Role of microRNAs in fluoropyrimidine-related toxicity: what we know.

Although more than half a century has passed since the discovery of fluoropyrimidines, they are still used in the treatment of many types of cancer, and it is estimated that annually two million patients undergo fluoropyrimidine-based chemotherapy. The toxicity resulting from the use of fluoropyrimidines affects about 30-40% of patients, which in some cases may prove to be lethal. The key player in fluoropyrimidine toxicity is DPD activity, and patients with deficits are more likely to develop significant adverse events. In addition to genotyping DPYD variants associated with DPD deficiency, overexpression of miR-27 has also been shown to be a predictive factor for fluoropyrimidine toxicity. This review aims to relate what we know so far about the involvement of miRNA in fluoropyrimidine toxicity and to open new perspectives in this field.

How often we diagnose allergy to ranitidine?

H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article emphasizes the importance of recognizing ranitidine as a cause of anaphylaxis and the advantages and limits of allergological evaluation to establish a positive diagnose. We reviewed a series of published cases of ranitidine-induced hypersensitivity reactions, starting from a clinical case presentation. Moreover, we analyzed the ranitidine related adverse events in the Eudravigilance European database of adverse reactions. Most of the allergic reactions induced by ranitidine are type I HR with immediate onset after exposure, with variable clinical presentation. But in a few cases, there were also described delayed reactions, some after occupational exposure. The article underlines the importance of allergy evaluation to avoid future contact with the drug to reduce the risk of more severe reactions. The suspected reactions should be reported, allowing pharmacovigilance systems to analyse them and to establish further recommendations for clinicians.

Role of pentraxin-3 in risk assessment of patients with metabolic syndrome.

BACKGROUND: Inflammation plays a major role in the development of metabolic syndrome (MetS) and its progression. Recent studies have shown that pentraxin-3 (PTX-3), osteoprogerin (OPG), and tumor necrosis factor-alpha (TNF-α) are key factors in MetS pathophysiology, but evidence for endorsing their clinical use is currently unclear and insufficient. AIM: The study aimed to evaluate the association between the inflammatory biomarkers' levels and the severity of MetS. METHODS: The study was observational, transversal, prospective, cohort, and analytical type. We enrolled 80 patients (M:F = 1, mean age = 55 ± 10.77 years) who met MetS criteria. The study protocol included: medical history, physical examination, 6-min walk test distance (6MWTD), biochemical tests, electrocardiogram, echocardiography, and carotid ultrasonography. We also performed plasmatic measurement of PTX-3, OPG, and TNF-α, in addition to standard biochemical tests. RESULTS: Subjects with severe MetS had higher values of body mass index (BMI) and waist circumference (p < 0.001, p = 0.001). PTX-3 levels were significantly higher in patients with severe MetS (p = 0.03) and the values were not influenced by age or gender. OPG positively correlated with BMI (r = 0.264, p = 0.018). 6MWTD was lower in patients with severe MetS (p = 0.005), whereas CCA-IMT was higher in this group of patients (p = 0.005). In addition, the receiver operating characteristic (ROC) curve analysis for PTX-3 identified a cut-off value of 10.7 ng/dl that differentiates between mild and severe MetS [AUC 0.656; sensitivity =47.1% (95% CI = 36.1%-62.3%); specificity = 78.9% (95% CI = 54.4%-93.9%)]. CONCLUSION: PTX-3 was correlated with the severity of MetS, with other inflammatory parameters and cardiovascular tests. CCA-IMT and 6MWTD are useful in differentiating between mild and severe MetS.

LINKS BETWEEN RENIN-ANGIOTENSIN SYSTEM GENETIC POLYMORPHISMS AND LEPTIN SECRETION IN OBESE HEART FAILURE PATIENTS.

Chronic heart failure (CHF) and obesity are two conditions frequently associated and which, despite all the advances made in their management in the recent years, their prevalence continues to rise. Obese patients present unique challenges in the diagnosis of CHF and also therapeutic particularities. The genetic differences may be a possible explanation for the fact that some people, irrespective of their lifestyle and common classical cardiovascular risk factors, are more susceptible to develop heart failure. Moreover, the adipose tissue, a huge endocrine organ which secretes adipokines, is also a well-established source of all renin-angiotensin-aldosterone system components, being strongly involved in the pathogenesis of CHF. That is why this review will explore the possible links between the RAS genetic polymorphisms and leptin secretion in obese HF patients, trying to bring a more precise understanding of this relationship, which will undoubtedly facilitate a more appropriate treatment of HF in obese patients. We also try to explain the possible incriminated mechanisms, and plausible biological explanations for the relationship between RAS genetic polymorphisms and adipokines secretion in obese heart failure patients.

