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Metabolic regulation occurs through precise control of enzyme activity. Allomorphy is a post-translational fine control mechanism where the catalytic rate is governed by a conformational switch that shifts the enzyme population between forms with different activities. β-Phosphoglucomutase (βPGM) uses allomorphy in the catalysis of isomerisation of β-glucose 1-phosphate to glucose 6-phosphate via β-glucose 1,6-bisphosphate. Herein, we describe structural and biophysical approaches to reveal its allomorphic regulatory mechanism. Binding of the full allomorphic activator β-glucose 1,6-bisphosphate stimulates enzyme closure, progressing through NAC I and NAC III conformers. Prior to phosphoryl transfer, loops positioned on the cap and core domains are brought into close proximity, modulating the environment of a key proline residue. Hence accelerated isomerisation, likely via a twisted anti/C4-endo transition state, leads to the rapid predominance of active cis-P βPGM. In contrast, binding of the partial allomorphic activator fructose 1,6-bisphosphate arrests βPGM at a NAC I conformation and phosphoryl transfer to both cis-P βPGM and trans-P βPGM occurs slowly. Thus, allomorphy allows a rapid response to changes in food supply while not otherwise impacting substantially on levels of important metabolites., (© 2024. The Author(s).)

Atrial fibrillation (AF) is associated with oxidative stress and inflammation. Paraoxonase-1 (PON1), circulates in blood bound to high-density lipoproteins and reduces systemic oxidative stress. The aim of this study was to evaluate PON1 serum concentration and PON1 arylesterase activity (AREase) in patients with AF. We studied a group of 67 patients with symptomatic paroxysmal or persistent AF admitted for cardioversion and a control group of 59 patients without AF. Clinical parameters, lipid profile, PON1 concentration and AREase were evaluated. A significant difference in serum PON1 concentration and in AREase was found among the two groups. In a multivariate linear regression model, the presence of AF was associated with low PON1 concentration (P = .022). The body mass index was also independently associated with PON1 values (P < .001). Only the high-density lipoproteins-cholesterol level was independently associated with AREase (P = .002). PON1 serum concentrations and AREase were diminished in patients with AF, and the presence of AF was independently associated with low PON1 values., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cardiovascular assessment of oncological patients suggests that cancer can lead to subclinical damage of the heart. The aim of the present study was to analyze the value of baseline cardiovascular biomarkers in patients with newly diagnosed colon cancer prior to treatment. Additionally, another aim was to establish baseline cut-off alert values for this low-intensity neoplastic damage. A total of 51 patients with newly diagnosed colon cancer, without history of cardiac disease, were enrolled in a prospective, cross-sectional study. All patients underwent clinical, biochemical and basic echocardiographic evaluation before starting treatment. Patients were assessed for myocardial damage using high-sensitivity troponin T (hs-TnT), creatine kinase-MB (CK-MB) and N-terminal-pro B-type natriuretic peptide (NT-proBNP). A group of 28 healthy controls was included for comparison. Cardiac ultrasound revealed similar left ventricular (LV) ejection fraction but enlarged LV chambers compared with the control group (LV at end systole, 29.50 vs. 26.00 mm; LV at end diastole, 44.50 vs. 38.00 mm; P<0.001 in both cases). The levels of cardiovascular biomarkers of myocardial damage were higher in the patients than in the control group (CK-MB, 17.00 vs. 11.00 IU/l, P<0.001; hs-TnT, 8.20 vs. 3.00 ng/l, P<0.001; NT-proBNP, 155.40 vs. 48.50 pg/ml, P=0.001). In multivariate analysis, CK-MB and hs-TnT retained statistical significance (P=0.004 and P=0.045, respectively). Moreover, it was demonstrated that new cut-offs for hs-TnT (8.00 ng/l) and NT-proBNP (220.00 pg/ml) can identify cardiac damage in patients ≥65 years old. Thus, the present study confirmed the hypothesis that a basic cardiovascular assessment of treatment-naïve patients with colon cancer can identify important pre-treatment myocardial impact. Adapted cut-off values should be set for cardiovascular biomarkers in the cancer population, different from those currently accepted for acute coronary syndromes or heart failure., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Radulescu et al.)

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.

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.

