Numerous studies have shown the pharmacological effects of pomegranate, such as: anti-cancer, cholesterol-lowering, anti-diabetic, and antihypertensive features. Pomegranate consumption has also revealed some adverse effects. This systematic review aimed to explore the adverse effects of pomegranate reported in clinical studies.

The keywords "pomegranate", "Punica granatum", "side effect", "clinical trial", and "case report or case series" were searched for in valid databases. Reports about adverse effects of pomegranate were also collected from several international registries.

This systematic review included a total of 66 clinical articles. Eleven articles have reported side effects of pomegranate. Twenty-one articles have recorded no side effects in the pomegranate group while 34 articles have not mentioned any side effects for this plant. The study also included 7 case report studies. The most common side effects included gastrointestinal problems, flu-like symptoms, and urinary problems. In case report studies, the most significant reported side effect was allergic reaction.

In summary, pomegranate and its extract seem to be safe according to the reported adverse effects. Meanwhile, conducting more robust controlled trials with pomegranate products and documentation of any probable side effect is warranted.

Statins represent the cornerstone of pharmacotherapy for the prevention of atherosclerotic cardiovascular disease. These medications not only reduce low-density lipoprotein cholesterol (LDL-C) via inhibition of 3-hydroxy-3-methylglutarate attached to CoA reductase, the key rate-limiting step in the cholesterol biosynthetic pathway, but also upregulate expression of the low-density lipoprotein receptor, improving serum clearance. Given LDL-C is a causal risk factor for the development of atherosclerosis, these complementary mechanisms largely explain why statin therapy leads to reductions in major adverse cardiovascular events. However, decades of basic and clinical research have suggested that statins may exert other effects independent of LDL-C lowering, termed pleiotropic effects, which have become a topic of debate among the scientific community. While some literature suggests statins may improve plaque stability, reduce inflammation and thrombosis, decrease oxidative stress, and improve endothelial function and vascular tone, other studies have suggested potential harmful pleiotropic effects related to increased risk of muscle-related side effects, diabetes, hemorrhagic stroke, and cognitive decline. Furthermore, the introduction of newer, non-statin LDL-C lowering therapies, including ezetimibe, proprotein convertase subtilisin/Kexin Type 9, and bempedoic acid, have challenged the statin pleiotropy theory. This review aims to provide a historical background on the development of statins, explore the mechanistic underpinnings of statin pleiotropy, review the available literature, and provide up to date examples that suggest statins may exert effects outside of LDL-C lowering and the cardiovascular system.

To investigate different etiologies and management of the rhabdomyolysis in children.

Eight pediatric rhabdomyolysis cases who applied to the Dokuz Eylul University Faculty of Medicine Department of Pediatric Nephrology with different etiologies between January 2004 and January 2012 were evaluated in terms of age, gender, admission symptoms, physical examination findings, factors provoking rhabdomyolysis, number of rhabdomyolysis attacks, laboratory results, family history and the final diagnosis received after the treatment.

Average diagnosis ages of eight cases were 129 (24-192) ± 75.5 mo and five of them were girls. All of them had applied with the complaint of muscle pain, calf pain, and dark color urination. Infection (pneumonia) and excessive physical activity were the most important provocative factors and excessive licorice consumption was observed in one case. In 5 cases, acute kidney injury was determined and two cases needed hemodialysis. As a result of the further examinations; the cases had received diagnoses of rhabdomyolysis associated with mycoplasma pneumoniae, sepsis associated rhabdomyolysis, licorice-induced hypokalemic rhabdomyolysis, carnitine palmitoyltransferase II deficiency, very long-chain acyl-CoA dehydrogenase deficiency, congenital muscular dystrophy and idiopathic paroxysmal rhabdomyolysis (Meyer-Betz syndrome).

It is important to distinguish the sporadic and recurrent rhabdomyolysis cases from each other. Recurrent rhabdomyolysis cases should follow up more regardful and attentive.

