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Cocaine abuse remains a significant worldwide public health problem with serious socio-economic consequences. According to the latest World Drug Report 1 , 0. In addition to its intense excitatory effect on the nervous system, cocaine has non-negligible adverse effects on the cardiovascular, gastrointestinal, respiratory, musculoskeletal and renal systems 2 , 3. BE is an active metabolite with sub-lethal toxicities on multiple targets. A previous in vivo study showed that BE is a stronger vasoconstrictor than cocaine itself 5 , hence the cerebral arteries are more sensitive 6. According to another study, the incidence of seizure is highly related to the presence of BE 7. Also, the latest research has found that even low concentrations of BE can significantly change the expression levels of proteins related to calcium homeostasis and oxidative emergency 8. These studies pointed out that BE has remarkable sub-lethal toxic effects in vivo. Moreover, BE can remain in the body for a considerably longer period compared to the parent drug and can be detected in urine up to 4 days after last cocaine use. For this reason, BE is commonly used as a marker to screen individuals for a history of cocaine consumption or estimate the scale of the cocaine market 9. BE is poisonous and exhibits durable influences, which means that the removal or degradation of it into biologically inactive molecules is critical for cocaine detoxification. BE is often excreted from the urine as one of the major substance forms of cocaine, and the environment is the ultimate destination. Unlike cocaine, BE is an amphoteric ion which is extremely stable in the human body and the natural environment Consequently, the expelled BE is often detected in urban water systems in western and central European cities 1. BE then enters the receiving water bodies including surface water, ground water and even drinking water sources, as proven by several monitoring studies. The eco-toxicity of BE on diverse model aquatic species was evaluated at concentrations similar to those detected in surface waters 13 , 15 - Increased evidence has confirmed that BE exhibits significant toxic effects on aquatic animals and plants. More importantly, it is reasonable to speculate that sustaining BE exposure in the environment could influence animals, plants, crops in the food chain and ultimately influence humans. Given the sub-lethal toxic effects of BE on humans and the environment, there is a pressing need to identify efficient methods to either adsorb or degrade it in situ. Techniques such as active sludge reactors, reactive barrier, Fenton reaction, hydrogen peroxide H 2 O 2 treatment, ozone oxidation, and enzymatic degradation have been developed to transform BE into non-toxic products 18 , Multiple technologies are usually incorporated to increase the removal efficiency against illicit drugs and their metabolites during water treatment In recent years, enzymatic degradation is a useful strategy for BE detoxification both in vivo and in vitro The effective enzymes against BE are suitably used in environmental protection by developing transgenic plants. BE elimination for humans and the environment has hopefully attracted attention and become a key aspect in cocaine abuse treatment. This study aimed to describe possible solutions to prevent further toxic effects of BE during cocaine detoxification treatment. The discovery and development of highly effective methods for cocaine detoxification treatment are critical. The search was not limited to either English-language articles or publication date. Ninety-two articles were found and evaluated for inclusion independently by both authors and journals. Seventy-seven articles with strong relationships were selected for detailed evaluation. We did not assess the quality of the included studies. After the search, we constructed a list depending on the areas presented in the included studies. The first authors conducted an initial screening of the included studies by reading the titles and abstracts and decided whether they were relevant for our purposes. The entire team then carried out a second screening of the full-texts. Ultimately, detailed information was selected and presented here. Cocaine toxicity has been studied extensively, as has been shown in previous reviews 3 , yet BE toxicity has been less explored. However, according to limited toxicology studies, BE exhibits different mechanisms of adverse effects on the cardiovascular system, nervous system and infants Figure 2. Importantly, BE seems more toxic to certain organs such as cerebral arteries and infants. Moreover, chronic cocaine toxicity might be due to the presence of its toxic metabolite BE. Thus, it is necessary to re-estimate the toxic effects of BE in vivo. Clinically, cocaine is a vasoconstrictor. However, it has been reported that BE has more vasoconstriction effects compared to the parent drug and other drugs such as norcocaine and norepinephrine 5. BE has been shown to cause a significant decrease in the arterial diameter of isolated cerebral arteries of cats and fetal sheep 6 , 20 , Cerebral artery segments are more sensitive to BE than cocaine and other cocaine metabolites 6. A previous in vitro study has demonstrated that BE cause a However, another study pointed out cocaine and BE exert vasoconstrictor effects through