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Abstract

Introduction

Aluminum phosphide (AlP) is a chemical compound that can cause death in some countries. AlP inhibits the functioning of cytochrome C oxidase in the mitochondria of cardiomyocytes, leading to toxicity. Oxidative stress and ROS production, as well as inflammatory signaling, mediate the mechanisms of AlP-related toxicity in the poisoned patient. Unfortunately, there are no approved medicines available to treat AlP poisoning yet. To address this issue, researchers have explored various interventions to reduce the toxicity associated with AlP tablets.

Methods

We systematically searched relevant databases for English articles published between 2013 and 2024.

Results

The evaluated treatments included correcting oxidative stress parameters, enhancing exogenous antioxidant capacity, modifying electrocardiographic abnormalities, and improving heart contraction strength. Our evaluation indicated that compounds like Triiodothyronine, Vasopressin and milrinone, Iron sucrose, Acetyl-l-carnitine, Melatonin, Fresh red blood cell transfusion, Minocycline, Moringa oleifera extract, Dihydroxyacetone, Selegiline, Nanocurcumin, Levosimendan, Exenatide, Taurine, Cannabidiol and Edaravone are effective in lessening AlP-induced cardiotoxicity.

Conclusion

Based on the present study’s findings and the evaluation of clinical studies, dihydroxyacetone, fresh red blood cell infusion, Oil-based disinfection, and gastric lavage have the most potential to save patients’ lives and treat acute aluminum phosphide. However, there is a need for more research in this regard.

Graphical Abstract

Keywords

Aluminum phosphide phosphine cardiotoxicity in vivo mitochondrial dysfunction

Introduction

The use of pesticides has significantly increased in recent decades, resulting in better agricultural yields worldwide. However, due to their toxic nature, both intentional and unintentional poisoning from these chemicals have caused significant morbidity and mortality. Many countries are exposed to pesticide use’s psychological, social, and economic impacts.¹ AlP (Aluminum Phosphide) is a commonly used pesticide globally to protect grains and crops from pests and insects.² AlP, a member of the metal phosphides family, which includes magnesium, calcium, and zinc phosphide, is the most lethal.³ Due to broad availability, intentional and unintentional poisoning with AlP is one of the critical causes of its fatal poisoning in different countries with different income levels, including Egypt, India, and Iran.^4,5

When AlP is taken orally, it quickly releases the highly poisonous phosphine (Ph₃) gas, which disrupts cellular respiration. PH₃ hinders mitochondrial processes by impeding cytochrome oxidase activity and adenosine triphosphate (ATP) production. In addition, phosphine causes oxidative stress by increasing the production of reactive oxygen species (ROS) and inhibiting enzymatic antioxidants like catalase (CAT), glutathione reductase (GR), and superoxide dismutase (SOD). Imbalanced redox status leads to lipid peroxidation, which causes damage to many cellular structures and increases cellular death.⁶

The toxic effects of AlP poisoning frequently manifest as dysfunction in multiple organs, with the liver, kidneys, and heart being particularly susceptible to its harmful impact.⁷ Clinically, acute AlP poisoning manifested with severe metabolic acidosis and refractory cardiogenic shock.⁸ Within the first 24 h after poisoning, cardiovascular collapse or cardiac arrest is the most common damaging consequence leading to death.⁹ Therefore, it is crucial to identify cardiovascular manifestations such as congestive heart failure (CHF), irregular heartbeats, rapid heartbeats, hypotension with refractory response, and abnormal electrocardiograms (ECGs).¹⁰

The heart’s muscle cells, known as cardiac muscle cells, require significant energy to function properly.¹¹ This energy is essential for controlling the heartbeat and muscle contractions, which is done through a process called excitation-contraction coupling.¹² Compared to other organs, the heart contains a high concentration of mitochondria necessary to meet its constant energy demands and maintain the circulatory system. Research shows that mitochondria generate a substantial amount of energy that heart cells rely on to sustain metabolism and function.¹³ In addition to energy production and calcium regulation, mitochondria also play a crucial role in regulating apoptosis and necrosis, making it critical to maintain their integrity and protect cardiomyocytes from death. However, cardiac muscle cells are susceptible to mitochondrial dysfunction and oxidative stress due to their mitochondrial richness and low antioxidant defense ability. As a result, they are more likely to be affected by toxic drugs and compounds.¹⁴ The cardiac dysfunction caused by AlP poisoning is mainly due to cardiomyocyte death resulting from mitochondrial damage, as demonstrated in Figures 1 and 2.

Figure 1.

