Prolonged Treatment Of Patients Research Articles

Exploring Remission Dynamics and Prognostic Factors in Lichen Planopilaris: A Retrospective Cohort Study

Introduction: Lichen planopilaris (LPP) is a common type of primary cicatricial alopecia. Previous studies focused on the epidemiology, clinical characteristics, and treatment of LPP. A lack of knowledge regarding LPP outcomes and prognostic factors remained. Methods: To delineate the rate and timing of remission in LPP, as well as the prognostic factors for achieving remission, a retrospective cohort study was conducted. The study included 126 patients, from a single tertiary center, diagnosed with LPP between January 2010 and December 2022, who were followed up for a minimum of 6 months. Results: There were 89 (70.6%) women and 37 (29.4%) men included in this study. The mean age of the patients was 47.92 ± 14.2 years. The mean time from disease onset to diagnosis was 33.85 (±30) months, indicating significant diagnostic delays. The mean duration of follow-up was 34.13 ± 22.7 months. Among the cohort, 43 patients achieved complete remission (CR) during the follow-up period, whereas 83 patients did not. Of the 83 patients who did not achieve CR, 35 partially improved and 48 did not improve or worsened. The median time for achieving CR was 46 ± 18.8 months. Milder disease at presentation and comorbid lichen planus were associated with higher CR rates. Conclusion: This study demonstrates significant diagnostic delays that should be addressed as LPP causes irreversible alopecia, suggests disease severity and comorbid lichen planus as potential prognostic factors. Further, it emphasizes the limited efficacy of current treatments and the need for prolonged treatment in patients with LPP to achieve remission.

519 - Efficacy of prolonged ruxolitinib cream treatment for vitiligo among patients with limited or no initial response at 6 months

Abstract Introduction/Background Vitiligo is a chronic autoimmune disease characterized by melanocyte destruction, leading to skin depigmentation. Limited data are available regarding the efficacy of long-term topical vitiligo treatment. In 2 randomized, double-blinded, vehicle-controlled phase 3 studies in adults and adolescents (aged ≥12 y) with nonsegmental vitiligo (TRuE-V1 [NCT04052425]; TRuE-V2 [NCT04057573]), ruxolitinib cream application resulted in statistically superior improvements in repigmentation versus vehicle in the primary and all key secondary endpoints at Week 24 and was well tolerated. In the open-label period of TRuE-V1/TRuE-V2 (Weeks 24–52) and the TRuE-V long-term extension (LTE; Weeks 52–104) study (NCT04530344), further improvements in facial and body repigmentation (as assessed by Vitiligo Area Scoring Index [VASI] responses) were observed through Week 104 among patients who continued to apply ruxolitinib cream. Objectives In this pooled analysis, we evaluated shifts in facial and total body VASI (F-VASI/T-VASI) responses among patients with vitiligo who had limited or no repigmentation at Week 24 and who continued to apply ruxolitinib cream for an additional 80 weeks. Methods In TRuE-V1/TRuE-V2, patients were randomized 2:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Patients who completed TRuE-V1/TRuE-V2 were eligible to enroll in the TRuE-V LTE. Patients who did not achieve ≥90% improvement in F-VASI at Week 52 continued to apply open-label 1.5% ruxolitinib cream until Week 104. Patients initially randomized to apply ruxolitinib cream who had <25% improvement from baseline in F-VASI or T-VASI at Week 24 and had non-missing VASI assessments at the evaluated time points were included in this analysis. Shifts in F-VASI and T-VASI were assessed among patients with no facial/body repigmentation or worsening depigmentation (≤0% improvement in F-VASI/T-VASI) and patients with limited facial/body repigmentation (>0%–<25% improvement in F-VASI/T-VASI) at Week 24. Results Among patients with no facial repigmentation at Week 24, improvements in F-VASI at Weeks 52 and 104 were observed in 77.8% (49/63) and 97.1% (34/35) of patients, respectively. Among patients with limited facial repigmentation at Week 24, F-VASI improvements at Weeks 52 and 104 were observed in 64.0% (32/50) and 83.3% (30/36) of patients, respectively. Across both groups, 54.9% (39/71) of patients achieved ≥75% improvement from baseline in F-VASI (F-VASI75) at Week 104. Among those with no body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 79.6% (39/49) and 93.3% (28/30) of patients, respectively. For those with limited body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 64.5% (80/124) and 81.6% (62/76) of patients, respectively. Across both groups who had <25% improvement in total body repigmentation at Week 24, 50.0% (53/106) of patients achieved ≥50% improvement in T-VASI (T-VASI50) at Week 104. Conclusions In the TRuE-V studies, ruxolitinib cream application for an additional 80 weeks resulted in improved repigmentation among patients with nonsegmental vitiligo who had limited or no repigmentation at Week 24. These 2-year TRuE-V results highlight the importance of prolonged treatment in patients with vitiligo, even when minimal or no repigmentation is achieved after 6 months of treatment.

Efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma with fungal sensitization.

Fungal sensitization (FS) exacerbates asthma in patients who have elevated type 2 inflammatory response. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases. This post hoc analysis, funded by the manufacturers of dupilumab, was conducted to assess dupilumab efficacy in patients from the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) and TRAVERSE open-label extension (NCT02134028) study who had uncontrolled, moderate-to-severe asthma with type 2 inflammatory phenotype (defined as blood eosinophil count ≥150 cells/μL or FeNO ≥25 ppb) and with FS (defined as IgE specific to Alternaria alternata, Aspergillus fumigatus or Cladosporium herbarum >0.35 IU/mL). We evaluated annualized rate of severe exacerbations (AER), change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1 ), asthma control (per 5-item Asthma Control Questionnaire [ACQ-5]) and biomarker levels (blood eosinophil count, fractional exhaled nitric oxide [FeNO], total IgE, fungal-specific IgEs, thymus and activation-regulated chemokine [TARC] and eotaxin-3). Dupilumab vs. placebo reduced AER, improved pre-BD FEV1 and asthma control (ACQ-5), and reduced serum IgE levels, blood eosinophil count, TARC, eotaxin-3 and FeNO in patients both with and without FS after 52 weeks of treatment in QUEST. Reductions in asthma exacerbation rates and improvements in all other variables were sustained over the TRAVERSE open-label extension study. Dupilumab demonstrated efficacy during prolonged treatment in patients with uncontrolled, moderate-to-severe asthma with FS.

TRIAZOLE RESISTANCE IN ASPERGILLUS FUMIGATUS-A COMPREHENSIVE REVIEW

Aspergillus fumigatus is a common ubiquitous fungal pathogen present in the environment including soil, decaying leaves, compost, grain crops and household dust. It can turn opportunistic in immunocompromised individuals causing allergic diseases, respiratory problems and invasive blood stream infections. Being saprophytic, it propagates by producing minute grey-green conidia that can become airborne and reach humans. In majority of cases, aspergillosis due to this organism can heal with treatment by antifungals. The azole compounds, one of the most important antifungal drugs, generally target the 14-α sterol demethylase enzyme, encoded by the cyp51A gene of the fungus, causing impaired membrane ergosterol synthesis. However in recent years the situation has turned grave due to development of azole resistant fungal species both in the environment as well as in the clinics. The main mechanism of resistance in A. fumigatus involves incorporation of tandem repeats in the promoter region of cyp51A, along with point mutations in the gene sequence. Resistant isolates tend to arise either due to excessive use of azole fungicides in the agricultural fields, from where they reach human through sporulation; or by prolonged treatment of patients with azole drugs. The early diagnosis of aspergillosis is very crucial for successful treatment of a patient. The article brings forth a comprehensive study of this organism, the mechanism of development and spread of azole resistant fungal isolates, genetic basis of development of azole resistance, detection of resistant strains and finally drugs used to combat the fungal infection.

