Role of a gitogenin-type steroidal saponin (3-O-ß-d-glucopyranosyl (1→2)-ß-d-glucopyranosyl (1→4)-ß-d-galactopyranoside-25R,5α-spirostane-2α,3ß-diol), isolated from the leaves of Malvastrum coromandelianum in regulating thyrotoxicosis in rats.

The hitherto unknown role of saponin in the regulation of thyrotoxicosis has been revealed in chemically-induced thyrotoxic rats. l-T4 (l-thyroxine) administration at pre-standardized dose of 500-µg/kg body weight for 12days increased the levels of thyroid hormones, enhanced the activity of hepatic 5'-monodeiodinase I (5'DI) and glucose-6-phosphatase (G-6Pase) as well as lipid peroxidation (LPO) with a parallel decrease in the levels of antioxidative enzymes. However, administration of the isolated saponin for 15days ameliorated the T4-induced alterations in serum thyroid hormones, hepatic LPO, G-6-Pase and 5'DI activity, and improved the cellular antioxidant status, indicating its antithyroidal and antioxidative potential. These effects of the test compound were comparable to a reference antithyroid drug, Propylthiouracil (PTU), suggesting that the test saponin may act as a potent anti-thyroid agent.

Cocrystals of 6-methyl-2-thiouracil: presence of the acceptor-donor-acceptor/donor-acceptor-donor synthon.

The results of seven cocrystallization experiments of the antithyroid drug 6-methyl-2-thiouracil (MTU), C(5)H(6)N(2)OS, with 2,4-diaminopyrimidine, 2,4,6-triaminopyrimidine and 6-amino-3H-isocytosine (viz. 2,6-diamino-3H-pyrimidin-4-one) are reported. MTU features an ADA (A = acceptor and D = donor) hydrogen-bonding site, while the three coformers show complementary DAD hydrogen-bonding sites and therefore should be capable of forming an ADA/DAD N-H...O/N-H...N/N-H...S synthon with MTU. The experiments yielded one cocrystal and six cocrystal solvates, namely 6-methyl-2-thiouracil-2,4-diaminopyrimidine-1-methylpyrrolidin-2-one (1/1/2), C(5)H(6)N(2)OS·C(4)H(6)N(4)·2C(5)H(9)NO, (I), 6-methyl-2-thiouracil-2,4-diaminopyrimidine (1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4), (II), 6-methyl-2-thiouracil-2,4-diaminopyrimidine-N,N-dimethylacetamide (2/1/2), 2C(5)H(6)N(2)OS·C(4)H(6)N(4)·2C(4)H(9)NO, (III), 6-methyl-2-thiouracil-2,4-diaminopyrimidine-N,N-dimethylformamide (2/1/2), C(5)H(6)N(2)OS·0.5C(4)H(6)N(4)·C(3)H(7)NO, (IV), 2,4,6-triaminopyrimidinium 6-methyl-2-thiouracilate-6-methyl-2-thiouracil-N,N-dimethylformamide (1/1/2), C(4)H(8)N(5)(+)·C(5)H(5)N(2)OS(-)·C(5)H(6)N(2)OS·2C(3)H(7)NO, (V), 6-methyl-2-thiouracil-6-amino-3H-isocytosine-N,N-dimethylformamide (1/1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4)O·C(3)H(7)NO, (VI), and 6-methyl-2-thiouracil-6-amino-3H-isocytosine-dimethyl sulfoxide (1/1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4)O·C(2)H(6)OS, (VII). Whereas in cocrystal (I) an R(2)(2)(8) interaction similar to the Watson-Crick adenine/uracil base pair is formed and a two-dimensional hydrogen-bonding network is observed, the cocrystals (II)-(VII) contain the triply hydrogen-bonded ADA/DAD N-H...O/N-H...N/N-H...S synthon and show a one-dimensional hydrogen-bonding network. Although 2,4-diaminopyrimidine possesses only one DAD hydrogen-bonding site, it is, due to orientational disorder, triply connected to two MTU molecules in (III) and (IV).

Homeopathic and integrative treatment for feline hyperthyroidism--four cases (2006-2010).

Hyperthyroidism is a frequent veterinary problem, particularly in elderly cats. Homeopathic treatment and other integrative modalities were provided for four hyperthyroid cats whose owners did not want conventional treatment. Symptomatic homeopathic treatment with Thyroidinum was helpful in one cat. All cats were prescribed an appropriate individualized homeopathic remedy. All four cats showed resolution of clinical signs; three attained normal thyroid hormone levels. Three cats later received acupuncture and/or herbal medicines; two cats later received symptomatic homeopathic remedies. Two cats are thriving after over 3.5 and 4.25 years of treatment; two were euthanized for unrelated problems after 3 and 4 years of treatment. Homeopathic and complementary therapies avoid the potential side effects of methimazole and surgical thyroidectomy, they are less costly than radioactive iodine treatment, and they provide an option for clients who decline conventional therapies.

