A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness.

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.

Population pharmacokinetics and exposure-response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID-19.

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two-compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across severe acute respiratory syndrome-coronavirus 2 variants.

Imaging in fetal genital anomalies.

Genital anomalies are a heterogeneous group of congenital pathologies that have become increasingly relevant since the Chicago Consensus of 2005. Their postnatal diagnosis has developed significantly in the last two decades, while prenatal diagnosis seems to be underdeveloped, with few protocols available, fragmented scientific literature, and low diagnostic rates. This review aims to examine the current status of this subspecialty from the perspective of prenatal imaging. Indications for the evaluation of fetal genitalia can be divided into medical and non-medical reasons. Medical reasons include sex-linked disorders, detection of other anomalies, relevant family history, or multiple pregnancy. Non-medical reasons include parental request for sex disclosure. Disclosure of fetal sex may be associated with ethical, legal, and medical issues. The main imaging technology used is 2D ultrasound, although there are other complementary techniques such as 3D, MRI, or Color Doppler. Regarding working methodology, several authors have drawn attention to the lack of standardized protocols and guidelines. Most guidelines tend to limit their recommendations to study indications and ethical issues. Technical proposals, measurements, or working methods have not yet been standardized. Fetal sex determination is usually divided into early and late gestation. Early gestation is based on the sagittal sign. Late gestation is based on direct visualization. There are several measurements to describe male and female genitalia, such as penile length, bilabial diameter, or scrotal diameter. Prenatal diagnosis of genital pathologies presents some particularities such as the wide spectrum of phenotypes, the high frequency of associated deformities, or the time of diagnosis. Some of the most frequent pathologies are ambiguous genitalia, fetal sex discordance, hypospadias, micropenis, clitoromegaly, ovarian cysts, hydro(metro)colpos, and cloacal anomalies. Higher-quality studies and direction from scientific societies through the implementation of clinical guidelines are needed.

Efficacy and Safety of Extracorporeal Membrane Oxygenation in Patients under Mechanical Ventilation with COVID-19 and Severe Acute Respiratory Distress Syndrome: A Health Technology Assessment.

We aimed to assess the efficacy and safety of extracorporeal membrane oxygenation (ECMO) in patients under mechanical ventilation with COVID-19 and severe acute respiratory distress syndrome (ARDS). A systematic review of the literature published in PubMed, Cochrane Library and LILACS databases, was performed. A manual search was also conducted using the reference lists of the studies included in the full-text assessment, as well as a grey-literature search on Google. Additionally, websites of state institutions and organizations developing clinical practice guidelines and health technology assessments were reviewed. The ClinicalTrials.gov website was screened along with the websites of the International Clinical Trial Registry Platform and the National Registry of Health Research Projects of the Peruvian National Institute of Health. No restrictions were applied in terms of language, time, or country. A total of 13 documents were assessed, which included 7 clinical practice guidelines, 3 health technology assessments, 1 systematic review, 1 randomized clinical trial, and 1 observational study. A critical appraisal was conducted for each document. After this, we considered that the currently available evidence is insufficient for a conclusion supporting the use of ECMO in patients under mechanical ventilation with severe ARDS associated to COVID-19 in terms of mortality, safety, and quality of life.

Stretched penile length at birth: a systematic review.

BACKGROUND: Micropenis is an endocrinological condition that is habitually observed at birth. Diagnosis is made by measuring the stretched penile length, a method established 80 years ago. Discrepancies in the normative data from recent studies raise the need for a current revision of the methodology. OBJECTIVES: The aims of this systematic review were to compare the different normative data of SPL at birth, to examine the methodological aspects of the technique and to evaluate the independent variables that may be involved. METHODS: Searches were performed using MEDLINE, EMBASE, Scielo, the Cochrane Library and Web of Science. A combination of the relevant medical terms, keywords and word variants for "stretched penile length", "penile length", "penile size", "newborn" and "birth" were used. Eligibility criteria included normative studies that used the stretched penile length (SPL) measurement on a population of healthy, full-term newborns during the first month of life. The outcomes studied included characteristics of the studies, methodological aspects and independent variables. RESULTS: We identified 49 studies comprising 21,399 children. Significant discrepancies are observed between the different studies. Methodological aspects seem to be consistent and similar. The main independent variables appear to be ethnic group and gestational age. Main limitations were the absence of studies of entire world regions such as Europe or South America, and the heterogeneity of the ethnic background that complicates the analysis. CONCLUSIONS: It seems advisable to suggest the creation of customized reference charts for each specific population instead of resorting to the classic cut-off points.

