Value-based decision-making for orphan drugs with multiple criteria decision analysis: burosumab for the treatment of X-linked hypophosphatemia.

OBJECTIVE: Burosumab is an orphan medicinal product (OMP) approved in Europe for the treatment of X-linked hypophosphatemia (XLH). The aim of this study was to assess the value of burosumab versus conventional therapy for the treatment of paediatric XLH, through a multi-criteria decision analysis (MCDA) framework for health technology assessment (HTA) of OMPs in Portugal. METHODS: The MCDA framework considered 14 criteria related to disease burden, therapeutic value and economic burden. A multidisciplinary panel of national stakeholders participated in a two-phase exercise. In the first phase, relative weights and part-worth utilities for the criteria and their levels were elicited and a reimbursement likelihood function was calibrated through adaptive conjoint analysis. In the second phase, burosumab and conventional therapy were assessed against the criteria, providing a global value score (0-100) and reimbursement likelihood (0-100%) for both. RESULTS: Of the 14 criteria, disease burden, therapeutic value and economic burden criteria represented 27.29%, 57.17% and 15.53% of the total weight in the decision, respectively. All disease burden and some therapeutic value criteria, typically not included in traditional HTA, represented 47.88% of the total weight. Burosumab was unanimously considered superior to conventional therapy, with an average (range) global value score of 84.96 (82.48-86.54) against 48.06 (43.37-57.68), and reimbursement likelihood of 97.50% (96.78%-98.32%) against 43.66% (31.48%-68.73%), respectively. CONCLUSIONS: MCDA represents a powerful tool in HTA decision-making for OMPs. The results of this MCDA acknowledge burosumab as a disease-modifying drug, deemed superior to conventional therapy for the treatment of paediatric XLH.

Estrogen receptor beta and G protein-coupled estrogen receptor 1 are involved in the acute estrogenic regulation of arginine-vasopressin immunoreactive levels in the supraoptic and paraventricular hypothalamic nuclei of female rats.

The ovarian hormone 17ß-estradiol is known to regulate the release, expression and immunoreactivity of arginine-vasopressin (AVP) in the supraoptic and paraventricular hypothalamic nuclei of rodents. Previous studies have shown that estrogen receptor α is involved in the effects of chronic estradiol administration on arginine-vasopressin immunoreactivity in the female rat hypothalamus. In this study we have examined the effect of an acute administration of estradiol or specific agonists for estrogen receptors α, ß and G protein-coupled estrogen receptor 1 on the immunoreactivity of arginine-vasopressin in the hypothalamus of adult ovariectomized female rats. Acute estradiol administration resulted in a significant decrease in the number of arginine-vasopressin immunoreactive neurons in the supraoptic and paraventricular nuclei after 24 h. The effects of the specific estrogen receptors agonists suggest that the action of estradiol on arginine-vasopressin immunoreactivity is mediated in the supraoptic nucleus by G protein-coupled estrogen receptor 1 and in the paraventricular nucleus by both estrogen receptor ß and G protein-coupled estrogen receptor 1. Thus, in contrast to previous studies on the effect of chronic estrogenic treatments, the present findings suggest that estrogen receptor ß and G protein-coupled estrogen receptor 1 mediate the acute effects of estradiol on arginine-vasopressin immunoreactivity in the hypothalamus of ovariectomized rats.

Correlation between infection rate of triatominies and Chagas Disease in Southwest of Bahia, Brazil: a warning sign?

