendency to irritate the digestion, particularly the stomach. Using alcohol at the same time one is taking such drugs is likely to increase the frequency and severity of these problems. Furthermore, alcohol can increase the risk of experiencing other serious side effects from cortisone and related substances. Anyone using steroidal anti-inflammatory drugs should avoid alcoholic drinks.
(Holt GA. 1998, 82; Pronsky, Z. 1991, 60.)

• research: Research looking at individuals with chronic liver disease, some alcohol related and others not, found a marked deficiency of 11 beta-Hydroxysteroid dehydrogenase. 11 beta HSD, found predominantly in the liver and kidney, is responsible for the shuttling of active cortisol to cortisone. Stewart et al concluded that glucocorticoid excess in patients with chronic alcohol-related liver disease may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism.
(Stewart PM, et al. J Clin Endocrinol Metab 1993 Mar;76(3):748-751.)

nutrient affected by drug: Food

• nutritional concerns: Digestive upset is a common side effect reported by individuals using corticosteroids. The likelihood and severity of this distress can be reduced by taking the drug after eating a meal, with the best results obtained by taking it before 9 a.m.
(Threlkeld DS, ed. Apr 1991; Nesbitt LT Jr. Dermatol Clin 1995 Oct;13(4):925-939.)

nutrient affected by drug: Dietary Protein

• mechanism: Steroidal anti-inflammatory drugs induce increased gluconeogenesis which in turn leads to protein wasting.

• nutritional support: Diet can be one of the most important strategies to minimize side effects from long-term glucocorticosteroid therapy. Many physicians have been taught to recommend a high protein diet to counter potential protein wasting. However, this may be ill-advised as a generic solution given some of the conditions being treated with the drugs. For example, many patients with rheumatoid arthritis benefit from a low protein vegan diet. Likewise, patients with SLE (lupus) often suffer from kidney damage which can be exacerbated by higher dietary protein intake. Even so, it would generally be safe to advise that vegetable protein be increased in the diet, and fats and carbohydrates limited.
(Trovato A et al. Am Family Phys 1991;44:1651-1658; Nesbitt LT Jr. Dermatol Clin 1995 Oct;13(4):925-939.)

References

Anstead GM. Steroids, retinoids, and wound healing. Adv Wound Care 1998 Oct;11(6):277-285. (Review)
Abstract: Glucocorticoids (corticosteroids) cause dehiscence of surgical incisions, increased risk of wound infection, and delayed healing of open wounds. They produce these effects by interfering with inflammation, fibroblast proliferation, collagen synthesis and degradation, deposition of connective tissue ground substances, angiogenesis, wound contraction, and re-epithelialization. These actions are mediated by the antagonism of various growth factors and cytokines. Vitamin A restores the inflammatory response and promotes epithelialization and the synthesis of collagen and ground substances. However, vitamin A does not reverse the detrimental effects of glucocorticoids on wound contraction and infection. In this paper, the known mechanisms of the interaction of glucocorticoids and retinoids are reviewed. The mutually inhibitory interplay between glucocorticoids and retinoids may serve to regulate the processes of inflammation, immunity, and connective tissue repair.

Atukorala TM, Basu TK, Dickerson JW. Effect of corticosterone on the plasma and tissue concentrations of vitamin A in rats. Ann Nutr Metab 1981;25(4):234-238.
Abstract: The administration of large doses of corticosterone to normal adult male rats resulted in a rapid loss of vitamin A from the plasma, liver, adrenals and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. The steroid-mediated depression of plasma and tissue contents of vitamin A was reversed when animals were treated with corticosterone in combination with vitamin A.

Berchtold P, Seitz M. [Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. Schweiz Med Wochenschr 1996 Sep 21;126(38):1603-1609. [Article in German] (Review)

Brooks SM, Sholiton LJ, Werk EE Jr, Altenau P. The effects of ephedrine and theophylline on dexamethasone metabolism in bronchial asthma. J Clin Pharmacol 1977 May-Jun;17(5-6):308-318.
Abstract: The effect of ephedrine (nine patients) and theophylline (seven patients) on dexamethasone metabolism was studied before and after three weeks of drug therapy in 16 asthmatics. Five patients were studied similarily but treated with placebo. After treatment with ephedrine, there was a mean decrease in plasma dexamethasone half-life (t1/2) of 132 minutes, or 36 per cent (P less than 0.025), and mean increase in metabolic clearance rate (MCR) of 148 liters/day, or 42 per cent (P less than 0.001). Increase in the excretion of urinary radioactivity, predominantly in the conjugated fractions, was noted. In contrast, theophylline and placebo therapy resulted in no significant changes in dexamethasone t1/2 or MCR. The rate of urinary excretion of radioactivity was reduced after theophylline treatment. Since ephedrine accelerates labeled dexamethasone clearance while theophylline does not, caution is necessary when prescribing ephedrine for asthmatics requiring long-term therapy with dexamethasone and probably other corticosteroids. It would appear from the present investigation that theophylline is a more appropriate bronchodilator for these patients.

Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996 Dec 15;125(12):961-968.
Abstract: BACKGROUND: Therapy with low-dose corticosteroids is commonly used to treat allergic and autoimmune diseases. Long-term use of corticosteroids can lead to loss of bone mineral density and higher risk for vertebral fractures. Calcium and vitamin D3 supplementation is rational therapy for minimizing bone loss, but little evidence for its effectiveness exists. OBJECTIVE: To assess 1) the effects of supplemental calcium and vitamin D3 on bone mineral density of patients with rheumatoid arthritis and 2) the relation between the effects of this supplementation and corticosteroid use. DESIGN: 2-year randomized, double-blind, placebo-controlled trial. SETTING: University outpatient-care facility. PATIENTS: 96 patients with rheumatoid arthritis, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/d). INTERVENTION: Calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) or placebo. MEASUREMENTS: Bone mineral densities of the lumbar spine and femur were determined annually. RESULTS: Patients receiving prednisone therapy who were given placebo lost bone mineral density in the lumbar spine and trochanter at a rate of 2.0% and 0.9% per year, respectively. Patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone mineral density in the lumbar spine and trochanter at a rate of 0.72% (P = 0.005) and 0.85% (P = 0.024) per year, respectively. In patients receiving prednisone therapy, bone mineral densities of the femoral neck and the Ward triangle did not increase significantly with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone mineral density at any site in patients who were not receiving corticosteroids. CONCLUSION: Calcium and vitamin D3 prevented loss of bone mineral density in the lumbar spine and trochanter in patients with rheumatoid arthritis who were treated with low-dose corticosteroids.

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. Endocrinol Jpn 1990 Jun;37(3):331-341.
Abstract: We investigated the pharmacokinetics of prednisolone (PSL) in six healthy men, with or without glycyrrhizin (GL), to confirm whether GL influences the metabolism of PSL in humans. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS, equivalent to 0.075 mg/kg of PSL), with or without 200 mg of GL. Blood samples were taken from a peripheral vein at 5, 10, 15, 30 and 45 min, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after PSL-HS infusion. The concentration of total PSL in the plasma was analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined, using noncompartmental analysis. GL was found to increase significantly the concentration of total PSL at 6, 8 h, and of free PSL at 4, 6, and 8 h after PSL-HS infusion. GL was also found to modify the pharmacokinetics of PSL. After the administration of GL, the area under the curve (AUC) increased, total plasma clearance (CL) decreased, and the mean residence time (MRT) was prolonged. However, only those of AUC, CL, and MRT of free PSL were significantly different. The volume of distribution at a steady-state (Vdss) of both total and free PSL showed no evident change. This suggests that GL increases the plasma PSL concentrations by inhibiting the metabolism of PSL and that it potentiates pharmacological effects of PSL.

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn 1991 Apr;38(2):167-174.
Abstract: The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of PSL in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral GL four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after the start of PSL-HS infusion. The concentrations of total PSL in plasma were analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined by non-compartment analysis. Oral administration of GL was found to significantly increase the concentrations of total PSL at 6, 8 h, and of free PSL at 4, 6 and 8 h after PSL-HS infusion. Moreover, oral administration of GL was also found to modify the pharmacokinetics of both total and free PSL. After oral administration of GL, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of GL increases the plasma PSL concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.

Chesney RW, Mazess RB, Hamstra AJ, DeLuca HF, O'Reagan S. Reduction of serum-1,25-dihydroxyvitamin-D, in children receiving glucocorticoids. Lancet 1978 Nov 25;2(8100):1123-1125.
Abstract: Serum-1,25-dihydroxyvitamin-D3 (1,25-[OH]2D3) was subnormal in children receiving long-term glucocorticoid treatment for various glomerular diseases, including nephrotic syndrome. In children with chronic glomerulonephritis not treated with glucocorticoids who had similar serum-creatinine with glucocorticoids who had similar serum-creatinine concentrations, serum-1,25-dihydroxyvitamin-D3 concentrations resembled those in healthy controls, indicating that glomerular renal disease per se does not account for reduced serum-1,25(OH)2DE concentrations in steroid-treated patients. The reduction in concentration of this most active vitamin-D metabolite correlated with the dose of steroid administered and with reduction in forearm bone mineral content measured by the photon absorption technique. Reduced serum-1,25-(OH)2D3 concentration may be important in the pathogenesis of steroid-induced osteopenia.

