Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients.

Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (Cmax) of ≥25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC24) of ≥70 mg · h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a Cmax target of >25 mg/liter than an AUC24 target of ≥70 mg · h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required.

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing.

To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, -3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.

Population pharmacokinetic modelling, Monte Carlo simulation and semi-mechanistic pharmacodynamic modelling as tools to personalize gentamicin therapy.

Population pharmacokinetic modelling, Monte Carlo simulation and semi-mechanistic pharmacodynamic modelling are all tools that can be applied to personalize gentamicin therapy. This review summarizes and evaluates literature knowledge on the population pharmacokinetics and pharmacodynamics of gentamicin and identifies areas where further research is required to successfully individualize gentamicin therapy using modelling and simulation techniques. Thirty-five studies have developed a population pharmacokinetic model of gentamicin and 15 studies have made dosing recommendations based on Monte Carlo simulation. Variability in gentamicin clearance was most commonly related to renal function in adults and body weight and age in paediatrics. Nine studies have related aminoglycoside exposure indices to clinical outcomes. Most commonly, efficacy has been linked to a Cmax/MIC ≥7-10 and a AUC24/MIC ≥70-100. No study to date has shown a relationship between predicted achievement of exposure targets and actual clinical success. Five studies have developed a semi-mechanistic pharmacokinetic/pharmacodynamic model to predict bacteria killing and regrowth following gentamicin exposure and one study has developed a deterministic model of aminoglycoside nephrotoxicity. More complex semi-mechanistic models are required that consider the immune response, use of multiple antibiotics, the severity of illness, and both efficacy and toxicity. As our understanding grows, dosing of gentamicin based on sound pharmacokinetic/pharmacodynamic principles should be applied more commonly in clinical practice.

Tuber luomae, a new spiny-spored truffle species from the Pacific Northwest, USA.

Tuber luomae, a new truffle species known only from the Pacific Northwest, USA, is distinguished by spiny, non-reticulate spores and a two-layered peridium - the outermost layer (pellis) consists of inflated, globose to subpolygonal cells and the inner (subpellis) of narrow hyphae. ITS sequence analyses show that it has phylogenetic affinity to other Tuber species in the Rufum clade. The only other members of the Rufum clade with a strongly developed peridiopellis of large, inflated cells are the southern European T. malacodermum and T. pustulatum and the northern Mexican T. theleascum. We find it interesting that this peridial structure that is uncommon in the Rufum clade has been found in geographically disjunct species.

Role of Fe(III) in aqueous solution or deposited on ZnO surface in the photoassisted degradation of rhodamine B and caffeine.

Iron (III) was incorporated, to the surface of a synthesized ZnO, using two nominal molar percentages of Fe (III): 1% and 5% Fe relative to ZnO. Samples dried and calcined at 200 °C and 400 °C for 2 h, were characterized by XRD, XPS, XRF, N2-adsorption-BET and (UV-vis)-DRS. Photocatalytic activities of the catalysts were assessed based on the degradation of rhodamine B (RhB) and caffeine (CAF) in aqueous solution under two irradiation conditions: UV and visible light illumination. Prior to the photocatalytic tests, the interaction of each one of the substrates with either Fe(III) or Fe(II) was studied in homogeneous medium under UV-illumination and oxygenated environment. It was found that Fe (III) can play an important role in homogeneous media in the photoassisted degradation, both of rhodamine B and caffeine, while Fe (II) does not exert a relevant role in the photoassisted degradation of the referred substrates. Fe-ZnO samples display similar or poorer performance than pure ZnO in the presence of UV light for both studied substrates. The phenomenon can be attributed to the formation of either goethite or ZnFe2O4 at the ZnO surface where the coupled Fe3+/Fe2+ can act as recombination centers for the photogenerated charges. On the contrary, all Fe-ZnO samples showed enhanced photocatalytic activity under visible illumination which seems to be independent of the iron content. In this context, the mechanisms for photoassisted degradation of both the substrates in homogeneous medium and photocatalytic degradation are discussed, as well as the role of Fe in the photodegradation processes.

Percepción y prevalencia del consumo de cigarrillos electrónicos en estudiantes de Medicina / Electronic cigarettes perception and prevalence among medical students

Diversos estudios advierten de la relación a corto plazo entre el uso de los cigarrillos electrónicos y enfermedades pulmonares, cardiovasculares, además de su potencial adictivo. No existen estudios al respecto en estudiantes universitarios chilenos. MÉTODOS: Este estudio descriptivo transversal, mide la prevalencia de consumo, percepción de riesgo, motivaciones y actitudes del uso de cigarrillos electrónicos en estudiantes de Medicina, mediante un cuestionario online. RESULTADOS: Se analizaron 354 sujetos, 32,9% han utilizado cigarrillos electrónicos alguna vez en la vida, 6,8% en el último año y 1,1% en el último mes. La edad media de inicio fue 18,0 ± 2,2 años. Respecto a las percepciones positivas hacia los cigarrillos electrónicos: 37,1% cree que ayudan a la gente a dejar de fumar; 39,7% que son menos peligrosos que los cigarrillos y 19,0% que son menos adictivos. El consumo de cigarrillos electrónicos alguna vez en la vida se asoció al consumo de tabaco y percepciones positivas hacia cigarrillos electrónicos (efectivo para dejar de fumar y menos adictivos que los cigarrillos). Las principales motivaciones al consumo fueron "simplemente porque sí", "porque me gusta el sabor", "me lo recomendó un amigo/familiar" y "porque me relaja". CONCLUSIÓN: Se sugiere prohibir la promoción de los cigarrillos electrónicos como una opción menos dañina y adictiva que el cigarrillo, tampoco como alternativa para dejar de fumar, puesto que la evidencia científica no es suficiente para respaldar tales afirmaciones. Este estudio puede contribuir a la prevención de consumo de cigarrillos electrónicos en poblaciones jóvenes.

INTRODUCTION: Several studies warn of the short-term relationship between the use of electronic cigarettes and lung and cardiovascular diseases, in addition to their addictive potential. There are no studies in this regard in Chilean university students. METHODS: This cross-sectional descriptive study measures the prevalence of consumption, risk perception, motivations and attitudes of e-cigarette use in medical students, using an online questionnaire. RESULTS: We analyzed 354 subjects, 32.9% have used electronic cigarettes once in their lives, 6.8% in the last year and 1.1% in the last month. The mean age of onset was 18.0 ± 2.2 years. Regarding positive perceptions towards e-cigarettes: 37.1% believe they help people quit smoking; 39.7% that they are less dangerous than cigarettes and 19.0% that they are less addictive. E-cigarette use was once in a lifetime associated with tobacco use and positive perceptions toward e-cigarettes (effective for quitting smoking and less addictive than cigarettes). The main motivations for consumption were "simply because I do", "because I like the taste", "it was recommended to me by a friend/family member" and "because it relaxes me". CONCLUSION: It is suggested to ban the promotion of e-cigarettes as a less harmful and addictive option than cigarettes, nor as an alternative to quitting smoking, since scientific evidence is not sufficient to support such claims. This study may contribute to the prevention of e-cigarette use in young populations.

HPV, histologic grade and age. Risk factors for the progression of cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the clinical significance of human papillomavirus (HPV) type, grade of cervical intraepithelial neoplasia (CIN) and age on the progression of CIN. STUDY DESIGN: Clinical follow-up data, histopathologic diagnosis, polymerase chain reaction (PCR) and HPV DNA typing were available on 194 patients, 119 with CIN 2/moderate dysplasia and 75 with CIN 3/severe dysplasia. RESULTS: HPV 16 was observed most frequently (47.0%) in progressed CIN, while HPV-negative cases (57.7%) were most frequently regressed. HPV positivity (P = .0466), especially HPV 16 positivity (P = .0104), was significantly more frequent than HPV negativity in the progression group. The rate of CIN progression was higher with HPV (50.5%) than without HPV (35.4%). Of the CIN cases with HPV 16, 56.5% progressed, while 30.8% of the CIN cases with HPV 6 and/or 11 and 35.4% of the CIN cases without HPV progressed. The probability of progression was 1.87-fold higher in the HPV-positive group than that in the HPV-negative group (P = .03). Multiple logistic regression analysis revealed that HPV (odds ratio 2.23, P = .0103) and grade of the lesion (odds ratio 3.30, P = .0002) in the initial biopsy strongly and independently correlated with progression of CIN. CONCLUSION: HPV status and histologic grade are independent predictive risk factors for progression and may be useful in the management of CIN.