Goitrogenic/antithyroidal potential of green tea extract in relation to catechin in rats.

Catechins are flavonoids found in abundance in green tea, have elicited high interest due to their beneficial effects on health. Though flavonoids have been reported to have an antithyroid effect and also to be goitrogenic there have been no reports about the effect of green tea on rat thyroid. The present study was designed to examine whether high doses of green tea has any harmful effect on thyroid physiology. For this purpose green tea extract was administered orally to male albino rats for 30 days at doses of 1.25 g%, 2.5 g% and 5.0 g%, respectively. Similarly, pure catechin was administered at doses of 25, 50 and 100mg/kg body weight which is equivalent to above doses of green tea extract. Lower body weight gain associated with marked hypertrophy and/or hyperplasia of the follicles was noted in the high dose of green tea and catechin treated groups. Decreased activity of thyroid peroxidase and 5'-deiodinase I and substantially elevated thyroidal Na,K+ATPase activity have been observed. Moreover, serum T3 and T4 levels were found to reduce followed by significant elevation of serum TSH. Taken together, these results suggest that catechin present in green tea extract might behave as antithyroid agent and possibly the consumption of green tea at high dose could alter thyroid function adversely.

Antithyroid drugs and their analogues protect against peroxynitrite-mediated protein tyrosine nitration--a mechanistic study.

In this paper, the effect of some commonly used antithyroid drugs and their analogues on peroxynitrite-mediated nitration of proteins is described. The nitration of tyrosine residues in bovine serum albumin (BSA) and cytochrome c was studied by Western blot analysis. These studies reveal that the antithyroid drugs methimazole (MMI), 6-n-propyl-2-thiouracil (PTU), and 6-methyl-2-thiouracil (MTU), which contain thione moieties, significantly reduce the tyrosine nitration of both BSA and cytochrome c. While MMI exhibits good peroxynitrite (PN) scavenging activity, the thiouracil compounds PTU and MTU are slightly less effective than MMI. The S- and Se- methylated compounds show a weak inhibitory effect in the nitration of tyrosine, indicating that the presence of a thione or selone moiety is important for an efficient inhibition. Similarly, the replacement of N-H moiety in MMI by N-methyl or N-m-methoxybenzyl substituents dramatically reduces the antioxidant activity of the parent compound. Theoretical studies indicate that the substitution of N-H moiety by N-Me significantly increases the energy required for the oxidation of sulfur center by PN. However, such substitution in the selenium analogue of MMI increases the activity of parent compound. This is due to the facile oxidation of the selone moiety to the corresponding selenenic and seleninic acids. Unlike N,N'-disubstituted thiones, the corresponding selones efficiently scavenge PN, as they predominantly exist in their zwitterionic forms in which the selenium atom carries a large negative charge.

Preparation, characterization, and in vitro release of new transdermal methimazole as alternative to oral delivery.

Our objective has been the development and study of the stability of transdermal methimazole formulae as alternative to oral administration. Preparation of F-127 and PLO Pluronic gel (Pluronic lecitin organogel) are described, as well as their characteristics from transmission electron microscopy. The possible structural and rheological changes to both transdermal forms were studied in terms of composition, temperature and time. The trial period was from 24 hr to 3 months after preparation. Furthermore, identical tests were carried out on formulae conserved for 1 year after production to check their integrity. Studies of release in vitro were carried out showing that the selected excipients do not pose an obstacle to the cession of methimazole, even though the PLO samples were made more slowly.

Antiperoxidative, antithyroidal, antihyperglycemic and cardioprotective role of Citrus sinensis peel extract in male mice.

An extract of Citrus sinensis (CS) peel was evaluated for its efficacy in ameliorating L-thyroxine (L-T(4)) induced tissue lipid peroxidation (LPO), hyperthyroidism and hyperglycemia in mice. In a preliminary investigation, of the three different doses of CS (12.5 mg/kg, 25 mg/kg and 50.0 mg/kg) peel extract, 25 mg/kg was found to be the most effective and antiperoxidative, while 50 mg/kg was proved to be hepatotoxic. Therefore in the pilot experiment the effects of 25 mg/kg/day of CS for 10 days were studied in L-T(4) induced hyperthyroid animals. L-T(4) (500 microg/kg/day for 10 days) increased the levels of thyroxine (T(4)) and triiodothyronine (T(3)) with a concomitant increase in serum glucose concentration, alpha-amylase activity, heart/body weight ratio (HW/BW), kidney/body weight ratio (KW/BW) and cardiac as well as hepatic LPO. However, it decreased the concentration of different serum lipids such as total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C). Administration of CS extract (25 mg/kg/day) in hyperthyroid animals reversed most of these observations revealing the ameliorating potential of CS extract against various adverse effects of hyperthyroidism. It appears that the test extract primarily acts through its antioxidative/free radical-scavenging, antithyroidal and HDL-C stimulating properties.

