A Fatal Consequence: Amiodarone-Induced Multiorgan Toxicity.

Amiodarone is commonly used nowadays for the treatment of atrial fibrillation (AF). The wide use of this medication has led to the occurrence of adverse events, including pulmonary toxicity, hepatotoxicity, thyroid dysfunction, and many others. Higher doses of Amiodarone of ≥400 mg/day have been linked to increased complications. We present a case of a 70-year-old male with multivessel coronary artery disease (CAD) with ischemic cardiomyopathy and severe peripheral artery disease (PAD) who underwent an elective left femoral to posterior tibial bypass surgery followed by percutaneous coronary intervention (PCI) complicated by new-onset AF. The patient was loaded with 150 mg of intravenous (IV) Amiodarone followed by 360 mg infusion over six hours for chemical cardioversion. The patient was then maintained on oral Amiodarone 400 mg/day until the day of presentation when he complained of progressive dyspnea. Imaging was significant for diffuse ground glass opacities and interstitial thickening. The echocardiogram revealed an improved ejection fraction (EF) of 40% from 20%. The patient had worsening oxygenation despite adequate IV diuresis and developed severe acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (MV). A bronchoscopy with bronchoalveolar lavage (BAL) showed diffuse alveolar hemorrhage (DAH) with a high lymphocyte count and negative infectious disease testing. Lab tests revealed elevated liver enzyme levels. There were also changes in thyroid function from baseline with elevated free T4 at 1.83 ng/dL (0.8-1.4 ng/dL), suppressed thyroid stimulating hormone (TSH) at 0.109 mIU/mL (0.4-4 mIU/mL), negative anti-thyroglobulin (TG) antibodies, and anti-thyroid peroxidase (TPO) antibodies indicating a type 2 Amiodarone-induced thyrotoxicosis. Unfortunately, the patient's condition deteriorated further despite appropriate treatment, and it was ultimately followed by his demise. Severe, fatal cases of Amiodarone toxicity are scarce, but more reports are being seen. We strongly believe clinicians should have a high index of suspicion for Amiodarone-related adverse events in elderly males with cardiopulmonary comorbidities. It is imperative to have an increased understanding, greater vigilance, and closer monitoring of pulmonary function tests (PFTs), laboratory tests, and imaging studies.

Serious Multiorgan Toxicity Caused by Mixed Herbal Tea Ingestion: A Case Report.

Recent years have witnessed a growing trend in the use of complementary and alternative herbal products. However, the ingestion of some herbal products may cause a wide spectrum of adverse effects. We report a case of multiorgan toxicity following the ingestion of mixed herbal tea. A 41-year-old woman presented to the nephrology clinic with complaints of nausea, vomiting, vaginal bleeding, and anuria. She had consumed a glass of mixed herbal tea three times a day after meals for three days, to lose weight. Initial clinical and laboratory findings showed serious multiorgan toxicity including hepatotoxicity, bone marrow toxicity, and nephrotoxicity. Although herbal preparations are marketed as natural products, they may cause various toxic effects. There should more efforts to raise public awareness about the possible toxic effects of herbal preparations. Clinicians should consider the ingestion of herbal remedies as an etiology when encountering patients with unexplained organ dysfunctions.

Polyphenol-rich Spondias mombin leaf extract abates cerebral ischemia/reperfusion-induced disturbed glutamate-ammonia metabolism and multiorgan toxicity in rats.

Introduction: This study investigated the protective properties of Spondias mombin leaf extract (SML), in cerebral ischemia/reperfusion (I/R) mediated toxicity in the brain, liver, and kidney of male Wistar rats. Materials and methods: Animals were subjected to 30 min of bilateral common carotid artery occlusion followed by 24 h of reperfusion (BCCAO/R). The animals were divided into sham, I/R, and I/R treated with SML (25, 50 and 100 mg/kg) or quercetin (20 mg/kg) groups. Animals were sacrificed after 24 h of reperfusion and markers of organ toxicity (urea creatinine, glutamine synthetase (GS), glutaminase (GA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), acetylcholinesterase (AChE)) were measured in the brain regions (cortex, striatum, and hippocampus), liver, and kidney. Results and discussion: BCCAO/R significantly (p < 0.0001) inhibited the glutamate-glutamine cycle and mediated toxicity in the cerebral cortex, striatum, hippocampus, liver, and kidney of rats. Post-treatment with SML significantly (p < 0.0001) reversed glutamate-glutamine cycle inhibition and ameliorated cerebrohepatorenal toxicity in ischemic rats. Conclusion: Cerebral I/R significantly mediated cerebral, hepatic, and renal toxicity through the inhibition of glutamate-ammonia detoxification in rats, and SML protected against this post-ischemic glutamate-ammonia mediated multiorgan toxicity.

Carbendazim toxicity in different cell lines and mammalian tissues.

