Identification of candidate reference chemicals for in vitro steroidogenesis assays.

The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis. Candidate reference chemicals were identified from a review of H295R and gonad-derived in vitro assays used in methods validation and published in the scientific literature. A total of 29 chemicals affecting androgen and estrogen levels satisfied all criteria for positive reference chemicals, while an additional set of 21 and 15 chemicals partially fulfilled criteria for positive reference chemicals for androgens and estrogens, respectively. The identified chemicals included pesticides, pharmaceuticals, industrial and naturally-occurring chemicals with the capability to increase or decrease the levels of the sex hormones in vitro. Additionally, 14 and 15 compounds were identified as potential negative reference chemicals for effects on androgens and estrogens, respectively. These candidate reference chemicals will be informative for performance-based validation of in vitro steroidogenesis models.

Adrenal Suppression With Chronic Topical Corticosteroid Use in Psoriasis Patients.

BACKGROUND: Topical corticosteroids (TCS) are typically used for extended periods of time for chronic skin conditions, including psoriasis. Chronic TCS use may result in side effects similar to those of systemic corticosteroids. Patients may have subclinical adrenal suppression and be unaware of their risk in the case of serious trauma.
OBJECTIVE: The objective of this study was to investigate the real world effects of chronic TCS use and its effects on adrenal suppression in a chronic disease such as psoriasis.
MATERIALS: This retrospective study utilized data from screening visits of a psoriasis clinical trial in which subjects had been on chronic TCS.
RESULTS: In this study, subjects with moderate to severe psoriasis affecting 16-20% of total body surface area (BSA) and using high-potency TCS at screening had a lower post-cosyntropin cortisol level (18.83 mcg/dL) compared to those with moderate psoriasis involving 10-15% of total BSA and using lower potency TCS at screening (23.22 mcg/dL; P=0.03). Both subject groups had lower post-cosyntropin cortisol levels compared to normal, healthy adults (P<0.001 for both).
CONCLUSION: This suggests that real world chronic use of high potency TCS over a larger BSA may result in silent adrenal suppression.

J Drugs Dermatol. 2016;15(8):945-948.

Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis.

The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme-coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19.

Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation.

Inhibition of 17α-hydroxylase/17,20-lyase (CYP17), which dictates the proceeding of androgen biosynthesis, is recommended as an effective treatment for androgen-dependent diseases. However, androgen depletion by selective CYP17 inhibition is accompanied with corticosteroid elevation, which increases risk of cardiovascular diseases. In this study, we evaluated the likelihood of polyphenols as a CYP17 inhibitor without cardiovascular complications. All examined polyphenols significantly inhibited CYP17 in human adrenocortical H295R cells, but their effects on androgen and cortisol biosynthesis were diverse. Resveratrol was the most potent CYP17 inhibitor with an approximate IC50 of 4 µM, and the inhibition might weigh on the 17α-hydroxylase activity more than the 17,20-lyase activity. Resveratrol also inhibited 21α-hydroxylase (CYP21) essential for corticosteroid biosynthesis but to a lesser extent, thus preventing the occurrence of cortisol elevation following CYP17 blockade. Although transcriptional down-regulation was important for α-naphthoflavone-mediated CYP17 inhibition, resveratrol inhibited CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein also inhibited CYP17 and CYP21 although less potent than resveratrol. Daidzein was the only polyphenol showing inhibition of 3ß-hydroxysteroid dehydrogenase type II (3ßHSD2). The exceptional 3ßHSD2 inhibition led to dehydroepiandrosterone accumulation alongside daidzein-caused androgen biosynthetic impairment. In contrast, androgen and cortisol secretion was increased or remained normal under α-naphthoflavone and ß-naphthoflavone treatments, suggesting that CYP17 inhibition was counteracted by increased substrate generation. α-naphthoflavone and ß-naphthoflavone also enhanced the formation of cortisol from 17-hydroxyprogesterone and testosterone from androstenedione. Our findings suggest a potential application of resveratrol in androgen deprivation therapy.

[Influence of metanandamide on steroidogenesis in rat adrenocorticocytes in vitro].