Practical recommendations for screening and management of functional disorders of the adrenal cortex in cases of SARS-CoV-2 infections

Erkrankungen der Nebennierenrinde erfordern im Rahmen der Severe-acute-respiratory-syndrome-coronavirus-2(SARS-CoV-2)-Pandemie eine besondere Aufmerksamkeit. Zum einen können SARS-CoV-2-Infektionen sich auch extrapulmonal manifestieren und endokrine Störungen – insbesondere im Bereich der Nebennierenrinde – verursachen. Zum anderen sind Patienten mit einer vorbestehenden Nebennierenrindeninsuffizienz oder einem Hyperkortisolismus durch eine schwerwiegende Infektion wie etwa mit SARS-CoV‑2 besonders gefährdet, zusätzliche Komplikationen oder einen schwerwiegenderen Verlauf einer akuten SARS-CoV-2-Infektion mit erhöhter Mortalität zu erleiden. Insbesondere bei hämodynamisch instabilen Patienten mit SARS-CoV-2-Infektion müssen deshalb auch Erkrankungen der Nebennieren differenzialdiagnostisch erwogen und gegebenenfalls abgeklärt werden, falls diese nicht bereits anamnestisch bekannt sind. Weiterhin kann auch die Therapie einer SARS-CoV-2-Infektion mit hohen Glukokortikoiddosen über einen längeren Zeitraum eine sekundäre Nebennierenrindeninsuffizienz verursachen. Wir stellen hier deshalb eine Praxisempfehlung zur Erkennung und Therapie von Nebennierenfunktionsstörungen bei Patient*innen mit SARS-CoV-2-Infektion vor.

TRIAZOLE RESISTANCE IN ASPERGILLUS FUMIGATUS-A COMPREHENSIVE REVIEW

Aspergillus fumigatus is a common ubiquitous fungal pathogen present in the environment including soil, decaying leaves, compost, grain crops and household dust. It can turn opportunistic in immunocompromised individuals causing allergic diseases, respiratory problems and invasive blood stream infections. Being saprophytic, it propagates by producing minute grey-green conidia that can become airborne and reach humans. In majority of cases, aspergillosis due to this organism can heal with treatment by antifungals. The azole compounds, one of the most important antifungal drugs, generally target the 14-α sterol demethylase enzyme, encoded by the cyp51A gene of the fungus, causing impaired membrane ergosterol synthesis. However in recent years the situation has turned grave due to development of azole resistant fungal species both in the environment as well as in the clinics. The main mechanism of resistance in A. fumigatus involves incorporation of tandem repeats in the promoter region of cyp51A, along with point mutations in the gene sequence. Resistant isolates tend to arise either due to excessive use of azole fungicides in the agricultural fields, from where they reach human through sporulation; or by prolonged treatment of patients with azole drugs. The early diagnosis of aspergillosis is very crucial for successful treatment of a patient. The article brings forth a comprehensive study of this organism, the mechanism of development and spread of azole resistant fungal isolates, genetic basis of development of azole resistance, detection of resistant strains and finally drugs used to combat the fungal infection.

Clinical features of BPPV and their influence on the choice of the doctor’s tactics

BPPV is the most common cause of recurrent vertigo. Except vertigo attacks main clinical symptoms of BPPV can include autonomic symptoms and imbalance, which sometimes complicate the diagnosis of BPPV. A total of 640 patients (504 (78.8%) women) aged from 20 to 86 years old, mean age 56.43±0.54 years with BPPV were included and diagnosed by roll and Dix-Hallpike tests. Among them 144 (22.5%) patients were inpatient and 496 (77.5%) patients were outpatient. The detailed patient intake comprised the disease onset, the type of dizziness, vertigo triggers, autonomic symptoms, similar attacks in the past and previously made definite diagnosis of BPPV. The period from the appearance of the first symptoms to the correct diagnosis was assessed. The majority of patients (75.3%) consult a neurologist at the initial visit. Only 30.6% of patients had a correct diagnosis within a week of the onset of the disease. Initial BPPV symptoms included persistent dizziness that increased with head turns (38.8%), nausea and vomiting (21.6%), significant increase in blood pressure (13.4%), persistent imbalance while walking (73.4%). Inpatients more frequently had constant continuous dizziness, high blood pressure, severe nausea and vomiting, and the onset of symptoms in the morning when getting out of bed (p<0.05). Initial BPPV symptoms may be similar to other diseases. Focusing on medical history and complaints leads to frequent diagnostic errors, unnecessary hospitalization and prolonged treatment of patients. Positional tests are necessary for the correct diagnosis of BPPV.

