Fibroblast growth factor-21 improves insulin action in non-lactating ewes

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFa) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in non-lactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 ERK1/2 following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21 resistant state.

From clinical guidelines to practice. Clinical experience in treatment of patients with allergic rhinitis

Introduction. Antihistamines are the most commonly prescribed class of medications for the treatment of allergic rhinitis (AR). However, they are also widely used in the treatment of inflammatory diseases of the ENT organs. One such drug is levocytirizine, (R) an enantiomer of cetirizine, which is a selective antagonist of peripheral histamine H1-receptors. This article analyzes the properties of levocytirizine in terms of safety and efficacy in allergic rhinitis.Aim of the study is to assess the efficacy of levocetirizine in patients with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) versus placebo, and safety for patients with allergic rhinitis.Materials and methods. In this, double-blind, placebo-controlled study, 52 patients with year-round allergic rhinitis and 28 patients with seasonal allergic rhinitis were randomized to receive levocetirizine 5 mg/day once or placebo. Mean overall measures of five symptoms (nasal congestion, nasal itching, itchy eyes, rhinorrhea, and sneezing) were compared between treatment groups at 1, 2, and 4 weeks. All individual symptom scores were also examined.Results. Levocetirizine showed a significant improvement in the condition of patients with CAR and SAR over the entire treatment period compared to placebo. Assessment of individual symptoms showed statistically significant differences in favor of levocetirizine. Conclusion. Levocetirizine is an effective, safe, and well-tolerated drug for the treatment of allergic rhinitis.

1083. Phase 1b Results of Pharmacokinetics, Pharmacodynamics, and Safety for LBP-EC01, a CRISPR-Cas3 Enhanced Bacteriophage Cocktail Targeting Escherichia coli that Cause Urinary Tract Infections

Background LBP-EC01 is the first CRISPR-engineered bacteriophage product to successfully complete Phase 1b testing in a clinical program designed to address infections caused by E. coli initially targeting urinary tract infections (UTIs). Thirty-six subjects were enrolled in this randomized, double blind study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of LBP-EC01 in patients with lower urinary tract colonization caused by E. coli. Methods Results No drug-related Treatment Emergent Adverse Events (TEAEs) were observed. All nondrug related TEAEs were Grade 2 or below and there were no tolerability signals associated with LBP-EC01.A modified ITT (mITT) population was defined to assess PK in subjects treated with LBP-EC01 (n=17). Subjects were removed from the PK analysis who had missing or insufficient colonization at baseline (n=3), were exposed to antibiotics during screening or study conduct (n=3) or exhibited a non-drug related SAE (n=1). Of these subjects, 12 were found to be sensitive to LBP-EC01 and of these, 10 (83%) showed phage amplification. A PD analysis compared the mITT populations of LBP-EC01 vs. placebo (n=6) and showed that the LBP-EC01 arm had a decrease in E. coli that was greatest within 24 hours of initial treatment and remained below baseline across the entire treatment period. The placebo arm showed increased levels of E. coli and higher variability over the treatment period. An average difference of 2-3 log (100x to 1,000x) existed in urine E. coli concentration (CFU/mL) between the LBP-EC01 and placebo arms across the duration of the treatment period. Conclusion LBP-EC01 has proved to be safe and well-tolerated in this Phase 1b study of subjects colonized by E. coli. In addition, phage amplification was observed in patients with E. coli isolates sensitive to LBP-EC01, demonstrating a clear proof of mechanism. Finally, the apparent difference in PD effect between LBP-EC01 and placebo which was irrespective of MDR status, provides promise that LBP-EC01 may someday be an excellent option for patients suffering from UTIs caused by E. coli, especially in strains that are resistant to conventional antibiotics. Disclosures Dave ousterout, PhD, InceptorBio (Advisor or Review Panel member, Shareholder)Locus Biosciences (Employee, Shareholder)

The Antifungal Activity of Loquat (Eriobotrya japonica Lindl.) Leaves Extract Against Penicillium digitatum

This study was performed to determine the antifungal activity of loquat (Eriobotrya japonica Lindl) leaf extract (LLE) against the citrus postharvest pathogen Penicillium digitatum (P. digitatum). The LLE exhibited an antifungal activity against P. digitatum, with a minimum inhibitory concentration (MIC) of 0.625 mg/ml and a minimum fungicidal concentration (MFC) of 1.25 mg/ml. Significant inhibitory effects of LLE on mycelial growth and spore germination of P. digitatum were seen in a dose-dependent manner. Simultaneously, to investigate possible antifungal mechanisms by LLE, we analyzed their influence on morphological changes, cell membrane permeability, cell wall and cell membrane integrity, and adenosine phosphates (ATP, ADP, and AMP) levels. Alterations, such as sunken surface and malformation, occurred in the LLE-treated P. digitatum spores. Furthermore, intracellular inclusion content decreased after LLE treatment, indicating an increase in cell membrane permeability. Besides, the LLE treatment induced a significant decline in the level of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP) with a noticeable addition of extracellular ATP, ADP, and AMP during the entire treatment period. Overall, the results manifested that the antifungal activity of LLE against P. digitatum can be attributed to the derangement of cell membrane permeability and disordered energy metabolism. This is the first report on the mechanism of antifungal activity of LLE and could be useful in the development of targeted fungicides from natural origin.

