Miracle-dz/UniFAR-FTUs huggingface dataset:
S2RPgrmc1: the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling

Introduction: S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome-related protein that binds directly to heme and various pharmacological compounds. S2RPgrmc1 also associates with cytochrome P450 proteins, the EGFR receptor tyrosine kinase and the RNA-binding protein PAIR-BP1. S2RPgrmc1 is induced in multiple types of cancer, where it regulates tumor growth and is implicated in progesterone signaling. S2RPgrmc1 also increases cholesterol synthesis in non-cancerous cells and may have a role in modulating drug metabolizing P450 proteins. Areas covered: This review covers the independent identification of S2R and Pgrmc1 and their induction in cancers, as well as the role of S2RPgrmc1 in increasing cholesterol metabolism and P450 activity. This article was formed through a PubMed literature search using, but not limited to, the terms sigma-2 receptor, Pgrmc1, Dap1, cholesterol and aromatase. Expert opinion: Multiple laboratories have shown that S2RPgrmc1 associates with various P450 proteins and increases cholesterol synthesis via Cyp51. However, the lipogenic role of S2RPgrmc1 is tissue-specific. Furthermore, the role of S2RPgrmc1 in regulating P450 proteins other than Cyp51 appears to be highly selective, with modest inhibitory activity for Cyp3A4 in vitro and a complex regulatory pattern for Cyp21. Cyp19/aromatase is a therapeutic target in breast cancer, and S2RPgrmc1 activated Cyp19 significantly in vitro but modestly in biochemical assays. In summary, S2RPgrmc1 is a promising therapeutic target for cancer and possibly cholesterol synthesis but research to date has not identified a major role in P450-mediated drug metabolism.
Renal drug–drug interactions: what we have learned and where we are going

Introduction: Transporters make a significant contribution to the pharmacokinetic and pharmacodynamic profiles of xenobiotics. The kidney, through the combination of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of some drugs. A growing number of transporter-mediated drug–drug interactions (DDIs) have been described including a subset proposed to occur during the process of active tubular secretion in the renal proximal tubule (PT). Areas covered: An overview of transporters expressed in the human PT is provided. Methodologies for studying transporters are discussed with an emphasis on recent advances in more pharmacologically relevant systems. The molecular mechanisms for known renal DDIs are explored, highlighting commonly implicated transporters. Expert opinion: Clinically relevant renal DDIs are rare. While unlikely to affect most new drug candidates, it is difficult to prospectively predict when renal DDIs are likely to occur. Efforts to identify new transporters and establish predictive model systems have resulted in a rapid evolution in our understanding of renal DDIs. For example, the multidrug and toxin extrusion transporter 1 (MATE1) has emerged as a key transporter in the active tubular secretion of xenobiotics. We are headed toward a time when renal DDIs can be better predicted by preclinical studies.
Xenobiotic-induced liver injury and fibrosis

Introduction: Many different drugs and xenobiotics (chemical compounds foreign to an organism) can injure the bile duct epithelium and cause inflammatory bile duct diseases (cholangiopathies) ranging from transient cholestasis to vanishing bile duct syndrome, sclerosing cholangitis with development of biliary fibrosis and cirrhosis. Animal models of xenobiotic-induced liver injury have provided major mechanistic insights into the molecular mechanisms of xenobiotic-induced cholangiopathies and biliary fibrosis including primary biliary cirrhosis and primary sclerosing cholangitis. Areas covered: In this review, the authors discuss the basic principles of xenobiotic-induced liver and bile duct injury and biliary fibrosis with emphasis on animal models. A PubMed search was performed using the search terms “xenobiotic,” “liver injury,” “cholestasis,” and “biliary fibrosis. ” Reference lists of retrieved articles were also searched for relevant literature. Expert opinion: Xenobiotic-induced cholangiopathies are underestimated and frequently overlooked medical conditions due to their often transient nature. However, biliary disease may progress to vanishing bile duct syndrome, biliary fibrosis, and cirrhosis. Moreover, xenobiotics may prime the liver for subsequent liver disease by other agents and may also contribute to the development of hepatobiliary cancer though interaction with resident stem cells.
An update on the ability of St. John's wort to affect the metabolism of other drugs

