Efficacy and safety of tildrakizumab for plaque psoriasis with continuous dosing, treatment interruption, dose adjustments and switching from etanercept: results from phase III studies.

BACKGROUND: Chronic psoriasis may require medication adjustments over time. OBJECTIVES: To evaluate the efficacy/safety of tildrakizumab in subgroups from the reSURFACE studies (N = 1862) that received continuous dosing, higher/lower dosing, treatment interruption/reinitiation and initiation. METHODS: Responders [Psoriasis Area and Severity Index (PASI) ≥ 75%] and partial responders (PASI ≥ 50% to < 75%) in Part 3 of the reSURFACE studies (weeks 28-52 or week 64) who received tildrakizumab 200 mg or 100 mg were rerandomized to the same dosage (T100/T100 or T200/T200), a higher/lower dosage (T100/T200 or T200/T100) or placebo (PBO) (T100/PBO or T200/PBO). Patients receiving PBO who relapsed were reinitiated to tildrakizumab. Etanercept (ETN) week-28 partial responders and nonresponders (PASI < 50%) received tildrakizumab 200 mg (ETN/T200). RESULTS: Among T100/T100 and T200/T200 week-28 partial responders, the proportion of patients who achieved as-observed PASI 75 responses increased over time. Among T100/T200 week-28 partial responders, PASI 75 responses increased from week 32 (38·5%) to week 52 (63·2%) and remained consistent in T200/T100 week-28 responders. Among patients who relapsed in the T100/PBO and T200/PBO groups, 86% and 83% of those who reinitiated tildrakizumab achieved PASI 75 by week 64, respectively. Among ETN/T200 week-28 partial responders, PASI 75 responses (nonresponder imputation) increased from week 32 (24·1%) to week 52 (74·7%). PASI 90, PASI 100 and Physician's Global Assessment responses were consistent with PASI 75 results. Treatment was well tolerated. CONCLUSIONS: Patients generally fared well with tildrakizumab maintenance, reinitiation, dose adjustment or initiation. What's already known about this topic? Tildrakizumab demonstrated significant efficacy vs. placebo with a positive safety profile during the first 28 weeks of treatment in two randomized double-blind trials. What does this study add? Treatment scenarios with tildrakizumab, such as long-term continuous dosing (up to 64 weeks), treatment interruption/reinitiation and switching from another biologic, can be part of the management of plaque psoriasis with a reasonable expectation of efficacy and tolerability.

Efficacy of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials at weeks 12 and 28.

BACKGROUND: Efficacy of tildrakizumab for plaque psoriasis was demonstrated in randomized, placebo-controlled trials. OBJECTIVE: To consolidate tildrakizumab efficacy results by pooling data. METHODS: Data (N = 2081) from tildrakizumab 100 mg, tildrakizumab 200 mg and placebo groups in three trials were pooled. RESULTS: Proportions of Psoriasis Area and Severity Index (PASI) 75 responders at week 12 were better with tildrakizumab 100 mg (62.3%) and tildrakizumab 200 mg (64.8%) vs. placebo (5.6%; P < 0.0001) and for PASI 90, PASI 100 and Physician's Global Assessment (PGA) 'clear' or 'minimal' vs. placebo (P < 0.0001). Responses increased from weeks 12 to 28. Week 12 PASI and PGA responses to tildrakizumab vs. placebo were numerically greater in patients with lower vs. higher bodyweight and were better with tildrakizumab 200 mg than tildrakizumab 100 mg for patients with higher bodyweight. Week 12 PASI 75 responses vs. placebo with tildrakizumab 100 mg were similar between patients with (55.0%) or without (56.7%) prior biologics. PASI 90, PASI 100 and PGA responses were generally higher in patients without prior biologics. Week 8 PASI 50 response predicted PASI 90 response. CONCLUSION: Pooled data confirmed the efficacy of tildrakizumab for moderate-to-severe plaque psoriasis.

Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials.

