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Direct oral anticoagulants have been an increasingly used class of drugs in the setting of nonvalvular atrial fibrillation, defying vitamin K antagonists' monopoly when it comes to anticoagulation, due to its several limitations. Direct oral anticoagulants have entered the market as a non-inferior and safer option in comparison with vitamin K antagonists, as their respective phase III clinical trials proved. The aim of this article was to update and summarize data on their clinical pharmacology and to review real-world data to know their comparative effectiveness and safety. We performed a systematic review using PubMed, Google Scholar, Embase and Web Of Science as search engines. Regarding pharmacodynamics, there were no substantial changes reported from their original profile. There were many advances in the knowledge about clinical pharmacokinetics of direct oral anticoagulants which has had a direct impact on their clinical use, mainly related to drug-drug interactions. In real-world setting, Direct Oral Anticoagulants have shown to be non-inferior in preventing thromboembolic events compared to Vitamin K antagonists. In regards to safety, DOACS have shown a lower bleeding risk relative to Warfarin. Comparison between DOACS has demonstrated Rivaroxaban to have the highest bleeding risk. Overall, the evidence gathered showed little changes from the original data presented in phase III clinical trials, concluding that their real-world use coincides in great manner with them. This article is protected by copyright. All rights reserved.

BackgroundHyperbaric oxygen (HBO2) therapy has been proposed to treat hypoxaemia and reduce inflammation in COVID-19. Our objective was to analyse safety and efficacy of HBO2in treatment of hypoxaemia in patients with COVID-19 and evaluate time to hypoxaemia correction.MethodsThis was a multicentre, open-label randomised controlled trial conducted in Buenos Aires, Argentina, between July and November 2020. Patients with COVID-19 and severe hypoxaemia (SpO2≤90% despite oxygen supplementation) were assigned to receive either HBO2treatment or the standard treatment for respiratory symptoms for 7 days. HBO2treatment was planned for ≥5 sessions (1 /day) for 90 min at 1.45 atmosphere absolute (ATA). Outcomes were time to normalise oxygen requirement to SpO2≥93%, need for mechanical respiratory assistance, development of acute respiratory distress syndrome and mortality within 30 days. A sample size of 80 patients was estimated, with a planned interim analysis after determining outcomes on 50% of patients.ResultsThe trial was stopped after the interim analysis. 40 patients were randomised, 20 in each group, age was 55.2±9.2 years. At admission, frequent symptoms were dyspnoea, fever and odynophagia; SpO2was 85.1%±4.3% for the whole group. Patients in the treatment group received an average of 6.2±1.2 HBO2sessions. Time to correct hypoxaemia was shorter in treatment group versus control group; median 3 days (IQR 1.0–4.5) versus median 9 days (IQR 5.5–12.5), respectively (p2group at day 3 compared with the control group was 23.2 (95% CI 1.6 to 329.6; p=0.001) Treatment had no statistically significant effect on acute respiratory distress syndrome, mechanical ventilation or death within 30 days after admission.ConclusionOur findings support the safety and efficacy of HBO2in the treatment of COVID-19 and severe hypoxaemia.Trial registration numberNCT04477954.

Obesity prevalence is increasing worldwide in both males and females, in different regions, and across the age spectrum. It is usually defined by a body mass index (BMI) of 30 Kg/m2 or higher, and ...

RESUMEN Introducción: Los trastornos intraventriculares de la conducción constituyen una manifestación habitual en los pacientes con enfermedad de Chagas con función ventricular izquierda conservada. Se desconoce si su presencia puede estar asociada a una mayor actividad inflamatoria. Objetivos: Determinar si existe una correlación entre los niveles de interleuquinas y la presencia de trastornos intraventriculares de la conducción en pacientes con serología positiva para enfermedad de Chagas y fracción de eyección ventricular izquierda conservada. Material y métodos: Se evaluó a 22 pacientes con edades comprendidas entre 21 y 80 años, seropositivos para enfermedad de Chagas, de más de 20 años de evolución y fracción de eyección ventricular izquierda mayor del 50%. Se analizó, además, un grupo control de 14 individuos sanos. Se determinaron las concentraciones en plasma de IFN-γ, IL-1β, IL-6, IL-10, IL-12 (p70), IL-15, IL-17A, MCP-1/CCL2, MIP-1 a/CCL3, TNF-a e IL-2. Se consideró trastornos intraventriculares de la conducción a la presencia de bloqueo de rama derecha, hemibloqueo anterior izquierdo o bloqueo de rama izquierda. Resultados: De los 22 pacientes con serología positiva para enfermedad de Chagas, 10 presentaron trastornos de la intraventriculares de la conducción (45,4%). En el grupo con trastornos intraventriculares de la conducción, se observaron niveles elevados de interleuquinas de alto efecto inflamatorio como INF-γ, IL-15, IL-2 (p70), IL-12, MP1-a, en comparación al grupo control, además de presentar altos valores de IL-10 como mecanismo modulador de una respuesta inmunitaria excesiva. Conclusiones: La asociación entre niveles elevados de interleuquinas y la presencia de trastornos intraventriculares de la conducción plantea un posible proceso inflamatorio crónico para su desarrollo en pacientes chagásicos con fracción de eyección ventricular izquierda conservada. ABSTRACT Background: Intraventricular conduction disturbances are common in patients with Chagas disease and preserved left ventricular ejection fraction, but their association with higher inflammatory activity is unknown. Objectives: The aim of this study was to determine the presence of an association between interleukin levels and intraventricular conduction disturbances in patients with positive serology for Chagas disease and preserved left ventricular function. Methods: Twenty-two patients between 22 and 80 years of age with positive serology test for Chagas disease with more than 20 years progression and left ventricular ejection fraction ≥50% were included in the study and compared with a control group of 14 healthy individuals. Plasma levels of IFN-γ, IL-1β, IL-6, IL-10, IL-12 (p70), IL-15, IL-17A, MCP-1/CCL2, MIP-1 a/CCL3, TNF-a and IL-2 were measured in patients and controls. Right bundle branch block, left anterior hemiblock or left bundle branch block were considered intraventricular conduction disturbances. Results: Among the 22 patients with positive serology for Chagas disease, 10 presented intraventricular conduction disturbances (45.4%). This group had elevated levels of interleukins with high inflammatory effect such as INF-γ, IL-15, IL-2, IL-12, MIP-1 a, compared with the control group, and high levels of IL-10 as a regulatory mechanism of an excessive immune response. Conclusions: The association between elevated levels of inflammatory interleukins and intraventricular conduction disturbances suggests that chronic inflammation may play a role in the development of these abnormalities in patients with positive serology for Chagas disease and preserved left ventricular ejection function.

Background: Monogenic Diabetes (MFD) represents close to 2% of all the cases of diabetes diagnosed in people younger than 45 years old. Maturity-Onset Diabetes of the Young (MODY), neonatal diabetes, and several syndromic forms of diabetes are included among the most accounts for about typical forms of MDF. MODY is the most frequent type of MFD, with MODY 1, 2, 3, and 5 being the most prevalent forms. The aim of this narrative review is to describe pregnancy associated changes in the pharmacological profile of the antidiabetic drugs used in women with the most frequent MODY subtypes. Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1970 first semester. Results: Pregnancy introduces changes in the pharmacodynamic and pharmacokinetic profile of some of the treatments used in MODY. MODY 3 (also known as HNF1-A MODY) is the most frequent MDF. MODY 3 patients are highly sensitive to Sulfonylureas (SU). This is also the case for MODY pregnant women. This high sensitivity to SU is also registered in patients with MODY 1 (HNF4-A MODY). Pharmacodynamic changes have been proposed to explain this behavior (Epac2 hyperactivity). However, changes in expression/activity of the metabolizing CYP2C9 cytochrome and/or alterations in the drug transporters oatp1 (Slc21a1), Lst-1 (Slc21a6), OATPD (SLC21A11), and oat2 may better explain, at least in part, this phenomenon by an increase in the concentration of the active drug. Conclusion: Conclusion: The impact of changes in the pharmacological behavior of drugs like SU and other metabolized/transported by mechanisms altered in a pregnancy complicated by MODY is unknown. However, switching-to-insulin recommendation formulated for MODY 1 and 3 seems to be justified. Further research in this field is needed for a better understanding of changes in drug activity associated with this particular subset of patients with MFD.

Pathologies linked to the renin-angiotensin system are frequent, and the drugs used in them are numerous and show great variability in therapeutic effects and adverse reactions. Genetic variants have been detected in the angiotensinogen gene (6), angiotensin-converting enzyme (9), angiotensinconverting enzyme 2 (1), and angiotensin receptor Type 1 (4) among others. However, the large number of studies that have analyzed each of them makes it complex and almost impossible to consider all the existing information. This manuscript aims to review the effects of the different known variants on the expected response of different drugs as a basis for the future development of therapeutic guidelines that seek to implement therapeutic individualization strategies on the renin-angiotensin system.

Objective: To evaluate frequency and risk factors for dextropropoxyphene-induced QT-interval prolongation in the clinical setting. Design: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. Setting: General ward of a public hospital of metropolitan Buenos Aires. Patients, Participants: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. Interventions: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. Main Outcome Measure: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. Results: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. Conclusions: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.

Background The liver is the major metabolic clearance organ for chemical agents from the human body. Pregnancy is associated with several physiological changes that may affect one or more of these factors, and also induces changes in the hepatic clearance of certain drugs. The aim of this paper was to review some of the currently available information in the field to provide some insights about the relevance of these changes on the clearance of some drugs. Methods A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1970 first semester. Results Gestational Diabetes Mellitus (GDM) is a frequent disease commonly associated with other entities as obesity, hypertension, dyslipidemia, non-alcoholic fatty liver disease, prothrombotic conditions, changes in intestinal microbiome. These entities, together with the glycemic fluctuations associated with GDM might affect the determinants of the hepatic clearance (hepatic blood flow, the unbound fraction of drugs, and the hepatic intrinsic clearance). GDM is frequently associated with multi-drug treatments. While many of these drugs are cleared by the liver, little is known about the clinical relevance of these GDM associated pharmacokinetic changes. Conclusion Considering the frequency of the disease and the effects that these pharmacokinetic changes might have on the mother and child, the need for further research seems advisable. In the meantime, cautious clinical judgment in the management of drug administration in women affected by this disease is recommended.

Background The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. Method Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. Results Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. Conclusion ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.

Introduction: The obesity epidemic continues to grow. Bariatric surgery is part of the arsenal to treat the disease. Surgery results in an effective option for patients with severe obesity but also when obesity is associated with significant comorbidities. Weight regain is frequent after bariatric surgery. Consequently, the addition of anti-obesity drugs to prevent and manage weight regain are commonly recommended even when the quality of the evidence supporting this recommendation is relatively weak. Areas covered: The aim of this review is to summarize the available evidence concerning long-term pharmacotherapy of obesity in patients that have undergone bariatric surgery with a focus on pharmacological prevention and management of weight regain. The etiology and epidemiology of weight regain are summarized, as well as the available information about the benefits and risks of long-term pharmacotherapy in the prevention and management of recidivism. Expert opinion: The available information, mainly obtained from observational studies and small trials, is encouraging but calls for a prudent approach in the selection of appropriate agents for each individual patient and a careful follow-up to detect adverse reactions or drug interactions. Results from well-designed trials are upcoming. In the meantime, a cautious, individualized approach is advisable. Fil: Gutt, Susana. Hospital Italiano; Argentina Fil: Scharaier, Silvio. Hospital Italiano; Argentina Fil: Gonzalez Bagnes, María Florencia. Instituto Universitario CEMIC. Facultad de Medicina; Argentina Fil: Yu, Ming. Instituto Universitario CEMIC. Facultad de Medicina; Argentina Fil: González, Claudio Daniel. Instituto Universitario CEMIC. Facultad de Medicina; Argentina. Universidad de Buenos Aires; Argentina Fil: Di Girolamo, Guillermo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional. - Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiologicas "prof. Dr. Alberto C. Taquini". Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional.; Argentina