Background and Purpose: In Romania, robust data about the prevalence of obesity and heart failure are lacking, especially in the elderly; therefore, this study aims to analyze the profile of overweight and obese patients aged >65 years admitted to a Romanian hospital for worsening heart failure, and also their risk in the presence of comorbidities., Patients and Methods: This cross-sectional study was conducted in 126 consecutive elderly patients with overweight and obesity admitted to a Romanian hospital for worsening heart failure. They were divided into three groups: with reduced (<40%) - HFrEF, mid-range (40-49%) - HFmrEF and preserved (≥50%) ejection fraction - HFpEF. Obesity was defined according to the body mass index (BMI) status: obesity, ≥30 kg/m 2 ; overweight, 25-29.9 kg/m 2 . The Charlson Comorbidity Index (CCI) was calculated to evaluate the severity of comorbidity, with a score ranging from 2 (only heart failure present and age >65 years) to 30 (extensive comorbidity)., Results: NT-proBNP values are negatively correlated with BMI only in patients with HFpEF. Creatinine clearance (p=0.0166), the presence of atrial fibrillation (p=0.0095) and NYHA functional class were independent predictors of increased NT-proBNP values. CCI score is negatively correlated with NT-proBNP values in patients with HFmrEF (r= -0.448, p=0.009) and HFpEF (r= -0.273, p=0.043). The CCI risk was not significantly different between the three groups., Conclusion: Elderly heart failure patients with overweight or obesity have particular characteristics in terms of NT-proBNP values and presence of comorbidities. In the studied population, NT-proBNP levels were strongly influenced by renal function, NYHA functional class, the presence of atrial fibrillation and left ventricular ejection fraction., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Dădârlat-Pop et al.)

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.

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., Competing Interests: The authors declare that they have no conflict of interest.

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.

Background/aims: Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX)., Methods: Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide., Results: The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor., Conclusion: FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies., (© 2016 S. Karger AG, Basel.)

Purpose: To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics., Methods: This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods., Results: Fluvoxamine pretreatment increased Cmax and AUC0-∞  of nebivolol (Cmax: 1.67 ± 0.690  vs 2.20 ± 0.970  ng/mL; AUC0-∞: 12.1 ± 11.0  vs 19.3 ± 19.5  ng*h/mL ) and of its active metabolite (Cmax: 0.680  ± 0.220  vs 0.960 ± 0.290  ng/mL; AUC0-∞: 17.6 ±20.1  vs 25.5 ± 29.9  ng*h/mL). Apart from Cmax,AUC0-t and AUC0-∞, the other pharmacokinetic parameters (tmax, kel and t½) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake., Conclusions: Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Introduction: The present study aimed at evaluating the biodistribution of Tween(®) 20-gold nanoparticle (GNP) conjugates and their potential toxicity on the bone marrow before moving on to Phase I clinical trials., Materials and Methods: Tween(®) 20-conjugated GNPs were injected intravenously for 21 days in male Crl:CD1(ICR) mice. Body weight of the mice was evaluated each day. After the sub-chronic Tween(®) 20-GNPs administration, blood samples were harvested, and a full blood count was done individually. Total Au quantity from all major organs was assessed using inductively coupled plasma mass spectrometry. One femur and the sternum obtained from each animal were used for histological assessment., Results: Our data showed that the Tween(®) 20-GNP conjugates were found in large quantities in the bladder. Au was shown to accumulate in the hematopoietic bone tissue, with significant side effects such as leucopoiesis and megakaryopoiesis. The mice had a higher white blood cell and platelet count as opposed to the control group. This suggested that the previously described leukopenic effects of isoflurane were overridden by the leucopoietic effects of Tween(®) 20-GNPs., Conclusion: It was uncertain whether the mice were reactive to Au as it is a foreign substance to the tissues or whether the side effects observed were a precursor condition of a more severe hematological condition. Au was found to be hepatotoxic, urging the need for further studies in order to achieve better in vivo compliance and exploit the immense potential of GNPs in cancer pharmacology.

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.

Purpose: To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers., Methods: An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods., Results: Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively., Conclusions: These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

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.

Background and Aims: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles., Materials and Methods: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay., Results: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein., Conclusion: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic.

Background/aims: The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction., Methods: This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest., Results: Bupropion plus nebivolol increased the mean peak plasma concentrations (Cmax) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant., Conclusion: The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation., (© 2016 S. Karger AG, Basel.)

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.

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.

Introduction: Nebivolol, a third-generation β-blocker, is subject to extensive first-pass metabolism and produces active β-blocking hydroxylated metabolites, like 4-OH-nebivolol. It is primarily a substrate of CYP2D6, a metabolic pathway that is under polymorphic genetic regulation. The objective of this study was to assess the metabolizer phenotype and to evaluate the interphenotype bioavailability and metabolism of nebivolol., Material and Methods: Forty-three healthy volunteers were included in this open-label, non-randomized clinical trial and each volunteer received a single dose of 5 mg nebivolol. Non-compartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The phenotypic distribution was assessed based on the AUC (aria under the curve) metabolic ratio of nebivolol/4-OH-nebivolol and statistical analysis. An interphenotype comparison of nebivolol metabolism and bioavailability was performed based on the pharmacokinetic parameters of nebivolol and its active metabolite., Results: Nebivolol/4-OH-nebivolol AUC metabolic ratios were not characterized by a standard normal distribution. The unique distribution emphasized the existence of two groups and the 43 healthy volunteers were classified as follows: poor metabolizers (PMs)=3, extensive metabolizers (EMs)=40. The phenotype had a marked impact on nebivolol metabolism. The exposure to nebivolol was 15-fold greater for PMs in comparison to EMs., Conclusion: 40 EMs and 3 PMs were differentiated by using the pharmacokinetic parameters of nebivolol and its active metabolite. The study highlighted the existence of interphenotype differences regarding nebivolol metabolism and bioavailability.

