An updated examination of the perception of barriers for pharmacogenomics implementation and the usefulness of drug/gene pairs in Latin America and the Caribbean.

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

Profilaxis tromboembólica en pacientes posparto. Estudio de corte transversal en tres instituciones en Colombia / Thromboembolic prophylaxis in post-partum patients. Cross-sectional study in three institutions in Colombia

Describir el nivel de riesgo de enfermedad tromboembólica en pacientes posparto y hacer una aproximación al uso actual de la tromboprofilaxis.Materiales y métodos: estudio descriptivo de corte transversal. Se incluyeron pacientes que fueron hospitalizadas para atención de parto entre agosto de 2012 y abril de 2013 en tres instituciones generales de alta complejidad en Bogotá y Medellín. Se aplicó la Guía de manejo del Royal College Obstetrics & Gynecology (RCOG) para establecer el riesgo de enfermedad tromboembólica. Las pacientes fueron evaluadas en el posparto y clasificadas en alto, intermedio y bajo riesgo. Se midió la frecuencia real de aplicación de tromboproilaxis. Los resultados se presentan como proporciones.Resultados: se evaluaron un total de 3516 pacientes, el 1,9 % de las pacientes fueron clasificadas como de alto riesgo, 42 % de riesgo medio y 56,1 % de riesgo bajo. La tromboprofilaxis solo se aplicó a un 7,4 % de las pacientes con alto riesgo y riesgo intermedio.Conclusión: según los criterios de la Guía del RCOG, un 43,9 % de las pacientes tendrían indicación de tromboprofilaxis; sin embargo, solo un 7,4 % de ellas la recibió. Se requieren estudios complementarios para evaluar los riesgos y beneficios del uso de la tromboprofilaxis según la guía del Reino Unido...

To describe the risk of thromboembolic disease in post-partum patients and examine the current use of thromboprophylaxis.Materials and methods: Descriptive cross-sectional study that included patients admitted for delivery care between August 2012 and April 2013 in three high-complexity general healthcare institutions in Bogotá and Medellín. The Royal College of Obstetrics & Gynaecology (RCOG) Management Guideline was applied for determining the risk of thromboembolic disease. Patients were assessed during the post-partum period and classified as high, intermediate and low risk. The actual frequency of the use of prophylaxis was measured. Results are presented as proportions.Results: Overall, 3516 patients were assessed and 1.9 % were classified as high risk, 42 % as intermediate risk and 56.1 % as low risk. Thromboprophylaxis was only used in 7.4 % of patients with high or intermediate risk.Conclusion: According to the criteria of the RCOG guidelines, 43.9 % of the patients had an indication for thromboprophylaxis and yet only 7.4 % of them received it. Further studies are required to assess the risk and evaluate the benefits and risks of giving thromboprophylaxis in accordance with the United Kingdom guidelines...

Aplicación de terapia VAC por dehiscencia de herida quirúrgica en paciente intervenido de cistectomía / No disponible

No disponible

Una solución a los riñones poliquísticos: nefrectomía / No disponible

No disponible

Perception of Adolescent Patients on Cooperation During Orthodontic Treatment: A Qualitative Study / Percepción de los Pacientes Adolescentes sobre Cooperación Durante el Tratamiento Ortodóncico: Un Estudio Cualitativo

The objective of the present study was to identify the fundamental factors associated with patient cooperation during orthodontic treatment. A qualitative study was carried out, following a hermeneutical approach, using focus groups as the data collection instrument. Sample selection consisted of adolescent patients undergoing orthodontic treatment at CES University Dental Clinics in Medellin, Colombia. Each focus group was directed by trained psychologists. Transcriptions were carried out and afterwards analyzed. Two focus groups, each consistent of 17 patients ranging between 11 and 18 years of age, who were in active orthodontic treatment were evaluated. Five significant factors associated with patient cooperation were identified which included, knowledge, empathy, esthetics, friendly environment, and inclusion in treatment.

El objetivo del presente estudio fue identificar los factores fundamentales relacionados con la cooperación de los pacientes adolescentes durante el tratamiento de ortodoncia. Se realizó un estudio cualitativo, utilizando grupos focales como el instrumento de recolección de datos. La selección de la muestra consistió en pacientes adolescentes que reciben tratamiento de ortodoncia en la clínica de Ortodoncia de la Universidad, CES, Medellín, Colombia. Cada grupo focal fue dirigido por psicólogos entrenados y fue grabado para luego realizar la transcripción de cada uno. Fueron evaluadosos dos grupos focales, cada uno de 17 pacientes entre los 11 y 18 años de edad, que estaban en tratamiento activo de ortodoncia. Se identificaron cinco factores importantes relacionados con la cooperación del paciente, estos fueron: el conocimiento que el profesional demuestra tener frente a su paciente, la empatía entre el ortodoncista y el paciente, la estética, el ambiente clínico favorable y la inclusión de los pacientes en el tratamiento.

Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges.

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir.

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.

Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1.

The 3435C-->T polymorphism at the multidrug resistance gene 1 (MDR1) was examined in 74 patients with human immunodeficiency virus who initiated atazanavir therapy. The MDR1 genotype distribution at position 3435 was 28% CC, 45% CT, and 27% TT. Plasma levels of atazanavir were significantly higher in patients with genotype CC than in those with CT or TT, and bilirubin levels correlated with atazanavir concentrations.

Compatibiliity and stability of furosemide and dexamethasone combined in infusion solutions.

AIM: The goal of palliative care is the achievement of the best quality of life for patients and their families. For this, the administration of drugs by subcutaneous infusion is frequently used since many patients have great difficulties in taking drugs orally and regular intramuscular injections are painful. Usually, drugs are combined in infusion solutions. The objective was therefore to study the compatibility and stability of dexamethasone sodium phosphate (CAS 2392-39-4) and sodium furosemide (CAS 54-31-9) combined in solutions destined to subcutaneous administration in palliative medicine. METHODS: Twelve different solutions were assessed during 15 days. Drug admixtures were prepared in polypropylene syringes using 0.9 % saline as diluent and stored at 4 degrees C and 25 degrees C in the dark. Initial concentrations were 3.33-10.0 mg/ ml for sodium furosemide (dose range 40-120 mg/day) and 0.33-3.33 mg/ml (dose range 4-40 mg/day) for dexamethasone sodium phosphate. Quantification of both drugs was performed by high-performance liquid chromatography. RESULTS: After 5 days of storage at both temperatures, the maximum losses obtained were lower than 10 % for both drugs. However, after 15 days, slight precipitation/turbidity was observed in all mixtures. At this time, maximum losses of 20 % were obtained for both drugs. CONCLUSION: These results confirm the stability of mixtures prepared with sodium furosemide (< or = 120 mg/day) and dexamethasone sodium phosphate (< or = 40 mg/day) for a period of 5 days and with independence of their storage at 4 degrees C or 25 degrees C.

Pharmacogenetics in HIV therapy.

Administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, as well as different rates of drug-associated toxicity. The reasons for the large interindividual variability in drug levels are multifactorial, and involve differences in gender metabolism, concomitant medications, drug compliance, underlying diseases, and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the interindividual variation in the body disposition of drugs. One of the main goals is to give grounds to individualized therapy. The majority of pharmacogenetic traits so far have involved drug metabolism. An example of this is the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid. This variation is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which may split the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretrovirals have focused on metabolizing enzymes and transporter proteins in the cell membrane. Herein, we review the genetic polymorphisms known to be associated with altered pharmacokinetics of antiretrovirals, which may influence the efficacy and toxicity of these drugs.

Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients.

Ribavirin (RBV) in combination with pegylated interferon alpha (pegIFN) is currently the standard treatment of hepatitis C virus (HCV) infection. The development of anemia requires a reduction in RBV doses in a substantial proportion of patients, limiting their chances of treatment response. The primary goal of this study was to assess if early monitoring of RBV plasma levels could help to predict anemia as well as early HCV RNA response in HIV/HCV-coinfected individuals. The secondary goal was to evaluate if antiretroviral drugs might influence RBV plasma levels. Plasma RBV concentrations were measured at weeks 4 and 12 in 98 HIV/HCV-coinfected individuals who initiated therapy with pegIFN-2a (180 microg/wk) plus RBV (800-1200 mg/d). RBV plasma levels correlated with RBV dose per kilogram of body weight (P = 0.02). Larger drops in hemoglobin levels were independently associated with higher RBV plasma levels and zidovudine (ZDV) use (P < 0.001). Likewise, higher RBV levels (P = 0.007) and HCV genotype 3 (P < 0.001) were found to be independent predictors of virologic response at week 4. Similar findings were obtained at week 12. Patients receiving ZDV concomitantly showed significantly higher RBV plasma concentrations compared with those who did not (3.28 mug/mL vs. 2.51 mug/mL; P = 0.002). RBV levels were not significantly altered by the coadministration of other nucleoside/nucleotide analogues. In summary, RBV plasma levels correlate with the development of anemia and with the achievement of an early virologic response. Therefore, early therapeutic drug monitoring might help to tailor RBV dosages, improving the efficacy and safety of anti-HCV treatment.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects.