The general process of AlP-mediated cytotoxicity. AlP was shown to significantly decrease the activities of mitochondrial complexes I, II, and IV. Additionally, it was observed that AlP led to an increase in reactive oxygen species levels and initiated the process of apoptosis. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen atoms. Adenosine triphosphate (ATP) is a nucleotide molecule that is a primary energy carrier in cells. Upon hydrolysis, ATP is converted into adenosine diphosphate (ADP), releasing energy that cellular processes may use.

Figure 2.

The process of cardiotoxicity caused by rice tablets. After the rice tablet is exposed to liquids and stomach acid, phosphine gas is released. In the first 24 h after poisoning, the most common consequence is the collapse of the cardiovascular system or cardiac arrest. This dysfunction is caused by a decrease in ATP production and an increase in the level of reactive oxygen species.

In the absence of an antidote, the treatment for phosphide poisoning is limited to providing supportive measures. Regrettably, acute AlP poisoning is linked to a significant fatality rate.¹⁵ Therefore, it is imperative to implement treatment approaches grounded in the mechanism of acute AlP poisoning.^16,17 This systematic review aims to identify substances that possess cardioprotective properties against AlP toxicity in vivo models.

Methods

In this comprehensive review, the authors followed the PRISMA checklist to ensure impartiality in extracting data using inclusion and exclusion criteria.

Search strategy

We searched for articles in English published between 2013 and 2024 on April 13, 2024. Our study utilized various databases, including PubMed, Science Direct, Google Scholar, and Scopus. We used specific keywords, such as (“aluminum phosphide” OR phosphine OR “rice tablet”) AND (toxicity OR poisoning) AND (cardiotoxicity OR cardiovascular OR cardiotoxic OR “Myocardial toxicity”) during our search. During our search, we found 254 articles, which we then reviewed by title and abstract. We excluded manuscripts that did not meet our inclusion criteria and assessed the full text of the remaining papers. Our protocol required two authors (S. AB and M.A) to conduct the full-text review and extract data.

Criteria for inclusion and exclusion

We conducted an independent scan of the databases to identify relevant keywords. We excluded clinical and case report studies, in-vitro studies, reviews, non-English articles, biomonitoring studies, and studies that focused on the effect of poisoning on organs other than the heart. Our inclusion criteria for this systematic analysis required original research that examined therapeutic interventions with cardioprotective effects in in-vivo studies. We reviewed all publications that met our inclusion criteria and excluded studies with a sample size of only one.

Data extraction

We extracted the first author’s name, country, research date, intervention, dose, exposure route, type of study, type of animal, and main findings and recorded them in Table 1. Two reviewers (S. AB and M.A) independently extracted the data. In cases of disagreement, we consulted the third author. If we could not access the full text of an article, we emailed the authors.

Table 1.

Description of collected studies.

