Overcoming Challenges of Implementing Closed System Transfer Device Clinical In-Use Compatibility Testing for Drug Development of Antibody Drug Conjugates.

Closed system transfer devices (CSTD) are a supplemental engineering control designed to reduce occupational exposure of hazardous drugs and are currently implemented in accordance with evolving regulations. Owing to the novelty and complexity of these devices and their importance in clinical in-use testing, here we evaluated FDA-approved CSTD, assessing product quality through stability indicating assays to determine any drug product incompatibilities. Six devices were used in a simulated compounding and administration of a late-phase IgG1 antibody-drug conjugate (ADC) and the resulting samples were analyzed for visible and subvisible particle counts by light obscuration and micro-flow imaging, physical stability by size exclusion chromatography, and biological activities by relative potency. Potential challenges included improper fit of CSTD components, loss of product to void volume, and material incompatibility. Results showed compatibility of the ADC with the 6 CSTD evaluated. One CSTD introduced subvisible particles into the ADC during compounding that were identified through morphological assessment as silicone oil. This study highlights the importance of clinical in use testing with new devices and proposes strategies to mitigate the risk of drug product incompatibility with CSTD.

Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients.

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production.

Guselkumab: First Global Approval.

Guselkumab (Tremfya™) is a human monoclonal IgG1λ antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies.

With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans.

Nuevos biológicos en el tratamiento del asma de control difícil / No disponible

No disponible

Eficacia y seguridad de pembrolizumab en el tratamiento de pacientes con diagnóstico de melanoma maligno con enfermedad metastásica o irresecable, sin tratamiento sistémico previo / Efficacy and safety of pembrolizumab in the treatment of patients with malignant melanoma with metastatic or unresectable disease without previous systemic treatment

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologias en Salud e Investigaciones (IETSI) ha recibido la solicitud de evaluar el uso de pembrolizumab para su uso en pacientes con diagnóstico de melanoma maligno con enfermedad metastásica o irresecable, sin tratamiento sistémico previo, dentro del sistema de EsSalud, indicación actualmente no contemplada en el Petitorio Farmacológico de EsSalud. Generalidades: Los melanomas a nivel mundial representam un problema de salud pública vigente y creciente. De hecho su incidencia no sólo ha aumentado en las últimas décadas sino que también ha aumentado su mortlidad, comparado con otros tipos de cáncer. Tecnología Sanitaria de Interés: Pembrolizumab: Pembrolizumab es un anticuerpo monoclonal humanizado de tipo inmunoglobulina G4 (IgG4) (HuMAb) que actúa sobre la via del receptor de muerte programada 1 (PD-1) bloqueando su interación con PD-L1 y PD-L2. Dado que el receptor PD-1 es un regulador negativo de la actividad de los linfocitos T, al bloquearlo permite la reactivación de la inmunidad anti-tumor. METODOLOGÍA: Estrategia de Búsqueda: El protocolo de esta revisión sistemática y revisado coon el equipo técnico de IETSI. Las siguientes fuentes han sido revisadas y consultadas con la intención de buscar la mejor evidencia disponible: Canadian Agency for Drugs and Technologies in Health (CADTH), Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, European Society for Medical Oncology (ESMO) de Europa, Medline/Pubmed, National Comprehensive Cancer Network (NCCN) de los Estados Unidos, National Guideline Clearinghouse (NCG) de los Estados Unidos, Nationa Institute for Health and Care Excellence (NICE) del Reino Unido, Scopus, Scottish Medicines Consortium (SMC) de Escocia, Sociedad Española de Oncologia Médica (SEOM) de Espanã, Translating Research into Practice (TRIP Database), Web of Science. RESULTADOS: Luego de revisar un total de 77 referencias resultados de nuestra búsqueda bibliográfica, se filtraron 35 estudios, de los cuales sólo seis fueron finalmente seleccionados para nuestro análisis, incluyendo dos ensayos clínicos, tres guías clínicas y uuna evaluación de tecnología. Sinopsis de la Evidencia: Al realizar la búsqueda amplia de guías de prática clínica en Googl Académico así como en las bases de datos revisadas se encontró una gran varidad de guías específicas para el maenejo de pacientes con melanoma maligno. Sin embargo, entre las guías revisadas sólo se encontró tres en las cuales se listó pembrolizumab como una alternativa de tratamiento para el maenjo de pacientes con melanoma maligno irresecable o metastásico, elaboradas respectivamente por SEOM de España, ESMO de Europa y NCCN de los Estados Unidos por lo que a continuación resumiremos lo que plantea esta guía. CONCLUSIONES: A la fecha no se dispone de evidencias que sustenten el uso de pembrolizumab como uma alternativa más eficaz y segura a la quimioterapia con dacarbacina (DTIC) en el tratamiento de los pacientes con diagnóstico de melanoma maligno irresecable o metastásico, sin tratamiento sistémico previo. El Instituto de Evaluación de Tecnologías en Salud e Investigaciones-IETSI, no aprueba el uso de pembrolizumab como tratamiento para los pacientes con diagnóstico de melanoma maligno irresecable o metastásico, sin tratamiento sistémico previo.

