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LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.
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Epóxido Hidrolasas , Plasma , Humanos , Neutrófilos , PielRESUMEN
OBJECTIVE: Brief interventions could reduce adolescents' risk of depression and alcohol-related harms, but evidence of their feasibility and acceptability for low-and middle-income countries is lacking. To address this gap, we conducted a feasibility trial of the ASPIRE intervention, a four-session multi-component counselling intervention for South African adolescents. METHOD: We recruited 117 adolescents who met our inclusion criteria. Participants were randomly assigned to the ASPIRE intervention or a comparison condition. Outcomes were assessed at baseline, six-week, and three-month post-randomization time points. Primary outcomes were based on feasibility of study procedures and intervention delivery (assessed on seven predetermined progression criteria). Clinical outcomes (risk of depression and alcohol harms) were secondary. RESULTS: Despite modifications to all study procedures arising from Covid-19 restrictions, five of the seven key progression criteria were fully met, including: feasibility of data collection and outcome measures, counsellor competencies, randomization and blinding, adverse advents, and acceptability of the intervention. The progression criterion for recruitment and intervention retention were not fully met. CONCLUSION: Findings suggest that the ASPIRE intervention was generally feasible to deliver and acceptable to adolescents. However, modifications to the trial design and intervention delivery are needed to optimize the validity of a definitive randomized controlled trial of the ASPIRE intervention.
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Intervención en la Crisis (Psiquiatría) , Depresión , Humanos , Adolescente , Depresión/terapia , Estudios de Factibilidad , Sudáfrica , ConsejoRESUMEN
LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5-2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20-80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after â¼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T1/2) was observed. The long T1/2 and saturable binding to blood cells, which causes a highly nonlinear blood-to-plasma distribution, reflect a strong impact of target binding on drug distribution at lower concentrations. Skin biopsy and blister fluid concentration data indicated saturable binding in the former but not the latter, suggesting saturable binding in tissues beyond blood. Major excretion of LYS006 (â¼90% of dose) through urine at steady state triggered renal transporter investigations that identified LYS006 as a substrate of organic anion transporter (OAT)3, OAT4, breast cancer resistance protein, and multidrug resistance-associated protein 4. Seven metabolites were identified in human plasma and urine, comprising only 4% of the dose recovered in urine at steady state. SIGNIFICANCE STATEMENT: Pharmacokinetic data from a first-in-human study combined with in vitro work support dose and regimen selection for patient studies with LYS006 and provide guidance on drug interaction investigations and other clinical pharmacology work needed for further development. Mass balance information at steady state without the use of a radiolabel, skin concentrations, and identification of the major clearance pathway, as well as the transporters driving elimination, make this a particularly conclusive early study despite nonlinear pharmacokinetics impacted by target binding.
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Proteínas de Neoplasias , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Interacciones Farmacológicas , Administración OralRESUMEN
Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single-virus or -gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human virus genes. We found that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-κB and interferon regulatory factor 3 (IRF3). We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins. IMPORTANCE Infectious diseases caused by viral pathogens exacerbate health care and economic burdens. Numerous viral biomolecules suppress the human innate immune system, enabling viruses to evade an immune response from the host. Despite our current understanding of viral replications and immune evasion, new viral proteins, including those encoded by uncultivated viruses or emerging viruses, are being unearthed at a rapid pace from large-scale sequencing and surveillance projects. The use of medium- and high-throughput functional assays to characterize immunosuppressive functions of viral proteins can advance our understanding of viral replication and possibly treatment of infections. In this study, we assembled a large viral-gene library from diverse viral families and developed a high-content assay to test for inhibition of innate immunity pathways. Our work expands the tools that can rapidly link sequence and protein function, representing a practical step toward early-stage evaluation of emerging and understudied viruses.
