. 2022 Jun 21;14(7):1313. doi: 10.3390/pharmaceutics14071313

Table 5.

Drugs affecting mitochondrial redox, their clinical manifestations, and relevant in vitro and in vivo studies.

Modules	Alterations	Pharmacology	Drugs	Clinical Manifestations	C_max	Models	Dose	Time	References
Redox	Decrease in antioxidant enzyme level	NSAIDs	Naproxen	-	100 µM	Isolated rat heart mitochondria	25 μM		[60]
			Celecoxib	Thrombosis, MI, stroke	3–5 µM	Isolated rat heart mitochondria	50 μM		[60]
			Diclofenac	-	3.55 μM	Isolated rat heart mitochondria	25 μM		[60]
Redox	Decrease in antioxidant enzyme level	β-adrenoceptor agonists	Isoproterenol	HF	0.01 μM	Male Wistar rats (SC)	100 mg/kg, BID	12 h	[118]
Redox	Inhibition of antioxidant enzyme	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	Male Wistar rats (IP)	2.5 mg/kg/2 d	2 w	[95]
						Kunming mice (IP)	2 mg/kg	10 d	[102]
						-	-	-	[199]
						Male BALB/c mice (IP)	5 mg/kg/w	2 w	[200]
						Male Wistar rats (IV)	45 mg/kg	48 h	[203]
			Idarubicin	CMP, MI, CHF, VA, decreased LVEF	23.22 μM	Rats (IV)	5 mg/kg/w	6 w	[110]
Redox	Inhibition of antioxidant enzyme	Alkylating agent	Cyclophosphamide	HMC, CMP	143 μM	Male Wistar rats	200 mg/kg	1 w	[170]
Redox	Inhibition of antioxidant enzyme	Alkylating agent	Cyclophosphamide	HMC, CMP	143 μM	Male Wistar rats (IP)	200 mg/kg	1 w	[171]
Redox	Inhibition of antioxidant enzyme	Chemotherapeutic agents	Cisplatin	Decreased LVEF, arrhythmias, ECA, myocarditis, CMP	27.54 μM	NRVMs	200 μM	24 h	[183]
			As₂O₃	QT prolongation TdP, CMP, tachycardia	12.1 μM	BALB/c mice (IV)	1 mg/kg/2 d	6 d	[204]
			As₂O₃	QT prolongation TdP, CMP, tachycardia	12.1 μM	Isolated mitochondria from H9c2	5 μM	24 h	[141]
Redox	Inhibition of antioxidant enzyme	TKIs	Sunitinib	Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP	0.25 μM	NRVMs	67% of GSH was oxidized at 23 µM	24 h	[174]
Redox	Inhibition of antioxidant enzyme	NRTIs	Zidovudine	CMP	4 μM	Male OF1 mice (oral)	10 mg/kg/d	35 d	[205]
Redox	Inhibition of antioxidant enzyme	Addictive drugs	Cocaine	Arrhythmias, angina, MI, HF	0.76–0.94 µM	H9c2	1.79 mM	24 h	[177]
Redox	Inhibition of antioxidant enzyme	β-adrenoceptor agonists	Isoproterenol	HF	0.01 μM	Male Wistar rats (SC)	100 mg/kg, BID	12 h	[83]
Redox	ROS elevation	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	Beef heart submitochondrial preparations	-	-	[206]
			DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	-	-	-	[199]
			Daunorubicin	CMP, MI, CHF, VA, pericarditis, myocarditis	89 μM	-	-	-	[207]
			Idarubicin	CMP, MI, CHF, VA, decreased LVEF	23.22 μM	-	-	-	[207]
Redox	ROS elevation	Chemotherapeutic agents	Cisplatin	Decreased LVEF, arrhythmias, ECA, myocarditis, CMP	27.54 μM	NRVMs	200 μM	24 h	[183]
			Etoposide	Hypotension	17 μM	HiPSC-CMs	10 μM	48 h	[169]
			As₂O₃	QT prolongation TdP, CMP, tachycardia	12.1 μM	Male BALB/c mice	2 mg/kg (14 d); 4 mg/kg (7 d)		[84]
						Isolated mitochondria from H9c2	5 μM	24 h	[141]
						H9c2	5 μM	24 h	[184]
Redox	ROS elevation	Monoclonal antibody	Trastuzumab	CMP, LVD, CHF	2.59 mM	H9c2	200 nM	24 h	[185]
Redox	ROS elevation	TKIs	Sorafenib	Bleeding, hypertension, QT prolongation, CHF, CI, MI	16.6 μM	NRVMs	4.5 µM	10 min	[32]
Redox	ROS elevation	NSAIDs	Diclofenac	Hypertension, arrhythmias	3.55 μM 7.9 µM	Isolated rat heart mitochondria	25 μM	5 min	[60]
						H9c2	10 µM	1.5 h	[157]
						Isolated rat heart mitochondria	10 µg/mL	1 h	[115]
						C57BL/6 mice (oral)	15 mg/kg/d	4 w	[175]
						Immortalized human cardiomyocytes	100 μM	24 h	[85]
			Naproxen	-	100 µM	Isolated rat heart mitochondria	25 μM	5 min	[60]
			Celecoxib	Thrombosis, MI, stroke	3–5 µM	Isolated rat heart mitochondria	25 μM	5 min	[60]
Redox	ROS elevation	NRTIs	Zidovudine	CMP	4 μM	H9c2	50 μM	3 passages	[152]
						TMPK-overexpressing H9c2 cells	100 µM	24 h	[131]