Three-stage revision arthroplasty for the treatment of fungal periprosthetic joint infection: outcome analysis of a novel treatment algorithm

Aims Fungal periprosthetic joint infections (fPJIs) are rare complications, constituting only 1% of all PJIs. Neither a uniform definition for fPJI has been established, nor a standardized treatment regimen. Compared to bacterial PJI, there is little evidence for fPJI in the literature with divergent results. Hence, we implemented a novel treatment algorithm based on three-stage revision arthroplasty, with local and systemic antifungal therapy to optimize treatment for fPJI. Methods From 2015 to 2018, a total of 18 patients with fPJI were included in a prospective, single-centre study (DKRS-ID 00020409). The diagnosis of PJI is based on the European Bone and Joint Infection Society definition of periprosthetic joint infections. The baseline parameters (age, sex, and BMI) and additional data (previous surgeries, pathogen spectrum, and Charlson Comorbidity Index) were recorded. A therapy protocol with three-stage revision, including a scheduled spacer exchange, was implemented. Systemic antifungal medication was administered throughout the entire treatment period and continued for six months after reimplantation. A minimum follow-up of 24 months was defined. Results Eradication of infection was achieved in 16 out of 18 patients (88.8%), with a mean follow-up of 35 months (25 to 54). Mixed bacterial and fungal infections were present in seven cases (39%). The interval period, defined as the period of time from explantation to reimplantation, was 119 days (55 to 202). In five patients, a salvage procedure was performed (three cementless modular knee arthrodesis, and two Girdlestone procedures). Conclusion Therapy for fPJI is complex, with low cure rates according to the literature. No uniform treatment recommendations presently exist for fPJI. Three-stage revision arthroplasty with prolonged systemic antifungal therapy showed promising results. Cite this article: Bone Jt Open 2021;2(8):671–678.

PROCEDURE AND ALGORITHMIZATION OF RATIONAL CHOICE OF REHABILITATION MEASURES DURING TREATMENT GYNECOLOGICAL DISEASES

С развитием высоких медицинских технологий возрастает роль лечащего врача (ЛВ), который по-прежнему остается лицом, принимающим решение (ЛПР). Однако применение математических методов моделирования и адаптивных методов принятия решений должно увязываться с логикой деятельности ЛВ, доступно для практического использования, освобождать ЛВ от "рутинной" работы и способствовать более целенаправленному и эффективному лечебному процессу. Вот почему, прежде всего, при выборе рациональных реабилитационных мероприятий в условиях неполной априорной информации требуется интеллектуальная поддержка принимаемых решений ЛВ. Реабилитационные мероприятия при лечении гинекологических заболеваний выбираются из определенного множества медикаментозных, физиотерапевтических и хирургических мероприятий. Задача управления лечением в виде оптимизационной задачи позволяет формализовать процесс принятия решений при неоднородности задачи управления на начальном этапе, однако, при выборе лечения имеют место разного рода неопределенности, что требует применения адаптивного подхода. Для интеллектуальной поддержки выбора тактики лечения гинекологических заболеваний в условиях неполной априорной информации и ряда неопределенностей рекомендуется использовать для повышения эффективности принимаемых решений методы формализации априорной информации, поступающей от ЛВ, для настройки вероятностей привлечения критериев оптимизации, вероятности использования того или иного вида лечебного воздействия, математических моделей процессов лечения гинекологических заболеваний для организации и реализации имитационного эксперимента по принимаемым ЛВ решениям на весь период лечения (стратегия лечения) с использованием ЭВМ в диалоговом режиме в ускоренном масштабе времени и на каждый шаг лечения (тактика лечения) в реальном масштабе времени как по информации, поступающей от ЛВ, так и с использованием адаптивных алгоритмов выбора текущих целей лечения, вида лечебных воздействий и их величины. Таким образом, в статье рассматриваются задачи рационального (оптимального) планирования и выбора реабилитационных мероприятий при лечении гинекологических заболеваний на основе автоматизированного принятия решений With the development of high medical technologies, the role of the attending physician (PD) increases, who remains the decision-maker (DM). However, the use of mathematical modeling methods and adaptive decision-making methods should be linked to the logic of the drug's activity, be available for practical use, free the drug from "routine" work and contribute to a more purposeful and effective treatment process. That is why, first of all, when choosing rational rehabilitation measures in conditions of incomplete a priori information, intellectual support for the decisions made by the dispensary is required. Rehabilitation measures in the treatment of gynecological diseases are selected from a certain set of medication, physiotherapy and surgical measures. The problem of treatment management in the form of an optimization problem allows one to formalize the decision-making process when the control problem is heterogeneous at the initial stage, however, when choosing a treatment, there are various kinds of uncertainties, which requires an adaptive approach. For intellectual support of the choice of tactics for the treatment of gynecological diseases in conditions of incomplete a priori information and a number of uncertainties, it is recommended to use methods of formalizing a priori information from the drug to increase the efficiency of decisions made, to adjust the probabilities of invoking optimization criteria, the likelihood of using one or another type of therapeutic effect, mathematical models processes of treatment of gynecological diseases for the organization and implementation of a simulation experiment on the decisions made by the drug for the entire treatment period (treatment strategy) using a computer in an interactive mode in an accelerated time scale and for each step of treatment (treatment tactics) in real time as according to information received from drugs, and using adaptive algorithms for choosing the current goals of treatment, the type of therapeutic effects and their magnitude. Thus, the article deals with the tasks of rational (optimal) planning and selection of rehabilitation measures in the treatment of gynecological diseases based on automated decision making