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Inmunidad Innata , Virus , Humanos , FN-kappa B , Evasión Inmune , Virus/genética , Proteínas Virales/genética , Genes ViralesAsunto(s)
Glucurónidos , Zidovudina , Ácidos Indolacéticos , Penicilina G , Piridinas , Receptores de ProstaglandinaRESUMEN
BACKGROUND: Like many low- and middle-income countries, almost half of the proportion of the South African population is under the age of 25. Given the peak age of onset for most mental health problems is in adolescence, it is vital that adolescents have access to mental health counselling. There are several initiatives to increase access to mental health counselling in South Africa, primarily through the integration of counselling for common mental disorders (CMD) into primary health care services, but adolescents (15-18 years of age) generally do not utilize these services. To address this gap, we will undertake a study to explore the feasibility of conducting a trial of the effectiveness of a community-based mental health counselling intervention for adolescents at-risk for a CMD. METHODS: The study is a feasibility trial of the ASPIRE intervention, a four-session blended multi-component counselling intervention adapted for South African adolescents at risk for depression and alcohol use disorders. We will enrol 100 adolescents from community settings and randomly assign them to the ASPIRE intervention or a comparison condition. Feasibility measures, such as rates of recruitment, consent to participate in the trial and retention, will be calculated. Qualitative interviews with participants and counsellors will explore the acceptability of the intervention. The primary outcomes for a subsequent trial would be reductions in symptoms of depression and days of heavy drinking which will be measured at baseline, 6 weeks, and 3 months post-randomization. DISCUSSION: This feasibility trial using a mixed-methods design will allow us to determine whether we can move forward to a larger effectiveness trial of the ASPIRE intervention. TRIAL REGISTRATION: The trial is registered with the Pan African Clinical Trials Registry (PACTR20200352214510). Registered 28 February 2020-retrospectively registered, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9795.
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Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.
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Adyuvantes Farmacéuticos/metabolismo , Ácidos Indolacéticos/metabolismo , Riñón/metabolismo , Tasa de Depuración Metabólica/fisiología , Probenecid/metabolismo , Piridinas/metabolismo , Eliminación Renal/fisiología , Adyuvantes Farmacéuticos/farmacología , Adulto , Estudios Cruzados , Interacciones Farmacológicas/fisiología , Femenino , Humanos , Ácidos Indolacéticos/farmacología , Riñón/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Probenecid/farmacología , Piridinas/farmacología , Eliminación Renal/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation. METHODS: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue. DISCUSSION: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Adolescente , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Sudáfrica , Uganda , ZimbabweRESUMEN
This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.
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Ciclosporina/farmacocinética , Ácidos Indolacéticos/farmacocinética , Piridinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ciclosporina/administración & dosificación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Ácidos Indolacéticos/administración & dosificación , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Adulto JovenRESUMEN
This study aimed to assess the association between suicidal ideation among mothers living with HIV in Zimbabwe and the cognitive development of their children. Participants were mother-child dyads recruited from two rural districts in Zimbabwe. Data were collected at baseline and 12 months follow-up. Suicidal ideation was assessed using item-10 from the Edinburgh postnatal depression scale. Mixed-effects linear regression was used to assess the association of child cognitive outcomes at follow-up (using the Mullen scales of early learning) with maternal suicidal ideation. Mothers with suicidal ideation at baseline (n = 171) tended to be younger, unmarried, experienced moderate to severe hunger, had elevated parental stress and depression symptoms compared with non-suicidal mothers (n = 391). At follow-up, emerging maternal suicidal ideation was associated with poorer child cognitive outcomes (adjusted mean difference - 6.1; 95% CI - 10.3 to - 1.8; p = 0.03). Suicidal ideation affects child cognitive development and should be addressed, particularly in HIV positive mothers.
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Infecciones por VIH , Ideación Suicida , Adulto , Niño , Cognición , Depresión/epidemiología , Femenino , Humanos , Estudios Longitudinales , Madres , Embarazo , Factores de Riesgo , Zimbabwe/epidemiologíaRESUMEN
BACKGROUND: HIV infection in a family may affect optimum child development. Our hypothesis is that child development outcomes among HIV-exposed infants will be improved through a complex early childhood stimulation (ECS) programme, and income and loans saving programme for HIV positive parents. METHODS: The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe. Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a group ECS parenting programme, an internal savings and lending scheme (ISALS) and case-management home visits by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0-24 months) where the infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process evaluation was conducted. DISCUSSION: The results of this cluster-randomised trial will provide important information regarding the effects of multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited environments. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry ( www.pactr.org ), registration number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered).
