Optimal assessment share structured of Pharmacoeconomics for medical drugs according to minimax criterion

Objective: To develop a comprehensive methodology for the optimal assessment of the share of the use of medicines, based on the procedure for ranking drugs according to the pharmacoeconomic point scale and the minimax criterion was applied. Methods: The author’s approach is based on the minimax principle and allows solving the problem of optimizing the pharma drug portfolio based on available data, without the need to obtain the parameters of the Markowitz model associated with correlation analysis of data. Results: The authors obtained the optimal distribution of medicines in group A, B: 37% to 63%, which the authors consider a promising recommendation for a pharmaceutical company. The use of a similar approach, which does not contradict the Markowitz methodology, but allows us to reasonably accept the parameters of the model and give the optimal solution for the share distribution of drugs in medical practice. Conclusion: These mathematical tools, justified and equipped with an alternative confirmation, the minimax task can and should take a significant place in the complex pharma-analytical methodology of the management of large companies supplying concomitant drugs to the Russian and foreign market. (AU)

Genetic Obesity in Pregnant Ay Mice Does Not Affect Susceptibility to Obesity and Food Choice in Offspring.

Maternal diet and obesity (MO) may influence taste preferences and increase the susceptibility to obesity in offspring, but the impact of MO per se to these influences is poorly understood. We evaluated the influence of MO on food choice and susceptibility to obesity in offspring when mothers consumed a standard diet (SD). Mice with the Lethal yellow mutation (Ay/a) develop obesity consuming an SD. Metabolic parameters were assessed in pregnant and lactating Ay/a (obesity) and a/a (control) mothers. Metabolic response to the consumption of a sweet-fat diet (SFD: SD, lard, and sweet biscuits) and the choice of components of this diet were evaluated in their male and female offspring. Compared to control mothers, pregnant obese mothers had higher levels of insulin, leptin, and FGF21. MO increased food intake and liver expression of lipogenesis genes in male offspring consuming the SD. SFD consumption caused obesity development and insulin resistance, increased liver expression of glycolytic and lipogenesis genes, and affected hypothalamic expression of anorexigenic and orexigenic genes. In offspring of both sexes, MO had no effect on food choice and metabolic response to SFD intake. Therefore, when obese mothers consume a balanced diet, MO does not affect food choice and development of diet-induced obesity in offspring.

Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice.

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21's beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.

The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression.

The preference for high-calorie foods depends on sex and contributes to obesity development. Fibroblast growth factor 21 (FGF21) beneficially affects taste preferences and obesity, but its action has mainly been studied in males. The aim of this study was to compare the effects of FGF21 on food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with diet-induced obesity. Mice were injected with FGF21 or vehicle for 7 days. Body weight, choice between standard (SD) and high-fat (HFD) diets, blood parameters, and gene expression in white (WAT) and brown (BAT) adipose tissues, liver, muscles, and the hypothalamus were assessed. Compared to males, females had a greater preference for HFD; less WAT; lower levels of cholesterol, glucose, and insulin; and higher expression of Fgf21, Insr, Ppara, Pgc1, Acca and Accb in the liver and Dio2 in BAT. FGF21 administration decreased adiposity; blood levels of cholesterol, glucose, and insulin; hypothalamic Agrp expression, increased SD intake, decreased HFD intake independently of sex, and increased WAT expression of Pparg, Lpl and Lipe only in females. Thus, FGF21 administration beneficially affected mice of both sexes despite obesity-associated sex differences in metabolic characteristics, and it induced female-specific activation of gene expression in WAT.

Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice.

Fasting is often used for obesity correction but the "refeeding syndrome" limits its efficiency, and molecular mechanisms underlying metabolic response to different food availability are under investigation. Sex was shown to affect hormonal and metabolic reactions to fasting/refeeding. The aim of this study was to evaluate hormonal and transcriptional responses to fasting and refeeding in male and female C57Bl/6J mice. Sex asymmetry was observed both at the hormonal and transcriptional levels. Fasting (24 h) induced increase in hepatic Fgf21 gene expression, which was associated with elevation of plasma FGF21 and adiponectin levels, and the upregulation of expression of hepatic (Pparα, Cpt1α) and muscle (Cpt1ß, Ucp3) genes involved in fatty acid oxidation. These changes were more pronounced in females. Refeeding (6 h) evoked hyperinsulinemia and increased hepatic expression of gene related to lipogenesis (Fasn) only in males and hyperleptinemia and increase in Fgf21 gene expression in muscles and adipose tissues only in females. The results suggest that in mice, one of the molecular mechanisms underlying sex asymmetry in hepatic Pparα, Cpt1α, muscle Cpt1ß, and Ucp3 expression during fasting is hepatic Fgf21 expression, and the reason for sex asymmetry in hepatic Fasn expression during refeeding is male-specific hyperinsulinemia.