BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• intravenózní imunoglobuliny * terapeutické užití   MeSH
• lidé MeSH
• myasthenia gravis * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• hormony kůry nadledvin MeSH
• intravenózní imunoglobuliny * MeSH

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID-19) mainly due to respiratory muscle weakness, older age and long-term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID-19 in MG patients and risk of MG exacerbation during COVID-19. METHODS: We evaluated clinical features and outcomes after COVID-19 in 93 MG patients. RESULTS: Thirty-five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID-19. Higher forced vital capacity (FVC) values tested before COVID-19 were shown to be protective against severe infection (95% CI 0.934-0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047-1.232). Long-term chronic corticosteroid treatment worsened the course of COVID-19 in MG patients (95% CI 1.784-111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448-2.935), mycophenolate mofetil (95% CI 0.91-12.515) and ciclosporin (95% CI 0.029-2.212) did not influence the course of COVID-19. MG patients treated with rituximab had a high risk of death caused by COVID-19 (95% CI 3.216-383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885-10.87). CONCLUSIONS: As the most important predictors of severe COVID-19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long-term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.

• Klíčová slova
• COVID-19, corticosteroids, immunosuppression, myasthenia gravis, rituximab,
• MeSH
• COVID-19 * terapie   MeSH
• koronavirové infekce * MeSH
• lidé MeSH
• myasthenia gravis * komplikace   farmakoterapie   epidemiologie   MeSH
• pasivní imunizace MeSH
• SARS-CoV-2 MeSH
• senioři MeSH
• sérologická léčba covidu-19 MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.

• Klíčová slova
• Eculizumab, Japanese patients, MG-ADL, MG-QoL15, Myasthenia gravis, Open-label extension study,
• MeSH
• Asijci MeSH
• dospělí MeSH
• humanizované monoklonální protilátky škodlivé účinky   terapeutické užití   MeSH
• inhibitory komplementu škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myasthenia gravis farmakoterapie   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Japonsko MeSH
• Názvy látek
• eculizumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• inhibitory komplementu MeSH

BACKGROUND: Myasthenia gravis (MG) is the autoimmune disorder in which the thymus is considered the pathogenic organ. Thymectomy (TE) is a therapeutic option for MG and often ameliorates clinical symptoms. METHODS: We evaluated clinical features and outcomes after TE in patients without thymoma and the influence of TE with or without concomitant immunotherapy on the CD4(+)CD25(+) regulatory T cell subpopulation of lymphocytes in peripheral blood in defined followed groups of nonthymomatous MG patients. RESULTS: A total of 46 patients with generalized MG who underwent transsternal TE were identified. Neurologic outcomes after TE were favorable for the majority of patients mainly from the group treated with corticosteroids or combined immunosuppressive treatment. TEs with immunosuppressive treatment in MG patients were associated with increased percentages of CD4(+)CD25(+) cells (p<0.001). No significant change in the postoperative levels of CD4(+)CD25(+) cells was observed in thymectomized patients who preoperatively only received pyridostigmine. Also their clinical response to TE after 2 years of follow-up was worst of all followed groups. CONCLUSIONS: The exact mechanism by which TE ameliorates symptoms of MG is yet not clear. These observations indicate that increased percentages of CD4(+)CD25(+) T cells in MG may be related to disease stability and that TE and synergistic effect with concomitant, continuing immunotherapy augmented the proportion of CD4(+)CD25(+) T cells. On the basis of our observations TE alone is not enough to increase the number of circulating CD4(+)CD25(+) regulatory T cells and to establish complete stable remission.

• Klíčová slova
• CD4(+) CD25(+) regulatory T-lymphocytes, Combined immunosuppressive treatment, Corticosteroids, Myasthenia gravis, Pyridostigmine, QMG score, Thymectomy,
• MeSH
• antigeny CD4 MeSH
• dospělí MeSH
• hodnocení výsledků zdravotní péče * MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• myasthenia gravis krev   farmakoterapie   chirurgie   MeSH
• následné studie MeSH
• počet CD4 lymfocytů MeSH
• počet lymfocytů MeSH
• receptor interleukinu-2 - alfa-podjednotka MeSH
• regulační T-lymfocyty * MeSH
• thymektomie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD4 MeSH
• hormony kůry nadledvin MeSH
• IL2RA protein, human MeSH Prohlížeč
• imunosupresiva MeSH
• receptor interleukinu-2 - alfa-podjednotka MeSH

The detection of low density lipoprotein-4 (LRP4) antibodies in double seronegative (dSN) myasthenia gravis (MG) patients has provided new insights in the diagnosis and treatment of MG. However, there are limited data regarding the clinical presentation and treatment response in dSN MG patients with LRP4-antibodies. We present a case series of three Caucasian dSN MG patients with positive LRP4-antibodies sharing a common ethnic background that presented with isolated ocular symptoms (MGFA I). The demographic and clinical characteristics, the diagnostic work-up as well as the treatment response during a follow-up period of 12-24 months are described in detail. All patients were treated successfully with acetylcholinesterase inhibitors (AcheI) and prednisone with two exhibiting full remission of their symptoms, while the remaining exhibited mild residual diplopia. Notably, we documented no signs of generalized disease progression, while no patient required immunosuppressive treatment. In conclusion, the distinct clinical phenotype of our patients highlights the clinical relevance of screening for LRP4-antibodies in patients presenting with isolated ocular MG independent of age and gender, since it may lead to the timely diagnosis of MG and prompt initiation of effective therapy with ACheI and corticosteroids.

