Prophylactic Treatment Regimens Research Articles

“Hermes” - Hemophilia Related Mental Illness: A Cross-Sectional, Multicenter Study in Switzerland

Background: The availability of clotting factor concentrates and prophylactic home treatment for patients with hemophilia (PWH) A and B in developed countries greatly improved clinical outcomes. As the life expectancy of affected patients has increased, the management of comorbidities has become a greater focus within the comprehensive care setting. However, most studies focus on somatic complications. The past two decades revealed a growing body of work reporting increased prevalence of mental health problems in PWH. Given the severity and chronicity of the disease, internalizing disorders (i.e. anxiety, depression) as well as externalizing disorders (i.e. substance dependency, irritability and aggression) seem to go hand in hand with hemophilia. We aimed to assess the prevalence of comorbid mental health problems among PWH in Switzerland. We investigated age effects on this relationship as well as potentially influencing factors (illness factors and environmental factors) that may account for these. We also aimed to assess health-related quality of life (HRQoL) and age dependency in this setting. We are heading to identify targets of prevention/early intervention of mental health problems and foster improvement of evidence-based interdisciplinary treatment in PWH. Methods:This multicenter, cross-sectional study was conducted within six hemophilia treatment centers in Switzerland. Study participants were aged 6-99 years with congenital hemophilia of any severity. All participants or their legal guardians provided written informed consent, and the study was approved by the cantonal medical ethics committee of the responsible states. Participants aged 12 or older underwent a detailed personal psychological assessment followed by completing an online survey utilizing validated psychological measures (HRQoL, psychosocial functioning, somatic comorbidities/parental factors). Participants younger than 12 years underwent a detailed personal psychological assessment with one parent/legal guardian followed by an online survey to be completed by their parent/guardian. In all participants younger than 18 years, we assessed one parent/legal guardian additionally. Results:A total of n=164 PWH participated in the study (133 adult and 31 pediatric participants). Data analyses showed a median age of 39.26 years (SD 20.41). The majority of participants had hemophilia A (n=134, 82%), while hemophilia B was diagnosed in n=30 (18%) of participants. A severe hemophilia was reported in n=85 (52%), a moderate in n=31 (19%) and a mild hemophilia in n=48 (29%). Prophylactic treatment regimen was used in n=97 (59%). Out of n=156 participants with completed neuropsychiatric diagnostic interview, n=38 (24%) participants showed a psychiatric disorder over lifetime. This was significantly associated with disease severity, being more prevalent in moderate and severe hemophilia. We could not detect an association with age, so age does not moderate this association. In n=153 participants with available data on HRQoL, we found a lower HRQoL also to be associated with disease severity (moderate and severe). Moderation analyses could not confirm an association with age. Conclusion:Our data show an association of (lifetime) psychiatric diagnoses and a lower health-related quality of life in hemophilia depending on disease severity. This association is evident in moderate and severe hemophilia and is independent of age despite recent progress in development and use of new therapies going along with suggested lower hemophilia disease burden. Further analyses including somatic and treatment factors as well as parenting are ongoing and will be presented.

Generation of Human Regulatory Dendritic Cells from Cryopreserved Healthy Donor Cells and Hematopoietic Stem Cell Transplant Recipients.

