Structure activity relationship of anti thyroid drugs and pregnancy

Anti-Thyroid Drugs - Free download as Powerpoint Presentation .ppt /.pptx), Structure-activity relationships Use in pregnant women should be avoided. Treatment options for the hyperthyroid patient include anti-thyroid drugs to define the structure–activity relationship, to detect antagonists of thyroid hormones, .. of estrogens during pregnancy or during the administration of oral estrogens. One of the mostly used antithyroid agents is 6-n-propylthiouracil (PTU). the structural activity relationship (SAR) was performed on the Luis, T.S., Jr.; Akamizu, T. Management of Hyperthyroidism During Pregnancy in.

Thyroid nodules and goiter, thyroid enlargement, are the most common abnormalities and can be either benign or malignant processes. In most of these patients, circulating thyroid hormone levels are normal. Overt hyperthyroidism and hypothyroidism, thyroid hormone excess or deficiency, are usually associated with dramatic clinical manifestations.

Milder disease often has a more subtle clinical presentation and is identified based on abnormal biochemical tests of thyroid function. Screening of the newborn population for congenital hypothyroidism occurs in all developed countries, and when followed by the prompt institution of appropriate thyroid hormone replacement therapy, has dramatically decreased the incidence of mental retardation and cretinism.

Maternal and neonatal hypothyroidism, due to iodine deficiency, remains the major preventable cause of mental retardation worldwide, although much progress has been made in eradicating iodine deficiency. Treatment of the hypothyroid patient consists of thyroid hormone replacement.

Treatment options for the hyperthyroid patient include anti-thyroid drugs to decrease hormone synthesis and secretion, destruction of the gland by the administration of radioactive iodine, or surgical removal. In most patients, disorders of thyroid function can be either cured or have their diseases controlled. Likewise, thyroid malignancies are most often localized and resectable.

ANTITHYROID DRUGS (Propylthiouracil and Carbimazole)

Metastatic disease often responds to radioiodide treatment but may become highly aggressive and unresponsive to conventional treatment. Newer therapies that target specific genetic mutations in malignancies have shown significant activity in both medullary and papillary thyroid cancers. Surgery and radioiodine are not recommended treatment modalities during pregnancy. Untreated hyperthyroidism during pregnancy leads to developmental toxicity which includes spontaneous abortion, prematurity, growth restriction, and fetal death [ 12 ].

structure activity relationship of anti thyroid drugs and pregnancy

It is not clear if untreated hyperthyroidism during pregnancy leads to structural malformations [ 34 ]; however one dataset suggested that the risk of malformations was greater than expected among infants from untreated than treated pregnancies [ 5 ].

Additionally, there is concern that one of the medical therapeutic strategies, MMI, may be a weak developmental toxicant, producing structural malformations [ 6 ], as well as fetal goiter.

Part of this concern stems from the observation that CMI is a weak developmental toxicant and one of its metabolites is MMI. On the one hand, as just mentioned, treatment of hyperthyroidism during pregnancy may result in developmental toxicity, as the available drugs cross the placenta and can cause fetal goiter. On the other hand, while the data remain unclear, there is evidence suggesting that maternal hypothyroidism is associated with impaired fetal neurodevelopment.

Consequently the clinician must balance the use of the antithyroid medications against the potential developmental consequences of inadequate or aggressive therapy, with a limited set of therapeutic options.

structure activity relationship of anti thyroid drugs and pregnancy

A thoughtful review and analysis of literature by Mandel has demonstrated that these assumptions are not correct [ 26 ]. Given the uncommon nature of Graves' disease in pregnancy and the weak link between the antithyroid medications and malformations, we have taken a different approach to assess the potential developmental toxicity of the drugs which are being used to treat the disease in pregnancy.

Several years ago we created datasets to evaluate the structural determinants of developmental toxicity in experimental animals and humans [ 9 — 13 ]. Statistical analyses demonstrated that animal models are reasonable predictors of human developmental toxicity [ 14 ], and that rules could be agreed upon among experts in developmental toxicity for evaluating animal and human data [ 9 ].

structure activity relationship of anti thyroid drugs and pregnancy

Subsequently we evaluated the utility of structure-activity relationship SAR models generated by MultiCASE for studying and predicting developmental toxicity in diverse species including humans [ 12 ]. This later dataset of chemicals assessed for human developmental toxicity has subsequently been utilized to create a more transparent and robust model of developmental toxicity using the categorical-SAR cat-SAR expert system.

Briefly, the cat-SAR expert system diverges from other SAR expert systems wherein there is a high degree of user flexibility in both learning set development and model parameterization [ 15 ].

Cat-SAR analysis allows the user to specify adjustable modeling attributes including the selection of size of the 2-dimensional fragments, whether or not to include hydrogen atoms in the analysis, and rules for identifying important fragments for the final model. Hence, the selection of compounds included in the learning set and control over various model attributes provides the user with the ability to rigorously explore the relationships between chemical structure and biological activity.

Application of the cat-SAR expert system to a toxicological or pharmacological endpoint is thus not constrained wherein a given set of data must fit the attributes of a predefined and often proprietary modeling process. Human Developmental Toxicity Dataset Data on human developmental toxicity were derived from the teratogen information system and a database that utilized the US FDA guidelines as described previously [ 12 ]. The chemicals in this database were specifically characterized with respect to risk for human developmental toxicity including death, growth retardation and functional and structural abnormalities.

Cat-SAR models are built through a comparison of structural features found amongst categorized compounds in the model's learning set. Generically, these categories are toxicologically active and inactive compounds.

Essentially, the cat-SAR approach is transparent in the development of the learning set, the identification of fragments, and the determination of significant or important ones. Moreover, the approach allows user intervention and model optimization throughout the modeling process. This method includes the ability to examine the entire fragment base and to explore and optimize the fragments that have perceived biological relevance. Moreover, since cat-SAR analyzes categorical data and 2-dimensional fragments rather than intact chemicals, the program can examine noncongeneric datasets that are divided into categories of activity rather than degrees of potency as in the case of quantitative SAR QSAR.

Thus, unlike Hansch and conformational molecular field analysis CoMFA approaches that require continuous-type data, cat-SAR works by identifying molecular attributes associated with biological activity by comparing attributes of active e. The models and subsequent predictions based on this dichotomy can then be used to examine structural features associated with teratogenicity and predict the likelihood of teratogenic activity of unknown compounds, respectively.

Overall, the cat-SAR models discussed herein for developmental toxicity demonstrate a high degree of predictivity and mechanistically interpretability and can be useful for screening new drug candidates for developmental toxicity as well as for investigating their therapeutic and toxic mechanisms of action.

structure activity relationship of anti thyroid drugs and pregnancy

Learning Set Development The cat-SAR models are built through a comparison of structural features found amongst two designated categories of compounds in the model's learning set. As mentioned, for these analyses the categories were developmental-toxicity and nondevelopmental-toxicity. The cat-SAR learning set consists of the chemical name, its structure as a MOL2 file, and its categorical designation e.

Typically, organic salts are included as the freebase and simple mixtures and technical grade preparations may be included as the major or active component, metals, metalo-organic compounds and polymers, and mixtures of unknown composition are not included. HQSAR allows the user to select attributes for fragment determination including atom counts i.