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BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. METHODS: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). RESULTS: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. CONCLUSIONS: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.
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Inmunoglobulinas Intravenosas/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Caprilatos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Death due to cerebral stroke afflicts a large number of neuronal populations, including glial cells depending on the brain region affected. Drugs with a wide cellular range of protection are needed to develop effective therapies for stroke. Human alpha 1-antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory, anti-apoptotic and immunoregulatory activities. This study aimed to test whether hAAT can protect different kind of neurons and glial cells after the oxygen and glucose deprivation (OGD). METHODS: Addition of hAAT to mouse neuronal cortical, hippocampal and striatal cultures, as well as glial cultures, was performed 30â¯min after OGD induction and cell viability was assessed 24â¯h later. The expression of different apoptotic markers and several inflammatory parameters were assessed by immunoblotting and RT-PCR. RESULTS: hAAT had a concentration-dependent survival effect in all neuronal cultures exposed to OGD, with a maximal effect at 1-2â¯mg/mL. The addition of hAAT at 1â¯mg/mL reduced the OGD-mediated necrotic and apoptotic death in all neuronal cultures. This neuroprotective activity of hAAT was associated with a decrease of cleaved caspase-3 and an increase of MAP2 levels. It was also associated with a reduction of pro-inflammatory cytokines protein levels and expression, increase of IL-10 protein levels and decrease of nuclear localization of nuclear factor-kappaB. Similar to neurons, addition of hAAT protected astrocytes and oligodendrocytes against OGD-induced cell death. CONCLUSIONS: Human AAT protects neuronal and glial cells against OGD through interaction with cytokines. GENERAL SIGNIFICANCE: Human AAT could be a good therapeutic neuroprotective candidate to treat ischemic stroke.
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Embrión de Mamíferos/citología , Glucosa/deficiencia , Interleucinas/antagonistas & inhibidores , Neuronas/citología , Fármacos Neuroprotectores/farmacología , Oxígeno/metabolismo , alfa 1-Antitripsina/farmacología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Embrión de Mamíferos/metabolismo , Humanos , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Necrosis , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de Tripsina/farmacologíaRESUMEN
BACKGROUND: In this study, two fibrin sealant products, Fibrin Sealant Grifols (FS Grifols 80 mg/mL fibrinogen; 500 IU/mL thrombin) and Evicel (fibrinogen 55-85 mg/mL; thrombin 800-1200 IU/mL) were studied for efficacy in achieving hemostasis at a targeted bleeding site (TBS) on parenchymous or soft tissue in pediatric surgeries. METHODS: This phase 3, single-blind, active comparator, non-inferiority trial compared the number of patients achieving hemostasis at a TBS at four (T4 - primary endpoint), seven (T7) and 10 (T10) minutes after application, Safety and tolerability were assessed by recording adverse events during and after procedures. Eligible patients were <18 years old undergoing elective, open, non-cardiac thoracic, abdominal or pelvic surgeries. Preterm (<37 weeks gestation) and newborn (0-27 days) infants were eligible. RESULTS: At T4, 98.7% of FS Grifols group (n = 91) and 95.4% of the Evicel group (n = 87) achieved hemostasis. All patients with residual bleeding at T4 were undergoing soft tissue surgery. All patients achieved hemostasis by T7. At T10, all patients achieved hemostasis except one (FS Grifols (no observation recorded)). There were no incidents of persistent bleeding. For FS Grifols, 26.5% of patients had treatment-emergent adverse events (TEAEs) and 18.4% for Evicel. One TEAE (moderate procedural pain - FS Grifols group) was considered possibly related to study treatment. Three patients died for reasons unrelated to the study medications. CONCLUSIONS: FS Grifols was safe and effective at achieving hemostasis in pediatric patients having parenchymous or soft tissue surgeries. The efficacy of FS Grifols was non-inferior to Evicel. LEVEL OF EVIDENCE: I.