Background and Aims: To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers., Methods: 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period., Results: Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively., Conclusions: Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

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., (© 2014 John Wiley & Sons Ltd.)

The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as "nonresponders" if they failed to achieve improvement ≥50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68-0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy.

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.

This article briefly reviews some of the mechanisms involved in the pathogenesis of neurological diseases, i.e. damage mechanisms (DM), and their interactions and overlap with protection and reparatory processes (i.e. endogenous defence activities). A relationship between DM and endogenous defence activity (EDA) regarding therapy principles will also be described. Currently, it is difficult to find the correct therapeutic approach for brain protection and recovery, especially because we do not fully understand all of the endogenous neurobiological processes, the complete nature of the pathophysiological mechanisms and the links between these two categories. Moreover, we continue to use a simplistic and reductionist approach in this respect. Endogenous neurobiological processes, such as neurotrophicity, neuroprotection, neuroplasticity and neurogenesis, are central to protection and recovery and represent the background of EDA. The biological reality of the nervous system is far more complex. In fact, there is an endogenous holistic process of neuroprotection and neurorecovery that should be approached therapeutically in an integrated way. The current tendency to exclusively frame drug activity in terms of single mechanisms and single focus effect might distract from other paradigms with greater explanatory power and hinder the development of more effective treatment strategies. A change of concept is required in pharmacological brain protection and recovery. Prospective considerations include an integrated pharmacological approach, focusing on drugs with multimodal activity and pleiotropic neuroprotective effect which are biological drugs, rather than single mechanism drugs, which usually are chemical drugs., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Impulse control disorders (ICDs) represent an important medical challenge. The authors of the present paper restricted themselves to present an overview of the neurocircuitry that is involved in ICDs and to present information about the mechanisms of neuroplasticity that are the substrate of the ICDs. Understanding the networks involved in ICDs at the level of the cellular and molecular mechanisms of neural and synaptic plasticity may facilitate the understanding of the ways in which various conditions favour the habit formation and compulsivity that are associated with neurological disorders. The psychological, sociological and forensic dimensions of ICDs are beyond the scope of this paper., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Functional severity in ankylosing spondylitis (AS) patients is variable and difficult to predict early. The aim of our study was to assess whether a combination of baseline clinical factors and genetic markers may predict the development of severe functional status in AS. We performed a cross-sectional association study on AS patients included in the Spanish National Registry of Spondyloarthropathies--REGISPONSER. Bath Ankylosing Spondylitis Functional Index (BASFI) was standardized by adjusting for disease duration since the first symptoms (BASFI/t). We considered as severe functional status the values of BASFI/t in the top of the 60th (p60), 65th (p65), 70th (p70), and 75th (p75) percentile. We selected 384 single nucleotide polymorphisms (SNPs) distributed in 190 genes to be analyzed. The study cohort included 456 patients with mean age 50.8(± 10.5) years and with mean disease duration since first symptoms 24.7 (± 10.1) years. Older age at disease onset and neck pain at baseline showed statistical significant association with severe BASFI/t. Polymorphisms associated in the allele frequencies test with severe BASFI/t in all classifications were: rs2542151 (p60 [P = .04], p65 [P = .04], p70 [P = .001] and p75 [P = .001]) and rs2254441 (p60 [P = .004], p65 [P = .02], p70 [P = .01] and p75 [P<.001]).. Genotype association, after adjustment for covariates, found an association in three of the four patients' classifications for rs2542151 and in two of the classifications for rs2254441.Forward logistic regression did not identify any model with a good predictive power for severe functional development.In our study we identified clinical factors and 24 polymorphisms associated with development of severe functional status in AS patients. Validation of these results in other cohorts is required.

