Archive for December 19, 2009

Trends in Patterns of Dengue Transmission over 4 Years in a Pediatric Cohort Study in Nicaragua

The Journal of Infectious Diseases  1 January 2010  V.201  N.1  p.5-14

Angel Balmaseda,1 Katherine Standish,2 Juan Carlos Mercado,1 Juan Carlos Matute,1 Yolanda Tellez,1

Saira Saborío,1 Samantha N. Hammond,2 Andrea Nuñez,1 William Avilés,2 Matthew R. Henn,4 Edward C. Holmes,5,6 Aubree Gordon,7 Josefina Coloma,7 Guillermina Kuan,3 and Eva Harris7

1Departamento de Virología, Centro Nacional de Diagnóstico y Referencia, Ministry of Health, 2Sustainable Sciences Institute, and 3Centro de Salud Sócrates Flores Vivas, Managua, Nicaragua; 4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge; 5Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, University Park; 6Fogarty International Center, National Institutes of Health, Bethesda, Maryland; and 7Division of Infectious Diseases, School of Public Health, University of California, Berkeley

Background. Dengue is the most prevalent mosquito-borne viral disease in humans and a major urban public health problem worldwide.

Methods. A prospective cohort study of 3800 children initially aged 2–9 years was established in Managua, Nicaragua, in 2004 to study the natural history of dengue transmission in an urban pediatric population. Blood samples from healthy subjects were collected annually prior to the dengue season, and identification of dengue cases occurred via enhanced passive surveillance at the study health center.

Results. Over the first four years of the study, seroprevalence of anti-dengue virus (DENV) antibodies increased from 22%–40% in the 2-year-old cohort and 90%–95% in the 9-year-old cohort. The incidence of symptomatic dengue cases and the ratio of inapparent to symptomatic DENV infection varied substantially from year to year. The switch in dominant transmission from DENV-1 to DENV-2 was accompanied by an increase in disease severity but, paradoxically, a decrease in transmission. Phylogeographic analysis of full-length DENV-2 sequences revealed strong geographic clustering of dengue cases.

Conclusions. This large-scale cohort study of dengue in the Americas demonstrates year-to-year variation of dengue within a pediatric population, revealing expected patterns in transmission while highlighting the impact of interventions, climate, and viral evolution.


December 19, 2009 at 10:56 pm Leave a comment

Pharmacokinetic Properties of Azithromycin in Pregnancy

Antimicrobial Agents and Chemotherapy  1 Jan 2010  V.54  N.1  p.360-366

Sam Salman,1 Stephen J. Rogerson,2 Kay Kose,3 Susan Griffin,3 Servina Gomorai,3 Francesca Baiwog,3 Josephine Winmai,3 Josin Kandai,3 Harin A. Karunajeewa,1,4 Sean J. O’Halloran,5 Peter Siba,3 Kenneth F. Ilett,1,5 Ivo Mueller,3 and Timothy M. E. Davis1*

School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia,1 Faculty of Medicine, University of Melbourne, Melbourne, Australia,2 Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea,3 Western Health, Melbourne, Australia,4 Clinical Pharmacology and Toxicology Laboratory, Path West Laboratory Medicine, Nedlands, Australia5

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy. To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a three-compartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC0-) (28.7 and 31.8 mg·h liter–1 for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC0-. These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.


December 19, 2009 at 10:52 pm Leave a comment

Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers

Antimicrobial Agents and Chemotherapy  1 Jan 2010  V.54  N.1  p.254-258

Sherene Min,1 Ivy Song,1 Julie Borland,1 Shuguang Chen,1 Yu Lou,1 Tamio Fujiwara,2 and Stephen C. Piscitelli1*

GlaxoSmithKline, Research Triangle Park, North Carolina,1 Shionogi & Co., Ltd., Osaka, Japan2

S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC0-) and maximum concentration of the drug in plasma (Cmax) ranged from 16.7 µg·h/ml (coefficient of variation [CV], 15%) and 1.5 µg/ml (CV, 24%) at a 10-mg dose to 76.8 µg·h/ml (CV, 19%) and 6.2 µg/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C) with a 50-mg dose was 1.6 µg/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 µg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.



December 19, 2009 at 10:51 pm Leave a comment

ISQ Prevención y Seguridad del paciente en el Pre, Intra y Post-quirúrgico


Documento de Consenso de la SADI 119 pág.


Preparación quirúrgica

Pre inducción anestésica



December 19, 2009 at 1:10 am Leave a comment


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