Effects Of Aminoglutethimide Research Articles

Effect of Aminoglutethimide on Neutrophils in Rats: Implications for Idiosyncratic Drug-Induced Blood Dyscrasias

Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced agranulocytosis. Although AMG does not cause agranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2'-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells in the bone marrow, which was confirmed by differential staining with CD45 and CD71. AMG treatment stimulated an increase in colony forming unit granulocyte-macrophage and colony forming unit granulocyte ex vivo. There was also a marked increase in the number of activated neutrophils in the circulation expressing the extravasation marker CD62L. These findings indicate that AMG affects neutrophil production, release, and function. Similar effects on neutrophil kinetics in clozapine-treated rats have previously been found, and transient neutrophilia has been observed in patients taking other drugs associated with idiosyncratic agranulocytosis; therefore, the changes observed with AMG may be biomarkers to predict the risk that a drug will cause agranulocytosis.

Influence of aminoglutethimide and spironolactone on the efficacy of carbamazepine and diphenylhydantoin against amygdala-kindled seizures in rats

Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin.The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations.The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone.

Effects of Aminoglutethimide on Levels of Messenger Ribonucleic Acid of CaBP-D28K and of Vitamin D3 Receptor in the Shell Gland of Laying Hen.

Effects of Aminoglutethimide on Levels of Messenger Ribonucleic Acid of CaBP-D28K and of Vitamin D3 Receptor in the Shell Gland of Laying Hen.

Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters.

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)-amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide-treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre-)-neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N-nitrosobis(2-oxopropyl)amine-induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful.

Development of tolerance to the CNS effects of aminoglutethimide in mice

Initially, there is a high incidence of CNS-depressant side-effects when the aromatase inhibitor, aminoglutethimide, is used in the treatment of patients with advanced breast cancer. Tolerance to these effects develops with continued dosing. This study examines the development of tolerance to various indices of CNS depression with the drug in mice. Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity. On repeated dosing with the drug, tolerance to these various activities occurred. The tolerance was found to be dose-dependent in the rotarod and righting reflex tests and time-dependent in the locomotor and body temperature tests. Although the results do not allow a determination of whether this clearly demonstrated phenomenon in the mouse is primarily functional or dispositional, the slow onset (14 days) for complete tolerance may be indicative of a functional mechanism.

The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in post-orchiectomy prostatic cancer patients.

Aminoglutethimide has been used in combination with hydrocortisone in patients with advanced prostatic cancer with the rationale that it causes a 'medical adrenalectomy'. Both objective and subjective responses have been recorded. We have examined the effect of AG and HC alone and in combination on plasma androgen levels throughout the day in two studies on 11 such patients. Whilst AG combined with HC led to a significant suppression of both testosterone and androstenedione levels, the suppression with HC alone was significantly greater, indicating that any beneficial clinical effects of AG in these patients is not due to its suppression of adrenal androgen secretion.

Effects of aminoglutethimide and 4-hydroxyandrostenedione on [formula omitted] aromatization by human breast cancers [Poster 42

Aminoglutethimide inhibited in vitro aromatization of testosterone by human breast cancers but had negligible effects on conversion to 4-androstenedione, 5α-dihydrotestosterone, and 5α-andro-stanediols. In 21 of 25 cancers, 4-hydroxyandrostenedione (4-OHA) also produced marked dose-related inhibition of aromatase. No consistent effects were observed on other aspects of testosterone metabolism although, in individual tumors, marked effects on conversion to Δ 4-androstenedione were evident.

Effects of aminoglutethimide on breast cancer cell growth

Effects of aminoglutethimide on breast cancer cell growth

Comparative effects of aminoglutethimide and ketocomazole on the androgeh, estrogem and glucocorticoid biosynthesis in dispersed cell systems

Comparative effects of aminoglutethimide and ketocomazole on the androgeh, estrogem and glucocorticoid biosynthesis in dispersed cell systems

Endocrine effects of Aminoglutethimide (Ag) plus Hydrocortisone (HC) versus high dose of hydrocortisone in postmenopausal breast cancer

Endocrine effects of Aminoglutethimide (Ag) plus Hydrocortisone (HC) versus high dose of hydrocortisone in postmenopausal breast cancer

Effects of aminoglutethimide and tolbutamide on the metabolism of radiolabelled C19 steroids by piglet testis microsomes

Effects of aminoglutethimide and tolbutamide on the metabolism of radiolabelled C19 steroids by piglet testis microsomes

Effects of aminoglutethimide on ovarian histology in the rat.