Open-legs axial plane: A standardized methodology and reference values for fetal genital biometry in mid-trimester ultrasound.

BACKGROUND: Evaluation of the external genitalia is an important part of prenatal ultrasound. However, there is no standardized methodology that includes biometric measurements and normative data to be able to carry out this evaluation. OBJECTIVE: To develop a standardized methodology for fetal genital biometry and obtain reference values for use in mid-trimester ultrasound. STUDY DESIGN: A prospective cross-sectional study was used. 273 male and 253 female fetuses of normal, singleton pregnancies at 18 to 22 weeks were included. Measurements of fetal penis length, penile width and transverse scrotal diameter in male fetuses and bilabial diameter in female fetuses were performed by transabdominal ultrasound. Reference values were calculated for each gestational week. RESULTS: Realization of the open-legs axial plane is described as a working methodology. Normative data for penile length, penile width, transverse scrotal diameter and bilabial diameter are defined, including mean, minimum and maximum values, range, and 5th, 10th, 90th and 95th percentiles. CONCLUSIONS: We have provided a standardized methodology using the open-legs axial plane, which would integrate the main measurements. In addition with the normative data constructed from their use, we hope to be able to improve the external genitalia assessment and diagnosis of genital anomalies in mid-trimester ultrasound.

Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1-3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3-altered Advanced/Metastatic Urothelial Carcinoma.

BACKGROUND: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition. OBJECTIVE: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. INTERVENTION: Oral infigratinib 125 mg/d for 21 d every 28 d. DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical outcomes were compared in groups with/without hyperphosphatemia. RESULTS AND LIMITATIONS: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. CONCLUSIONS: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. PATIENT SUMMARY: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.

Safety, pharmacokinetics and pharmacodynamics of selgantolimod, an oral Toll-like receptor 8 agonist: a Phase Ia study in healthy subjects.

BACKGROUND: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers. METHODS: Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3 or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, PK and PD activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted. RESULTS: Single doses of 0.5-5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose. CONCLUSIONS: Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB. Australian New Zealand Clinical Trials Registration: ACTRN12616001646437.

Efficacy and Safety in the Continued Treatment With a Biosimilar Drug in Patients Receiving Infliximab: A Systematic Review in the Context of Decision-Making From a Latin-American Country.

Introduction: Biological products, including infliximab (INF), are a therapeutic option for various medical conditions. In the Peruvian Social Security (EsSalud), infliximab is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, ulcerative colitis and Crohn's disease (in cases refractory to conventional treatment). Biosimilars are a safe and effective alternative approved for these diseases in patients who start treatment with infliximab. Nevertheless, there are people in treatment with the biological reference product (BRP), in whom the continuing therapy with a biosimilar biological product (BBP) must be evaluated. Objectives: To synthesize the best available evidence, calculate a preliminary financial impact and conduct technical discussions about the interchangeability into biosimilar in patients receiving treatment with original infliximab for medical conditions approved in EsSalud. Methodology: We carried out a systematic review of controlled clinical trials. Primary search was performed in Pubmed- MEDLINE, SCOPUS, WOS, EMBASE, TRIPDATABASE, DARE, Cochrane Library, NICE, AHRQ, SMC, McMaster-PLUS, CADTH, and HSE until June-2018. We used the Cochrane Collaboration tool to assess the risk of bias. Also, we implemented a preliminary financial analysis about the impact of biosimilar introduction on institutional purchasing budget. Moreover, technical meetings with medical doctors specialized in rheumatology, gastroenterology and dermatology were held for discussing findings. Results: In primary search, 1136 records were identified, and 357 duplicates were removed. From 799 records, we excluded 765 after title and abstract evaluation. From 14 full-text appraised documents, we included five clinical trials in the risk of bias assessment: four studies evaluated CTP-13 and one tested SB2. Two double-blind clinical trials reported no differences in efficacy and safety profiles between maintenance group (INF/INF) and interchangeability group in all diseases included (INF/CTP-13) and rheumatoid arthritis (CTP13 and SB2). In the other three studies, open-label extension of primary clinical trials, no differences were founded in efficacy and safety profiles between CTP-13/CTP-13 and INF/CTP-13 groups. In financial analysis, the inclusion of biosimilars implied savings around S/7´642,780.00 (1USD=S/3.30) on purchasing budget of EsSalud. In technical meetings, beyond certain concerns, specialists agreed with the findings. Conclusions: Evidence from clinical trials support that there are no differences in efficacy or safety of continuing the treatment with Infliximab BRP or exchanging into its biosimilar in patients with medical conditions approved in EsSalud. Financial analysis shows that the biosimilar introduction produce savings in purchasing institutional budget. Therefore, based on cost-opportunity principle, exchanging into biosimilar in patients receiving the original Infliximab, is a valid therapeutic alternative in the Peruvian Social Security.