The extensive production and use of harmful pesticides in agriculture to improve crop yield has raised concerns about their potential threat to living components of the environment. Pesticides cause serious environmental and health problems both to humans and animals. Carbendazim (CBZ) is a broad spectrum fungicide that is used to control or effectively kill pathogenic microorganisms. CBZ is a significant contaminant found in food, soil and water. It exerts immediate and delayed harmful effects on humans, invertebrates, aquatic animals and soil microbes when used extensively and repeatedly. CBZ is a teratogenic, mutagenic and aneugenic agent that imparts its toxicity by enhancing generation of reactive oxygen species generation. It elevates the oxidation of thiols, proteins and lipids and decreases the activities of antioxidant enzymes. CBZ is cytotoxic causing hematological abnormalities, mitotic spindle deformity, inhibits mitosis and alters cell cycle events which lead to apoptosis. CBZ is known to cause endocrine-disruption, embryo toxicity, infertility, hepatic dysfunction and has been reported to be one of the leading causes of neurodegenerative disorders. CBZ is dangerous to human health, the most common side effects upon chronic exposure are thyroid gland dysfunction and oxidative hepato-nephrotoxicity. In mammals, CBZ has been shown to disrupt the antioxidant defense system. In this review, CBZ-induced toxicity in different cells, tissues and organisms, under in vitro and in vivo conditions, has been systematically discussed.

MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review).

Triptolide is the main bioactive constituent isolated from the Chinese herb Tripterygium wilfordii Hook F., which possesses a variety of pharmacological properties. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRNAs are implicated in several intracellular processes, whereby their dysregulation contributes to pathogenesis of various diseases. Thus, miRNAs have great potential as biomarkers and therapeutic targets for diseases, and are implicated in drug treatment. Previous studies have reported that specific miRNAs are targeted, and their expression levels can be altered following exposure to triptolide. Thus, miRNAs are emerging as crucial mediators in the pharmacological activities of triptolide. The present review summarizes current literature on miRNAs as target molecules in the pharmacological activities of triptolide, including antitumor, anti-inflammatory, immunosuppressive, renal protective, cardioprotective, antiangiogenesis activities and multiorgan toxicity effects. In addition, the diverse signaling pathways involved are discussed to provide a comprehensive understanding of the underlying molecular mechanisms of triptolide in the regulation of target miRNAs.

Repeated Remote Ischemic Conditioning Reduces Doxorubicin-Induced Cardiotoxicity.

OBJECTIVES: This study investigated the cardioprotective effect of repeated remote ischemic preconditioning (rRIC) on doxorubicin-induced cardiotoxicity in mice. BACKGROUND: Doxorubicin is an effective chemotherapeutic agent for a wide range of tumor types but its use and dosing are limited by acute and chronic cardiotoxicity. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models, but the effectiveness of rRIC in doxorubicin-induced cardiotoxicity has not been fully elucidated. METHODS: rRIC was performed on mice before and after doxorubicin administration. Cardiac function was assessed by echocardiography and myocardial biology was tested by molecular approaches. RESULTS: Doxorubicin administration induced acute cardiotoxicity, as indicated by reduced cardiac function, reduced myocyte cross-section area and increased extracellular collagen deposition, increased circulating cardiac muscle damage markers, and decreased heart weight. Doxorubicin also adversely affected other organs, including the kidney, liver, and spleen, as evaluated by circulating markers or organ weight loss. rRIC not only abrogated doxorubicin-induced cardiotoxicity (left ventricular ejection fraction, doxorubicin 47.5 ± 1.1%, doxorubicin + rRIC 51.6 ± 0.7%, p = 0.017), but also was associated with multiorgan protection. Within the myocardium, rRIC attenuated doxorubicin-induced cardiomyocyte apoptosis, reduced inflammation, and increased autophagy signaling. CONCLUSIONS: rRIC may be a promising approach to reduce doxorubicin-induced cardiotoxicity.

Improved drug carriage and protective potential against Cisplatin-induced toxicity using Boldine-loaded PLGA nanoparticles.