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Desarrollo Infantil , Crianza del Niño , Infecciones por VIH/terapia , Padres/educación , Adulto , Fármacos Anti-VIH/uso terapéutico , Cognición , Manejo de la Enfermedad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Infecciones por VIH/psicología , Humanos , Renta , Lactante , Recién Nacido , Pobreza , Evaluación de Programas y Proyectos de Salud , Población Rural , ZimbabweRESUMEN
Bio and aqueous applications of ionic liquids (IL) such as catalysis in micelles formed in aqueous IL solutions or extraction of chemicals from biologic materials rely on surface-active and self-assembly properties of ILs. Here, we discuss qualitative relations of the interfacial and bulk structuring of a water-soluble surface-active IL ([C8MIm][Cl]) on chemically controlled surfaces over a wide range of water concentrations using both force probe and X-ray scattering experiments. Our data indicate that IL structuring evolves from surfactant-like surface adsorption at low IL concentrations, to micellar bulk structure adsorption above the critical micelle concentration, to planar bilayer formation in ILs with <1 wt % of water and at high charging of the surface. Interfacial structuring is controlled by mesoscopic bulk structuring at high water concentrations. Surface chemistry and surface charges decisively steer interfacial ordering of ions if the water concentration is low and/or the surface charge is high. We also demonstrate that controlling the interfacial forces by using self-assembled monolayer chemistry allows tuning of interfacial structures. Both the ratio of the head group size to the hydrophobic tail volume as well as the surface charging trigger the bulk structure and offer a tool for predicting interfacial structures. Based on the applied techniques and analyses, a qualitative prediction of molecular layering of ILs in aqueous systems is possible.
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BACKGROUND: Since the introduction of single incision laparoscopy (SIL), there has been disagreement among professional societies regarding a general recommendation for the use of this minimally invasive method. OBJECTIVES: Determination of evidence-based advantages of SIL compared to multiport laparoscopy (MPL). MATERIALS AND METHODS: Description of recent technical developments and evaluation of prospective randomized clinical trials and valid meta-analyses with regard to organ-specific procedures. In addition, an expert opinion is provided based on 4209 SIL interventions. RESULTS: SIL is nowadays applied in all fields of general and visceral surgery. Due to the initial enthusiasm, methodologically weak studies were often published in the literature. Any beneficial effect of SIL on reduced perioperative morbidity is not clearly confirmed, yet. A better cosmetic outcome is either obvious (in SIL liver resections) or nearly unverifiable (in SIL cholecystectomies). CONCLUSION: SIL has proven feasible and safe after getting through the learning curve. Scientific evidence is currently insufficient to justify SIL without reservation in particular without the individual technical experience of the surgeon.
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Laparoscopía/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Colecistectomía Laparoscópica/instrumentación , Colecistectomía Laparoscópica/métodos , Estética , Medicina Basada en la Evidencia , Hepatectomía/instrumentación , Hepatectomía/métodos , Humanos , Laparoscopía/instrumentación , Curva de Aprendizaje , Metaanálisis como Asunto , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Secondary bladder neck sclerosis represents one of the more frequent complications following endoscopic, open, and other forms of minimally invasive prostate surgery. Therapeutic decisions depend on the type of previous intervention (e.g., radical prostatectomy, TURP, HoLEP, radiotherapy, HIFU) and on associated complications (e.g., incontinence, fistula). Primary treatment in most cases represents an endoscopic bilateral incision. No specific advantages of any type of the applied energy (i.e., mono-/bipolar HF current, cold incision, holmium/thulium YAG laser) could be documented. Adjuvant measures such as injection of corticosteroids or mitomycin C have not been helpful in clinical routine. In case of first recurrence, a transurethral monopolar or bipolar resection can usually be performed. Recently, the ablation of the scared tissue using bipolar vaporization has been recommended providing slightly better long-term results. Thereafter, surgical reconstruction is strongly recommended using an open, laparoscopic, or robot-assisted approach. Depending on the extent of the bladder neck sclerosis and the underlying prostate surgery, a Y-V/T-plasty, urethral reanastomosis, or even a radical prostatectomy with new urethravesical anastomosis should be performed. Stent implantation should be reserved for patients who are not suitable for surgery. The final palliative measure is a cystectomy with urinary diversion or a (continent) cystostomy.
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Terapia por Láser , Complicaciones Posoperatorias/patología , Prostatectomía , Resección Transuretral de la Próstata , Obstrucción del Cuello de la Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Humanos , Masculino , Complicaciones Posoperatorias/cirugía , Reoperación , Factores de Riesgo , Esclerosis , Obstrucción del Cuello de la Vejiga Urinaria/cirugíaRESUMEN
Foot pad dermatitis (FPD) is a widespread disease in poultry and important for economic and animal welfare reasons. It is well recognized that using non-starch polysaccharide (NSP)-degrading enzymes can affect excreta/litter quality (not only in terms of moisture content but also regarding water evaporation) at high stocking densities and might help to prevent FPD and further negative effects of NSP. This study aimed to evaluate effects of a carbohydrase complex (CC) in different dietary inclusion rates on performance, digesta viscosity and foot pad health in broilers from 9 to 37 days of life. In total, 240 broilers were divided into 12 floor pens of 20 birds and received one of four different experimental diets. The four wheat- and soyabean meal-based diets only differed in the inclusion rate of CC: 0%, 50%, 100% and 500% of the recommended dose of CC (Endo-1,4-ß-xylanase and Endo-1,3(4)-ß-glucanase; 50 g/t). The addition of CC led to a significant decrease of digesta viscosity in the proximal small intestine, a tendency of improved feed conversion ratio, and significantly favoured FPD-scores (Treatment 2). At the higher tested inclusion rate of CC (500% of recommended dose), the FPD score was worser than in the treatments with 50% and 100% of the recommended enzyme dosage. No improvements among treatments were observed in terms of body weight and dry matter content of excreta and litter at the end of trial. The low positive effects on foot pad health in this study were presumably associated with the low NSP content in the experimental diets (soluble arabinoxylans: 7.38 g/kg as fed). In conclusion, the addition of the evaluated CC reduced digesta viscosity. An improvement of foot pad health could only be seen in the treatment with 50% of the recommended enzyme dosage in the diet.
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Alimentación Animal/análisis , Pollos , Enfermedades del Pie/veterinaria , Contenido Digestivo/química , Glicósido Hidrolasas/farmacología , Enfermedades de las Aves de Corral/prevención & control , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Dermatitis/prevención & control , Dermatitis/veterinaria , Dieta/veterinaria , Suplementos Dietéticos , Endo-1,4-beta Xilanasas , Enfermedades del Pie/prevención & control , Glicósido Hidrolasas/administración & dosificación , ViscosidadRESUMEN
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.
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Hepatocitos/metabolismo , Ácidos Indolacéticos/farmacocinética , Microsomas Hepáticos/metabolismo , Piridinas/farmacocinética , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Biotransformación , Heces/química , Voluntarios Sanos , Humanos , Técnicas In Vitro , Ácidos Indolacéticos/sangre , Ácidos Indolacéticos/orina , Masculino , Tasa de Depuración Metabólica , Metaboloma , Persona de Mediana Edad , Unión Proteica , Piridinas/sangre , Piridinas/orina , Eliminación Renal , Distribución Tisular , Adulto JovenRESUMEN
BACKGROUND: The international multicentre registry ECSPECT (European Consensus of Single Port Expertise in Colorectal Treatment) was established to evaluate the general feasibility and safety of single-port colorectal surgery with regard to preoperative risk assessment. METHODS: Consecutive patients undergoing single-port colorectal surgery were enrolled from 11 European centres between March 2010 and March 2014. Data were analysed to assess patient-, technique- and procedure-dependent parameters. A validated sex-adjusted risk chart was developed for prediction of single-port colorectal surgery-related conversion and complications. RESULTS: Some 1769 patients were enrolled, 937 with benign and 832 with malignant conditions. Procedures were completed without additional trocars in 1628 patients (92·0 per cent). Conversion to open surgery was required in 75 patients (4·2 per cent) and was related to male sex and ASA fitness grade exceeding I. Conversions were more frequent in pelvic procedures involving the rectum compared with abdominal procedures (8·1 versus 3·2 per cent; odds ratio 2·69, P < 0·001). Postoperative complications were observed in a total of 224 patients (12·7 per cent). Independent predictors of complications included male sex (P < 0·001), higher ASA grade (P = 0·006) and rectal procedures (P = 0·002). The overall 30-day mortality rate was 0·5 per cent (8 of 1769 patients); three deaths (0·2 per cent; 1 blood loss, 2 leaks) were attributable to surgical causes. CONCLUSION: The feasibility and safety, conversion and complication profile demonstrated here provides guidance for patient selection.