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Background: Oral medications, intravenous medications, and invasive interventions are effective means of neuropathic pain control. In patients with pain refractory to more conventional approaches, cingulum bundle ablation is an alternative treatment modality not routinely considered by providers. Case Description: A 42-year-old woman with history of cervical cancer in remission presented with intractable left lower extremity pain. Workup revealed radiation-induced left iliopsoas osteosarcoma complicated by deep venous occlusion and thrombosis. Her pain remained intractable to pharmacologic therapies and more invasive pain control interventions. A multidisciplinary decision was made to pursue bilateral subcortical cingulum bundle radiofrequency ablation. After a technically successful surgery, the patient exhibited improved pain control as evidenced by a decline in her numerical rating scale of pain and analgesic medication requirements. Conclusion: Cancer-related neuropathic pain often requires treatment with multiple modalities involving multidisciplinary teams. In select refractory cases, cingulum bundle ablation may be an effective alternative treatment modality.
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Dolor en Cáncer , Neoplasias , Neuralgia , Dolor Intratable , Humanos , Adulto , Femenino , Manejo del Dolor , Dolor Intratable/etiología , Resultado del Tratamiento , Neoplasias/complicacionesRESUMEN
An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and several types of somatic cells. Among these, granulosa cells play a key role in follicle formation and support for oogenesis. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human induced pluripotent stem cells (hiPSCs), a method of generating granulosa cells has been elusive. Here, we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of hiPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is sufficient to generate granulosa-like cells. Our granulosa-like cells have transcriptomes similar to human fetal ovarian cells and recapitulate key ovarian phenotypes including follicle formation and steroidogenesis. When aggregated with hPGCLCs, our cells form ovary-like organoids (ovaroids) and support hPGCLC development from the premigratory to the gonadal stage as measured by induction of DAZL expression. This model system will provide unique opportunities for studying human ovarian biology and may enable the development of therapies for female reproductive health.
Ovaries are responsible for forming the eggs humans and other mammals need to reproduce. Once mature, the egg cell is released into the fallopian tube where it can be potentially fertilized by a sperm. Despite their crucial role, how eggs are made in the ovary is poorly understood. This is because ovaries are hard to access, making it difficult to conduct experiments on them. To overcome this, researchers have built artificial ovaries in the laboratory using stem cells from the embryos of mice which can develop into all cell types in the adult body. By culturing these embryonic stem cells under special conditions, researchers can convert them in to the two main cell types of the developing ovary: germ cells which go on to form eggs, and granulosa cells which help eggs grow and mature. The resulting lab-grown ovary can make eggs that produce live mice when fertilized. This approach has also been applied to human induced pluripotent stem cells (iPSCs), adult human cells which have been reprogrammed to a stem-like state. While this has produced human germ cells, generating human granulosa cells has been more challenging. Here, Pierson Smela, Kramme et al. show that activating a specific set of transcription factors (proteins that switch genes on or off) in iPSCs can make them transition to granulosa cells. First, the team tested random combinations of 35 transcription factors which, based on previous literature and genetic data, were likely to play a role in the formation of granulosa cells. This led to the identification of a small number of factors that caused the human iPSCs to develop features and carry out roles seen in mature granulosa cells; this includes producing an important reproductive hormone and supporting the maturation of germ cells. Pierson Smela, Kramme et al. found that growing these granulosa-like cells together with germ cells (also generated via iPSCs) resulted in structures similar to ovarian follicles which help eggs develop. These findings could help researchers build stable systems for studying how granulosa cells behave in human ovaries. This could lead to new insights about reproductive health.