Acute graft versus host disease (GVHD) remains a significant complication following hematopoietic stem cell transplant (HSCT), despite improved human leukocyte antigen (HLA) matching and advances in prophylactic treatment regimens. Previous studies have shown promising results for future regulatory dendritic cell (DCreg) therapies in the amelioration of GVHD. This study evaluates the effects of cryopreservation on the generation of DCreg, the generation of young and older DCreg in serum-free media, and the feasibility of generating DCreg from young and older HSCT patient monocytes. DCregs were generated in X-vivo 15 serum-free media from donor or patient monocytes. This study includes the use of monocytes from young and older healthy, donor, and HSCT patients with varying hematological diseases. Phenotypic differences in cell populations were assessed via flow cytometry while pro-inflammatory and anti-inflammatory cytokine production was evaluated in culture medium. The number of DCreg generated from cryopreserved monocytes of healthy donors was not significantly different from freshly isolated monocytes. DCreg generated from cryopreserved monocytes had comparable levels of co-stimulatory molecule expression, inhibitory molecule expression, and cytokine production as freshly isolated monocytes. Young and older healthy donor monocytes generated similar numbers of DCreg with similar cytokine production and phenotype. Although monocytes from older HSCT patients generated significantly fewer DCreg, DCreg from young and older HSCT patients had comparable phenotypes and cytokine production. Monocytes from young and older myelodysplastic syndrome (MDS) patients generated reduced numbers of DCreg compared to non-MDS-derived DCreg. We demonstrate that the cryopreservation of monocytes from HSCT patients of varying hematological diseases allows for the cost-effective generation of DCreg on an as-needed basis. Although the generation of DCreg from MDS patients requires further assessment, these data support the possibility of in vitro-generated DCreg as a therapy to reduce GVHD-associated morbidity and mortality in young and older HSCT recipients.

For adults with bronchiectasis, how do intermittent prophylactic antibiotic treatment regimens compare with placebo?

For adults with bronchiectasis, how do intermittent prophylactic antibiotic treatment regimens compare with placebo?

Urinary tract infection following intradetrusor onabotulinumtoxina injection for non-neurogenic urgency incontinence: single- vs. multi-dose prophylactic antibiotic treatment regimens.

Urinary tract infection is one of the most common adverse events following onabotulinumtoxinA injection for urgency incontinence. Our hypothesis was that those undergoing injection for urgency incontinence who received more than one dose of prophylactic antibiotics have lower post-procedure urinary tract infection rates compared to those who receive a single dose. We conducted a multi-center retrospective cohort study in females who underwent onabotulinumtoxinA injection for non-neurogenic urgency incontinence to evaluate the effect of single- vs. multi-dose prophylactic antibiotic regimens on the risk of post-procedure urinary tract infection. The primary outcome was the rate of urinary tract infection within 30 days of injection. Our sample size calculation required 136 subjects per group. Two hundred eighty-one patients were included from four centers. The single-dose cohort included 145 patients (51.6%), and the multi-dose cohort included 136 patients (48.4%). The mean age was 65 years, and patients were primarily Caucasian (81.4%). There was no difference in the rate of urinary tract infections diagnosed within 30 days of injection between the cohorts (single dose 13.8% vs. multi-dose 10.3%, p = 0.369). Those with a positive urine culture within 30 days of injection had a 15.2 times greater odds of having a post-procedure infection than those who did not (95% CI 3.19-72.53). There was no significant difference between the two cohorts in terms of adverse health events following injection. In females with non-neurogenic urgency incontinence undergoing onabotulinumtoxinA injection, multi-dose prophylactic antibiotic regimens were not associated with lower post-procedure urinary tract infection rates.

Comparative study utilizing different post-breeding treatment regimens in cyclic Arabian mares.

Background and Aim:Post-breeding treatment is the most common practice in the reproductive management of mares. Oxytocin, uterine lavage, and intrauterine (I/U) antibiotic are usually used as prophylactic therapy. This study aimed to determine the most efficient prophylactic treatment regimen among six treatment protocols applied during natural breeding of cyclic Arabian mares.Materials and Methods:The current study was conducted on cyclic Arabian mares that were subdivided into three age categories (n=968): Category I (5-10 years, n=380), Category II (11-15 years, n=361), and Category III (≥16 years, n=227). Six prophylactic treatments were applied after 4 h of breeding. According to the treatment regimen, treated mares (n=483) were divided into six treatment groups: A (n=80), treated with I/U antibiotic (1 g gentamicin); B (n=81), I/U lavage (normal saline 500 mL); C (n=83), intramuscular (I/M) oxytocin (10 IU); D (n=82), I/U antibiotic and I/M oxytocin; E (n=78), I/U lavage and I/M oxytocin; and F (n=79), I/U lavage with I/U antibiotic and I/M oxytocin. Non-treated mares were classified as controls (n=485). Ultrasonography was performed to monitor pregnant mares 30 and 60 days after mating, and mares were followed until foaling.Results:Pregnancy and foaling results reveals that in age Category I, treatment with oxytocin alone or oxytocin with I/U lavage showed the highest pregnancy and foaling rates (p<0.01). In age Category II, the highest pregnancy and foaling rates were observed in lavage treatment (p<0.01), whereas, in age Category III, the good pregnancy and foaling rates were monitored in treatment with oxytocin and I/U lavage (p<0.01).Conclusion:Treatment with systemic I/M oxytocin is ideal in early age group mares (5-10 years of age). However, irrespective of the age categories, all mares exhibited high pregnancy and foaling rates after treatment with systemic I/M oxytocin and I/U lavage with normal saline (0.9%) 4 h post-breeding.

