A contributory role of oxidative stress and protection by antioxidant nutrients have been suspected in cataract formation. Ganoderic acid A (GAA), an effective lanostane triterpene, is widely reported as an antioxidant. The aim of this study is to investigate the potential effects of GAA on cataract formation. After lens epithelial cells (LECs) were exposed to UVB radiation for different periods, cell viability, apoptosis-related protein levels, malondialdehyde (MDA) and superoxide dismutase (SOD) activities were monitored. We found that cell viability, the Bcl-2/Bax ratio and SOD activity were increased, while Cleaved caspase-3 levels and MDA activity were decreased compared with those in UVB-impaired LECs after GAA treated. Furthermore, GAA activated PI3K/AKT in UVB-impaired LECs and effectively delayed the occurrence of lens opacity in vitro. In conclusion, these findings demonstrated that GAA exhibited protective functions in SRA01/04 cells and rat lenses against UVB-evoked impairment through elevating cell viability and antioxidant activity, inhibiting cell apoptosis, activating the PI3K/AKT pathway and delaying lens opacity.
Animals ; Apoptosis ; Cataract/prevention & control* ; Cell Line ; Cell Survival ; Epithelial Cells/radiation effects* ; Heptanoic Acids/pharmacology* ; Humans ; Lanosterol/pharmacology* ; Lens, Crystalline/radiation effects* ; Malondialdehyde/metabolism* ; Rats ; Superoxide Dismutase/metabolism* ; Ultraviolet Rays/adverse effects*

OBJECTIVE: To analyze the clinical manifestation and genetic mutation of a child with tyrosinemia type I but without elevated succinylacetone. METHODS: Clinical data of the patient was collected. Tandem mass spectrometry and gas chromatography mass spectrometry were used to analyze the blood amino acid and urine organic acid component of the proband. DNA was extracted from the child and his parents and used for mutation analysis. RESULTS: The proband was of acute type, with features including hepatomegaly, jaundice, anemia and tendency of bleeding. Serum levels of Tyrosine, Methionine and Phenylalanine were 397.12 μmol/L, 896.16 μmol/L and 292.52 μmol/L, respectively, which all distinctly exceeded the normal levels. The level of phenyllactic acid and 4-hydroxyphenyl-lactic acid of proband's urine were 17.4 μmol/L and 417.0 μmol/L, respectively, which also exceeded the normal levels, but the level of succinylacetone was within the normal range. Compound heterozygous mutations of the FAH gene, namely c.634delT (p.L212Wfs*20) and c.455G>A (p.W152X), were detected in the proband, which were both predicted to be pathogenic and were inherited from her father and mother, respectively. CONCLUSION For children with tyrosinemia type I, detection of urine succinylacetone by gas phase mass spectrometry can be negative. The diagnosis of tyrosinemia type I must rely on genetic testing and/or enzymatic assaying.
DNA Mutational Analysis ; Female ; Genetic Testing ; Heptanoates ; Humans ; Male ; Tyrosinemias

Atorvastatin is one of the most widely prescribed medications for dyslipidemia treatment. In Korea, post combined therapy with ezetimibe, a 73-year-old woman was reported by a community pharmacy to have experienced visual field defect, which recovered after drug discontinuation. She had never experienced this symptom before, and several studies have reported an association between use of statins and visual disorders such as blurred vision, diplopia, and cataract. Blockage of cholesterol accumulation, oxidative stress, or myopathy is expected to be a cause of this symptom. Naranjo scale, Korean causality assessment algorithm (Ver.2), and World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria were the three tools used to determine causality between the visual disorder and atorvastatin. The results represent ‘probable’, ‘certain’, and ‘probable/likely’ causality, respectively. Our results, in combination with a review of literature, indicate that ocular adverse effects are highly likely related to atorvastatin.
Aged ; Atorvastatin Calcium ; Cataract ; Cholesterol ; Diplopia ; Drug-Related Side Effects and Adverse Reactions ; Dyslipidemias ; Ezetimibe ; Female ; Global Health ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Korea ; Muscular Diseases ; Oxidative Stress ; Pharmacies ; Vision Disorders ; Visual Fields