Chagas disease, caused by the Trypanosoma cruzi, has a wide distribution in South America, and its main method of control is the elimination of triatomines. It is presented here the geographic distribution and the rate of natural infection by T. cruzi of triatomines collected and evaluated from 2008 to 2013 in southwest of Bahia. Triatomines were captured in the intradomiciliary and peridomiciliary areas of five cities located in the southwest of Bahia state, identified, and analyzed for the presence of trypanosomatids in their feces. During the study period the number of patients suspected for acute Chagas disease was recovered from the Notifiable Diseases Information System (SINAN). 8966 triatomines were captured and identified as belonging to eight species. Twenty-six presented themselves infected, being Triatoma sordida the most abundant and with the highest percentage of infection by T. cruzi. Tremedal was the city with the highest number of cases of acute Chagas' disease reported to SINAN. All cities showed triatomines infected with T. cruzi, so there is considerable risk of vectorial transmission of Chagas disease in the southwestern Bahia state, evidencing the need for vector transmission control programs and preventive surveillance measures.

Adrenomedullin and nitric oxide: implications for the etiology and treatment of primary brain tumors.

Gliomas, defined as tumors of glial origin, represent between 2-5 percent of all adult cancer and comprise the majority of primary brain tumors. Infiltrating gliomas, with an incidence of more than 40 percent of brain tumors, are the most common and destructive primary brain tumors for which conventional therapies have not significantly improved patient outcome. In fact, patients suffering from malignant gliomas have poor prognoses and the majority have local tumor recurrence after treatment. Tumor growth and spread of tumor cells depend basically upon angiogenesis and on functional abnormalities of tumor cells in the control of apoptosis, as they are paradigmatic for their intrinsic resistance to multiple pro-apoptotic stimuli. Therefore, promising strategies for treatment of brain cancer would be directed to appropriate neutralization of angiogenesis and sensibilization of cancer cells to undergo apoptosis. However, despite advances in this field, high-grade gliomas remain incurable with survival often measured in months. Therefore there is a need to discover new and more potent cocktails of drugs to target the key molecular pathways involved in glioma angiogenesis and apoptosis. This review deals with the effects of two groups of molecules closely linked to neural tissue, which have been implicated in brain cancer: nitric oxide and peptides of the adrenomedullin family. These molecules exert vasodilatory and proangiogenic actions. Adrenomedullin also has antiapoptotic functions at appropriate concentrations. The inhibition of these functions, in the case of cancer, may provide new pharmacological strategies in the treatment of this disease.

Progesterone regulates the phosphorylation of protein phosphatases in the brain.

Previous studies have shown that progesterone modulates the activity of different kinases and the phosphorylation of Tau in the brain. These actions of progesterone may be involved in the hormonal regulation of neuronal differentiation, neuronal function, and neuroprotection. However, the action of progesterone on protein phosphatases in the nervous system has not been explored previously. In this study we have assessed the effect of the administration of progesterone to adult ovariectomized rats on protein phosphatase 2A (PP2A) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the hypothalamus, the hippocampus, and the cerebellum. Total levels of PP2A, the state of methylation of PP2A, and total levels of PTEN were unaffected by the hormone in the three brain regions studied. In contrast, progesterone significantly increased the levels of PP2A phosphorylated in tyrosine 307 in the hippocampus and the cerebellum and significantly decreased the levels of PTEN phosphorylated in serine 380 in the hypothalamus and in the hippocampus compared with control values. Estradiol priming blocked the effect of progesterone on PP2A phosphorylation in the hippocampus and on PTEN phosphorylation in the hypothalamus and the hippocampus. In contrast, the action of progesterone on PP2A phosphorylation in the cerebellum was not modified by estradiol priming. These findings suggest that the regulation of the phosphorylation of PP2A and PTEN may be involved in the effects of progesterone on the phosphorylation of Tau and on the activity of phophoinositide-3 kinase and mitogen-activated protein kinase in the brain.

Estrogen receptor alpha is involved in the estrogenic regulation of arginine vasopressin immunoreactivity in the supraoptic and paraventricular nuclei of ovariectomized rats.