It is known from literature about antioxidant, anti-inflammatory, membrane protective and adreniregulatory properties of N-acetylethanolamines, but data concerning their participation in regulation of steroidogenesis are insufficient. In order to study the influence of a synthetic analogue of endogenous canabinoid anandamide - metanandamide - on the intensity of steroidogenesis the influence of different concentrations of the drug on the contents of 11-hydroxicorticosteroides (11-HCS) in the culture medium after incubation of adrenal tissue in rats of both sexes was investigated. The quantitative determination of 11-HCS was conducted by fluorometric micromethod. It was shown that the incubation of tissue sections with metanandamide leads to a reduction of 11-HCS in males and an increase of their content in females. It was concluded that the inhibition of corticosteroid secretion and synthesis in males may be due to reduction of cAMP and inhibition of cAMP-dependent protein kinase A (PKA) under the effect of metanandamide. The opposite and dose-dependent effects of the preparation in females may be connected with the estrogen influence on the mechanisms of drug effect realization.

High-throughput fluorescence-based screen to identify factors involved in nuclear receptor recruitment to response elements.

The glucocorticoid receptor is an inducible transcription factor which plays important roles in many -physiological processes. Upon activation, GR interacts with regulatory elements and modulates the expression of genes. Although GR is widely expressed in multiple tissues, its binding sites within chromatin and the genes it regulates are tissue specific. Many accessory proteins and cofactors are thought to play a role in dictating GR's function; however, mechanisms involved in targeting GR to specific sites in the genome are not well understood. Here we describe a high-throughput fluorescence-based method to identify factors involved in GR loading at response elements. This screen utilizes a genetically engineered cell line that contains 200 repeats of a glucocorticoid response promoter and expresses GFP-tagged GR. Upon treatment with corticosteroids, GFP-GR forms a steady-state distribution at the promoter array, and its concentration at this focal point can be quantitatively determined. This system provides a novel approach to identify activities important for GR loading at its response element using siRNA libraries to target factors that enhance or inhibit receptor localization.

New therapeutic targets in dermatoporosis.

Dermatoporosis is a novel term proposed to describe the chronic cutaneous insufficiency/fragility syndrome characterized by an extreme skin atrophy. Dermatoporosis is principally due to chronological aging and long-term and unprotected sun exposure, but it may also result from the chronic use of topical and systemic corticosteroids. We have recently proposed a membrane organelle, hyalurosome, composed of molecules involved in hyaluronate (HA) metabolism and cell signaling in the keratinocytes, such as principal HA receptor CD44, heparin-binding epidermal growth factor (HB-EGF), HB-EGF receptor erbB1 and HA synthase 3 (HAS3), which is functionally defective in dermatoporosis and may be a target for intervention. Several lines of evidence suggest that hyalurosome is located in keratinocyte filopodia, thin, actin-rich plasma membrane protrusions implicated in cell motility. We have recently shown that keratinocyte filopodia are downregulated by corticosteroids in vitro. Intermediate size HA fragments (HAFi) inhibited the downregulation of filopodia induced by corticosteroids. Topical HAFi prevented the skin atrophy induced by topical corticosteroids in mice without interfering with their anti-inflammatory effect. Topical treatment with HAFi 1% of atrophic forearm skin of dermatoporosis patients for 1 month resulted in a significant clinical improvement and induced the expression of hyalurosome molecules. Topical retinaldehyde (RAL) and HAFi showed a synergy in HA production and pro-HB-EGF expression in mouse skin and in the correction of skin atrophy in dermatoporosis patients. Uncovering the molecular mechanisms implicating hyalurosome seems to be crucial to better understand the pathogenesis of dermatoporosis and to develop new therapeutic strategies.

CYP2S1 is negatively regulated by corticosteroids in human cell lines.

