Anticholinesterase Drugs Research Articles

Influence of galantamine in the inflammatory process and tissular lesions caused by Trypanosoma cruzi QM2 strain.

INTRODUCTION: Trypanosoma cruzi infection triggers an inflammatory process with exacerbated production of cytokines that stimulate inflammatory and anti-inflammatory signals, including the efferent anti-inflammatory signal known as the anti-inflammatory cholinergic pathway. Thus, the use of anticholinesterase drugs, such as galantamine, could minimize the inflammatory process caused by this disease. METHODS For the study at 30, 60, and 90 days, 120 Swiss mice were divided into three groups. Each group was subdivided into four subgroups: uninfected/untreated (CTRL), uninfected/treated (GAL), infected/untreated (INF), and infected/treated (GAL/INF). The infected groups were inoculated intraperitoneally with 0.1 ml of mouse blood containing 5 × 104 trypomastigote forms of the T. cruzi QM2 strain. The galantamine-treated groups received 5 mg/kg of galantamine orally, through pipetting. From each subgroup, the parameters of parasitemia, histopathological analysis, butyrylcholinesterase activity (BuChE), and functional study of the colon were evaluated. RESULTS: BuChE performance was observed when AChE was suppressed, with increased activity in the GAL/INF group similar to the INF group on the 30th day post infection, thus corroborating the absence of a significant difference in parasitic curves and histopathological analysis. CONCLUSIONS: The presence of an inflammatory process and nests of amastigotes, as well as evidence of reactivity to ACh and NOR, suggest that galantamine did not interfere with the colonic inflammatory response or even in colonic tissue parasitism at this stage of Chagas disease.

Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease.

Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2μM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Perioperative use of physostigmine to reduce opioid consumption and peri-incisional hyperalgesia: a randomised controlled trial

BackgroundSeveral studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing postoperative opioid consumption. In addition, the anti-cholinesterase drug physostigmine that increases synaptic acetylcholine concentrations has anti-inflammatory effects. MethodsIn this randomised placebo-controlled trial including 110 patients undergoing nephrectomy, we evaluated the effects of intraoperative physostigmine 0.5 mg h−1 i.v. for 24 h on opioid consumption, hyperalgesia, pain scores, and satisfaction with pain control. ResultsPhysostigmine infusion did not affect opioid consumption compared with placebo. However, the mechanical pain threshold was significantly higher (2.3 [sd 0.3]) vs 2.2 [0.4]; P=0.0491), and the distance from the suture line of hyperalgesia (5.9 [3.3] vs 8.5 [4.6]; P=0.006), wind-up ratios (2.2 [1.5] vs 3.1 [1.5]; P=0.0389), and minimum and maximum postoperative pain scores at 24 h (minimum 1.8 [1.0] vs 2.4 [1.2]; P=0.0451; and maximum 3.2 [1.4] vs 4.2 [1.4]; P=0.0081) and 48 h (minimum 0.9 [1.0] vs 1.6 [1.1]; P=0.0101; and maximum 2.0 [1.5] vs 3.2 [1.6]; P=0.0029) were lower in the study group. Pain Disability Index was lower and satisfaction with pain control was higher after 3 months in the physostigmine group. ConclusionsIn contrast to previous trials, physostigmine did not reduce opioid consumption. As pain thresholds were higher and hyperalgesia and wind-up lower in the physostigmine group, we conclude that physostigmine has anti-hyperalgesic effects and attenuates sensitisation processes. Intraoperative physostigmine may be a useful and safe addition to conventional postoperative pain control. Clinical trial registrationEudraCT number 2012-000130-19.

Potential drug interactions between hydroxychloroquine and anticholinesterase drugs

BackgroundOne of the main aggravating factors in the Covid‐19 pandemic is the lack of effective treatments capable of promoting a cure to date. Unfortunately, contrary to the recommendations of WHO and health authorities, in Brazil the use of Hydroxychloroquine in the treatment of SarsCov‐2 has been approved.MethodWe selected guidelines with recommendations for treatment of Covid 19, with an emphasis on the proposed treatments. Then we evaluate the main drug interactions and their potential risks.ResultThe risk of using Hydroxychloroquine in patients with Alzheimer's Disease is high, both due to the aspect of the disease itself, but also due to the drug interactions found.ConclusionHydroxychloroquine is not recommended for patients with Alzheimer's Disease.