P069 ONTAMALIMAB, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1, PROVIDES SUSTAINED EXPOSURE FOLLOWING LONG-TERM TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS

Abstract Introduction Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters. Methods A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated. Results The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss. Conclusion The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.

Endoscopic papillectomy for tumors of the major duodenal papilla

Aim.To evaluate an effectiveness of endoscopic papillectomy (EA) for benign ampullary tumors.Material and methods.There were 45 patients with ampullary tumors who underwent endoscopic papillectomy in 2014–2018. Mean dimension of tumor was 2.25 ± 1.75 cm.Results.Papillectomy was successfully performed in all cases. En-bloc resection was completed in 24 cases (53%), while 21 (47%) patients had a piecemeal resection. Pancreatic duct stenting was carried out in 30 (67%) cases. Postoperative complication rate was 31%. Postoperative bleeding occurred in 8 (18%) cases, perforation in 4 (8.9%) cases, acute pancreatitis in 2 (4.4%) cases. Mortality was 4.4 % (n= 2). Local recurrence rate within 4-year period was 2.2% (n= 1). Mean length of hospital-stay was 13 days (13 ± 11) considering prolonged treatment of patients with complicated postoperative period.Conclusion.Endoscopic papillectomy is effective minimally invasive treatment of benign ampullary tumors. Regardless considerable morbidity rate, all of them may be effectively managed by medication or endoscopic procedure. EP can be considered as a first-line treatment of benign ampullary tumors.

Abstract 141: Resuscitation Time Bias in an Observational Study of Mechanical Chest Compression CPR

Recent observational studies have found associations between poorer outcomes and treatment that included mechanical CPR devices, contradicting findings from randomized trials. Resuscitation time bias is a systematic error occurring in observational studies of interventions applied to pulseless patients later in resuscitation attempts. Previous observational studies lack data on duration of resuscitation, a factor strongly related to outcome. We retrospectively analyzed cardiac arrest data to learn how resuscitation time and device use relate to clinical outcomes, and determine whether resuscitation time bias was present. Methods and Results: We analyzed data from all 49 patients with ventricular fibrillation, out-of-hospital cardiac arrest treated by our emergency medical service in one year. We compared 19 patients who received only standard manual CPR (the sCPR group) to 30 patients who received manual followed by mechanical CPR (the mCPR group). Response to CPR differed between groups even before device application. All sCPR patients achieved return of spontaneous circulation (ROSC), and did so after a median (IQR) of 3.3 (2.2-5.1) minutes of manual CPR. Patients in the mCPR group failed to get ROSC through 6.9 (5.3-11.0) min of manual CPR; mCPR patients that did get ROSC did so after 11.2 (5.7-23.8) additional minutes of CPR, delivered by a mechanical device. mCPR patients also received significantly more defibrillations and ALS drugs. ROSC and survival to hospital discharge were higher in the sCPR than the mCPR group (100% vs. 70%, P = 0.008; 74% vs. 43%, P = 0.045). Conclusion: Only patients remaining pulseless after early resuscitation efforts received mechanical CPR. Consequently, mechanical CPR devices assisted by facilitating prolonged treatment of patients who already had lower chances of survival before device application. Resuscitation time bias was present, and must be considered when interpreting registry reports comparing sCPR and mCPR.