Background: Metformin is sometimes used as an alternative to insulin in gestational diabetes mellitus (GDM). It is also used to achieve ovulation in polycystic ovary syndrome (PCOS). Pre-natal exposure to metformin results from its continuation after a successful ovulation in women with PCOS, its maintenance in women with pre-gestational diabetes or the installation of metformin in GDM. Little is known about the potential consequences of metformin exposure on pregnancy outcomes and offspring development. The aim of this review is to summarize the metformin effects on pregnancy outcomes and offspring development. Gaps in the available evidence and unanswered questions are also discussed. Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1995 first semester. Results: Several factors limit the effect of metformin on embryos. In contrast, placental transport of metformin is effective allowing for a higher fetal exposure; the impact of this finding remains unclear. It seems that the interruption of metformin after a pregnancy diagnosis in women with PCOS is not associated with a higher miscarriage risk and it continuation does not seem to impair the maternal metabolic prognosis or prevent emerging GDM. Conclusions: It seems to have no sense to prolong the use of metformin after a pregnancy diagnosis in women with PCOS. Patients with GDM may be treated with metformin under on judicious basis, and a careful attachment to clinical guidelines and regulations is recommended. The long-term effects of pre-natal exposure to metformin on the offspring remain uncertain. Fil: González, Claudio Daniel. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina Fil: Alvariñas, Jorge. Sociedad Argentina de Diabetes; Argentina Fil: Gonzalez Bagnes, Maria Florencia. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Di Girolamo, Guillermo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiologicas "prof. Dr. Alberto C. Taquini".; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

In recent years, several cases of torsade de pointes have been associated with many opioids. However, to present no cases have been reported with tramadol. Objective: To evaluate the effect of tramadol on QT-interval in the clinical setting. Research Design and Methods: Medical history and comorbidities predisposing to QT interval prolongation were registered for patients requiring medical assistance that involved tramadol administration. Ionograms and ECGs were performed at baseline and intratreatment; QT interval was analyzed after correction with Bazzet, Fridericia, Framinghan and Hogdes formula. Results: 115 patients were studied (50.4% males) All patients had received tramadol 150-400 mg/day during 3.0-5.0 days at the moment of intratreatment control. Plasma concentrations of tramadol were 201-1613 ng/mL. Intratreatment electrocardiographic control, as mean ± SD (range), showed QTcB 372±32 (305 to 433), QTcFri 356±37 (281 to 429), QTcFra 363±33 (299 to 429), QTcH 362±30 (304 to 427), ΔQTcB 26±40 (-73 to 110), ΔQTcFri 24±48 (-97 to 121), ΔQTcFra 22±42 (-81 to 109) and QTcH 22±38 (-68 to 110) ms. QTc interval presents high correlation with plasma tramadol concentrations (for QTc, R>0.77). Renal failure was associated with a relative risk for ΔQTc > 30 ms of 1.90 (IC95% 1.31-2.74) and for ΔQTc > 60 ms of 4.74 (IC95% 2.57-8.74). No patient had evidence of arrhythmia during the present study. Conclusion: Tramadol produces QTc interval prolongation in good correlation with plasma drug concentrations; renal failure is a risk factor for higher concentration and QT prolongation by tramadol.

Objective To compare the pharmacokinetics, relative bioavailability (RB), immunogenicity, and safety after a single dose of test or reference formulation of teriparatide in healthy human volunteers in order to demonstrate whether both products are similar. Research design and methods We compared pharmacokinetic parameters, immunogenicity, and safety after a single dose of two formulations (Osteofortil® and Forteo®) of teriparatide in a randomizedsequence, open-label, two-period crossover study in 24 healthy volunteers. The washout period between formulations was 7 days. Blood samples were collected at baseline and 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150 minutes, and 3 and 4 hours after administration. Teriparatide concentrations were determined using ELISA. Adverse events were monitored. Results Geometric mean (90% CI) Cmax for test and reference formulations were 165.86 (153.35 - 212.13) and 175.37 (164.04 - 221.04) pg/mL, the AUC0-t was 14,932 (5,275 - 15,752) and 14,153 (1,861 - 16,875) pg×min/mL, and the AUC0-∞ was 16,147 (15,047 - 18,799) and 15,467 (14,473 - 18,126) pg×min/mL, respectively. The test/reference ratios (90% CI) for Cmax, AUC0-t, and AUC0-∞ were 94.58% (85.29 - 104.87), 105.5% (97.77 - 113.84), and 104.4% (96.97 - 112.39), respectively No subject reported adverse events. Conclusion Test formulation met pharmacokinetic criteria for bioequivalence.

Aim: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population. Methods: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs. Results: As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p

Objective: The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. Research Design and Methods: Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. Results: Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. Conclusion: QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.

Stroke is one of the most prevalent neurological diseases worldwide, especially among the elderly population. There are various mechanisms that enhance motor recovery after a stroke. In clinical practice, we have the opportunity to enhance plasticity by designing specific rehabilitation programs. Areas covered: There are a variety of drugs commonly administered to people after the acute phase of a stroke. These drugs may modify motor performance. Herein reviewed is the evidence concerning motor enhancement or decline in stroke patients, produced by drugs commonly used in rehabilitation settings. An extensive review of animal and human studies is performed. Expert commentary: Many of the clinical trials carried out were underpowered. Modest evidence supports the claim that there are agents that can affect motor rehabilitation after a stroke. Amphetamine-like agents, serotonin reuptake inhibitors, and levodopa might improve motor outcomes, while antipsychotics, some antiepileptic drugs, and GABAmimetic drugs could impair the recovery process. To draw definite recommendations, more comprehensive knowledge about the efficacy, long-term effects, and safety of these drugs is required. There are also other interesting molecules that open a promising field for basic and clinical research, in the search for new therapeutic options.

