Antabuse for Lyme Disease: The Way Forward

Despite leadership by dedicated lay organization and patient-based advocacy groups, the way forward for prospective candidates for disulfiram treatment has been difficult. This article provides the background, overview of disulfiram, in particular its intended use in post-treatment Lyme disease syndrome after a standard of care course of antibiotics fails to alleviate symptoms of tick borne disease. A series of recommendations are offered to guide patients and clinicians.

World Journal of Neuroscience that precipitate glial and neuronal apoptosis and an array of neurologic changes recreating the clinical, serologic, and neuropathologic picture of human Lyme disease [3].
The recurrence or emergence of systemic and nervous system symptoms after a standard of care course of therapy may occur with an enduring positive or indeterminate two-tier Lyme serology or other biomarkers in the cerebrospinal fluid (CSF), and abnormal findings in neuroimaging, electrodiagnostic and autonomic studies correlative with central, peripheral and autonomic nervous system (CNS, PNS and ANS) symptoms and signs [8] [9] have led to reconsideration of post-treatment Lyme disease syndromes (PTLDS).
It is not well understood why some patients experience PTLDS, however the varied presentation no doubt incorporates at least four etiopathogenic mechanisms, singly or in combination in affected cases including persistent but difficult to detect infection [10], host-induced immunity targeting non-viable spirochetes or their remnants [11], a triggered immune response that lasts well after the infection similar to Group A beta hemolytic streptococcus (GABHS) infection in rheumatic heart disease and pediatric autoimmune neuropsychiatric disorder (PANDAS) [12] [13]; and as some might argue, causes unrelated to infection or immunity [14].
The antibiotic treatment of patients with PTLDS has been stymied by negative randomized placebo-controlled trials that fail to show significant, sustained benefit of antibiotic retreatment [15] [16], yet this may be related in part to the antibiotic regimens used, the limitations of current antibody-based assays, polymerase chain reaction (PCR), and culture techniques to determine successful eradication of B. burgdorferi.

Disulfiram for PTLDS
Among highly active compounds investigated in vitro with high-throughput screening of four compound libraries (Library of Pharmacologically Active Compounds, the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol Food and Drug Administration [FDA]) to inhibit >90% of B. burgdorferi growth at a concentration of <25 µM [17], disulfiram (Antabuse®) emerged in 2016 as a lead candidate based upon a favorable minimum inhibitory concentration and minimum bactericidal concentration against B. burgdorferi in vitro. The narrow antibacterial spectrum of disulfiram-based disulfides derived from disulfiram was later appreciated [18].
Disulfiram is an oral prescription drug for the treatment of alcohol abuse disorders [19]. Upon absorption, disulfiram and its metabolites inhibit aldehyde dehydrogenase enzymes that oxidize acetaldehyde from ethanol metabolism into acetic acid. The inactivation of hepatic ALDH leads to buildup of toxic acetaldehyde in the body, which manifests "hangover" symptoms of headache and nausea that deters alcohol consumption [20]. Disulfiram is readily cleaved by thiol-bearing substances such as cysteine enzymes which result in the simulta-World Journal of Neuroscience neous addition and release of diethyldithiocarbamate (DDC) which potentiates the antibacterial activity of disulfiram as both a standalone and combination bactericidal agent [21]. Diethyldithiocarbamate is a very strong chelator of transition divalent metal ions, mainly copper (II) (Cu), and the in vitro cytotoxicity of disulfiram is Cu-dependent. When DDC contacts Cu, the chelating reaction between them triggers the generation of reactive oxygen species (ROS) [22], which damage DNA, protein and lipids leading to cell death. ROS are extremely transient species with very short lifetime due to their high chemical reactivity and can only penetrate very short distance in tissues [23]. Moreover, the reaction of disulfiram and Cu must take place inside or adjacent to the target cells. In addition to ROS generated from DDC and Cu reaction, bio (N, N-diethyldithiocarbamato) copper (II) (Cu-DDC), the end product derived from DDC and Cu reaction, is also cytotoxic [24] [25].

Side Effects and Contraindications
Concern for the development of peripheral neuropathy so noted anecdotally in up to a third of patients with PTLDS treated with disulfiram had led to concern regarding the initiation of treatment in those with pre-existing neuropathy and the most appropriate manner of screening patients who may be prone to, or have existing neuropathy. Caution dictates that prior to start of disulfiram therapy, candidates with PTLDS be screened with a careful history, clinical neurological examination and three limb electrodiagnostic studies to delineated a large

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Recommendations
It is possible to forward several recommendations based upon the current knowledge base.