Investigation of the antiviral activity of the recombinant human interferon lambda 1 in human conjunctiva cell culture

The aim of the study was to determine the efficacy of recombinant human interferon lambda 1 (IFN-λ1) against human adenovirus serotype 5 in a culture of human conjunctival cells Chang conjunctiva clone 1-5c-4. Material and methods. The study design consisted of three experimental schemes, reflecting a prophylactic and two options for a therapeutic and prophylactic treatment regimen (with the constant presence of the virus in the culture medium and with its removal after adsorption). The antiviral activity of IFN-λ1 was determined by the number of viable cells after exposure to the virus (MTT test). Results and discussion. It has been established that IFN-λ1 has antiviral activity against human adenovirus in vitro under a prophylactic and therapeutic-prophylactic scheme of administration at an infection dose of 1 and 10 TCID50 (50% tissue culture infectious dose), but not at an infection dose of 100 TCID50. The antiviral effect of the use of IFN-λ1 in a therapeutic and prophylactic regimen at an infection dose of 1 TCID50 was comparable to that of IFN-α. At the same time, both interferons did not have a toxic effect on the cell culture even at a concentration of 84 and 58 μg/ml, respectively. The antiviral activity and the absence of cytotoxic action provide the basis for further study of the possibility of development of based on IFN-λ1 drug for eye conjunctiva viral diseases treatment.

Latent tuberculosis infection among contacts of patients with multidrug-resistant tuberculosis in New South Wales, Australia.

BackgroundContacts of an individual with active tuberculosis (TB) disease have a higher risk of developing latent TB infection (LTBI) or active TB disease. Contact tracing is a public health measure that seeks to identify exposed contacts, screen them for co-prevalent TB and consider prophylactic treatment to prevent progression from LTBI to active TB disease. The investigators sought to determine the prevalence of LTBI and active TB disease among contacts of patients with multidrug-resistant (MDR)-TB in New South Wales, Australia.MethodologyA retrospective cohort study was performed among the contacts of patients diagnosed with MDR-TB between 2000 and 2016, inclusive, at seven chest clinics. Medical records were used to identify eligible contacts. Outcomes of screening and prophylactic treatment regimens offered to MDR-TB contacts with LTBI were characterised. Collected data included demographic information, screening tests results and initial management.ResultsIn total, 247 contacts of 55 MDR-TB patients were identified. LTBI was identified in 105 contacts (42.5%). Preventive treatment was received by 20 contacts with LTBI (32.3%) in the form of various regimens, ranging from one to three antimicrobials, with various doses and durations. One contact with LTBI who was untreated progressed to active TB disease during the study period, according to clinic notes.ConclusionContacts of MDR-TB patients have a high prevalence of LTBI. Management of these contacts varies substantially in New South Wales, reflecting a lack of definitive evidence for preventive therapy. Further research is required to determine the optimal management of this population.