Prolonged treatment of patients with cancer associated thromboembolism (CAT). mapping of treatment landscape based on a German statutory health insurance (SHI) claims data analysis [CERTIFICAT

e18855Background: CAT is a common complication of cancer and its therapy with impact on overall prognosis. Since 2003 (CLOT, NEJM) low molecular weight heparin (LMWH) instead of vitamin K antagonis...

Діагностика цитолітичного синдрому у хворих на туберкульоз легень

Introduction. The liver is one of the most important organs of the human body, performing a number of important functions. Among the common liver diseases, infiltrative pathologies we distinguished: fatty degeneration, lymphomas, amyloidosis, sarcoidosis and tuberculosis. Characterizing liver disease, the manifestations of disorders are divided into syndromes that help to diagnose a particular disease of the liver and determine its causes. In particular – the cytolytic syndrome (CS).The aim of the study – to examine the CS markers in the case of liver dysfunction in patients with newly diagnosed lung tuberculosis prior to treatment and after two months of therapy with first-line anti-tuberculosis drugs.Methods of the research. Two groups of people were examined: the 1st control group of practically healthy donors – 34 people; and the 2nd – patients with newly diagnosed pulmonary tuberculosis prior to treatment and after two months of therapy with first-line anti-tuberculosis drugs (31 people). All patients underwent standard biochemical blood tests, ultrasound of the liver in dynamics. The spectrum of biochemical blood test parameters included determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and γ-glutamyltranspeptidase (GGTP).Results and Discussion. The obtained data testifying to occurrence of CS in newly diagnosed tuberculosis patients before the start of treatment are confirmed by the tendency to increase the levels of AST and GGTP. Especially such changes are observed after intensive therapy with antituberculous drugs. There are likely changes in such markers as ALT, LDH and GGTP.Conclusions. It is established that tuberculous intoxication can affect the functional state of the liver. After prolonged treatment of patients with pulmonary tuberculosis, an increase in the indices of such markers of cytolysis as ALT, LDH and GGTP is observed. Disturbance of liver function during therapy may be due to the hepatotoxic effect of anti-tuberculosis drugs, which necessitates the appointment for patients hepatoprotectors.

Continued Use of Tinzaparin at Therapeutic Doses for Prophylaxis of Venous Thromboembolism in Patients with Intolerance to Antivitamins K