Aminoglutethimide, a corticosteroid inhibitor, administered at a daily dose of 150 mg per kg body weight, showed a dramatic interference with ovarian histology in the rat. The drug caused thinning of the germinal epithelium and disruption of the layers of the follicular cells. It also resulted in the appearance of cytoplasmic vacuoles and distortion of follicle cell nuclei. In the corpus luteum, it caused shrinkage of the lutein cells, resulting in large spaces between the cords of cells. It also arrested immature follicles at various stages of their development. Our results indicate that aminoglutethimide, by modifying ovarian structure in the rat, interferes with the ovulation process.

Effects of aminoglutethimide on cervical dilatability and serum immunoreactive relaxin in pregnant rats.

Administration of aminoglutethimide (AG) at a daily sc dose of 20 mg/kg to rats from the 10th to 20th days of pregnancy resulted in fetal wastage, increased placental weights, and decreased placental alkaline phosphatase. In an effort to determine the endocrine problems relating to these abnormalities, serum relaxin (R) and progesterone (P) levels were determined by RIA and cervical distensibility was measured: All three parameters were subnormal in AG-treated rats. Therapy with estrogen (E) or (P) failed to correct any of the physiological problems associated with AG treatment, but a combination of these steroids increased fetal survival to control levels. However, cervical dilation in preparation for parturition failed to occur. Relaxin therapy alone increased cervical dilation but did not enhance fetal survival. A combination of E, P, and R maintained a normal complement of fetuses and provided normal cervical dilation. None of the treatments prevented placental enlargement but P treatment tended to maintain normal placental alkaline phosphatase.

Formation of free and sulphated oestrogens in porcine testicular microsomes: effects of aminoglutethimide on the pathway from 19-hydroxyandrost-4-enedione

Formation of free and sulphated oestrogens in porcine testicular microsomes: effects of aminoglutethimide on the pathway from 19-hydroxyandrost-4-enedione

Effects of aminoglutethimide and its metabolite, N-acetylaminoglutethimide, on bovine adrenocortical and human placental cytochromes P-450scc

The ability of aminoglutethimide to inhibit cholesterol conversion to pregnenolone was lost upon acetylation of the arylamine nitrogen. This appears to be due to failure of N-acetyl-d-aminoglutethimide to bind to cytochrome P-450scc, since it does not produce the altered low spin form of the enzyme formed upon binding of d-aminoglutethimide. These findings provide further evidence for a role of the free arenamine function in aminoglutethimide and related inhibitors.

Regulation of low-density lipoprotein receptors in cultured bovine adrenocortical cells

Bovine adrenocortical cells in monolayer culture produce cortisol and respond to corticotropin (ACTH) by an increase in cortisol secretion. Several lines of evidence are indicative that much of the cholesterol that serves as precursor for steroid hormone biosynthesis by these cells is derived from low-density lipoprotein (LDL) cholesterol that is taken up endocytotically by means of specific receptors localized in bovine adrenocortical plasma membranes. ACTH stimulated this process concomitant with an increase in steroid production. In the absence of LDL, ACTH had no effect on steroid biosynthesis. ACTH action in bovine adrenocortical cells resulted in an increase in the number of LDL receptor sites in the membrane fractions, whereas the dissociation constant for LDL binding was not changed. Chloroquine and NH 4Cl, considered to be inhibitors of lysosomal degradative activity, caused an increase in the number of [ 125I]iodoLDL binding sites in the plasma membrane but the effect of ACTH was still apparent in the presence of these agents. These results are suggestive that the lifetime of the LDL receptor is increased when lysosomal activity is inhibited. When aminoglutethimide was added to block cholesterol side-chain cleavage activity and inhibit steroid production, the number of [ 125I]iodoLDL binding sites in the membrane fractions prepared from bovine adrenocortical cells cultured in the presence of ACTH was reduced to 50% of that in cells maintained in aminoglutethimide-free medium. However, under these conditions the number of binding sites was still significantly greater than in cells maintained in the absence of ACTH. The effects of aminoglutethimide on uptake and degradation of [ 125I]iodoLDL were similar to the effects on the number of [ 125I]iodoLDL binding sites. Based on these results, we conclude that the action of ACTH to stimulate LDL metabolism in bovine adrenocortical cells results from an increase in the number of LDL binding sites in the plasma membranes. This action of ACTH appears to be, at least in part, independent of cholesterol utilization for cortisol biosynthesis. However, the effect of aminoglutethimide is indicative that changes in the intracellular cholesterol concentration might modulate the action of ACTH to increase the number of LDL binding sites and therefore to stimulate LDL degradation.

