Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence

Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and highlighted the pathological situations in which statin therapy should be avoided. In this context, preventive or substitutive therapies should also be evaluated.

Assessment of Lipid Profile and Serum Creatinine Kinase in Subjects with Hyperlipidemia on Moderate Intensity Statin Therapy Attending a Postgraduate Teaching Hospital in South India

Atherosclerosis of large and medium sized arteries are believed to be the major reason behind the development of Coronary Artery Diseases and Hyperlipidemia has been found to be one of the most important contributing factors. Appropriate lifestyle changes along with proper drug therapy lead to a considerable reduction in mortality rate due to coronary artery disease. Reduction of LDL Cholesterol is the primary goal of cholesterol-lowering therapy, but most of the patients are usually unable to achieve the treatment goals with lifestyle modifications alone; and in such situations, drug therapy is essential to prevent the disease progression and further future complications. The aim of the study was to demonstrate impact of three moderate intensity statins on lipid profile and biomarker representing muscle toxicity. It was a prospective observational study conducted in a tertiary care teaching hospital in south India. Patients of both gender falling the age group between 30 and 70 years with newly diagnosed Hyperlipidemia attending the Department of Medicine OPD, were enrolled in the study. Total 229 participants were enrolled in study and all the drug treatment were found to be effective in achieving the treatment goal; at the same time Rosuvastatin 10 mg treatment group exhibited better efficacy along with minimal muscle toxicity.

Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis

Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos.

Muscle toxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection

Background Although voriconazole is a widely used azole antifungal agent in clinical practice, its side effect of muscle toxicity is extremely rare. The present study demonstrates an adverse effect of progressive myotoxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection.Case presentation A 78-year-old male was admitted to our hospital due to recurrent cough and expectoration for four months. His previous chest CT scan indicated alveolar opacities and multiple cavitary nodules in the right lower lobe. Pulmonary fungal infection was considered due to weakly positive results of serum galactomannan and 1,3 β-D-glucan test,with no evidence of malignant tumor, tuberculosis, or Wegener's granulomatosis. The patient experienced diffuse myalgia with significantly elevated muscle enzymes after voriconazole administration for 13 days, and recovered uneventfully due to immediate voriconazole cessation and enhanced intravenous fluid infusion. Furthermore, the pulmonary cavitary nodules were consistent with the pathological findings of cryptogenic organizing pneumonia.Conclusions Voriconazole-associated myotoxicity should be considered when a patient presents with evidence of muscle injury during voriconazole administration. Morever, although invasive pulmonary fungal infection can often show multiple nodules with cavities in CT scan, the initiation of anti-fungal agents should be cautious before the pathological features of multiple cavitary nodules are identified, in order to avoid potential serious adverse events.

A Case of Transient Visual Disturbance and Ocular Paresis after Endoscopic Sinus Surgery

Endoscopic sinus surgery (ESS) is widely used as standard surgical treatment for chronic rhinosinusitis. Orbital complications of varying degrees occurred during ESS have been widely reported. If the orbital symptoms occurred immediately after surgery, ocular damage associated with surgery is suspected if the patient’s preoperative ocular function was patent. If immediate action is not taken, permanent visual loss might develop, so it is very important to diagnose orbital complications and take appropriate action. In our case, there was no definite intraorbital hemorrhage when sudden visual loss was noted. The symptoms were fully recovered without further treatment and it is clinically suspected to be caused by transient ocular muscle toxicity of local anesthetics.

Rhabdomyolysis and acute kidney injury induced by the association of rosuvastatin and abiraterone: A case report and review of the literature

Introduction Abiraterone acetate is an inhibitor of androgens biosynthesis, approved as first-line treatment in castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. Abiraterone has been rarely associated with severe rhabdomyolysis, but the mechanism of muscle toxicity is unknown. Case report We hereby present a case of severe rhabdomyolysis resulting in acute on chronic kidney injury following abiraterone initiation in a patient previously under rosuvastatin. Management and outcome Rhabdomyolysis was resolutive after rosuvastatin and abiraterone discontinuation, and kidney function recovered. There was no recurrence of muscle toxicity after re-initiation of abiraterone alone. Discussion Abiraterone selectively inhibits CYP17 as well as the hepatic transporter OATP1B1. OATP1B1 is an efflux transporter, whose function is to extract several drugs from the portal blood, allowing them to undergo hepatic metabolism. We hypothesize that abiraterone-induced inhibition of plasmatic uptake of rosuvastatin by OATP1B1 increased plasmatic concentration of rosuvastatin, leading to toxicity on muscle cells. We therefore suggest that the association between rosuvastatin and abiraterone should be avoided.

Muscle Toxicity of Drugs: When Drugs Turn Physiology into Pathophysiology

Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that symptoms of patients may be drug related and to be aware that inter-individual differences in susceptibility to drug-induced toxicity exist. The most prevalent and well-documented drug class with unintended myotoxicity are the statins, but even today new classes of drugs with unintended myotoxicity are being discovered. This review will start off by explaining the principles of drug-induced myotoxicity and the different terminologies used to distinguish between grades of toxicity. The main part of the review will focus on the most important pathogenic mechanisms by which drugs can cause muscle toxicity, which will be exemplified by drugs with high risk of muscle toxicity. This will be done by providing information on key clinical and laboratory aspects, muscle electromyography patterns and biopsy results, and pathological mechanism and management for a specific drug from each pathogenic classification. In addition, rather new classes of drugs with unintended myotoxicity will be highlighted. Furthermore, we will explain why it is so difficult to diagnose drug-induced myotoxicity, and which tests can be used as a diagnostic aid. Lastly, a brief description will be given of how to manage and treat drug-induced myotoxicity.