propylthiouracil and Cardiovascular-Diseases

We hypothesize that variation in oral sensation influences chronic disease risk by impacting dietary behaviors. Bitterness of 6-n-propylthiouracil (PROP) and fungiform papilla (FP) number serve as genetic taste markers. Data support that nontasters (who taste PROP as least bitter or have lowest FP number) show dietary behaviors that increase CVD risk (e.g. higher alcohol intake, greater preference for and intake of high-fat and sweet foods) and have greater measured CVD risk (e.g. higher blood pressure, less favorable serum lipids). Taste genetics interacts with environmental factors (e.g. taste-related pathologies) to affect oral sensation, dietary behaviors and disease risk. The generalizability of oral sensory and CVD risk relationships has begun to be tested on diverse samples.

Topics: Cardiovascular Diseases; Feeding Behavior; Food Preferences; Humans; Propylthiouracil; Risk Factors; Taste; Taste Buds

Sensations from foods and beverages drive dietary choices, which in turn, affect risk of diet-related diseases. Perception of these sensation varies with environmental and genetic influences. This observational study aimed to examine associations between chemosensory phenotype, diet and cardiovascular disease (CVD) risk. Reportedly healthy women (n = 110, average age 45 ± 9 years) participated in laboratory-based measures of chemosensory phenotype (taste and smell function, propylthiouracil (PROP) bitterness) and CVD risk factors (waist circumference, blood pressure, serum lipids). Diet variables included preference and intake of sweet/high-fat foods, dietary restraint, and diet quality based on reported preference (Healthy Eating Preference Index-HEPI) and intake (Healthy Eating Index-HEI). We found that females who reported high preference yet low consumption of sweet/high-fat foods had the highest dietary restraint and depressed quinine taste function. PROP nontasters were more likely to report lower diet quality; PROP supertasters more likely to consume but not like a healthy diet. Multivariate structural models were fitted to identify predictors of CVD risk factors. Reliable latent taste (quinine taste function, PROP tasting) and smell (odor intensity) variables were identified, with taste explaining more variance in the CVD risk factors. Lower bitter taste perception was associated with elevated risk. In multivariate models, the HEPI completely mediated the taste-adiposity and taste-HDL associations and partially mediated the taste-triglyceride or taste-systolic blood pressure associations. The taste-LDL pathway was significant and direct. The HEI could not replace HEPI in adequate models. However, using a latent diet quality variable with HEPI and HEI, increased the strength of association between diet quality and adiposity or CVD risk factors. In conclusion, bitter taste phenotype was associated with CVD risk factors via diet quality, particularly when assessed by level of food liking/disliking.

Topics: Adult; Blood Pressure; Cardiovascular Diseases; Diet; Feeding Behavior; Female; Healthy Volunteers; Humans; Lipids; Middle Aged; Models, Psychological; Phenotype; Propylthiouracil; Quinine; Risk Factors; Smell; Taste; Waist Circumference

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.

Topics: Acetamides; Animals; Cardiovascular Diseases; Drug Discovery; Enzyme Inhibitors; Humans; Peroxidase; Pyrimidinones; Rats, Wistar

This study sought to prospectively evaluate the prevalence of cardiovascular abnormalities in patients with overt hyperthyroidism before and after antithyroid therapy.. Overt hyperthyroidism is associated with recognized cardiovascular effects believed to be reversed by antithyroid therapy; however, increasing data suggest significant long-term cardiovascular mortality.. A total of 393 (312 women, 81 men) consecutive unselected patients with overt hyperthyroidism were recruited and compared with 393 age- and gender-matched euthyroid control subjects. Hyperthyroid patients were re-evaluated after antithyroid therapy. Findings in patients and matched control subjects were compared at presentation, after treatment when patients had subclinical hyperthyroidism biochemically, and when patients were rendered biochemically euthyroid. All had a structured cardiovascular history and examination, including measurements of blood pressure (BP) and pulse rate. All had resting 12-lead electrocardiogram and 24-h digital Holter monitoring of cardiac rhythm.. A higher prevalence of cardiovascular symptoms and signs, as well as abnormal hemodynamic parameters, was noted among hyperthyroid patients at recruitment compared with control subjects. Cardiac dysrhythmias, especially supraventricular, were more prevalent among patients than among control subjects. Palpitation and dyspnea, postural decrease in systolic pressure, and atrial fibrillation (AF) remained more prevalent in treated hyperthyroid subjects with subclinical hyperthyroidism compared with control subjects, and remained more prevalent after restoration of euthyroidism. Predictors for successful reversion to sinus rhythm in those with AF associated with hyperthyroidism were lower BP measurements at recruitment and an initial hypothyroid state induced by antithyroid therapy. Mortality was higher in hyperthyroid subjects than in control subjects after a mean period of follow-up of 66.6 months.. Cardiovascular abnormalities are common in patients with overt hyperthyroidism at presentation, but some persist despite effective antithyroid therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antithyroid Agents; Carbimazole; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Hyperthyroidism; Iodine Radioisotopes; Male; Middle Aged; Prevalence; Propylthiouracil; Prospective Studies