Results Of Multicenter Clinical Trials Research Articles

Therapeutic aspects of melatonin applications

The results of multicenter clinical trials show the broad potential of melatonin since discovery of this adaptogen to the present day. Melatonin is a neuropeptide that is synthesized mainly in the small brain gland, the pineal gland, and has a unique effect in humans and animals. Using melatonin, the pineal gland participates in the organization of circadian periodism and regulation of cyclic processes, acting as an intermediary between the pacemaker mechanism of the suprachiasmatic nuclei (SCN) and peripheral organs. The pineal gland and the SCN of the hypothalamus form part of the system of the so-called biological clock of the body, which plays a key role in the mechanisms of regulation of the biological clock via circadian rhythms and ageing. Initially, melatonin was only considered a hormone involved in the synchronization of the mechanisms of the circadian rhythm, but later it was found that, in addition to this hormonal function, it takes part in the regulation of the seasonal cycle in animals and humans.At present, melatonin drugs have shown high efficacy and safety in various sleep-wake disorders regardless of their genesis, disorganization of circadian rhythms, stress adjustment disorders, rapid change of time zones, shift work and in complex therapy of patients with cerebrovascular diseases.The article considers the multimodal capabilities of melatonin, including adaptogenic, biorhythmogenic, hypnotic, immunostimu-lating, antioxidant effects. The role of melatonin in the treatment of various central nervous system disorders, including neurodegenerative diseases, has been determined.The review emphasizes the wide-ranging effects of melatonin and offers great opportunities for measuring melatonin as a biomarker for early detection and follow-up of various diseases.

Latest findings of treatment and prevention of medication-related osteonecrosis of the jaw : Results of multicenter clinical trials

Latest findings of treatment and prevention of medication-related osteonecrosis of the jaw : Results of multicenter clinical trials

ОБЗОР БЕЗОПАСНОСТИ АТОРВАСТАТИНА: СОВРЕМЕННЫЕ ВЗГЛЯДЫ

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. According to the World Health Organization, in 2016 about 17.9 million people died from CVD, and this accounted for 31% of all deaths in the world. Dyslipidemia is one of the main risk factors of atherosclerosis, asymptomatic and acute ischemic heart disease (IHD), cerebrovascular accidents, and sudden cardiac death. The results of multicenter clinical trials (RCT) conducted in the Russian Federation and abroad have demonstrated that one of the effective methods of primary and secondary prevention of CVD, as well as reducing the risk of complications in the high and very high-risk patients, is the use of lipidlowering drugs belonging to HMG-CoA reductase inhibitors (statins). The article presents the results of an analysis of publications describing the safety of Atorvastatin, recognized as one of the most effective drugs in the group. Particular attention is paid to the mechanisms of insulin resistance, hepatotoxicity and statin-induced myopathies.

Intra- and Inter-Physician Agreement in Therapeutic Decision for Sleep Apnea Syndrome

BackgroundLarge variation in diagnostic procedures and treatment recommendations may hinder the management of obstructive sleep apnea (OSA) and also compromise correct interpretation of the results of multicenter clinical trials, especially in subjects with non-severe OSA. The aim of this study was to analyze the therapeutic decision-making between different sleep physicians in patients with AHI<40events/h. MethodsSix experienced senior sleep specialists from different sleep centers of Spain were asked to make a therapeutic decision (CPAP treatment) based on anonymized recordings of patients with suspected OSA that has previously performed a sleep study. The clinical data was shown in an online database and included anthropometric features, clinical questionnaires, comorbidities, physical examination and sleep study results. Intra- and inter-observer decision-making were analyzed by the Fleiss tm) Kappa statistics (Kappa). ResultsA total of 720 medical decisions were taken to analyze the agreement between sleep professionals. Overall intra-observer evaluation reliability was almost perfect (Kappa=0.83, 95% CI, 0.75•0.90, p<0.001). However, overall inter-observer concordance decreased to moderate agreement (Kappa=0.46, 95% CI, 0.42•0.51, p<0.001). Nevertheless, it was especially low when considering AHI<15events/h. ConclusionsThis study demonstrates a good intra-observer concordance in the therapeutic decision-making of different sleep physicians treating patients with low/moderate OSA. However, when analyzing inter-observer agreement the results were considerably worse. These findings underline the importance of developing improved consensus management protocols.