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Células Madre Pluripotentes Inducidas , Factores de Transcripción , Humanos , Femenino , Factores de Transcripción/metabolismo , Ovario/metabolismo , Oogénesis , Diferenciación CelularRESUMEN
PURPOSE: To qualitatively explore exercise barriers and facilitators experienced by rural female cancer survivors from the program interventionist and recipient perspective for the purpose of enhancing exercise program implementation and uptake in rural settings. METHODS: A descriptive qualitative study design was utilized. Focus groups were conducted prior to implementation of an evidence-based exercise program by a rural non-research cancer clinical site. Nineteen rural female cancer survivors (mean age = 61.7 ± 10.9 years) and 11 potential interventionists (mean age = 42.3 ± 15.3 years) completed focus groups (stratified by participant role). Focus groups were audio recorded, transcribed, coded, and analyzed using inductive thematic analysis with NVivo 11. RESULTS: Cancer survivors identified 12 barrier themes (cancer specific adverse effects, lack of support, lack of knowledge, perceived negative aspects of exercise, cost, lack of resources, motivation, inconvenience, lack of program flexibility, time, weather, safety) and eight facilitator themes (knowledge, ease of access, resources, awareness, cost, options, organized, fun) related to exercise. Interventionists identified seven barrier themes (cost, transportation, lack of cancer survivor and interventionist knowledge, fear, motivation, lack of support, lack of resources) and four facilitator themes (resources, support, knowledge, motivation). Narratives revealed differing role-specific perspectives on shared themes between survivors and interventionists as well as potential implementation strategies for enhancing exercise participation and exercise program uptake among rural female cancer survivors. CONCLUSION: Exploring multi-level stakeholder perspectives on cancer survivors' exercise needs and related strategies yields important information for organizations to consider when implementing exercise programs in rural contexts.
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Terapia por Ejercicio/métodos , Neoplasias/terapia , Adulto , Supervivientes de Cáncer , Femenino , Grupos Focales , Humanos , Motivación , Neoplasias/mortalidad , Investigación Cualitativa , Población RuralRESUMEN
This prospective cohort study enrolled people living with HIV initiating antiretroviral therapy (ART) containing the integrase inhibitors, dolutegravir (DTG) or elvitegravir (EVG) and administered the Montreal Cognitive Assessment (MoCA) at baseline and again after approximately six months to compare changes in MoCA scores. The proportion of patients found to have cognitive impairment, as indicated by a MoCA score <26/30, on each agent were also compared and comparisons were made between changes in each domain assessed by the MoCA (visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation). Thirty-five evaluable participants were enrolled, 18 on DTG and 17 on EVG. The median [interquartile range(IQR)] age was 44 (32 to 54) years, 63% were male, 57% were African American. The median (IQR) MoCA score at baseline was 25 (23 to 27) with no difference between groups (p=0.249). The median (IQR) change in MoCA score was 0 (-1 to 2) for DTG and 1 (0 to 3) for EVG (p = 0.183). Of those on DTG, 8 (44%) had MoCA scores <26 on follow-up compared to 11 (65%) on EVG (p = 0.229). There were no significant differences in changes in any of the individual MoCA domains.
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Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Adulto , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , Estudios Prospectivos , Piridonas , QuinolonasRESUMEN
Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs.
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Enfermedades Transmisibles , Infecciones por VIH , Medicina , Infecciones por VIH/tratamiento farmacológico , Humanos , Pacientes Internos , Políticas , Estados UnidosRESUMEN
Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP's active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = -0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.
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Adenina/análogos & derivados , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , VIH/efectos de los fármacos , Organofosfatos/farmacocinética , Profilaxis Pre-Exposición , Personas Transgénero , Adenina/administración & dosificación , Adenina/farmacocinética , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Monitoreo de Drogas , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Persona de Mediana Edad , Organofosfatos/administración & dosificación , Distribución Tisular , Resultado del Tratamiento , Adulto JovenRESUMEN
The antiretroviral combination of emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) was approved by the U.S. Food and Drug Administration for use as pre-exposure prophylaxis (PrEP) in individuals at high risk for acquiring human immunodeficiency virus (HIV) in July 2012. Since then, Centers for Disease Control and Prevention guidelines for the use of PrEP have been published and implemented into clinical practice throughout the United States. A number of published open-label and PrEP demonstration projects have evaluated the real-world use of PrEP including analysis of the barriers to its use and addressing major concerns. Despite the approval of FTC/TDF for PrEP, its use for this indication relies on patient and provider acceptance, and its effectiveness requires patient adherence and retention in care during periods of high-risk behaviors. Concerns regarding the use of PrEP in healthy individuals persist and include medication adverse effects including renal dysfunction and bone mineral density loss; risk compensation leading to HIV infections, sexually transmitted infections, and unintended pregnancies; and the development of drug resistance in the event of seroconversion. The cost-effectiveness of PrEP continues to be assessed with the greatest cost-effectiveness remaining in those at highest risk of acquiring HIV. Additionally, cases of HIV acquisition in individuals who are adherent to PrEP highlight scenarios in which PrEP is not 100% effective including against the transmission of drug-resistant HIV strains. This review examines data on the implementation of PrEP outside the setting of clinical trials with the aim of providing clinicians with a summary of the current barriers and opportunities for PrEP use with a specific focus on the role of pharmacists in the optimization of PrEP implementation.