Goitrogenic content of Indian cyanogenic plant foods & their in vitro anti-thyroidal activity.

BACKGROUND & OBJECTIVES: Consumption of cyanogenic foods has been considered as one of the etiological factors in certain instances for the persistence of endemic goitre. The present study was undertaken to study the cyanogenic glucosides, glucosinolates and thiocyanate content in edible portion of certain selected plant foods of Indian origin. Further in vitro anti-thyroidal activity using raw, boiled and cooked extracts of these plants with and without excess iodide was also studied. METHODS: Cyanogenic plant foods generally vegetables were collected from different areas of West Bengal and Tripura. Cassava was obtained from Meghalaya and Kerala and their cyanogenic glucosides, glucosinolates and thiocyanate were estimated. Thyroid peroxidase activity (TPO) of human thyroid was assayed from microsomal fraction following I3- from iodide. The anti-TPO activities of the plants were assayed after adding raw, boiled and cooked extracts in the assay medium with and without extra iodide. Relative antithyroidal potency of the plant extracts was also evaluated in terms of the concentration (IC50) necessary to produce 50 per cent inhibition of TPO activity. PTU equivalence of the plant foods was also determined. RESULTS: Cabbage and cauliflower were rich in glucosinolates, bamboo shoot and cassava were rich in cyanogenic glucosides, mustard, turnip and radish were relatively rich in thiocyanate however all the constituents were present in each plant. Boiled extracts showed maximum inhibition of TPO activity followed by cooked and raw extracts. Excess iodide was found relatively effective for raw extract but less effective for boiled and cooked extracts in reversing anti-TPO activity. Inhibition constant (IC50) was found highest with bamboo shoot and least with cabbage. INTERPRETATION & CONCLUSION: Raw, boiled and cooked extracts of the plants showed anti-thyroidal activity in vitro. Excess iodide reversed the anti-TPO activity to same extent but could not neutralise it.

Enhanced rat Hershberger assay appears reliable for detection of not only (anti-)androgenic chemicals but also thyroid hormone modulators.

Development of an internationally recognized standard for the Hershberger assay as a screening tool to detect potential (anti-)androgenic chemicals is in progress. In the present preliminary study, we evaluated the reliability of the enhanced Hershberger assay to detect thyroid hormone modulating activity, while concentrating attention on possible confounding influence on evaluation of (anti-)androgenic activity. Castrated or testosterone propionate (TP; 0.2 or 0.25 mg/kg/day)-injected castrated male Crj:CD(SD) IGS rats (seven weeks of age) were dosed for 10 days by oral gavage with vehicle (corn oil) or the following chemicals: propylthiouracil (PTU; 2.5 mg/kg/day), a potent inhibitor of thyroid hormone synthesis, phenobarbital (PB; 125 mg/kg/day) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE; 100 mg/kg/day), two hepatic enzyme inducers that enhance the clearance of thyroid hormones. PTU markedly increased thyroid weights, and decreased serum T3 and T4, and increased serum TSH, also causing marked microscopic alteration of the thyroid gland. In comparison, PB and p,p'-DDE only significantly affect serum T4 and revealed some histopathological findings. The alterations appeared to be more robust in the presence of TP. Furthermore, data for p,p'-DDE demonstrated its anti-androgenic effects, whereas PTU and PB had little or no effects on the weights of androgen-related accessory glands/tissues: the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, glans penis, Cowper's glands, and levator ani plus bulbocavernosus (LABC) muscles. Weight of the LABC muscles was decreased by PB treatment in TP-treated castrated rats. These findings in the present study suggests that the enhanced Hershberger assay, with evaluation of thyroid histopathology and weights, and hormone levels, appears to be reliable for screening for not only (anti-)androgenic chemicals but also thyroid hormone modulators. In order to evaluate whether the sensitivity and specificity of such a thyroid assay is great enough for routine screening purposes, future experiments including dose-response studies using lower dose levels have to be performed.

Atom level electrotopological state indexes in QSAR: designing and testing antithyroid agents.

PURPOSE: To design antithyroid agents with less side effects, the electrotopological-state (E-state) indexes of thiourylene moiety (SN&S) was utilized as a guideline to develop five acrylic thiourylene-type compounds with reduced antioxidant property. METHODS: These agents were synthesized and screened for antithyroid activity in rats using 125I-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorphonuclear leukocytes (PMNLs) were also conducted to reveal antioxidant properties of the tested compounds. RESULTS: A linear relationship between the in vitro literature value of the formation constants of thiourylene-type compounds with iodine (Kc) and the SN&S was observed and utilized in designing those agents. At least one of the compounds (abouthiouzine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2-thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil with respect to the rate of 125I-discharge and 125I-uptake, respectively. In addition, chemiluminescence studies on PMNLs revealed that abouthiouzine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. CONCLUSIONS: The E-state approach provides guidelines to economize efforts and cost of designing new antithyroid drugs.