Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.

Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression.

Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.

To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30ng/mL and 21ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.

BACKGROUND: High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. OBJECTIVE: Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. METHODS: Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. RESULTS: The cytochrome P450 (CYP) 2D6 phenotype explained 52 % of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28 % higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26 % with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. CONCLUSIONS: Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.

Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment.

BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.

BACKGROUND: Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS: We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS: We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION: Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING: Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation.

NlmCategory="UNASSIGNED">Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01, P=0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n=395, OR=2.08, P=0.02) and in non-kidney transplant recipients (OR=2.09, P=0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n=1215, OR=1.56, P=0.02), new-onset hyperlipidemia (n=1007, OR=1.76, P=0.007), and lower high-density lipoprotein-cholesterol (n=1214, β=-0.08, P=0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.The Pharmacogenomics Journal advance online publication, 8 December 2015; doi:10.1038/tpj.2015.82.

Pharmacogenetic and clinical study on adverse effects induced by psychotropic drugs

Second-generation antipsychotics (SGAs) have become the first-line antipsychotic treatment for psychotic disorders due to their better overall tolerance compared to classical antipsychotics. However, metabolic side effects such as weight gain are frequently described during treatment with SGAs and/or other psychotropic drugs including some antidepressants and mood stabilizers, which may also result in poor adherence to treatment. The aim of this work was to investigate different methods to predict common side effects, in particular weight gain during treatment with weight gain inducing psychotropic drugs. Firstly, clinical data were used to determine the potential predictive power of a one month weight gain on weight increase after three and 12 months of treatment (n=351 patients). A fast and strong weight gain of >5% after a period of one month (>5%WG) was found to be the best predictor for an important weight gain at three (>15%) and 12 months (>20%). Similar analyses in an independent cohort of psychiatric adolescents (n=42), showed that a comparable >4% weight gain at one month is the best predictor for an important weight gain at three months (>15%). Secondly, we aimed to determine whether an extensive analysis of genes could be used, in addition to clinical factors, to predict patients at risk for >5%WG or for type 2 diabetes (T2D). Adding genetic markers to clinical variables to predict >5%WG increased significantly the area under the curve (AUC) of the analysis (AUCfinai:0.92, AUCdmicai:0.75, pcO.OOOl, n=248). Conversely, genetic risk scores were found to be associated with T2D (OR: 2.5, p=0.03, n=285) but without a significant increase of AUC'when compared to the prediction based to clinical factors alone. Finally, therapeutic drug monitoring was used to predict extrapyramidal symptoms during risperidone treatment (n=150). Active moiety (sum of risperidone and of its active metabolite 9- hydroxyrisperidone plasma concentrations) of >40 ng/ml should be targeted only in case of insufficient response. These results highlight different approaches for personalizing psychotropic treatments in order to reduce related side effects. Further research is needed, in particular on the identification of genetic markers, to improve the implementation of these results into clinical practice. Résumé Les antipsychotiques atypiques (APA) sont devenus le traitement antipsychotique de première intention pour le traitement des psychoses, grâce à un profil d'effets secondaires plus favorables comparé aux antipsychotiques typiques. Néanmoins, d'autres effets indésirables d'ordre métabolique (ex. prise pondérale) sont observés sous APA, stabilisateurs de l'humeur et/ou certains antidépresseurs, pouvant aussi limiter l'adhérence au traitement. L'objectif de ce travail est d'explorer différentes méthodes permettant de prédire des effets secondaires courants, en particulier la prise de poids durant un traitement avec des psychotropes pouvant induire un tel effet. Dans une première partie, des données cliniques ont été évaluées pour leurs potentiels prédictifs d'une prise de poids à un mois sur une prise de poids à trois et 12 mois de traitement (n=351 patients). Une prise de poids rapide et forte >5% à un mois (PP>5%) s'est avérée être le meilleur prédicteur pour une prise pondérale importante à trois (>15%) et 12 (>20%) mois de traitement. Des analyses similaires dans une cohorte pédiatrique (n=42) ont indiqué une prise de poids >4% à un mois comme le meilleur prédicteur pour une prise pondérale importante (>15%) à trois mois de traitement. Dans une deuxième partie, des marqueurs génétiques, en complément aux données cliniques, ont été analysés pour leur contribution potentielle à la prédiction d'une PP>5% et au dépistage du diabète de type 2 (DT2). L'ajout de variants génétiques aux données cliniques afin de prédire une PP>5% a augmenté significativement l'aire sous la courbe (ASC) de l'analyse (ASCflnai:0.92, ASCC|inique:0.75, p<0.0001, n=248). Concernant le DT2, un score génétique est associé au DT2 (OR: 2.5, p=0.03, n=285), néanmoins aucune augmentation significative de l'ASC n'a été observée par rapport à l'analyse avec les données cliniques seules. Finalement, des mesures de concentrations plasmatiques de médicaments ont été utilisées pour prédire la survenue de symptômes extrapyramidaux sous rispéridone (n=150). Cette analyse nous a permis d'établir qu'une concentration plasmatique de rispéridone associée à son métabolite actif >40 ng/ml ne devrait être recherchée qu'en cas de réponse clinique insuffisante. Ces différents résultats soulignent différentes approches pour personnaliser la prescription de psychotropes afin de réduire la survenue d'effets secondaires. Des études supplémentaires sont néanmoins nécessaires, en particulier sur l'identification de marqueurs génétiques, afin d'améliorer l'implémentation de ces résultats en pratique clinique. Résumé large publique Les antipsychotiques atypiques et autres traitements psychotropes sont couramment utilisés pour traiter les symptômes liés à la schizophrénie et aux troubles de l'humeur. Comme pour tout médicament, des effets secondaires sont observés. L'objectif de ce travail est d'explorer différentes méthodes qui permettraient de prédire la survenue de certains effets indésirables, en particulier une prise de poids et la survenue d'un diabète. Dans une première partie, nous avons évalué l'effet d'une prise de poids précoce sur une prise de poids au long terme sous traitement psychotrope. Les analyses ont mis en évidence dans une population psychiatrique qu'une prise de poids à un mois >5% par rapport au poids initial permettait de prédire une prise pondérale importante après trois (>15%) et 12 (>20%) mois de traitement. Un résultat semblable a. été observé dans un autre groupe de patients exclusivement pédiatriques. Dans une deuxième partie, nous avons évalué la contribution potentielle de marqueurs génétiques à la prédiction d'une prise pondérale de >5% après un mois de traitement ainsi que dans la survenue d'un diabète de type 2. Pour la prise de poids, la combinaison des données génétiques aux données cliniques a permis d'augmenter de 17% la précision de la prédiction, en passant de 70% à 87%. Concernant la survenue d'un diabète, les données génétiques n'ont pas amélioré la prédiction. Finalement, nous avons analysé la relation possible entre les concentrations sanguines d'un antipsychotique atypique couramment utilisé, la rispéridone, et la survenue d'effets secondaires (ici les tremblements). Il est ressorti de cette étude qu'une concentration plasmatique du médicament supérieure à 40 ng/ml ne devrait être dépassée qu'en cas de réponse thérapeutique insuffisante, au risque de voir augmenter la survenue d'effets secondaires du type tremblements. Ces résultats démontrent la possibilité de prédire avec une bonne précision la survenue de certains effets secondaires. Cependant, en particulier dans le domaine de la génétique, d'autres études sont nécessaires afin de confirmer les résultats obtenus dans nos analyses. Une fois cette étape franchie, il serait possible d'utiliser ces outils dans la pratique clinique. A terme, cela pourrait permettre au prescripteur de sélectionner les traitements les mieux adaptés aux profils spécifiques de chaque patient.

Psychiatrie [New developments in psychiatry].

Three issues are discussed: i) While number of psychiatric beds has been reduced in most countries and although treatments proposed in psychiatric hospitals have evolved, they continue to be viewed as asylums implementing constraints. Considering this prevents their adequate use and leads to patients' stigmatisation, promotion of a better knowledge of contemporary hospital treatments is needed. 2) In addition, most psychiatric disorders emerging during adolescence and early adulthood, it is important to develop accessible care on university campuses. 3) While risk of weight gain and metabolic syndrome under neuroleptics or mood stabilisers is known, there is a need for the development of <red flags> that are easy to identify. A 5% increase in weight during the first month of treatment indicates the risk for important later weight gain.

Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.

One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes. We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue. We used data from 751 studies including 4,372,000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-7.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target. Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries. Wellcome Trust.

Spinal Cord T-Cell Infiltration in the Rat Spared Nerve Injury Model: A Time Course Study.

The immune system is involved in the development of neuropathic pain. In particular, the infiltration of T-lymphocytes into the spinal cord following peripheral nerve injury has been described as a contributor to sensory hypersensitivity. We used the spared nerve injury (SNI) model of neuropathic pain in Sprague Dawley adult male rats to assess proliferation, and/or protein/gene expression levels for microglia (Iba1), T-lymphocytes (CD2) and cytotoxic T-lymphocytes (CD8). In the dorsal horn ipsilateral to SNI, Iba1 and BrdU stainings revealed microglial reactivity and proliferation, respectively, with different durations. Iba1 expression peaked at D4 and D7 at the mRNA and protein level, respectively, and was long-lasting. Proliferation occurred almost exclusively in Iba1 positive cells and peaked at D2. Gene expression observation by RT-qPCR array suggested that T-lymphocytes attracting chemokines were upregulated after SNI in rat spinal cord but only a few CD2/CD8 positive cells were found. A pronounced infiltration of CD2/CD8 positive T-cells was seen in the spinal cord injury (SCI) model used as a positive control for lymphocyte infiltration. Under these experimental conditions, we show early and long-lasting microglia reactivity in the spinal cord after SNI, but no lymphocyte infiltration was found.

Gênero Physalis - uma revisão sobre vitaesteróides

This review describes results on the chemistry and spectroscopic data of some ergostane derivatives named withasteroids which have been obtained from Physalis genus. The main aim of this report is concerned with the description and characterization of Physalins. These natural product substances are C28 seco steroid lactone type compounds that have been shown biological activities against human illness such as immuno-deficiency, neoplasic tumors, inflammatory process and tropical endemic diseases. Physalins appear to be a source for new drugs to be apply as medicine.

A cascata dos fosfoinositídeos

Inositol is a polyalcohol required for the proper formation of cell membranes. In the body, its plays an important role in the transmission of nerve impulses, its also helps in the transporting of fats within the body. In mammals, inositol exists as phosphorylated derivatives, various phosphoinositides, and in its free form. Agonist stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is the first step in the transmembrane signalling mechanism when cells respond to external stimuli. Under control of activated phospholipase C (PLC) via G-protein, two second messengers D-myo-inositol 1,4,5-triphosphate [Ins(1,4,5)P3] and diacylglycerol are released into the cell. From Ins(1,4,5)P3, enzymatic process under phosphatases or kinases control affords subsequent inositol phosphate metabolites. During the last decade the synthesis of modified inositol phosphate derivatives has been strongly investigated. This paper reviews principal aspects about synthesis and biological functions of these biomolecules.