Pharmacokinetics, Pharmacodynamics, Tolerability, and Food Effect of Cenerimod, a Selective S1P1 Receptor Modulator in Healthy Subjects.

The pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a potent sphingosine-1-phosphate subtype 1 receptor modulator, were investigated in three sub-studies. Two double-blind, placebo-controlled, randomised studies in healthy male subjects were performed. Cenerimod was administered either as single dose (1, 3, 10 or 25 mg; Study 1) or once daily for 35 days (0.5, 1, 2 or 4 mg; Study 2). A two-period cross-over, open-label study was performed to assess the food effect (1 mg, Study 3). The pharmacokinetic profile of cenerimod was characterised by a tmax of 5.0-6.2 h. Terminal half-life after single and multiple doses ranged from 170 to 199 h and 283 to 539 h, respectively. Food had no relevant effect on the pharmacokinetics of cenerimod. A dose-dependent decrease in lymphocyte count was observed after initiation of cenerimod and reached a plateau (maximum change from baseline: -64%) after 20-23 days of treatment. Lymphocyte counts returned to baseline values at end-of-study examination. One serious adverse event of circulatory collapse (25 mg dose group, maximum tolerated dose: 10 mg) and adverse events of mild-to-moderate intensity were reported. Treatment initiation was associated with transient decreases in heart rate and blood pressure at doses >1 and ≥10 mg, respectively.

Octava cesárea en una misma paciente / Eighth cesarean section in the same patient

La tasa de cesáreas está aumentando en todo el mundo desde hace décadas. El deseo en muchas regiones o países de tener un alto número de hijos junto con la falta de medidas contraceptivas efectivas está provocando la aparición de un nuevo tipo de paciente, la gestante con cesárea múltiple repetida. En algunos países suponen ya un 4-6% de todas las embarazadas. Las complicaciones en estas pacientes son frecuentes y la morbilidad está aumentando. Pese a ello, los datos sobre los riesgos y para el manejo de esta paciente son aún muy limitados. Presentamos el caso de una paciente de 39 años que fue sometida a su octava cesárea (AU)

Cesarean rate is increasing worlwide in the last decades. Women's desire of large families and the lack of adequate contraception is producing a new patient's type: pregnant with multiple repeat cesarean section Ir represents 4-6% pregnancies in some countries and regions. Complications are common in this patients and there is a elevated morbidity. Despite this, data about risks and a properly management are very limited. We present the case of a patient who underwent her eight cesareansection (AU)

Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans.

1. Ponesimod [(R)-5-[3-chloro-4-(-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one] is an orally administered, selective S1P1 receptor modulator that blocks the egress of lymphocytes from lymphoid organs and reduces the availability of circulating effector T/B-cells. 2. The mass balance, pharmacokinetics and metabolism of 40 mg (14)C-ponesimod were investigated in six healthy male subjects. The total radioactivity in whole blood, plasma, urine, faeces and expired CO2 was determined by liquid scintillation counting. Metabolite profiling was performed by high-performance liquid chromatography and detection by mass spectrometry. 3. The majority of the radioactivity (% of administered dose) was recovered in faeces (57.3-79.6%), followed by urine (10.3-18.4%) and a small proportion in CO2 from expired air (0.6-1.9%). The average cumulative recovery (mass balance) of (14)C-associated radioactivity in faeces and urine was 77.9% of the administered dose. Unchanged ponesimod made up 25.9% of total radioactivity in faeces; none was detected in urine. Ponesimod was extensively metabolised and two pharmacologically inactive metabolites, M12 (ACT-204426) and M13 (ACT-338375), were detected in the circulation. M12 corresponded to 8.1% and M13 to 25.7% of the total drug-related radioactive exposure (AUC0-∞) in plasma. M12 was highly abundant in faeces (22.3% of total radioactivity) and to a smaller extent in urine (2.5% of total radioactivity).