	Author/country/year/	Intervention/dose/exposure route	Type of study/type of animal	The main finding
1	Baghaei et al.¹⁸ Iran 2014	Novel mixed herbal medicine (IMOD^TM) (13, 20 and 30 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	IMOD has been found to improve the cardiovascular properties that AlP has disrupted. Additionally, IMOD restored cardiac energy by reestablishing cellular ATP levels and reducing stress indicators linked to oxidative stress. These findings provide further evidence for the potential effectiveness of IMOD as a therapeutic intervention to treat acute AlP poisoning
2	Abdolghaffari et al.¹⁹ Iran 2015	Triiodothyronine (1, 2 and 3 μg/kg) gavage (PO)	Experimental male Wistar rats	Triiodothyronine at a dose of 3 μg/kg showed a notable improvement in ECG readings and various parameters linked to oxidative stress. T₃ administration may enhance mitochondrial activity and ATP synthesis in cardiac cells. Introducing triiodothyronine decreased cell death, specifically apoptosis, by hindering caspase activity and maintaining cell viability
3	Jafari et al.²⁰ Iran 2015	Vasopressin and milrinone (AVP) (1.0, 2.0, 3.0, 4.0, 8.0 U/kg) and milrinone (0.125, 0.25, 0.5, 0.75, 1.0 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Exposure to AlP resulted in abnormalities in the ECG and decreased heart rate and blood pressure. AVP and milrinone both significantly amplified these effects in all treated groups. The groups that received treatment demonstrated significant improvements in the biomarkers associated with oxidative stress, complex IV function, ADP/ATP ratio, and the activity of caspase-3 and caspase-9
4	Solgi et al.²¹ Iran 2015	Iron sucrose (10 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Iron sucrose can interact with respiratory chain complexes located inside mitochondria. This interaction allows it to function as an electron acceptor, which, in turn, changes the direction of electron flow. The results of this study provide further evidence to support the theory that iron sucrose can help restore normal functioning of the mitochondrial electron transport chain and ATP levels within cells. Therefore, it may be a viable therapeutic option for reducing the harmful effects of AlP poisoning
5	Baghaei et al.²² Iran 2016	Acetyl-l-carnitine (ALCAR) (100, 200, and 300 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Applying ALCAR decreased the oxidative stress markers caused by AlP poisoning. It also resulted in a rise in the production of ATP. Analysis using flow cytometry and caspase cleavage indicated that ALCAR protected against cardiomyocyte apoptosis that AlP instigated
6	Asghari et al.²³ Iran 2017	Melatonin (20, 30, 40 and 50 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Melatonin doses of 40 and 50 mg/kg significantly improved mitochondrial functions, oxidative stress indicators, and caspase 3 and 9 activity. Moreover, an enhancement in the ADP/ATP balance was also observed. The potential of melatonin to mitigate the oxidative harm resulting from AlP in cardiac tissue was demonstrated. This was achieved by stabilizing intracellular ATP and preventing oxidative stress
7	Rahimi et al.²⁴ Iran 2018	Fresh red blood cell transfusion intravenously (IV)	Experimental male Wistar rats	The fatality rate was significantly reduced when rats intoxicated with AlP (4 ± 15 mg/kg) were administered fresh packed red blood cells (RBCs) (1.5 mL) 1 hour later. The administration of packed RBCs resulted in improvements in blood pH, bicarbonate (HCO₃^-), sodium (Na⁺), and calcium (Ca²⁺) concentrations. The level of plasma troponin decreased, and ECG changes were reversed by 15° after the administration of packed RBCs in rats intoxicated with AlP
8	Haghi-Aminjan et al.²⁵ Iran 2018 Article 43	Minocycline (40, 80, 120 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	The results obtained from this research suggest that minocycline has the potential to be a therapeutic solution for reducing AlP-induced abnormalities in the heart’s ECG, improving the kidney’s mitochondrial erobic metabolic function, and reducing the levels of LDH activity and lactate. Minocycline alleviates the release of cytochrome C and the apoptotic response
9	Gouda et al.²⁶ Egypt 2018	Moringa oleifera extract (Lam) 100 mg/kg gavage (PO)	Experimental male Wistar rats	Rats not given therapy were compared to those that received Lam treatment. The heart tissue of intoxicated rats was protected by the Lam treatment, as demonstrated by increased levels of antioxidants and decreased generation of malondialdehyde (MDA)
10	Ahmadi et al.²⁷ Iran 2018	Dihydroxyacetone (DHA) gavage And N-acetyl cysteine intraperitoneally (IP)	Experimental male Wistar rats	All rats poisoned with AlP survived after receiving DHA administration, and any abnormalities observed in their ECG and hemodynamics were successfully prevented
11	Maleki et al.²⁸ Iran 2019	Selegiline (1, 5, 10 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Enhancing mitochondrial function and redox status through the administration of selegiline can relieve cardiovascular and gastrointestinal injuries caused by AlP in rats
12	Fakhraei et al.²⁹ Iran 2019	Nanocurcumin (10, 20 and 50 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Nanocurcumin effectively reversed increases in MDA, superoxide dismutase (SOD), reactive oxygen species (ROS), and glutathione (GSH)
13	Haydari et al.³⁰ Iran 2020	Ethanolic extract of Echinophora cinerea (E. cinerea extract) (100, 200, and 400 mg/kg gavage (PO)	Experimental male Wistar rats	Ingesting rice tablets can cause bradycardia, hypotension, and abnormal heart conduction. Echinophora cinerea extract can help alleviate these symptoms. Additionally, the extracts of E. cinerea enhance the body’s ability to combat oxidative damage resulting from rice tablet poisoning, thereby increasing the levels of antioxidant enzymes
14	Armandeh et al.³¹ Iran 2021	Levosimendan 12, 24, 48 µg/kg intraperitoneally (IP)	Experimental male Wistar rats	Levosimendan significantly improved apoptosis, malondialdehyde levels, lactate levels, troponin I levels, and complex IV enzymatic activity after exposure to AlP poisoning. The study demonstrated that levosimendan can enhance mitochondrial activity and alleviate the cardiotoxic effects of AlP
15	Bameri et al.³² Iran 2021	Exenatide (0.05, 0.1, and 0.2 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Exenatide treatment at all dosage levels improved the ADP/ATP ratio, complex I and IV activity, and apoptosis incidence. Exenatide administration reduced malondialdehyde, lactate, troponin I, and B-type natriuretic peptide (BNP) levels in the animals exposed to poisoning and its primary effects
16	Samadi et al.³³ Iran 2021	Taurine (20, 50, 100, and 200 mg/kg) intraperitoneally (IP)	Experimental male Wistar rats	Supplementing with taurine is advantageous in reversing health issues associated with AlP poisoning, including problems with blood pressure, heart rate, and ECG. Taurine administration can alleviate the effects of AlP on numerous cellular factors, such as the ADP/ATP ratio, mitochondrial membrane potential, cytochrome C release, and indicators of oxidative stress
17	Shehaby et al.³⁴ Egypt 2021	Trimetazidine with hyperinsulinemia–euglycemia (PO), N‐acetyl cysteine (IV) and vitamin C (PO)	Experimental White adult male rabbits	According to the research results, the combined therapy exhibits significant cardioprotective, antioxidant, and hepatoprotective characteristics, which can effectively manage hemodynamic abnormalities and hyperglycemia in people with acute AlP poisoning
18	Hooshangi Shayesteh et al.³⁵ Iran 2022	Cannabidiol (CBD) 5, 25, 50, and 100 μg/kg intravenous (IV)	Experimental male Wistar rats	The text discusses the positive effects of CBD treatment on rats administered with AlP. The CBD treatment improved the hemodynamic function of rats by restoring hemoglobin levels and mitochondrial activity, which helped reduce oxidative damage and mitigate the initiation of apoptosis in cardiac tissue
19	Jafari-Garageshlaghi et al.³⁶ Iran 2022	Quercetin (QCN) 10, 50 and 100 mg/kg BW gavage (PO)	Experimental male Wistar rats	QCN administration demonstrated a noteworthy enhancement in ECG anomalies, such as T-wave inversion, bigeminy in R waves, and arrhythmias induced by AlP. Applying QCN led to a significant decrease in oxidative/nitrosative stress and histopathological harm caused by AlP
20	Rahimi Kakavandi et al.³⁷ Iran 2022	Edaravone (EDA) 20, 30 and 45 mg/kg intraperitoneally (IP)	Experimental male Wistar rats	The application of EDA showcased considerable improvements in the performance of complex I and IV and in the incidence of apoptosis and necrosis. Furthermore, there were noticeable impacts on reactive oxygen species (ROS), lactate levels, and troponin I levels following AlP intoxication

