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1.
J Clin Pharmacol ; 61(4): 547-554, 2021 04.
Article in English | MEDLINE | ID: mdl-33029796

ABSTRACT

Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which pediatric hydroxyurea pharmacokinetics have primarily been studied. Plasma hydroxyurea levels were quantified in 14 participants aged 4-19 years using high-performance liquid chromatography. Blood collections were scheduled 20 minutes, 1 hour, and 4 hours after the first dose, on pharmacokinetic day 1 (PK1), and again 2-3 months later if still on hydroxyurea (PK2). Six participants had PK1 and PK2 data at all 3 postdose timed collections, 5 only had PK1 samples, and 3 only had PK2 samples. Total pancreatectomy with islet autotransplantation participants had reduced and delayed absorption compared with sickle cell anemia participant data from the Hydroxyurea Study of Long-Term Effects, regardless of timing or dosing methodology. Total pancreatectomy with islet autotransplantation participants had different pharmacokinetic profiles at PK1 versus PK2, with lower dose-normalized exposures than previously reported in sickle cell anemia. These results suggest variability exists in hydroxyurea absorption and bioavailability in total pancreatectomy with islet autotransplantation patients, suspected to be primarily because of Roux-en-Y reconstruction, and suggest that more pharmacokinetic data are needed for scenarios when hydroxyurea is prescribed to children without sickle cell anemia.


Subject(s)
Hydroxyurea/administration & dosage , Hydroxyurea/pharmacokinetics , Islets of Langerhans Transplantation/adverse effects , Pancreatectomy/adverse effects , Thrombocytosis/etiology , Thrombocytosis/prevention & control , Adolescent , Anemia, Sickle Cell/drug therapy , Child , Child, Preschool , Female , Humans , Hydroxyurea/blood , Male , Prospective Studies , Transplantation, Autologous , Young Adult
2.
J Pediatr ; 222: 236-239, 2020 07.
Article in English | MEDLINE | ID: mdl-32171562

ABSTRACT

Lactation is contraindicated for women with sickle cell anemia receiving hydroxyurea therapy, despite sparse pharmacokinetics data. In 16 women who were lactating volunteers, we documented hydroxyurea transferred into breastmilk with a relative infant dosage of 3.4%, which is below the recommended 5%-10% safety threshold. Breastfeeding should be permitted for women taking daily oral hydroxyurea.


Subject(s)
Anemia, Sickle Cell/drug therapy , Hydroxyurea/pharmacokinetics , Lactation/drug effects , Milk, Human/metabolism , Adult , Anemia, Sickle Cell/metabolism , Antineoplastic Agents/pharmacokinetics , Antisickling Agents , Female , Humans , Milk, Human/drug effects
3.
Am J Hematol ; 94(8): 871-879, 2019 08.
Article in English | MEDLINE | ID: mdl-31106898

ABSTRACT

Hydroxyurea is FDA-approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight-based dosing with step-wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center study designed to prospectively validate a novel personalized PK-guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9-26 months), and PK-guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3-9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK-guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK-guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight-based dosing.


Subject(s)
Anemia, Sickle Cell/drug therapy , Antisickling Agents/administration & dosage , Antisickling Agents/blood , Hydroxyurea/administration & dosage , Models, Biological , Adolescent , Anemia, Sickle Cell/blood , Antisickling Agents/therapeutic use , Area Under Curve , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Monitoring , Female , Humans , Hydroxyurea/blood , Hydroxyurea/therapeutic use , Infant , Male , Maximum Tolerated Dose , Practice Guidelines as Topic , Prospective Studies , Young Adult
4.
Exp Mol Med ; 50(2): e444, 2018 02 16.
Article in English | MEDLINE | ID: mdl-29504610

ABSTRACT

Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD-RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.