Effectiveness of magnetic fluid hyperthermia against Candida albicans cells.

Candida albicans is one of the most frequently isolated fungal pathogens causing opportunistic infections in humans. Targeted magnetic fluid hyperthermia (MFH) is a promising method in thermal therapy facilitating selective heating of pathogen cells like C. albicans. In the paper, we used meso-2,3-dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles (MNPs) and functionalised anti-C. albicans immunomagnetic nanoparticles (IMNPs) to investigate the potential of MFH in combating C. albicans cells in vitro. Using Mössbauer spectroscopy it was found that synthesised MNPs exhibited superparamagnetic phenomena. On the basis of calorimetric experiments, the maximum SAR (specific absorption rate) was found and a proper concentration of MNPs was established to control the temperature. MFH based on both DMSA-coated MNPs and functionalised anti-C. albicans IMNPs was more effective in combating C. albicans cells in vitro than thermostat hyperthermia. Especially promising results were obtained using functionalised IMNPs, which eradicated most of the pathogen colonies at the temperature of 43 °C.

Secondary hypogammaglobulinemia in Waldmann's disease treated with subcutaneous immunoglobulins.

Primary intestinal lymphangiectasia (PIL) is rare disorder characterized by congenital malformation or obstruction of intestinal lymphatic drainage; it is responsible for protein losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL management. The administration of intravenous immunoglobulins does not always lead to satisfactory plasma levels and therefore the replacement therapy with immunoglobulins is controversial. We describe here the case of a patient with PIL and severe hypogammaglobulinemia treated with immunoglobulins. The striking aspect of this case is the clinical and serological benefit obtained with the subcutaneous compared to the intravenous immunoglobulins administration.

The gut microbiome as a target for regulatory T cell-based immunotherapy: induction of regulatory lymphocytes by oral administration of anti-LPS enriched colostrum alleviates immune mediated colitis.

BACKGROUND: Gut-derived bacterial endotoxin is an important cofactor in the pathogenesis of IBD. Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance and can prevent and alleviate IBD. To determine the immune modulatory effect of anti-LPS enriched hyperimmune colostrum, its ability to induce Tregs and alleviate immune mediated colitis. METHODS: Immune-mediated colitis was induced in mice by intra-colonic instillation of Trinitrobenzene Sulfonate (TNBS). Four groups of mice were orally administered with two dosages of IgG-enriched colostrum fractions. The fractions were harvested from cows immunized against LPS derived from intestinal Escherichia coli bacteria (Imm124E). Control mice received non-immunized colostrum or vehicle (PBS). Treatment was administered one day following sensitization and four additional days following the administration of TNBS. The following parameters in the mice were tracked: body weight, bowel histology, serum cytokine levels and regulatory T cells. RESULTS: Oral administration of Imm124E hyperimmune colostrum ameliorated immune-mediated colitis. Significant amelioration of weight reduction was noted in treated mice. Oral administration of Imm124E improved bowel histology. Both the extent of the disease, inflammation score, and colitis damage and regeneration scores decreased in Imm-124E treated animals. These effects were associated with an increase in serum IL10 anti inflammatory cytokine levels, and an increase in CD4 + CD25+ and CD4 + Foxp3+ Tregs. CONCLUSIONS: Oral administration of Imm124E promoted Tregs and alleviated bowel inflammation in immune mediated colitis. The present data suggests that the microbiome may serve as a target for Tregs-based immunotherapy.

Recombinant Enzyme Replacement Therapy in Hypophosphatasia.

Hypophosphatasia (HPP) is a rare monogenetic and multisystemic disease with involvement of different organs, including bone, muscle, kidney, lung, gastrointestinal tract and the nervous system. The exact metabolic mechanisms of the effects of TNAP deficiency in different tissues are not understood in detail. There is no approved specific treatment for HPP; therefore symptomatic treatment in order to improve the clinical features is of major interest. Enzyme replacement therapy (ERT) is a relatively new type of treatment based on the principle of administering a medical treatment replacing a defective or absent enzyme. Recently ERT with a bone targeted recombinant human TNAP molecule has been reported to be efficient in ten severely affected patients and improved survival of life threatening forms. These results are very promising especially with regard to the skeletal phenotype but it is unclear whether ERT also has beneficial effects for craniosynostosis and in other affected tissues in HPP such as brain and kidney. Long-term data are not yet available and further systematic clinical trials are needed. It is also necessary to establish therapeutic approaches to help patients who are affected by less severe forms of HPP but also suffer from a significant reduction in quality of life. Further basic research on TNAP function and role in different tissues and on its physiological substrates is critical to gain a better insight in the pathogenesis in HPP. This and further experiences in new therapeutic strategies may improve the prognosis and quality of life of patients with all forms of HPP.

Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study.

BACKGROUND: Safety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice. OBJECTIVE: We sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis. METHODS: We conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated. RESULTS: For 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%). LIMITATIONS: Possible incompleteness of chart details and small study population limit the conclusiveness of findings. CONCLUSION: Biologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials.

A randomized clinical trial evaluating metabolism of colostral and plasma derived immunoglobulin G in Jersey bull calves.

BACKGROUND: Intravenous plasma administration has been recommended in healthy or sick calves with failure of passive immunity. HYPOTHESIS: IV administered plasma-derived immunoglobulin G (IgG) undergoes increased catabolism as reflected by a rapid decrease in serum IgG concentration with an increase in fecal IgG concentrations within 48 h. ANIMALS: Thirty newborn Jersey calves. Fifteen were fed colostrum (CL group) and 15 were given bovine plasma IV (PL group). MATERIALS AND METHODS: Randomized clinical trial. Calves in the CL group were fed 3 L of colostrum once, by oroesophageal tubing. Calves in the PL group were given plasma IV at a dosage of 34 mL/kg. Serum and fecal samples were collected at 0 h, 6 h, 12 h, 48 h, 5 d, and 7 d. Serum and fecal IgG concentrations were determined by radial immunodiffusion. RESULTS: Calves in the CL group maintained serum IgG concentrations consistent with adequate transfer of immunity (≥1,000 mg/dL) throughout the study period. Calves in the PL group achieved median IgG concentrations of ≥1,000 mg/dL at 6 h but the concentrations were <1,000 mg/dL by 12 h. Calves in the PL group were 5 times more likely to experience mortality compared to the CL group (hazard ratio = 5.01). Fecal IgG concentrations were not different between the 2 groups during the first 48 h (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Catabolism of plasma derived IgG occurs rapidly during the first 12 h after transfusion. Fecal excretion did not explain the fate of the plasma derived IgG.

Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23.

CONTEXT: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. OBJECTIVE: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. DESIGN: Two sequential open-label phase 1/2 studies were done. SETTING: Six academic medical centers were used. PARTICIPANTS: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). INTERVENTION: KRN23 was injected sc every 28 days. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. RESULTS: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. CONCLUSIONS: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Heat-treated (in single aliquot or batch) colostrum outperforms non-heat-treated colostrum in terms of quality and transfer of immunoglobulin G in neonatal Jersey calves.