BACKGROUND: Short-term interleukin-23p19 inhibition by tildrakizumab improves plaque psoriasis and appears to be well tolerated. OBJECTIVES: Safety and tolerability were assessed for up to 64 weeks of tildrakizumab therapy using pooled data from three randomized controlled trials for moderate-to-severe psoriasis. METHODS: Data pools for the placebo-controlled (up to 16 weeks) and full trial periods (up to 64 weeks) were analysed (n = 2081). RESULTS: In the placebo-controlled period, frequencies of treatment-emergent adverse events (TEAEs; range 47·9-54·0%), serious TEAEs (range 1·4-2·3%), discontinuations due to AEs (range 0·6-1·9%), major adverse cardiovascular events (MACEs; range 0·0-0·1%) and severe infections (range 0·0-0·3%) were comparable between tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept. In the full trial period, exposure-adjusted rates (patients per 100 patient-years) for TEAEs, serious TEAEs and discontinuations due to AEs with tildrakizumab 100 mg and 200 mg were lower than or comparable with the placebo rates, and lower than with etanercept. Exposure-adjusted rates of MACEs (range 0·0-0·5) and severe infections (range 0·9-2·0) were comparable among groups. No TEAEs of inflammatory bowel disease or suicide were reported. Candida skin infections were infrequent at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept groups, respectively, in the placebo-controlled period, and exposure-adjusted rates of 0·2, 0·7, 0·0 and 0·0, respectively, in the full trial period. Oral candidiasis was also infrequent. CONCLUSIONS: Up to 64 weeks of tildrakizumab was well tolerated, with low rates of serious TEAEs, discontinuations due to AEs, and AEs of clinical interest.

Mycosis Fungoides: Experience in a Pediatric Hospital. / Micosis fungoide. Experiencia en un hospital pediátrico.

Mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is unusual in children. OBJECTIVES: We aimed to describe the epidemiologic, clinical, histopathologic, and immunophenotypic characteristics of MF as well as treatments and course of disease in a pediatric case series. MATERIAL AND METHOD: Data for all patients admitted to our pediatric hospital (Hospital Dr. J. P. Garrahan) in Argentina with a clinical and histopathologic diagnosis of MF between August 1988 and July 2014 were included. RESULTS: A total of 14 patients were diagnosed with MF. The ratio of boys to girls was 1:1.33. The mean age at diagnosis was 11.23 years (range, 8-15 years). The mean time between onset and diagnosis was 3.5 years (range, 4 months-7 years). All patients had hypopigmented MF and 42% also presented the features of classic MF. Seven (50%) had the CD8+ immunophenotype exclusively. Seventy-eight percent were in stage IB at presentation. Phototherapy was the treatment of choice. Four patients relapsed at least once and skin lesions progressed in 3 patients. All patients improved. CONCLUSIONS: MF is unusual in children. The hypopigmented form is the most common. Diagnosis is delayed because the condition is similar to other hypopigmented diseases seen more often in childhood. Although prognosis is good, the rate of recurrence is high, so long-term follow-up is necessary.

Characterization of micellar systems produced by new amphiphilic conjugates of poly(ethylene glycol).

This study proposes polymeric micelles produced using new amphiphilic conjugates between amino- or carboxy-mPEG2000 and three different α-lipoamino acids (PEG-LAA). The characterization of these colloidal systems showed CMC values, in the order of 10(-5 )M, that are interesting in the view of an in vivo administration. The PEG-LAA micelles also showed a good stability at 37 °C and upon dilution in aqueous media. Using a colored probe as a model lipophilic compound, the loading efficiency and in vitro release profile were also outlined.

Successful Outpatient Treatment of Full-thickness, Necrotic, Lower- extremity Ulcers Caused by Traumatic Hematomas in Anticoagulated Patients.

UNLABELLED: Outpatient wound care centers are encountering patients with more complex wounds and an increased incidence of concomi- tant complicating comorbidities. As the population ages, patients with chronic wounds are presenting with multiple active disease processes that cause initiation of the wounds, impede wound healing, and pre- clude safely proceeding with surgical procedures, under anesthesia, to treat those wounds. METHODS: Four warfarin-anticoagulated patients presented with large, full-thickness, necrotic, lower extremity wounds induced by hematomas from blunt trauma. Two of the wounds under- went scalpel debridement under local anesthesia while continuing anticoagulation. Following brief initial wound care with normal saline wet-to-moist dressing changes, continuous negative pressure therapy at 125 mmHg was initiated and continued for all wounds until the ex- pansive tissue defects were decreased for 23.8 ± 3.2 days. All wounds were treated with application of a living bilayered skin substitute (LSS) in an outpatient setting while maintaining therapeutic anticoagulation. RESULTS: All wounds completely epithelialized (100% closure) by 39.0 ± 21.9 weeks. One wound was completely relieved of its deep tissue defect to total epithelialization with one application of LSS. The largest wound (21.0 cm x 14.5 cm x 2.8 cm) with the greatest undermining (5 cm) was relieved of its tissue defect with a combination of nega- tive pressure therapy and three applications of the LSS. The second largest wound (8.6 cm x 24.0 cm x 2.1 cm), which had an exposed knee joint capsule, required two applications of LSS. These results indicate that patients with large, full-thickness, necrotic, lower extrem- ity wounds caused by traumatic hematomas while on anticoagulation therapy, can be appropriately managed as outpatients with aggressive sharp debridement under local anesthesia, negative pressure therapy for relief of the tissue defect, and bilayered skin substitute application to induce epithelial coverage. CONCLUSION: This approach eliminates the need for cessation of anticoagulation therapy and the use of more complex surgical procedures, such as myocutaneous flaps and skin grafts in patients with multiple underlying comorbid conditions.

Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease.

Despite significant advances in antiviral treatment, solid organ transplant (SOT) recipients remain at heightened risk for developing late cytomegalovirus (CMV) disease. Elevated inhibitory immune signaling suggests a state of immune impairment in SOT recipients, who do not control CMV infection and develop severe clinical symptoms after discontinuation of antiviral prophylaxis. We longitudinally monitored the negative immune modulator programmed death (PD)-1 receptor on both CD4 and CD8 T cells, co-expressing the CD137 surface marker of recent activation, in a liver transplant cohort. Liver recipients who progressed to CMV disease expressed elevated levels of PD-1 on CD137(+) CD4 and CD8 T cells, following stimulation with either full-length peptide libraries or CMV lysate. This novel approach, applicable to a multitude of human leukocyte antigen types, enhances the usefulness of the PD-1 measurements as a clinical strategy to predict late CMV disease. In parallel, we detected an increased level of the immunosuppressive cytokine interleukin (IL)-10, in plasma of liver recipients diagnosed with CMV disease. CMV-specific T cells were still functional when both PD-1 and IL-10 were upregulated; however they showed a marked proliferation deficit, which may limit their ability to contain viremia and lead to CMV disease. Our preliminary observations support further investigation of dual monitoring of PD-1 and IL-10, as potential immune markers of CMV disease.

Entamoeba histolyticaEhGEF1 structure and mutational analysis: New specific residues critical for function.

This paper reports the EhGEF1-EhRacG and EhGEF1-EhRho1 molecular complexes from Entamoeba histolytica. The not conserved amino acids Gln201,Tyr299, Gln302, Lys312, Asn313, Phe314 and Ile324 were localized, by means of an in silico computational analysis, at the interface of the exposed face from the DH domain of EhGEF1, which are important to establish the contact with its target GTPases EhRacG and EhRho1. Functional studies of nucleotide exchange of Phe314Ala mutant showed a decrement of 80% on EhRacG GTPase; in contrast the Ile324Ala mutant exhibited a reduction of 77%, specifically on EhRho1; meanwhile the Gln302Ala mutant showed a reduction of approximately 50% on the exchange activity for both GTPases. Moreover, the functional studies of the protein EhGEF1 mutants in the conserved residues Thr194Ala, Asn366Ala and Glu367Ala indicated that contrary to what has been reported for other systems, the mutation of these residues did not alter considerably its catalytic activity.

Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis.

Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the expression of ANGII receptors - AT1 and AT2 - and their relationship with prognosis. We studied 133 tumours from patients with diagnosis of astrocytoma who underwent surgery from 1997 to 2002. AT1 and AT2 were expressed in 52 and 44% of the tumours, respectively, when determined by both reverse transcriptase-polymerase chain reaction and immunohistochemistry. Ten per cent of low-grade astrocytomas were positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (P<0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of high-grade astrocytomas (P=0.01). AT1-positive tumours showed higher cellular proliferation and vascular density. Patients with AT1-positive tumours had a lower survival rate than those with AT1-negative (P<0.001). No association to survival was found for AT2 in the multivariate analysis. Expression of AT1 and AT2 is associated with high grade of malignancy, increased cellular proliferation, and angiogenesis, and is thus related to poor prognosis. These findings suggest that ANGII receptors might be potential therapeutic targets for high-grade astrocytomas.

Calidad de las prescripciones de medicamentos opioides posterior a una intervención educativa en médicos residentes / [Quality of opioid medication prescriptions after an educational intervention in resident doctors]

Objetivo: Evaluar el impacto de una intervención educativa en la calidad de las prescripciones de medicamentos opioides. Métodos: Se aplicó el instrumento IAM (Índice de Adecuación de la Medicación) a 10 médicos residentes de la subespecialidad de medicina paliativa y del dolor para determinar la calidad de las prescripciones de analgésicos opioides, antes y después de haber realizado una intervención educativa (IE) en farmacoterapia racional. Resultados: Se analizaron un total de 181 prescripciones, 55 antes y 126 después de la IE. Se mejoraron las puntuaciones del nivel de acuerdo en todos los ítems del perfil descriptivo de los médicos participantes. La calidad de la prescripción aumentó del 14,5% al 73%, mejorando en todas las áreas, excepto la duplicidad de tratamientos. Conclusiones: La IE mejoró la calidad de las prescripciones y el perfil prescriptivo de los médicos participantes. El instrumento IAM es útil para determinar la calidad de las prescripciones de opioides. (AU)

Objective: To assess the impact of an educational intervention on the quality of opioid drug prescriptions. Methods: The MAI (Medication Adequacy Index) instrument was applied to 10 resident physicians of the Palliative and Pain Medicine Subspeciality to determine the quality of opioid analgesic prescriptions before and after an educational intervention (EI) in rational pharmacotherapy. Results: A total of 181 prescriptions were analyzed, 55 before and 126 after the EI. The level of agreement scores improved for all items of the physicians’ descriptive profile. Prescription quality increased from 14.5% to 73%, improving in all areas except for duplicity of treatment. Conclusions: The EI improved the quality of the prescriptions and the physicians’ prescribing profile. The MAI instrument is useful to determine the quality of opioid prescriptions. (AU)

Gastric mucosa injury quantification in an ischemia - Reperfusion experimental model.

Gastric ischemia - reperfusion (I/R) injury is an important clinical problem, which is developed in more than 80% of critically ill patients. I/R is caused by interruption of blood supply to an organ or tissue followed by blood reflow into the exposed area, leading to multiple organ failure and death. Gastric reactance has been proposed to measure tissue injury caused by ischemia. The present study evaluates a new method to quantify gastric tissue damage due to I/R, and assess its relation to gastric reactance changes. Twenty Wistar rats were randomly assigned to 4 groups: control, ischemia, I/R 30 min, I/R 1 h. Local gastric ischemia was induced by clamping the celiac artery for 30 min and reperfusion was done for 30-60 min. In all groups, gastric impedance was measured, and then gastric mucosa samples were taken for light microscopy. There were statistical significant differences (p <;0.05) among the groups with respect to the index of gastric injury proposed, which was greater in I/R 1 h group. Also, impedance parameters increased in I/R groups with respect to control, and ischemia groups. The proposed index of gastric injury allowed gastric mucosa damage quantification, and it was related with gastric impedance increase, which is an objective method to evaluate tissue injury.