Homeopathic treatment for prolonged postoperative coma: a case report.

Coma is the state of unrousable unconsciousness. There are variations in the degree of coma and the findings and signs found on the patient's clinical examination depend on the underlying cause of the disorder. The Glasgow Coma scale evaluates the best motor, verbal and eye answers of the patient. A patient is considered to be in a coma if his Glasgow Coma Scale is below 8 points. The progress that we have made throughout the years has also led to complications that can culminate in a major catastrophe like death, permanent brain damage, coma. A study performed reached the conclusion that prior comorbidity, older age, intraoperative hypotension, and cardiovascular surgery may predispose patients to postoperative coma. The article presents a case of postoperative coma treated successfully with homeopathy. Although a rare complication, postoperative coma is a severe, death-leading condition, causing immense suffering on both the patient and the patient's family. A multidisciplinary and thorough approach is necessary for these patients, but even after a well-conducted therapy, this condition leads to the death of the patient.

New pharmacological strategies in rheumatic diseases.

Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. Abbreviations: ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor.

Credibility judgments in web page design - a brief review.

Today, more than ever, knowledge that interfaces appearance analysis is a crucial point in human-computer interaction field has been accepted. As nowadays virtually anyone can publish information on the web, the credibility role has grown increasingly important in relation to the web-based content. Areas like trust, credibility, and behavior, doubled by overall impression and user expectation are today in the spotlight of research compared to the last period, when other pragmatic areas such as usability and utility were considered. Credibility has been discussed as a theoretical construct in the field of communication in the past decades and revealed that people tend to evaluate the credibility of communication primarily by the communicator's expertise. Other factors involved in the content communication process are trustworthiness and dynamism as well as various other criteria but to a lower extent. In this brief review, factors like web page aesthetics, browsing experiences and user experience are considered.

Comparative animal study of the antinociceptive efficacy of lamotrigine and gabapentin for the management of pain.

UNLABELLED: Pain relief using drugs with high efficacy provides significant improvement in the patients' lives. Drugs like lamotrigine (LTG) and gabapentin (GBP) have the ability to overcome the symptoms of neuropathic pain. AIM: The present study offers a comparative analysis of LTG and GBP efficacy in a rat model of nociceptive pain after single administration. METHOD: Sixty-three Wistar-Bratislava rats randomized into 7 groups were included: a control group treated with saline solution and 6 groups treated with different doses of LTG and GBP. Nociceptive responses to thermal and mechanical stimulations were evaluated before and after drug administration, at different time intervals, using paw pressure and hot plate tests. The obtained data were statistically analyzed, with significance at p value < 0.05. RESULTS: LTG 100 mg/kg and 50 mg/kg presented a significant analgesic effect in both mechanical and thermal tests, 1 and 2 hours after administration. GBP 100 mg/kg increased latency time in hot plate test. The effect of both anticonvulsant drugs occurred rapidly after administration, but had a short duration. CONCLUSIONS: LTG and GBP had an analgesic effect in a single dose administration. The effect of LTG was more evident since it was observed in both tests. Their effect was dose dependent.

Pharmacogenetics aspects of oral anticoagulants therapy.

RATIONALE: Vitamin K antagonists (VKA), such as warfarin and acenocoumarol, are widely used for the prevention and treatment of thromboembolic diseases and they are some of the most commonly prescribed types of medications. They are characterized by narrow therapeutic indices and inter-individual or intra-individual variability in response to the treatment. OBJECTIVE: to establish the influence of several genetic factors on VKA efficacy and adverse reactions. METHODS AND RESULTS: The metabolism of VKA differs depending on their chemical structure: indandiones derivatives (fluindione) or coumarin derivatives (acenocoumarol, phenprocoumon or warfarin). They are mostly metabolized in hepatocytes via a monooxygenase, cytochrome P450 2C9 (CYP2C9), resulting in inactive products. The gene encoding CYP2C9 is polymorphic, its genetic variants being associated with differences in the enzymatic activity of CYP2C9. The most important in terms of their frequency in the general population are CYP2C9*2 and CYP2C9*3. Both alleles are associated with a marked decrease in CYP2C9 enzyme activity. VK epoxide reductase (VKOR) is an enzyme with an important role in VK metabolism. Various polymorphisms in the VKORC1 gene have been described. VKORC1*2 haplotype seems to be the most important in relation to the variability in response to VKA. DISCUSSIONS: Various studies have shown a relationship between the genotype and the mean warfarin maintenance dosing: in patients carrying 2C9*1/*2 alleles, the dose is reduced by 18-40% in patients carrying 2C9*2/*2 alleles, by 21-49% in patients carrying 2C9*1/*3 alleles. The A allele of the c.-1639G>A polymorphism in the VKORC1 gene is associated with the need for a lower dose of acenocoumarol in patients on anticoagulant therapy. ABBREVIATIONS: SNP = Single Nucleotide Polymorphism, VKA = vitamin K antagonists, C1 - VKORC1 = vitamin K epoxide reductase complex subunit, INR = International Normalized Ratio.