RATIONALE Several opioid analgesics have been related to the prolongation of cardiac repolarization, a condition which can be fatal. In order to establish a correct estimation of the risk/benefit balance of therapeutic doses of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene, it was necessary to develop an analytical method to determinate plasma concentrations of these opioids. METHODS Here we describe a method which incorporates strong alkaline treatment to obtain norpropoxyphene amide followed by a one-elution step solid-phase extraction, and without further derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI-MS) in selected-ion monitoring mode. Quantification was performed with 500 μL of plasma by the addition of deuterated analogues as internal standards. RESULTS The proposed method has been validated in the linearity range of 25-1000 ng/mL for all the analytes, with correlation coefficients higher than 0.990. The lower limit of quantification was 25 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 2.0-12.0% and 6.0-15.0%, respectively. The accuracy, in terms of relative error, was within a ± 10% interval. The absolute recovery and extraction efficiency ranged from 81.0 to 111.0% and 81.0 to 105.0%, respectively. CONCLUSIONS A GC/MS method for the rapid and simultaneous determination of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma was developed, optimized and validated. This procedure was shown to be sensitive and specific using small specimen amounts, suitable for application in routine analysis for forensic purposes and therapeutic monitoring. To our knowledge, this is the first full validation of the simultaneous determination of these opioids and their metabolites in plasma samples.

Background: Differences in drug response among patients are common. Most major drugs are effective in only 25 to 60 percent of the patients, in part due to the CYP enzymes, whose activity vary up to 50-fold between individuals for some index metabolic reactions. Several factors affect CYP activity, among which genetic polymorphisms have been studied as the major cause for long time. Age, gender, disease states, and environmental influences such as smoking, concomitant drug treatment or exposure to environmental chemicals are also important. Methods: This article reviews the available literature on multiple phenotypes assessment as an important tool to predict possible therapeutic failures or toxic reactions to conventional drug doses during patient evaluation. Results: Probe drugs can be used in various combinations allowing for the in vivo assessment of multiple pathways of drug metabolism in a single experiment, configuring a new tool known as phenotyping "cocktails". There are several drug cocktails with different advantages and disadvantages. Most of them have sufficient clinical evidence and data validation to support their use in clinical setting as a surrogate for the risk of adverse reaction in the course of therapy, leading to a better balance between efficacy and safety. Conclusion: Probes characteristics and metabolic ratio measurements are important in the evaluation of phenotyping cocktails as near-future applications.

Obesity is one of the major problems of health policy in different countries. Pharmacological attempts have been made to help affected people without a definitive solution. Some agents--either with peripheral or central effect--are available in the market. On July 2012, the FDA approved two novel preparations for obese patients: (1) topiramate-phentermine--the first one an anticonvulsant and the second one a sympathomimetic amine--and (2) lorcaserin, a 5-HT2CR agonist. Both preparations emerged as new options for weight management.Based on the complex biology of eating behavior, in this review we discuss the features, mechanisms of action, pharmacokinetics, advantages and possible disadvantages of these new agents.With differences in efficacy (higher for the topiramate-phentermine combination), both preparations are active in reducing appetite and body weight, as well as in improving comorbidities. Additional information will be collected from Phase IV surveillance. Focus on cardiovascular, neuropsychiatric (for both introductions) and embrio-fetal safety (especially for topiramate) is expected.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of heterogeneous drugs largely known for their anti-inflammatory, antipyretic, and analgesic effects, which are met by means of the inhibition of the cyclooxygenase (COX) enzymes. Even when their use in patients with diabetes mellitus is limited due to relevant adverse events, some pharmacological and metabolic effects of NSAIDs have been further studied to be potentially beneficial in the prevention and/or treatment of diabetic subjects. Effects on endogenous glucose production, peripheral insulin resistance, pancreatic islet, and systemic inflammation and the insulin clearance have been reported. In this article, we overview the scientific literature of the last 5 years regarding the potential effects of NSAID treatment on diabetes prevention/treatment. The selected papers showed information in both humans and animal models. Furthermore, we included papers that suggest new areas for further investigation, and we discussed our own suggestions on this matter.

Objective: To describe a patient in whom initiation of micronized fenofibrate precipitated mycophenolate induced neutropenia. Case Summary: A 57-year-old man was admitted to the hospital because of febrile neutropenia. He had undergone kidney transplantation seventeen years ago. The patient's immunosuppressive maintenance regimen consisted of mycophenolate mofetil (MMF) 500 mg three times a day, and meprednisone 4 mg daily. His medical history included, hypertension treated with losartan 50mg daily, and dyslipidemia treated with ezetimibe 10mg /simvastatin 20mg for four years (until 2 weeks before admission when micronized fenofibrate 200 mg per day was started because of persistently elevated triglycerides levels. On presentation temperature was 37.8oC and initial laboratory tests showed 3130 White Blood Cell Count(WBC)/μL with neutropenia (absolute neutrophil count (ANC) 313/μL) Fenofibrate and mycophenolate mofetil were discontinued, piperacillin tazobactam 4.5gr three times a day and granulocyte stimulation factor 300 μg/day were started. Three days after admission WBC was 7280/μL, neutrophils: 22%, ANC: 1160/mm3. Mycophenolate mofetil was restarted and granulocyte stimulation factor was discontinued. One month after discharge his WBC was 4480/μL and ANC 1926/μL. Discussion: The initiation of fenofibrate in a patient on stable and therapeutic doses of mycophenolate may have precipitated mycophenolate induced neutropenia, a well described, dose dependent phenomenon. Mycophenolic acid (MPA) displays a complex pharmacokinetic profile susceptible to potential significant interactions with fenofibrate. Since approximately 99% of MPA and fenofibrate bind to albumin, displacement may occur, leading to increased free MPA. Second competition of fenofibric acid for UGT1A9 an enzyme implicated in conjugation of MPA may have decreased its metabolism. The combination of these two effects may increase the risk of dose dependent neutropenia. Using the Interaction Probability Scale (DIPS), the interaction was designated as probable. Conclusions: Until further evidence is available, when fenofibrate is started in a renal transplant patient on mycophenolate careful monitoring should be considered to avoid potentially fatal complications.

