RESUMEN
Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies directed against coagulation factor VIII. The treatment is based on recombinant activated factor VII and activated prothrombin complex concentrate. However, mainly in older patients, severe thrombotic complications have been reported. Here we report the different therapeutic approaches in 4 cases of elderly patients with AHA and co-morbidities.
Asunto(s)
Hemofilia A/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada/métodos , Factor VIII , Femenino , Hemofilia A/sangre , Humanos , Masculino , Metilprednisolona/uso terapéutico , Prednisona/uso terapéutico , Estudios RetrospectivosRESUMEN
We examine the self-assembly of a peptide A6H comprising a hexa-alanine sequence A6 with a histidine (H) "head group", which chelates Zn(2+) cations. We study the self-assembly of A6H and binding of Zn(2+) ions in ZnCl2 solutions, under acidic and neutral conditions. A6H self-assembles into nanotapes held together by a ß-sheet structure in acidic aqueous solutions. By dissolving A6H in acidic ZnCl2 solutions, the carbonyl oxygen atoms in A6H chelate the Zn(2+) ions and allow for ß-sheet formation at lower concentrations, consequently reducing the onset concentration for nanotape formation. A6H mixed with water or ZnCl2 solutions under neutral conditions produces short sheets or pseudocrystalline tapes, respectively. The imidazole ring of A6H chelates Zn(2+) ions in neutral solutions. The internal structure of nanosheets and pseudocrystalline sheets in neutral solutions is similar to the internal structure of A6H nanotapes in acidic solutions. Our results show that it is possible to induce dramatic changes in the self-assembly and chelation sites of A6H by changing the pH of the solution. However, it is likely that the amphiphilic nature of A6H determines the internal structure of the self-assembled aggregates independent from changes in chelation.
Asunto(s)
Quelantes/química , Péptidos/química , Tensoactivos/química , Zinc/química , Alanina/química , Histidina/química , Concentración de Iones de Hidrógeno , Tamaño de la Partícula , Péptidos/síntesis química , Propiedades de SuperficieRESUMEN
OBJECTIVE: To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). METHODS: Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. RESULTS: Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. CONCLUSION: RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Crioglobulinemia/terapia , Factores Inmunológicos/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , Azatioprina/uso terapéutico , Terapia Combinada , Crioglobulinemia/complicaciones , Crioglobulinemia/patología , Ciclofosfamida/uso terapéutico , Farmacorresistencia Viral/efectos de los fármacos , Sustitución de Medicamentos , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Plasmaféresis , Inducción de Remisión , Rituximab , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
A family of four biscarbamates (AA) and four bisphenols (DD) were synthesized, and H-bonding interactions between all AAâ¢DD combinations were characterized using (1)H NMR titrations in carbon tetrachloride. A chemical double mutant cycle analysis shows that there are no secondary electrostatic interactions or allosteric cooperativity in these systems, and the system therefore provides an ideal platform for investigating the relationship between chemical structure and chelate cooperativity. Effective molarities (EMs) were measured for 12 different systems, where the number of rotors in the chains connecting the two H-bond sites was varied from 5 to 20. The association constants vary by less than an order of magnitude for all 12 complexes, and the variation in EM is remarkably small (0.1-0.9 M). The results provide a relationship between EM and the number of rotors in the connecting chains (r): EM ≈ 10r(-3/2). The value of 10 M is the upper limit for the value of EM for a noncovalent intramolecular interaction. Introduction of rotors reduces the value of EM from this maximum in accord with a random walk analysis of the encounter probability of the chain ends (r(-3/2)). Noncovalent EMs never reach the very high values observed for covalent processes, which places limitations on the magnitudes of the effects that one is likely to achieve through the use of chelate cooperativity in supramolecular assembly and catalysis. On the other hand, the decrease in EM due to the introduction of conformational flexibility is less dramatic than one might expect based on the behavior of covalent systems, which limits the losses in binding affinity caused by poor preorganization of the interaction sites.
RESUMEN
Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder, characterized by spiking fever, skin rash, and arthritis. First-line treatment consists of corticosteroids. Methotrexate is commonly used in resistant cases or as a steroid-sparing drug. The availability of biologic drugs in the rheumatic diseases, such as anti-TNFs and IL-1ra, has allowed to treat very refractory cases of AOSD and provided new clues for the pathophysiology. However, anakinra and anti-TNFs may also fail or may be contraindicated in AOSD, and other treatment strategies are then necessary. Given that T cell activation may be a relevant part of the AOSD pathophysiology, abatacept, CTLA4IgFc, was administered in a 57-year-old man with AOSD failing traditional DMARDs and to anti-IL-1 and anti-TNF therapies, with a good outcome.
Asunto(s)
Antirreumáticos/uso terapéutico , Inmunoconjugados/uso terapéutico , Enfermedad de Still del Adulto/tratamiento farmacológico , Abatacept , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Radiografía , Inducción de Remisión , Enfermedad de Still del Adulto/diagnóstico por imagenRESUMEN
OBJECTIVE: Predictors of response to biologics in rheumatoid arthritis (RA) is an important issue in the current era. Rituximab (RTX) has been demonstrated effective and safe in active RA, resistant to traditional or biologic DMARDs. METHODS: Fifty-seven patients with active longstanding RA were treated with RTX after traditional DMARD or anti-TNF alpha therapy failure. RESULTS: Number of anti-TNF treatment previously failed (p=0.005), HAQ (p=0.013), rheumatoid factor (RF) (p=0.0002) and anti-CCP (p=0.006) were associated with an ACR response > or =50 at the end of 6th month by univariate analysis. Multivariate analysis confirmed that the number of anti-TNF previously failed, baseline HAQ and RF, but not anti-CCP were associated with an ACR response > or =50. EULAR moderate/good response was associated with ESR value (p=0.036), HAQ (p=0.032), and RF (p=0.01) by univariate analysis, while only RF positivity was associated with EULAR moderate/good response by multivariate analysis. CONCLUSIONS: RF positivity rather than anti-CCP positivity is a predictor of response to RTX, suggesting that RF-positive patients with low disability may obtain a clinical response when treated to RTX after the first anti-TNF agent failure or after traditional DMARD therapies. Larger studies are required to confirm these results.