Results

The search processes

Our search process involved searching through Google Scholar, Scopus, Science Direct, and PubMed databases. This resulted in finding 254 articles, out of which 118 articles were excluded as they were duplicates. The remaining articles were thoroughly analyzed based on their title and abstract, and 23 articles were excluded as they were reviews, book chapters, and Letters to the editor. We then proceeded to analyze the full text of 113 papers, and two individuals also assessed the quality of the studies. After careful consideration, 20 articles were selected for this systematic review, and we conducted the PRISMA checklist. Furthermore, the PRISMA diagram visually shows the database search process, as seen in Figure 3.

Figure 3.

The diagram of the inclusion-exclusion studies.

Discussion

As shown in Figure 2, the cardiovascular system is the primary organ affected by AlP toxicity. The toxic effects of AlP include disruption of cardiac energy homeostasis, which is a significant symptom. In addition, AlP interferes with the electron transport chain and disrupts the activity of cytochrome c oxidase, an enzyme that plays a vital role in the electron transport chain. This disorder leads to a decrease in ATP levels, which leads to a reduction in heart function. Cardiotoxicity caused by AlP causes lipid peroxidation (LPO) by reducing energy levels and producing free radicals such as ROS and oxidative stress. People exposed to AlP may have various cardiovascular complications, including experience treatment-resistant hypotension, dysrhythmias, and heart problems, ultimately leading to cardiomyocyte death. Most heart cells are cardiomyocytes, which comprise about 75% of their cellular composition and are essential to facilitate blood circulation throughout the body. Cardiomyocytes contain a significant number of mitochondria, which are vital cell organelles. Cardiomyocytes rely on oxidative phosphorylation as the primary mechanism for energy production, and mitochondria are responsible for about 90% of this energy production.³⁸ Numerous studies have investigated and confirmed several mechanisms that justify the toxicity of AlP tablets, as depicted in Figure 4.

Figure 4.

Mechanisms of toxicity caused by AlP tablets.