Blastoferon, in the following referred to as the test product, is a pharmaceutical product of interferon beta la (CAS 220581-49-7) currently marketed as a biosimilar to the innovator Interferon beta la product (referred to as the reference product). Pharmacokinetics and pharmacodynamIcs assays are critically relevant to demonstrate similarity between biopharmaceuticals. The aims of the present study were to investigate the bioavailability (BA) of the test product (either absolute or relative to the innovator product) and to compare the extent of increase of neopterin concentration following administration of either product. Two studies were performed: initially, an absolute BA assay with i.v. and s.c. injection of test product to 12 healthy subjects. Second, a formal relative BA study with s.c. injections of 88 microg of both products to 24 healthy volunteers. Blood samples for pharmacokinetic and pharmacodynamic profiling were drawn at different intervals after injection. Interferon beta (IFNB) concentrations were determined by ELISA. In the absolute BA study, a single s.c. dose of 44 microg of the test product resulted in a median bioavailable fraction of 29%, a median T(max) of 4 h (4-6) and a C(max) of 3.69 (3.27-4.41) IU x ml(-1). In the relative BA study, values for the test product were: median T(max) of 3 h (2-18), C(max) of 5.39 (4.99-6.31) IU x ml(-1), AUC (0-72) of 142.86 (134.16-190.15) IU x h x ml(-1) and AUC(0-infinity) of 190.95 (174.23-303.13) IU x h x ml(-1). The corresponding values for the innovator product were: T(max) of 3 h (1-24), C(max) of 4.44 (4.12-5.40) IU x ml(-1), AUC(0-72) of 128.77 (121.18-170.92) IU x h x ml(-1) and AUC(0-affinity) of 192.61 (183.04-286.46) IU x h x ml(-1). The AUC(0-72) ratio was 111% (CI 90%: 106-116), the AUC(0-affinity) was 99% (CI 90%: 92-107) and the C(max) ratio was 121% (CI 90%: 112-131). IFNB1a increased neopterin levels in both studies. Both products induced side-effects commonly reported for IFN with no serious adverse events. This study presents pharmacokinetics parameters of the test product and demonstrates similar bioavailability of IFNB1a for both pharmaceutical products.

To evaluate the relative bioavailability of a new formulation containing 5 mg mosapride and 10 mg rabeprazole (T) and compare it with the branded formulations of both drugs co-administered in separate tablets (R) to meet the regulatory requirements of bioequivalence in Argentina.A randomized-sequence, open-label, two-period crossover study was conducted on 24 healthy Caucasian volunteers in a fasting state. A single oral dose of either T or R formulations was followed by a 7-day washout period. Blood samples for mosapride were collected before administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 24 h after administration. Samples for rabeprazole were taken baseline and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8 and 10 h after dosing. Mosapride and rabeprazole concentrations were determined using a validated LC-MS/MS method. Adverse events were monitored based on clinical parameters and volunteer reports.The geometric means (90% CI) C(max) for mosapride in T and R were 23.13 (20.05-39.45) and 23.09 (21.69-32.37) ng/mL, the AUC(0-)(t) were 70.80 (66.23-102.37) and 70.81 (66.35-93.26) ng h/mL and the AUC(0-∞) were 74.05 (69.29-106.11) and 74.98 (70.43-97.77) ng h/mL. For rabeprazole T and R the C(max) were 197.42 (186.12-239.91) and 195.50 (186.08-250.07) ng/mL, the AUC(0-)(t) were 294.90 (275.13-374.15) and 296.96 (280.11-387.89) ng h/mL and the AUC(0-∞) were 301.12 (280.78-380.82) and 304.07 (286.60-394.21), respectively. No differences were detected between the formulations. The T/R ratios (90% CI) for C(max), AUC(0-)(t) and AUC(0-∞) were 100.17% (82.35-121.84), 99.99% (87.58-114.16) and 98.77% (87.02-112.11) for mosapride, and 100.99% (85.14-119.77), 99.31% (84.74-116.38) and 99.03% (85.07-115.28) for rabeprazole. No subject complained of adverse events.In this single-dose study, the mosapride/rabeprazole tablets (test formulation) met the criterion for bioequivalence with the reference formulations. Study limitations include single-dose, open-label design, and a small sample of healthy volunteers.

Purpose: The objective of the present study was to quantify the reported cardiovascular adverse reactions and adverse reactions to cardiovascular drugs to help to design and implement monitoring and prevention strategies. Methods: The pharmacovigilance unit (PU) is a peripheral effector of National Pharmacovigilance Center and receives adverse drug reactions notifications from 10 teaching hospitals. Data on adverse reactions beginning in 2004 and notified to the PU were extracted from the database. Cardiovascular adverse drug reactions and adverse reactions to cardiovascular drugs were identified using Medical Dictionary for Regulatory Activities (MedDRA), and the Anatomical Therapeutic Chemical (ATC) Classification System respectively. The reports of adverse reactions were classified according to their seriousness. Results: From 2004 to 2010, 2516 notifications were received (2383 adverse reactions, 106 lack of efficacy, 26 quality failures). These notifications included 151 cardiovascular adverse reactions and 594 adverse reactions caused by cardiovascular drugs. In the first group, of the 151 cardiovascular adverse reactions through MedDRA SOC classification caused by all ATC group classes, 118 (78.2%) were caused by non cardiovascular drugs. Among them antimicrobials (27,2%) and neurologic drugs (21,2%) were the most frequent. 22 (14.6%) adverse reactions were serious. Long QT syndrome, peripheral edema, hypotension, tachycardia, and bradycardia, were the most frequent. In the second group, of the 594 reports identifying adverse reactions involving all MedDRA SOCs but caused only by cardiovascular drugs, 559 reports (94.1%) were non cardiovascular adverse reactions. Enalapril and furosemide accounted for 65.2% there were 33 (5.6%) serious adverse reactions. The most frequent adverse reactions were hyponatremia, impaired renal function, hypokalemia, metabolic alkalosis, asymptomatic elevation of liver enzymes, hyperkalemia, hyperglycemia, edema, and cough. Conclusion: Non-cardiovascular adverse reactions were the most frequent manifestation of adverse drug reactions caused by cardiovascular drugs and cardiovascular adverse reactions were most often caused by non cardiovascular drugs. This report highlights the importance of systematic evaluation of adverse drug reactions.