Most potential linear B cell epitopes of Env glycoproteins of feline immunodeficiency virus are immunogenically silent in infected cats.

A battery of sixty-six 20- to 23-amino acid synthetic peptides, partially overlapping by 10-12 amino acids, spanning the entire sequence of the envelope (Env) glycoproteins of the Petaluma isolate of feline immunodeficiency virus (FIV-Pet), has been used to map Env linear B cell epitopes. By screening FIV-infected cat sera for anti-peptide reactivity, the existence of two immunodominat domains, namely the V3 region of the surface (SU) glycoprotein and the domain including the highly conserved sequence QNQFF of the transmembrane (TM) glycoprotein, was detected; antibody-binding sites were also mapped in the domain overlapping the cleavage site between SU and TM encompassing the V6 variable region. Moreover, at least two novel linear B epitopes, the former spanning residues 427M-H446 and the latter spanning residues 737N-N756 and likely representing a "type-specific" determinant, have been revealed. The battery of synthetic peptides was then used to immunize outbred Swiss mice in the attempt to reveal other potential sites of immunogenicity of the Env glycoproteins. Analysis of peptide-immunized mouse sera for anti-peptide reactivity revealed more numerous B cell epitopes, generally mapping in different peptides, as compared with those defined in the feline system. None of the mouse anti-peptide sera, however, proved neutralizing for FIV-Pet.

The Bartsocas-Papas syndrome: autosomal recessive form of popliteal pterygium syndrome in a male infant.

We report on an additional patient with the severe autosomal recessive form of the popliteal pterygium syndrome. The patient was diagnosed at birth and had all of the phenotypic manifestations of this rare syndrome. Clinical findings and natural history suggest this is a distinct genetic entity.

Enzyme support systems for biosensor applications based on gold-coated nylon meshes.

A novel experimental protocol for enzyme immobilization based on the use of a very permeable support is described and applied to the development of an acetylcholinesterase (AChE) based biosensor. In this system, the enzyme was immobilized onto a gold-coated nylon mesh via a self-assembled monolayer of a bifunctional reagent, cystamine, preadsorbed onto the gold surface. This support has been characterized by optical microscopy and electrochemical measurements of permeability. In the assembled biosensor, the AChE modified mesh was placed over a glassy carbon electrode and the response to 4-aminophenylacetate, used as substrate, was monitored via the enzymatic reaction product, 4-aminophenol, by oxidation at +0.25 V vs. SSCE. This approach to biosensor design has been extended to the determination of organophosphorus and carbamate pesticides by their inhibition of AChE enzymatic activity.

Extended theoretical analysis of irreversible protein thermal unfolding.

The theoretical analysis of the protein denaturation model which includes an irreversible, exothermic and rate-limited step has been improved and applied to the DSC profile of Azurin. The two-step nature of the irreversible denaturation of globular proteins is usually depicted in the following simplified scheme: N <--> U <--> F, which is known as the Lumry and Eyring model. In most of the works concerning the thermal unfolding of proteins, it is usually assumed that the irreversible step of the process does not take place significantly during the short time the protein spends in the temperature range of the DSC transition, or if this is not the case, that this irreversible step occurs with a negligible thermal effect. As we will show, this last assumption cannot be accepted acritically; in fact we have found that in the case of Azurin an evident exothermic effect occurs at the end of the transition. In order to fit the experimental Cp(exc) profile of Azurin, we have analyzed a model in which the exothermic effects of the irreversible step and the variations of DeltaH with temperature are taken into account. Our model was first tested simulating a series of profiles and considering the effects of the variation of the parameters on the shape of the curves, and successfully used to fit the experimental calorimetric profile of Azurin.

An alternative approach in the structure-based predictions of the thermodynamics of protein unfolding.