Corball M, O'Dwyer P, Brady MP. The interaction of vitamin A and corticosteroids on wound healing. Ir J Med Sci 1985 Aug;154(8):306-310.

Davis RH, DiDonato JJ, Johnson RW, Stewart CB. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr Med Assoc 1994 Dec;84(12):614-621.
Abstract: Aloe vera at doses of 100 and 300 mg/kg daily for 4 days blocked the wound healing suppression of hydrocortisone acetate up to 100% using the wound tensile strength assay. This response was because of the growth factors present in A. vera masking the wound healing inhibitors such as sterols and certain amino acids. The sterols showed good anti-inflammatory activity (-36%) in reducing the croton oil-induced ear swelling. This activity displayed a dose-response relationship.

Davis RH, Parker WL, Murdoch DP. Aloe vera as a biologically active vehicle for hydrocortisone acetate. J Am Podiatric Med Assoc 1991 Jan;81(1):1-9.
Abstract: Aloe vera, as a biological vehicle for hydrocortisone 21-acetate, was tested topically and systemically against acute inflammation. Systemically, the combination of A. vera and hydrocortisone produced a maximum 88.1% inhibition of edema. Polymorphonuclear leukocyte infiltration was reduced 91.1%. The topical inhibition of edema peaked at 97%. The possibility that A. vera has significant potential as a biologically active vehicle for steroids is discussed.

Donchenko HV, Chahovets' RV. Changes in ubiquinone content of the liver caused by cortisone acetate in normal and vitamin A-deficient rats. Fed Proc Transl Suppl 1965 Nov-Dec;24(6):983-985.

Dostal M, Blahova S. Embryotoxicity of cortisone combined with vitamin E. Folia Morphol (Praha) 1986;34(2):132-140.

Edwards CR, Teelucksingh S. Glycyrrhetinic acid and potentiation of hydrocortisone activity in skin. Lancet 1990 Aug 4;336(8710):322-323. (Letter)

Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg 1968 Mar;167(3):324-328.

Gennari R, Alexander JW. Arginine, glutamine, and dehydroepiandrosterone reverse the immunosuppressive effect of prednisone during gut-derived sepsis. Crit Care Med 1997 Jul;25(7):1207-1214.
Abstract: OBJECTIVE: Corticosteroids are used broadly in clinical practice but may profoundly impair resistance to infections. In contrast, arginine and glutamine are safe and effective immunonutrients that can improve resistance to infection in both animals and humans. This study assessed whether arginine and/or glutamine, with or without dehydroepiandrosterone, a natural endogenous steroid, could reverse the susceptibility to infection caused by prednisone in a burned animal model. DESIGN: Prospective, randomized study. SETTING: A laboratory approved by the American Association for the Accreditation of Laboratory Animal Care at the Shriners Burns Institute, Cincinnati Unit. SUBJECTS: Adult female Balb/c mice, weighing 18 to 22 g. INTERVENTIONS: Animals were prefed an arginine- and/or glutamine- or a glycine-supplemented diet for 14 days. Dehydroepiandrosterone (25 mg/kg/day) and/or prednisone (10 mg/kg/day) were given on days -4 to 0 before animals were given a gavage of 10(9) 111indium-oxine-radiolabeled or -unlabeled Escherichia coli and 20% total body surface area burn injury. Survival rate and the extent of translocation of E. coli were determined. MEASUREMENTS AND MAIN RESULTS: Feeding with diets supplemented with arginine, glutamine, and arginine plus glutamine and treatment with dehydroepiandrosterone reversed the susceptibility to infections caused by prednisone and burn injury. The beneficial effects were mediated by enhanced killing of translocated bacteria and/or by an improved gut barrier function. CONCLUSIONS: Dietary supplementation can reverse the susceptibility to infections caused by prednisone. Both arginine and glutamine as well as dehydroepiandrosterone may be useful therapeutic agents for preventing infections in steroid-treated patients.