BACKGROUND/AIMS: To define the effect of statins on interleukin 1β (IL-1β)-induced osteoclastogenesis and elucidate the underlying mechanisms. METHODS: Bone marrow cells were obtained from 5-week-old male ICR (Institute for Cancer Research) mice, and they were cultured to differentiate them into osteoclasts with macrophage colony-stimulating factor and the receptor activator of nuclear factor (NF)-κB ligand in the presence or absence of IL-1β or atorvastatin. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the effects of atorvastatin on osteoclastogenesis were investigated using reverse transcription polymerase chain reaction and immunoblotting for osteoclast specific molecules. RESULTS: Atorvastatin significantly reduced the number of TRAP-positive multinucleated cells as well as the bone resorption area. Atorvastatin also downregulated the expression of the NF of activated T-cell c1 messenger RNA and inhibited the expression of osteoclast-specific genes. A possible underlying mechanism may be that atorvastatin suppresses the degradation of the inhibitors of NF-κB and blocks the activation of the c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; thus, implicating the NF-κB and mitogen-activated protein kinases pathway in this process. CONCLUSIONS: Atorvastatin is a strong inhibitor of inflammation-induced osteoclastogenesis in inflammatory joint diseases.
Acid Phosphatase ; Animals ; Atorvastatin Calcium* ; Bone Marrow Cells ; Bone Resorption ; Dentin ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Immunoblotting ; Interleukins ; JNK Mitogen-Activated Protein Kinases ; Joint Diseases ; Macrophage Colony-Stimulating Factor ; Male ; Mice ; Mitogen-Activated Protein Kinases ; Osteoclasts* ; Osteoprotegerin ; Phosphotransferases ; Polymerase Chain Reaction ; Reverse Transcription ; RNA, Messenger ; T-Lymphocytes

Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA-induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation.
Animals ; Atorvastatin Calcium* ; Brain ; Cardiovascular Diseases ; Cell Death ; Cyclooxygenase 2 ; Hippocampus ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Kainic Acid ; Mice ; Neurons* ; Phosphorylation ; Prevalence ; Seizures

BACKGROUND: The proportion of pharmaceutical expenditure out of total health-care expenditure in South Korea is high. In 2016, 25.7% of national health insurance (NHI) spending was for pharmaceuticals. Given the increasing demands for the access to newly introduced medicines and following increase in pharmaceutical spending, the management of NHI pharmaceutical expenditure is becoming more difficult. METHODS: This study analyzed the data claimed to NHI for pharmaceutical reimbursement from 2010 to 2016. RESULTS: The policy implications with respect to the trends and problems in spending by drug groups were elicited. First, the proportion of off-patent drugs spending which were treated to chronic disease was much higher than anti-cancer drug spending. Second, the spending to the newly introduced high-costed medicine increased, however, current price-reduction mechanism was not sufficient to manage their expenditure efficiently. CONCLUSION: Our system seems to need several revisions to improve the efficiency of pharmaceutical expenditure and to cope with high-costed medicines. This study suggested that the prices of off-patent drugs need to be regularly readjusted and the Price-Volume Agreement System should be operated more flexibly as well.
Atorvastatin Calcium ; Chronic Disease ; Health Expenditures ; Imatinib Mesylate ; Korea ; National Health Programs