The use of genomics to predict adverse drug reactions (ADRs) has been the subject of much research over the last decade. Concerns about the muscular safety of statins, a highly prescribed group of drugs, are partially related to their high exposure. Many studies have identified a variety of genetic markers related to statin-induced myopathy. However, only polymorphisms in the SLCO1B1 gene (which encodes the carrier responsible for the hepatic uptake of statins, which, in turn, contributes to the regulation of plasma levels of SLCO1B1) were strongly associated with statin-induced muscular adverse effects. These was found to be most prominent for simvastatin. The strength of these findings relies on the use of modern genetic approaches, such as well-designed, case-controlled and genome-wide association studies. Nevertheless, the clinical use of this information is far from known at present and needs to be evaluated.The links between genetic polymorphisms (i.e., SLCO1B1 gene) and statin-induced muscle ADRs and the methodological issues involved in the establishment of such an association are explored.Despite there being a statin-gene association for myopathy, in the case of some statins the usefulness of this information still needs to be proven.

Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics.Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug-drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug-drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants.Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject.

Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.

The prevalence of overweight and obesity in children and adolescents is increasing rapidly, while the short- and long-term morbid outcomes make these entities a major public health concern. Initial steps in therapy are based on dietary and lifestyle intervention. In the presence of an insufficient progress, medication or - eventually - surgery may be recommended. Three drugs are currently used: orlistat, metformin, and sibutramine; other candidates are in development. However, trials assessing the efficacy and safety of the current medications are frequently affected by methodological limitations, in particular insufficient power and period of follow-up.The efficacy and safety of antiobesity drugs currently used for children and adolescents are reviewed. Additional information on upcoming agents is presented.This is an exhaustive review of current state on controversial issues regarding drugs used in children and adolescent obesity, specifically related with their efficacy and safety.The efficacy of these drugs is modest. Our knowledge of their efficacy and safety comes from clinical trials affected by insufficient follow-up (1 year or less); very often, these trials are of limited power. Further data from larger and longer well-designed clinical trials would be advisable.

QT interval prolongation is one of the most important causes of withdrawal of drugs from the market, due to its association with Torsades de Pointes (TdP), a potentially fatal arrhythmia. Although many antimicrobial drugs are capable of inducing this type of arrhythmia, the importance of this effect is usually underestimated. Macrolides, quinolones, azoles, pentamidine, protease inhibitors, antimalarial drugs and cotrimoxazole are the anti-infective agents more frequently associated with this adverse effect. Despite the fact that the risk of QT prolongation and TdP under single antimicrobial therapy is low, these drugs are so extensively used that sporadic cases of this arrhythmia are reported. Moreover, antimicrobial drugs are susceptible to pharmacokinetic and pharmacodynamic interactions with other drugs, which may increase the risk of this arrhythmia. Therefore, physicians must be familiar with not only the antimicrobial drugs capable of producing QT interval prolongation, but also their potential interactions. In addition, patient's specific risk factors of prolonging QT interval or producing TdP must be taken into account. This article reviews the role of anti-infective drugs in QT prolongation, focusing on QT prolongation mechanisms, potential drug interactions, and patients' predisposing factors to this arrhythmia.

The assessment about the proarrhythmic risk associated with a particular drug is a major requirement for drugs under development, since many drugs have been withdrawn from market or got under strict pharmacological vigilance because of such a risk. Predicting the development of a life-threatening arrhythmia is a hard task but, in the case of TdP ("Torsades de Pointes"), there are some useful markers. Among them, the prolongation of the QT interval and its heart rate correction (QTc) are the most remarkable. Actually, QT prolongation is considered the surrogate marker of TdP from the clinical and regulatory standpoint. ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The regulatory information about preclinical safety evaluation is contained in ICH S7B. Both guidelines have been a matter of intense debate. False negative and false positive results have been found within the preclinical and clinical field. There still are grey areas in which further research would be necessary. Improvement of tools that may contribute to complement the data from the human ether-a-go-go-related gene HERG channel and QT/QTc studies, such as concentration-QT relationship (CQT) studies and other innovative techniques, will be more than welcome.

Prokinetic agents are a very large family of drugs with different mechanisms of action. Only QT prolongation by cisapride has made notable impact and deserved its partial restriction and/or withdrawal from the market. Postmarketing surveillance initially showed that cisapride was generally safe and well tolerated, but in the past decade, more recent data have shown some risk in the patient populations. QT prolongation by prokinetic agents can raised from different mechanisms: some involve increased plasma concentrations of cisapride due to increased bioavailability by inhibiting P glycoprotein, and inhibition of metabolism or deficit in the elimination. On the other hand, pharmacodynamic interactions can also enhance the arrhythmogenic effect of cisapride. The present article presents the mechanisms and reviews the main interactions studied so far, and the role of pharmacovigilance in the detection of rare clinical events. We emphasize the need for physicians to look for conditions (either clinical or not) prone to increase the risk of QT interval prolongation.

The long QT syndrome (LQTS) is characterized by a prolonged QT interval, as well as a propensity to develop syncope and sudden cardiac death caused by the malignant polymorphic ventricular arrhythmia called torsades de pointes (TdP). The QT interval is measured from the onset of the QRS complex to the end of the T wave and can be affected by both ventricular conduction velocities as well as by the velocity of repolarization. In most cases, QT prolongation is caused by factors that prolong the duration of the action potential, mainly by delaying the repolarization phase 3. The molecular mechanism is partially known. There are two well described mechanisms: blocking of the ion channel cavity of HERG; or causing an abnormal protein trafficking required for the location of HERG subunits in cell membrane. Both of them impair the I(Kr) current. However the blockade of ion channels is not the only condition to generate TdP. Other factors may play an important role, e.g. myocardium heterogeneity, drug-drug interaction, genetic polymorphism, and Electrolyte disturbances. Several drugs had been subject of withdrawal because QT-prolongation and arrhythmia. Understanding of processes involved in drug-induced QT prolongation is needed for the study and prevention of life-threatening arrhythmias.