Cytochrome P450s are monooxygenase proteins involved in the metabolism of both exogenous and endogenous compounds. CYP2S1 can metabolize eicosanoids in the absence of both NADPH and NADPH cytochrome P450 reductase, and can also activate the anticancer agent 1 AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxy anthracene-9,10-dione]. CYP2S1 is mainly expressed in extrahepatic tissues such as the trachea, lung, stomach, small intestine, spleen, skin, breast, kidney and placenta. Furthermore, increased expression of CYP2S1 occurs in several tumors of epithelial origin, making the characterization of CYP2S1 regulation relevant to the treatment of disease. We report that the synthetic glucocorticoid receptor ligand dexamethasone (DEX) represses CYP2S1 expression. The ED(50) is between 1 nM and 3 nM and maximal repression is reached by 48 h. Other corticosteroids are also effective at repressing CYP2S1. We show that repression by DEX is mediated by the glucocorticoid receptor and requires histone deacetylase activity.

Clinical and molecular pharmacology of etomidate.

This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis.

Neuroprotective effects vary across nonsteroidal antiinflammatory drugs in a mouse model of developing excitotoxic brain injury.

Glutamate excitotoxicity is among the main cellular mechanisms leading to perinatal insults in human newborns. We used intracerebral injection of the glutamatergic glutamate N-methyl-D-aspartate-receptor agonist ibotenate to produce excitotoxic lesions mimicking the acquired white matter lesions seen in human preterm infants. We evaluated whether nonsteroidal antiinflammatory drugs (NSAIDs) protected against glutamate excitotoxicity. Aspirin (0.01-100 microg/d), indomethacin (0.1-10 microg/d), paracetamol (10-100 microg/d), or NS-398 (12.5 microg/d) was given daily before ibotenate (P1 to P5) or after ibotenate (P5 to P9). Lesion size was measured on Cresyl Violet-stained brain sections collected on P10. None of the drugs tested alone or in combination increased lesion size. Pretreatment with low- or high-dose aspirin and post-treatment with paracetamol or NS-398 protected against white matter lesions, whereas cortical lesions were decreased by pretreatment with low- or high-dose aspirin or post-treatment with NS-398. The corticosteroid betamethasone (0.18 microg/d) was neuroprotective when given before or after ibotenate and this effect was reversed by concomitant aspirin therapy (10 microg/d). In conclusion, perinatal NSAID administration may have beneficial effects on brain injury if appropriately timed.

Activation of the proopiomelanocortin gene with ketoconazole as a treatment for Parkinson's disease: a new hypothesis.

Parkinson's disease is a neurodegenerative process characterized by progressive degeneration of the substantia nigra and concurrent loss of neuromelanin in these structures. The present hypothesis suggests that progression of Parkinson's disease may be reduced by enhancing the regional levels of neuroprotective factors derived from proopiomelanocortin (POMC). One practical means to accomplish this goal may be administration of ketoconazole or other inhibitors of corticosteroid synthesis at doses sufficient to stimulate hypophyseal secretion of POMC. The POMC constituents adrenocorticotropic hormone (ACTH) and melanocycle-stimulating hormone (MSH), which mobilize neuromelanin generation and lipotropins, those motivating lipid components of neuromelanin and endorphin, which then together stimulate and protect neural components of the substantia nigra.

Advances in the medical management of Cushing's syndrome.

BACKGROUND: Management of Cushing's syndrome, that is, excess cortisol secretion, has undergone considerable advances since the pioneering studies by Harvey Cushing. Surgery is clearly first choice for all etiologies of Cushing's syndrome, and medical therapy is largely administered in the interim between other therapeutic options. The limited use of medical therapy is a consequence of the lack of a truly efficacious compound to restrain adrenocorticotrophic hormone or cortisol secretion, but this will hopefully change in the near future as molecules developed over the past few years are tested. CONCLUSION: This paper illustrates present and perspective medical treatments for Cushing's syndrome.

Pharmacological treatment of hypercortisolism.

PURPOSE OF REVIEW: To consider the current status and types of drug therapy aimed at restoring eucortisolaemia in patients with Cushing's syndrome. RECENT FINDINGS: Advances such as laparoscopic adrenalectomy modify the exact placing of drug therapy among the wide variety of therapies available to treat patients with Cushing's syndrome because of different causes; nonetheless, it is now clear that hypercortisolism, per se, if present for any length of time, modifies the future prognosis of the patient, even after cure of the Cushing's syndrome. Thus, early diagnosis and restoration of eucortisolsm are critical. There are three main types of drug therapy: steroidogenesis inhibitors, glucocorticoid antagonists and neuromodulatory compounds. Currently, steroidogenesis inhibitors such as metyrapone and ketaconazole are most commonly the first choice if drug therapy is to be used, but at least for the most common form of Cushing's syndrome, Cushing's disease, the neuromodulatory compounds such as cabergoline show potential. SUMMARY: Pharmacological therapy for Cushing's syndrome remains critically important for normalizing cortisol levels while awaiting the impact of more definitive treatment.

Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor.

The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4-5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor.

Attenuation of the effects of corticosteroids on declarative memory with lamotrigine.

An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.

Uso de corticosteróides em cirurgia / Use of corticosteroids in surgery

Introdução: o efeito antinflamatório dosglicocorticóides tem implicações clínicas que interferem de forma decisiva na evolução de pacientes submetidosa procedimentos cirúrgicos. Objetivos: realizar uma revisão sobre o uso adequado de corticosteróides emcirurgia. Métodos: Foram coletados e analisados artigos referentes ao emprego de corticoterapia em pacientescríticos, bem como pacientes submetidos a procedimentos eletivos. Todos os artigos foram extraídos do banco de dados Medline.Discussão: Apesar de seusinúmeros efeitos colaterais, é clara na literatura a participação dos corticosteróides na modulação doprocesso inflamatório sistêmico durante uma situação de estresse. A administração de tais drogas durante oprocedimento cirúrgico deriva do seu emprego prévio em pacientes em sepse e cujo prognóstico sofreuconsiderado impacto após sua indicação em maior escala. Conclusões: Concluímos que o uso de corticosteróides nas doses e intervalos definidos promove benefícios a homeostasia dos pacientes submetidos aprocedimento cirúrgicos, bem como, evolução pósoperatória com menor morbidade .

Background: the anti-inflamatory effect of the glicocorticoids have clinical implication in the evolution of patients that go under surgical procedures. Objective: Review the appropriate use of glucocorticoids in surgery.Methods: articles focused in corticotherapy in critically illpatients as well as corticotherapy in patients that go under elective procedures were selected and analyzed. All the articles were selected from Medline data base. Discussion:Despite of its large number of collateral effect, it’s well defined in the literature the use of corticosteroids in themodulation of the systemic inflammatory process along a situation of stress. The administration of this drugs alongthe surgical procedure comes from its usage in patients with sepsis which prognosis suffered important impact after its indication in large scale. Conclusions: we concluded that the use of corticosteroids in doses and defined period of time has benefits in the homeo stasis of patients submitted to surgical procedures as well as a less morbidityin the postoperative time .

[Cationic antimicrobial peptides as molecular immunity factors: multi-functionality].

Cationic antimicrobial peptides (AMP) of mammals (defensins, cathelicidins, protegrins and many others) are regarded as important components of congenital immunity. AMP are multifunctional molecules, capable of killing microorganisms directly by acting as endogenic, natural antibiotics ("immediate immunity"); in addition, they may take part in congenital and adaptive immune reactions (immunoregulation) and function as signal molecules, involved into tissue reparation, inflammation (including sepsis), blood coagulation and other important processes in the body. The molecular mechanisms of the direct antimicrobial action of AMP are considered. In addition to antimicrobial and immunoregulating action, AMP have influence on immunoneuroendocrine interactions, taking part in the pathogenesis of stress reactions (corticostatic action), as well as play the role of regulatory peptides of adaptogenic action. The many-sided character of the action of AMP opens prospects to the creation of new medicinal remedies on their basis. Such requirements are met by the Russian preparation "Superlymph" (a complex of natural cytokines), containing protegrin-like AMP.

Why does acute hyperglycemia worsen the outcome of transient focal cerebral ischemia? Role of corticosteroids, inflammation, and protein O-glycosylation.