[Early treatment of secondary hyperparathyroidism in moderate renal insufficiency: low-phosphorus diet versus calcium carbonate]. / Tratamiento precoz del hiperparatiroidismo secundario en insuficiencia renal moderada: dieta baja en fósforo frente a carbonato cálcico.

Calcitriol deficiency and phosphorus retention are mechanisms involved in the pathogenesis of renal hyperparathyroidism. The aim of this study was to evaluate the effect of dietary phosphorus restriction versus calcium carbonate treatment for one month on PTH and calcitriol levels in patients with mild renal failure. We studied two groups of patients: Group I: 21 patients (14M/7F); mean age 61 years old; mean glomerular filtration rate 51 ml/min. Their diet contained phosphorus 700 mg/day. Group II: 30 patients (21M/9F); mean age 58; mean glomerular rate 56 ml/min. They were divided in two subgroups: 18 patients treated with calcium carbonate 2.5 g/day and 12 patients with 5 g/day. Serum PTH, calcitriol, 25(OH)D3, calcium, phosphorus and urinary excretion of calcium and phosphorus were measured before and after a 30 day period. The low phosphorus diet (Group I) resulted in a significant decrease in PTH levels (81.3 +/- 35 vs 71 +/- 39 pg/ml, p < 0.05) and significant increase in calcitriol levels (22.4 +/- 4.4 vs 33.4 +/- 7.5 pg/ml, p < 0.05). In our study calcium carbonate treatment (Group II) had no effect on PTH and calcitriol levels.

[Clinical experience with icodextrin. Multicenter study]. / Experiencia clínica con icodextrina. Estudio multicéntrico.

UNLABELLED: The aim of this study was to analyse our experience with icodextrin in Andalusia, Spain. The study includes 51 patients (30 women and 21 men) on peritoneal dialysis (21 on CAPD and 30 on Automated Peritoneal Dialysis) treated with icodextrin for 10.3 +/- 7 months (0-41 months). Their mean age was 57 +/- 18 years (18-86 years). We have recorded the appearance of side effects, and the evolution of several biochemical parameters at baseline and after 6, 12 ans 18 months from initiation of icodextrin. We also studied drainage fluid from 12 patients after an icodextrin exchange. RESULTS: There were side effects (all cutaneous) in 4 out of 51 patients (7.8%). Two of the affected suffered from cutaneous hypersensitivity reactions, and icodextrin had to be suspended; the other two had exfoliative dermatitis affecting hands and feet that disappeared without have to withdraws icodextrin. Biochemical parameters: Serum sodium levels decreased from baseline to six months (138 +/- 6 mEq/l vs 136 +/- 3 mEq/l; p = 0.006), and then persisted at the same levels throughout the rest of the study period. There was a slight but significant decreased of serum HDL-cholesterol at six months vs baseline (55 +/- 26 mg/dl vs 51 +/- 20 mg/dl, p = 0.04), and a further decrease at twelve months vs six months (42 +/- 15 mg/dl vs 51 +/- 13 mg/dl, p = 0.054). There were no significant variations of glucose, osmolality, cholesterol, LDL-cholesterol (tendency to increase), triglycerides, beta 2 m and weight (tendency to increase; p = 0.08). In relation with the icodextrin exchange: average ultrafiltration 296 +/- 119 ml (ranging from 104 to 480 ml), creatinine clearance 1.9 +/- 0.5 litres (20.5% of daily creatinine clearance), urea clearance 2.08 +/- 0.5 litres (18.7% of daily urea clearance), total protein losses 3.2 +/- 0.9 g, albumin losses 1.4 +/- 0.5 g; urea and creatinine clearances were negatively correlated with ratios D/P4 of urea and creatinine of PET and positively correlated with ratio G4/G0. In conclusion, side effects are scarce with the use of icodextrin. As described in other studies, there is a trend to a slight decrease in serum sodium. The long-term use of icodextrin does not-prevent weight gain or deterioration of patients on peritoneal dialysis, despite the diminution of glucose load.