Effects of aminoglutethimide, metyrapone, and ascorbic acid on testicular metabolism of cholesterol

The effects of aminoglutethimide (AG), metyrapone (MET), and ascorbic acid (AA) on the conversion of labeled cholesterol to testosterone (T) by the mature rat testis were examined and compared under identical in vitro conditions. In cell-free testicular homogenates, formation of labeled T from cholesterol-4- 14C was depressed in a dose-related manner by AG and MET in concentrations ranging from 0.03 to 1.0 m M; AG was the more potent inhibitor at each concentration tested. Within this range of concentrations, AA induced a slight stimulation of the conversion of cholesterol-4- 14C to T, with inhibition demonstrable only above 5.0 m M. Halfmaximal inhibition of T formation was attained with 0.1, 0.3, and 6.4 m M concentrations of AG, MET, and AA, respectively. When the synthesis of T was almost completely prevented by any of these agents, no accumulation of known intermediates between cholesterol and T could be demonstrated. Under these conditions, MET had no effect on the conversion of pregnenolone-4- 14C to T or several T precursors or on the rate of metabolic degradation of testosterone-4- 14C. Since the generation of the six-carbon fragment resulting from side chain cleavage of cholesterol-26- 14C by rat testicular mitochondrial suspensions was also inhibited by AG, MET, and AA, the depression of steroid production affected by these agents in the testis appears to be related to their capacity to block the reaction cholesterol pregnenolone, as previously demonstrated in the adrenal and ovary. AG, MET, and AA thus inhibit cholesterol cleavage in adrenal and gonadal tissues as well as 11β-hydroxylation in the adrenal. In view of the similarities between the enzyme systems affected, it is likely that AG, MET, and AA exert their inhibitory effects on steroid-forming tissues through similar mechanisms.

54. Effects of aminoglutethimide on the side-chain cleavage of hydroxylated sterols; an experimental approach to congenital lipoid adrenal hyperplasia

54. Effects of aminoglutethimide on the side-chain cleavage of hydroxylated sterols; an experimental approach to congenital lipoid adrenal hyperplasia

Role of the adrenal cortex in maturation of the lymphoid system and immunological competence; the effects of aminoglutethimide in suckling mice.

AbstractNewborn rats and mice have rudimentary peripheral lymphoid tissues and are immunologically incompetent. The lymphoid system matures late in the third week after birth, shortly before weaning. The adrenal cortex also is relatively inactive neonatally and begins to secrete glucocorticoids in a mature fashion two weeks after birth. These experiments were designed to test the hypothesis that adrenal glucocorticoids induce maturation of the lymphoid system and immunological competence during the third postnatal week. Mice 10–12 days old were injected daily for 4–11 days with aminoglutethimide, an inhibitor of steroid biosynthesis. The adrenal glands and lymphoid tissues were prepared for histological examination 24 hours after the last injection and evaluated without knowledge of the treatment received. Aminoglutethimide caused adrenal dysplasia with a frequency proportional to dose. Effective doses also inhibited growth, and slightly larger doses were fatal. Therefore it was concluded that large doses of aminoglutethimide caused adrenal insufficiency, but the completeness of this insufficiency in surviving animals was not ascertained. Three phases in postnatal maturation of the lymphoid system were identified by examination of untreated littermate controls and reference to previous work. During the first week after birth, the thymus‐dependent lymphoid tissues grow by immigration of thymus‐derived cells that soon have the capacity for cell‐mediated immunity. During the second postnatal week, a new population of wandering lymphoid cells, presumptively derived from bone marrow, settles in lymphoid organs in response to antigenic stimulation, to form primary lymphoid nodules and a few plasma cells. Late in the third week after birth the machinery for humoral antibody synthesis matures with the appearance of germinal centers and numerous plasma cells, coincident with a great increase in production of immunoglobulin. This third phase of maturation was retarded in mice injected with near‐fatal doses of aminoglutethimide. Because these mice suffered neither involution of lymphoid tissue nor suppression of proliferation in thymus or thymus‐dependent lymphoid‐tissue, it was concluded that the effects of aminoglutethimide upon the development of germinal centers and plasma cells were selective and specific. Therefore these experiments support the hypothesis that glucocorticoid secretion plays a decisive role in maturation of immunological competence during the third week after birth in mice. This role appears to be the potentiation of cellular proliferation and differentiation of B cells in response to antigens, culminating in antibody synthesis. Maturation of adrenal glucocorticoid synthesis has also been implicated in the initiation of physiological involution of the thymus and cessation of intestinal absorption of antibodies during the third postnatal week in rats and mice.

Effects of aminoglutethimide (Elipten Ciba), a steroid biosynthesis blocking agent, on adrenal glands in Cushing's syndrome.

Seven adrenal glands removed from 4 patients suffering from a central-type Cushing's syndrome after various periods of aminoglutethimide (AGL) treatment were subjected to conventional morphological and histochemical, particularly enzyme histochemical, studies and to biochemical incubation studies.