Ameliorating Insulin Signalling Pathway by Phytotherapy
Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa in Ethnopharmacology of Wild Plants, 2021
The plant is a perennial herb growing up to 1.5 m, belonging to family Umbelliferae. It is also known as asafoetida, and has a pungent smell, lending it the trivial name of stinking gum. Morphologically, leaves contain spacious sheathing petioles. The height of the flowering stem is 2.5–3 m long and hallow. The pale greenish-yellow coloured flower is in large compound umbels. The shape of the fruits are oval, flatform, thin, reddish brown in colour and contains a milky juice. Generally, this plant is rich in resin, endogeneous gum, and volatile oil. The resin portion is a mixture of sinotannols ‘A’ and ‘B’, ferulic acid, ferulsinaic acid and umbelliferone, while volatile oil portion contains organosulfide compounds, such as 2-butyl-propenyl-disulfide, diallyl sulfide, diallyl disulfide and dimethyl trisulfide (Mahendra and Bisht 2012). Figure 15.12 shows a few chemical compounds contained on F. asafoetida.
An Overview of the NIAID/NIH Chemical Medical Countermeasures Product Research and Development Program *
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
Through NIH support, several small and large animal models of intoxication by metabolic poisons have been developed and validated over the past decades. In vivo models have ranged from small, such as rodents and rabbits (Crankshaw et al., 2007;Cronican et al., 2015; Lee et al., 2008), to large animals such as swine and sheep (Bebarta et al., 2014; Bhandari et al., 2014; Haouzi et al., 2015). Using these models, a number of compounds have demonstrated efficacy in promoting overall survival after exposure. These promising compounds include: dimethyl trisulfide (DMTS), methylene blue, cobinamide, methemoglobin, sodium nitrite, and sulfanegen (Chan et al., 2015; Chenuel et al., 2015; Cronican et al., 2015; Judenherc-Haouzi et al., 2016; Kovacs et al., 2016; Nagasawa et al., 2007). The mechanistic action of most of the identified therapies is to either scavenge or detoxify the target chemical threat by metabolism while it is still in circulation before cellular respiration is severely affected. When removal from the circulatory system is not possible, attempts at mitigating the potential chronic or longer-term neurological impacts of intoxication have identified carnosic acid, a pro-electrophilic compound, as a viable therapy (for cyanide poisoning). Carnosic acid is hypothesized to protect the brain by specifically upregulating central antioxidant enzymes to reduce the neuronal cell loss that commonly occurs after seizure activity (Zhang et al., 2015). While most of the efficacy demonstrated to date has been for either hydrogen sulfide or cyanide, the vitamin B12 analog cobinamide has been shown to enhance survival after poisoning by both of those chemicals (Bebarta et al., 2014; Brenner et al., 2014).
Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity
Published in Clinical Toxicology, 2019
Tara B. Hendry-Hofer, Alyssa E. Witeof, Dennean S. Lippner, Patrick C. Ng, Sari B. Mahon, Matthew Brenner, Gary A. Rockwood, Vikhyat S. Bebarta
Nithiodote®, an FDA approved therapy for cyanide poisoning, contains sodium nitrite and sodium thiosulfate [3]. Sodium thiosulfate acts as a sulfur donor, converting cyanide to the less toxic, renally excreted compound thiocyante [4–6]. Thiosulfate relies on the sulfur transferase rhodanese, which is primarily found in the mitochondria of the liver and kidneys. Furthermore, thiosulfate is minimally lipophilic, limiting its ability to penetrate the cell and blood–brain barrier, a target organ of cyanide toxicity [4,7]. Dimethyl trisulfide (DMTS), like the FDA approved drug sodium thiosulfate, has been found to be therapeutic following cyanide poisoning [8]. Similar to sodium thiosulfate, DMTS, a sulfur-based molecule found in garlic, onion and other plants, acts as a sulfur donor making it an antagonist for cyanide, converting cyanide to the less toxic compound thiocyanate [9,10]. However, compared to thiosulfate, DMTS has been shown to clear cyanide with greater efficiency, making it a potentially ideal candidate drug for cyanide toxicity [8,9].
A novel aqueous dimethyl trisulfide formulation is effective at low doses against cyanide toxicity in non-anesthetized mice and rats
Published in Clinical Toxicology, 2022
D. S. Lippner, D. M. Hildenberger, M. O. Rhoomes, J. N. Winborn, H. Dixon, J. McDonough, G. A. Rockwood
Much work has been focused upon identifying an effective CN countermeasure that can be administered IM [28–33] since IM administration with certain types of autoinjectors can be rapidly performed by minimally trained personnel. Dimethyl trisulfide (DMTS) is a natural compound that is found to be generally safe by the FDA when consumed orally [34,35] and has been extensively studied as a CN medical countermeasure using various animal models [28,36–40]. While effective, the earlier, non-aqueous DMTS formulations exhibited some limitations with stability [37,41], or bioavailability [28,36]. The studies presented in this manuscript introduce a novel aqueous 10% DMTS formulation (developed by Southwest Research Institute, San Antonio, TX) that has recently demonstrated stability out to 24 months when stored in ampoules (unpublished data) and improved bioavailability profiles in rodents (described as a “proprietary formulation of DMTS”) [42], and determine whether this aqueous formulation exhibits efficacy in various rodent models at lower IM doses than previous formulations. Moreover, we exhibit the efficacy of this DMTS formulation when it is administered at a set delay in rats, which can better simulate real-life scenarios for CN countermeasure treatment.
DMTS is an effective treatment in both inhalation and injection models for cyanide poisoning using unanesthetized mice
Published in Clinical Toxicology, 2018
Susan M. DeLeon, Jason D. Downey, Diane M. Hildenberger, Melissa O. Rhoomes, Lamont Booker, Gary A. Rockwood, Kelly A. Basi
Evaluation of CN medical countermeasures has traditionally been conducted in models in which animals are injected or infused with CN salts [29,30]. Though this type of model is not necessarily reflective of real-world exposures, it is still an instructive model, allowing for tight control of exposure parameters (i.e., precise volume of CN administration). In addition, acute CN exposure models typically require the animals to be anesthetized. Anesthesia can reduce heart and respiratory rate [31,32], which is a very different condition from someone who has been exposed to CN. Indeed, isoflurane has been shown to protect against acute CN exposure, as well as interfere with the protection afforded by sodium nitrite [27]. For this reason, we developed a model of acute CN inhalation intoxication, using a highly toxic agent system (HTAS) from CH Technologies, in unanesthetized mice. Use of the nose-only exposure inhalation system allows the ability to execute brief exposures while limiting the conduits of CN entry into the animal. This model was used to support the development of dimethyl trisulfide (DMTS) as a candidate countermeasure for CN poisoning by providing a model of acute CN exposure that better represents a real-world mass casualty scenario. DMTS has previously been demonstrated as an efficacious CN countermeasure that can be delivered via intramuscular (IM) injection in an injection-based model of CN toxicity [33]. As a means of comparison, we also include the results of the new formulation in the KCN injection model. Here we show that a new, more concentrated formulation of DMTS is efficacious in a KCN injection model, as well as in two lethal HCN inhalation paradigms, and is highly effective by intramuscular injection.
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