different mechanisms. Cocaine was also reported to cause vasoconstriction by stimulating the sympathetic nervous system, followed by decreasing the reuptake of neurotransmitters including dopamine, epinephrine and norepinephrine BE induced vasoconstriction is mediated by several complicated mechanisms that require further investigation. Furthermore, BE-induced vasoconstriction may be involved in other sub-lethal toxicities such as neurotoxicity and cardiovascular disease. Cocaine-induced seizures commonly occur after cocaine consumption and are characterized by intense brain activity and repeated or rhythmic jerking muscle movements. Seizures have always been considered one of the serious effects of cocaine poisoning, in addition to psychosis and cardiovascular effects 2 , 23 - Cocaine is a psychostimulant and psychotomimetic compound 28 that may induce acute and chronic psychiatric and neurological effects, including psychosis, agitation and seizures The mechanisms underlying the neurotoxicity of cocaine are not fully understood since several intracellular biochemical processes appear to be involved 30 - However, BE is assumed to be responsible for seizures, as cocaine only has a 6 hours half-life in the body, whereas seizure usually occurs later after cocaine intake 7 , Scientists assume that BE-induced seizures occur via different mechanisms Compared to equimolar amounts of cocaine, BE-induced seizures occur more frequently and have a significantly longer latency 7. BE could also inhibit embryos from developing into blastocysts at one or two cellular stages Also, BE causes maternal and fetal hypertension However, BE was found in the urine and not cocaine. Cocaine was only detected in the urine of lethargic newborns Therefore, some studies hypothesized that BE might cause behavioral changes in newborns and their hypotheses had been confirmed Due to the incomplete development of the blood-brain barrier, the effect of BE on the fetal brain may be greater than the maternal effects. In pharmacokinetic studies, the concentration of BE in the fetal brain was higher than in the maternal brain 38 - 40 , which is consistent with the differences in fetal and maternal bodies A clinical study demonstrated that BE could persist in the urine of neonates for up to 48— hours after exposure but only persists for 27 hours in the urine of adults The placenta may cause this phenomenon since BE is retained by the placenta and then subsequently leaches into the fetal and maternal circulation Parolini et al. The swimming activity of individuals and the reproduction of the population were investigated at two concentrations of BE 0. At high BE concentrations, the activity of D. BE exposure also induced a marked increase in apoptotic or necrotic cell frequency at a concentration of 1. BE exposure also induced a notable increase in cell mortality. In zebrafish embryo cells, cell mortality was significantly increased at BE concentration of above 0. A notable increase in the size of lipid droplets of D. The accumulated lipid droplets indicated abnormal lipid synthesis or metabolism Furthermore, a proteomics study showed that exposure to BE for 14 days changed the protein profile of the gills of D. Diverse proteins involved in different systems had also shown alteration. The normally low-expressed actin isoforms take part in multiple important cell survival processes, such as structure conservation, motility, cellular organization and intracellular transport Moesin is an integrin that plays biological roles in regulating basic cellular functions, including motility, adhesion, cellular signaling and cellular morphology Exposure to BE also affected calcium homeostasis. The precursor of calreticulin was found to be over-expressed at the tested BE concentrations. Proteins affecting apoptosis, like Galectin 7, were over-expressed at even lower concentrations of BE 8 , Adenosyl-homocysteinase was over-expressed at two BE concentrations, affecting amino acid metabolism 8 , The expression of two enzymes involved in glycolysis, namely enolase and GAPDH, were down-regulated after BE exposure, suggesting that BE may reduce the tolerance of zebra mussels to environmental stresses by decreasing energy metabolism 8 , Low expression of EF-2, a protein involved in protein biosynthesis, was speculated to disrupt the metabolic pathways of zebra mussels and subsequently reduce the resistance to environmental changes 8 , Regarding another aquatic species, Parolini et al. Proteins belong to eye lens constituents, lipid transport and energy metabolism were also significantly altered in the BE group and the cocaine and EME groups A significant increase of DNA fragmentation in cells from D. Significant DNA strand break was also observed in embryo cells at tested concentrations from 0. Regarding fixed DNA damage, apoptotic, necrotic and micronuclei frequency increased, which followed both time and concentration dependencies 17 , Solid evidence has suggested that the adverse effects to macromolecules are mainly caused by BE-induced oxidative stress. In , Parolini et al. In their study, the neutral red retention assay showed a significantly decreased trend of lysosomal membrane stability at both tested concentrations 0. For detailed biomarkers, the activities of three antioxidant phase I enzymes, namely catalase CAT , superoxide dismutase SOD and glutathione peroxidase GPx , as well as the phase II detoxifying enzyme glutathione S-transferase GST , were altered imbalanced depending on the dose The activities of these defense enzymes were also imbalanced in zebrafish embryo cells after BE exposure in a concentration range of 0. Clearer patterns of these oxidative status biomarkers were observed on D. The indirect evidence, obtained by measuring the lipid peroxidation LPO and protein carbonyl content PCC , also indicated that substantial oxidative damages were caused after BE exposure 15 , 17 , 49 , 51 , Taken together, BE has been shown to exhibit toxic effects on freshwater animals by elevating ROS levels and interrupting the balance of the antioxidant system. These results suggest that BE-induced oxidative stress may be the major reason for the toxicity of aquatic organisms. The toxicity of BE to freshwater plants has been less studied. However, based on a few studies, BE exposure caused developmental inhibition for certain plants. It was found that BE exposure caused a decrease in the viability of fern cells. After 48 hours of BE exposure in a concentration range of 0. A previous study had shown that at concentrations of 0. Exposure to BE also induced a high percentage of micronucleated cells in V. Therefore, the activated sludge reactor is commonly used to eliminate BE and other illicit drugs or their metabolites in the water treatment process, combined with pre-treatment and other methods. The reactive barrier is another low-cost BE clearance method. The reactive barrier is set at the bottom of an infiltration basin to promote the adsorption of BE, and consists of aquifer sand, vegetable compost, clay and iron oxide dust 56 , and exhibits notable BE removal efficiency. However, the disadvantage of this method is that it takes a long time to completely remove BE, taking about 48 h in the test The Fenton reaction is one of the advanced oxidation processes, which can be used for pretreatment before biological level treatment and can also be used as a tertiary treatment process However, the researchers found that the products peroxides, oxidant by-products polluted with river water may cause greater toxicity 44 , 58 , Therefore, BE by-products produced by peroxide may still exhibit potential toxicity, and this treatment process requires further treatment before discharge. Ozone oxidation has been mostly applied in drinking water treatment plants DWTPs , and the efficiency of BE removal has been reported. Researcher believes that the low removal efficiency might be due to the absence of ozone-reactive sites and electron-absorbing groups in ozone 61 , and similar results were obtained in a study later conducted by another group The study continued to carry out toxicological experiments to prove that it was not toxic to humans at this concentration Most WWTPs will combine multiple technologies to remove drugs. Recently, a long-term monitoring program was undertaken in Australia to characterize the fate of emerging drugs of addiction including BE, the major metabolite of cocaine. Different secondary and tertiary treatment technologies were investigated to remove of BE in sewage The treated water could be directly used for horticulture, public place irrigation, and non-potable water purposes As shown in Table 1 , this work enables a performance comparison between multiple combined wastewater treatment processes. In previous studies, a few efficient and stable cocaine-metabolizing enzymes were designed and developed based on human BChE or bacterial cocaine esterase CocE , which showed rapid detoxification efficiency against cocaine 64 - For the clinical treatment of cocaine overdose and addiction, using an efficient metabolic enzyme is considered a promising strategy 71 - Chen et al. To improve the efficiency of BChE, their study constructed mutants to increase the efficiency of hydrolyzing cocaine, and at the same time, increase the degree and rate of BE degradation in vitro and in vivo Furthermore, in vivo experiments verified that E accelerated BE hydrolysis to ecgonine in a dose-dependent manner The BChE-FC fusion or catalytic antibody analogs fusion proteins were further constructed to extend the time of action in the organism. Researchers believe that other mutants with better catalytic activity would be constructed through continuous research The enzymatic degradation of BE seems to be an effective and eco-friendly elimination method that offers potential in the clinical treatment of cocaine overdose and environmental governance. BE is the main toxic metabolite of cocaine after a dose consumption. It has a similar molecular structure to cocaine, which is the major reason for long-term toxicities on the cardiovascular system, central nervous system, fetus, etc. In fact, BE causes more notable decreases in arterial diameter, suggesting it is a more potent vasoconstrictor than cocaine and other drugs, and as a result, cerebral artery segments showed higher sensitivity to BE than cocaine itself. Also, BE-induced seizure has a longer latency and frequency, and thus, seizure incidence after cocaine consumption is supposed to be primarily caused by BE. BE has a strong inhibitory effect on embryos in the early stages of development. Also, BE causes hypertension for both the mother and fetus, which may be correlated with the strong vasoconstrictive effect. In some studies, BE appears to pass the blood-brain barrier of the newborn