Mild exercise plus levothyroxine ameliorate deficits of spatial navigation, anxiety profile, and hippocampal BDNF in hypothyroid male offspring rats.

PURPOSE: Levothyroxine (LEV) monotherapy cannot completely improve cognitive and behavioral impairments induced by hypothyroidism, whereas a combination therapy of exercise and LEV may ameliorate these deficits. This study aimed to determine the effects of mild-intensity forced exercise and LEV treatment on the anxiety profile and cognitive functions in male offspring of hypothyroid dams. METHOD: Twenty-four female rats (mothers) were randomly divided into sham (healthy) and hypothyroidism groups and then placed with male rats to mate. The presence of vaginal plaque confirmed pregnancy (gestational day, GD 0). 6-propyl-2-thiouracil (PTU, 100 ppm) was added to the drinking water of the hypothyroidism group from GD 6 to the 21st postnatal day (PND). The sham group received tap water. On PND 21, serum T4 levels of mothers, and 10 pups were measured to confirm hypothyroidism. Sixty-four male pups were left undisturbed for 30 days and then were divided into eight groups that received saline or LEV (50 µg/kg, i.p.) with or without forced mild-intensity exercise. After 14 days of interventions, anxiety-like behaviors, spatial learning and memory, and hippocampal brain-derived neurotrophic factor (BDNF) levels were evaluated. FINDING: A pre and postnatal PTU-induced model of hypothyroidism increased anxiety-like behaviors, impaired spatial learning and memory, and decreased hippocampal BDNF levels in male offspring rats. LEV alone increased BDNF levels and improved spatial learning. Exercise alone increased BDNF levels, improved spatial learning and memory, and decreased anxiety-like behaviors. Exercise plus LEV more effectively improved anxiety-like behaviors and spatial learning than exercise or LEV alone. CONCLUSION: Practically, these pre-clinical findings highlight the importance of the combination of exercise and LEV regimen in treating patients with hyperthyroidism.

Long-term pharmacological torpor of rats with feedback-controlled drug administration.

The maintenance of pharmacological torpor and hypothermia (body temperature 28 °C - 33 °C) in rats for a week is presented. For this purpose, our laboratory has developed a device (BioFeedback-2) for the feed-back controlled multiple injections of small doses of a pharmacological composition that we created earlier. On the 7th day, the rat spontaneously come out of the pharmacological torpor, the body temperature returned to normal, and on the 8th day, the animal could consume food and water. The proposed approach for maintaining multi-day pharmacological torpor can be applied in medicine, as well as for protecting astronauts during long missions in space.

Safety of antithyroid drugs in pregnancy: update and therapy implications.

Introduction: The thionamide antithyroid drugs, methimazole (MMI), its pro-drug derivative carbimazole (CMZ), and propylthiouracil (PTU) are the mainstay of treatment for hyperthyroidism in pregnancy. However, antithyroid drugs carry risks of adverse effects that can affect fetal and maternal well-being.Areas covered: This review provides an update on the safety of antithyroid drugs in pregnancy, focusing on the most serious concerns of severe liver disease and congenital anomalies.Expert opinion: PTU-induced liver disease is uncommon but can run a catastrophic course in pregnancy with a risk of liver failure and threats to maternal or fetal survival. Acute pancreatitis is a relatively rare occurrence that has been linked to thionamide use in a handful of reports in non-pregnant individuals. Observational studies on the risk of birth defects with antithyroid drug exposure in pregnancy overall show an increase in birth defect risk with exposure to CMZ/MMI, and to a lesser extent, PTU. Further studies are required to determine whether the currently recommended approach of switching between thionamide drugs in pregnancy improves outcomes. Ultimately, a preventative strategy of offering definitive therapy to hyperthyroid women of childbearing potential offers the best approach to truly reduce the risks of antithyroid drug adverse effects in pregnancy.

Preference for and sensitivity to flavanol mean degree of polymerization in model wines is correlated with body composition.