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Fármacos Anti-VIH/uso terapéutico , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición/métodos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Análisis Costo-Beneficio , Prescripciones de Medicamentos/estadística & datos numéricos , Farmacorresistencia Viral Múltiple , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/efectos adversos , Infecciones por VIH/virología , Humanos , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: Integrase strand transfer inhibitors (INSTI) are currently being investigated for the treatment of HIV in pregnancy. The purpose of this study is to evaluate the differences in maternal and infant outcomes in HIV-positive mothers treated with INSTI-containing antiretroviral therapy (ART) during pregnancy compared to protease inhibitor (PI)-containing ART. METHODS: A retrospective, cohort study of INSTI- and PI-based ART used in pregnancy between 2007 and 2015 was performed. The primary objective was to evaluate the differences in viral load (VL) suppression prior to delivery. Secondary endpoints included time to and duration of VL suppression and safety parameters in both mothers and infants. For the primary analysis, the two arms were matched 1:2 INSTI to PI based on the presence or absence of viremia at the time of pregnancy determination. Additional analysis was performed on the entire matched and unmatched dataset. RESULTS: Twenty-one patients were matched (7 INSTI and 14 PI). There were no significant differences between groups with respect to the proportion of patients with VL suppression prior to delivery (71.4% INSTI vs. 92.9% PI, p = 0.247), and there were no significant differences in any of the secondary endpoints. Patients with documented adherence issues were statistically more likely to not be virologically suppressed prior to delivery (p = 0.002). CONCLUSION: No differences in efficacy or safety were found between patients treated with INSTIs compared to PIs. This study supports the further investigation of the use of INSTIs during pregnancy to reduce HIV transmission.
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In this paper we report new data on peat carbon (C), nitrogen (N) and phosphorus (P) concentrations and accumulation rates for 15 sites in the UK. Concentrations of C, N and P measured in peat from five ombrotrophic blanket mires, spanning 4000-10,000years to present were combined with existing nutrient data from ten Scottish ombrotrophic peat bogs to provide the first UK perspective on millennial scale macronutrient concentrations in ombrotrophic peats. Long-term average C, N and P concentrations (0-1.25m) for the UK are 54.8, 1.56 and 0.039wt%, of similar magnitude to the few published comparable sites worldwide. The uppermost peat (0-0.2m) is enriched in P and N (51.0, 1.86, and 0.070wt%) relative to the deeper peat (0.5-1.25m, 56.3, 1.39, and 0.027wt%). Long-term average (whole core) accumulation rates of C, N and P are 25.3±2.2gCm-2year-1 (mean±SE), 0.70±0.09gNm-2year-1 and 0.018±0.004gPm-2year-1, again similar to values reported elsewhere in the world. The two most significant findings are: 1) that a regression model of N concentration on P concentration and mean annual precipitation, based on global meta data for surface peat samples, can explain 54% of variance in N concentration in these UK peat profiles; and 2) budget calculations for the UK peat cores yield an estimate for long-term average N-fixation of 0.8gm-2year-1. Our UK results, and comparison with others sites, corroborate published estimates of N storage in northern boreal peatlands through the Holocene as ranging between 8 and 15Pg N. However, the observed correlation of N% with both mean annual precipitation and P concentration allows a potential bias in global estimates that do not take this into account. The peat sampling data set has been deposited at the NERC Data Centre (Toberman et al., 2016).