Uso de radiotrazador de medicina nuclear fluor 18 fluorodexosiglucosa (f18-fdg) en tomografias de emision de positrones (pet) en oncología / Use of nuclear fluor radiotherapy radiodermal 18 fluorodexosiglucose (f18-fdg) in positron emission tomography (PET) in oncology

INTRODUCCIÓN: Antecedentes: l presente informe expone la evaluación del radiotrazador de medicina nuclear Fluor-18-Fluorodexosiglucosa (F-18 FDG) en tomografías de emisión de positrones (PET). Se realiza esta evaluación considerando la necesidad manifestada por el Servicio de Medicina Nuclear del Hospital Nacional Edgardo Rebagliati Martins y del Hospital Nacional Guillermo Almenara Yrigoyen. Aspectos Generales: Las imágenes PET o Tomografías de Emisión de Positrones son técnicas de diagnóstico por imágenes no invasiva de la medicina nuclear, la cual, a través de una substancia emisora de positrones llamada radiotrazador, genera una imagen de su distribución tridimensional en los tejidos. Su evaluación, cuantificación e interpretación es realizada por el médico nuclear. La caracterización bioquímica y biológica de los tejidos, ofrece al médico tratante un tipo de información fundamentalmente diferente que la provista por las imágenes anatómicas. En la actualidad, la mayoría de los tomógrafos PET son equipos que combinan dos tecnologías: PET y TC (Tomografía computarizada) en un único dispositivo con el que se generan simultáneamente imágenes funcionales y anatómicas de los órganos en estudio. Tecnología Sanitaria de Interés: El radiofármaco emisor de positrones F-18 Fluorodexosiglucosa es un análogo de la glucosa y contiene el ingrediente activo 2-deoxy-2-[18F]fluoro-D-glucosa o F-18 FDG). Decae por emisión de positrones y tiene una vida media de 109.7 minutos. METODOLOGÍA: Estrategia de Busqueda: Se realizó una búsqueda de la literatura con respecto a la especificidad, sensibilidad y seguridad de PET-CT usando el F-18 FDG como radiotrazador. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: TranslatingResearchintoPractice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y HealthSystemsEvidence. Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The National Guideline of Clearinghouse, The Canadian Agency for Drugs and Technologies in Health (CADTH),The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov, para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Evaluacion de Tecnología: Administración de Medicamentos y Drogas (FDA) del año 1999 (última actualización en el 2010) 3: La evidencia de mejor calidad encontrada fue esta revisión de 18F Fluoro-2-Deoxyglucosa (18-FDG) como agente de diagnóstico de imágenes PET en la evaluación de malignidad de la Administración de Medicamentos y Drogas (FDA por sus siglas en inglés), la cual aprobó su uso como radiofármaco en las áreas de oncología, cardiología y neurología. CONCLUSIONES: s imágenes PET o Tomografías de Emisión de Positrones son técnicas de diagnóstico por imágenes no invasivas de la medicina nuclear, las cuales usan compuestos llamados radiotrazadores para la generación de imágenes. El radiotrazador emisor de positrones F-18 Fluorodexosiglucosa es un análogo de la glucosa, el cual permite identificar tejidos malignos y benignos en el área evaluada, ya que una glicólisis acelerada o menor capacidad de producir energía aeróbicamente son características de células malignas (cancerígenas). La caracterización bioquímica y biológica de los tejidos, ofrece al médico tratante un tipo de información fundamentalmente diferente que la provista por las imágenes anatómicas, por lo que las guías de práctica clínica a nivel \r\ninternacional recomiendan actualmente el uso del radiotrazador tanto para fines se estadiaje como de seguimiento y respuesta al tratamiento oportunas. El uso del radiotrazador de medicina nuclear Fluor 18 Fluorodexosiglucosa (F-18 FDG) en tomografías de emisión de positrones (PET) para el diagnóstico, \r\nestadiaje, y respuesta al tratamiento en enfermedades oncológicas, está recomendado en guías de práctica clínicas internacionales. Sin embargo, es interesante notar que la evidencia científica de sensibilidad y especificidad que respalda dichas recomendaciones es escasa y variable para muchas de las patologías oncológicas. No obstante ello, esta tecnología imagenológica es ampliamente usada en oncología, especialmente para evaluar la respuesta a tratamiento. Cabe resaltar, que la evidencia revisada es consistente respecto a la seguridad del F-18 FDG. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación- IETSI, aprueba el uso de F 18 Fluorodexosiglucosa como radiotrazador para la realización de PET-CT en el manejo oncológico.