Возможности применения ингибиторов фактора роста эндотелия сосудов при лечении детей с ретинопатией недоношенных

The article addresses current treatment modalities for threshold retinopathy of prematurity (ROP) and aggressive posterior retinopathy of prematurity (APROP), in particular, intravitreal administration of vascular endothelial growth factor (VEGF) inhibitors. The results of multicenter clinical trials evaluating pegaptanib, bevacizumab, and ranibizumab are discussed. The clinical effect of intravitreal anti-VEGF drugs was compared to the efficacy of laser retinal photocoagulation. In children with ROP, anti-VEGF drugs are equal or even superior to the conventional laser retinal photocoagulation in terms of clinical efficacy. No negative effects of anti-VEGF drugs on ocular tissues or vasculature development in premature children were demonstrated. Moreover, several studies show the potential efficacy of intravitreal anti-VEGF drugs plus avascular zone photocoagulation for APROP. Finally, our experience with intravitreal ranibizumab for threshold ROP and plus disease in a patient who was followed-up for subsequent 9 years is described.Keywords: retinopathy of prematurity, plus disease, aggressive posterior retinopathy of prematurity, anti-VEGF drugs, ranibizumab.For citation: Zhukova O.V., Mal’tseva I.A., Zolotarev A.V. Vascular endothelial growth factor inhibitors for retinopathy of prematurity. Russian Journal of Clinical Ophthalmology. 2020;20(4):216–220. DOI: 10.32364/2311-7729-2020-20-4-216-220.

Intra- and Inter-Physician Agreement in Therapeutic Decision for Sleep Apnea Syndrome

BackgroundLarge variation in diagnostic procedures and treatment recommendations may hinder the management of obstructive sleep apnea (OSA) and also compromise correct interpretation of the results of multicenter clinical trials, especially in subjects with non-severe OSA. The aim of this study was to analyze the therapeutic decision-making between different sleep physicians in patients with AHI<40events/h. MethodsSix experienced senior sleep specialists from different sleep centers of Spain were asked to make a therapeutic decision (CPAP treatment) based on anonymized recordings of patients with suspected OSA that has previously performed a sleep study. The clinical data was shown in an online database and included anthropometric features, clinical questionnaires, comorbidities, physical examination and sleep study results. Intra- and inter-observer decision-making were analyzed by the Fleiss’ Kappa statistics (Kappa). ResultsA total of 720 medical decisions were taken to analyze the agreement between sleep professionals. Overall intra-observer evaluation reliability was almost perfect (Kappa=0.83, 95% CI, 0.75–0.90, p<0.001). However, overall inter-observer concordance decreased to moderate agreement (Kappa=0.46, 95% CI, 0.42–0.51, p<0.001). Nevertheless, it was especially low when considering AHI<15events/h. ConclusionsThis study demonstrates a good intra-observer concordance in the therapeutic decision-making of different sleep physicians treating patients with low/moderate OSA. However, when analyzing inter-observer agreement the results were considerably worse. These findings underline the importance of developing improved consensus management protocols.

Contemporary paradigm of rational stroke treatment

Stroke was and remains one of the world's leading medical and social problems. Nowadays we are watching permanent sometimes cardinal changes in view about etiology, pathogenetic mechanisms and therapy of patients with stroke. In this work there have been elucidated contemporary theoretical and practical aspects of stroke treatment and prophylaxis based on the results of multicenter clinical trials and experience of leading foreign and native specialists. Much attention is devoted to the pharmacotherapy of patients with stroke. It is showed that application of neuroprotective drugs is of great importance, among which antihypoxants with pleiotropic action play a crucial role (mexidol).

Хронический миелолейкоз: многолетний опыт таргетной терапии

Background & Aims. Interpretation of key aspects of pathogenesis of chronic myeloid leukemia (CML) and development and introduction of target therapy have changed the prognosis of this once fatal disease dramatically. Results of numerous clinical trials demonstrated substantial superiority of tyrosine kinase inhibitors over previous therapy techniques. At the same time, clinical trials had limitations in patient enrollment, as well as treatment conditions and duration. The analysis of our clinical experience in CML target therapy (over the period from 2003 till 2015) is an important argument for introduction of novel drugs into routine clinical practice. The aim of the study is to analyze our own experience in CML target therapy and to compare our results with clinical trials data. Methods. Outpatient’s cards and case histories of CML patients treated in the Russian Scientific Research Institute of Hematology and Transfusiology over last 12 years were analyzed in this work. Published results of multi-center clinical trials evaluating the use of tyrosine kinase inhibitors in CML were used for a comparative analysis. The primary morbidity rate and the prevalence of CML, results of first and subsequent treatment lines were studied with assessment of survival rates, adverse events, and the nature of the response (hematologic, cytogenetic and molecular). Results. The experience in treatment of 208 CML patients was analyzed. The use of imatinib led to clinical and hematological remission (complete hematologic response) was achieved in 95 % of patients. The frequency of complete cytogenetic responses (CCyR) was 69 %, and that of major molecular responses (MMR) was 58 %. The overall 5-year survival (OS) was 86.4 %, the 10-years OS was 67.5 %. The use of nilotinib during the second line permitted to achieve CCyR in 61 % of patients, and the MMR in 55 % of cases. The two-year OS was 96 % and the 5-year OS was 68 %.

Guest editorial: Management of malignant lymphoma is continuously improving

This issue of IJH contains four ‘‘Progress in Hematology(PIH)’’ review articles describing the management ofmalignant lymphoma, with a focus on recent clinical trials.Malignant lymphoma, characterized by its marked hetero-geneity, is the most frequent hematologic malignancy inthe world. Among the various subtypes of malignantlymphoma, the following three are clinically important:Hodgkin lymphoma, follicular lymphoma (FL), and diffuselarge B cell lymphoma (DLBCL). The current and futuremanagement of these three major subtypes are discussed byinternationally distinguished lymphoma experts who havecontributed to the establishment of the current standardmanagement of each subtype. In addition, the current andfuture management of NK/T cell lymphoma is discussed byDr. Yamaguchi, based on clinical trials recently publishedby her group.Current issues to be addressed in the management ofmalignant lymphoma differ somewhat from disease todisease. In Hodgkin lymphoma, continuous efforts toestablish more effective chemotherapy with or withoutradiotherapy have yielded high cure rates in patients withlocalized and advanced diseases. Drs. Eichenauer andEngert of the German Hodgkin Study Group (GHSG)prepared a comprehensive review article regarding thecurrent standard management, based mainly on clinicaltrials conducted by GHSG. Treatment strategies forHodgkin lymphoma are scientifically discussed, andupdated information, including that on ongoing clinicaltrials, should help readers to better understand the mostsuccessful history of using non-surgical treatment modali-ties in clinical oncology.In FL, which remains incurable in most patients, theissues are somewhat different from those in Hodgkinlymphoma. Anti-CD20 monoclonal antibodies, such asrituximab, and radioimmunotherapy have markedly pro-longed survival. In the second PIH article, Drs. Salles andGhesquie`res of Groupe d’Etudes des Lymphomes del’Adulte (GELA), which has recently been renamed theLymphoma Study Association (LYSA), summarize recentadvances in the management of patients with FL, based onthe results of recent clinical trials including the PRIMAStudy, which revealed the efficacy of maintenance use ofrituximab [1]. Considering the marked heterogeneity of FL,the prolonged median survival time probably exceeding15 years under the current treatment modalities, and theemergence of several less toxic but highly effective agents,personalized approaches will be more important in thetreatment of FL in the future.Since the establishment of rituximab plus CHOP as astandard therapy for DLBCL [2], progress has been lessremarkable. In the third PIH article in this issue,Drs. Roschewski, Dunleavy, and Wilson of the NationalCancer Institute in the United States present an excellentreview of further progress in the treatment of DLBCL. Animproved understanding of the biology of DLBCL hasrevealed a number of oncogenic driver mutations and sig-naling pathways essential for growth of the lymphoma cell.As many of these signaling pathways can be targeted bysmall molecule inhibitors, treatment of DLBCL may be instore for a paradigm shift.Finally, Dr. Yamaguchi in Japan summarizes newlydevelopedtreatmentstrategiesforNK/Tcelllymphoma,basedon the results of multicenter clinical trials. NK/T cell lym-phoma is a distinct disease subtype with dismal prognosis

The Proceedings Of The 19Th International Conference On Chelation Held In London, United Kingdom: Major Changes In Iron Chelation Therapy In The Last 25 Years Using Deferiprone (L1) Has Resulted In The Complete Treatment Of Iron Overload

Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations.