Bitterness and astringency (dryness) are characteristic sensory attributes of flavanol-rich foods. The degree of polymerization (DP) of flavanols influences their bitter and astringent sensations. Smaller DP compounds can enter the papillae on the tongue, eliciting a bitter response. Larger DP compounds are sterically inhibited from entering papillae and instead interact with oral proteins, cause precipitation, and elicit astringent sensations. Previous research has indicated that bitterness preference is related to health status, density of fungiform papillae on the tongue, and sensitivity to bitter compounds such as 6-n-propyl-thiouracil (PROP). The purpose of this study was to examine trends in liking, bitterness intensity, and astringency intensity of wine-like products with flavanols of different DP using a consumer sensory panel. Participants (n = 102) were segmented by phenotypes: body fat percentage (BF%), body mass index (BMI), PROP sensitivity, and stated bitter food preference. Differences in wine liking, perceived bitterness intensity, and astringency intensity were observed between three model wine samples of varying flavanol mean degrees of polymerization (mDP, i.e. the average size (polymer length) of flavanol compounds in a mixture). Specifically, with increased mDP, overall liking and bitterness liking decreased, with concurrent increased perception of bitterness and astringency intensity. Greater differences between phenotypes were observed when participants were segmented by BF% and BMI classification, than when segmented by PROP sensitivity classification. Reduced ability to detect differences in bitterness and astringency were noted in participants of higher weight status. Overall, these data suggest that weight status in adults is a greater predictor of liking of flavanol-rich foods than bitterness sensitivity (as determined by PROP classification), and that reduced perception of bitterness and astringency associated with weight gain may impact selection and preference for these foods.

Rats are unable to discriminate quinine from diverse bitter stimuli.

Compounds described by humans as "bitter" are sensed by a family of type 2 taste receptors (T2Rs). Previous work suggested that diverse bitter stimuli activate distinct receptors, which might allow for perceptually distinct tastes. Alternatively, it has been shown that multiple T2Rs are expressed on the same taste cell, leading to the contrary suggestion that these stimuli produce a unitary perception. Behavioral work done to address this in rodent models is limited to Spector and Kopka (Spector AC, Kopka SL. J Neurosci 22: 1937-1941, 2002), who demonstrated that rats cannot discriminate quinine from denatonium. Supporting this finding, it has been shown that quinine and denatonium activate overlapping T2Rs and neurons in both the mouse and rat nucleus of the solitary tract (NTS). However, cycloheximide and 6-n-propylthiouracil (PROP) do not appear to overlap with quinine in the NTS, suggesting that these stimuli may be discriminable from quinine and the denatonium/quinine comparison is not generalizable. Using the same procedure as Spector and Kopka, we tasked animals with discriminating a range of stimuli (denatonium, cycloheximide, PROP, and sucrose octaacetate) from quinine. We replicated and expanded the findings of Spector and Kopka; rats could not discriminate quinine from denatonium, cycloheximide, or PROP. Rats showed a very weak ability to discriminate between quinine and sucrose octaacetate. All animals succeeded in discriminating quinine from KCl, demonstrating they were capable of the task. These data suggest that rats cannot discriminate this suite of stimuli, although they appear distinct by physiological measures.

Prepubertal PTU treatment in rat increases Sertoli cell number and sperm production.