Effects of ethnicity and sex on the pharmacokinetics and pharmacodynamics of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod: a clinical study in Japanese and Caucasian subjects.

The aim of this study was to evaluate the relative pharmacokinetic (PK) and pharmacodynamic (PD) properties of a single dose of ponesimod, an oral and selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, in Japanese and Caucasian healthy subjects and explore the effects of sex on PK. Subjects received a single 40-mg dose of ponesimod in a single-centre, open-label, parallel-group study design. Ten Japanese and 10 Caucasian healthy subjects (age: 22-45 years, 1:1 sex ratio) participated in the study and were matched for body weight (±10%). Ponesimod concentration in plasma was determined by liquid chromatography tandem mass spectrometry, and PK parameters were obtained by non-compartmental analysis. Total lymphocyte count served as PD marker. Adverse events (AEs), laboratory values, electrocardiography (12-lead ECG), and vital signs were assessed for safety and tolerability. Administration of ponesimod resulted in similar PK parameters between the two ethnic groups, with a 16% higher exposure [AUC0-∞ of 7,368 ng ∙ h/ml (95% CI: 6,059-8,962) vs. 6,353 ng ∙ h/ml (4,950-8,154)] and a 17% longer terminal elimination half-life [32.9 h (30.1-36.0) vs. 28.1 h (23.4-33.6)] in Japanese compared to Caucasian subjects. Exposure was slightly higher in female subjects [7,488 ng ∙ h/ml (5,983-9,371)] than in male subjects [6,252 ng ∙ h/ml (5,031-7,771)]. The maximum mean lymphocyte count decrease from baseline, observed 6 h after receiving the dose in both groups, was similar in Japanese subjects (61.8%) and Caucasians (62.5%). The maximum mean heart rate (ECG) reduction from baseline was similar, with a difference of 4.2 bpm between Caucasian and Japanese subjects, observed 2.5 h after receiving the dose in both ethnic groups. There were no clinically relevant changes in other safety variables. No serious AEs were reported during the study. This study showed that the PK and PD profile of ponesimod was similar in Japanese and Caucasian subjects. No unexpected safety findings were reported. No dose adjustment is deemed necessary for Japanese subjects compared to Caucasians.

Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive.

PURPOSE: To determine the effects of steady-state concentrations of the selective S1P1 receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 µg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive. METHODS: Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis. RESULTS: Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of Cmax and AUC0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of Cmax and AUC0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline. CONCLUSION: No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.

Efectividad de los bloqueadores solares en la prevención de las lesiones de piel no oncológicas / Effectiveness of sunscreens in the prevention of non-oncological skin lesions