Chronic kidney disease and cognitive impairment

Chronic kidney disease (CKD) affects 25% of people aged over 70 years. Cognitive impairment (CI) is frequent in patients with CKD and affects 30% to 60% of patients treated by hemodialysis. The link between CKD and CI is explained by common risk factors, such as hypertension and diabetes, but also by CKD-specific risk factors through vascular, degenerative, and toxic mechanisms. In patients with non-dialyzed CKD, albuminuria is more strongly linked to CI occurrence than glomerular filtration rate. Vascular dementia is the main cause of CI in patients with CKD, but incidence of Alzheimer's disease has also been found higher in patients with end-stage of kidney disease than in the general population. Executive functions, orientation and attention are the most frequently affected cognitive domains in patients with CKD. Occurrence of CI in older patients with CKD could be prevented by controlling blood pressure or the use of anticoagulant drugs in case of atrial fibrillation, which is particularly frequent in patients with CKD, in order to prevent cerebrovascular lesions. Nephrological care could also influence the occurrence of neurological complications. Anticholinesterasic drugs and memantine should be used with caution in patients with CKD, because most of these drugs accumulates in case of low glomerular filtration rate. Due to the poor prognosis of patients with CI and end-stage of kidney disease treated by dialysis or kidney transplantation, a cognitive assessment should be proposed to older patients with severe CKD in order to discuss the initiation and the type of renal replacement therapy with both patients and caregivers.

Efeitos do rocurônio, sugamadex e complexo rocurônio‐sugamadex sobre a coagulação em ratos

Background and objectivesSugammadex is an alternative pharmacological drug capable of reversing neuromuscular blockades without the limitations that are presented by anticholinesterase drugs. Coagulation disorders that are related to treatment with sugammadex were reported. The exact mechanism of the effects on coagulation are not fully understood. The objective of this research is to evaluate the effects of rocuronium, sugammadex and the rocuronium‐sugammadex complex on coagulation in an experimental model in rats. MethodsThis is an experimental randomized animal study. Wistar rats were randomly assigned into the following groups: the Control Group; the Ssal Group – 0.5 mL of intravenous saline; the Sugammadex Group – intravenous sugammadex (100 mg.kg‐1); and the Rocuronium‐Sugammadex Group – intravenous solution with rocuronium (3.75 mg.kg‐1) and sugammadex (100 mg.kg‐1). Anesthesia was performed by using isoflurane with controlled ventilation. Coagulation factors were measured 10 minutes after the end of the preoperative preparation and 30 minutes after the administration of the drugs in accordance with the chosen groups. ResultsPlatelet counts, prothrombin times and activated partial thromboplastin times were similar between the groups and between the moments within each group. There were reductions in the plasma fibrinogen levels between sample times 1 and 2 in the Rocuronium‐Sugammadex group (p=0.035). ConclusionsThe rocuronium‐sugammadex complex promoted reductions in plasma fibrinogen counts, although the levels were still within normal limits.

Effects of rocuronium, sugammadex and rocuronium-sugammadex complex on coagulation in rats

Background and objectivesSugammadex is an alternative pharmacological drug capable of reversing neuromuscular blockades without the limitations that are presented by anticholinesterase drugs. Coagulation disorders that are related to treatment with sugammadex were reported. The exact mechanism of the effects on coagulation are not fully understood. The objective of this research is to evaluate the effects of rocuronium, sugammadex and the rocuronium-sugammadex complex on coagulation in an experimental model in rats. MethodsThis is an experimental randomized animal study. Wistar rats were randomly assigned into the following groups: the Control Group; the Ssal Group – 0.5mL of intravenous saline; the Sugammadex Group – intravenous sugammadex (100mgkg−1); and the Rocuronium-Sugammadex Group – intravenous solution with rocuronium (3.75mgkg−1) and sugammadex (100mgkg−1). Anesthesia was performed by using isoflurane with controlled ventilation. Coagulation factors were measured 10minutes after the end of the preoperative preparation and 30minutes after the administration of the drugs in accordance with the chosen groups. ResultsPlatelet counts, prothrombin times, and activated partial thromboplastin times were similar between the groups and between the moments within each group. There were reductions in the plasma fibrinogen levels between sample times 1 and 2 in the Rocuronium-Sugammadex group (p=0.035). ConclusionsThe rocuronium-sugammadex complex promoted reductions in plasma fibrinogen counts, although the levels were still within normal limits.