[Rare hemoglobinopathies in Costa Rica]. / Hemoglobinopatías poco communes en Costa Rica.

Among the rare hemoglobinopathies found in Cost Rica are those of the Alfa, Beta, and Delta chains. Among these, Hb Cubujuquí, an undescribed variant, is of special interest. There was an association between the different thalassemic syndromes and their combinations with abnormal hemoglobins.

Prevalence of serum IgG antibodies for the E7 and L2 proteins of human papillomavirus type 16 in cervical cancer patients and controls.

Relationship between the prevalence of the antibodies to HPV16E7 and L2 proteins and the development of cervical cancer was examined. Sera from 57 patients with invasive cervical cancer and from 200 age-matched healthy blood donors (16 to 64 years old) were examined for antibodies against E7 and L2 proteins of human papillomavirus (HPV) type 16. Bacterially expressed fusion antigens were used in a Western immunoblot assay. Ten (18%) of the patients and 10 (5%) of the controls were positive for only E7. Each eighteen of the patients (32%) and of the controls (9%) were positive for only L2. Three of the patients and 2 of the controls were positive for both E7 and L2 antibody reactivity. The patients' prevalence of antibodies for the E7 and L2 proteins was significantly higher than that of the controls (E7: chi 2 = 14.3, p < 0.01; L2: chi 2 = 23.8, p < 0.01). On the other hand, neither sex specific difference in the antibody prevalence was observed, nor was there any difference in the antibody prevalence with age. Our findings indicate that antibodies to the HPV16L2 proteins could be a parameter for cervical cancer development as well as those to the HPV16E7 proteins.

Prevalence of HPV DNA in cervical lesions in patients from Ecuador and Japan.

Cervical cancer is about 6 times more frequent in Ecuador than in Japan. We investigated the association between infection by the human papillomavirus (HPV) and the genesis of cervical cancer in specimens of lesions of the cervical epithelium obtained from patients in Ecuador and Japan. We also examined the results of HPV DNA detection and typing by the polymerase chain reaction (PCR) performed under the same technical conditions in areas with differing rates of cervical cancer. Purified tissue DNA from paraffin-embedded samples was amplified by PCR with universal and type-specific primers. HPV DNA was detected in 8 (20%) of 40 normal cervical epithelial samples from Ecuadorian patients, 19 (45%) of 42 low-grade squamous intraepithelial lesions (LSIL), 16 (50%) of 32 high-grade squamous intraepithelial lesions (HSIL), and 38 (81%) of 47 invasive squamous cell carcinomas (SCC) compared with 3 (10%) of 30 normal cervical specimens from Japanese patients, 107 (51%) of 210 HSILs, and 45 (71%) of 63 SCCs. The prevalence of HPV types 16 and 18 rose significantly with increasing histological grade (p < 0.05). The prevalence of HPV DNA decreased with increasing age in both Ecuadorian and Japanese patients. The detection rate and type-specific distribution of HPV DNA were not correlated with geographic location. Findings suggest that risk factors associated with poverty and underdevelopment may influence the prevalence of HPV infection and the sequence of events after HPV infection culminating in cervical cancer. These factors may help to explain the differing geographic distribution of this disease.

G6PD-Puerto Limón: a new deficient variant of glucose-6-phosphate dehydrogenase associated with congenital nonspherocytic hemolytic anemia.

A new glucose-6-phosphate dehydrogenase (G6PD) variant with total deficiency associated with congenital nonspherocytic hemolytic anemia was found in a Costa Rican family. The study of the partially purified enzyme revealed thermal instability, increased G6P affinity, abnormal pH optimum, increased utilization of analogues, and a chromatographic behavior that differs from all the variants previously described. Thus, this new variant was designated G6PD Puerto Limón.