Hahn M, Lorez H, Fischer G. Effect of calcitriol in combination with corticosterone, interleukin-1beta, and transforming growth factor-beta1 on nerve growth factor secretion in an astroglial cell line. J Neurochem 1997 Jul;69(1):102-109.
Abstract: In astrocytes, nerve growth factor (NGF) synthesis has been described to be stimulated by the cytokines interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) and inhibited by corticosterone. As all three factors are present in the brain under certain conditions, we investigated the effect of their combined application on NGF secretion in the astroglial cell line RC7 and, in addition, studied the effect of calcitriol (1alpha,25-dihydroxyvitamin D3). Calcitriol stimulated NGF secretion, whereas corticosterone reduced basal levels of NGF secretion as well as inhibited the NGF secretion induced by IL-1beta, calcitriol, and TGF-beta1. Calcitriol had an additive effect when applied together with IL-1beta and a synergistic effect when applied with TGF-beta1. Moreover, calcitriol not only counteracted the inhibitory effect of corticosterone on NGF secretion stimulated by TGF-beta1 but even augmented it to a level more than threefold higher than that reached with TGF-beta1 alone. Due to the trophic effect of NGF on basal forebrain cholinergic neurons, these findings might be of therapeutic relevance under conditions where cholinergic function is impaired and the endogenous levels of corticosterone, IL-1beta, or TGF-beta1 are elevated.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 82-83.

Homma M, Oka K, Niitsuma T, Itoh H. A novel 11 beta-hydroxysteroid dehydrogenase inhibitor contained in saiboku-to, a herbal remedy for steroid-dependent bronchial asthma. J Pharm Pharmacol 1994 Apr;46(4):305-309.
Abstract: To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD.

Hudson JQ, Small RE, Buckley L. Perceptions of pharmacists about adverse effects of corticosteroid therapy: focus on osteoporosis. J Am Pharm Assoc (Wash) 1998 Nov-Dec;38(6):710-716.
Abstract: OBJECTIVE: To assess the perceptions of pharmacists regarding the adverse effects of corticosteroids, in particular corticosteroid-induced osteoporosis. DESIGN: Mailed survey of a random sample of pharmacists. SETTING: Richmond, Virginia. PARTICIPANTS: 350 community and hospital pharmacists. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Respondents' knowledge of adverse effects of corticosteroid therapy in men, premenopausal women, and postmenopausal women; the content of respondents' usual patient counseling for low- and high-dose therapy; and respondents' opinions of regimens for prevention of osteoporosis. RESULTS: Pharmacists associated gastritis, weight gain, and mood changes with corticosteroid use in a hypothetical 45-year-old man or 45-year-old premenopausal woman. For a hypothetical 65-year-old postmenopausal woman, pharmacists more frequently counseled about weight gain, osteoporosis, and gastritis. Patient counseling focused on these adverse effects for both low-dose (5 to 10 mg/day) and high-dose (> or = 30 mg/day) prednisone use. Osteoporosis was considered more likely in patients receiving high-dose corticosteroids on a long-term basis. CONCLUSION: Pharmacists responding to this survey frequently overlooked the association between low- and high-dose corticosteroid use and decreased bone density. Educational efforts are needed so that pharmacists can fulfill their potential for educating patients, monitoring corticosteroid therapy, and detecting drug-induced complications.

Jubiz W, Meikle AW. Alterations of glucocorticoid actions by other drugs and disease states. Drugs 1979 Aug;18(2):113-121.
Abstract: Glucocorticoids are used in physiological and pharmacological amounts in the management of a variety of clinical conditions. Concomitant utilisation of other drugs or the presence of some diseases may affect the physiological action of the steroid in the tissues. Phenytoin, phenobarbitone, ephedrine and rifampicin accelerate the metabolism of glucocorticoids thereby decreasing their biological activity. A similar phenomenon occurs in patients with hyperthyroidism. In contrast, glucocorticoid action is enhanced in hypothyroid patients and in those with hepatic damage as the result of a defect in the clearance of the hormone from blood. In turn, glucocorticoids antagonise the effects of cholinesterase inhibitors and ganglion blocking agents. The above mentioned effects should be kept in mind whenever glucocorticoids are utilised in the diagnosis and management of endocrine or non-endocrine conditions.

Kano K, Suda T. Serum 25 (OH) D and 24,25 (OH)2 levels in childhood nephrosis under different therapeutic regimens of steroid administration. Eur J Pediatr 1982 Mar;138(2):162-165.
Abstract: The effect of prednisone therapy on serum levels of 25-hydroxyvitamin D [25(OH)D] and 24,25-dihydroxyvitamin D [24,25(OH)2D] was investigated in 16 children with nephrotic syndrome. These serum levels were significantly lower in patients before prednisone therapy than in age- and season-matched normal subjects. Patients receiving daily prednisone therapy had lower serum levels than those receiving alternate-day prednisone therapy at the time when the total amounts of the steroid administered attained 1,500 or 2,000 mg/m2 of body surface area. Daily doses of 40 mg/m2 of prednisone for 3 days caused a significant decrease in serum 25(OH)D levels. Withdrawal of the steroid for 4 consecutive days was followed by a significant recovery of the serum levels. These results suggest that alternate-day prednisone therapy rather than daily treatment should be used in clinical practice to help maintain normal vitamin D metabolism.