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Very high baseline HIV-1 RNA viral loads require potent and robust antiretroviral regimens to achieve virological suppression. The coformulated single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is recommended by the US Department of Health and Human Services for the treatment of HIV-1 in treatment-naive adults and adolescents regardless of baseline CD4(+) T-cell count and viral load. We report two cases of HIV-infected, treatment-naive patients, with baseline HIV-1 RNA viral loads >1,000,000 copies/ml who were initiated on the single tablet regimen EVG/COBI/FTC/TDF, but failed to attain viral load suppression and developed resistance to the components of EVG/COBI/FTC/TDF.
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Fármacos Anti-VIH/uso terapéutico , Combinación Elvitegravir, Cobicistat, Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , ARN Viral/sangre , Carga Viral , Fármacos Anti-VIH/administración & dosificación , Combinación Elvitegravir, Cobicistat, Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The riverine transport of particulate organic matter (POM) is a significant flux in the carbon cycle, and affects macronutrients and contaminants. We used radiocarbon to characterise POM at 9 riverine sites of four UK catchments (Avon, Conwy, Dee, Ribble) over a one-year period. High-discharge samples were collected on three or four occasions at each site. Suspended particulate matter (SPM) was obtained by centrifugation, and the samples were analysed for carbon isotopes. Concentrations of SPM and SPM organic carbon (OC) contents were also determined, and were found to have a significant negative correlation. For the 7 rivers draining predominantly rural catchments, PO14C values, expressed as percent modern carbon absolute (pMC), varied little among samplings at each site, and there was no significant difference in the average values among the sites. The overall average PO14C value for the 7 sites of 91.2 pMC corresponded to an average age of 680 14C years, but this value arises from the mixing of differently-aged components, and therefore significant amounts of organic matter older than the average value are present in the samples. Although topsoil erosion is probably the major source of the riverine POM, the average PO14C value is appreciably lower than topsoil values (which are typically 100 pMC). This is most likely explained by inputs of older subsoil OC from bank erosion, or the preferential loss of high-14C topsoil organic matter by mineralisation during riverine transport. The significantly lower average PO14C of samples from the River Calder (76.6 pMC), can be ascribed to components containing little or no radiocarbon, derived either from industrial sources or historical coal mining, and this effect is also seen in the River Ribble, downstream of its confluence with the Calder. At the global scale, the results significantly expand available information for PO14C in rivers draining catchments with low erosion rates.
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Carbono/análisis , Monitoreo del Ambiente , Ríos/química , Contaminantes Químicos del Agua/análisis , Material Particulado/análisisRESUMEN
BACKGROUND: Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women. METHODS: A total of 8 healthy females given DTG 50 mg daily for 5-7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices. RESULTS: BP areas under the concentration-time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9-10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF. CONCLUSIONS: DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.
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Fármacos Anti-VIH/farmacocinética , Cuello del Útero/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Vagina/efectos de los fármacos , Adolescente , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Femenino , Infecciones por VIH/prevención & control , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/sangre , Inhibidores de Integrasa VIH/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Oxazinas , Piperazinas , Piridonas , Adulto JovenRESUMEN
OBJECTIVES: To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN: A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS: Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS: BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and â¼2-fold greater than the PA-IC90. RF AUCs were â¼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. CONCLUSIONS: DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained â¼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.
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Colon/efectos de los fármacos , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Recto/efectos de los fármacos , Semen/efectos de los fármacos , Adulto , Colon/inmunología , Relación Dosis-Respuesta a Droga , Inhibidores de Integrasa VIH/sangre , Compuestos Heterocíclicos con 3 Anillos/sangre , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , Recto/inmunología , Semen/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence. METHODS: Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined. RESULTS: The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively. CONCLUSIONS: ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence.
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Adenina/análogos & derivados , Fármacos Anti-VIH/sangre , Células Sanguíneas/metabolismo , Desoxicitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Organofosfonatos/sangre , Adenina/sangre , Adenina/farmacocinética , Adulto , Fármacos Anti-VIH/farmacocinética , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Difosfatos/sangre , Difosfatos/farmacocinética , Emtricitabina , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Organofosfonatos/farmacocinética , Polifosfatos/sangre , Polifosfatos/farmacocinética , TenofovirRESUMEN
The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real-time. Although the development of drug resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.
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PURPOSE OF REVIEW: The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development). RECENT FINDINGS: Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400 âmg dosing has been shown to be clinically superior to 800 âmg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions. SUMMARY: Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.