Background: Levothyroxine has a narrow therapeutic index; therefore, precise and accurate assessment of the bioequivalence of different levothyroxine products is critical. Bioavailability estimates of levothyroxine formulations might be affected by baseline concentrations of the hormone. Objectives: The aim of this study was to assess the bioequivalence of 100 µg of a test (T4 Montpellier ® 100, Quimica Montpellier S.A., Buenos Aires, Argentina) and reference (Synthroid ® , Abbott Laboratories, Abbott Park, Illinois) formulation of levothyroxine. We also compared 2 methods of levothyroxine measurements: without and with baseline correction for endogenous levothyroxine. Methods: This randomized, open-label, 2-sequence, crossover study with a 65-day washout period was carried out in healthy, white, euthyroid volunteers following a single dose of sodium levothyroxine 600 µg. Blood samples were collected at 30 and 15 minutes prior to administration, and 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 48 hours to determine thyroxine; serum thyrotropin (TSH) concentrations were determined 30 minutes before administration and 48 hours after administration. Serum concentrations of thyroxine were determined through radioimmunoassay and serum TSH concentrations were determined by a validated 2-site immunoradiometric assay. The formulations are considered to be equivalent if the 90% CI ratios for C max and AUC 0-last are within 80% to 125%, per the US Food and Drug Administration (FDA). Adverse event monitoring was performed throughout the study by assessing clinical parameters (eg, blood pressure, electrocardiogram) and patient reports. Results: A total of 24 volunteers (16 male, 8 female; mean [SD] age, 30.2 [4.6] years [range, 21-40 years]; mean [SD] weight, 71.71 [7.52] kg [range, 58-83 kg]) were included in the study. Without adjustment for baseline levels of endogenous levothyroxine, geometric mean C max for the test and reference formulations were 8.92 and 9.39 µg/dL, respectively; AUC 0-last values were 368.40 and 383.37 µg/mL · h -1 . The 90% CI of the geometric mean for the percent ratios (test: reference) of C max and AUC 0-last were 95.1% (90% CI, 91.9–98.3) and 96.1% (90% CI, 94.0–98.2), respectively. With adjustment for baseline levels of endogenous levothyroxine, the geometric mean C max for the test and reference formulations were 3.16 and 3.39 µg/dL, respectively; AUC 0-last values were 88.33 and 95.60 µg/mL · h -1 . Despite performing the adjustment, the 90% CI of the geometric mean for Cmax and AUC 0-last test:reference ratios were 93.1% (90% CI, 84.9–102.2) and 92.4% (90% CI, 85.2–100.2), respectively. No significant between-group differences were found with regard to pharmacokinetic parameters. No adverse events were observed or reported. Conclusion: The results of this study suggest that the test formulation was bioequivalent to the reference formulation of levothyroxine in these healthy volunteers, according to the US FDA definition of bioequivalence. This was supported by the analysis of concentration-time profiles without and with correction for basal endogenous levothyroxine.

The bioequivalence of two 600-mg oxcarbazepine oral formulations (Aurene, Ivax Argentina, [test]; and Trileptal, Novartis Laboratories, [reference]) were assessed through the simultaneous determination of oxcarbazepine and the active metabolite 10,11-dyhydro-10-hydroxy-carbamazepine derivative (MHD). 12 healthy male volunteers received a single oral dose of 600 mg of each formulation, in a balanced, randomized, paired, crossover design, with a 7-day wash out period. Oxcarbazepine and MHD concentrations were established at 0.5,1, 1.5, 2, 3, 4, 6, 8, 24 and 48 h post dose by high performance liquid chromatography (HPLC). The regression coefficient determined for oxcarbazepine calibration curves was 0.9933 +/- 0.0236; and for MHD, was 0.9897 +/- 0.0017. The working range for both oxcarbazepine and its metabolite was from 0.1 to 10.0 microg/ml. The quantification limit was 0.1 microg/ml. The 90% confidence interval (CI) geometric mean for oxcarbazepine C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 74.1-146.2%, 85.6-171.5% and 89.6-169.8%, respectively, and the 90% CI geometric mean for MHD C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 84.0-122.3, 93.2-117.9 and 96.5-116.7, respectively. These results established the bioequivalence of two oxcarbazepine formulations from MHD kinetic data used in 12 healthy volunteers, while it was not possible to establish bioequivalence with oxcarbazepine. MHD quantification is preferred to that of the oxcarbazepine in order to assess bioequivalence, as the metabolite is responsible for the antiepileptic activity, presents linear kinetics in the therapeutic range, has lower intra-individual variability and higher plasma levels and half life than the parent drug.

Diabetes mellitus is a chronic disease that usually requires multiple insulin injections to achieve adequate glycaemic control. This represents a major cause of reduced compliance to treatment. Consequently, other routes for insulin administration have been explored. During recent years, much progress in the development of inhaled insulin has been made. Inhaled insulin has shown favourable properties, such as a rapid onset of action, improved bioavailability and good tolerability; thereby providing satisfaction and ease of administration. However, long-term safety of inhaled insulin needs to be assessed, and the cost would be higher than injectable insulin. Nasal, oral and transdermal insulins are undergoing early phases of pharmacological development. The purpose of this review is to describe the latest developments in the area of non-invasive routes for insulin delivery.

Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving beta-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.

Pregnancies complicated by diabetes mellitus (DM) include pregestational DM and gestational DM, defined as carbohydrate intolerance of variable severity first detected during pregnancy. DM leads to poor pregnancy outcome. The aim of treatment is to control maternal hyperglycaemia and to imitate postprandial insulin release. Rapid-acting insulin analogues are suitable therapeutic candidates, as they are able to reduce postprandial hyperglycaemia (predictive of adverse pregnancy outcome). There is no excess risk of adverse fetal or maternal outcomes when compared with regular insulin. Data suggest that rapid-acting insulin analogues do not transfer to human placenta. Because of the reduced risk of hypoglycaemia and improved postprandial and overall glucose control, insulin analogues could be considered the rapid-acting in-sulin choice during pregnancy.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are recognized as highly effective in reducing low-density lipoprotein cholesterol (LDL-C) and non-high-density li...