Thymomatous myasthenia gravis: 10-year experience of a single center.

To summarize the clinical features of thymomatous myasthenia gravis (T-MG), examine the association between MG and thymoma, and identify the related factors or predictors for long-term prognosis of T-MG. A retrospective, observational study was conducted on 100 patients with T-MG and 96 patients with non-T-MG (NT-MG) between January 1, 2009 and December 31, 2019. The baseline characteristics were recorded for each patient. Logistic regression was used to measure the association between all clinical variables and T-MG prognosis. Between the T-MG and NT-MG groups, age at onset (45.66±11.53years vs 39.06±14.39years); age >40years (72.0% vs. 40.6%); AChR-Ab positive rate (100.0% vs. 83.3%); Myasthenia Gravis Foundation of America (MGFA) classification at the worst condition (≥grade III, 61.0% vs. 33.0%); thyroid dysfunction (7.0% vs. 20.8%); and outcome (complete stable remission+pharmacologic remission+improvement, 74.0% vs. 93.7%) were statistically significant (P<.05). Presence of thymoma (OR=0.196, 95%CI=0.076-0.511, P=.001) was a risk factor for MG. Male sex, post-operative complications, higher grade of MGFA classification, and thymoma Masaoka-Koga pathological stage were risk predictors for long-term prognosis of T-MG (P<.1). Use of preoperative anticholinesterase drugs (OR=5.504, 95%CI=1.424-21.284, P=.013) was identified as an independent predictor for T-MG. T-MG is clinically different from NT-MG, and thymoma is considered a risk factor for MG. Preoperative anticholinesterase drug use is a protective factor for long-term prognosis of T-MG. A comprehensive understanding of the characteristics of T-MG will likely help improve its prognosis.

New sandwich-type polymeric potassium-dicyanoargentate(I) complex: synthesis, characterization and enzymatic activity.

Coordination compounds containing dicyanoargentate(I) have remarkable biological potential due to their therapeutic antibacterial, antifungal, antibiofilm, and anticancer properties. In this study, a new dicyanoargentate(I)-based complex was synthesized and characterized by various procedures (elemental, thermal, FT-IR for complex) involving crystal analysis of the complex. In addition, the biological activity of this new compound on the acetylcholinesterase (AChE) enzyme, an important enzyme for the nervous system, was investigated. When the infrared (IR) spectrum of the complex is examined, the OH vibration peak resulting from H2O molecules in the structure at 3948-3337 cm−1 and at 2138 cm−1, along with a CN peak coordinated to Ag, can be seen, indicating that the mass remaining in the thermal degradation of the complex at 1000 ◦ C is the weight corresponding to the metal mixture consisting of K+Ag (calc.: 68.06). The crystal method revealed that the complex has a sandwich-like, polymeric chemical structure with layers formed by K+ cations and [Ag(CN)2H2O]− anions. Therefore, the AChE enzyme has potential therapeutic uses in improving ACh levels in brain cells, in reducing various side effects, and in improving cognitive impairment, especially in advanced Alzheimer’s disease patients. In this study, the activity of this newly synthesized complex on AChE was also investigated. As a result of this research, [Ag(CN)2(H2O)K] had 0.0282 ± 0.010 μM Ki values against AChE. The compound was therefore a good inhibitor for the AChE enzyme. This type of compound can be used for the development of novel anticholinesterase drugs.