The number of Sertoli cells (SCs) ultimately determines the upper limit of sperm production in the testis. Previous studies have shown that thyroid hormones (TH) receptors are abundantly expressed in developing SCs; therefore, it was highly significant to discover that transient neonatal hypothyroidism induced by the goitrogen 6-n-propyl-2-thiouracil (PTU) can extend SCs proliferation beyond the first 2 weeks postnatal and increase testis weight and sperm production. Further studies concluded that treatment must begin before day 8 post birth in rats. Recent studies, however, showed that SCs present in the transition region at the rete testis exhibit a more immature phenotype and have prolonged mitotic activity, which led to the hypothesis that SCs in this region will retain the capacity to respond to PTU treatment over a longer period of time. In the present study, male Wistar rats were treated with PTU from days 21 to 40 and were evaluated at 40 and 160 days of age. Similar to neonatal rat SCs, it was demonstrated that prepubertal SCs in the transition region have a high mitotic activity and are highly sensitive to TH levels. This delayed, transient hypothyroidism resulted in significantly increased testis weight, SCs number and daily sperm production. The results demonstrate for the first time that Sertoli cells showing plasticity in the transition region can be stimulated to increase proliferation and contribute to a late stage surge in testis weight and sperm output.

Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves' disease influencing the therapeutic efficacy.

Graves' disease is an organ-specific autoimmune disease with hyperthyroidism, diffuse goiter and autoantibodies against TSH receptor, thyroid peroxidase (TPO) and/or thyroglobulin (Tg). Graves' hyperthyroidism is characterized by T3 dominance due to the conversion of T4 into T3 through type 1 and 2 deiodinase enzymes (DIO1, DIO2). Methimazole (MMI) and propylthiouracil (PTU) therapies inhibit thyroid hormone synthesis blocking the activity of deiodinase and TPO enzymes. The study investigated the occurrence of autoantibodies against DIO2 peptides (cys- and hom-peptides) with the effect of antithyroid drugs on their frequencies in 78 patients with Graves' disease and 30 controls. In hyperthyroidism, the presence of DIO2 peptide antibodies was as follows: 20 and 11 cases out of 51 for cys- and hom-peptide antibodies, respectively, of whom 8 cases possessed antibodies against both peptides. Antithyroid drugs differently influenced their frequencies, which were greater in PTU than in MMI (3/6 vs 13/45 cases, P < 0.016 for cys- and 0/6 vs 2/45 cases for hom-peptide antibodies). Antibodies against both peptides demonstrated more reduced levels of anti-TPO (P < 0.003) and anti-Tg antibodies (P < 0.002) compared with those without peptide antibodies. PTU compared with MMI increased the levels of TSH receptor antibodies (32.5 UI/l vs 2.68 IU/l, P < 0.009). MMI treatment led to more reduced FT3 levels and FT3/FT4 ratios in hyperthyroid Graves' ophthalmopathy (P < 0.028 for FT3, P < 0.007 for FT3/FT4 ratio). In conclusion, the presence of DIO2 peptide antibodies is connected to Graves' hyperthyroidism influencing the levels of antibodies against TPO, Tg and TSH receptor, as well as the therapeutic efficacy of antithyroid drugs.

Fetal thyroid disorders: Pathophysiology, diagnosis and therapeutic approaches.

Fetal thyroid disorders while uncommon in general, have significant morbidity and profound effects in the neonate. Pregnancy provides the opportunity not only for the diagnosis of these conditions but also for therapeutic interventions. In careful balance, these disorders range from hypothyroidism to hyperthyroidism, both may manifest with fetal thyroid goiters as well. The intrauterine therapeutic approach of these must also weight the balance in this range as well as the maternal well being which may also express thyroid dysfunction. In this review we explore the different fetal manifestations of thyroid disease, describe the pathophysiology and therapeutic approaches both in practice and in development.

A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats.

AIMS: To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor. MATERIALS AND METHODS: We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle. KEY FINDINGS: After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C-23 °C. The hypothermic state may continue on average for 16-17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4-8 days later they were restored. SIGNIFICANCE: Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.

Exacerbated liver injury of antithyroid drugs in endotoxin-treated mice.