The objective of this randomized clinical trial was to describe the effect on colostrum characteristics and passive transfer of IgG in neonatal calves when using the Perfect Udder colostrum management system (single-aliquot treatment; Dairy Tech Inc., Greeley, CO) compared with a negative control (fresh refrigerated or fresh frozen colostrum) and a positive control (batch heat-treated colostrum). First-milking Jersey colostrum was pooled to achieve 31 unique batches with a minimum of 22.8 L per batch. The batch was then divided into 4 with 3.8 L allocated to each treatment group: (1) heat-treated in Perfect Udder bag at 60°C for 60 min and then stored at -20°C (PU); (2) heat-treated in a batch pasteurizer (Dairy Tech Inc.) at 60°C for 60 min and then stored at -20°C in Perfect Udder bag (DTB; positive control); (3) fresh frozen colostrum stored at -20°C in Perfect Udder bag (FF; negative control); and (4) fresh refrigerated colostrum stored at 4°C in Perfect Udder bag (FR; negative control). Colostrum from all treatments was sampled for analysis of IgG concentration and bacterial culture immediately after batch assembly, after processing, and before feeding. Newborn Jersey calves were randomly assigned to be fed 3.8 L of colostrum from 1 of the 4 treatment groups. A prefeeding, 0-h blood sample was collected, calves were fed by esophageal tube within 2 h of birth, and then a 24-h postfeeding blood sample was collected. Paired serum samples from 0- and 24-h blood samples were analyzed for IgG concentration (mg/mL) using radial immunodiffusion analysis. The overall mean IgG concentration in colostrum was 77.9 g/L and was not affected by treatment. Prefeeding total plate counts (log10 cfu/mL) were significantly different for all 4 treatments and were lower for heat-treated colostrum (PU=4.23, DTB=3.63) compared with fresh colostrum (FF=5.68, FR=6.53). Total coliform counts (log10 cfu/mL) were also significantly different for all 4 treatments and were lower for heat-treated colostrum (PU=0.45, DTB=1.08) compared with fresh colostrum (FF=3.82, FR=4.80). Mean 24-h serum IgG concentrations were significantly higher for calves in the PU (41.0 mg/mL) and DTB (40.6 mg/mL) groups compared with FF (35.1 mg/mL) and FR (35.5 mg/mL) groups. Mean apparent efficiency of absorption of IgG was significantly higher for the PU (37%) and DTB (37%) groups compared with the FF (32%) and FR (32%) groups. Calves fed heat-treated colostrum (PU or DTB) experienced significantly improved AEA and serum IgG concentrations.

Impact of colostrum and plasma immunoglobulin intake on hippocampus structure during early postnatal development in pigs.

The first milk, colostrum, is an important source of nutrients and an exclusive source of immunoglobulins (Ig), essential for the growth and protection from infection of newborn pigs. Colostrum intake has also been shown to affect the vitality and behaviour of neonatal pigs. The objective of this study was to evaluate the effects of feeding colostrum and plasma immunoglobulin on brain development in neonatal pigs. Positive correlations were found between growth, levels of total protein and IgG in blood plasma and hippocampus development in sow-reared piglets during the first 3 postnatal days. In piglets fed an elemental diet (ED) for 24h, a reduced body weight, a lower plasma protein level and a decreased level of astrocyte specific protein in the hippocampus was observed, as compared to those that were sow-reared. The latter was coincident with a reduced microgliogenesis and an essentially diminished number of neurons in the CA1 area of the hippocampus after 72h. Supplementation of the ED with purified plasma Ig, improved the gliogenesis and supported the trophic and immune status of the hippocampus. The data obtained indicate that the development of the hippocampus structure is improved by colostrum or an Ig-supplemented elemental diet in order to stimulate brain protein synthesis and its development during the early postnatal period.

Comparison of serum immunoglobulin G half-life in dairy calves fed colostrum, colostrum replacer or administered with intravenous bovine plasma.