OBJECTIVESThe low molecular weight heparins (LMWH) are typically administered at fixed doses like thromboprophylaxis or at doses adjusted to the weight of the patient in order to obtain a therapeutic effect. Generally they do not require laboratory monitoring, although it could be considered in special situations (renal failure, extreme weights, pregnant women). The LMWH do not affect the APTT, so it has been proposed to determine the anti-factor Xa activity when it is necessary to monitor its effect. The anti-factor Xa activity should be determined approximately 4 hours after sc administration of the LMWH that it is employed, concurring with the peak of activity. The therapeutic range of the anti-factor Xa activity is between 0.6 and 1 IU / mL when LMWH is administered every 12 hours. At single daily dose is less clear, although it seems that lies above 1 IU / mL.Nowadays, LMWH are the anticoagulant of choice during pregnancy. Numerous in vitro and in vivo studies have shown the existence of an antineoplastic effect of heparin. LMWH is commonly used for prolonged treatment of thrombosis associated with cancer.METHODSThe main aim of our study is to evaluate the efficacy of tinzaparin sodium at therapeutic doses in preventing VTE in renal failure, active cancer and/or patients with contraindications to oral anticoagulation. The dose has been therapeutic and adjusting it has been made in terms of anti-factor Xa levels obtained monthly. Hemorrhagic or thrombotic complications and other possible side effects have been assessed.Until now, a total of 70 patients, 42 men and 28 women aged between 30 and 95 years old, have received tinzaparin sodium treatment. The main reason of anticoagulation are: atrial fibrillation and atrial flutter (with or without valve disease), VTE (with or without thrombophilia), stroke and transient ischemic attacks and mechanical prosthetic aortic and mitral valves (some of the patients carrying a double metal prosthesis). There was 1 resistance and 1 allergic reaction to anti-vitamin K. 4 of the patients were pregnant and 14 had renal failure. Prior to initiation of therapy, analytical determinations were performed, including: blood count, blood coagulation and biochemistry to assess renal function (urea and creatinine).20 patients (14 were anticoagulated by atrial fibrillation, 2 for bearing a mechanical aortic prosthesis and 4 because of DVT, 1 of which had also a TEP) had active cancer or were in remission from their neoplasia (3 multiple myeloma, 1 LAM, 1 CMML, 4 renal tumors, 1 lung cancer, 5 prostate cancers, 1 hepatocellular carcinoma, 2 colon cancer, 1 endometrial adenocarcinoma and 1 retroperitoneal leiomyosarcoma). 1 with MDS was treated with LMWH because he had intra- and extrahepatic portal vein thrombosis.RESULTSSome of the patients had received prior treatment with anti-vitamin K (INR objective depending on pathology) but, in other cases, the low molecular weight heparin was the only treatment since the beginning of their anticoagulation. All the patients had received 175 IU / Kg of Tinzaparin Sodium once a day as initial dose, then the dose was adjusted according to the anti-factor Xa levels. They were controlled until 31/07/2015.In terms of side effects, 8 patients presented complications: 3 mucosal bleeding, 2 episodes of stroke in a patient, hemoptysis, deep vein thrombosis and 2 bleeding at the puncture site of heparin, which have not required discontinuation of therapy. When these complications occurred, we proceeded to the corresponding heparin dose adjustment based on new determinations of anti-factor Xa.CONCLUSIONSAlthough only in 70 cases, the results obtained confirm the efficacy, safety and cost-effectiveness of the continuous use of LMWH. Determination of anti-factor Xa levels are considered very useful for dose adjustment parameter. In our study, tinzaparin sodium has proved to be very useful in preventing venous thromboembolism associated or not with cancer, in patients with conditions requiring anticoagulation and presenting contraindications to the use of anti-vitamin K.The results obtained have demonstrated that tinzaparin is safe and, most likely, further studies will provide valuable confirmation data to support the use of low molecular weight heparins in the prolonged treatment of patients who require oral anticoagulation and can not receive it. DisclosuresNo relevant conflicts of interest to declare.

Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimizing systemic activity

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions characterized by chronic, uncontrolled inflammation of the gastrointestinal tract. Reported prevalence is high in the United States and northern Europe, while the incidence varies greatly across the rest of Europe. Glucocorticosteroids are the standard treatment for IBD, but due to adverse events their use can be limited. However, new formulations of glucocorticosteroids have been developed to reduce systemic activation. The aim of this review was to assess and summarize the efficacy and safety of new formulations of glucocorticosteroids. A MEDLINE search identified publications focused on new formulations of nonsystemic steroid-based drugs for IBD and benefits and limitations of each of the new glucocorticosteroid formulations were identified. Budesonide has good efficacy and is an established treatment for Crohn's disease; it has been shown to be beneficial for the induction of remission in these patients, although it is not recommended for the maintenance of induced remission. Glucocorticosteroids are not recommended for the maintenance of remission in patients with IBD. However, a recent study suggested that beclomethasone dipropionate may be effective for prolonged treatment in patients in the postacute phase of Crohn's disease who were treated with a short course of systemic steroids. The efficacy of fluticasone propionate and prednisolone metasulphobenzoate in IBD is not well established given the small number of patients enrolled in the few published clinical trials. While the tolerability of these glucocorticosteroids is favourable, more research comparing these new agents with traditional systemic glucocorticosteroids is warranted.

