Polypharmacy and Drug Interactions in the COVID-19 Pandemic.

The COVID-19 pandemic generated a great impact on health systems. We compared evolution, polypharmacy, and potential drug-drug interactions (P-DDIs) in COVID-19 and non-COVID-19 hospitalizations during first wave of pandemic. Prescriptions for hospitalized patients ≥ 18 years (COVID-19 and non-COVID-19 rooms) between April and September 2020 were included. The computerized medical decision support system SIMDA and the physician order entry system Hdc.DrApp.la were used. Patients in COVID-19 rooms were divided into detectable and non-detectable, according to real-time reverse transcription polymerase chain reaction (RT-PCR). Number of drugs, prescribed on day 1, after day 1, and total; polypharmacy, excessive polypharmacy, and P-DDIs were compared. 1,623 admissions were evaluated: 881 COVID-19, 538 detectable and 343 non-detectable, and 742 non-COVID-19. Mortality was 15% in COVID-19 and 13% in non-COVID-19 (RR [non-COVID-19 vs. COVID-19]: 0.84 [95% CI] [0.66-1.07]). In COVID-19, mortality was 19% in detectable and 9% in non-detectable (RR: 2.07 [1.42-3.00]). Average number of drugs was 4.54/patient (SD ± 3.06) in COVID-19 and 5.92/patient (±3.24) in non-COVID-19 (p<0.001) on day 1 and 5.57/patient (±3.93) in COVID-19 and 9.17/patient (±5.27) in non-COVID-19 (p<0.001) throughout the hospitalization. 45% received polypharmacy in COVID-19 and 62% in non-COVID-19 (RR: 1.38 [1.25-1.51]) and excessive polypharmacy 7% in COVID-19 and 14% in non-COVID-19 (RR: 2.09 [1.54-2.83]). The frequency of total P-DDIs was 0.31/patient (±0.67) in COVID-19 and 0.40/patient (±0.94) in non-COVID-19 (p=0.022). Hospitalizations in the COVID-19 setting are associated with less use of drugs, less polypharmacy and less P-DDIs. Detectable patients had higher mortality.

Clinical and biochemical short-term effects of hyperbaric oxygen therapy on SARS-Cov-2+ hospitalized patients with hypoxemic respiratory failure.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been proposed to address COVID-19- associated respiratory failure. However, its biochemical effects are poorly known. METHOD: 50 patients with hypoxemic COVID-19 pneumonia were divided into C group (standard care) and H group (standard care plus HBOT). Blood was obtained at t = 0 and t = 5 days. Oxygen saturation (O2 Sat) was followed up. White blood cell (WC) count, lymphocytes (L) and platelets (P) and serum analysis (glucose, urea, creatinine, sodium, potassium, ferritin, D dimer, LDH and CRP) were carried out. Plasma levels of sVCAM, sICAM, sPselectin, SAA and MPO, and of cytokines (IL-1ß, IL-1RA, IL-6, TNFα, IFNα, IFNγ, IL-15, VEGF, MIP1α, IL-12p70, IL-2 and IP-10) were measured by multiplex assays. Angiotensin Converting Enzyme 2 (ACE-2) levels were determined by ELISA. RESULTS: The average basal O2 Sat was 85 ± 3%. The days needed to reach O2 Sat >90% were: H: 3 ± 1 and C: 5 ± 1 (P < 0,01). At term, H increased WC, L and P counts (all, H vs C: P < 0,01). Also, H diminished D dimer levels (H vs C, P < 0,001) and LDH concentration (H vs C, P < 0.01]. At term, H showed lower levels of sVCAM, sPselectin and SAA than C with respect to basal values (H vs C: ΔsVCAM: P < 0,01; ΔsPselectin: P < 0,05; ΔSAA: P < 0,01). Similarly, H showed diminished levels of TNFα (ΔTNFα: P < 0,05) and increased levels of IL-1RA and VEGF than C respect to basal values (H vs C: ΔIL-1RA and ΔVEGF: P < 0,05). CONCLUSION: Patients underwent HBOT improved O2 Sat with lower levels of severity markers (WC and platelets count, D dimer, LDH, SAA). Moreover, HBOT reduced proinflammatory agents (sVCAM, sPselectin, TNFα) and increased anti-inflammatory and pro-angiogenic ones (IL-1RA and VEGF).

Development and Implementation of the Hdc.DrApp.la and SIMDA Programs to Reduce Polypharmacy and Drug-drug Interactions in Patients Hospitalized in Internal Medicine.

OBJECTIVES: We evaluated polypharmacy and possible drug-drug interactions (p-DDIs) in hospitalized patients before and after using the SIMDA Computerized Medical Decision Support System (CMDSS). MATERIALS AND METHODS: We included the prescriptions of ≥ 18 years hospitalized patients in the internal medicine department. We developed and implemented the Hdc.DrApp Physician Order Entry System and the CMDSS SIMDA, which detects p-DDIs and signals dosage adjustment based on renal function. To evaluate the impact of the CMDSS, we made a comparison Before (Survey) / After (Intervention): Survey between Oct/22/2019, and Mar/21/2020, and Intervention between Apr/4/2020 and Sep/3/2020. We analyze prescriptions from the first day and after the first day. We compared the number of drugs, polypharmacy (≥ 5 drugs), excessive polypharmacy (≥ 10 drugs), and p-DDIs. We evaluated differences with the X2 test, Yates correction, Fisher's exact test, ANOVA, and post hoc tests according to their characteristics. RESULTS: We evaluated 2,834 admissions: Survey 1,211 and Intervention 1,623. The number of drugs per patient was 6.02 (± 3.20) in Survey and 5.17 (± 3.22) in Intervention (p < 0.001) on the first day and 9.68 (± 5.60) in Survey and 7.22 (± 4.93) in Intervention (p < 0.001) throughout the hospitalization. Polypharmacy was present in 64% of the Survey and 53% of Interventions (RR: 0.83 (0.78-0.88); and excessive polypharmacy in 14% of the Survey and 10% of Intervention (RR: 0.73, 0.60-0.90). The frequency of total p-DDIs was 1.91/patient (± 4.11) in Survey and 0.35 (± 0.81) in the Intervention (p < 0.001). CONCLUSIONS: We developed and implemented the Hdc.DrApp and SIMDA systems that were easy to use and allowed us to quantify and reduce polypharmacy and p-DDIs.

Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers.

Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and Cmax of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for Cmax , AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25-30 h for each formulation).

Hyperbaric oxygen as an adjuvant treatment for patients with COVID-19 severe hypoxaemia: a randomised controlled trial.

BACKGROUND: Hyperbaric oxygen (HBO2) therapy has been proposed to treat hypoxaemia and reduce inflammation in COVID-19. Our objective was to analyse safety and efficacy of HBO2 in treatment of hypoxaemia in patients with COVID-19 and evaluate time to hypoxaemia correction. METHODS: This 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 HBO2 treatment or the standard treatment for respiratory symptoms for 7 days. HBO2 treatment 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. RESULTS: The 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; SpO2 was 85.1%±4.3% for the whole group. Patients in the treatment group received an average of 6.2±1.2 HBO2 sessions. 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 (p<0.010). OR for recovery from hypoxaemia in the HBO2 group 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. CONCLUSION: Our findings support the safety and efficacy of HBO2 in the treatment of COVID-19 and severe hypoxaemia. TRIAL REGISTRATION NUMBER: NCT04477954.

Precision Medicine in the Renin-Angiotensin System: Therapeutic Targets and Biological Variability.

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.

Dextrophropoxyphene effects on QTc-interval prolongation: Frequency and characteristics in relation to plasma levels.

OBJECTIVE: To evaluate frequency and risk factors for dextropropoxypheneinduced 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.

Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid-phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses.

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.

In vivo Phenotyping Methods: Cytochrome P450 Probes with Emphasis on the Cocktail Approach.

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.

Meperidine-induced QTc-interval prolongation: prevalence, risk factors, and correlation to plasma drug and metabolite concentrations
.

A prolongation of the QTc-interval has been described for several opioids, including pethidine (meperidine). OBJECTIVE: To evaluate in the clinical setting the frequency and risk factors associated with the QT-interval prolongation induced by meperidine. RESEARCH DESIGN AND METHODS: We recruited patients requiring meperidine administration and recorded their medical history and comorbidities predisposing to QT-interval prolongation. Ionograms and electrocardiograms (ECGs) were performed at baseline and during treatment; QT was corrected using the Bazzet, Fridericia, Framinghan, and Hogdes formulas. We measured meperidine and normeperidine by gas chromatography. Values are expressed as mean ± SD (range). RESULTS: 58 patients were studied (43.1% males). All patients received meperidine at a dose of 304 ± 133 (120 - 480) mg/day. Meperidine and normeperidine concentrations were 369 ± 60 (265 - 519) and 49 ± 17 (15 - 78) ng/mL, respectively. Intratreatment control found QTcB 370 ± 30 (305 - 433), QTcFri 353 ± 35 (281 - 429), QTcFra 360 ± 30 (299 - 429), QTcH 359 ± 27 (304 - 427), ΔQTcB +9 ± 42 (-90 to +136), ΔQTcFri +4 ± 45 (-86 to +137), ΔQTcFra +5 ± 40 (-77 to +129), and ΔQTcH +7 ± 40 (-76 to +129) ms. Meperidine concentration correlated with QTc-interval (R > 0.36) and ΔQTc (R > 0.69) but the correlation was even better for normeperidine concentration, QTc (R > 0.52) and ΔQTc (R > 0.81). Depending on the QTc correction formula used, 13 - 15 patients (22.41 - 25.86%) presented ΔQTc values > 30 ms, and 7 - 8 patients (12.07- 13.79%) showed ΔQTc values > 60 ms. Renal failure was associated with risk for ΔQTc > 30 ms of 3.74 (IC95% 1.73 - 8.10) and for ΔQTc > 60 ms of 4.27 (IC 95% 1.26 - 14.48). No patient developed arrhythmias during the study. CONCLUSIONS: Meperidine treatment causes ECG changes (QTc-interval prolongation) in high correlation with normeperidine plasma concentration. Renal failure increases the risk.
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Drug-induced QT Interval Prolongation in the Intensive Care Unit.

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.

A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients.

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<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate. CONCLUSION: Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

Comparative bioavailability of two tablet formulations of emtricitabine/tenofovir in healthy, fasting volunteers: a single-dose, randomized-sequence, open-label crossover study.

OBJECTIVE: To evaluate the relative bioavailability of a new formulation of emtricitabine (EMT) 200 mg and tenofovir disoproxil fumarate (TNF) 300 mg and to compare with reference formulation to meet regulatory criteria in Argentina. METHODS: A randomized-sequence, open-label, twoperiod crossover study was conducted on 24 healthy Caucasian volunteers in a fasting state. A single oral dose of T or R formulations was followed by a 7-day washout period. Samples were collected at baseline, 0.25, 0.50, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 7, 12, 24, and 48 hours after administration. EMT and TNF were determined by LC-MS/MS. RESULTS: Geometric means (90% CI) Cmax for EMT in test and reference were 1,891.22 (1,777.1 - 2,187.31) and 1,830.31 (1,721.19 - 2,134.01) ng/mL, the AUC0-t were 10,283.07 (9,624.29 - 11,566.34) and 10,518.76 (9,942.79 - 11,578.30) ng × h/mL and the AUC0-∞ were 10,615.14 (9,948.56 - 11,866.26) and 10,804.12 (10,221.04 - 11,864.85) ng × h/mL, respectively. For TNF test and reference, Cmax geometric means (CI range) were 202.91 (187.91 - 255.78) and 212.04 (195.98 - 264.87) ng/mL, AUC0-t were 1,429.96 (1,334.63 - 1,680.00) and 1,420.75 (1,326.76 - 1,622.18) ng × h/mL and AUC0-∞ were 1,657.11 (1,551.60 - 1,921.75) and 1,631.84 (1,523.95 - 1,857.97), respectively. No differences were detected between the formulations. The test/reference ratios (90% CI) for Cmax, AUC0-t, and AUC0-∞ were 103.33% (95.7 - 111.6), 97.76% (93.6 - 102.1), and 98.25% (94.3 - 102.4) for EMT, and 95.70% (85.9 - 106.6), 95.20% (83.4 - 108.6) and 91.10% (80.7 - 102.7) for TNF. CONCLUSIONS: In this single-dose study, the EMT/TNF tablets (test formulation) met the standard 90% CI criterion for bioequivalence with the reference formulation.

Relative bioavailability between two teriparatide formulations in healthy volunteers.

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.

Tramadol Induced QTc-Interval Prolongation: Prevalence, Clinical Factors and Correlation to Plasma Concentrations.

UNLABELLED: 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.

Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice.

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.

Age-distribution and genotype-phenotype correlation for N-acetyltransferase in Argentine children under isoniazid treatment.

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.

Adverse drug reactions as a reason for admission to an internal medicine ward in Argentina.

BACKGROUND: Adverse Drug Reactions (ADR) are a major cause of morbidity and mortality worldwide. In spite of this, ADR are largely underreported and unrecognized. PURPOSE: Identify and characterize ADR related admissions to our internal medicine ward using a proactive multidisciplinary pharmacovigilance approach. METHODS: Within 24 hrs of admission 1045 patients admitted to the Internal Medicine Ward between August 2010 and February 2012 were screened for possible or probable ADR related admissions. RESULTS: Probable ADR accounted for 112 of 1045 admissions (10.7%, 95% Confidence Interval [CI]: 8.8-12.6%), of which only 16 (14.3%) were classified as unavoidable. NSAIDs were the drug group more commonly implicated in probable ADR-related admissions (17.0%), followed by antiplatelets (16.1%). In-hospital mortality of patients admitted due to probable ADR was 8.0% (95% CI: 2.9-13.1%). During this study period, 6% of internal medicine ward and 4% of critical care unit beds were occupied by patients with probable ADR. The estimated cost of care of these patients was 641,000 US dollars (USD). CONCLUSION: ADR are a frequent reason for admission to an Internal Medicine Ward in Argentina. The culprit drugs and interactions are similar to those reported in the literature. The cost is substantial and most of the ADR are potentially avoidable.

Severe neutropenia in a renal transplant patient suggesting an interaction between mycophenolate and fenofibrate.

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 37.8°C 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/mm(3). 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.