BACKGROUND: Cisplatin is a widely-used potent anti-cancer drug having severe side-effects precluding its sustained use. OBJECTIVES: Poly (lactide-co-glycolide) (PLGA)-nanoparticles loaded Boldine, an antioxidant ingredient of ethanolic extract of Boldo plant (Peumus boldus) was tested in cancer mice model, Mus musculus to examine if it could reduce unwanted Cisplatin-induced toxicity in normal tissue. MATERIAL AND METHODS: Nano-encapsulation of Boldine was done by following the standardized solvent displacement method. Physico-chemical characterization of PLGA-encapsulated nano-Boldine (NBol) was accomplished through analyses of various spectroscopic techniques. Status of major antioxidant enzymes, functional markers, and lipid peroxidation (LPO) was also determined in certain tissue and serum samples. Percentage of cells undergoing cytotoxic death, Reactive oxygen species (ROS) accumulation and mitochondrial functioning were analyzed in both normal and cancer mice. Nanoscale changes in chromatin organization were assessed by Transmission electron microscopy (TEM). mRNA and protein expressions of Top II, Bax, Bcl-2, Cyt c, caspase 3 were studied by RT-PCR, immunoblot and immunofluorescence. RESULTS: NBol had faster mobility, site-specific action and ability of sustained particle release. NBol readily entered cells, prevented Cisplatin to intercalate with dsDNA resulting in reduction of chromatin condensation, with corresponding changes in ROS levels, mitochondrial functioning and antioxidant enzyme activities, leading to reduction in Deoxyribose nucleic acid (DNA) damage and cytotoxic cell death. Expression pattern of apoptotic genes like Top II, p53, Bax, Bcl-2, cytochrome c and caspase-3 suggested greater cytoprotective potentials of NBol in normal tissues. CONCLUSIONS: Compared to Boldine (Bol), NBol had better ability of drug carriage and protective potentials (29.00% approximately) against Cisplatin-induced toxicity. Combinational therapeutic use of PLGA-NBol can reduce unwanted Cisplatin-induced cellular toxicity facilitating use of Cisplatin.

Multiorgan toxicity induced by EtOH extract of Fructus Psoraleae in Wistar rats.

BACKGROUND: The fruits of Psoralea corylifolia L. (Fructus Psoraleae, FP) has a long history and a wide range of applications in the treatment of osteoporosis and leukoderma. Although it is well known that FP could cause hepatotoxicity and reproductive toxicity, less is known about its potential toxicity on multiple organs. PURPOSE: This study aims to determine the multiorgan toxicity of EtOH extract of FP (EEFP) and to investigate the underlying mechanisms through a systematic evaluation in Wistar rats. STUDY DESIGN AND METHODS: Wistar rats were orally administered with the EEFP at doses of 1.5, 1.0 and 0.5 g/kg for 28 days. Histopathologic and clinicopathologic analyses were performed, and the hormone levels in serum and the mRNA levels of enzymes related to the production of steroid hormones in adrenal glands were detected. The area of each band of adrenal glands and the steroid levels in the adrenal glands were also measured. RESULTS: After the treatment, both the histopathologic and clinicopathologic examination showed that EEFP caused liver, prostate, seminal vesicle and adrenal gland damage. Among the enzymes involved in the regulation of adrenal steroid hormone production, NET, VMAT2, and CYP11B1 were upregulated, while CYP17A1 was downregulated. Among the adrenal steroid hormones, COR and NE were upregulated, while levels of DHT and serum ACRH and CRH decreased. CONCLUSION: Our results indicated that adrenal gland, prostate, and seminal vesicles could also be the target organs of FP-induced toxicity. Abnormal enzyme and hormone production related to the hypothalamic pituitary adrenal (HPA) axis caused by the EEFP may be the potential toxic mechanism for changes in the adrenal gland and secondary sex organs of male rats.

Amiodarone-induced multiorgan toxicity with ocular findings on confocal microscopy.

Amiodarone is an antiarrhythmic medication that can adversely effect various organs including lungs, thyroid gland, liver, eyes, skin, and nerves. The risk of adverse effects increases with high doses and prolonged use. We report a 54-year-old female who presented with multiorgan toxicity after 8 months of low dose (200 mg/day) amiodarone treatment. The findings of confocal microscopy due to amiodarone-induced keratopathy are described. Amiodarone may cause multiorgan toxicity even at lower doses and for shorter treatment periods.

Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overview.

A large number of investigations have demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and degenerative diseases including cardiovascular dysfunctions, acute and chronic stress, gastrointestinal distress, neurological disorders, pancreatitis, various stages of neoplastic processes and carcinogenesis including detoxification of carcinogenic metabolites. GSP exhibited potent free radical scavenging abilities in both in vitro and in vivo models. GSP exerted significant in vivo protection against structurally diverse drug and chemical-induced hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity and spleentoxicity. GSP also protected against idarubicin and 4-hydroxyperoxy-cyclophosphamide-induced cytotoxicity toward human normal liver cells. GSP exhibited selective cytotoxicity toward selected human cancer cells, while enhancing the growth and viability of normal cells. GSP exhibited potent modulatory effects of pro-apoptotic and apoptotic regulatory bcl-XL, p53, c-myc, c-JUN, JNK-1 and CD36 genes. Long-term exposure to GSP may serve as a novel chemoprotectant against three stages of DMN-induced liver carcinogenesis and tumorigenesis including initiation, promotion and progression. GSP may selectively protect against oxidative stress, genomic integrity and cell death patterns in vivo. These results demonstrate that GSP may serve as a novel therapeutic intervention against carcinogenesis.