A new approach for a first-order prediction of the thermodynamic properties of small globular proteins has been developed. The method put forward here has been shown to be successful in predicting, within acceptable margins of uncertainty, the denaturational heat capacity changes of a given protein if its amino acid composition is known. If compared with other models this method has the following advantages: (1) no details about the three-dimensional structure of the protein are required; (2) comparison with the thermodynamic properties of small model compounds is not necessary; (3) the temperature dependence of the denaturational heat capacity change is taken into account. Moreover, the equations developed have allowed us to point out the errors that can be made if the temperature-dependence of the denaturational heat capacity change is not taken into account in the calculation of the unfolding thermodynamic functions.

Anomalous phase transition in dipalmitoylphosphatidylethanolamine/palmitoylphosphatidylcholine/water system.

An anomalous phase transition with a marked rise in specific heat, the isobaric thermal expansion coefficient, and the compressibility coefficient at 62.5 degrees C for an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and 1-palmitoyl-sn-glycero-3-phosphocholine (PLPC), in water (34 wt.%) has been shown by differential scanning calorimetry, scanning dilatometry and isothermal compressibility measurements. This transition occurs 15 degrees C above a first-order transition observed in the same system. (31)P and (2)H nuclear magnetic resonance results are consistent with the occurrence of 'defects' in the bilayer in the temperature range between the first and the anomalous phase transitions. It is proposed that conically, PLPC molecules prefer regions with high curvature in the defective bilayer, while DPPE molecules are mostly confined to the flat regions of the bilayers.

Survival of Staphylococcus aureus in oral administration liquid medicaments and influence of count medium on survival.

The survival of Staphylococcus aureus was studied in 30 oral administration liquid medicaments (15 syrups and 15 solutions) to determine the effectiveness of the preservatives, the influence of the culture medium used in the enumeration of the surviving microorganisms, and the loss of the enzyme coagulase, phosphatase, DNase (deoxyribonuclease), and thermonuclease. Samples were inoculated with 6.3-6.5 x 10(5) viable cells per milliliter and were stored at room temperature for 60 days. Aliquots were taken for analysis at 0, 15, 22, 30, and 60 days after samples were inoculated. The enumeration of S. aureus was made by most probable number method (MPN) with six liquid culture media: triptone soy (TS), TS with 10% NaCl (TSS), TS and TSS with 0.2% catalase, Mannitol salt, and Tellurite-mannitol-glycine. The survival of S. aureus was lower in solutions than in syrups, decreased with the storage time, and depended on the culture medium utilized in the enumeration. Nonselective media were more sensitive than selective ones; that is, a better percentage of recovery was achieved with TS and the catalase medium. The preservative was effective in 93.3% of the samples. Coagulase was the most stable enzyme and phosphatase, DNase, and thermonuclease disappeared during the storage period.

Determination of levamisole in animal tissues using liquid chromatography with ultraviolet detection.

An efficient and sensitive liquid chromatographic method is described for the determination of the anthelminthic drug levamisole, in muscle, liver, kidney and fat of sheep, pigs and poultry, using thiabendazole as internal standard. Samples were extracted by homogenizing with chloroform, and were applied to Supelco Si solid-phase extraction columns and eluted with methanol. Chromatographic analysis was performed on a LiChrospher 60 RP-Select B column using methanol/ammonium acetate buffer 0.05 M (55/65, v/v) as mobile phase and reading at 220 nm. The quantification limit for the assay was 4 ng/g. Mean recoveries were about 84% for liver, 85% for kidney, 89% for muscle and 84% for fat. The assay has been used for statutory testing purposes.

New microencapsulated sunscreens: technology and comparative evaluation.

The aim of this work is to obtain new technologically improved microencapsulated sunscreens characterised by UV-radiation stability, good substantivity, low toxicity, a better tolerability and easiness to formulation. For this purpose we prepared two different systems using semisynthetic Hyaluronic Acid (HA) benzyl ester and a synthetic polymer (patent pending). We obtained these systems using two different methodologies: emulsification/solvent evaporation and emulsification/solvent extraction. The comparison between the two formulated systems was carried out in terms of their chemical-physical and biological properties.