Despite many efforts, lethality remains high, reaching rates of over 50%, and no effective antidote is available. However, experimental and clinical studies have shown that magnesium sulfate, melatonin, N-acetylcysteine, glutathione, sodium selenite, vitamins C and E, triiodothyronine, liothyronine, vasopressin, milrinone, boric acid, -carnitine and coconut oil, they may act as antidotes by reducing the harmful oxidative properties of AlP.³⁹

Although our review focused on studies in animal models, many in vitro studies have also been conducted to investigate the protective effects of compounds against AlP toxicity. For instance, in a recent study, chrysin significantly reduced the toxicity of AlP in isolated cardiomyocytes and mitochondria. This protective effect of chrysin is related to its anticancer, antioxidant, and cardiovascular disorder protection effects.⁴⁰ In another study, the effect of resveratrol on AlP toxicity was investigated. It was shown that resveratrol significantly exhibited cytoprotective effects against AlP-induced HCM cytotoxicity. The protective benefits of resveratrol can be attributed to its multiple mechanisms, including antioxidant defense, promotion of endothelial function, protection of mitochondria, Regulation of autophagy, control of calcium homeostasis, regulation of inflammation, and regulation of cellular senescence⁴¹ Animal models can be used to confirm the impact and clinical use for a more detailed investigation of these compounds’ protective effects.

As mentioned before, cardiovascular poisoning is the most important cause of death caused by AlP poisoning. Electrocardiographic (ECG) abnormalities, histopathological changes, severe hypotension, left ventricular hypokinesia, changes in QT dispersion, and congestive heart failure occur due to phosphine poisoning.⁴² It is crucial to predict the survival of poisoned patients to adopt the appropriate treatment process. The results of a prospective cohort study on patients showed that both left ventricular ejection fraction (LVEF) and global LV hypokinesia significantly affect survival in AlP-poisoned patients. Echocardiography was superior in accuracy to ECG changes, so paying attention to the parameters related to echocardiography in poisoned patients can predict the mortality of patients and help in adopting the appropriate treatment process.⁴³

In this review article, As shown in Table 1, We have evaluated a wide range of effective interventions for cardiotoxicity caused by AlP in an animal model to find the most effective intervention, which will be discussed further. In the main findings section of Table 1, most interventions have improved the parameters measured in AlP poisoning. Armende et al.’s findings in an animal study show that levosimendan may reduce AlP-induced cardiac effects by modulating mitochondrial activity and improving cardiac function.³¹ Previous studies have shown that thyroid hormone (TH) plays a vital role in the functioning of mitochondria in cardiac cells.⁴⁴ Recent evidence suggests that TH treatment can promote the growth of new mitochondria in the heart and increase the total number of mitochondria in the myocardium.

Additionally, T₃ can improve the function of mitochondrial enzymes and trigger protein synthesis, particularly regarding mitochondrial respiratory complexes (I, II, IV, and V), cytochrome, phospholipid, and mitochondrial DNA content. These mechanisms can further enhance mitochondrial respiration and oxidative phosphorylation (OXPHOS), leading to an increase in the activity of bio-energetic enzymes within mitochondria and, ultimately, a boost in ATP production.⁴⁵ Levosimendan has demonstrated efficacy in difficult physiological conditions, such as acidosis and sepsis.^46,47 Levosimendan’s ability to cause calcium sensitivity of contractile proteins highlights its potential advantages, leading to a favorable inotropic impact. Levosimendan directly impacts contractility and improves the functionality of shocked myocardial tissue.⁴⁸ Activating adenosine triphosphatase-sensitive potassium channels by Levosimendan induces coronary and systemic vasodilation.⁴⁹

The toxic effects of AlP can lead to heart failure as a secondary complication. Milrinone, a phosphodiesterase III inhibitor, has been found to improve the hemodynamic condition of acute heart failure by exerting inotropic effects in cases of acute poisoning.⁵⁰ As reported in previous studies, inotropic agents have been observed to increase myocardial contractility while exhibiting lower levels of cardiac oxygen consumption compared to catecholamines.⁵¹ The effects of phosphodiesterase III inhibitors are distinct from catecholamines as they raise intracellular cAMP levels through a mechanism different from the adrenaline pathway.⁵² In cases of acute AlP poisoning, using milrinone, a phosphodiesterase III inhibitor, can enhance cardiac contractility and address hypotension. AVP administration in low doses has been found to enhance the effectiveness of catecholamines infusion, such as norepinephrine, and improve vascular tone in patients with septic and hemorrhagic shock.⁵³ This hormone causes vasoconstriction, leading to increased systemic vascular resistance and elevated blood pressure, through two primary mechanisms. The first process involves the activation of V1 receptors located in smooth muscle cells, elevating intracellular calcium ion (Ca²⁺) levels by stimulating the phosphatidylinositol-bisphosphate (PIP2) pathway. The second process involves the inhibition of ATP-sensitive potassium and KATP channels in smooth muscle cells, which promotes myocytes’ depolarization, leading to vasoconstriction.⁵⁴

Various positive inotropic agents have been evaluated for the treatment of cardiotoxicity caused by AlP. These agents comprise digoxin⁵⁵ and dopamine.⁵⁶ Studying alternative inotropic medications is feasible because it allows one to investigate their efficacy in treating AlP poisoning and determine whether they can improve the chances of survival and reduce the mortality rate. Dobutamine, amrinone, and enoximone are among the medications that possess inotropic characteristics and can be included in this list.

