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Disulfiram: Mechanisms, Applications, and Challenges
Background: Since disulfiram’s discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were “disulfiram” and “Antabuse”. Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948–2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a “repurposed” agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.
Journal Article
Recent Progress in Lyme Disease and Remaining Challenges
Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.
Journal Article
Randomized sham-controlled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive–compulsive disorder
In open trials, 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) improved symptoms and normalized cortical hyper-excitability of patients with obsessive–compulsive disorder (OCD). Here we present the results of a randomized sham-controlled double-blind study. Medication-resistant OCD patients (n=21) were assigned 4 wk either active or sham rTMS to the SMA bilaterally. rTMS parameters consisted of 1200 pulses/d, at 1 Hz and 100% of motor threshold (MT). Eighteen patients completed the study. Response to treatment was defined as a ⩾25% decrease on the Yale–Brown Obsessive Compulsive Scale (YBOCS). Non-responders to sham and responders to active or sham rTMS were offered four additional weeks of open active rTMS. After 4 wk, the response rate in the completer sample was 67% (6/9) with active and 22% (2/9) with sham rTMS. At 4 wk, patients receiving active rTMS showed on average a 25% reduction in the YBOCS compared to a 12% reduction in those receiving sham. In those who received 8-wk active rTMS, OCD symptoms improved from 28.2±5.8 to 14.5±3.6. In patients randomized to active rTMS, MT measures on the right hemisphere increased significantly over time. At the end of 4-wk rTMS the abnormal hemispheric laterality found in the group randomized to active rTMS normalized. The results of the first randomized sham-controlled trial of SMA stimulation in the treatment of resistant OCD support further investigation into the potential therapeutic applications of rTMS in this disabling condition.
Journal Article
Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome
Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.
Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.
nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.
Journal Article
Neuropsychiatric Lyme Disease and Vagus Nerve Stimulation
Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10–30% experience post-treatment symptoms and 5–10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.
Journal Article
A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease
studies report that disulfiram is effective in killing
. Case series suggest disulfiram may help to reduce the symptoms of patients with persistent symptoms despite prior antibiotic treatment for Lyme disease. This pilot study assessed safety, tolerability, and signs of clinical response.
Participants with a history of previously treated Lyme disease and persistent fatigue were randomly assigned in a double-blinded fashion to either Group A (disulfiram for 4 weeks and placebo for 4 weeks) or Group B (disulfiram for 8 weeks). Primary outcome endpoint was at 10 weeks with a follow-up at 14 weeks. The primary aim was to assess safety and tolerability. A clinical aim assessed signs of clinical improvement using well-validated measures, focusing on improvement in fatigue and quality of life. Target enrollment was 24 participants.
940 individuals were screened, 11 were enrolled and nine participated in the trial. Dosing started low and increased based on response and tolerance to a maximum of 500 mg daily. Safety. Two participants discontinued medication due to clinical worsening, one of whom was briefly hospitalized. Three additional participants were withdrawn from treatment due to lab test abnormalities. Tolerability. Only three of nine participants completed the full course of treatment (two in Group A and one in Group B). Lower doses were better tolerated than the highest dose. Clinical response. Of nine participants, clinically meaningful improvement was noted in fatigue for six and in quality of life for four. Among the six fatigue responders, improvement was also noted on a multiple domain symptom index (six of six), overall symptom burden (five of six), and functional impairment (four of six). The study was terminated early due to end of project funding, higher than expected adverse events, and recognition that sufficient information was gathered to inform future studies.
This study reveals the risks associated with disulfiram, especially at higher doses, while suggesting potential clinical benefits among some participants. Efficacy could not be assessed given the small sample size and the lack of a placebo-control group.
https://clinicaltrials.gov/study/NCT03891667?cond=Lyme%20Disease&intr=disulfiram&rank=1, NCT03891667.
Journal Article
Proposed research classification criteria for Lyme disease in infection associated chronic illness studies
Research on patients with persistent symptoms despite prior treatment for Lyme disease can be challenging to interpret given the diversity of criteria selected to characterize Lyme disease and to define the syndrome of those with persistent symptoms. Because most research studies only include patients with well-documented prior Lyme disease, the generalizability of the study results is limited, excluding the larger group of patients often seen in community practice who do not meet these stringent enrollment criteria. Researchers at the Lyme and other Tick-borne Diseases Clinical Trials Network (LTD-CTN) recognized early on that a research classification system was needed to facilitate the design of studies that are more inclusive. This paper presents a proposed research classification system.
Criteria used in published clinical research on previously treated Lyme disease were reviewed. Clinical expertise was provided by principal investigators in the LTD-CTN. Further input was obtained from a diverse panel of stakeholders in the field, including clinicians, academic researchers, and patient advocates. This classification system was developed based on feedback collected from all these sources.
The new research classification system proposes criteria for Lyme disease at different levels of diagnostic certainty: well-defined, probable, possible, and uncertain. Criteria for ascertainment for each classification level and additional factors to be considered in patient selection for research are described.
The proposed research classification system should improve the quality and generalizability of clinical research by providing clear case definitions for enrollment of a more diverse group of patients with sequelae from Lyme disease.
Journal Article
Perinatal transmission of Borrelia burgdorferi: advancing scientific and clinical understanding of Lyme disease in pregnancy
Perinatal transmission of Borrelia burgdorferi sensu lato (Bb), the spirochetal agent of Lyme disease, is an issue of public health importance and research significance. This alternate mode of transmission and the potential risk of adverse pregnancy outcomes were communicated within public health spheres following the first suspected case in 1985. Subsequent studies in reservoir and non-reservoir animal hosts, in addition to case reports of perinatal morbidity and mortality in humans brought further attention to the field. Decades later, however, the incidence and epidemiologic impact of perinatal transmission of Bb, as well as the clinical spectrum and potential long-term health sequelae of gestationally exposed children, remain understudied and poorly defined. In June 2022, a Banbury Conference on Perinatal Transmission of Lyme disease was convened at Cold Spring Harbor Laboratory in New York. This manuscript conveys conference findings and research recommendations to advance scientific and clinical understanding of this important issue.
Journal Article