more easily, which causes more fetal toxicity. At the same time, BE can exist in the body for a relatively long time and is used as an indicator of cocaine consumption. Thus, the toxicity effects of long-term BE exposure in the body should be investigated more extensively. BE is one of the major illicit drug metabolites found in the environment, primarily the aquatic system. Considering the increased use of cocaine worldwide and an incessant BE input in freshwater, a consequent increase in concentration is expected. Exposure of BE seems a sort of pseudo-persistence to aquatic organisms. Numerous studies have been carried out to evaluated the critical aspect of the environmental risk of BE. Notable adverse effects, such as abnormal synthesis or metabolism of lipids, genetic damage and protein expression alteration, are related to oxidative stress after BE exposure. Importantly, in vivo studies toward aquatic model species, the zebrafish embryos, showed that BE is more toxic than cocaine. These studies highlighted the relationships between biochemical, behavioral, and reproductive endpoints. In contrast, the studies concerning BE toxicity on plants are few, with growth inhibition being the major adverse effect. The use of BE-polluted surface waters as irrigation and drinking water sources should cause considerable anxiety of persistent exposure of BE to humans. Fortunately, numerous methods of BE elimination have been developed and applied in different processes, including wastewater, drinking water, and clinical emergency treatment. WWTPs play a critical role in the removal of BE to minimize discharge into the receiving environment. Currently, the methods currently used in water treatment processes are activated sludge reactors, photochemical methods, reaction barriers, etc. The removal mechanisms involved are biodegradation, adsorption, photochemistry decomposition, Fenton reaction, etc. Several studies have shown that activated sludge processes with effluent disinfection, such as IFAS with chlorination and MBR with UV, were the most efficient in eliminating the targeted compounds than other more conventional secondary treatment processes. Additional tertiary treatments appear to be effectively achieve near-complete removal of BE and other drugs in recycled waters destined for agricultural irrigation and other regulated municipal uses. Additional tertiary stage using dissolved air flotation—filtration DAFF and chlorination would increase the removal efficiency to nearly complete in WWTPs. Current technologies in each step have limitations, and a fourth step with advanced technology should be applied for better clearance. Removal methods still require further improvement, and advanced technologies should be expanded globally. For clinical treatment of cocaine overdose, accelerating BE metabolism seems a promising therapy method. A recent study focusing on identifying and engineering the natural enzyme with inherent BE metabolism activity showed the prospective potential of enzymatic metabolism Human BChE with inherent BE metabolism activity was redesigned to improve both activity and duration in vivo , the data showed a promising starting point of effective BE metabolism. Emphasizing that BE is a long-lasting toxic metabolite in vivo , ideal enzyme therapy for cocaine overdose should not only hydrolyze cocaine itself in a short period, but also can degrade BE into non-toxic molecules to prevent persistent toxicity. However, it is still extremely challenging to efficiently treat cocaine overdose using current enzyme products due to the enzyme activity and stability. We expect that new enzymes with higher BE removal efficiency in vivo could be developed for clinical use and environmental governance. Findings from the present review showed that BE is a significant toxic metabolite to humans and the environment. To obtain a better understanding of the adverse effects of BE, more extensive studies focusing on the mechanisms of BE toxicity are needed in the future. However, according to current research, few studies investigated the potential effects of BE exposure on humans from the environment. Finally, the BE elimination methods with high removal efficiency are not well-established during water treatment, which may cause subsequent ecotoxicity. More importantly, the clinical treatment of cocaine overdose requires detoxification of cocaine and simultaneous degradation of BE. Reporting Checklist: The authors have completed the Narrative Review reporting checklist. The authors have no conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Figure 1 Benzoylecgonine is the main toxic metabolite of cocaine. Figure 2 Sublethal toxicity of BE to human and aquatic organisms. BE shows strong vasoconstriction effect in body, induces seizures and fetal toxicity in mechanisms that are different to cocaine. BE also has significant adverse effects on aquatic animals and plants, such reproduction toxicity, viability inhibition, cell death effect via inducing oxidation stress. Sub-lethal toxicity and elimination of the cocaine metabolite, benzoylecgonine: a narrative review. Ann Palliat Med ;10 6
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Benzoylecgonine (BE) is the main toxic metabolite after cocaine consumption, with a longer retention time in the body and environment than cocaine itself.
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