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Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , VIH-1/enzimología , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Oxazinas , Piperazinas , Piridonas , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Quinolonas/administración & dosificación , Quinolonas/farmacocinética , Raltegravir Potásico , Estados UnidosRESUMEN
The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence.
Asunto(s)
Antiinfecciosos Locales/farmacología , Antiinfecciosos Locales/farmacocinética , Infecciones por VIH/prevención & control , VIH , Adenina/análogos & derivados , Adenina/química , Adenina/farmacocinética , Adenina/farmacología , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Antiinfecciosos Locales/química , Femenino , Humanos , Ratones , Organofosfonatos/química , Organofosfonatos/farmacocinética , Organofosfonatos/farmacología , Tenofovir , Resultado del Tratamiento , Cremas, Espumas y Geles Vaginales/administración & dosificación , Cremas, Espumas y Geles Vaginales/farmacocinéticaRESUMEN
BACKGROUND: Adequate bone volume is imperative for the osseointegration of endosseous implants, but postextraction resorption and remodeling may challenge implant placement. The use of bone biomaterials has been advocated to fill extraction sites and to enhance primary implant stability during osseointegration. The objective of the case series was to evaluate bone formation histologically and biomechanically in extraction sites following implantation of three commercially available bone biomaterials to compare their ability to allow guided bone regeneration. METHODS: Thirty-six periodontally involved teeth were extracted from eight healthy non-smoking subjects. At least two bone biomaterials, a synthetic sponge based on polylactic-polyglycolic acid technology (FIS), bovine porous bone mineral (BPBM), or a natural coral derivative physically and chemically transformed into a calcium carbonate ceramic (COR), and one non-grafted control were applied to the extraction sockets within each subject and were covered by an expanded polytetrafluoroethylene device. The devices were removed after 2 months, and trephine biopsies were obtained from each site 4 months later. At that time, endosseous implants were placed in 25 of the sites, and healing abutments were placed; measurements were taken 4 to 6 months later with an electronic mobility testing device. RESULTS: The percentage of residual biomaterial was 5.6% +/- 8.9% for FIS (P <0.001), 20.2% +/- 17.0% for BPBM (P <0.05), and 12.0% +/- 16.4% for COR (P <0.001). The amount of residual biomaterial after 6 months showed a significant relationship with the insertion torque measurements during the first third of implant insertion (P <0.05) and with values of the electronic mobility testing device at the abutment connection (P = 0.05). Histologically, new bone apposition was seen on BPBM particles. FIS sites showed similar ingrowth of blood vessels and osteocytes as empty controls. CONCLUSION: All sites revealed good primary stability at implant insertion and proper implant rigidity at abutment placement, indicating that early implant osseointegration was not influenced by the application of bone biomaterials used in this study.
Asunto(s)
Materiales Biocompatibles , Regeneración Ósea , Sustitutos de Huesos , Implantación Dental Endoósea , Regeneración Tisular Guiada Periodontal/métodos , Alveolo Dental/cirugía , Adulto , Pérdida de Hueso Alveolar/prevención & control , Animales , Matriz Ósea/trasplante , Carbonato de Calcio , Bovinos , Implantes Dentales , Retención de Prótesis Dentales , Femenino , Humanos , Ácido Láctico , Masculino , Membranas Artificiales , Persona de Mediana Edad , Minerales , Oseointegración , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Extracción DentalRESUMEN
"Golden Rice" is a variety of rice engineered to produce beta-carotene (pro-vitamin A) to help combat vitamin A deficiency, and it has been predicted that its contribution to alleviating vitamin A deficiency would be substantially improved through even higher beta-carotene content. We hypothesized that the daffodil gene encoding phytoene synthase (psy), one of the two genes used to develop Golden Rice, was the limiting step in beta-carotene accumulation. Through systematic testing of other plant psys, we identified a psy from maize that substantially increased carotenoid accumulation in a model plant system. We went on to develop "Golden Rice 2" introducing this psy in combination with the Erwinia uredovora carotene desaturase (crtI) used to generate the original Golden Rice. We observed an increase in total carotenoids of up to 23-fold (maximum 37 microg/g) compared to the original Golden Rice and a preferential accumulation of beta-carotene.