• Klíčová slova
• Antibodies, Diagnosis, LRP4, Myasthenia, Ocular, Treatment,
• MeSH
• blefaroptóza farmakoterapie   imunologie   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• diplopie farmakoterapie   imunologie   MeSH
• dospělí MeSH
• glukokortikoidy terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• myasthenia gravis farmakoterapie   imunologie   MeSH
• prednison terapeutické užití   MeSH
• proteiny související s LDL-receptory imunologie   MeSH
• pyridostigmin-bromid terapeutické užití   MeSH
• senioři nad 80 let MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• glukokortikoidy MeSH
• LRP4 protein, human MeSH Prohlížeč
• prednison MeSH
• proteiny související s LDL-receptory MeSH
• pyridostigmin-bromid MeSH

• MeSH
• lidé MeSH
• myasthenia gravis krev   farmakoterapie   imunologie   MeSH
• nervosvalové spojení imunologie   MeSH
• prednison terapeutické užití   MeSH
• proteiny související s LDL-receptory imunologie   MeSH
• protilátky krev   MeSH
• receptory cholinergní imunologie   MeSH
• senioři MeSH
• sérologické testy MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• LRP4 protein, human MeSH Prohlížeč
• prednison MeSH
• proteiny související s LDL-receptory MeSH
• protilátky MeSH
• receptory cholinergní MeSH

INTRODUCTION: Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer's disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. AREAS COVERED: This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. EXPERT OPINION: Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies).

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa analýza   metabolismus   MeSH
• chemické bojové látky farmakologie   MeSH
• chemické techniky analytické metody   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• cholinesterasy analýza   metabolismus   MeSH
• lidé MeSH
• myasthenia gravis farmakoterapie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• referenční hodnoty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• butyrylcholinesterasa MeSH
• chemické bojové látky MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH

INTRODUCTION: Both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are present in the body in large amounts. AChE is an important part of the cholinergic nervous system taking place in the central and peripheral nervous system. AChE is a target of several toxins such as insecticide carbofuran, nerve agents, sarin, soman, tabun and VX. Beside toxins, drugs for treatment of Alzheimer's disease and myasthenia gravis, such as galantamine, donepezil, rivastigmine, tacrine, huperzine, pyridostigmine and neostigmine, are known. AREAS COVERED: The review gives an overview of the importance of the cholinergic nervous system, the biochemistry of AChE and the role of AChE inhibitors. Current efforts to introduce potent drugs for Alzheimer's disease therapy and reduce toxicity, while keeping the maximal pharmacological effect, are also discussed. EXPERT OPINION: The current research effort into AChE inhibitors can be divided into two categories. First, new toxins useful for agricultural purposes and second, novel drugs that need to be prepared, although there is less interest in the new toxins. The research for drugs for Alzheimer's disease needs to focus on inhibitors that reduce the deposition of amyloid plaques, but do not initiate AChE expression.

• MeSH
• acetylcholin metabolismus   MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   enzymologie   MeSH
• chemie farmaceutická MeSH
• cholinesterasové inhibitory škodlivé účinky   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myasthenia gravis farmakoterapie   enzymologie   MeSH
• patenty jako téma MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zákonodárství lékové MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• acetylcholin MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH

This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC(50)) and was compared to the chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π-π or π-cationic interactions.

• MeSH
• acetylcholinesterasa chemie   genetika   metabolismus   MeSH
• ambenoniumchlorid chemie   farmakologie   MeSH
• benzenaminium, 4,4'-(3-oxo-1,5-pentandiyl)bis(N,N-dimethyl-N-2-propenyl-), dibromid chemie   farmakologie   MeSH
• butyrylcholinesterasa chemie   genetika   metabolismus   MeSH
• chinolinové sloučeniny chemie   farmakologie   terapeutické užití   MeSH
• cholinesterasové inhibitory chemie   farmakologie   terapeutické užití   MeSH
• edrofonium chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• myasthenia gravis farmakoterapie   MeSH
• rekombinantní proteiny chemie   genetika   metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ambenoniumchlorid MeSH
• benzenaminium, 4,4'-(3-oxo-1,5-pentandiyl)bis(N,N-dimethyl-N-2-propenyl-), dibromid MeSH
• butyrylcholinesterasa MeSH
• chinolinové sloučeniny MeSH
• cholinesterasové inhibitory MeSH
• edrofonium MeSH
• rekombinantní proteiny MeSH

Myasthenia gravis is very rare autoimmune disease of neuromuscular junction, which presents as a weakness and increased fatiquability of striated muscles. Formerly, myasthenia was largely constraining disease and often ended by death. Recently, advanced diagnostic methods and variety of therapeutic options allow the full compensation of the disease and the quality of patient life is restored. In this review, the methods used during the myasthenia treatment along with the description of the disease itself were detailed.

• MeSH
• acetylcholinesterasa terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• myasthenia gravis diagnóza   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• imunosupresiva MeSH
• monoklonální protilátky MeSH