Knowledge and perceptions of the COVID-19 pandemic among patients with myasthenia gravis: follow up survey

Introduction  We previously conducted a survey study in April 2020 at the beginning of the SARS-CoV-2 (COVID-19) pandemic to understand how it affected patients with myasthenia gravis (MG). Since then, significant advances have occurred in the following areas: knowledge about the SARS-CoV-2 virus, infection risk mitigation, patient management, risks for MG patients, and a global vaccination program. We conducted a follow-up survey in February 2021 to assess how these advances impacted the care and perception of MG patients.     Methods  We conducted a prospective online survey study of MG patients at a large academic practice in the Duke Health System.   Results  Seventy-eight patients participated in the survey including 55 from previous survey and 23 newly identified patients. The top reported change in the interaction with healthcare providers was an increase in telemedicine visits (74%). The median satisfaction score (0-100 scale) for telemedicine visits was 74. Ninety-six percent of survey participants expressed concern about pandemic and nearly half of participants showed anxiety based on Generalized Anxiety Disorder-7 score. The top 3 concerns related to COVID-19 were getting hospitalized (62%), exacerbation (62%) and death (53%).  Discussion   Although the results of follow-up survey were overall similar to the previous study, most of patients switched from in-person clinic visits to telemedicines. The overwhelmingly large portion of patients continue to have concern and anxiety for pandemic but the patients with severe symptoms have higher anxiety scores. Conclusion   This follow-up survey demonstrated the adjustment of MG patients to new methods of communication, significant psychological impact of COVID-19 on them and their good healthcare literacy. &nbsp

Knowledge and perceptions of the COVID-19 pandemic among patients with myasthenia gravis: follow up survey

Introduction  We previously conducted a survey study in April 2020 at the beginning of the SARS-CoV-2 (COVID-19) pandemic to understand how it affected patients with myasthenia gravis (MG). Since then, significant advances have occurred in the following areas: knowledge about the SARS-CoV-2 virus, infection risk mitigation, patient management, risks for MG patients, and a global vaccination program. We conducted a follow-up survey in February 2021 to assess how these advances impacted the care and perception of MG patients.     Methods  We conducted a prospective online survey study of MG patients at a large academic practice in the Duke Health System.   Results  Seventy-eight patients participated in the survey including 55 from previous survey and 23 newly identified patients. The top reported change in the interaction with healthcare providers was an increase in telemedicine visits (74%). The median satisfaction score (0-100 scale) for telemedicine visits was 74. Ninety-six percent of survey participants expressed concern about pandemic and nearly half of participants showed anxiety based on Generalized Anxiety Disorder-7 score. The top 3 concerns related to COVID-19 were getting hospitalized (62%), exacerbation (62%) and death (53%).  Discussion   Although the results of follow-up survey were overall similar to the previous study, most of patients switched from in-person clinic visits to telemedicines. The overwhelmingly large portion of patients continue to have concern and anxiety for pandemic but the patients with severe symptoms have higher anxiety scores. Conclusion   This follow-up survey demonstrated the adjustment of MG patients to new methods of communication, significant psychological impact of COVID-19 on them and their good healthcare literacy. &nbsp

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

To determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure–Response Relationships in Renal Transplant Patients

Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships

Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis

An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, autoantibodies, and natural or acquired (vaccine) protective antibodies in patients with autoimmune myasthenia gravis (MG) is lacking. Prior studies measured TPE effects in healthy volunteers or heterogeneous autoimmune diseases populations. We prospectively profiled plasma IgA, IgM, IgG, IgG subclasses (IgG1-4), acetylcholine receptor autoantibodies (AChR+), and protective antibodies in patients with AChR+ MG receiving TPE for an exacerbation. TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Ten patients were enrolled (median age=72.9 years; baseline MG-Composite=21; median TPE treatments=6 during their first course) and all improved. The maximum decrease in all immunoglobulins, including AChR autoantibodies, was achieved on the final day of the first TPE course (approximately 60–70% reduction). Three weeks post-TPE mean AChR autoantibody, total IgG, IgG1 and IgG2 titers were below the reference range and had not recovered to within 20% of baseline, whereas other measured immunoglobulins approached baseline values. We did not generally observe an “overshoot” of immunoglobulins above pre-TPE levels or accelerated recovery of pathologic AChR autoantibodies. Protective antibody profiles showed similar patterns as other IgGs and were detectable at levels associated with protection from infection. A slow return to baseline for IgGs (except IgG3) was observed, and we did not observe any obvious effect of concomitant medications on this recovery. Collectively, these findings enhance our understanding of the immunological effects of TPE and further supports the concept of rapid immunoglobulin depletion for the treatment of patients with MG

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI

Recommendations for myasthenia gravis clinical trials

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First-in-Human Studies of MW01-6-189WH, a Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury

A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation:

Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI)

Validation of the triple timed up‐and‐go test in Lambert‐Eaton myasthenia

Introduction There are no validated, practical, and quantitative measures of disease severity in Lambert‐Eaton myasthenia (LEM). Methods Data from the Effectiveness of 3,4‐Diaminopyridine in Lambert‐Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up‐and‐go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. Results The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4‐diaminopyridine free base. Worsening patient‐reported Weakness Self‐Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. Discussion The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM