Exposure to disulfiram and incidence of parkinsonism

Liu Z., Kang K., Shan S., Wang S., Li X., Yong H., Huang Z., Yang Y., Liu Z., Sun Y., Bai Y., Song F.

Exposure to carbon disulfide (CS2) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS2 exposure on parkinsonian pathology. Our results showed that CS2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, in vitro and in vivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS2 exposure. Taken together, our results demonstrate that CS2-mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.

Lanz J., Biniaz-Harris N., Kuvaldina M., Jain S., Lewis K., Fallon B.A.

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.

Mitchell E., Chohan H., Bestwick J.P., Noyce A.J.

Background: A substantial body of research has examined the relationship between alcohol consumption and risk of Parkinson’s disease (PD). Objective: To provide an updated systematic review and meta-analysis of observational studies examining the relationship between alcohol consumption and risk of PD. Methods: Eligible studies comparing PD risk in ever vs. never alcohol drinkers were sourced from six databases. Outcomes were pooled using standard meta-analysis techniques. Separate female and male estimates were generated from studies reporting sex-specific data. Additionally, cohort studies stratifying participants by quantity of alcohol intake were integrated in a dose-response analysis. Results: 52 studies were included, totaling 63,707 PD patients and 9,817,924 controls. Our meta-analysis supported a statistically significant overrepresentation of never drinkers among PD subjects; odds ratio (OR) for ever drinking alcohol 0.84 (95% confidence interval (CI) 0.76 – 0.92). A subgroup analysis revealed similar effect estimates in females and males. A further synthesis of seven cohort studies suggested a negative, dose-dependent association between alcohol and risk of PD. Conclusion: In the absence of a known neuroprotective pathway, there may be reason to doubt a true biological effect. The role of survivor bias, selection and recall bias, misclassification, and residual confounding requires consideration. Alternatively, observations might be attributable to reverse causation if those predestined for PD alter their alcohol habits during the preclinical phase. Major limitations of our study include high between-study heterogeneity (I2 = 93.2%) and lack of adjustment for key confounders, namely smoking status.

d’Errico A., Strippoli E., Vasta R., Ferrante G., Spila Alegiani S., Ricceri F.

Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics. All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design. The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00–3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76–3.21). These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

Kannappan V., Ali M., Small B., Rajendran G., Elzhenni S., Taj H., Wang W., Dou Q.P.

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

Bhandutia D., Nayok S.

IntroductionMr. X, a 39-year-old man presented to us with a history of alcohol use from the last 12-15 years in a dependence pattern with tolerance, uncomplicated withdrawal symptoms and salience. He was detoxified, given parenteral thiamine supplements and oral lorazepam to reduce withdrawal symptoms. He was contemplating to quit alcohol and thus about 4-5 days after his detoxification, tablet acamprosate 1998 mg/day was added, in three divided dosages. He was discharged after 10 days and had no withdrawal signs or cerebellar deficits. In the next follow-up after two weeks, he reported to be abstinent from alcohol, but now complained of new onset coarse tremors and excessive salivation. He had no other extra pyramidal or cerebellar symptoms, no hepatic or renal dysfunction and no neurological deficits. The Patient had a drooling score of 6 on Drooling Severity and Frequency Scale(DSFS).ObjectivesAcamprosate and naltrexone are the only two drugs approved by the US Food and Drug Administration for achieving abstinence in patients with Alcohol Dependence Syndrome. Acamprosate is well tolerated and has a few drug interactions. It has a comparatively benign side effect profile which includes diarrhea, intestinal cramps, itching, dizziness, muscle weakness, headache, flatulence, nausea, anxiety, and insomnia. Here we report hypersalivation and coarse tremors as unusual side effects of acamprosate.MethodsCross-sectionalResultsHere we report hypersalivation and coarse tremors as unusual side effects of acamprosate.ConclusionsThe probable mechanism responsible for this is thought to be acamprosate induced decrease in dopamine release in ventral tegmental area due to diminished glutamate activity.DisclosureNo significant relationships.

Mason B.

Fairbanks J., Umbreit A., Kolla B.P., Karpyak V.M., Schneekloth T.D., Loukianova L.L., Sinha S.

Pathologic alcohol use affects more than 2 billion people and accounts for nearly 6% of all deaths worldwide. There are three medications approved for the treatment of alcohol use disorder by the US Food and Drug Administration (FDA): disulfiram, naltrexone (oral and long-acting injectable), and acamprosate. Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. Baclofen, a γ-aminobutyric acid B receptor agonist used for spasticity and pain, received temporary approval for alcohol use disorder in France. Despite effective pharmacotherapies, less than 9% of patients who undergo any form of alcohol use disorder treatment receive pharmacotherapies. Current evidence does not support the use of pharmacogenetic testing for treatment individualization. The objective of this review is to provide knowledge on practice parameters for evidenced-based pharmacologic treatment approaches in patients with alcohol use disorder.

Iavicoli S., Valenti A., Barillari C., Fortuna G., Boccuni V., Carnevale F., Riva M.A., Kang S., Tomassini L.

The aim of this study is to illustrate the historical role of the International Commission on Occupational Health (ICOH) congresses as an arena where national and international occupational medicine can dialogue and as the first example of scientific transferability of the research and prevention results that have had such an impact on global public health.We used the ICOH Heritage Repository, in which ICOH congress proceedings (from the first congress in Milan in 1906 to the last congress, held in Dublin in 2018), are organised in an orderly way, updated and easily accessible according to open access logic.We describe studies by three physicians who submitted significant scientific work to ICOH congresses, one on the battle against ancylostomiasis (Volante, 1906), the second (Quarelli, 1928) on carbon disulphide poisoning, and the third (Viola, 1969) on the carcinogenicity of vinyl chloride monomer. Priority is given to Italian cases, on account of the authors' obvious familiarity with the issues.The visibility offered in ICOH conferences and their published proceedings has boosted the international spread of their findings, contributing to the scientific transferability of the research results and influencing the development of policies and prevention interventions that have had a great impact on global public health.

Mochizuki H., Choong C., Masliah E.

α-synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive. Prodromal intervention to inhibit the accumulation of pathogenic protein may advantageously provide a better outcome. However, treatment prior to onset is not ethically justified as standard practice at present. In this review, we initiate a refined concept to define early pathogenic state of αSyn accumulation before occurrence of brain damage as a disease criterion for αSyn dysregulation disease.

Peelaerts W., Bousset L., Baekelandt V., Melki R.

Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis.

Goedert M., Jakes R., Spillantini M.G.

In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

Blanc P.D.

When a new technology makes people ill, how high does the body count have to be before protectives steps are taken? This disturbing book tells a dark story of hazardous manufacturing, poisonous materials, environmental abuses, political machinations, and economics trumping safety concerns. It explores the century-long history of “fake silk” or cellulose viscose, used to produce such products as rayon textiles and tires, cellophane, and everyday kitchen sponges. The book uncovers the grim history of a product that crippled and even served a death sentence to many industry workers while also releasing toxic carbon disulfide into the environment. Viscose, an innovative and lucrative product first introduced in the early twentieth century, quickly became a multinational corporate enterprise. The book investigates the viscose rayon industry's practices from the beginning through two highly profitable world wars, the midcentury export of hazardous manufacturing to developing countries, and the current “greenwashing” of viscose rayon as an eco-friendly product. This book brings to light an industrial hazard whose egregious history ranks with those of asbestos, lead, and mercury.

Jiao Y., N. Hannafon B., Ding W.

Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence indicates that DSF possesses a great potential for the treatment of human cancers. DSF's anticancer activity has been demonstrated in both in vitro and in vivo model systems, and has been tested in human clinical trials for various cancer types. It is also evident that DSF can sensitize tumor cells to radiotherapy and enhance the cytotoxicity of anticancer drugs, thus DSF may serve as an adjuvant therapy. The key to DSF's anticancer action relates to its ability to suppress cancer stem cells by targeting aldehyde dehydrogenase (ALDH), a marker of cancer stem cells, and inhibit proteasome activity in cancer cells by forming complexes with metal ions. In addition, DSF targets epigenetic mechanisms and modulates cellular signaling pathways to slow down tumor progression. DSF also induces apoptosis, inhibits cancer cell proliferation, and suppresses cancer cell metastasis. Considering that the pharmacokinetics of DSF are well-established and a safety profile has been recorded, this compound is an attractive "old" drug that has great potential for rapid development into a new cancer therapeutic. This article provides a brief review of the history of DSF use in humans, evidence for its anticancer activities, the molecular mechanisms of DSF action that have been illustrated by recent studies, and the potential for repurposing DSF as a new chemotherapeutic drug in the near future.

Tran A.T., Rison R.A., Beydoun S.R.

Neuropathy is a rare adverse side effect of disulfiram therapy and is under-recognized. There have been few case reports documenting this side effect. Two cases of disulfiram peripheral neuropathy are discussed. The first case is that of a 25-year-old Caucasian woman who was exposed to disulfiram therapy for a total of 8 months and developed pain and stiffness that prevented her from walking. The second case is that of a 46-year-old Caucasian woman who developed sudden-onset numbness in her lower extremities with progression to pain. Her symptoms improved over the course of 2 months after cessation of disulfiram therapy. In both cases, symptoms improved after cessation of disulfiram therapy. Disulfiram neuropathy occurs in persons with a history of chronic alcohol use. It is under-recognized and often attributed to alcoholic neuropathy given its comorbidity with alcoholic neuropathy. A greater understanding of this side effect may reduce neurologic complications related to disulfiram neuropathy and aid in early withdrawal of this offending agent.