						Human cardiomyocytes	10 µM	48 h	[198]
			Didanosine	CMP	12 μM	H9c2	50 μM	3 passages	[152]
Redox	ROS elevation	Addictive drugs	Ethanol			H9c2	184.34 mM	24 h	[177]
			Cocaine	Arrhythmias, angina, MI, HF	0.76–0.94 µM	H9c2	1.79 mM	24 h	[177]
						Isolated rat heart mitochondria	2 × 7.5 mg/kg/d	8 d	[178]
						Isolated rat heart mitochondria	2 × 7.5 mg/kg/d	7 d	[179]
Redox	ROS elevation	β-adrenoceptor agonists	Isoproterenol	HF	0.01 μM	Isolated rat heart mitochondria	85 mg/kg/d	2 d	[187]
Redox	ROS elevation	β receptor blocker drugs	Propranolol	Cardiotoxicity	0.22 μM	Isolated rat heart mitochondria	5 µg/mL	5 min	[119]
		β receptor blocker drugs	Atenolol	Cardiotoxicity	4.99 μM	Isolated rat heart mitochondria	5 µg/mL	30 min	[119]
		Macrolide antibiotics	Azithromycin	Arrhythmia	0.32–0.87 μM	Isolated rat heart mitochondria	25 μM	15 min	[120]
			Clarithromycin	TdP	2.67–13.37 μM	Isolated rat heart mitochondria	25 μM	15 min	[120]
			Erythromycin	TdP	11 μM	Isolated rat heart mitochondria	25 μM	15 min	[120]
Redox	ROS elevation	Diabetes medication	Pioglitazone	HF	2.6 μM	Isolated rat heart mitochondria	12.5 µg/mL	5 min	[122]
Redox	ROS elevation	Local anesthetics	Bupivacaine (marcaine)	VF	0.7 μM	H9c2	1 mM	24 h	[208]
Redox	Nitrozative stress	Anthracyclines	Epirubicin	CHF	5.68 mM	Male Wistar rats (IP)	10 mg/kg	10 d	[209]
Redox	Nitrozative stress	Alkylating agent	Cyclophosphamide	HMC, CMP	143 μM	Male Wistar rats (IP)	200 mg/kg	1 w	[171]
Redox	8OHdG adducts in mtDNA	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	SD rats (IP)	2 mg/kg/w	6 w	[210]
Redox	Lipid peroxidation	Anthracyclines	DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	Male Wistar rats (IP)	2.5 mg/kg/2 d	2 w	[95]
			DOX	CHF, decreased LVEF, ST, myocarditis, CMP	15.3 μM	Male Wistar rats (IV)	45 mg/kg	48 h	[203]
			Daunorubicin	CMP, MI, CHF, VA, pericarditis, myocarditis	89 μM	Male SD rats	2.5 mg/kg/w	5 w	[211]
			Idarubicin	CMP, MI, CHF, VA, decreased LVEF	23.22 μM	Male SD rats (IV)	5 mg/kg/w	6 w	[110]
Redox	Lipid peroxidation	Alkylating agent	Cyclophosphamide	HMC, CMP	143 μM	Male Wistar rats	200 mg/kg	1 w	[170]
Redox	Lipid peroxidation	Chemotherapeutic agents	Cisplatin	Decreased LVEF, arrhythmias, ECA, myocarditis, CMP	27.54 μM	NRVMs	200 μM	24 h	[183]
Redox	Lipid peroxidation	NSAIDs	Diclofenac	Hypertension, arrhythmias	7.9 µM	Isolated rat heart mitochondria	50 μM	1 h	[60]
			Diclofenac	Hypertension, arrhythmias	7.9 µM	Isolated rat heart mitochondria	10 µg/mL	1 h	[115]
			Naproxen	-	100 µM	Isolated rat heart mitochondria	100 μM	1 h	[60]
			Celecoxib	Thrombosis, MI, stroke	3–5 µM	Isolated rat heart mitochondria	100 μM	1 h	[60]
Redox	Lipid peroxidation	NRTIs	Zidovudine	CMP	4 μM	Male OF1 mice (oral)	10 mg/kg/d	35 d	[205]
Redox	Lipid peroxidation	β-adrenoceptor agonists	Isoproterenol	CHF, decreased LVEF, ST, myocarditis, CMP	0.01 μM	Rat, subcutaneously (SC)	100 mg/kg, BID	12 h	[118]
Redox	Lipid peroxidation	β-adrenoceptor agonists	Isoproterenol	CHF, decreased LVEF, ST, myocarditis, CMP	0.01 μM	Male Wistar rats (SC)	100 mg/kg, BID	12 h	[83]

Abbreviations: ROS: reactive oxygen species; NRTIs: nucleoside reverse transcriptase inhibitors; NSAIDs: nonsteroidal anti-inflammatory drugs; TKIs: tyrosine kinase inhibitors; DOX: doxorubicin; CHF: congestive heart failure; LVEF: left ventricular ejection fraction; HF: heart failure; LVD: left ventricular dysfunction; TdP: torsades de pointes; MI: myocardial infarction; CMP: cardiomyopathy; VF: ventricular fibrillation; CI: cardiac ischemia; ST: sinus tachycardia; HMC: hemorrhagic myocarditis; ECA: electrocardiographic alterations; VA: ventricular arrhythmia; HA: heart attack; IP: intraperitoneal; IV: intravenously; SC: subcutaneously; BID: twice daily; w: week; d: day; h: hours.