Myasthenia Crisis Vs Cholinergic Crisis: Challenges in Crisis Management Without Plasmapheresis or Intravenous Immunoglobulin (IVIG)

Introduction: Myasthenia gravis (MG) is an acquired autoimmune disorder clinically characterized by skeletal muscle weakness &amp; fatigability on exertion with prevalence as high as 2–7 in 10,000 and women are affected more frequently than men (~3:2). Over 12-16% of generalized MG patients experience crisis once in their lifetime. A serious complication of myasthenia gravis is respiratory failure. This may be secondary to an exacerbation of myasthenia (myasthenia crisis) or to treatment with excess doses of a cholinesterase inhibitor (cholinergic crisis). Case Report: Thirty-two years old woman refereed from a private hospital to ED for further treatment with myasthenia in crisis, after nine days of treatment in the previous ICU. Patient already in intubation with mechanical ventilation and history of the treatment of a high dose of multiple anticholinesterase drugs and steroids without plasmapheresis or immunoglobulin intravenous. During admission, diarrhea was present, with no sign of GI infection. On the third day of admission, the patient performed a Spontaneous Breathing Trial and was a success then extubated. Then two day after extubation, the patient falls to respiratory failure and need mechanical ventilation. Anticholinesterase test was performed, and it shows no improvement in clinical signs, and diagnose as Cholinergic Crisis. After re-adjustment of anticholinesterase drug with a lower dose, clinically, the respiratory condition improved, and on the 10th day of admission, the patient was succeed extubated. At 12nd days of ICU admission, patient discharge from ICU. Discussion: Myasthenia and Cholinergic Crisis is a severe and life-threatening condition characterized by generalized muscle weakness with a respiratory compromise that requires ventilatory support. Respiratory failure may be present in the cholinergic crisis without cholinergic symptoms (miosis, diarrhea, urinary incontinence, bradycardia, emesis, lacrimation, or salivation). The most important management aspect of Myasthenia patients in crisis is the recognition and treatment of myasthenia vs cholinergic crisis.

Myasthenia Crisis Vs Cholinergic Crisis: Challenges in Crisis Management Without Plasmapheresis or Intravenous Immunoglobulin (IVIG)

Introduction: Myasthenia gravis (MG) is an acquired autoimmune disorder clinically characterized by skeletal muscle weakness &amp; fatigability on exertion with prevalence as high as 2–7 in 10,000 and women are affected more frequently than men (~3:2). Over 12-16% of generalized MG patients experience crisis once in their lifetime. A serious complication of myasthenia gravis is respiratory failure. This may be secondary to an exacerbation of myasthenia (myasthenia crisis) or to treatment with excess doses of a cholinesterase inhibitor (cholinergic crisis). Case Report: Thirty-two years old woman refereed from a private hospital to ED for further treatment with myasthenia in crisis, after nine days of treatment in the previous ICU. Patient already in intubation with mechanical ventilation and history of the treatment of a high dose of multiple anticholinesterase drugs and steroids without plasmapheresis or immunoglobulin intravenous. During admission, diarrhea was present, with no sign of GI infection. On the third day of admission, the patient performed a Spontaneous Breathing Trial and was a success then extubated. Then two day after extubation, the patient falls to respiratory failure and need mechanical ventilation. Anticholinesterase test was performed, and it shows no improvement in clinical signs, and diagnose as Cholinergic Crisis. After re-adjustment of anticholinesterase drug with a lower dose, clinically, the respiratory condition improved, and on the 10th day of admission, the patient was succeed extubated. At 12nd days of ICU admission, patient discharge from ICU. Discussion: Myasthenia and Cholinergic Crisis is a severe and life-threatening condition characterized by generalized muscle weakness with a respiratory compromise that requires ventilatory support. Respiratory failure may be present in the cholinergic crisis without cholinergic symptoms (miosis, diarrhea, urinary incontinence, bradycardia, emesis, lacrimation, or salivation). The most important management aspect of Myasthenia patients in crisis is the recognition and treatment of myasthenia vs cholinergic crisis.

Bioactivity and molecular docking studies of some nickel complexes: New analogues for the treatment of Alzheimer, glaucoma and epileptic diseases

The interaction of the coordination compounds with biological molecules resulted in the investigation of the drug potential of these molecules. In this study, enzyme inhibition of DSA (1–3) coordination compounds that were previously investigated for their anticancer and antibacterial properties was investigated. Also, DSA (1–3) had Ki values of 635.30 + 152.62, 184.01 + 90.05, and 163.03 ± 60.01 µM against human carbonic anhydrase I, 352.23 ± 143.09, 46.2 ± 15.47, and 54.117 ± 18.80 µM against AChE, 310.64 ± 97.35, 35.54 ± 7.01, and 101.51 ± 15.314 µM against BChE, respectively. The biological activity values of these compounds against enzymes whose name are AChE, BChE, and hCAI were compared. Ellman and Verporte methods were used for the study of these enzymes. Cholinesterase inhibitors, also known as anti-cholinesterase and cholinesterase blocking drugs, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. They may be used as drugs for Alzheimer's and myasthenia gravis. It is a common method for comparing biological activity values of nickel complexes with molecular docking calculations. Nickel complexes were studied against enzymes that are human carbonic anhydrase isozyme I for ID 2CAB (hCA I), butyrylcholinesterase for ID 1P0I (BChE), and acetylcholinesterase for ID 1EEA (AChE), respectively.

Prevalence of Alzheimer's disease according to anticholinesterase drug usage from 2012 to 2017 in the state of Paraná, Brazil

Introduction: Alzheimer's disease (AD) is a public health problem in Brazil due to the growing number of older adults in this population. Knowing the prevalence of AD in the Paraná state is essential to improve patients’ quality of life. The objective of the study was to estimate AD prevalence in the state of Paraná, based on the prescription of anticholinesterases, from 2012 to 2017. Methods: Patients diagnosed with AD, aged 60 years or over, who used Brazil’s Unified Public Health System (SUS) and received AD medication from the Department of Pharmaceutical Assistance of the state of Paraná, from 2012 to 2017, were the target population of the present study. The medication data were collected from the Computerized system management and Monitoring of Exceptional Drugs (SISMEDEX), and the population’s data were collected from the Brazilian Institute of Geography and Statistics (IBGE). Results: The sample consisted of 52,687 patients, and the median prevalence of AD in the established period for the state was 642.6/100,000 inhabitants (0.64%). In all ages and macro-regions, women showed the highest prevalence rates. The median prevalence for women in the established period was 755.4/100,000 inhabitants (0.75%). Among men, the median prevalence was 510.2/100,000 inhabitants (0.51%). In the temporal analysis of prevalence, between 2012 and 2017, a reduction of 23% was found in the state rate. The prevalence rate of Paraná for AD is nine times lower than the Brazilian average. Conclusions: Paraná’s prevalence rate for AD is lower than the rates of Brazil and the world, suggesting that AD is underdiagnosed in most municipalities of this state.

Acetylcholinesterase inhibition prevents alterations in cardiovascular autonomic control and gastric motility in L-NAME-induced hypertensive rats

AimsAutonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. Materials and methodsDaily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6–12 animals per group; total number of animals used: 78). Key findingsL-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SignificanceAcetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.

Analysis of clinical manifestations and diagnosis of late-onset myasthenia gravis