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BACKGROUND AND AIMS: Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite its prevalence, especially among patients with chronic obstructive pulmonary disease, AATD is still underdiagnosed. The aim of this study is to identify individuals with lung disease and severe AATD in central-eastern Europe. METHODS: Subjects with respiratory symptoms that could be indicative of AATD provided blood samples as dried blood spot. The alpha1 -antitrypsin (AAT) concentration was determined by nephelometry and, if lower than 1.70 mg/dL in dried blood spot (equivalent to 1.04 g/L in serum), polymerase chain reaction was used to detect the PiS and PiZ alleles. Isoelectric focusing was used for confirmation of doubtful genotype results. RESULTS: From 13 countries, 11 648 subjects were included. Genotyping of 1404 samples with AAT levels <1.70 mg/dL revealed 71 (5.06%) PiS, 151 (10.8%) PiZ, 1 (0.071%) PiSS, 8 (0.57%) PiSZ and 32 (2.28%) PiZZ. Phenotyping of 1363 samples negative for the S and Z alleles or with PiS and PiZ genotype showed two (0.147%) PiZ(rare) and two (0.147%) Pi(null)(null). The countries with the highest rate of severe AATD were Croatia, Russia and Slovakia. By regions, the Baltic countries area showed the highest rate of both PiZ and severe AATD (2.45% and 1.20%, respectively) while the lowest rates were observed in the Balkan Peninsula (0.48% and 0.31%, respectively). CONCLUSION: This study confirms the need for targeted testing of symptomatic patients and provides AATD genotype data from countries for which only some estimates of prevalence were available until now.
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Enfermedades Pulmonares/diagnóstico , Deficiencia de alfa 1-Antitripsina/diagnóstico , Adulto , Europa (Continente)/epidemiología , Femenino , Humanos , Focalización Isoeléctrica , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/epidemiología , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Nefelometría y Turbidimetría , alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/epidemiologíaRESUMEN
In this report, we describe the recombinant SLO expression as a fusion protein with a C-terminal hexahistidine tag and its purification using immobilized metal affinity expanded bed adsorption (STREAMLINE(trade mark) Chelating). In order to facilitate downstream processing of the purification, an efficient fermentation process was developed focusing on the achievement of high yields of soluble protein. The purification strategy resulted in a 40% recovery of active recombinant SLO and the protein was purified eight-fold. SDS-PAGE and Western-blot analysis of the purified protein revealed the presence of a 75 Mr form, which was the estimated relative Mass of the recombinant SLO.
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Quelantes/química , Cromatografía de Afinidad/métodos , Níquel/química , Estreptolisinas/aislamiento & purificación , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Western Blotting , Cromatografía de Afinidad/instrumentación , Electroforesis en Gel de Poliacrilamida , Escherichia coli , Fermentación , Histidina , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/aislamiento & purificación , Estreptolisinas/genéticaRESUMEN
BACKGROUND: Alpha1-antitrypsin deficiency (AATD) is an underdiagnosed genetic disorder that results in early-onset emphysema due to low serum levels of alpha1-proteinase inhibitor (alpha1-PI), leading to increased activity of tissue-damaging neutrophil elastase. Clinical outcomes of AATD may be improved by administering alpha1-PI augmentation therapy. Here, we describe the design of the ongoing Study of ProlAstin-c Randomized Therapy with Alpha-1 augmentation (SPARTA), a phase 3 trial designed to evaluate progression of lung tissue loss in patients with severe AATD receiving human alpha1-PI (Prolastin(®)-C) versus placebo, using whole-lung computed tomography (CT) densitometry. STUDY DESIGN: SPARTA is a randomized, placebo-controlled trial assessing the efficacy and safety of two separate doses of Prolastin-C (60 and 120 mg/kg) administered weekly over 3 years in patients aged 18-70 years with a diagnosis of AATD and clinical evidence of pulmonary emphysema. The primary measure of efficacy (change from baseline whole-lung 15th percentile lung density [PD15]) will be determined by CT lung densitometry measured at total lung capacity. Secondary efficacy variables will be the evaluation of severe chronic obstructive pulmonary disease exacerbations, as defined by American Thoracic Society/European Respiratory Society criteria, and PD15 of the basal lung region using CT densitometry. Adverse events will be collected and documented. CONCLUSIONS: The SPARTA trial is designed to evaluate the long-term (3-year) efficacy of 2 separate doses of Prolastin-C for the treatment of emphysema in patients with AATD. Protocol number: GTi1201. CLINICAL TRIALS IDENTIFIER: NCT01983241.