Blockade of the Neonatal Fc Receptor (FcRn) Represents an Effective Mechanism for the Removal of Pathogenic Autoantibodies in Primary Immune Thrombocytopenia

Introduction: The neonatal Fc receptor, FcRn is ubiquitously expressed, & is responsible for maintaining the half-life of IgG & albumin, by rescuing these proteins from intracellular lysosomal degradation. Blockade of the interaction of FcRn with IgG would be expected to prevent salvage of both non-pathogenic and pathogenic IgG. Patients with primary immune thrombocytopenia (ITP) have autoantibodies against platelet membrane proteins such as the cell adhesion receptor CD61/CD41 (GPIIb/IIIa). Rozanolixizumab (a high affinity IgG4 monoclonal antibody (mAb) that specifically inhibits IgG binding to FcRn) is currently being evaluated in phase 2 clinical studies in patients with ITP. The aim of the current study was to understand the in vitro properties of rozanolixizumab & to explore the in vivo effects of a surrogate anti-mouse FcRn mAb (murinized “4464”) in a mouse model of ITP.Methods: The affinity of rozanolixizumab for FcRn was tested using surface plasmon resonance technology (Biacore), with the antibody captured by an anti-Fc immobilized on the sensor chip & soluble FcRn in solution, whilst the affinity of fluorescently labelled rozanolixizumab for human FcRn expressed on the surface of Madin-Darby canine kidney (MDCK) cells was measured by flow cytometry. Recycling & transcytosis of human IgG (hIgG) was also assessed in FcRn-transfected MDCK cells. For IgG tracking experiments, endothelial & epithelial cell lines were incubated with an AF647-conjugated IgG for 24 hours in the presence or absence of rozanolixizumab. Prior to imaging, nuclei were labelled using Hoechst at 37°C & cells were then visualized by fluorescence microscopy. Phagocytosis of anti-human MHC I (W6/32)-coated platelets by THP-1 cells was assessed by flow cytometry at 1 hour. The effect of rozanolixizumab on IgG recycling in vivo was assessed in the human FcRn-transgenic (hFcRn-Tg) mouse: hIgG at 500mg/kg was administered IV to mice on day 1 & dosed with antibodies on day 2; serial bleeds were then taken at multiple time points post antibody dosing & levels of hIgG, albumin & rozanolixizumab were quantified using LC-MS/MS. For the induction of ITP in mice, animals received an anti-CD41 antibody (MWReg30), delivered by osmotic minipump (~1µg of antibody delivered every 24 hours) & the anti-mouse FcRn mAb (4464) was administered at 30mg/kg either on days 0, 2 & 4 (prophylactic dosing) or on days 3 & 5 (therapeutic dosing); IVIg (1g/kg) was also evaluated & control mice received either PBS or an isotype-matched control mAb (101.4). Daily blood samples were taken to assess platelet numbers.Results: Rozanolixizumab has a high affinity for FcRn in a protein-protein (Biacore) assay with a KD of ~25pM at both pH6.0 & pH7.4; in the cell-based assay, the affinity was 1nM at both pH's. Rozanolixizumab efficiently inhibited the recycling & transcytosis of IgG in human FcRn-transfected MDCK cells (IC50 0.4nM & 1.1nM, respectively). Confocal microscopy experiments showed that there was an increased accumulation of IgG in cells in the presence of rozanolixizumab, relative to an isotype control mAb, & that the IgG was co-localized in lysosomes where it appeared to be degraded. FcRn has been postulated to play a direct role in phagocytosis, but the phagocytosis of opsonized platelets by THP-1 cells was unaffected by blockade with rozanolixizumab. Treatment with rozanolixizumab resulted in a dose-dependent accelerated clearance of hIgG in the hFcRn-Tg mouse; hIgG levels in all treated groups were significantly lower vs PBS controls from 24 hours post-dosing until the end of the experiment 8 days post dosing (p<0.01). No effect on albumin levels occurred in these mice. In the mouse model of ITP, both prophylactic & therapeutic treatment regimens with 4464 resulted in an increased number of platelets compared to control animals that received either PBS or 101.4. Animals that received 4464 from day 0 had significantly greater platelet numbers than control animals on days 4 & 5 (p<0.05); therapeutic dosing gave a significantly greater platelet number than control animals on day 5 (p<0.05).Conclusion: Rozanolixizumab is a high affinity mAb that inhibits the IgG recycling function of FcRn in vitro &in vivo . An anti-mouse FcRn mAb demonstrated efficacy in a mouse model of ITP. These data support the evaluation of rozanolixizumab in patients with ITP, & a phase 2 clinical study is currently ongoing in this patient population. DisclosuresEddleston:UCB Pharma: Employment. Greenslade:UCB Pharma: Employment. Qureshi:UCB Pharma: Employment. West:UCB Pharma: Employment. Atherfold:UCB Pharma: Employment. Amirkhosravi:UCB Pharma: Research Funding. Desai:UCB Pharma: Research Funding. Rivera-Amaya:UCB Pharma: Research Funding. Smith:UCB Pharma: Consultancy, Equity Ownership. Shock:UCB Pharma: Employment.

