RESUMEN
BACKGROUND: Interleukin-23 is thought to be critical to the pathogenesis of psoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal antibody that inhibits interleukin-23 by specifically targeting the p19 subunit and thus prevents interleukin-23 signaling, and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, in patients with moderate-to-severe plaque psoriasis. METHODS: We randomly assigned a total of 166 patients to receive subcutaneous injections of risankizumab (a single 18-mg dose at week 0 or 90-mg or 180-mg doses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). The primary end point was a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12. RESULTS: At week 12, the percentage of patients with a 90% or greater reduction in the PASI score was 77% (64 of 83 patients) for risankizumab (90-mg and 180-mg groups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab (P<0.001); the percentage of patients with a 100% reduction in the PASI score was 45% in the pooled 90-mg and 180-mg risankizumab groups, as compared with 18% in the ustekinumab group. Efficacy was generally maintained up to 20 weeks after the final dose of 90 or 180 mg of risankizumab. In the 18-mg and 90-mg risankizumab groups and the ustekinumab group, 5 patients (12%), 6 patients (15%), and 3 patients (8%), respectively, had serious adverse events, including two basal-cell carcinomas and one major cardiovascular adverse event; there were no serious adverse events in the 180-mg risankizumab group. CONCLUSIONS: In this phase 2 trial, selective blockade of interleukin-23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT02054481 ).
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Interleucina-12/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Ustekinumab/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Psoriasis/clasificación , Cuero Cabelludo/patología , Índice de Severidad de la Enfermedad , Ustekinumab/efectos adversosRESUMEN
BACKGROUND: The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. INTERPRETATION: In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. FUNDING: Boehringer Ingelheim.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). METHODS: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. CONCLUSIONS: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. TRIAL REGISTRATION NUMBER: NCT02047110; Pre-results.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antirreumáticos/administración & dosificación , Espondilitis Anquilosante/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Prueba de Estudio Conceptual , Inducción de Remisión , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
PURPOSE: The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). METHODS: The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. RESULTS: Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). CONCLUSIONS: Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.
Asunto(s)
Ligando de CD40/genética , Trasplante de Células Madre Hematopoyéticas , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Mutación/genética , Sistema de Registros , Adolescente , Adulto , Niño , Preescolar , Diarrea , Femenino , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/mortalidad , Síndrome de Inmunodeficiencia con Hiper-IgM/terapia , Masculino , Persona de Mediana Edad , Neutropenia , Análisis de Supervivencia , Estados Unidos , Adulto JovenRESUMEN
1,3,5-Trioxane-2,4,6-trione (cyclic trimer of CO2) is the product of a four-step synthesis: chlorination of isobutyraldehyde; cyclotrimerization of 2-chloro-2-methylpropanal; dehydochlorination of 2,4,6-tris(2-chloropropan)-2-yl-1,3,5-trioxane; ozonolysis at -80 °C of 2,4,6-tri(propan-2-ylidene)-1,3,5-trioxane. This trioxane-trione is detected in solution at temperatures between -80 to -40 °C, and its conversion to CO2 is monitored by (13)C NMR and FTIR. The CO2 trimer has a half-life of approximately 40 min at -40 °C.
RESUMEN
BACKGROUND: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Interleucina-23/metabolismo , Psoriasis/terapia , Piel/efectos de los fármacos , Adulto , Anticuerpos Monoclonales/efectos adversos , Biomarcadores/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/inmunología , Masculino , Persona de Mediana Edad , Placebos , Psoriasis/inmunología , Piel/patología , Resultado del TratamientoRESUMEN
In unstable emulsion systems, the determination of concentrations is a challenge. The use of standard methods like GC, HPLC, or titration is highly inaccurate and makes the acquisition of precise data for these systems complex. In addition, the handicap of high viscosity often comes into play. To overcome these fundamental limitations, the online FT-IR technique was identified in combination with chemometric modeling in order to improve accuracy. The reactor type used in this study is a bubble column reactor with up to four dispersed phases (solid catalyst, two liquid immiscible substrates, and a gaseous phase). The investigated reactions are solvent free enzymatic esterifications yielding myristyl myristate (10 mPa s) and high viscous polyglycerol-3-laurate (300-1500 mPa s), representative industrial products for cosmetic applications. For both reactions, chemometric models were successfully set up and reproducibly applied in the prediction of progress curves of a new set of experiments. This allows the automated determination of sensitive kinetic and thermodynamic data as well as reaction velocities in high viscous multiphase (bio)chemical systems.