ANTECEDENTES: El cáncer de piel es una de las neoplasias de alta importancia en salud pública, no solo por el incremento progresivo de su frecuencia, sino también por su importante repercusión a nivel de moratlidad, morbilidad y el subsecuente impacto económico en la sociedad. Asimismo, ha sido clasificado en dos grandes grupos: en melanoma y no melanoma, este último conformado por los carcinomas basocelular y espinocelular. Se han identificado una serie de factores de riesgo; como la exposición solar excesiva, los tipos de piel I y II, los cambios en un lunar previo, la tendencia a presentar pecas, la presencia de gran número de lunares, la inmunosupresión y antecedente personal o familiar de cáncer de piel, entre otras. En ese sentido, se han propuesto diversas actividades de prevención primaria, que incluyen campañas educativas dirigidas a disminuir o evitar la exposición solar e incrementar el uso de bloqueadores solares; así como actividades de prevención secundaria en búsqueda de un diagnóstico temprano por parte de los profesionales de la salud. Es importante, en dicho contexto que las políticas públicas sean informadas en la mejor evidencia disponible. Más aun, cuando existe controversia respecto al impacto de dichas intervenciones sobre el desarrollo de cáncer de piel. OBJETIVO: Evaluar la efectividad del uso de los bloqueadores solares en la prevención del melanoma maligno, carcinoma basocelular y carcinoma escamoso en la población general. METODOLOGÍA: Se realizó una sinopsis de revisiones sistemáticas (RS) siguiendo el modelo propuesto por Haynes et al. La búsqueda se realizó en MEDLINE y EMBASE hasta el 18 de enero 2013. Dos revisores independientes seleccionaron, después de la lectura de títulos y resúmenes, aquellos que cumplían con los criterios de inclusión y con el objetivo de la búsqueda. Después de la lectura en extenso, los dos revisores selecionaron los estudios que permanecerían en la sinopsis y extrajeron la información necesaria. En caso de haber discrepancias, un tercer investigador cumplió un rol dirimente. Se empleó la herramienta AMSTAR para la evaluación de la calidad de las RS. RESULTADOS: Se identificaron 38 artículos en MEDLINE y 23 en EMBASE. De estos, se seleccionaron 11 artículos, tras la evaluación de concordancia y la lectura de resúmenes y títulos. Posteriormente se realizó una lectura a texto completo, en la cual se excluyeron siete publicaciones debido a que correspondían a revisiones narrativas, a un modelo matemático de predicción de casos evitados o eran de baja calidad. No se encontró evidencia proveniente de revisiones sistemátcias de alta y media calidad sobre la asociación entre el uso de bloqueadores solares y el carcinoma espinocelular ni basocelular en población general. El uso de bloqueadores solares está asociado a un menor riesgo de carcinoma espinocelular en pacientes que tuvieron antecedentes de lesiones en piel inducidas por el sol, cuando la exposición solar no era intencional, En el análisis global no se encontró asociación entre el uso de bloqueadores y el riesgo de melanoma. En el análisis por subgrupos una de las revisiones encontró un leve efecto protector de los bloqueadores solares (OR: 0,76; IC95% [0,65-0,90]), cuando sólo se incluyeron en el análisis estudios que consideraban variables como la sensibilidad solar de la piel y antecedentes de quemaduras solares. Por otro lado, otra revisión encontró un mayor riesgo de melanoma en pacientes de países alejados del Ecuador (a más de 40° latitud) que usaban bloqueadores (OR: 1,6; IC95% [1,3­1,9]). CONCLUSIÓN: El uso de bloqueadores solares no es efectivo para la prevención de cáncer de piel en población general; pero es efectivo en la prevención de melanoma y carcinoma espinocelular en poblaciones específicas.(AU)

Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics.

Chronic kidney disease (CKD) is recognized to cause pharmacokinetic changes in renally excreted drugs; however, pharmacokinetic changes are also reported for drugs that are nonrenally eliminated. Few studies have investigated how uremic toxins may affect drug transporters and metabolizing enzymes and how these may result in pharmacokinetic/metabolic changes in CKD. Here, we investigated the effects of uremic toxins and human uremic serum on the transport of the prototypical transporter substrate [(3) H]-estrone sulfate and three Biopharmaceutics Drug Disposition Classification System (BDDCS) drugs, propranolol, losartan, and eprosartan. We observed a significant decrease in [(3) H]-estrone sulfate, losartan, and eprosartan uptake with some uremic toxins in both transfected cells and rat hepatocytes. The uptake of losartan was decreased in rat and human hepatocytes (28% and 48%, respectively) in the presence of hemodialysis (HD) serum. Time-course studies of losartan showed a 27%, 65%, and 68% increase in area under the curve (AUC) in the presence of HD serum, rifampin, and sulfaphenazole, respectively. Intracellular losartan AUC decreased significantly in the treatment groups, and the metabolite AUC decreased by 41% and 26% in rifampin- and sulfaphenazole-treated group, respectively. The intracellular AUC of eprosartan increased 190% in the presence of HD serum. These studies indicate that the uremic toxins contained in HD serum play an important role in drug disposition through drug transporters, and that there would be differential effects depending on the BDDCS classification of the drug.