We examined 516G>T polymorphisms at the gene encoding the cytochrome P450 in 100 human immunodeficiency virus-positive subjects who were receiving efavirenz (EFV). Elevated plasma EFV concentrations were found in 40% of subjects with the polymorphic homozygous genotype and 19% of subjects with the heterozygous genotype. Conversely, 20% of subjects with the wild-type genotype had subtherapeutic concentrations of EFV. CYP2B6-516 genotyping may help to identify subjects who have plasma EFV concentrations that are outside of the therapeutic range.

Atazanavir: the advent of a new generation of more convenient protease inhibitors.

Protease inhibitors (PIs) have created a new future for many HIV-infected patients. After the initial enthusiasm following its first approval, complex drug schedules and frequent toxicities of PIs prompted researchers to find alternative drugs. However, it is now clear that not all triple combinations are equally valid. Certain regimens based on the association of only reverse transcriptase inhibitors have shown high rates of virological failure, with the selection of cross-resistance mutations. The availability of new generation PIs, such as atazanavir, with improved safety profiles and more convenient administration schedules returns this drug family to the front of the HIV therapeutic armamentarium. Recent clinical studies support the assertion that atazanavir may display excellent behavior as part of first-line regimens in rescue interventions or in simplification strategies.

Predictors of virological response to atazanavir in protease inhibitor-experienced patients.

BACKGROUND: Atazanavir (ATV) is the latest approved HIV protease inhibitor (PI). Even though it is very convenient (only two capsules once a day), concerns have risen about its potency. METHOD: The clinical performance of ATV 400 mg once a day was examined in all PI-experienced patients who were included in the ATV expanded access program conducted in a single institution. The predictive value of baseline drug resistance HIV genotypes, ATV plasma trough levels, and the genotypic inhibitory quotient (GIQ) on the virological response at week 24 was assessed. RESULTS: Data from 92 patients were analyzed. ATV was prescribed as part of a rescue intervention (45%), a simplification strategy (11%), or an attempt to ameliorate hyperlipidemias (23%) or other toxicities (16%). Tenofovir (TDF) was concomitantly used with ATV in 78% of patients. None received ritonavir boosting. In patients with detectable viremia at baseline (65%), the median HIV RNA drop was 0.7 logs. The median ATV Cmin was 0.12 microg/mL (IQR, 0.05-0.22 microg/mL), which is clearly above the IC90 (90% inhibitory concentration) for ATV in wild-type viruses. The virological response did not correlate significantly with ATV Cmin. The median number of protease resistance mutations was lower in patients showing virological response than in nonresponders (1 vs. 5; p=.07). A higher HIV RNA drop was associated with a higher GIQ (p=.02; beta=-5.4; 95% CI, -10 to -1). Only 4 patients (4%) discontinued treatment due to ATV-related toxicities (hyperbilirubinemia in 1). Bilirubin levels were associated with ATV plasma concentrations (p=.05; beta=3.2; 95% CI, -0.1 to 6.5). The rate of hypertriglyceridemia and hypercholesterolemia declined significantly with respect to baseline. CONCLUSION: ATV is relatively safe and provides significant virological response in PI-experienced patients, mainly among those with a low number of protease resistance mutations. The GIQ predicts accurately the virological response in patients receiving ATV. Hyperbilirubinemia is associated with higher ATV plasma levels.

Combinations of nucleoside/nucleotide analogues for HIV therapy.

Nucleoside and nucleotide analogues are essential for the design of effective antiretroviral regimens. There are currently many options for the selection of such drug backbones, although not all combinations will display optimal results. The concomitant administration of certain drugs should be avoided due to high rates of toxicity (ddl/d4T, ddl/TDF), antagonism (AZT/d4T, 3TC/FTC) and/or a greater risk of virological failure (ddl/TDF, ABC/TDF). The understanding of the plasmatic and intracellular metabolism of nucleoside/nucleotide analogues is crucial for deciding the optimal posology of each drug and the better dual combinations to be selected. Interferences between the pathways involved into the intracellular activation of some nucleoside/nucleotide analogues may help to understand why certain drug combinations should be avoided.