Asunto(s)
Emulsiones/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Biotransformación , Enzimas/metabolismo , Esterificación , Cinética , Termodinámica , ViscosidadRESUMEN
BACKGROUND: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC). RESEARCH DESIGN AND METHODS: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared. RESULTS: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects. CONCLUSION: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.
Asunto(s)
Antiinflamatorios/farmacología , Benzamidas/farmacología , Glucocorticoides/farmacología , Piridinas/farmacología , Pirroles/farmacología , Receptores de Glucocorticoides/agonistas , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Ensayos Clínicos Fase I como Asunto , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Inflamación/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Osteocalcina/metabolismo , Prednisolona/efectos adversos , Prednisolona/farmacología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.
Asunto(s)
Cromosomas Humanos X , Hipergammaglobulinemia/genética , Hipergammaglobulinemia/inmunología , Inmunoglobulina G/sangre , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Adolescente , Ligando de CD40/genética , Niño , Preescolar , Diarrea/complicaciones , Ligamiento Genético , Humanos , Hipergammaglobulinemia/complicaciones , Hipergammaglobulinemia/terapia , Inmunoglobulina A/sangre , Inmunoglobulina M/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/terapia , Lactante , Infecciones/complicaciones , Masculino , Mutación , Neoplasias/complicaciones , Neutropenia/complicaciones , Sistema de RegistrosRESUMEN
The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150 mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r-alone group) were also pooled with group B subjects from 3 similar phase I drug-drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC(0-12,ss)) and steady-state maximum measured plasma concentration over a dosing interval (C(max,ss)) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C(12,ss)) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355.
Asunto(s)
Azepinas/farmacocinética , Inhibidores de la Proteasa del VIH/farmacocinética , Piridinas/farmacocinética , Pirimidinonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Ritonavir/farmacocinética , Adulto , Azepinas/efectos adversos , Azepinas/sangre , Disponibilidad Biológica , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/sangre , Semivida , Humanos , Lopinavir , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Piridinas/sangre , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Pirimidinonas/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/sangre , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Ritonavir/sangre , Adulto JovenRESUMEN
The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355/r (150/100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC(0-24,ss) , C(max,ss) and C(0-12,ss) were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC(0-24,ss) , C(max,ss) and C(24,ss) were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC/TDF resulted in an 18% increase in AUC(0-12,ss) , 14% increase in C(max,ss) and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacocinética , Azepinas/farmacocinética , Desoxicitidina/análogos & derivados , Inhibidores de la Proteasa del VIH/farmacocinética , Organofosfonatos/farmacocinética , Piridinas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Ritonavir/farmacocinética , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/sangre , Adenina/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa/efectos adversos , Azepinas/efectos adversos , Azepinas/sangre , Estudios Cruzados , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Interacciones Farmacológicas , Emtricitabina , Femenino , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/sangre , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Organofosfonatos/administración & dosificación , Organofosfonatos/efectos adversos , Organofosfonatos/sangre , Piridinas/efectos adversos , Piridinas/sangre , Reproducibilidad de los Resultados , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/sangre , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Ritonavir/sangre , Tenofovir , Adulto JovenRESUMEN
Classification is a very useful statistical tool for information extraction. In particular, multicategory classification is commonly seen in various applications. Although binary classification problems are heavily studied, extensions to the multicategory case are much less so. In view of the increased complexity and volume of modern statistical problems, it is desirable to have multicategory classifiers that are able to handle problems with high dimensions and with a large number of classes. Moreover, it is necessary to have sound theoretical properties for the multicategory classifiers. In the literature, there exist several different versions of simultaneous multicategory Support Vector Machines (SVMs). However, the computation of the SVM can be difficult for large scale problems, especially for problems with large number of classes. Furthermore, the SVM cannot produce class probability estimation directly. In this article, we propose a novel efficient multicategory composite least squares classifier (CLS classifier), which utilizes a new composite squared loss function. The proposed CLS classifier has several important merits: efficient computation for problems with large number of classes, asymptotic consistency, ability to handle high dimensional data, and simple conditional class probability estimation. Our simulated and real examples demonstrate competitive performance of the proposed approach.