Simulated Thin Pericardial Bioprosthetic Valve Leaflet Deformation Under Static Pressure-Only Loading Conditions: Implications for Percutaneous Valves

Percutaneous aortic valve (PAV) replacement is currently being investigated as an endovascular alternative to conventional open-chest valve surgery for patients with severe aortic stenosis. The results of multi-center clinical trials of PAV devices have been encouraging. However, there are serious adverse events associated with this procedure. Furthermore, long-term durability and safety of PAV need to be studied carefully. In this study, we developed a thin pericardial bioprosthetic valve model, which has similar design features of PAV. We utilized this model to investigate PAV deformation under static, pressure-only loading conditions using Finite Element method. Mechanical properties of PAV leaflet were obtained from planar biaxial testing of glutaraldehyde treated thin bovine pericardium (BP) and porcine pericardium (PP), and characterized by the Fung-elastic model. Simulations were performed to examine the effects of tissue thickness and anisotropy on the valve deformation and stress distribution. The results indicated peak stress and strain occurred in the vicinity of commissures. The peak maximum principal stresses (MPS) were reduced with the increase of leaflet tissue thickness, by 36% and 59% from the mean thickness to 0.35 mm for BP and PP, respectively. The PAV with BP leaflet had a lower peak MPS than that with PP leaflet. Moreover, leaflet material orientation had a significant influence on the peak MPS of PAV.

Clinical application of magnetocardiography

Magnetocardiography is a noninvasive contactless method to measure the magnetic field generated by the same ionic currents that create the electrocardiogram. The time course of magnetocardiographic and electrocardiographic signals are similar. However, compared with surface potential recordings, multichannel magnetocardiographic mapping (MMCG) is a faster and contactless method for 3D imaging and localization of cardiac electrophysiologic phenomena with higher spatial and temporal resolution. For more than a decade, MMCG has been mostly confined to magnetically shielded rooms and considered to be at most an interesting matter for research activity. Nevertheless, an increasing number of papers have documented that magnetocardiography can also be useful to improve diagnostic accuracy. Most recently, the development of standardized instrumentations for unshielded MMCG, and its ease of use and reliability even in emergency rooms has triggered a new interest from clinicians for magnetocardiography, leading to several new installations of unshielded systems worldwide. In this review, clinical applications of magnetocardiography are summarized, focusing on major milestones, recent results of multicenter clinical trials and indicators of future developments.

Ultrasound contrast agents for hepatic imaging with nonlinear modes

The continuing development of nonlinear imaging, as well as a whole new generation of contrast agents, holds out great prospects in improving liver imaging. Optimization of the equipment settings for different classes of contrast agents is essential in the detection and characterization of focal liver lesions. On the basis of the preliminary results of multicenter clinical trials, it is reasonable to assume that their application in specific clinical settings will impact favorably on patient management.

Relationship Between Event Rates and Treatment Effects in Clinical Site Differences Within Multicenter Trials: An Example from Primary Pneumocystis carinii Prophylaxis

The results of multicenter clinical trials may differ across participating clinical sites. We present a diagnostic approach for evaluating this diversity that emphasizes the relationship between the observed event rates and treatment effects. We use as an example a trial of sequential strategies of Pneumocystis prophylaxis in human immunodeficiency virus infection with 842 patients randomly allocated to start prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or pentamidine. Prophylaxis failure rates varied significantly across the 30 clinical sites (0–30.3%, p = 0.002 by Fisher’s exact test) with prominent variability in the pentamidine arm (0–63.6%). Starting with oral regimens was better than starting with pentamidine in sites with high rates of events, whereas the three strategies had more similar efficacy in other sites. Sites enrolling fewer patients had lower event rates and had more patients who withdrew prematurely or were lost to follow-up. In a hierarchical regression model adjusting for random measurement error in the observed event rates, starting with trimethoprim/sulfamethoxazole was predicted to be increasingly better than starting with aerosolized pentamidine as the risk of prophylaxis failure increased ( p = 0.01), reducing the risk of failure by 47% when the failure rate of pentamidine was 30%, whereas the two regimens were predicted to be equivalent when the failure rate was 17%. Differences in event rates could reflect a combination of heterogeneity in diagnosis, administration of treatments, and disease risk in patients across sites. The evaluation of clinical site differences with a systematic approach focusing on event rates may give further insight in the interpretation of the results of multicenter trials beyond an average treatment effect. Control Clin Trials 1999;20:253–266