Drug-induced liver injury is a major concern in clinical studies as well as in post-marketing surveillance. Previous evidence suggested that drug exposure during periods of inflammation could increase an individual's susceptibility to drug hepatoxicity. The antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU) can cause adverse reactions in patients, with liver as a usual target. We tested the hypothesis that MMI and PTU could be rendered hepatotoxic in animals undergoing a modest inflammation. Mice were treated with a nonhepatotoxic dose of LPS (100 µg/kg, i.p) or its vehicle. Nonhepatotoxic doses of MMI (10, 25 and 50 mg/kg, oral) and PTU (10, 25 and 50 mg/kg, oral) were administered two hours after LPS treatment. It was found that liver injury was evident only in animals received both drug and LPS, as estimated by increases in serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and TNF-α. An increase in liver myeloperoxidase (MPO) enzyme activity and tissue lipid peroxidation (LPO) in addition of liver glutathione (GSH) depletion were also detected in LPS and antithyroid drugs cotreated animals. Furthermore, histopathological changes including, endotheliitis, fatty changes, severe inflammatory cells infiltration (hepatitis) and sinusoidal congestion were detected in liver tissue. Methyl palmitate (2 g/kg, i.v, 44 hours before LPS), as a macrophage suppressor, significantly alleviated antithyroids hepatotoxicity in LPS-treated animals. The results indicate a synergistic liver injury from antithyroid drugs and bacterial lipopolysaccharide coexposure.

Propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis mimicking Kawasaki disease.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rare in children and is characterised as necrotising vasculitis predominantly affecting small and medium-sized vessels. Propylthiouracil (PTU), an antithyroid drug, has been implicated in drug-induced AAV. In contrast, Kawasaki disease (KD) is a common systemic vasculitis, typically observed in children, which affects the medium-sized vessels, including the coronary arteries. An 11-year-old girl who developed AAV while receiving PTU therapy for Graves' disease is described. She was admitted to hospital following a 2-day history of fever, cervical adenopathy, cheilitis and papular rash, 3 weeks after an increase in the PTU dose. Despite discontinuation of PTU and the administration of intravenous antibiotic therapy, her clinical condition deteriorated and over the next 2 days she developed severe diarrhoea, conjunctival injection and swelling and redness of the right index finger. Additional findings included liver dysfunction, hydrops of the gallbladder, coagulopathy and urine abnormalities, suggesting glomerulonephritis. She met the diagnostic criteria for KD and received intravenous immunoglobulin (IVIG) combined with prednisolone, with rapid resolution of clinical and laboratory parameters. Peeling of the right index fingertip became evident on Day 12 of admission. Serial ultrasound cardiography demonstrated no evidence of cardiac involvement. A high titre of myeloperoxidase ANCA was detected in the patient's serum on admission, and the titre decreased during the convalescent stage. This case demonstrates that children with PTU-associated AAV may present with clinical features mimicking KD, and that IVIG along with corticosteroid therapy may be effective in treating patients with drug-induced severe systemic AAV.

Bioavailability of propylthiouracil from two formulation tablets.

Bioavailability studies were performed for 50 mg propylthiouracil tablets (Jelfa, Poland) versus 50 mg propycil tablets (Solvay, Germany). An open-label, two-phase, crossover study was conducted with 15 healthy subjects. All subjects were randomly assigned a drug assignment number from I to XV, which was used throughout the experimental period. Dosing periods for both formulation tablets: Propylthiouracil, Jelfa vs. Propycil, Solvay were separated by at least 7 days washout period. Following single dose drug administration, venous blood samples were obtained at the required times for 12 h and the drug serum levels were determined by HPLC and used for PK analysis. PK parameters were calculated by the computer program TopFit 2.0. HPLC chromatograms show retention times for propylthiouracil and methylthiouracil (internal standard) of 5.97 and 2.75 min, respectively at 20 °C, providing adequate separation from each other and from endogenous serum components. Pharmacokinetic parameters for both tablets were not significantly different. Serum concentration-time profiles are superimposed for the above tablets according to an open one-compartment body model. EBA for Propythiouracil Jelfa tablets vs. Propycil tablets was 96.8%, and not significantly different. Some authors applied a two-compartment body model for the calculation of propylthiouracil pharmacokinetic parameters, which approach is not rational according to our data.