In calves, passive immunity of immunoglobulins can be acquired through ingestion of colostrum or colostrum replacers. Plasma can been used to supplement immunoglobulins in healthy or sick calves. Serum half-life of colostral derived immuglobulin G (IgG) is estimated to be 20 days. Half-life of IgG is important in determining response to antigens and timing of vaccination in calves. To date studies evaluating half-life of colostrum replacer or plasma derived IgG are lacking. The objectives of this study were to compare the serum half-life of IgG derived from colostrum, colostrum replacer and plasma in dairy calves reared up to 35 days of age. Thirty Jersey calves were randomly assigned to receive colostrum or colostrum replacer by oroesophageal tubing or plasma by intravenous administration. Serum samples were collected at 2, 5, 7, 10, 14, 21, 28 and 35 days. Serum IgG concentrations were determined by radial immunodiffusion. The results indicated that half-life for IgG in colostrum fed (28.5 days) or plasma transfused calves (27.3 days) was longer than colostrum replacer fed calves (19.1 days). Further studies are required to evaluate pathogen specific immunoglobulins in order to recommend vaccination timing in calves fed colostrum replacers.

[Management of severe alcoholic hepatitis]. / Management bei schwerer alkoholischer Hepatitis.

Severe alcoholic hepatitis is still associated with high mortality and presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. The management of these patients includes at first hand several supportive measures as treatment of alcohol withdrawal, administration of fluid and vitamins and admission to an intensive care unit in the unstable patient. Glucocorticoids have been since decades the most intensively studied therapy in alcoholic hepatitis and are effective in certain subgroups. Indication for such a therapy is usually defined on a Maddrey Discriminant Function > 32. The Lille score at day 7 is used to decide whether corticosteroid therapy should be stopped or continued for a 1 month course. Nutritional supplementation is also likely to be beneficial. The main progress in better understanding its pathophysiology has come from cytokine studies. Various proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) or interleukin-1 (IL-1) have been proposed to play a role in this disease. This advancement has recently led to pilot studies investigating anti-TNF drugs such as pentoxifylline, infliximab (anti-TNF antibody) or etanercept in the treatment of this disease. These studies revealed besides for pentoxifylline rather negative results. Despite this fact, targeting of certain cytokines such as IL-1 remains an attractive treatment concept for this devastating disorder in the future.

Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.

OBJECTIVE: We sought to assess whether the type of TNF inhibitor therapy (soluble receptor versus monoclonal antibody) has an effect on MI risk; and determine whether length of TNF inhibitor therapy has an effect on MI risk. DESIGN: Retrospective cohort study. SETTING: Between January 1, 2004 and November 30, 2010. PARTICIPANTS: At least 3 ICD9 codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI). INTERVENTION: None. MAIN OUTCOME MEASURE: Incident MI. RESULTS: In the 3 subgroups of TNF inhibitors, 976 received etanercept; 217 received monoclonal antibody; and 480 received etanercept or monoclonal antibody, in addition, 5075 received topical therapy and 2097 received oral therapy. In the Cox proportional hazards analysis, etanercept (HR, 0.53; 95% CI, 0.31-0.92) was associated with a significant reduction of MI risk, compared to topical agents and, monoclonal antibody only (HR, 0.25; 95% CI, 0.06-1.03), and etanercept or monoclonal antibody (HR, 0.53; 95% CI, 0.27-1.06) were associated with a non-significant reduction of MI risk compared to topical agents. Using year 1 as reference, those who received TNF inhibitor therapy at year 2 (HR, 1.15; 95% CI, 0.30-4.44), at year 3 (HR, 1.89; 95% CI, 0.64-5.58), and at year 4 and above (HR, 1.16; 95% CI, 0.46-2.94) had a non-significant increase of MI risk. CONCLUSIONS: Treatment with etanercept, compared to treatment with topical agents, was associated with a significant decreased risk of MI in psoriasis patients. Treatment with monoclonal antibody and etanercept or monoclonal antibody, compared to treatment with topical agents, was associated with a non-significant decreased risk of MI risk in psoriasis patients. There were no statistically significant changes in risk of MI associated with length of TNF inhibitor treatment.