Introduction. Myasthenia gravis is one of the most common autoimmune neuromuscular diseases, the peak incidence is in the age of 20–40 years. However, studies show that throughout the world in recent decades there has been an increase in the prevalence and incidence of myasthenia gravis among older people.Purpose of the study – to evaluate the clinical manifestations and diagnostic features of myasthenia gravis in patients with an onset of diseases in the elderly.Materials and methods. The retrospective, non-interventional study included 315 patients over 18 years old with a reliable (3 out of 4 criteria) and an undoubted (4 out of 4 criteria) diagnosis of myasthenia gravis, the duration of the disease for up to 5 years, undergoing inpatient treatment from 2001 to 2017 years. The severity of the clinical manifestations of myasthenia gravis was assessed using the Myasthenia Gravis Foundation of America scale. We were taken into account the information about the first symptoms, duration of the period from the onset of the disease to the verification of the diagnosis, results of the examinations, the presence of concomitant diseases and treatment methods.Results. The most common symptom of myasthenia gravis in the group of patients with debut disease aged 60 years and older was ptosis (p &lt;0.001). The crises and pathology of the thymus were less common in elderly patients (p &lt;0.0001). The concentration of antibodies to acetylcholine receptors was the same (p = 0.05) among all patients. The level of antibodies to titin was increased in patients with lateonset (p = 0.0014). The presence of bronchopulmonary pathology made worse the course of myasthenia gravis in elderly people (p = 0.01), while cardiovascular and cerebrovascular diseases, as well as diabetes mellitus, did not occur (p &gt;0.005). At the first examination in the group of elderly patients among the incorrectly diagnoses prevailed: stroke or decompensation of chronic cerebral ischemia (p = 0.0002). With a comparable duration and severity of myasthenia gravis in different age groups, the combination of anticholinesterase drugs, glucocorticosteroids and azathioprine (p = 0.01) at a lower daily dose (100 mg) was more often used for the treatment of elderly patients compared with young and middle-aged groups (150 mg) (p = 0.03).Conclusion. Diagnosis of myasthenia gravis in elderly patients presents the greatest difficulties, and symptoms of manifestation during initial treatment are often regarded as a manifestation of vascular pathology. Despite the presence of concomitant diseases characteristic of this age group, myasthenia gravis does not differ in the severity of the course. To achieve remission and compensation of symptoms, elderly patients do not need large doses of symptomatic and pathogenetic drugs.

Subxiphoid completion thymectomy for refractory non-thymomatous myasthenia gravis.

BackgroundCompletion thymectomy may be performed in patients with non-thymomatous refractory myasthenia gravis (MG) to allow a complete and definitive clearance from residual thymic tissue located in the mediastinum or in lower neck. Hereby we present our short- and long-term results of completion thymectomy using subxiphoid video-assisted thoracoscopy.MethodsBetween July 2010 and December 2017, 15 consecutive patients with refractory non-thymomatous myasthenia, 8 women and 7 men with a median age of 44 [interquartile range (IQR) 38.5–53.5] years, underwent video-thoracoscopic completion thymectomy through a subxiphoid approach.ResultsPositron emission tomography (PET) showed mildly avid areas [standardized uptake value (SUV) more than or equal to 1.8] in 11 instances. Median operative time was 106 (IQR, 77–141) minutes. No operative deaths nor major morbidity occurred. Mean 1-day postoperative Visual Analogue Scale value was 2.53±0.63. Median hospital stay was 2 (IQR, 1–3.5) days. A significant decrease of the anti-acetylcholine receptor antibodies was observed after 1 month [median percentage changes −67% (IQR, −39% to −83%)]. Median follow-up was 45 (IQR, 21–58) months. At the most recent follow-up complete stable remission was achieved in 5 patients. Another 9 patients had significant improvement in bulbar and limb function, requiring lower doses of corticosteroids and anticholinesterase drugs. Only one patient remained clinically stable albeit drug doses were reduced. One-month postoperative drop of anti-acetylcholine receptor antibodies was significantly correlated with complete stable remission (P=0.002).ConclusionsThis initial experience confirms that removal of ectopic and residual thymus through a subxiphoid approach can reduce anti-acetylcholine receptor antibody titer correlating to good outcome of refractory MG.