Implant-associated osteomyelitis: Development, characterisation, and application of a porcine model.

Implant-associated osteomyelitis: Development, characterisation, and application of a porcine model.

Drugs that target early stages of Onchocerca volvulus: A revisited means to facilitate the elimination goals for onchocerciasis.

Several issues have been identified with the current programs for the elimination of onchocerciasis that target only transmission by using mass drug administration (MDA) of the drug ivermectin. Alternative and/or complementary treatment regimens as part of a more comprehensive strategy to eliminate onchocerciasis are needed. We posit that the addition of “prophylactic” drugs or therapeutic drugs that can be utilized in a prophylactic strategy to the toolbox of present microfilaricidal drugs and/or future macrofilaricidal treatment regimens will not only improve the chances of meeting the elimination goals but may hasten the time to elimination and also will support achieving a sustained elimination of onchocerciasis. These “prophylactic” drugs will target the infective third- (L3) and fourth-stage (L4) larvae of Onchocerca volvulus and consequently prevent the establishment of new infections not only in uninfected individuals but also in already infected individuals and thus reduce the overall adult worm burden and transmission. Importantly, an effective prophylactic treatment regimen can utilize drugs that are already part of the onchocerciasis elimination program (ivermectin), those being considered for MDA (moxidectin), and/or the potential macrofilaricidal drugs (oxfendazole and emodepside) currently under clinical development. Prophylaxis of onchocerciasis is not a new concept. We present new data showing that these drugs can inhibit L3 molting and/or inhibit motility of L4 at IC50 and IC90 that are covered by the concentration of these drugs in plasma based on the corresponding pharmacological profiles obtained in human clinical trials when these drugs were tested using various doses for the therapeutic treatments of various helminth infections.

The potential impact of gene therapy on health-related quality of life (HRQoL) domains in haemophilia

Abstract Introduction Haemophilia is an inherited bleeding disorder characterised by spontaneous bleeding, often leading to impaired health-related quality of life (HRQoL). Commonly used treatments include episodic and prophylactic treatment regimens. Gene therapies could soon become available, potentially creating a paradigm shift in patient management. Aim This paper proposes hypotheses about the potential impact of gene therapy on HRQoL domains in haemophilia, and how these impacts might differ compared with existing treatments. Methods An expert working group with 10 individuals experienced in haemophilia and HRQoL research was established to discuss potential impacts of gene therapy on HRQoL in general and for specific domains in haemophilia. As part of a one-day workshop, domains of three widely used patient-reported outcome (PRO) instruments were explored: the Haemo-QoL-A, the Patient Reported Outcomes, Burden and Experiences (PROBE), and the Haemophilia Activities List (HAL). Results The group expected a greater improvement in HRQoL from gene therapy compared with existing treatments for the following domains: physical/role functioning, worry, and consequences of bleeding (Haemo-QoL-A); haemophilia-related health and EQ-5D-5L (part of the PROBE); leg and arm function, and leisure activities (HAL). In contrast, the experts suggested that no change or potential deterioration might be observed for the emotional impact (HAL) and treatment concerns (Haemo-QoL-A) domains. Conclusions Current PRO instruments in haemophilia have limitations when applied in the context of gene therapy, and no single instrument fully captures the relevant HRQoL domains. However, the PROBE and Haemo-QoL-A were considered as the most suitable existing instruments. As haemophilia treatments evolve, further research should examine the potential effectiveness of existing PRO instruments as compared to the development of novel PRO measures.