Kumagai A, Nishino K, Yamamoto M, Nanaboshi M, Yamamura Y. An inhibitory effect of glycyrrhizin on metabolic actions of cortisone. Endocrinol Jpn 1966 Dec;13(4):416-419.

Kumagai A, Asanuma Y, Yano S, Takeuchi K, Morimoto Y, Uemura T, Yamamura Y. Effect of glycyrrhizin on the suppressive action of cortisone on the pituitary adrenal axis. Endocrinol Jpn 1966 Sep;13(3):234-244.

Kumagai A, Nanaboshi M, Asanuma Y, Yagura T, Nishino K. Effects of glycyrrhizin on thymolytic and immunosupressive action of cortisone. Endocrinol Jpn Mar;14(1):39-42.

Kuznetsova LM, Kovaleva VM. [Effect of cortisone on the content and conversion of vitamin A forms in rats]. Ukr Biokhim Zh 1965;37(3):397-404. [Article in Ukrainian]

Lee YS, Lorenzo BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996 Jan;59(1):62-71.
Abstract: INTRODUCTION: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. METHODS: Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. RESULTS: Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. CONCLUSION: Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.

Lems WF, Van Veen GJ, Gerrits MI, Jacobs JW, Houben HH, Van Rijn HJ, Bijlsma JW. Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers. Br J Rheumatol 1998 Jan;37(1):27-33.
Abstract: The administration of moderate to high doses of corticosteroids is associated with bone loss. This probably results from the uncoupling of bone formation (decreased) and bone resorption (unchanged or increased). We examined the effect of low-dose (10 mg/day) prednisone (LDP) and the possible mitigating effects of calcium and 1.25 (OH)2 vitamin D (calcitriol) on calcium and bone metabolism in eight healthy, young male volunteers. The study consisted of four observation periods: in the first period, LDP was prescribed during 1 week; in the second, third and fourth periods, calcium (500 mg/day), calcitriol (0.5 micrograms b.i.d.) and calcium in combination with calcitriol, respectively, were added to LDP. Bone formation was measured by means of serum osteocalcin, carboxy-terminal propeptide of type 1 procollagen (P1CP) and alkaline phosphatase, bone resorption by means of urinary excretion of calcium, hydroxyproline, (free and total) pyridinoline, (free and total) deoxypyridinoline and serum carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP). Dietary calcium and sodium intake were maintained at a stable level during the entire study period. Treatment with LDP led to a decrease in osteocalcin, P1CP and alkaline phosphatase (all P < 0.01). Urinary excretion of pyridinolines, hydroxyproline and serum 1CTP did not increase, but remained unchanged or slightly reduced (P < 0.05), depending on the time of measurement and the marker of bone resorption. Parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%; P < 0.01). Urinary excretion of calcium increased during treatment with LDP and calcitriol (P < 0.05) and calcium/calcitriol (P < 0.05). It is concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly. The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.

Lund B, Andersen RB, Friis T, Hjorth L, Jorgensen FS, Norman AW, Sorensen OH. Effect of 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on intestine and bone in glucocorticoid-treated patients. Clin Endocrinol (Oxf) 1977 Dec;7 Suppl:177s-181s.
Abstract: The effect of 1alpha-hydroxyvitamin D3 (1alpha-OHD3) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the intestinal calcium absorption was studied in twenty patients with rheumatoid arthritis treated with prednisone at daily doses of 5--15 mg for 1/2--20 years. The fractional calcium absorption, measured before and after the treatment with the vitamin D compounds, increased in nineteen of the twenty patients. This was, however, accompanied by marked rises in the urinary calcium excretion. There was no correlation between the fractional calcium absorption and the duration of the prednisone treatment or the doses given.

Nanahoshi M. [Effect of glycyrrhizin on the action cortisone]. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319. [Article in Japanese]