Introduction: Hypericum perforatum (HP), more commonly known as St. John's wort, is a popular medicinal herb used for the treatment of depression. HP affects the pharmacokinetics of many drugs by inducing cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C19, CYP2C9, and the P-glycoprotein (P-gp) transporter. Areas covered: This review focuses on drugs that are metabolized by CYP3A4, CYP2C19, CYP2C9 and P-gp as their plasma concentrations show the effects of concomitant use of HP. For the purpose of this review, all electronic databases such as PubMed, Scopus, Google Scholar and Cochrane library were searched to identify in vitro, in vivo or human studies about the effects of HP on the metabolism of drugs. Data collected were published between 1966 and January 2012. Expert opinion: There are a number of drugs whose metabolism is reduced by HP. The authors point out that metabolic interactions between HP and drugs are not always unfavorable and sometimes have benefits (e.g., reduction of irinotecan toxicity and increase in clopidogrel responsiveness). HP does not have a significant influence on the kinetics of drugs such as carbamazepine, ibuprofen and theophylline. The use of HP preparations is not recommended in people who are taking immunosuppressants or cardiovascular drugs. With other medications, it is recommended that practitioners should only use HP preparations with a low hyperforin content and under careful monitoring. It is also recommended that because of the reduction in the bioavailability of oral contraceptives administered concurrently with HP, women who use HP preparations should use additional preventive methods to avoid unintended pregnancy.
Fronto-Temporal Lobar Degeneration: Fronto-Temporal Dementia, Progressive Aphasia, Semantic Dementia.

Fronto-Temporal Lobar Degeneration: Fronto-Temporal Dementia, Progressive Aphasia, Semantic Dementia. Edited by: j s snowden, david neary, and d m mann. (Pp 227; £55.00). Published by Churchill Livingstone, Edinburgh 1996. ISBN 0443047650. The three editors of this book have played a central part in the renaissance of interest in the clinical, neuropsychological, and neuropathological aspects of non-Alzheimer dementias. This book is based on their truly remarkable experience of some 200 patients with lobar atrophy studied over the past decade, 40 of whom have reached postmortem. It represents, therefore, an unequalled source of information and is essential reading for all …
PlaCor PRT measurement of shear-activated platelet aggregate formation in stable patients treated with single and dual antiplatelet therapy

Abstract Shear forces play a key role in thrombus formation and shear-based tests may better reflect physiological conditions in vivo compared with agonist-based tests. We evaluated the PlaCor PRT®, a novel platelet reactivity test based on shear-induced platelet aggregation, in patients with stable coronary artery disease (CAD) treated with single (SAPT) and dual antiplatelet therapy (DAPT). We examined 100 patients with multiple risk factors for CAD and/or documented stable CAD: 38 treated with SAPT, aspirin 100 mg qd, 62 treated with DAPT, aspirin 100 mg + clopidogrel 75 mg qd, compared with age- and sex-matched healthy volunteers without antiplatelet therapy (HV, n = 35). Measures of shear-induced platelet aggregation were performed with the PlaCor PRT®. In 25 patients in SAPT, the PlaCor test was also performed before and after a 12-hour-loading dose of clopidogrel 600 mg. The mean ± SD PRT time (seconds) in HV was 78 ± 13 and was significantly lower compared with SAPT (118 ± 16, p = 0.030) and to DAPT patients (242 ± 11, p < 0.0001). A statistically significant difference was also reported between SAPT and DAPT patients (p < 0.0001). After a loading dose of clopidogrel, the PRT time of SAPT patients increased significantly from 112 ± 20 to 254 ± 17, p < 0.0001. 2.7 and 26% of patients were considered as “poor responders” to single and dual antiplatelet therapy, respectively. This study shows that in patients with multiple risk factors for CAD and/or documented stable CAD, SAPT and DAPT play an important role in reducing platelet aggregation mediated by shear forces as evaluated with the novel PlaCor PRT®. Further studies will be required to confirm and assess the extent of these findings in patients with acute coronary syndromes.
The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs

Introduction: The flavonoids are a large group of dietary plant compounds with suggested health benefits. There is accumulating evidence that many of these flavonoids can interact with the major drug transporters (and metabolizing enzymes) in the body, leading to alterations in the pharmacokinetics of substrate drugs, and thus their efficacy and toxicity. Areas covered: This review summarizes and updates the reported in vitro and in vivo interactions between common dietary flavonoids and the major drug-effluxing ABC transporters; these include P-glycoprotein, breast cancer resistance protein and multidrug resistance proteins 1 and 2. In contrast to previous reviews, the ADME of flavonoids are considered, along with their glycosides and Phase II conjugates. The authors also consider their possible interactions with the ABC transporters in the oral absorption, distribution into pharmacological sanctuaries and excretion of substrate drugs. Electronic databases, including PubMed, Scopus and Google Scholar were searched to identify appropriate in vitro and in vivo ABC transporter–flavonoid interactions, particularly within the last 10 years. Expert opinion: Caution is advised when taking flavonoid-containing supplements or herbal remedies concurrently with drugs. Further clinical studies are warranted to explore the impact of flavonoids and their metabolites on the pharmacokinetics, efficacy and toxicity of drugs.
Successful treatment of secondary Helicobacter pylori eradication for chronic immune thrombocytopenic purpura

Eradication of Helicobacter pylori (H. pylori) is one of the useful treatments of H. pylori-positive chronic immune thrombocytopenic purpura (ITP) [1, 2], and considered as a first-line treatment in Japan [3]. However, there are few reports concerning the efficacy of secondary eradication of residual H. pylori for chronic ITP. Here, we report a case of successful secondary eradication of residual H. pylori for chronic ITP. A 78-year-old man was referred to our hospital because of progressive thrombocytopenia. Initial investigations revealed normal hemoglobin (13.0 g/dl) and leukocyte count (3.5 10/l) and differentiation, but decreased platelet count to 51 10/l. Based on the clinical manifestation, laboratory tests and findings of bone marrow aspiration and biopsy, the patient was diagnosed as having chronic ITP. Because H. pylori infection was present by detecting anti-H.pylori IgG antibody, H. pylori eradication was selected as an initial treatment for ITP with amoxicillin, clarithromycin and proton pomp inhibitor (PPI). The patient had no gastrointestinal manifestation that associated with H. pylori infection or eradication. Two weeks after eradication, the platelet count increased to 88 10/l. However, H. pylori remained positive by the urea breath test. Six months after the first eradication, ITP was exacerbated with the decreased platelet count to 10 10/l, and the patient suffered from macroscopic hematuria. Although immunosuppressive therapy with prednisolone was recommended for the patient as a next therapeutic option, the patient declined any treatment other than secondary eradication of H. pylori. Therefore, after obtaining informed consent from the patient, we decided to treat the patient of secondary eradication with amoxicillin, metronidazole and PPI [4]. No serious adverse effect of this treatment was observed. Three months after the secondary eradication, the platelet count increased to 125 10/l without bleeding, and H. pylori had returned negative by the urea breath test. The platelet count remained normal 6 months after the second eradication. Eradication of H. pylori is now considered one of the first-line treatments for H. pylori-positive ITP, especially in Japan [3], and metronidazole was recommended as second-line therapy after failure of first-line eradication therapy in the Japanese guideline [4]. The duration of treatment will be shorter and less costly than immunosuppressive agents such as prednisolone, or trombopoietin receptor antagonists, and therefore less toxic in terms of long-term adverse effects. Although little is known about the efficacy of secondary eradication of residual H. pylori for ITP, it would be a useful treatment. Further investigation will be required.
Pharmacokinetic evaluation of capecitabine in breast cancer

Introduction: Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is adsorbed in its intact form through the intestine and metabolized to 5-FU in tumour cells. In metastatic breast cancer (MBC), capecitabine is an effective and well-tolerated therapeutic option both in monotherapy and in combination with chemotherapeutic or molecular-targeted agents. Areas covered: We summarized data on pharmacokinetics and pharmacodynamics of capecitabine. We also produced a general review of the most relevant clinical studies of capecitabine in MBC. A literature search was performed using PubMed database including selected articles published in English language up to October 2012. Expert opinion: The unique pharmacodynamic/pharmacokinetic features represent the bases of the reduced toxicity and the activity of capecitabine in several tumours. Although during the past 10 years there has been an increasing use of this drug in MBC both as single agent and in combination, encouraging results of well tolerated and active combinations with novel agents will lead to a more extensive and protracted use of capecitabine. In view of this, some aspects should be further clarified such as the optimal starting dose and the introduction of alternative schedules of treatment.
Exercise can seriously improve your mental health: Fact or fiction?

The World Health Organization predicts that depression will create the second greatest burden of disease by 2020, requiring cost-effective prevention and intervention strategies. The evidence to support the benefits of exercise in offering protection from depression and as an intervention in the treatment of mental illness is growing. The literature is reviewed with 11 prospective longitudinal studies that include measures of physical activity and depression at two or more time points showing a protective effect from physical activity. Fifteen randomized controlled trials (RCTs) and three meta-analyses provide evidence that exercise can reduce depression and that it can be as effective as cognitive therapy. Four RCTs report exercise as an intervention in alcohol addiction and two RCTs in the use of illicit drugs. While many of the studies reviewed have methodological weaknesses, including lack of concealment in randomization, limited use of intention to treat and blinding, the benefits of exercise far outweigh the risks. Neurobiological and psychological explanations as to why exercise should work are discussed. There is evidence that exercise protects against depression and is an effective intervention and adjunctive intervention for the treatment of mild to moderate depression. Exercise provides some health and psychological benefits as an adjunct to treatment in complex mental health problems such as alcohol and drug rehabilitation.
Sex determination & morphometric parameters of human mandible