Molecular approach to promising cholinesterase inhibitory effect of several amaryllidaceae alkaloids: Further re-investigation

All cholinesterase (ChE) inhibitory drugs in clinical use are nitrogenous compounds and among them, galanthamine as the latest anticholinesterase drug, contains a tetrahydroisoquinoline structure. For this reason, isoquinoline alkaloids seem to be attractive in search for novel drug candidates towards Alzheimer's disease (AD). Therefore, in the current work, we investigated inhibitory capacity of several alkaloids representing expanding group of biogenetically-related isoquinoline alkaloids from the Amaryllidaceae including lycorine, (+)-9-O-demethylhomolycorine, 6-hydroxybuphanisine, 9-O-demethoxymontanine, 3-epi-hydroxy-bulbispermine, tazettine, haemanthamine, (+)-haemanthidine, (-)-crinine, 8-hydroxy-9-methoxycrinine, and N-norgalanthamine against ChEs by microtiter enzyme inhibition assays. Our findings indicated that N-norgalanthamine is the most active one inhibiting both acetylcholinesterase (AChE, IC50 = 2.42 ± 0.16 µg/mL) and butyrylcholinesterase (BChE, IC50 = 20.87 ± 1.01 µg/mL) at 100 μg/mL, whereas IC50 values of galanthamine used as the reference were 1.33 ± 0.11 µg/mL and 37.69 ± 2.93 µg/mL for AChE and BChE, respectively. Beside this, 8-hydroxy-9-methoxycrinine was a strong inhibitor of AChE (IC50 = 6.92 ± 0.51 µg/mL), while (+)-9-O-demethylhomolycorine displayed a moderate BChE inhibition (IC50 = 83.57 ± 1.36 µg/mL). Relevantly, 8-hydroxy-9-methoxycrinine and N-norgalanthamine were docked into active gorges of hAChE (PDB: 4EY6) and hBChE (PDB: 4TPK), which pointed out the detail that N-norgalanthamine displayed a very similar binding mode of to that of galanthamine. Moreover, both AChE-inhibiting alkaloids were found to stably bind to hAChE active site occupying the middle of the gorge between the catalytic site and the peripheral anionic site. 8-Hydroxy-9-methoxycrinine was also docked into the active site of BChE. We can conclude that among the tested alkaloids, N-norgalanthamine with dual ChE inhibitory effect seems to be the most promising anti-Alzheimer candidate molecule for future experiments.

Features of depression development in myasthenia gravis.

The relative risk of developing depression in myasthenia gravis is 2.14 times higher than in the general population. The features of depression in myasthenia patients remain poorly understood and need to be clarified. The purpose of this work was to study the features of the development of depression in patients with myasthenia gravis. From 2014 to 2017, 182 patients with myasthenia gravis were examined. 147 (80.8%) patients had a generalized form of the disease, 35 (19.2%) had an ocular form. The clinical examination included assessment of complaints, medical history, neurological examination, as well as MGFA (Myasthenia Gravis Foundation of America) disease class and subclass of the disease determination. The severity of myasthenia gravis has been quantified according to the QMG score (Quantitative Myasthenia Gravis Score). All the patients were examined for the titer of antibodies to acetylcholine receptors (AchR) and muscle-specific tyrosine kinase (MuSK) by enzyme-linked immunosorbent assay (ELISA). Patients were also tested for the presence of antibodies to titin and SOX1 by indirect immunofluorescence. To detect depression the Beck depression inventory (BDI) was used. The mean depression score in the total sample was 16.0 (10.0; 24.0), which corresponds to a moderate depression level. The mean depression score in patients with ocular form was 6.0 (3.0; 11.0) points (ie, depression is absent), whereas in patients with generalized myasthenia gravis – 19.0 (12.0; 29.0) points (corresponds to moderate depression) (p &lt;0.001). The distribution of patients with mild depression was also uneven: significantly bigger part of the patients was recorded with myasthenia gravis of class I (ocular form) – 10 (28.6%), and with myasthenia gravis of class II – 23 (44.2%). Among the patients with myasthenia gravis of class III, only 13 (20.3%) patients were reported with mild depression and 1 (3.2%) with class IV, p&lt;0.001. The distribution of patients with moderate depression was the opposite of others: most patients had myasthenia gravis of class II – 12 (18.8%), and there were no patients with myasthenia gravis of class I. A similar tendency is also observed in the case of severe depression: patients with myasthenia gravis of class II – 23 (35.6%) dominated, to a lesser extent - patients with myasthenia gravis of class IV – 6 (19.4%). Among patients with ocular myasthenia gravis, only 1 (2.9%) patient was found to have severe depression. Severe depression was mainly recorded in patients with myasthenia gravis of class IV – 22 (71%) patients. The number of patients with severe depression has been decreased in the class of myasthenia gravis: 13 patients (20.3%) patients with ІІІ class, 1 (1.9%) with II class, no patients with class I. The degree of depression correlates with the clinical form of myasthenia gravis (ρ= -0.52; p&lt;0.001), class (ρ= -0.30; p&lt;0.001) and the subclass of the disease according to MGFA (ρ= -0.36; p&lt;0.001). A reliable correlation relationship was established between the quantitative evaluation of the severity of myasthenia gravis (according to the QMG score) and the results of the evaluation according to the BDI score in the total sample (ρ=0.73; p&lt;0.001). The assessment indicators on the QMG score and the BDI score significantly correlated in patients with ocular (ρ=0.36; p&lt;0.05) and generalized forms (ρ=0.67; p&lt;0.05). In addition, the level of depression correlates with the presence (ρ=0.15; p=0.040) and the titer of antibodies to AchR (ρ=0.42; p&lt;0.001), with the presence (ρ=0.18; p=0.016) and the titer of antibodies to MuSK-AB (ρ=0.19; p=0.011). No correlation was found between the presence of antibodies to titin and to SOX1 (ρ=0.14; p&lt;0.05 and ρ=0.07; p&lt;0.05, respectively). There are no relationships between the use of anticholinesterase drugs, prednisone, the combined use of prednisone with / without azathioprine with / without anticholinesterase drugs and the development of depression in patients with myasthenia gravis.