Nesbitt LT Jr. Minimizing complications from systemic glucocorticosteroid use. Dermatol Clin 1995 Oct;13(4):925-939. (Review)
Abstract: For proper use of systemic GCS, a basic knowledge of the normal HPA axis, as well as knowledge of the pharmacology, clinical usage guidelines, and adverse reactions of these agents is imperative. Both short-term (acute) and long-term side effects should be well known by the physician. The pros and cons of oral and parenteral therapy for various disorders and in various situations should be recognized. For long-term therapy, an intermediate-acting agent such as prednisone in single, early morning doses is most commonly used to minimize suppression of the HPA axis. Alternate-morning doses produce even less suppression if the disease process will respond. A through patient history, including general medical history and medications the patient is taking, is important to anticipate any potential problems. Weight and blood pressure should be checked initially and every 1 to 3 months thereafter. Blood glucose, electrolytes, and lipid studies, including triglycerides, should be done approximately every 6 months. An ophthalmology examination should be performed every year, and stool examination for occult blood and chest radiography can be obtained as indicated. Bone density studies might be necessary in patients who are at high risk for osteoporosis. Specific acute situations may dictate other studies. The patient on long-term GCS should be kept as active as possible, as mild-to-moderate exercise helps prevent certain side effects, such as osteoporosis. The dose of oral GCS is best given with food to prevent gastrointestinal irritation, and agents to decrease gastric acidity might be needed in certain situations. Exposure to infections should be prevented, where possible, and treatment initiated at the first sign of systemic or cutaneous infection. Pain should be evaluated early, especially abdominal pain or bone pain; MRI is indicated if aseptic necrosis of bone is suspected. Both trauma and severe sun exposure should be avoided. Consultation with other specialists is strongly recommended when the situation dictates. Diet is one of the most important strategies to minimize side effects from long-term GCS therapy. Vegetable protein should be increased in the diet, and fats and carbohydrates limited. Adequate calcium is imperative, and calcium supplementation is recommended for high-risk osteoporosis patients. Small amounts of vitamin D may be necessary to increase absorption of calcium. Restriction of sodium is also important, as is maintainance of dietary potassium. Supplemental potassium may be necessary in some patients, and a thiazide diuretic might be useful in patients with hypertension, edema, or osteoporosis. Vitamin C can be given to promote wound healing. A good doctor-patient relationship is important in managing the patient on long-term GCS. The patient must return for regular visits and be encouraged to promptly report any adverse reactions to the physician. If these criteria are maintained and the strategies noted previously are followed, problems from long-term therapy with GCS will be minimized.

Nuti R, Vattimo A, Turchetti V, Righi G. 25-Hydroxycholecalciferol as an antagonist of adverse corticosteroid effects on phosphate and calcium metabolism in man. J Endocrinol Invest 1984 Oct;7(5):445-448.
Abstract: The present study was performed in 30 patients who needed steroid therapy: courses of triamcinolone or DTM 8-15 given orally lasted 30 days. In 15 of these patients glucoactive corticosteroids were administered in combination with 5 micrograms/day of 25OH-vitamin D3 (25OHD3). 47Calcium oral test and 99mTc-MDP kinetics, as an index of bone turnover, were performed at the beginning of the therapy and after 30 days. At the end of treatment a significant improvement of intestinal radiocalcium transport together with a decrease in bone turnover in the group of patients treated with 25OHD3 was observed. As it concerns plasma calcium level, inorganic phosphate, the urinary excretion of calcium, phosphate and hydroxyproline no significant difference between the two groups examined were noticed. These results indicate that the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover may be counteracted by the combined administration of physiological doses of 25OHD3.

O'Regan S, Chesney RW, Hamstra A, Eisman JA, O'Gorman AM, Deluca HF. Reduced serum 1,25-(OH)2 vitamin D3 levels in prednisone-treated adolescents with systemic lupus erythematosus. Acta Paediatr Scand 1979 Jan;68(1):109-111.
Abstract: The serum levels of 1,25-(OH)2 vitamin D3 were assayed in samples from 12 adolescent patients with SLE. Subnormal levels were observed in 7 of these 12 patients. Low levels of the metabolically active polar metabolite of vitamin D3 may contribute to the development of osteopenia observed in this disease. The cumulative effects of the osteoporotic and anti vitamin D effects of long term steroid therapy in children with SLE may require the cautious administration of supplemental vitamin D.

Palmieri GM, Thompson JS, Eliel LP. Modifications of plasma magnesium by thyrocalcitonin, parathyroid extract and cortisone. Endocrinology 1969 Jun;84(6):1509-1511.

Pratesi C, Scali M, Zampollo V, Zennaro MC, De Lazzari P, Lewicka S, Vecsei P, Armanini D. Effects of licorice on urinary metabolites of cortisol and cortisone. J Hypertens Suppl 1991 Dec;9(6):S274-275.

Pronsky, Zaneta. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Rude RK, Gruber HE, Oldham SB. Cortisone-induced osteoporosis: effects on bone adenylate cyclase. Miner Electrolyte Metab 1993;19(2):71-77.