Several studies have been conducted to find the antidote for rice pill poisoning, which this article discusses to find the most effective and best. One of the most important therapeutic interventions is reacting with phosphine and preventing the release of phosphine or converting it to less dangerous bases, which has been considered in many studies. It has been suggested that gastric lavage with sodium bicarbonate and coconut oil can be effective and valuable.⁵⁷ A study reported that zinc phosphide poisoning was effectively treated by performing gastric lavage using olive oil and providing other supportive care as needed.⁵⁸ It is also possible to pay attention to the role of intravenous lipid emulsion in reducing PH₃ secretion and subsequently reducing mortality.⁵⁹ Oil-based disinfection and gastric lavage showed advantages over conventional lavage in terms of in-hospital mortality, endotracheal intubation, and survival time.⁶⁰ Limited evidence from a systematic review shows that gastric lavage with paraffin oil effectively reduces mortality.^16,61 Some assert that gastric washout using potassium permanganate can convert PH3 into a harmless phosphate through oxidation.⁶² The study by Heidari et al, which investigated the protective effect of sevelamer, showed that this compound can bond with AlP groups and function as an anion exchanger. The findings indicate that animals treated with sevelamer had a significantly higher survival rate than those poisoned with AlP. Examining serum indicators of organ damage revealed that sevelamer could mitigate toxicity and organ damage in afflicted animals.⁶³ In another study conducted by Vafaeipour et al. to evaluate the pulmonary and cardiac protective effects of Lugol’s solution on AlP-induced acute toxicity, it was shown to reduce tissue damage and oxidative stress in rats poisoned with AlP. Therefore, it can be assumed that Lugol is favorable because of its ability to react directly with PH₃.⁶⁴

Antioxidant molecules play a pivotal role in protecting mitochondria against harmful oxidative stress, thereby reducing the risk of potential cardiovascular damage. Studies have shown that melatonin may offer advantages over traditional antioxidants like vitamins E and C.¹⁵ As an antioxidant, calcitriol is critical in preventing oxidative stress-related issues such as protein oxidation, DNA damage, mitochondrial dysfunction, and LPO. Adequate levels of vitamin D have also been found to have the potential to reduce oxidative stress and mitigate mitochondrial dysfunction, which may help decrease susceptibility to various illnesses, including cardiotoxicity.⁶⁵

Each antioxidant has a different mechanism by which it exerts its antioxidant effect. NAC is a potent antioxidant that acts as a disulfide bonds reductant, ROS scavenger, and glutathione precursor.⁶⁶ L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is a vital structure in mitochondrial membranes essential for cellular respiration. Also, L-Carnitine scavenger ROS and decreases lipid peroxidation.⁶⁷ Vitamin E, or tocopherol, is a powerful antioxidant that reduces the generation of ROS during fat oxidation and free radical reactions.⁶⁸ Co Q10 or Ubiquinone is a constituent of mitochondrial membranes essential in oxidative phosphorylation and energy production at the cellular level. Also, Co Q10 selectively enhances systolic cardiac function.⁶⁹ Also, a systematic review study was conducted to investigate the effect of antioxidants on four antioxidants (N-acetyl cysteine (NAC), L-carnitine, vitamin E, and coenzyme Q10 (Co Q10)). The results showed that antioxidants significantly reduce the mortality caused by acute AlP poisoning by about three times.¹⁰ N-acetylcysteine (NAC) can increase glutathione reserves.