Composition, Anticholinesterase and Antipedicular Activities of Satureja capitata L. Volatile Oil

AbstractThe emergence of resistance for antipedicular agents and the need of potent acetylcholinesterase (AChE) therapeutics for the treatment of a neurodegenerative disorder such as Alzheimer disease has led researchers to the exploration of new therapeutic alternatives such as natural volatile oils. Therefore, the current investigation aimed to identify the components of Satureja capitata L. volatile oil (VO), and examine the VO anticholinesterase, and antipedicular activities. The plant phytoconstituents were identified using Gas chromatography mass spectrometry (GC-MS) method, while the anticholinesterase activity was determined against butyryl- and acetyl-cholinesterase using Ellman’s method. In addition, antipedicular activity was established using the diffusion method. The obtained GC-MS results identified 16 compounds in S. capitata VO with the major constituents being carvacrol, γ-terpinene, and p-cymene. Anticholinesterase analysis showed a marked inhibition potential against acetyl- and butyryl-cholinesterase enzymes with half maximal inhibitory concentration (IC50) values of 28.24±0.97 μg/ml and 92.31±1.22 μg/ml, respectively in comparison with the reference compound galantamine, which has IC50 values against the same enzymes of 5.21±0.07 μg/ml and 10.33±0.37 μg/ml, respectively. In addition, the VO, at a concentration of 20%, was effective against head lice, similar to benzyl benzoate, which resulted in 100% mortality. In addition, the VO completely inhibited the emergence of lice nits after 6 and 14 days. On the basis of the obtained results, S. capitata VO is a promising natural alternative to synthetic antipedicular and anticholinesterase drugs, which can be employed in drug development, and may lead to new candidates against head lice and neurodegenerative diseases.

Toxicidad cardiovascular por parches transdérmicos de rivastigmina. A propósito de dos casos clínicos

Rivastigmine, an anticholinesterase drug, improves cholinergic neurotransmission and is used in the treatment of Alzheimer’s and Parkinson’s diseases. In the Center for Information and Toxicological Advice there have been cases of intoxication due to the use of transdermal rivastigmine patches, which have increased in recent times. We present two clinical cases of acute intoxication by transdermal patches of rivastigmine in which serious cardiac arrhythmias were found, associating a decrease in plasma cholinesterase. The risks of the use of this medication are highlighted in order to be attentive to the first symptoms of intoxication, to be able to act timely and to prevent new events.