Sandre C, Geniteau-Legendre M, Scherrmann JM, Quero AM, Labarre C. Immunoreactivity of endogenous digitalis-like substances in cord blood sera studied with antidigitoxin monoclonal antibodies. Ther Drug Monit 1995 Feb;17(1):19-24.
Abstract: The presence of digitoxin-like immunoreactive substances, whose nature is yet unknown, has been demonstrated in the umbilical cord blood. We selected six antidigitoxin monoclonal antibodies (MAb) having different specificity profiles concerning digitoxin analogs and steroid hormones. These antibodies were tested in a digitoxin radioimmunoassay (RIA). With the help of this technique, we measured the concentrations of apparent digitoxin in the cord blood drawn either at birth or in utero from mothers not undergoing any digitalis treatment. In the cord blood of newborns, the concentrations of apparent digitoxin, measured by the two MAbs that have the highest cross-reactions with dehydroepiandrosterone (DHEA) (123A23 and 145A41), were two or three times higher than with the other antibodies. In the fetal cord blood, where the concentration of DHEA is five to seven times lower than that observed at birth, these antibodies revealed a threefold lower concentration of apparent digitoxin than that observed in blood drawn at birth. Furthermore, MAbs that had similar specificities towards digitoxin analogs and steroids showed different measurements of digitoxin-like concentrations. These observations suggest that digitoxin-like immunoreactive compounds detected by the RIA may constitute a group of different molecules, one of which would be the DHEA.

Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.
Abstract: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome preparation from human liver. The flavonoids were added in concentrations of 10, 50, 100, 250 and 500 mumol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibited by all the flavonoids tested. Addition of the flavonoids to the microsome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentrations tested of the respective flavonoid, there was approximately 75-85% inhibition of estriol formation. However, naringenin was a less potent inhibitor of 17 beta-estradiol metabolism as compared to quercetin and kaempferol. The most likely mechanism of action of the flavonoids on 17 beta-estradiol metabolism is inhibition of the cytochrome P-450 IIIA4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol. These hydroxylation processes represent the predominant steps of the hepatic metabolic conversion of endogenous as well as exogenous 17 beta-estradiol. This interaction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral administration of 17 beta-estradiol to women.

Soszynski P, Slowinska-Srzednicka J, Kasperlik-Zaluska A, Zgliczynski S. Endogenous natriuretic factors: atrial natriuretic hormone and digitalis-like substance in Cushing's syndrome. J Endocrinol 1991 Jun;129(3):453-458.
Abstract: In order to investigate the effect of chronic hypercortisolaemia on endogenous natriuretic factors (atrial natriuretic hormone (ANH) and the Na+/K+ pump inhibitor) digitalis-like substance (DLS), and their relation to hypertension, 28 patients with pituitary- or adrenal-dependent Cushing's syndrome and six patients on high-dose prednisone treatment were studied. Plasma ANH levels were increased in patients with Cushing's syndrome (36.0 +/- 1.4 (S.E.M.) ng/l) compared with those in healthy controls (28.6 +/- 1.3 ng/l, P less than 0.01). In prednisone-treated patients, ANH levels (43.8 +/- 4.5 ng/l) were higher than those in patients with Cushing's syndrome and in controls (P less than 0.05 and P less than 0.01 respectively). DLS measured by radioimmunoassay and binding of [3H]ouabain to erythrocytes was not altered in patients with hypercortisolaemia. Slightly decreased DLS activity in the erythrocyte 86Rb uptake inhibition assay was found in patients with Cushing's syndrome (52.9 +/- 2.7%) compared with that in controls (60.9 +/- 1.8%, P less than 0.02). With the exception of cortisol (r = 0.52, P less than 0.01), none of the other factors determined correlated with the mean arterial pressure in patients with Cushing's syndrome. Thus, a chronic excess of endogenous and exogenous glucocorticoids increases plasma levels of ANH, but does not substantially influence DLS activity or plasma levels. Neither natriuretic factor is directly related to hypertension in Cushing's syndrome.

Stewart PM, Burra P, Shackleton CH, Sheppard MC, Elias E. 11 beta-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease. J Clin Endocrinol Metab 1993 Mar;76(3):748-751.
Abstract: 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD), found predominantly in liver and kidney, is responsible for the shuttling of active cortisol to cortisone. A defect in this shuttle mechanism, e.g. after liquorice ingestion, results in an increase in the ratio of urinary cortisol [tetrahydrocortisol (THF)] to cortisone [tetrahydrocortisone (THE)] metabolites. The plasma cortisol half-life is prolonged, but concentrations remain normal because of a concomitant fall in cortisol production. Alcohol-induced pseudo-Cushing's syndrome is an ill defined cause of Cushing's syndrome. Because many of the documented cases have abnormal liver function tests, we have investigated whether abnormal hepatic 11 beta HSD activity may play a role in the pathogenesis of the condition. Fourteen patients with alcoholic (ALD) and 14 patients with non-alcoholic (CLD) chronic liver disease had marked deficiency of 11 beta HSD [5 alpha-THF + THF/THE: ALD, 1.94 +/- 0.38 (+/- SEM); CLD, 1.82 +/- 0.20] compared to controls (0.94 +/- 0.04; P < 0.01 and 0.001, respectively). In the CLD group, the daily cortisol production rate (as assessed by summation of principal cortisol metabolites) was reduced appropriately [median, 3,510; range, 1,101-8,940 micrograms/24 h; controls, 5,492 (range, 3,818-14,996) micrograms/24 h; P < 0.001], and normal 0900 h plasma cortisol and urinary free cortisol levels were maintained. However, in the ALD group, there was no concomitant fall in the cortisol production rate (sum of cortisol metabolites, 5,043 micrograms/24 h; range, 520-27,344). As a consequence, 0900 h plasma cortisol in the ALD group was significantly elevated (633 +/- 52 nmol/L) compared to values in the CLD group (487 +/- 48 nmol/L; P < 0.05) and controls (432 +/- 27 nmol/L; P < 0.001). Our findings of glucocorticoid excess in patients with chronic ALD may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism. The latter is mediated by defective hepatic 11 beta HSD activity; the former by either abnormal glucocorticoid feedback or stimulation of cortisol secretion at the level of the hypothalamus/pituitary.

Stewart PM, Mason JI. Cortisol to cortisone: glucocorticoid to mineralocorticoid. Steroids 1995 Jan;60(1):143-146.

Tam CS, Wilson DR, Hitchman AJ, Harrison JE. Protective effect on vitamin D2 on bone apposition from the inhibitory action of hydrocortisone in rats.Calcif Tissue Int 1981;33(2):167-172.

Tamura Y, Nishikawa T, Yamada K, Yamamoto M, Kumagai A. Effects of glycyrrhetinic acid and its derivatives on delta-4-5-alpha- and 5-beta-reductase in rat liver. Arzneimittelforschung 1979;29(4):647-649.
Abstract: The effect of glycyrrhetinic acid (GA) and its derivatives on delta 4-5 alpha- and 5 beta-reduction of cortisol, aldosterone and testosterone was investigated on rat liver preparations. In vitro studies demonstrated that GA and its derivatives inhibited 5 beta-reduction to a much greater extent than 5 alpha-reduction. When GA or glycyrrhizin (GL) were administered, 5 beta-reductase activity was significantly suppressed. On the contrary, 5 alpha-reductase was markedly increased though its meachnism remains to be clarified. In human beings 5 beta-reductase is quantitatively the major enzyme and plays an important role in the regulation of cortisol and aldosterone metabolism. Thus from the studies presented here, it can be presumed that the suppression of 5 beta-reductase activity by GA or GL administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol resulting in the synergism of these steroids and GA or GL.

Teelucksingh S, Mackie AD, Burt D, McIntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990 May 5;335(8697):1060-1063.
Abstract: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.

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Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Family Phys 1991;44:1651-1658. (Review)

Turnquist J, Ornoy A, Eini D, Schwartz Z. Effects of 1 alpha(OH)-vitamin D3 and 24,25(OH)2-vitamin D3 on long bones of glucocorticoid-treated rats. Acta Anat (Basel) 1992;145(1):61-67.

Vasdev S, Johnson E, Longerich L, Prabhakaran VM, Gault MH. Plasma endogenous digitalis-like factors in healthy individuals and in dialysis-dependent and kidney transplant patients. Clin Nephrol 1987 Apr;27(4):169-174.

Yamaguchi T. [Effect of various drugs on the abnormality induced by excessive intake of vitamin A. 1. Effect of cortisone]. Shikwa Gakuho 1967 Nov;67(11):1329-1339 [Article in Japanese]

Yeh JK, Aloia JF, Semla HM. Interrelation of cortisone and 1,25 dihydroxycholecalciferol on intestinal calcium and phosphate absorption. Calcif Tissue Int 1984 Sep;36(5):608-614.
Abstract: The interrelation of glucocorticoids and 1,25 dihydroxycholecalciferol (1,25(OH)2D3) on intestinal calcium and phosphate absorption was investigated. The active and passive transport of calcium and phosphate was evaluated by the in situ intestinal loop technique. Administration of cortisone resulted in a decrease of the luminal fluid and an increase of the luminal calcium and phosphate concentration. Under active transport conditions, administration of cortisone resulted in a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. The enhancement of bidirectional phosphate flux by cortisone was independent of 1,25(OH)2D3. An enhancement of water movement by cortisone resulted in an increase of luminal calcium and phosphate concentration which favors the passive diffusion of these ions. Enhanced calcium diffusion by cortisone compensates for the inhibitory effect of cortisone on vitamin D-dependent calcium transport. However, enhanced phosphate diffusion by cortisone is additive to the effect of 1,25(OH)2D3.