Thyroid Hormone Disruption in the Fetal and Neonatal Rat: Predictive Hormone Measures and Bioindicators of Hormone Action in the Developing Cortex.

Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid hormone (TH) disrupting chemicals. Though the developing brain is a known target of TH insufficiency, the relationship between THs in the serum and the central nervous system is not well characterized. To address this issue, dose response experiments were performed in pregnant rats using the goitrogen propylthiouracil (PTU) (dose range 0.1-10 ppm). THs were quantified in the serum and brain of offspring at gestational day 20 (GD20) and postnatal day 14 (PN14), two developmental stages included in OECD and EPA regulatory guideline/guidance studies. From the dose response data, the quantitative relationships between THs in the serum and brain were determined. Next, targeted gene expression analyses were performed in the fetal and neonatal cortex to test the hypothesis that TH action in the developing brain is linked to changes in TH concentrations within the tissue. Results show a significant reduction of T4/T3 in the serum and brain of the GD20 fetus in response to low doses of PTU; interestingly, very few genes were significantly different at any dose tested. In the PN14 pup significant reductions of T4/T3 in the serum and brain were also detected; however, twelve transcriptional targets were identified in the neonatal cortex that correlated well with reduced brain THs. These results show that serum T4 is a good predictor of brain THs, and offer several target genes that could serve as pragmatic readouts of T4/T3 dysfunction within the PN14 cortex.

Benchmark dose analysis of multiple thyroid toxicity endpoints in ovariectomized rats exposed to propylthiouracil.

Benchmark dose (BMD) analysis is generally recognized superior to generate a point of departure (PoD) to conduct risk assessment on environmental toxicants, comparing with the traditionally employed no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) methods. However, only a few studies compared the two on producing PoD of thyroid toxicity caused by environmental chemicals. Here, we presented BMD analyses on several thyroid toxicity endpoints caused by a model chemical - propylthiouracil (PTU). Adult female rats underwent ovariectomy were randomly assigned into groups receiving different doses of PTU (0, 0.1, 0.5, 1.0, and 5.0 mg/kg bw) through gavage for 8 days. Results show that PTU induces significant dose-dependent changes of serum total thyroxine (tT4), total triiodothyronine (tT3), thyroid stimulating hormones, liver type I 5'-deiodinonase (5'-DI) and malic enzyme (ME) activity with profound histopathological exacerbation. BMD and BMDL results (0.03 and 0.01 mg/kg bw respectively) from Hill model of liver 5'-DI activity were accepted based on selection criteria in the benchmark dose analysis. In summary, BMD analysis results in much lower PoD (0.01 mg/kg bw) than LOAEL (0.1 mg/kg bw) in PTU induced thyroid toxicity.

Time-intensity and reaction-time methodology applied to the dynamic perception and liking of bitterness in relation to body mass index.

There are very few studies which have considered perception temporality when relating perceived intensity and hedonic responses in relation to body mass index (BMI; kg/cm2). The aim of the present study was to determine the relationship between BMI with the dynamic perception and liking of bitter tasting solutions. For this purpose, two different categories of bitter products were applied: 6-n-propilthiouracil (PROP) solutions (0.010, 0.032 and 0.060 mmol/L) and commercial beverages (coffee, yerba mate infusion and grapefruit juice). The proposed methodology to evaluate perception and hedonic response was based on the measurement of reaction-time (R-T) and multiple-sip time-intensity (T-I) registers in people with a high BMI (25 < BMI < 30; overweight group) and a normal BMI (<25; normal-weight control group). The multiple-sip evaluation to describe perception of PROP solutions and liking of beverages was used as a more ecologically valid laboratory methodology to simulate a situation of usual consumption. In this sense, working with a multiple-sip design helped confirm that bitter taste has a cumulative effect since in every case the sip effect was significant when evaluating the maximum intensity; this effect was more important as the bitterness increased. Regarding the body weight group comparisons, the normal BMI group perceived bitter taste more intensely and the time to react to it was shorter (faster reaction) for both PROP solutions and the three beverages. Interestingly, even though the high BMI group rated the bitter taste as less intense, they had a lower level of acceptance than normal BMI. This result suggests that the hedonic rather than the sensory component might be playing a crucial role in the perception of bitter taste in individuals with high BMI.