The ovarian hormone estradiol regulates the expression of arginine vasopressin gene and the release of arginine vasopressin by magnocellular hypothalamic neurons. Magnocellular neurons express estrogen receptor beta and are contacted by afferent neurons that express estrogen receptor alpha. In this study we have assessed the effect of selective ligands for estrogen receptors to determine the subtype of estrogen receptor involved in the regulation of arginine vasopressin immunoreactivity in the supraoptic and paraventricular nuclei of ovariectomized rats. The volume fraction occupied by arginine vasopressin immunoreactive material was significantly increased in both nuclei in the animals treated with estradiol compared to the animals injected with vehicle. A similar result was obtained with an estrogen receptor alpha selective agonist. In contrast, the administration of an estrogen receptor beta selective agonist did not significantly affect arginine vasopressin immunoreactivity. This finding suggests that estradiol may regulate arginine vasopressin levels on the supraoptic and paraventricular nuclei by acting on afferent neurons expressing estrogen receptor alpha.

Decrease in PTEN and increase in Akt expression and neuron size in aged rat spinal cord.

PTEN is a tumor suppressor gene known to play an important role in the regulation of cell size. In this study we compared PTEN expression in the spinal cord of young (5 months old) vs. aged (32 months old) female rats and correlated them with alterations in neuron size and morphology in the same animals. Total and phosphorylated PTEN (pPTEN) as well as its downstream target phosphorylated Akt (pAkt) were assessed by Western blotting. Spinal cord neurons were morphometrically characterized. Total PTEN, pPTEN and total Akt expression were significantly higher in young rats than in aged animals. Expression of pAkt was stronger in aged animals. A significant increase in neuronal size was observed in large motoneurons of aged as compared with young rats. Our data show that in the spinal cord of rats, neuronal PTEN expression diminishes with advanced age while neuronal size increases. These results suggest that in the spinal cord, an age-related reduction in PTEN and increase of pAkt expression may be involved in the progressive enlargement of neurons.

Progesterone as a regulator of phosphorylation in the central nervous system.

Progesterone exerts a variety of actions in the central nervous system under physiological and pathological conditions. As in other tissues, progesterone acts in the brain through classical progesterone receptors and through alternative mechanisms. Here, we review the role of progesterone as a regulator of kinases and phosphatases, such as extracellular-signal regulated kinases, phosphoinositide 3-kinase, Akt, glycogen synthase kinase 3, protein phosphatase 2A and phosphatase and tensin homolog deleted on chromosome 10. In addition, we analyzed the effects of progesterone on the phosphorylation of Tau, a protein that is involved in microtubule stabilization in neurons.

Regulation of the phosphoinositide-3 kinase and mitogen-activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain.

Several growth factors, such as vascular endothelial growth factor, brain-derived neurotrophic factor, and insulin-like growth factor-I are involved in the actions of progesterone in the central nervous system. Previous studies in neuronal and glial cultures have shown that progesterone may regulate growth factor signaling, increasing the phosphorylation of extracellular-signal regulated kinase (ERK) and the phosphorylation of Akt, components of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI3K) signaling pathways, respectively. In this study, we have evaluated whether progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, regulate PI3K and MAPK signaling in the brain of ovariectomized rats in vivo. Significant increases in the phosphorylation of ERK, in the expression of the catalytic (p110) and the regulatory (p85) subunits of PI3K and in the phosphorylation of Akt were observed in the hypothalamus, the hippocampus, and the cerebellum 24 hr after progesterone administration. Progesterone metabolites partially mimicked the effect of progesterone and had a stronger effect on MAPK and PI3K signaling in the hypothalamus than in the other brain regions. These findings suggest that progesterone regulates MAPK and PI3K signaling pathways in the central nervous system in vivo by direct hormonal actions and by mechanisms involving progesterone metabolites.

Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase-3 and the microtubule-associated protein tau in the rat cerebellum.

Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5alpha-dihydroprogesterone (DHP) and 3alpha,5alpha-tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3beta (GSK3beta), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectomized rats did not affect Tau and GSK3beta assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3beta in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3beta, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3beta insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3beta in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3beta. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton.