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.

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

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.

Pharmacokinetics and pharmacodynamics of interferon beta 1a in Cebus apella.

BACKGROUND: Recombinant human interferon (hIFN beta) is indicated for the treatment of multiple sclerosis. Its effect presents species restriction, thus lacking biological activity on most mammals. Although there have been previous studies of the pharmacology of INF beta in Old World primates, no data exists on New World primates. Therefore, we explored its effect on Cebus apella, a New World monkey, describing the pharmacology of this molecule when injected by subcutaneous route in this species. METHODS: Safety, pharmacokinetics and pharmacodynamics of IFN beta were evaluated in nine Cebus apella individuals. RESULTS: A single subcutaneous injection of 12 x 10(6) IU of hIFN beta 1a resulted in a median AUC((0-48)) (area under the curve) of 14.82 ng/ml, a C(max) (maximum plasma concentrations) of 1.51 ng/ml and a T(max) (time to achieve maximum plasma concentrations) of 3 h. IFN beta was biologically active as demonstrated by an increase in neopterin levels. There were no safety concerns. CONCLUSIONS: New World non-human primates are a suitable animal model for the study of IFN beta pharmacology.

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.

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.

Sida: estado actual de los conocimientos

Modo de transmisión del HIV. Medidas de prevención. Clasificación del síndrome de inmunodeficiencia adquirida. Diagnóstico de SIDA. Cuadros clínicos según la clasificación del CDC, grupos I, II, III y IV. Niños infectados por HIV, Pruebas de diagnóstico de infección por HIV, Tratamientos actuales y en investigación. Investigaciones sobre la vacuna. Epidemiología y acciones para evitar la diseminación de la infección