Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A retrospective study on stored plasma from normal dogs and dogs with pituitary dependent hyperadrenocorticism (PDH), pituitary dependent hyperadrenocorticism controlled by mitotane (o,p'-DDD),* iatrogenic hyperadrenocorticism, and hypoadrenocorticism was conducted to determine if alterations in aldosterone production exist in these disorders. The plasma aldosterone concentration (PAC) was measured by radioimmunoassay immediately before and 1 hour after adrenocorticotropic hormone (ACTH) administration (0.5 IU/kg, intravenously [IV]). PACs increased significantly when ACTH was administered to normal dogs. Dogs with PDH had a lower baseline PAC, but their PAC increased to levels similar to that of normal dogs after ACTH administration. In dogs with PDH controlled by o,p'-DDD therapy, the response to ACTH was significantly less than that of normal dogs or dogs with untreated PDH. Dogs with iatrogenic hyperadrenocorticism had a lower baseline and post-ACTH PAC than normal dogs. Dogs with hypoadrenocorticism had a normal basal PAC, but showed no significant increase in PAC following ACTH administration. These findings suggest that PACs are significantly altered in a variety of adrenal diseases, and that the ACTH stimulation test may be useful when evaluating aldosterone secretion in adrenopathic disorders. In addition, at therapeutic dosages, o,p'-DDD treatment was associated with a decrease in basal and post-ACTH PACs in dogs with PDH.
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PMID:A retrospective study of aldosterone secretion in normal and adrenopathic dogs. 285 51

A case of a huge inoperable adrenocortical carcinoma which secreted testosterone without characteristic symptoms was treated with o,p'-DDD (2,2-bis(2-chlorophenyl-4 cholorophenyl) 1,1-dichloroethane). With this therapy, the tumor decreased in size which was confirmed by the computed tomography (CT). Eighteen months later, however, lethargy and logopathy appeared and the tumor grew again rapidly with the withdrawal of o,p'-DDD performed for the evaluation of these mental disturbances. The tumor then diminished gradually in size soon after the treatment was resumed and the above unfavorable symptoms were not developed again with the combined administration of a central nervous stimulant. During o,p'-DDD treatment, plasma testosterone and estrogen decreased, and plasma aldosterone also decreased but within the normal range. Plasma cortisol also tended to decrease despite hydrocortisone was administered. Plasma adrenocorticotropic hormone (ACTH) was maintained within the normal range for the first six months but then increased gradually. It decreased and became normal with the additional administration of hydrocortisone. The patient's normal menstruation at the preadministrative stage changed to oligomenorrhea, then amenorrhea after the treatment, but no endocrinological sign except for the menses was observed during the treatment.
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PMID:Adrenocortical carcinoma responded to treatment with o,p'-DDD--a case report. 609 39

Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12-15 kg that were treated daily with Mitometh or Mitotane (50-100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line, NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action.
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PMID:Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma. 845 85

Surgical excision of an ACTH-producing pituitary tumor is the optimal therapy for Cushing's disease. However, medical therapy may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. When medication is the only therapy, a major disadvantage is the need for lifelong therapy; in general, recurrence follows discontinuation of treatment. These compounds work through three broad mechanisms of action. "Neuromodulatory" compounds modulate corticotropin (ACTH) release from a pituitary tumor, steroidogenesis inhibitors reduce cortisol levels by adrenolytic activity and/or direct enzymatic inhibition and glucocorticoid antagonists block cortisol action at its receptor. In general, neuromodulatory compounds (bromocriptine, cyproheptidine, somatostatin and valproic acid) are not very effective agents for Cushing's disease. Treatment with a glucocorticoid antagonist and radiation therapy has been reported on a single patient only. Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide, are the agents of choice for medical therapy of Cushing's disease. In general, ketoconazole is the best tolerated of these agents and is effective as monotherapy in about 70% of patients. Mitotane and metyrapone may be effective as single agents, while aminoglutethimide generally must be given in combination. The intravenously-administered etomidate may used when patients cannot take medications by mouth.
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PMID:Medical therapy of Cushing's disease. 1267 4

Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells.
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PMID:Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function. 2381 13