Goal: The knowledge about the anatomy of the mandible and its variations in age, sex and race will help physicians, surgeons, medico-legal authorities and anthropologists to give correct interpretations for the diagnostic procedures in living. Methods: We collected the human mandible bones (N=80) from the department of Anatomy, SVIMS university and around the Tirupati region to study the morphological and morphometric features by using 22 different parameters. Results: Among 22 parameters Six dominating parameters that possibly explain the nature of the mandible are height of the ramus, body thickness, anthropometric arch width, inter incisor width, mandibular index and mandibular angle are useful to determine the unknown sex of the mandible upto an extent of 75.2% in south Indian population. The incidence of the above mentioned sex determination parameters considered together and treated statistically. Conclusion: The present study reveals that the mandible of unknown gender can be sexed to the extent of 75% accuracy by six dominating parameters and not to consider these for complete sex determination of the mandible bone in osteometric studies.
Canagliflozin, an inhibitor of sodium–glucose cotransporter 2, for the treatment of type 2 diabetes mellitus

Introduction: Canagliflozin is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. Areas covered: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metabolism, and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstracts from canagliflozin studies presented at large diabetes conferences. Expert opinion: Canagliflozin offers a relatively modest reduction in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body weight. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 if there are concerns or symptoms of volume-related side effects. Issues remain with observed increases in low-density lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in April 2013 and is undergoing evaluation by the European Medicines Agency.
Tailored antiplatelet therapy to improve prognosis in patients exhibiting clopidogrel low-response prior to percutaneous coronary intervention for stable angina or non-ST elevation acute coronary syndrome

Abstract Aim: To investigate whether an intensified antiplatelet regimen could improve prognosis in stable or non-ST elevation in acute coronary syndrome (ACS) patients exhibiting high on-treatment platelet reactivity (HTPR) on clopidogrel and treated with percutaneous coronary intervention (PCI). There is a wide variability in the platelet reactivity to clopidogrel and HTPR has been associated with a poor prognosis. Methods: In this observational study, 923 consecutive patients without ST-elevation myocardial infarction (STEMI) and adequately pre-treated with clopidogrel were screened for HTPR with multiple electrode aggregometry after assessment of the coronary anatomy. Patients were grouped based on their response to clopidogrel and the assigned antiplatelet strategy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or stent thrombosis. Results: HTPR was demonstrated in 237 patients (25.7%). Of these, 114 continued on conventional clopidogrel therapy, while the remaining 123 received intensified antiplatelet therapy with either double-dose clopidogrel (150 mg daily, n = 55) or the newer P2Y12-inhibitors, prasugrel or ticagrelor (n = 68) for at least 30 days after the index procedure. The median follow-up was 571 days (interquartile range, 373–746). Intensifying antiplatelet therapy reduced the rate of the composite endpoint (p < 0.001). After adjustment for potential confounders, HTPR in combination with conventional clopidogrel therapy remained independently associated with an increased risk of cardiovascular events (hazard ratio (HR), 2.92; 95% CI, 1.90–4.48), whereas intensified treatment reduced the risk to a level equivalent to that of patients exhibiting normal platelet reactivity (HR, 1.08; 95% CI, 0.59–1.99). Conclusion: Tailored antiplatelet therapy significantly reduced the event rate in patients exhibiting HTPR prior to PCI.
A mouse with humanized liver as an animal model for predicting drug effects and for studying hepatic viral infection: where to next?

Introduction: The mouse is a common model used in evaluating drug metabolism and hepatitis infectivity. However, these models have limited value due to species difference in hepatic functions, leading to the creation of the chimeric mouse 12 years ago. These models were unique in that their hepatocytes had been replaced with human (hu) hepatocytes (dubbed the ‘first-generation chimeric mouse'). Since then, the chimeric mouse has become a practical tool for this area of studies. However, some shortcomings have also been recognized. One major shortcoming is that the mouse cannot mimic hu-liver diseases due to immunodeficiency and also it is unable to provide sufficient amounts of blood for analysis compared to the rat. There are also issues around donor-to-donor variability of hu-hepatocytes such as variable engraftment efficiency. Areas covered: This review provides the current status of the first-generation chimeric mouse. Furthermore, the authors review studies intended to create a ‘second-generation of the chimeric mouse' in which inflammation/immune-response cells as well as hepatocytes are humanized. A brief comment is also made on studies aiming at producing chimeric rats. Finally, the authors consider induced pluripotent stem cells (iPS cells) as new sources of hu-hepatocytes. Expert opinion: The authors believe that the current rapid progress in the field of biotechnology should enable us to create a mouse model with a humanized liver that is made by iPS-derived hu-hepatocytes and hu-immune cells. This development will provide researchers with a model that will be able to effectively mimic human liver disease under experimental conditions.