Evaluation of efficacy of twice-weekly prophylactic treatment with BeneFIX® (recombinant factor IX) followed by once weekly in children with severe hemophilia B: Six-year data from a local registry

CONTEXT: Bleeding in severe hemophilia B is minimized by factor IX (FIX) replacement either as once- or twice-weekly prophylaxis. Recent trials have focused greater interest on once-weekly prophylaxis using standard recombinant FIX (rFIX) or enhanced half-life rFIX. Limited data are available on optimal prophylaxis regimens of FIX replacements for patients with hemophilia B.AIMS: This study aimed to evaluate the efficacy of once-weekly prophylaxis compared with twice-weekly prophylaxis with BeneFIX (rFIX) in children with severe hemophilia B.SETTINGS AND DESIGN: This study is a retrospective, two-period study from January 2012 to December 2017.SUBJECTS AND METHODS: The study assessed the efficacy of 3-year twice-weekly prophylaxis with BeneFIX (rFIX) in patients with severe hemophilia B followed by 3-year once-weekly prophylaxis, then comparing once weekly versus twice weekly at a given period. The primary efficacy endpoint was the annualized bleeding rate (ABR) and the secondary endpoint included Functional Independence Score for patients with Hemophilia (FISH) scoring.RESULTS: There was no statistically significant difference in the bleeding per year and the joint bleeding per year between once- and twice-weekly prophylactic treatment regimens (P > 0.05). There was no statistically significant difference in ABR between once- and twice-weekly prophylaxis, 11.9 and 9.1 bleeds per year, respectively (P > 0.05). In addition, there was no statistically significant difference in the hospitalization and school absence between once- and twice-weekly prophylactic treatment regimens (P > 0.05). There was no statistically significant difference in FISH score between once- and twice-weekly protocol (P > 0.05), but factor consumption was significantly higher in the twice-weekly protocol compared with once-weekly protocol (P < 0.001).CONCLUSIONS: Once-weekly prophylaxis was effective and tolerated prophylaxis for most patients included in this study. Once-weekly prophylaxis is an effective alternative to twice-weekly prophylaxis, and both the regimens reduce ABR in children with severe hemophilia B.

Wernicke’s Encephalopathy in Alcohol Use Disorder Patients after Liver Transplantation: A Case Series and Review of Literature

Wernicke’s encephalopathy (WE) is an acute neurological disorder resulting from thiamine deficiency, commonly found in alcohol use disorder (AUD) patients. Liver transplantation (LT) could represent a risk factor for the onset of WE in AUD patients, due to the onset of chronic depletion of thiamine in this population and the high metabolic demand of surgery and the postoperative period. However, few data are available about the risk of the onset of WE in AUD patients after LT. Here we report three cases of AUD patients who developed WE with confusion and delirium after LT. Prompt parenteral administration of thiamine led to a rapid improvement of the clinical condition and a complete remission of neurological symptoms after 3–4 days. In addition, a search of the available English literature was conducted in order to perform a review of the possible association between the onset of WE and LT in AUD patients. A prophylactic treatment regimen based on the administration of thiamine could be suggested in AUD patients before and after LT. Further studies are needed to determine the optimal regimen of thiamine in the prevention of WE in this setting.

Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy

Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1–10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1–15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings.

Guidelines for the prophylaxis of haemophilia A and B: new horizons and ambitions.

Guidelines for the prophylaxis of haemophilia A and B: new horizons and ambitions.