Subject(s)
Asthma/metabolism , Endoplasmic Reticulum Stress , Oxidation-Reduction , Phosphatidylinositol 3-Kinases/metabolism , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Asthma/etiology , Disease Models, Animal , Endoplasmic Reticulum Stress/drug effects , Lipid Peroxidation , Lipopolysaccharides/immunology , Membrane Proteins/metabolism , Mice , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Ovalbumin/immunology , Oxidative Stress/drug effects , Phosphoinositide-3 Kinase Inhibitors , Quinazolines/pharmacology , Reactive Oxygen Species/metabolism , Receptors, Cell Surface , Signal Transduction/drug effects
5.
Blood Cells Mol Dis ; 67: 135-142, 2017 09.
Article in English | MEDLINE | ID: mdl-28847416

ABSTRACT

Hydroxyurea is a potent disease-modifying therapeutic agent with efficacy for the treatment of sickle cell anemia. When administered at once-daily oral doses that lead to mild marrow suppression, hydroxyurea leads to substantial and sustained fetal hemoglobin induction, which effectively inhibits erythrocyte sickling. When escalated to maximum tolerated dose, hydroxyurea has proven laboratory and clinical effects for both children and adults with sickle cell anemia. However, there is substantial inter-patient variability with regard to the optimal dosing regimen, as well as differences in treatment-related toxicities and responses that may be explained by hydroxyurea pharmacokinetics and pharmacogenetics. Addressing the safety and efficacy of hydroxyurea treatment requires quantitative and accurate drug analysis, and various laboratory techniques have been established. We review the historical and current analytical techniques for measuring hydroxyurea concentrations accurately, and discuss clinical settings where quantitative analysis can increase understanding and safety of this important therapeutic agent, and ultimately improve patient outcomes.


Subject(s)
Anemia, Sickle Cell/drug therapy , Antisickling Agents/pharmacokinetics , Drug Monitoring/methods , Hydroxyurea/pharmacokinetics , Animals , Antisickling Agents/administration & dosage , Antisickling Agents/therapeutic use , Chromatography, High Pressure Liquid/methods , Humans , Hydroxyurea/administration & dosage , Hydroxyurea/therapeutic use , Mass Spectrometry/methods
6.
Clin Chem ; 62(12): 1593-1601, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27694393

ABSTRACT

BACKGROUND: Sickle cell anemia (SCA) is a life-threatening blood disorder characterized by the presence of sickle-shaped erythrocytes. Hydroxyurea is currently the only US Food and Drug Administration-approved treatment and there is a need for a convenient method to monitor compliance and hydroxyurea concentrations, especially in pediatric SCA patients. METHODS: We describe a novel approach to the determination of hydroxyurea concentrations in dried whole blood collected on DMPK-C cards or volumetric absorptive microsampling (VAMS) devices. Hydroxyurea was quantified by electrospray ionization LC-MS/MS using [13C15N2]hydroxyurea as the internal standard. Calibrators were prepared in whole blood applied to DMPK-C cards or VAMS devices. RESULTS: Calibration curves for blood hydroxyurea measured from DMPK-C cards and VAMS devices were linear over the range 0.5-60 µg/mL. Interassay and intraassay CVs were <15% for blood collected by both methods, and the limit of detection was 5 ng/mL. Whole blood hydroxyurea was stable for up to 60 days on DMPK-C cards and VAMS devices when frozen at -20 °C or -80 °C. Whole blood hydroxyurea concentrations in samples collected on DMPK-C cards or VAMS devices from SCA patients were in close agreement. CONCLUSIONS: This tandem mass spectrometry method permits measurement of hydroxyurea concentrations in small volumes of dried blood applied to either DMPK-C cards or VAMS devices with comparable performance. This method for measuring hydroxyurea from dried blood permits the evaluation of therapeutic drug monitoring, individual pharmacokinetics, and medication adherence using heel/finger-prick samples from pediatric patients with SCA treated with hydroxyurea.