INTRODUCTION Metabolic clearance of isoniazid (INH) may be up to 10 times faster in individuals who are rapid acetylators compared with slow acetylators. In addition, the acetylation phenotype has been suggested to change with age. A better knowledge of the age distribution of the acetylation genotype and phenotype in children requiring INH for tuberculosis treatment or prevention could be important to optimize safety and efficacy of INH use. OBJECTIVES The aim of the present study was to evaluate the genotype and phenotype of NAT2 in an Argentinean pediatric population rom Buenos Aires. In addition, we wanted to describe genotype-phenotype correlation, as well as its distribution at different ages. METHODOLOGY NAT2 genotyping was performed by RFLP technique, searching for common polymorphisms. Acetylisoniazid and isoniazid concentrations were measured by HPLC and NAT2 phenotype was defined from the ratio of both concentrations (Metabolic Ratio, MR). RESULTS Almost half of the patients (46.02%) possessed wild-type haplotype, with 17.05% of individuals having two fully functional alleles, 57.95% one fully functional allele and 25% with no fully functional allele. According to phenotype, most children (96.59%) were classified as fast acetylators, whereas 1.14% of the cases were intermediate and 2.27% slow acetylators. There was a positive association between age and MR (R = 0.52985, p < 0.000001) with a significant MR difference between age categories (p < 0.001). CONCLUSIONS We found a high proportion of rapid acetylators compared with other populations. Acetylator phenotype showed a positive correlation with age, with a significant change around the 4th year of life.

Lysine clonixinate (2-[3-chloro-o-toluidine] piridin-3 lysine carboxylate) is a nonsteroidal anti-inflammator drug acting mainly at the peripheral level. Preclinical and clinical pharmacologic studies have established the efficacy and tolerability of lysine clonixinate—good efficacy with a very low incidence of side effects. The efficacy of lysine clonixinate was assessed in patients on days 0, 2, 7, and 15 by rating swelling, warmth, redness, and pain on active and passive movement and pressure. Tolerability was assessed by anamnesis at each control day and by fecal occult blood determination at baseline and at the end of the study. The anti-inflammatory and analgesic efficacy of lysine clonixinate was statistically higher than that of aspirin as assessed on almost all clinical parameters. The greater efficacy of lysine clonixinate was associated with excellent tolerability—none of the 53 lysine clonixinate-treated patients showed occult blood in the feces whereas 19 to the 55 aspirin-treated patients showed positive fecal occult blood at the end of the study.

Diltiazem is a benzothiazepine calcium channel blocker with depressive activity on sinus and atrioventricular node fibers that is useful in the control of several types of arrhythmias. In an open-label uncontrolled trial, 34 patients with supraventricular tachyarrhythmias (15 with paroxysmal supraventricular tachycardia [PSVT], 17 with atrial fibrillation, and 2 with atrial flutter) were treated with diltiazem 150 μg/kg intravenous bolus once or repeated at the same dose within 20 and 40 minutes if the arrhythmia had not disappeared. Conversion to sinus rhythm was observed in 13 (86.7%) of 15 patients with PSVT, 4 (23.5%) of 17 patients with atrial fibrillation, and 1 (50.0%) of 2 patients with atrial flutter. Improvement or partial treatment success (ie, persistence of arrhythmia but with a ventricular rate lower than 100 beats/min) was observed in 8 patients with atrial fibrillation and 1 with atrial flutter. Five patients with atrial fibrillation and two with PSVT were considered to be treatment failures and received intravenous lanatoside C. No patient developed hypotension. Systolic and diastolic blood pressure increases averaged 10 mm Hg and were associated with hemodynamic improvement. Only four patients complained of transient headache and facial erythema after the first dose of diltiazem.

Background Currently, levodopa administered with decarboxylase inhibitors is the gold standard for the management of the motor symptoms of Parkinson's disease, a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In Argentina, only 1 commercial product is available with such composition; this study was contracted by the manufacturer to comply with new generic product regulations. Objective The aim of this study was to evaluate the fasting bioavailability of a new generic formulation of levodopa 200 mg/benserazide 50 mg tablets (test) and compare this generic formulation with the branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. Methods A randomized-sequence, open-label, 2-period, crossover study was conducted between August and October 2009 in healthy Caucasian volunteers (n = 24; 18 males, aged 21 to 42 years, with a body mass index ranging from 19.7 to 26.0 kg/m 2 ) in the fasted state. A single oral dose of the test or reference formulation was administered, and after a 7-day washout period, the other formulation was given. Blood samples were collected at baseline and at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 105 minutes and 2, 2.5, 3, 3.5, 4, and 6 hours after dosing. Levodopa plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection, without stereo-specificity assessment. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test/reference) for the C max and AUC 0–t of levodopa were within the 0.8 to 1.25 range. Adverse events were monitored throughout the study, based on clinical parameters and patient reports. Results The geometric means (90% CI) of the C max for the test and reference formulations were 2462.02 (2312.06–3492.40) and 2542.85 (2394.49–3231.29) ng/mL, respectively; the AUC 0–t was 3878.04 (3623.88–5393.09) and 3972.10 (3765.88–5393.02) ng/mL/h, respectively; and the AUC 0–∞ was 4610.37 (4315.71–6315.70) and 4728.96 (4502.17–6828.26) ng/mL/h, respectively. There were no significant differences in pharmacokinetic parameters between the 2 formulations. The test:reference ratios for C max , AUC 0–t , and AUC 0–∞ were 96.82% (90% CI, 83.87–111.77), 97.63% (90% CI, 85.95–110.91), and 97.49% (90% CI, 84.09–113.02), respectively. No clinically significant adverse events were reported; this finding is probably the result of subjects not believing that their side effects were severe enough to be reported and not because of a genuine and absolute lack of predictable side effects. Conclusions In this single-dose study, the test formulation of levodopa/benserazide tablets met the Argentinean criterion for bioequivalence to the reference formulation. (www.clinicaltrials.gov: NCT01327261).