Blastocystis is an enteric Straminopile in tropical, subtropical and developing countries. Metronidazole has been a chemotheraputic for blastocystosis. Failures in its regimens were reported and necessitate new studies searching for alternative therapeutic agents. Aim of current study is to investigate potential effects of Atorvastatin (AVA) compared to the conventional chemotherapeutic MTZ in experimentally Blastocystis-infected mice. Anti-Blastocystis efficacy of AVA was evaluated parasitologically, histopathologically and by transmission electron microscopy using MTZ (10 mg/kg) as a control. Therapeutic efficacy of AVA was apparently dose-dependent. Regimens of AVA (20 and 40 mg/kg) proved effective against Blastocystis infections with high reduction in Blastocystis shedding (93.4–97.9%) compared to MTZ (79.3%). The highest reductions (98.1% and 99.4%) were recorded in groups of combination treatments AVA 20–40 mg/kg and MTZ 10 mg/kg. Blastocystis was nearly eradicated by the 20th day post infection. Genotype analysis revealed that genotype I was most susceptible, genotype III was less. Histopathologic and ultrastructural studies revealed apoptotic changes in Blastocystis and significant improvement of intestinal histopathological changes more remarkable in combinational therapy groups. Thus, the present study offers AVA as a potential candidate for Blastocystis therapy combined with MTZ.
Animals ; Atorvastatin Calcium ; Blastocystis ; Blastocystis Infections ; Developing Countries ; Genotype ; Metronidazole ; Mice ; Microscopy, Electron, Transmission

BACKGROUND AND OBJECTIVES: Non-statin therapy plus lower intensity statin might be an alternative in patients with coronary artery disease (CAD). A recent data suggested an anti-inflammatory therapy can reduce recurrent cardiovascular events and pioglitazone is also an intriguing inflammatory-modulating agent. However, limited data exist on whether pioglitazone on top of statins further attenuates plaque inflammation. METHODS: Statin-naïve patients with stable CAD and carotid plaques of ≥3 mm were randomly prescribed moderate dose atorvastatin (20 mg/day), or moderate dose atorvastatin plus pioglitazone (30 mg/day) for 3 months. The primary endpoint was the change in the arterial inflammation of the carotid artery measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during 3 months. RESULTS: Of the 41 randomized patients, 33 underwent an evaluation by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT; 17 atorvastatin plus pioglitazone and 16 atorvastatin patients). The addition of pioglitazone significantly improved the insulin sensitivity and increased the high-density lipoprotein cholesterol after 3 months. Although a reduction in the (FDG) uptake by pioglitazone on top of atorvastatin in carotid arteries with plaque showed marginally statistical significance in the entire patient group (atorvastatin plus pioglitazone; −0.10±0.07 and atorvastatin −0.06±0.04, p=0.058), pioglitazone showed a further reduction of the fluorodeoxyglucose (FDG) uptake among patients who had a baseline FDG uptake above the median (atorvastatin plus pioglitazone; −0.14±0.04 and atorvastatin −0.03±0.03, p < 0.001). CONCLUSIONS: Pioglitazone demonstrated marginally significant anti-inflammatory effects in addition to moderate dose atorvastatin. This may have been due to the lack of power of the study. However, pioglitazone may have an anti-inflammatory effect in those patients with high plaque inflammation (Trial registry at ClinicalTrials.gov, NCT01341730).
Arteritis ; Atherosclerosis ; Atorvastatin Calcium ; Carotid Arteries ; Carotid Stenosis ; Cholesterol ; Coronary Artery Disease ; Electrons ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Inflammation ; Insulin Resistance ; Lipoproteins ; PPAR gamma

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (C(max,ss)) and the area under the curve within a dosing interval at steady state (AUC(τ,ss)) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799–1.2544) and 1.1154 (1.0079–1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227–1.0849) and 1.0176 (0.9465–1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.
Atorvastatin Calcium* ; Cholesterol ; Cross-Over Studies ; Drug Interactions* ; Dyslipidemias ; Ezetimibe* ; Humans ; Lipoproteins ; Male ; Pharmacokinetics ; Plasma ; Volunteers*

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.
Atorvastatin Calcium* ; Chromatography, Liquid ; Cross-Over Studies* ; Humans ; Male* ; Metformin* ; Patient Compliance ; Pharmacokinetics* ; Plasma ; Tablets* ; Therapeutic Equivalency