A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Nebivolol is a highly selective beta-blocker with additional vasodilator properties, widely used in the clinical practice for the treatment of hypertension and heart failure. Paroxetine is a second-generation antidepressant and a potent inhibitor of CYP2D6, the same isoenzyme involved in the metabolism of nebivolol. The objective of this study was to investigate the effect of multiple-dose paroxetine intake on the pharmacokinetics of nebivolol in healthy volunteers and its potential consequences upon nebivolol pharmacodynamics. METHODS: The study included 23 healthy subjects and was designed as an open-label, single-centre, non-randomized, two-period clinical trial. During period 1 (reference), each volunteer received a single dose of 5 mg nebivolol, whereas during period 2 (test), each volunteer received a single dose of 5 mg nebivolol and 20 mg paroxetine, after a pretreatment regimen with paroxetine (20-40 mg/day for 6 days). The pharmacokinetic parameters of nebivolol and its active metabolite were analysed by non-compartmental modelling. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest, after each nebivolol intake. RESULTS AND DISCUSSION: Pretreatment with paroxetine increased the mean peak plasma concentrations (Cmax ) for unchanged nebivolol (1·78 ± 1·17 vs. 4·24 ± 1·67 ng/mL) and for its active metabolite (0·58 ± 0·21 vs. 0·79 ± 0·24 ng/mL) compared to nebivolol alone. The time (tmax ) to reach Cmax was 1·37 ± 0·88 (h) and 3·11 ± 1·76 (h) for the parent compound and its active metabolite after nebivolol administered alone and 3·96 ± 1·76 (h), respectively, 7·33 ± 7·84 (h) after pretreatment with paroxetine. Also, the total areas under the curve (AUC0-∞ ) were significantly increased from 17·26 ± 43·06 to 106·20 ± 65·56 h ng/mL for nebivolol unchanged and 13·03 ± 11·29 to 74·56 ± 88·77 h ng/mL for its hydroxylated metabolite, before and after paroxetine intake. All the pharmacokinetic parameters presented statistically significant differences when paroxetine was administered with nebivolol. Nonetheless, statistical analysis did not show a significant difference between the vital signs measured during the two periods. WHAT IS NEW AND CONCLUSION: After pretreatment with paroxetine, the exposure to nebivolol was increased by 6·1-fold for the parent drug and 5·7-fold for the hydroxylated active metabolite. Paroxetine influenced nebivolol pharmacokinetics in healthy volunteers, but it did not have a significant effect on nebivolol pharmacodynamic parameters measured at rest, although the clinical relevance of this drug interaction needs further investigation.

Breath tests with novel 13C-substrates for clinical studies of liver mitochondrial function in health and disease.

Mitochondrial dysfunction determines the onset and progression of chronic deleterious conditions including liver diseases. The in vivo assessment of mitochondrial function, by providing more insight into the pathogenesis of liver diseases, would be a helpful tool to study specific functions and to develop diagnostic, prognostic and therapeutic strategies. The application of breath tests in the clinical setting to evaluate mitochondrial fitness may elegantly and noninvasively overcome the difficulties due to previous complex techniques and may provide clinically relevant information, i.e the effects of drugs presenting mitochondrial liabilities. Substrates meeting this requirement include alpha-ketoisocaproic acid and methionine, both decarboxylated by mitochondria. Long and medium chain fatty acids that are metabolized through the Krebs cycle and benzoic acid, which undergoes glycine conjugation, may also reflect the mitochondrial performance. This review focuses on the utility of breath tests to assess mitochondrial function in humans, thus contributing to unravel potential mechanisms associated with the dysfunction of this organelle network in the pathophysiology of liver diseases.