Prolonged treatment with pegylated interferon α 2b plus ribavirin improves sustained virological response in chronic hepatitis C genotype 1 patients with late response in a clinical real‐life setting in Japan

This study was conducted to clarify the factors related to sustained virological response (SVR) to pegylated interferon alpha 2b (PEG-IFN) plus ribavirin (RBV) combination therapy administered for 48 weeks in patients with chronic hepatitis C virus (CHCV) and to evaluate the usefulness of prolonged treatment in patients with late virological response (LVR). Of 2257 patients registered at 68 institutions, those with genotype 1 and high viral load were selected to participate in two studies. Study 1 (standard 48-week group, n = 1480) investigated SVR-determining factors in patients who received the treatment for </=52 weeks, whereas study 2 compared SVR rates between patients with LVR who received treatment for either 36-52 weeks (48-week group, n = 223) or 60-76 weeks (72-week group, n = 73). In study 1, SVR rate was 44.9%; that in male subjects (50.4%) was significantly (P < 0.0001) higher than in female subjects (36.4%). SVR rate significantly (P < 0.0001) decreased with 10-year age increments in both sexes. Multivariate logistic regression analysis revealed that age, F score, platelet count, and HCV load were SVR-related factors. In study 2, SVR rate in the 72-week group (67.1%) was significantly (P = 0.0020) higher than in the 48-week group (46.2%). Patients with CHCV genotype 1 infection should be treated with PEG-IFN plus ribavirin combination therapy as early as possible, and 72 weeks' treatment is recommended in patients with LVR regardless of age.

The Selective Proteasome Inhibitor Carfilzomib Is Well Tolerated in Experimental Animals with Dose Intensive Administration

Carfilzomib (CFZ) is a selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Phase I trials have demonstrated that doses of carfilzomib from 11 – 20 mg/m2 were well tolerated, inhibited blood CT-L activity by ≥80%, and resulted in objective anti-tumor responses in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) (Blood 110:409 & 411). In order to further characterize the safety profile of CFZ, studies in mice, rats and monkeys were conducted to assess the toxicologic consequences of acute and chronic administration. In both rats and monkeys, a single dose of CFZ (equivalent to 24 mg/m2) resulted in > 80% inhibition of CT-L activity in blood and tissues with recovery occurring in most tissues with a t1/2 of 24 hr. At this dose, monkeys developed a pre-renal azotemia within 24 hr, which was characterized by increases in serum creatinine, blood urea nitrogen (BUN) levels and urine specific gravity. These changes resolved in 72 hr, were not associated with histologic changes in the kidney, and were not exacerbated by consecutive daily administrations, suggesting that CFZ may not have a direct nephrotoxic effect. A single dose in either rats or monkeys induced a transient drop in platelets within 48 hr that resolved within 7 days and neither the level of nor recovery from this thrombocytopenia were affected by consecutive daily administration. This phenomenon has also been noted with bortezomib (BTZ), and is observed clinically with both compounds, suggesting that thrombocytopenia is a hallmark of inhibition of proteasome CT-L activity. However, in contrast to BTZ, which has been reported to induce both lymphopenia and neutropenia in animals, CFZ treatment in both rats and monkeys resulted in acute increases in circulating neutrophils and monocytes which rose within 24 hr of a single dose and returned to baseline in 3 – 4 days. We were unable to detect a significant induction of cytokines or chemokines capable of mediating leukocyte fluxes. However, since the acute phase proteins fibrinogen and C-reactive protein were elevated during the same time period of leukocyte flux, cytokines may play a role in this response. In chronic studies, CFZ was administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle to rats and monkeys for 6 and 9 cycles, respectively. This dosing schedule results in anti-tumor activity in mouse models of MM, NHL and solid tumors and is currently being utilized in Phase 2 studies in MM and solid tumors. In these chronic studies, transient pre-renal azotemia and increases in circulating neutrophils were manifest in monkeys at 24 mg/m2 following the first dose of both the first and last cycles of treatment. However, no histologic signs of nephropathy were seen in the kidneys of rats receiving 6 cycles of treatment. In addition, chronic administration of CFZ at doses equivalent to those currently administered in the clinic did not impact on the neurobehavioral function of rats and monkeys. There was no severe degeneration in the dorsal root ganglion or in the sciatic, sural, and peroneal nerves of CFZ treated rats. The data with CFZ are in distinct contrast to the axonal swelling, demyelination and severe neural degeneration that is induced by BTZ in rodents and monkeys. In the clinic, peripheral neuropathy associated with CFZ treatment appears to be less severe and possibly less frequent than what is seen with BTZ. Overall, studies in rodents and monkeys have been largely predictive of the clinical experience to date with CFZ. Together with anti-tumor activity in human tumor xenograft models, the toxicologic data support that CFZ administered at therapeutic doses is well tolerated and prolonged treatment of patients with this agent will be feasible.

