Assays in Endocrine Safety Pharmacology
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I.O.1 I.O.2 I.O.3 I.O.4 I.O.4.1 I.O.4.2 I.O.4.3 I.O.4.4 I.O.4.5 I.O.4.6 I.O.4.7 I.O.5
I.O.6 I.O.6.1 I.O.6.1.1 I.O.6.1.2 I.O.6.1.3 I.O.6.1.4 I.O.7 I.O.7.1 I.O.7.2
I.O.7.3
I.O.7.4
General Considerations . . . . . . . . Regulatory Toxicology Studies. . Mechanistic Studies . . . . . . . . . . . . Endocrine Survey . . . . . . . . . . . . . . Endocrine System Evaluation in Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . Determination of Hypothalamic Hormones . . . . . . Determination of Pituitary Hormone Contents . . . Dynamic Function Tests . . . . . . . . . Gonadotropin Release from Anterior Pituitary Cells . . . . . TSH Release from Anterior Pituitary Cells . . . . . GH Release from Anterior Pituitary Cells . . . . . Determination of Gonadal and Adrenal Steroid Hormones . . . . . . . . . . . . . . . . . . . . . . Hypothalamic-PituitaryGonadal Function . . . . . . . . . . . . . . Repeated Dose Study in Male and Female Rat . . . . . . . . . . Male Reproductive System . . . . . . . Testis Incubation and Androgen Biosynthesis . . . . . . Female Reproductive System . . . . FSH Receptor Binding and Effect on FSH Receptors . . . . . . . . . . . . . . . Hypothalamic-PituitaryAdrenal System . . . . . . . . . . . . . . . . Adrenal Steroid Excretion in Rats in a Repeated Dose Study . . . . . . . . Corticosterone Secretion in Dexamethasone Blocked Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corticosteroid Release from Adrenal Cell Suspensions in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . ACTH Receptor Affinity . . . . . . . . .
327 328 329 330
I.O.7.5
331
I.O.8.1
333
I.O.8.2 I.O.8.3
I.O.7.6 I.O.8
336 337
I.O.8.4
338
I.O.8.5
339
I.O.8.6
340
I.O.8.7
342 342 342 343 344 345 347 348 348
351
352 353
ACTH Secretion and Tissue Content . . . . . . . . . . . . . . . . . . . . . . . . . Adrenal Steroid Activity . . . . . . . . . Hypothalamic-PituitaryThyroid Function . . . . . . . . . . . . . . Pituitary Thyroid Evaluation in Rats in a Repeated-Dose Study TRH Radio-Immunoassay . . . . . . . TSH Receptor Assay and TSH RIA . . . . . . . . . . . . . . . . . . . Iodine Uptake and Release in Rats . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of Iodine Uptake into the Thyroid of Rats . . . . . . . . . . Thyroid Hormone Assays (T3 and T4) . . . . . . . . . . . . . . . . . . . . . Thyroid Function in Chronic Toxicology Studies . . .
354 355 355 355 357 358 359 360 361 362
I.O.1 General Considerations Studies on Endocrine Safety Pharmacology are part of the “Supplemental Safety Pharmacology Studies” described in the ICH guideline S7A. These supplemental studies are meant to evaluate potential adverse effects on organ system functions which are not addressed by the general methods of the core battery, or by repeateddose toxicity studies. The definition clearly requires that the specific pharmacology of the test substance be known before any decisions on the test articles of endocrine safety pharmacology are taken, for this specific case. The general pharmacology pr
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