Identificación e intervención terapéutica en afecciones del Sistema Osteomioarticular en Oghi, Pakistán / Identification and therapeutic intervention in affections of the Osteomioarticular System in Oghi, Pakistan

Se realizó un estudio de intervención pre-experimental del tipo antes-después en el Departamento de Fisioterapia del Hospital Integral de Campaña No.15 27 de Noviembre en Oghi, Pakistán, en el período de tiempo comprendido desde el 26 de diciembre de 2005 hasta el 5 de febrero del 2006 en pacientes mayores de 15 años afectados por enfermedades del sistema osteomioarticular, con el objetivo de identificar y aplicar tratamiento con equipos de alta tecnología, la muestra quedó conformada por 515 pacientes. Las variables estudiadas fueron edad, sexo, patologías, técnicas fisioterapéuticas, síntomas y signos y evaluación final; se concluye que el grupo de edad de 46 a 55 años y el sexo masculino predominaron en el estudio; las algias vertebrales, gonartrosis y poliartralgias fueron más frecuentes; además de las corrientes analgésicas, se empleó láser y kinesioterapia pasiva con mejor respuesta del dolor, la escoliosis antálgica y la limitación funcional. Se obtuvo un 93,8 por ciento de recuperación con evaluación aceptable, lo que constituyó un impacto social en ese medio.

A pre-experimental intervention before-after study was carried out to patients older than 15 years, affected by Osteomioarticular System diseases in the Physiotherapy Department of the Integral Field Hospital No.15, 27 of November Oghi, Pakistan with the aim of identifying and applying treatment by means of high tech equipment, during the period from December 26, 2005 to February 5, 2006. The sample consisted of 515 patients. The studied variables were age, sex, physiotherapeutic pathologies, techniques, symptoms and signs, and final evaluation; It was concluded that the group of ages from 46 to 55 years and the masculine sex were most prominent in this study; being spinal algias: gonarthrosis and polyarthralgias, more frequent, the analgesic currents: laser and passive kinesitherapy were more used, with better response to pain, the antalgic scoliosis and the functional limitation shown a 93.8 percent of recovery with acceptable evaluation, which constituted a social impact in that means.

Identificación e intervención terapéutica en afecciones del Sistema Osteomioarticular en Oghi, Pakistán / Identification and therapeutic intervention in affections of the Osteomioarticular System in Oghi, Pakistan

Se realizó un estudio de intervención pre-experimental del tipo antes-después en el Departamento de Fisioterapia del Hospital Integral de Campaña No.15 27 de Noviembre en Oghi, Pakistán, en el período de tiempo comprendido desde el 26 de diciembre de 2005 hasta el 5 de febrero del 2006 en pacientes mayores de 15 años afectados por enfermedades del sistema osteomioarticular, con el objetivo de identificar y aplicar tratamiento con equipos de alta tecnología, la muestra quedó conformada por 515 pacientes. Las variables estudiadas fueron edad, sexo, patologías, técnicas fisioterapéuticas, síntomas y signos y evaluación final; se concluye que el grupo de edad de 46 a 55 años y el sexo masculino predominaron en el estudio; las algias vertebrales, gonartrosis y poliartralgias fueron más frecuentes; además de las corrientes analgésicas, se empleó láser y kinesioterapia pasiva con mejor respuesta del dolor, la escoliosis antálgica y la limitación funcional. Se obtuvo un 93,8 por ciento de recuperación con evaluación aceptable, lo que constituyó un impacto social en ese medio(AU)

A pre-experimental intervention before-after study was carried out to patients older than 15 years, affected by Osteomioarticular System diseases in the Physiotherapy Department of the Integral Field Hospital No.15, 27 of November Oghi, Pakistan with the aim of identifying and applying treatment by means of high tech equipment, during the period from December 26, 2005 to February 5, 2006. The sample consisted of 515 patients. The studied variables were age, sex, physiotherapeutic pathologies, techniques, symptoms and signs, and final evaluation; It was concluded that the group of ages from 46 to 55 years and the masculine sex were most prominent in this study; being spinal algias: gonarthrosis and polyarthralgias, more frequent, the analgesic currents: laser and passive kinesitherapy were more used, with better response to pain, the antalgic scoliosis and the functional limitation shown a 93.8 percent of recovery with acceptable evaluation, which constituted a social impact in that means(AU)