Regarding the efficacy of NAC in AlP poisoning, there are conflicting reports, and only one documented case has been reported when the delivery of NAC, as part of treatment, failed to save the patient.⁷⁰ Marashi et al. recommended that using coenzyme Q10 (CoQ10) as an antioxidant could be regarded as an alternative therapy approach.⁷¹ According to their assertion, relying on prior research conducted on patients with heart failure with a similar condition to AlP poisoning, CoQ10 can also increase the systolic function of the heart and help save the poisoned person.⁷² Lately, vitamin E has been recognized as a powerful treatment for controlling people with AlP poisoning. A 21-year-old male who consumed a 3-g tablet of AlP was successfully treated by administering a combination of antioxidants. This treatment included a slow intravenous infusion of 1000 mg of vitamin C every 12 h, an intramuscular injection of 400 units of vitamin E, and an oral administration of NAC. The NAC dosage was 70 mg/kg every 4 h after an initial loading dose of 140 mg/kg for a maximum of 17 doses 57- When combined with additional supportive treatments, vitamin E at 400 mg BD intramuscularly (IM) was able to dramatically lower mortality in subjects exposed to AlP.⁷³ Integrating therapy regimens emphasizing the role of antioxidants is an essential approach for treating cases of AlP poisoning. This topic has been extensively studied. The study of Shehaby et al. showed that the use of combined treatment (oral trimetazidine-hyperinsulinemia-euglycemia, intravenous N-acetylcysteine and oral vitamin C) in cases of acute poisoning with AlP has significant benefits in protecting the liver, heart, and body against oxidative stress. In addition, this therapeutic approach seems effective in managing patients with hemodynamic abnormalities.³⁴

The role of compounds with antioxidant properties and cardioprotection in acute Alp poisoning is prominent. Much research has been done to investigate the antioxidant properties of melatonin. The ability of melatonin to cross different morphophysiological barriers and produce it in mitochondria is a defense against oxidative stress.⁷⁴ This indoleamine can destroy free radicals and dissolve in aqueous and organic phases. It has also been shown to regulate mitochondrial homeostasis significantly.⁷⁵ The effect of melatonin as an antioxidant and cardioprotective compound in acute Alp poisoning was investigated by Asghari et al., and its beneficial effects were emphasized. The effectiveness of melamine can be attributed to maintaining intracellular ATP balance and preventing oxidative damage. Studies have shown that Minocycline can exert the effects of increasing the activity of antioxidant enzymes, reducing the production of pro-inflammatory cytokines, inhibiting the activity of macrophages, and reducing the level of pro-apoptotic proteins. Minocycline also has a cardioprotective effect due to its radical scavenging activity and critical role in apoptosis and inflammatory pathways.⁷⁶ Therefore, considering the antioxidant and anti-inflammatory effects of a candidate Suitable for cardiac toxicity caused by Alp. One study by Haghi Aminjan et al. showed that minocycline could improve cardiac electrocardiographic abnormalities caused by AlP. Selegiline possesses antioxidant properties that inhibit mitochondrial-dependent apoptosis induced by oxidative stress.⁷⁷ It also inhibits hydroxyl radical generation, preventing cell death from GSH depletion.⁷⁸ The above results are consistent with the study that used selegiline as a cardioprotective agent in the AlP toxicity model, that selegiline may improve the redox status and mitochondrial function and potentially ameliorate AlP-induced cardiac and gastrointestinal damage in rats without significant effects on decrease the survival rate.²⁸

The significance of plants as a source of antioxidant compounds has garnered the attention of researchers.⁷⁹ Previous studies have demonstrated that herbal and natural compounds with antioxidant properties can protect the heart. A notable example is Moringa oleifera, commonly called ‘the miracle tree,’ owing to its diverse health benefits.⁸⁰ Lam contains various antioxidant components, including flavonoids, ascorbic acid, carotenoids, and phenolic compounds. The phenolic content of Moringa is responsible for its cardioprotective effect. By enhancing oxidative stress defense enzymes, preventing lipid membrane peroxidation,⁸¹ and inhibiting mitochondrial membrane disruption, Moringa reduces oxidative cardiac cell damage.⁸² The findings of this study show that Moringa oleifera extract (Lam) therapy effectively protects the heart tissue of rats exposed to poisoning, whose protective mechanism is related to the increase in antioxidant capacity and the reduction of MDA production.²⁶ Heydari et al. stated that the Echinophora cinerea extract has beneficial effects in reducing the symptoms of bradycardia, hypotension, and abnormal heart conduction caused by rice pill poisoning. Increasing the level of antioxidant enzymes is this compound’s most important protective mechanism.³⁰ Several studies have indicated that AlP poisoning causes oxidative stress in various body parts, particularly the heart. Algae’s antioxidant and anti-inflammatory properties have been studied extensively.⁸³ Studies have shown algae’s potential to combat oxidants; thus, their antioxidant capacity can help reverse the oxidant effects brought on by AlP poisoning.⁸⁴ As mentioned, plants and compounds of natural origin are suitable for treating antioxidant disorders due to their many sources of antioxidants. Still, rice pill poisoning is acute poisoning and requires immediate treatment. These compounds alone cannot be significantly effective in acute poisoning and save the patient’s life.