Propylthiouracil-coated biodegradable polymer inhibited neointimal formation and enhanced re-endothelialization after vascular injury.

BACKGROUND: The drug-eluting stent is a standard approach for the treatment of coronary artery disease. Propylthiouracil (PTU), an antithyroid drug, has been proven to suppress neointimal formation after balloon injury. MATERIALS AND METHODS: This study used a biodegradable polymer coating with PTU to test its effects on platelet function, re-endothelialization, and neointimal formation after vascular injury. Electrospinning was used to fabricate hybrid stents and generate PTU-loaded nanofibers. RESULTS: PTU-eluting stents maintained a stable release of PTU for 3 weeks. The PTU-coated stent markedly decreased the neointimal formation induced by vascular injury in the descending aorta of rabbits. Moreover, the PTU coating reduced platelet adhesion on the surface of the biodegradable membrane, which was reflected by the decreased expression of adhesion molecule in PTU-treated endothelial cells. The PTU coating enhanced re-endothelialization in injured aortas. In vitro, PTU exerted less suppressive effect on the proliferation and migration of endothelial cells than on those of vascular smooth muscle cells. Furthermore, treatment of endothelial cells with PTU induced phosphorylation (Ser1177) of endothelial nitric oxide synthase as well as its association with heat shock protein 90, supporting the protective role of PTU in endothelial function. The level of thyroid-stimulating hormone remained unchanged during the experimental period. CONCLUSION: This study indicates that PTU can be released locally and steadily in injured aortas, with some local effects but without systemic effects. Furthermore, PTU-coated stents may have beneficial effects on neointimal formation, endothelial cell, and platelet functions.

6-n-propylthiouracil taste disruption and TAS2R38 nontasting form in Parkinson's disease.

BACKGROUND: The few studies that evaluated taste function in Parkinson's disease (PD) showed inconsistent results. The inherited ability to taste the bitter compound of 6-n-propylthiouracil has been considered to be a paradigm of general taste perception. 6-n-propylthiouracil taste perception is mediated by the TAS2R38 receptor, and reduced 6-n-propylthiouracil sensitivity has been associated with several diseases not typically related to taste function. OBJECTIVES: We evaluated the 6-n-propylthiouracil taste perception and the TAS2R38 gene as genetic risk factors for the development of idiopathic PD in PD patients and healthy controls (HC). METHODS: The 6-n-propylthiouracil taste perception was assessed by testing the responsiveness, and the ability to recognize, 6-n-propylthiouracil and sodium chloride. The participants were classified for 6-n-propylthiouracil taster status and genotyped for the TAS2R38 gene. RESULTS: A significant increase in the frequency of participants classified as 6-n-propylthiouracil nontasters and a reduced ability to recognize bitter taste quality of 6-n-propylthiouracil were found in PD patients when compared with healthy controls. The results also showed that only 5% of PD patients had the homozygous genotype for the dominant tasting variant of TAS2R38, whereas most of them carried the recessive nontaster form and a high number had a rare variant. CONCLUSIONS: Our results show that 6-n-propylthiouracil taster status and TAS2R38 locus are associated with PD. The 6-n-propylthiouracil test may therefore represent a novel, simple way to identify increased vulnerability to PD. Moreover, the presence of the nontasting form of TAS2R38 in PD may further substantiate that disease-associated taste disruption may represent a risk factor associated with the disease. © 2018 International Parkinson and Movement Disorder Society.