OnabotulinumtoxinA Injections for Patients with Chronic Migraine During the COVID-19 Pandemic

Headaches are among the top prevalent conditions that physicians encounter in their daily practice. Migraine headaches affect nearly15% of the United States population (approximately 45 million).‎‎1,‎2 Over 50% of all patients with migraine report significant or severe impairment and disability.2 Migraine is the leading cause of years lived with disability among patients between ages 15 and 49 years old – the most productive years.‎‎3 According to the World Health Organization headache report, up to 4% of the world’s population experience chronic migraine (headaches occurring on at least 15 days per month with at least 8 of these headaches meeting migraine criteria).‎‎‎4 Approximately, 65% of patients with episodic migraine and 75% of patients with chronic migraine have missed family events and activities in the past month due to migraine-related impairment.‎‎5 Migraine also significantly impacts work-related activities. It has been estimated that 11% of patients with chronic migraine have been missing at least 1 day of work per week in the past 2 weeks‎.‎‎6 Based on migraine attack frequency and related disability, headache experts suggest offering prophylactic treatment options to patients with four migraine attacks per month or more. ‎‎7 Nevertheless, it has been estimated that only 26-29% of patients continue to adhere to their prophylactic treatment regimen at 6 months and only 17-20% continue to use their oral preventive medications at 12 months. ‎8,‎9 OnabotulinumtoxinA injection is an established FDA-approved therapy for chronic migraine prevention.

Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS-Hemo project.

The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02IU/mL, respectively. The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.

Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC50s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.

Hepatitis B seroprevalence in hematological oncology patients

Objectives: Hepatitis B virus (HBV) infection is still a serious public health problem today. Many factors such as frequent blood transfusion, hemodialysis, sexual contact, sterilization in surgical procedures, etc. are involved in the transmission of hepatitis B virus. In our study, HBV seroprevalence was evaluated retrospectively in order to provide vaccination of anti-HBs negative patients and to determine HBV prophylaxis in patients with hematological malignancy. Methods: A total of 499 patients were included in the study. HBsAg, anti-HBs, anti-HBc IgG, anti-HDV, HBV DNA values were measured by ELISA (enzyme-linked immunosorbent assay, Liason, Diasorin, Italy) with Real-Time PCR (Cobas-Tagman, Roche Switzerland) and recorded. The obtained datas were evaluated by SPSS for Windows 15.00 statistical program. A value of p &amp;lt;0.05 was accepted as a statistical significance value. Results: HBsAg positivity was found to be 3.4% (n = 17) in all patients. Appropriate treatment regimens were started to patients with HBsAg (+). There were 166 (33.3%) patients with anti-HBs (+). One hundred nineteen (23.8%) patients had anti-HBc IgG (+), 40 (33.6%) of them were started a prophylactic treatment regimen. Anti-HBs positivity were reported after vaccination in 48 (16.8%) patients. Occult hepatitis have not been detected in patients with anti-HBc IgG positivity. Conclusions: As a result of this study, anti-HBs negative patients with hematological malignancies were vaccinated. Patients and physicians should be informed about vaccination and hepatitis serology controls of hematological malignancy and other immunosuppressed patients. Sensitivity in this context should be increased in terms of prophylactic treatments.

Glycyrrhizic acid promotes neural repair by directly driving functional remyelination.

Natural compounds are a rich source of effective candidate drugs for the treatment of neurological disorders. Glycyrrhizic acid (GA), the major water-soluble ingredient isolated from Glycyrrhiza glabra, is reported to show anti-inflammatory and immunomodulatory activities. However, its effect on CNS demyelinating disease is unclear. In this study, we showed that GA ameliorated the clinical disease severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), especially at the chronic stage of clinical EAE. Histological evaluation demonstrated that, in the prophylactic treatment regimen, GA significantly inhibited inflammatory demyelination in the CNS. During the chronic stage when myelin and axon damage has already occurred, GA induced oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes, thus effectively accelerating remyelination. Evidence from the cuprizone-induced mouse model of de- and remyelination, ex vivo organotypic slice cultures, and in vitro OPC maturation experiments indicated that the observed efficacy of this compound resulted directly from enhanced remyelination rather than immune suppression. Furthermore, we found that GA promoted oligodendrocyte maturation through modulating GSK-3β signaling pathways. Our data led to the conclusion that GA could be used as a potential therapeutic candidate for the treatment of demyelinating diseases such as MS, which remains refractory to available treatments.