AlP poisoning can lead to metabolic acidosis, a dangerous condition that can be life-threatening. Maintaining plasma pH is crucial when treating patients with AlP poisoning because metabolic acidosis plays a significant role in its development.⁸⁵ Doctors can administer sodium bicarbonate based on the base deficit calculation to help raise circulation pH levels.⁸⁶ In another study, it has been suggested that gastric lavage with sodium bicarbonate and coconut oil can be effective and valuable.⁵⁷ Also, a randomized controlled trial showed that gastric disinfection with paraffin oil and 8.4% sodium bicarbonate could help reduce the severity of AlP poisoning, the need for intubation, mechanical ventilation, and vasopressors.⁸⁷ The study findings of Rahimi et al. suggest that close RBC infusion can help treat AlP poisoning and improve patient outcomes. ECG abnormalities were reversed in response to packed RBC infusion after AlP intoxication.²⁴ On the other hand, Zamani et al. stated an adult patient with AlP poisoning did not respond to traditional treatment and recovered after a complete blood exchange procedure.⁸⁸ Therefore, removing damaged red blood cells may be helpful in patients exposed to AIP and is indicated as one of the valuable treatments for AlP poisoning.

Dihydroxyacetone (DHA) is produced as DHA phosphate through the glycolysis pathway inside the cell, and it plays a vital role in the production of Adenosine triphosphate (ATP). The toxicity of PH₃ mainly arises from its ability to impede cellular ATP production. Nevertheless, the introduction of DHA into the glycolysis route has the potential to prevent the depletion of ATP and, therefore, avert an energy crisis in cells, preventing cell death. This is essential for organs more susceptible to ATP depletion, such as the heart and brain. An animal study conducted recently showed that DHA has a significant effect on decreasing mortality in animals.⁸⁹

A case report study demonstrated that patients with AlP poisoning received DHA in addition to the standard therapy management. Administering 7 g of DHA in a 50 mL sodium bicarbonate solution through gavage twice with a one-hour gap improved the clinical symptoms. This case report is the first to highlight the successful treatment of AlP poisoning using DHA.⁹⁰ Nevertheless, it was discovered that the administration of DHA to poisoned individuals had a considerable positive effect on severe acidosis and AlP-induced PaO2.⁹¹

Conclusion and future perspectives

This article comprehensively reviews the various studies conducted in vivo for treating AlP-induced cardiotoxicity. One of the critical factors in controlling AlP tablet poisoning is time. The ideal approach would be administering treatment as soon as possible to prevent further damage to the heart. Several strategies have been considered to regulate the cardiotoxicity of AlP tablets, including positive inotrope drugs, antioxidant compounds, and herbal compounds. However, in recent years, researchers have focused on preventing toxicity at the cellular and molecular level, particularly mitochondrial damage. Any compound that can reduce the rate of phosphine gas release or increase the rate of mitochondrial recovery and regeneration can be considered a cardioprotective agent in treating AlP poisoning.

Studies have suggested that compounds with antioxidant properties play a critical role in preventing cardiac toxicity during the AlP poisoning process, given the production of reactive oxygen species (ROS) and its impact on the heart. While most research in this field has focused on the use and effects of antioxidants, there is a need for more research in other areas.

Moreover, research on the role of metabolic acidosis and the correlation between different doses of aluminum phosphide and the severity of lactic acidosis, as well as management strategies, would enhance therapeutic approaches. Understanding the mechanisms by which AlP affects the heart and the various ways in which it can be prevented or treated is vital to improving patient outcomes.

Since the present study is a systematic review focused on all compounds and interventions effective on cardiotoxicity caused by AlP, similar research has yet to be conducted in this way. Most studies have focused on the effectiveness of antioxidant compounds and phosphine-release inhibitors. Investigating the synergistic effects of combined therapeutic approaches, such as inotropes, antioxidant compounds, and phosphine gas release inhibitors, could also lead to more effective and personalized interventions. Based on the present study’s findings and the evaluation of clinical studies, dihydroxyacetone, red blood cell infusion, Oil-based disinfection, and gastric lavage have the most potential to save patients’ lives and treat acute aluminum phosphide. However, there is a need for more research in this regard.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Saeed Aghebat-Bekheir

Mohammad Abdollahi

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Discovering the most impactful treatments for aluminum phosphide cardiotoxicity gleaned from systematic review of animal studies

Abstract

Introduction

Methods

Results

Conclusion

Keywords

Introduction

Methods

Search strategy

Criteria for inclusion and exclusion

Data extraction

Results

The search processes

Discussion

Conclusion and future perspectives

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References