The possibility that cerebrolysin, a mixture of several active fragments of neurotrophic factors and peptides induces neuroprotection following nanoparticles induced exacerbation of brain damage in heat stroke was examined in a rat model. For this purpose, the therapeutic efficacy of Cerebrolysin (2.5 or 5 ml/kg) recommended for stroke treatment was used in comparison with other drugs in standard doses recommended for such therapy in clinical situations e.g., levetiracetam (44 mg/kg), pregabalin (200 mg/kg), topiramate (40 mg/kg,i.p.) and valproate (400 mg/kg). Rats subjected to 4 h heat stress in a biological oxygen demand (BOD) incubator at 38 degrees C (Rel Humid 45-47%; Wind vel 22.4 to 25.6 cm/sec) developed profound behavioral symptoms of heat stroke e.g., hyperthermia, profuse salivation, prostration and gastric ulcerations in the stomach. These rats also exhibited marked brain pathology at this time. Thus, breakdown of the blood-brain barrier (BBB) to proteins associated with brain edema formation could be seen in these heat stressed rats as compared to control groups. The edematous brain areas showed profound neuronal damage and/or distortion in large areas of the neuropil. These pathological symptoms were further exacerbated in Cu or Ag nanoparticles treated group (50-60 nm particle size, 50 mg/kg, i.p./day for 7 days) after identical heat stress on the 8th day. Pretreatment with cerebrolysin (2.5 ml/kg, i.v.) daily for 3 days in normal rats before heat stress significantly reduced the behavioral stress symptoms and the breakdown of the BBB function, edema formation and neuronal injuries. However, the magnitude and intensity of these neuroprotective effects were much less intense in all other drug treated rats after similar heat stress. On the other hand, almost double dose of cerebrolysin (5 ml/kg) was needed to achieve comparable neuroprotection in nanoparticles treated animals after heat stress. Whereas, double dose of all other compounds was much less effective in inducing neuroprotection in nanoparticles treated heat-exposed animals. These observations are the first to show that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal and in nanoparticles treated group. Furthermore, cerebrolysin in double dose was the most effective in inducing neuroprotection in nanoparticles treated heat exposed rats on brain pathology as compared to double doses of other drugs. Taken together, our results show that cerebrolysin has the most superior neuroprotective effects on brain pathology in heat stroke in both normal and nanoparticles treated rats as compared to other contemporary neuroprotective agents, not reported earlier.

The drugs hepatotoxicity represents a major problem of the iatrogenic pathology, with various manifestations, directly through the hepatotoxic effect or through idiosycrasy reactions. The hepatic affection induced by chemotherapy appears in children in cases of prolonged therapy, chronic diseases, or other associated conditions. Hepatotoxicity clinically develops through hepatic disorder, cholestatic or mixed hepato-cholestatic manifestations and systematic affection. There are no specific hystological or biochemical characteristics for diagnostic of hepatotoxicity. The international criteria for asessing the hepatotoxicity includes the bilirubin, the transaminasis, GGT, FA, albumin and the flow on the vein. It has been noticed that these parameters are not enough for the right assesssment of the chemotherapics' hepatotoxicity. Thus it is required the abdominal ultrasonography and computerised tomography for the identification of billiary tract, vascularisation, associated conditions and the degree of fibrosis; also, the hepatic biopsy may be necessary. The ultrasound elastography is a method which can give information related to the elasticity/stiffness of the examined tissue and degree of fibrosis. Acustic radiation force imaging(ARFI) is an elastographic method which allows valid, accurate and flexible evaluation of liver stiffness, a quantification with a strong correlation with the fibrosis stage, not influenced by steatosis. In conclusion, the hepatic toxicity showed by alterated hepatic biochemical tests and by symptomes of hepatopathy needs a proper appreciation of the hepatic modifications, which can be obtained through hepatic biopsy or by assessing the hepatic elasticity through elastography. Thus, real-time elastography is an useful tool in assessing the chemotherapics hepatotoxicity in children with cancer.

The maintenance of the effects of Cerebrolysin, a peptidergic compound with neurotrophic activity, on cognitive performance and qEEG activity was investigated through a 12-week, open-label extension of a 4-week, randomised, placebo-controlled pilot study. Thirty-three out of 41 patients with mild-to-moderate severe probable vascular dementia (VaD) according to NINDS-AIREN participating in the double-blind phase of the study were also assessed at the follow-up visit at week 16. Patients received i.v. infusions of Cerebrolysin (10 or 30 mL) or placebo (saline) 5 days/week for 4 weeks. Neuropsychological evaluations and qEEG recordings were done at baseline, week 4 and week 16. The mean change in score from baseline in the ADAS-cog+ and the slow-to-fast qEEG power ratio (PR), used as an index of qEEG slowing, were the two primary endpoints. Correlations between changes in cognition and qEEG induced by the treatment were also assessed. At the week 16 follow-up visit, Cerebrolysin improved (p<0.05) cognitive performance at the 10-mL and 30-mL doses and reduced qEEG slowing significantly (p<0.05) at the 30-mL dose with respect to the placebo. In addition, a significant (p<0.05) positive correlation between the change from the baseline qEEG PR and ADAS-cog+ variables was observed at week 16. These results indicate a persistence of the beneficial effects of Cerebrolysin on cognition and qEEG activity in VaD patients for at least 12 weeks after treatment cessation, and they suggest the potential utility of qEEG parameters as biomarkers for VaD clinical trials., (Copyright © 2010 Elsevier B.V. All rights reserved.)