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Pulmón/patología , Enfisema Pulmonar , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina , Absorciometría de Fotón/métodos , Adulto , Anciano , Disponibilidad Biológica , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/tratamiento farmacológico , Enfisema Pulmonar/etiología , Proyectos de Investigación , Pruebas de Función Respiratoria , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/farmacocinética , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , alfa 1-Antitripsina/administración & dosificación , alfa 1-Antitripsina/efectos adversos , alfa 1-Antitripsina/farmacocinética , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/fisiopatologíaRESUMEN
UNLABELLED: SUMMARY BACKGROUND: Several lines of evidence support the involvement of inflammatory and immunologic abnormalities in chronic fatigue syndrome (CFS). Since recent studies have shown that α-1 antitrypsin (AAT) possesses anti-inflammatory properties, the potential therapeutic effect of AAT treatment on CFS has been investigated. CASE PRESENTATION: A 49-year-old woman diagnosed with CFS was treated with intravenous infusions of a human plasma-derived AAT concentrate (60 mg/kg body weight weekly for 8 consecutive weeks). The patient's monocyte elastase, a regulator of inflammatory processes, was 1170 U/mg. At completion of treatment, improvement in maximal workload was observed (54.0-71.7% of predicted). Additionally, amelioration in working memory (scores: 83-94) and perceptual organization (scores: 75-83) were detected on the Wechsler Adult Intelligence Scale-III test. Monocyte elastase decreased to a normal range (<150 U/mg). Improvement in functional capacity allowed the patient to work in part-time employment. CONCLUSION: These findings suggest a possible role for AAT in the treatment of CFS.
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OBJECTIVE: To assess clinical effect of a human plasma-derived alpha-1 antitrypsin (AAT) concentrate in reducing pain severity of patients with fibromyalgia (FM). METHODS: Thirteen subjects with FM completed a randomized, double-blind, placebo-controlled, crossover study which consisted of 9 weeks trial of AAT or placebo with a washout period of 6 weeks. Primary efficacy endpoint was change on pain severity score, assessed by a daily visual analogue scale (VAS) for pain. Other outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire, (FIQ), the Medical Outcomes Study Short Form 36 (SF-36), the Health Assessment Questionnaire Disability Index (HAQ-DI), the Hospital Anxiety and Depression Scale (HADS) and tiredness score evaluated by VAS. RESULTS: No statistically significant differences were observed in either pain severity or other secondary outcome measures in either of the treatment groups, or between treatment groups in either of the treatment periods. No carryover or order of intervention effect was observed from one treatment to the other. Both investigational interventions were generally well tolerated, and vital signs during the drug infusions were within the respective normal ranges. CONCLUSION: Treatment with a human plasma-derived AAT concentrate did not demonstrate significant improvement over placebo on reducing pain severity and other symptoms of FM. Further research should examine other FM subpopulations and drug doses.
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Fibromialgia/tratamiento farmacológico , Inhibidores de Serina Proteinasa/uso terapéutico , alfa 1-Antitripsina/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Proyectos Piloto , Placebos , Estudios Prospectivos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: The metrological traceability of values for the catalytic concentration of several enzymes assigned to a calibration material has been assured by following the recently published International Standard ISO 18153. METHODS: A traceable value with a measurement uncertainty was assigned for the catalytic concentration of alanine aminotransferase, creatine kinase, gamma-glutamyltransferase and lactate dehydrogenase in two materials from different sources. These are all measurable quantities, with the primary reference measurement procedure described by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and a primary calibrator giving metrological traceability to the SI unit of measurement. The metrologically traceable calibration was validated by measuring human serum samples using the primary reference measurement procedure and a routine commercial measurement procedure calibrated with the traceable materials. RESULTS: Results showed that the primary reference procedure, selected manufacturers' procedures and the end-user's routine procedure for each enzyme have the same analytical specificity. Four of eight commercial calibrators tested were commutable, whereas the others had a very small difference in absolute terms, indicating that these materials would be useful for calibration. CONCLUSION: The implementation of a reference system for enzyme measurements was demonstrated that assures the traceability of patient results to SI units.