POS0600 IMMUNOGENICITY OF RITUXIMAB BIOSIMILAR GP2013: A RARE EVENT, BUT NOT WITHOUT CONSEQUENCES ...

Background:The bioequivalence between rituximab (RTX) originator and its biosimilar GP2013 has been demonstrated in rheumatoid arthritis (RA) (1). A recent randomized controlled trial suggested in a selected population a very low immunogenicity of GP2013 in RA (<1%) (2).Objectives:To study in daily practice the risk of immunogenicity of patients treated with GP2013 for their chronic inflammatory rheumatic disorder.Methods:Prospective routine care study carried out between September 2018 and August 2020 in the Rheumatology department of Cochin Hospital. We consecutively included patients treated with the biosimilar RTX GP2013, systematically used in the department since March 2018. Samples were taken before each infusion in order to detect anti-RTX antibodies (Ab) and RTX residual concentrations by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag).Results:We included 159 consecutive patients treated with GP2013 (124 women, 78%) with a mean age of 59±13 years and a mean disease duration of 18±11 years. Among these 159 patients, 108 (68%) had RA and 51 had another disease (16 systemic sclerosis (SSc), 15 mixed connective tissue disease (MCTD), 5 systemic lupus (SLE), 5 inflammatory myopathies (MI), 5 undifferentiated polyarthritis, 2 juvenile idiopathic arthritis (JIA) and 3 primary Sjögren’s syndromes). 137 patients (86%) were receiving associated disease-modifying therapy (DMARD), mainly methotrexate (111/137 patients, 81%). 120 patients (75%) were in maintenance therapy with originator RTX (cumulative dose of RTX: 3.5±6g) before the switch to GP2013 in March 2018. Originator RTX was not re-established during the entire treatment period. The other 39 patients (25%) treated with GP2013 were naïve of originator RTX.The analysis of the first sample, performed before the second GP2013 infusion, identified 8 patients (5 RA, 1 SLE, 1 MCTD and 1 SSc) with positive anti-RTX antibodies (prevalence 5%), with rates varying between 6 and >100ng/mL and undetectable residual RTX concentrations. Among these 8 patients, 6 had previously received originator RTX and 2 were RTX-naïve patients. There was a trend for higher body mass index in patients with positive anti-RTX antibodies (28±7 vs. 25±6 kg/m2, p=0.12), and no association was observed between anti-RTX immunization and age, disease duration, combination with conventional DMARD, mean interval between infusions or cumulative RTX dose.Among the 8 immunized patients, two groups could be isolated: i) a group of 5 patients (3 RA, 1 SLE, 1 SSc) with low antibody levels (6-22 ng/mL) and no significant clinical consequences (absence of treatment discontinuation and loss of efficacy after 13±4 months of follow-up, only one minor allergic reaction) and ii) a group of 3 patients (2 RA, 1 MCTD) with a high antibody levels (≥100ng/mL) and meaningful clinical consequences: one severe allergic reaction during the second GP2013 infusion leading to treatment discontinuation, and a loss of efficacy with incomplete B depletion in 2 patients leading to RTX dose escalation from 500 mg to 1 g. Among the 151 patients not immunized at the time of the first sample, no severe allergic reaction and 6 minor allergic reactions were noted under GP2013.Conclusion:The immunogenicity of patients treated with RTX is a rare event with possible clinical and biological consequences, especially in patients with high antibody levels.References:[1]Smolen et al, Ann Rheum Dis 2017[2]Tony et al, Arthritis Care Res 2019Disclosure of Interests:None declared