Subject(s)
Anemia, Sickle Cell/blood , Dried Blood Spot Testing , Drug Monitoring , Hydroxyurea/blood , Radioisotope Dilution Technique , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry/methods , Anemia, Sickle Cell/drug therapy , Calibration , Chromatography, High Pressure Liquid , Humans , Hydroxyurea/therapeutic use
7.
Eur J Pharmacol ; 777: 104-12, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26948310

ABSTRACT

Endoplasmic reticulum (ER) stress and associated protein aggregation are closely associated with human diseases, including alterations in hepatic lipid metabolism. Inhibition of ER stress can have a significant effect on the prevention of hepatic dyslipidemia. Here, we studied the role of 4-phenylbutyric acid (4-PBA), a chemical chaperone, on ER stress-induced hepatic lipid accumulation. We studied ER stress induction following CCl4 exposure and delineated mechanisms of the CCl4-induced ER stress response in liver tissue from mice. CCl4 affected the formation of disulfide bonds through excessive hyper-oxidation of protein disulfide isomerase (PDI). Increased complex formation between PDI and its client proteins persisted in CCl4-exposed samples. Conversely, 4-PBA inhibited ER stress via secretion of apolipoprotein B and prevention of hepatic lipid accumulation. We also studied the mechanism-based pharmacokinetic and pharmacodynamic profiles and identified the ER stress-related proteins GRP78 and CHOP, along with plasma apolipoprotein B and triglyceride levels, as novel biomarkers of ER stress-induced hepatic lipid accumulation. ER stress and its clinical relevance for therapeutic approaches were well correlated with the activity of the ER stress regulator 4-PBA, which may be a promising drug candidate for the treatment of hepatic lipid accumulation, such as hepatic steatosis.


Subject(s)
Carbon Tetrachloride/adverse effects , Dyslipidemias/chemically induced , Dyslipidemias/drug therapy , Liver/drug effects , Liver/metabolism , Phenylbutyrates/pharmacology , Phenylbutyrates/pharmacokinetics , Animals , Apolipoproteins B/metabolism , Cytochrome P-450 CYP2E1/metabolism , Disease Models, Animal , Disulfides/chemistry , Dyslipidemias/metabolism , Dyslipidemias/pathology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Lipid Metabolism/drug effects , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Phenylbutyrates/therapeutic use , Protein Folding/drug effects , Reactive Oxygen Species/metabolism
8.
Sci Rep ; 4: 4362, 2014 Mar 12.
Article in English | MEDLINE | ID: mdl-24618639

ABSTRACT

The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.


Subject(s)
Glycine max/chemistry , Plant Extracts/pharmacology , Valproic Acid/analogs & derivatives , Valproic Acid/pharmacokinetics , Animals , Area Under Curve , Brain Chemistry , Drug Evaluation, Preclinical , Food-Drug Interactions , Glucuronosyltransferase/blood , Isoenzymes/blood , Male , Plant Extracts/chemistry , Rats , Rats, Sprague-Dawley , Valproic Acid/blood , gamma-Aminobutyric Acid/metabolism
9.
J Pharm Biomed Anal ; 89: 197-202, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24291111

ABSTRACT

IC87114 is a selective PI3Kδ inhibitor. A simple, sensitive and reliable LC-MS/MS method with rapid sample preparation was developed and validated for the determination of IC87114 in mouse plasma, bronchoalveolar lavage, and lung. Chromatographic separation was achieved using an Agilent Zorbax Eclipse XDB-C18 column (150mm×2.1mm internal diameter, 3.5µm particle size). Mass spectrometric detection was conducted by electrospray ionization in positive ion multiple reaction monitoring modes. The calibration curve was linear over a concentration range of 0.01-1000ng/mL for plasma/BAL and 0.1-250ng/mL for lung tissue. Recoveries were as high as 97.29%, 102.81% and 89.70% for plasma, BAL fluid and lung sample, respectively. The lower limit of quantification was 0.01ng/mL. Intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all concentrations. Finally, the method was successfully used in a pharmacokinetic study that measured IC87114 in mouse plasma, BAL fluid and lung tissue after administration of a single 1mg/kg intratracheal dose of IC87114. The percentage change for incurred sample reanalysis (ISR) was within ±15.0% and met the acceptance criteria for ISR.


Subject(s)
Adenine/analogs & derivatives , Chromatography, Liquid/methods , Lung/metabolism , Quinazolines/pharmacokinetics , Tandem Mass Spectrometry/methods , Adenine/biosynthesis , Adenine/metabolism , Adenine/pharmacokinetics , Animals , Bronchoalveolar Lavage/methods , Mice , Mice, Inbred C57BL , Quinazolines/metabolism
10.
Sci Rep ; 3: 3398, 2013 Dec 02.
Article in English | MEDLINE | ID: mdl-24292328

ABSTRACT

The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1⁻/⁻ mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1⁺/⁺ mice. BI-1⁻/⁻ mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1⁺/⁺ mice. To examine the involvement of BI-1 in the Ca²âº-sensitive MAO activity, thapsigargin-induced Ca²âº release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca²âº release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca²âº-associated MAO-A regulation.