Espasmo hemifacial: más de 10 años de tratamiento con toxina botulínica

The short-term beneficial and adverse effects of treatment with botulinum toxin (BT) in hemifacial spasm (HS) are well documented, but this is not the case with its long-term derivatives. AIMS. To describe the characteristics, the dose development, the side effects and the reason for giving up therapy in patients who have been on BT treatment for more than 10 years. We also sought to evaluate the effectiveness and safety of prolonged treatment in patients with HS. We reviewed the demographic and clinical characteristics of patients who had had HS for more than 10 years since follow-up began. We analysed the mean dose development of BT per visit and year, the number of sessions per year, side effects and reasons for dropping out. We focused our attention on cases with more than 10 years' continuous treatment. The percentage of patients who had been on treatment for over ten years was 53.7%. The mean dose of BT per year rose progressively, and was significant (p < 0.05) during the first four years of treatment. There was no significant increase in the number of sessions. Altogether 46 side effects were observed, ptosis being the most frequent. These occurred during the first years of the early stages of the technique. The most common cause of dropout was loss to follow-up in 22 patients, followed by death in 11 cases. BT is a feasible, safe treatment option (with very few benign side effects) in the prolonged treatment of patients with HS.

Imatinib mesylate in the treatment of advanced gastrointestinal stromal tumors

To evaluate the efficacy and safety of imatinib mesylate in the treatment of patients as preoperative supplement, or used alone for unresectable and/or metastatic gastrointestinal stromal tumors (GIST). A total of 51 cases with advanced GIST were proved pathologically. Among them, CD117 was detected positive in 47 patients and negative in 4 patients; 4 patients received imatinib mesylate before operation and 47 patients with unresectable and (or) metastatic GIST received oral imatinib mesylate daily at dose of 300-800 mg. One patient was lost in follow-up and the objective effect was evaluated in 50 patients. 3 of the 50 patients (6.0%) achieved complete response (CR), 34 (68%) had partial response (PR), 5 (10.0%) had stable disease (SD) and 8 (20.0%) had progression disease (PD). The median time to progression (mTTP) was 16 months during which most of the patients experienced benefit. 32 patients had been followed up for more then 1 year. The 1-year and 2-year survival rate were 95.3%, 89% respectively. 50 patients were valuable for the toxicity assessment according to the WHO standard. The main toxicity included grade I-II edema of periorbital area and lower limb in 72.0% (36/50) patients, leukopenia was present in 46% (23/50) and intratumoral bleeding in 4.0% (2/50). Other toxicities included mild fatigue (28.0%), abdominal pain (14.0%), efflorescence (18.0%), nausea and vomiting (18.0%). As an inhibitor of tyrosine kinase, imatinib mesylate is generally well tolerated and has been proved to be effective and safe during prolonged treatment of patients with advanced gastrointestinal stromal tumors. Its toxicity is acceptable.

We-P11:191 The results of prolonged treatment of patients with diabetes mellitus and arterial hypertension with perindopril

We-P11:191 The results of prolonged treatment of patients with diabetes mellitus and arterial hypertension with perindopril

5‐Fluoro‐2′‐deoxyuridine Has Effects on Mitochondria in CEM T‐Lymphoblast Cells

AbstractFor Abstract see ChemInform Abstract in Full Text.