BACKGROUND AND PURPOSE: Hyperglycemia adversely affects the outcome of stroke. Global ischemia data support that the harmful effect of hyperglycemia is mediated by glucose-induced elevated plasma glucocorticoids. Here we sought to evaluate the negative effects of hyperglycemia on transient focal ischemia in the rat, and to test whether these could be prevented by inhibition of either corticosteroid production or neutrophil infiltration. METHODS: Sprague-Dawley rats (n=217) were used. Ischemia was induced by 1 hour middle cerebral artery occlusion (n=196). Acute hyperglycemia was induced by IP injection of dextrose 30 minutes before ischemia. Neutrophil infiltration was blocked by neutropenia with vinblastine. Corticosterone synthesis was inhibited by chemical adrenalectomy with metyrapone. We measured MRI lesion and tissue infarct volumes, evaluated the neurological function, brain myeloperoxidase and matrix metalloproteinase-9 activities, and protein O-glycosylation. RESULTS: Hyperglycemia significantly enhanced MRI diffusion-weighted imaging alterations, increased cortical, but not subcortical, infarct volume, worsened neurological score, and enhanced brain myeloperoxidase and matrix metalloproteinase-9 activities. Metyrapone did not prevent hyperglycemic brain damage despite successful reduction of plasma corticosterone. Yet, metyrapone tended to reduce cortical infarction and apparent diffusion coefficient lesion volume, indicating some negative contribution of corticosterone. Blocking neutrophil infiltration was also ineffective to prevent the harmful effect of hyperglycemia. A new finding was that O-linked glycosylation of cerebral proteins was increased under hyperglycemia. CONCLUSIONS: In transient middle cerebral artery occlusion, the hyperglycemia-exacerbated brain damage cannot be fully explained by the negative effects of plasma corticosteroids or neutrophil infiltration. The contribution of other intrinsic effects of high glucose, such as brain protein O-glycosylation, deserves further investigation.

Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase.

Elevated aldosterone levels are key effectors for the development and progression of congestive heart failure and myocardial fibrosis. Recently, we proposed inhibition of aldosterone synthase (CYP11B2) as an innovative strategy for the treatment of these diseases. In this study, the synthesis and biological evaluation of E- and Z-(pyridylmethylene)tetrahydronaphthalenes and -indanes (1a,b-38a) is described. The activity of the compounds was determined using human CYP11B2, and the selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. The biological results revealed a few rather selective inhibitors of CYP11B1, some compounds inhibiting both CYP11B1 and CYP11B2, and a large number of highly selective inhibitors of CYP11B2. The most active inhibitor was the 3-pyridyl compound 5a (IC(50) = 7 nM). The pyrimidyl-substituted derivative 28a was found to be the most selective CYP11B2 inhibitor (IC(50) = 27 nM) in this series, showing a 120-fold selectivity for CYP11B1 (IC(50) = 3179 nM). Molecular modeling, i.e., examination of the electronic and steric features of selected compounds and homology modeling and docking, was used to understand the structure-activity/-selectivity relationships.

Hypoglycaemic effects of some plant extracts are possibly mediated through inhibition in corticosteroid concentration.

To unravel the possible mechanism of glucose lowering activity, effects of ten different plant extracts in the regulation of serum cortisol and glucose concentrations were evaluated in male mice. While the extracts of Inula racemosa, Boerhaavia diffusa and Ocimum sanctum decreased the serum concentration of both cortisol and glucose, Aegle marmelos, Azadirachta indica and Gymnema sylvestre extracts could exhibit hypoglycaemic activity without altering the serum cortisol concentration. It appears that the hypoglycaemic effects of former three plant extracts are mediated through their cortisol inhibiting potency, whereas the mechanism for other plant extracts could be different. Lipid-peroxidation was not enhanced by any of the plant extracts (some were in fact, antiperoxidative in nature). As I. racemosa, B. diffusa and O. sanctum exhibited antiperoxidative, hypoglycaemic and cortisol lowering activities, it is suggested that these three plant extracts may potentially regulate corticosteroid induced diabetes mellitus.