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are well tolerated, but associated with various statin-associated symptoms (SAS), including statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are "statin-associated symptoms" because they are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of statin users. Clinically important muscle symptoms, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the statin treatment, and using alternative lipid-lowering therapy.

We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3 widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80% (whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Grapefruit juice should not be contraindicated in people taking statins.

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are generally well tolerated as monotherapy. Statins are associated with two important adverse effects, asymptomatic elevation in liver enzymes and myopathy. Myopathy is most likely to occur when statins are administered with other drugs. Statins are substrates of multiple drug transporters (including OAT- -P1B1, BCRP and MDR1) and several cytochrome P450 (CYP) enzymes (including CYP3A4, CYP2C8, CYP2C19, and CYP2C9). Possible adverse effects of statins can occur due to interactions in concomitant use of drugs that substantially inhibit or induce their methabolic pathway. This review summarizes the most important interactions of statins.

The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC(50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without preincubation of inhibitor with microsomes. After preincubation, the IC(50) for PJ increased to 0.97% (P < .05), whereas the IC(50) for GFJ decreased to 0.41% (P < .05), suggesting mechanism-based inhibition by GFJ but not PJ. Pretreatment of volunteer subjects (n = 13) with PJ (8 oz) did not alter the elimination half-life, volume of distribution, or clearance of intravenous midazolam (2 mg). Administration of PJ also did not affect C(max), total area under the curve (AUC), or clearance of oral midazolam (6 mg). However, GFJ (8 oz) increased midazolam C(max) and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values. Thus, PJ does not alter clearance of intravenous or oral midazolam, whereas GFJ impairs clearance and elevates plasma levels of oral midazolam.

Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3Amediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitroin vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as dietary substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given dietary substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-dietary substance interactions appropriately.

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation. Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting. As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo. Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs. Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.

Approximately 10% of patients treated with statins experience some form of muscle-related side effects in clinical practice. These can range from asymptomatic creatine kinase (CK) elevation, to muscle pain, weakness, and its most severe form, rhabdomyolysis. Higher risk patients for statin myopathy are those older than 80, with a small body frame, on higher statin doses, on other medications, or with other systemic diseases including hepatic or renal diseases, diabetes mellitus, or hypothyroidism. The cause of statin myopathy is presumed to be the same for its variable presentation but has not been defined. In patients with myopathic symptoms, their symptoms and CK levels determine whether statin therapy can be continued or must be stopped.

Rhabdomyolysis is a condition that results from many underlying etiologies and can present in a myriad of ways to the emergency physician. However, some clinical and laboratory features are almost always present and, if noted, can help in making the diagnosis. This review article will focus on the presenting symptoms, the various etiologies, the underlying mechanisms, and the current management of pediatric rhabdomyolysis.

To summarize recent findings on pharmacokinetics, pharmacodynamics, drug-drug interactions and influence of lifestyle heterogeneity on adverse events in cholesterol-lowering therapy

The prevention of cardiovascular disease is critically dependent on lipid-lowery therapy, including statins, cholesterol absorption inhibitors, fibrates and nicotinic acid. Statins are the most prescribed drugs in lipid lowering therapy with variability in response and almost one third of the patients do not meet their treatment goals. The severe adverse effects of treatment with cerivastatin stimulated the search for new genes and gene variations affecting pharmacokinetics, drug-drug interactions and pharmacodynamics. Moreover, instead of monotherapy, combined therapy of statins with ezetemibe and niacin was considered. This led to the identification of CD13, NPC1L1 and HM74A as new targets and CYP2C8 and glucuronidation enzymes as potential targets for drug-drug interactions. Moreover multiple polymorphic sites and pleiotrophic gene targets were reinvestigated in larger cohorts and the relevant pathogenetic factors start to evolve.

Statin therapy is widely used and well tolerated by the majority of patients. To further reduce potential adverse effects and to increase efficacy, combined therapy concepts with ezetimibe or niacin are underway.