Long-Term Control of Urinary Free Cortisol With Osilodrostat in Patients With Cushing’s Disease: Final Results From the LINC 2 Study

Introduction: During the 22-week core LINC 2 study, the oral 11β-hydroxylase inhibitor osilodrostat normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease. This report describes long-term LINC 2 efficacy and safety results following an optional extension. Methods: Patients receiving clinical benefit at week 22 could enter the extension (that ran until Oct 22, 2019), continuing the same osilodrostat dose; dose adjustments were permitted based on efficacy and safety. Response rate (mUFC ≤ULN [controlled] or mUFC &gt;ULN but ≥50% decrease from baseline [BL; partially controlled]) was assessed over time. Efficacy/safety were assessed for all patients from core BL until study end. Results: Of 19 enrolled patients (female:male 14:5; mean [SD] age 36.8 years [8.4]), 16 entered the optional extension and 8 of them remained on treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2-351). Mean mUFC decreased from BL (9.9 x ULN) to ≤ULN by week 4 and remained stable throughout the study. All 19 patients achieved mUFC ≤ULN at least once during the study. At each assessment up to month 70 of the extension phase, 50-88% of ongoing patients were controlled, and up to 18% were partially controlled. Mean percentage change in clinical signs from BL (mean [SD]) to last assessment were: fasting plasma glucose, -10.8% (22.1) (from BL: 105.6 mg/dL [49.2]); HbA1c, -2.1% (9.0) (from BL: 5.7% [0.7]); systolic BP, -3.3% (12.6) (from BL: 132.6 mmHg [11.6]); diastolic BP, -2.0% (10.4) (from BL: 85.0 mmHg [6.5]); BMI, -5.9% (8.8) (from BL: 30.7 kg/m2 [7.0]). Overall, 9 patients discontinued treatment (n=2 core and n=7 extension), mostly because of AEs or no longer requiring treatment (n=3 each). The most common AEs during the entire treatment period were nausea (n=10), adrenal insufficiency, and headache (both n=9). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n=9) and 12 patients (mostly hypertension, n=4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or concomitant medication. Mean (SD) plasma ACTH increased from 1.8 x ULN (0.9) at BL to 7.1 x ULN (12.3) at week 22 and 6.9 x ULN (12.6) at last assessment. Mean (SD) 11-deoxycortisol increased from 1.2 x ULN (1.3) at BL to 13.6 x ULN (12.2) at week 22 and 3.6 x ULN (4.2) at last assessment. In females, mean (SD) testosterone increased from 0.8 x ULN (0.4) at BL to 2.4 x ULN (2.1) at week 22 and 1.0 x ULN (0.9) at last assessment. Two patients, both female, reported an AE of hirsutism. Conclusions: Rapid reductions in mUFC were sustained for up to 6 years of osilodrostat treatment and were accompanied by improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.

A Case of Successful Treatment of Gram-Negative Sepsis Associated with Toxic Myelosuppression in a Patient with HIV-Associated Non-Hodgkin’s Lymphoma

This article presents a clinical case of successful treatment of gram-negative sepsis in a patient with HIV-associated non-Hodgkin’s lymphoma. The patient was admitted to the intensive care unit in critical condition after the third course of polychemotherapy according to the ICE scheme. The severity of the condition was due to nosocomial pneumonia, septic shock, multiple organ failure, immunosuppression against the background of PCT and HIV infection, and the lack of specific treatment for HIV infection. Despite the absence of a positive blood culture throughout the entire treatment period, the diagnosis of sepsis was not in doubt, according to the criteria of the 2001 International Consensus Conference on Sepsis. The cause of the septic state was the combined effect of bacteria (Pseudomonas aeruginosa) and fungi (Candida albicans, Candida krusei) against the background of persistent HIV infection. The patient’s pneumonia was destructive and was twice aggravated by spontaneous pneumothorax. At the initial stage, intensive therapy led to positive dynamics. The severity of the systemic inflammatory response decreased, the acute respiratory insufficiency regressed, the X-ray pattern improved, and laboratory parameters stabilized. Despite the continued intensive therapy in the former volume on day 19, a sharply negative dynamics was noted, which led to a re-transfer of the patient to artificial ventilation of the lungs. The replacement of antibiotics and the specific treatment of HIV infection led to the patient’s recovery. In the future, chemotherapy was not carried out. Remission of the disease lasts six years.

Long-Term Efficacy and Safety of Deutetrabenazine for Chorea in Huntington’s Disease: Results From the ARC-HD Open-label Study

BackgroundChorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.MethodsPatients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.ResultsOf 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.ConclusionsThe type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel