Hypothalamic-pituitary-adrenal system

The methods described here are applied for Supplemental Safety Pharmacology Studies (ICH S7A), if the test substance has shown indications of effects on the hypothalamic-pituitary-adrenal system in the preceding pharmacology studies. The in vitro studies are generally performed with several increasing doses to investigate concentration-effect relationships. The preliminary information from these in vitro studies is then compared with the biological information available from in vivo for studies, to assess the need for additional animal studies based on repeated dose administration of the test compound. 

In the safety pharmacology protocol, the interaction of multiple endocrine systems in test animals is addressed. As discussed by Harvey (1996) and by Harvey and Everett (2003), effects on adrenocortical function are frequently found in toxicology studies, sometimes related to enzyme induction and effects on steroid biosynthesis (Loose et al. 1983, Nebert and Russell 2002, Weber et al. 1993). Test procedures in animals are required when there is a reason for concern. Frequently however the effects observed are due to stress rather than specific interaction with the target organ, and may involve effects on catecholamine release from the adrenal medulla (Tucker 1996). Recently, much new evidence has been accumulated from the testing of industrial chemicals with effects on adrenal steroid biosynthesis (Harvey and Johnson 2002). 

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Data of animal experiments discussed in this chapter suggest a variety of potential pharmacological targets for the treatment of pathological anxiety (Fig. 1). As the occurrence of traumatic events is usually unpredictable, it seems more promising to interfere with consolidation than with acquisition processes. In this context, the sympatho-adrenergic and the hypothalamic-pituitary-adrenal system are of particular interest. Both noradrenaline and corticosterone/cortisol are known to facilitate memory consolidation, in par-... 

CORTISOL ANTACONISTS AND LIMBIC-HYPOTHALAMIC-PITUITARY-ADRENAL SYSTEM STABILIZERS... 

Reus VI, Berlant JR Behavioral disturbances associated with disorders of the hypothalamic-pituitary-adrenal system, in Medical Mimics of Psychiatric Disorders. Edited by Extein I, Gold MS. Washington, DC, American Psychiatric Press,... 

Krishnan R, Ellinwood EH Jr, Laszlo J, Hood L, Ritchie J. Effect of gamma interferon on the hypothalamic-pituitary-adrenal system. Biol Psychiatry 1987 22(9) 1163-6. 

The opioids may modulate the actions of the immune system by effects on lymphocyte proliferation, antibody production, and chemotaxis. Natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. In general, these effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids. 

L. Mathematical modeling of the hypothalamic-pituitary-adrenal system activity. Math Biosci 2005,197 173-187. 

In the endocrine safety pharmacology for the hypothalamic pituitary adrenal system, the levels to be examined are ... 

Adrenal steroids chronic corticosteroid therapy with the equivalent of prednisolone 10 mg daily within the previous 3 months suppresses the hypothalamic-pituitary-adrenal system. Without steroid supplementation perioperatively the patient may fail to respond appropriately to the stress of surgery and become hypotensive (see Ch. 34). A single dose of etomidate depresses the hypothalamic-pituitary-adrenal axis for a few hours but this is not associated with an adverse outcome. 

In all these situations an i.v. infusion should be available for immediate use in case the above is not enough. These precautions should be used in patients who have received substantial treatment with corticosteroid within the past year, because their hypothalamic/pituitary/adrenal system, though sufficient for ordinary life, may fail to respond adequately to severe stress. If steroid... 

SUDO, N., CHiDA, Y., AiBA, Y., soNODA, j., OYAMA, N., YU, x.N. et al. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in tmce. Journal of Physiology - London 558 263-275. 

Ritchie, JC and Nemeroff, CB (1991) Stress, the hypothalamic-pituitary-adrenal axis and depression. In Stress, Neuropeptides and Systemic Disease (Eds McCubbin, JA, Kaufmann, PG and Nemeroff, CB), Academic Press, London, pp. 181-197. 

It is important to remember that adverse effects of topical corticosteroids may be systemic in nature and hypothalamic-pituitary-adrenal axis suppression can occur, especially when high-potency corticosteroids are used. Infants and small children may be more susceptible due to their increased skin sur-face body mass ratio.18 Topical corticosteroids may also cause striae, skin atrophy, acne, telangiectasias, and rosacea.2,10,18 Atrophy can result in thin, fragile, easily lacerated skin. Striae are caused by tearing of dermal connective tissue and are irreversible.18 Due to their significant adverse-effect profile, it has been recommended that no topical corticosteroid be used regularly for more than 4 weeks without review and reassessment.2... 

Imura, H and Fukata, J., Endocrine-paracrine interaction in communication between the immune and endocrine systems. Activation of the hypothalamic-pituitary-adrenal axis in inflammation. Eur. J. Endocrinol. 130,32-37 (1994). 

Hypothalamic-Pituitary-Adrenal (HPA) axis An integrated neuroendocrine system linking the hypothalamus (noradrenaline and corticotropin-releasing factor CRF) with the anterior pituitary (corticotropin or ACTH) and the adrenal cortex (cortisol). 

The sympathetic nervous system (SNS) and the hypothalamic-pituitary axis work together as important modulators of the immune system after exposure to stressors. Norepinephrine (NE) and epinephrine (EPI) (catecholamines from the SNS) and neuroendocrine hormones modulate a range of immune cell activities, including cell proliferation, cytokine and antibody production, lytic activity, and migration. This chapter will focus on these two major pathways of brain-immune signaling, briefly summarizing the evidence for SNS and hypothalamic-pituitary-adrenal (HPA) modulation of immune function, their influence on immune-mediated diseases, immune modulation in aging, and early life influences on these pathways. 

Karrow, N. A., Activation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system during inflammation and altered programming of the neuroendocrine-immune axis... 

Psychological stress may influence the immune system by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary axis (SAM). The well-described innervation of primary and secondary lymphoid tissues by the autonomic nervous system also has been implicated in stress-related modulation of the immune response. These pathways operate by producing biological mediators that interact with and affect cellular components of the immune system.13... 

Neuropsychological impairments in mood disorders, particularly those of working memory and executive function, are the most convincing and objective demonstrations of an impairment of consciousness. Since these impairments do not correlate with the severity of the mood disturbance and persist upon recovery they are not simply epiphenomena of the mood disturbance but rather may index trait pathology in susceptible individuals. It has previously been argued that mood disturbance and neuropsychological impairment may result from disturbances in two different neurochemical systems, the serotonin (5-HT) system and the hypothalamic-pituitary-adrenal (HPA) axis, between which there is a close interaction (McAllister-Williams et al., 1998). 

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