RESUMEN
Deficiency in CD40 ligand (CD40L) expression is associated with impaired T cell immunity in mouse models and in humans. Previous studies have indicated that this is due to the failure of induction of extrinsic costimulatory molecules. However, other studies have suggested that CD40L is an intrinsic costimulatory molecule. The X-linked hyper-IgM syndrome (XHIM) is a primary immunodeficiency caused by mutations in CD40L, resulting in impaired Ab production and T cell immunity. CD4+ T cells from female carriers of XHIM express a variable degree of normal CD40L based on random X chromosome inactivation. We have examined T cells from XHIM carriers to investigate whether CD40L supports T cell function by acting as an intrinsic costimulator or by induction of other costimulatory molecules by examining coexpression of CD40L and markers of T lymphocyte priming. These carriers provide a unique model for comparison of CD40L-expressing and -nonexpressing lymphocytes in that all factors, including immunological experience, are equivalent between the two populations. Our results show that compared with CD40L-deficient T cells, T cells that express CD40L normally have a minimal advantage in becoming primed, as defined by CD45 RO isoform expression and production of IFN-gamma and TNF-alpha. Conversely, CD40L-deficient T lymphocytes clearly were capable of becoming primed as defined by the same parameters. These findings imply that the intrinsic costimulatory activity of CD40L is not required for attaining primed status, and that CD40L primarily supports T cell function by inducing extrinsic factors that can be shared by CD40L-deficient cells.
Asunto(s)
Ligando de CD40/genética , Hipergammaglobulinemia/genética , Hipergammaglobulinemia/inmunología , Inmunoglobulina M/biosíntesis , Activación de Linfocitos/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Cromosoma X/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ligando de CD40/biosíntesis , Citocinas/biosíntesis , Femenino , Citometría de Flujo , Tamización de Portadores Genéticos , Ligamiento Genético , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Interfase/genética , Interfase/inmunología , Antígenos Comunes de Leucocito/biosíntesis , Masculino , Subgrupos de Linfocitos T/patologíaRESUMEN
OBJECTIVE: X-linked hyper-immunoglobulin M (X-HIM) syndrome is a rare genetic immunodeficiency syndrome caused by mutations in the gene encoding CD40 ligand (CD40L, CD154). Allogeneic hematopoietic stem cell transplantation (HSCT) offers the prospect of immune reconstitution in X-HIM syndrome. Standard HSCT using high-dose chemoradiotherapy can be followed by serious hepatic problems, including veno-occlusive disease, graft-versus-host disease, and/or drug-induced hepatotoxicity. In patients whose liver function is compromised before HSCT, such as in X-HIM syndrome caused by cholangiopathy and hepatitis related to opportunistic infections, there is a higher likelihood of hepatotoxicity. We explored nonmyeloablative HSCT in 2 patients with X-HIM syndrome. Nonmyeloablative HSCT without liver transplant for X-HIM syndrome, to our knowledge, has not been described previously. METHODS: Two children with X-HIM syndrome and persistent infections had documented cholangiopathy on liver biopsy. Both children underwent nonmyeloablative HSCT from HLA-matched siblings with fludarabine, busulfan, and anti-thymocyte globulin as their preparative regimen. Graft-versus-host disease prophylaxis consisted of cyclosporine. RESULTS: Both children are >2 years after their HSCT. One remains a mixed chimera, and the other shows 100% donor chimerism. Both children are now free of infections and are no longer dependent on intravenous gammaglobulin. Both show response to immunizations. Both have had resolution of their cholangiopathy. CONCLUSIONS: Nonmyeloablative HSCT from HLA-matched siblings can offer immune reconstitution without hepatotoxicity in patients with X-HIM syndrome and preexisting cholangiopathy. Even with stable mixed chimerism after allogeneic HSCT, patients may be able to enjoy a normal phenotype. Nonmyeloablative HSCT warrants additional study in X-HIM syndrome.