Subject(s)
Endoplasmic Reticulum Stress/drug effects , Membrane Proteins/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Animals , Calcium/metabolism , Cell Line , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Female , Hippocampus/drug effects , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Reactive Oxygen Species/metabolism , Thapsigargin/pharmacology
11.
Int J Mol Sci ; 14(1): 434-56, 2012 Dec 24.
Article in English | MEDLINE | ID: mdl-23263672

ABSTRACT

The endoplasmic reticulum (ER) is the major site of calcium storage and protein folding. It has a unique oxidizing-folding environment due to the predominant disulfide bond formation during the process of protein folding. Alterations in the oxidative environment of the ER and also intra-ER Ca2+ cause the production of ER stress-induced reactive oxygen species (ROS). Protein disulfide isomerases, endoplasmic reticulum oxidoreductin-1, reduced glutathione and mitochondrial electron transport chain proteins also play crucial roles in ER stress-induced production of ROS. In this article, we discuss ER stress-associated ROS and related diseases, and the current understanding of the signaling transduction involved in ER stress.


Subject(s)
Disease , Endoplasmic Reticulum Stress , Animals , Humans , Models, Biological , Reactive Oxygen Species/metabolism , Unfolded Protein Response
12.
Biol Pharm Bull ; 35(11): 1907-13, 2012.
Article in English | MEDLINE | ID: mdl-23123463

ABSTRACT

Hyperlipidemia is a major contributor for atherosclerosis and hypolipidemic drugs such as statin are highly prescribed to treat elevated lipid level in plasma. Rubus coreanus, which is widely cultivated in south eastern Asia, have been reported to show significant cholesterol lowering action in hyperlipidemic subjects. Our objective was to determine the cellular effect of Rubus coreanus extract (RCE) on cholesterol biosynthesis in human hepatic cells (HepG2) and to elucidate the molecular mechanism by which it causes change in cholesterol metabolism. RCE treatment lowered cholesterol biosynthesis as well as secretion from HepG2 cells. This effect was associated with lowering the release of apolipoproteins from hepatic cells. RCE treatment also showed an increase in phosphorylation of foxhead box protein 01 (FoXo-1) and 5-adenosine monophosphate-activated protein kinase (AMPK), thus lowering expression of phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase, which might be a major pathway for cholesterol biosynthesis inhibition. Apart from this; RCE also lowered sterol regulatory element-binding protein-1 (SREBP-1) expression in HepG2 cells, showing a long term regulation of cholesterol biosynthesis activity. These results indicate that one of the anti-hyperlipidemic actions of RCE is due to inhibition of cholesterol biosynthesis in hepatic cells and provides first documentation of a hypolipidemic bio-molecular action of Rubus coreanus.


Subject(s)
Cholesterol/metabolism , Fatty Acids/metabolism , Hypolipidemic Agents/pharmacology , Plant Extracts/pharmacology , Rosaceae , AMP-Activated Protein Kinases/metabolism , Apolipoprotein A-I/metabolism , Apolipoproteins B/metabolism , Forkhead Box Protein O1 , Forkhead Transcription Factors/metabolism , Glucose-6-Phosphatase/metabolism , Hep G2 Cells , Humans , Hypolipidemic Agents/analysis , Liver/cytology , Liver/metabolism , Plant Extracts/analysis , Protein Serine-Threonine Kinases/metabolism , Solvents/chemistry , Sterol Regulatory Element Binding Protein 1/metabolism , Water/chemistry
13.
J Bioenerg Biomembr ; 44(6): 623-7, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22914881

ABSTRACT

Mitochondria, also known as "Power House of cell," are crucial organelles, regulating energy metabolism. Recently, an involvement of mitochondria in cancer occurrence and metastasis has been proposed. The roles of mitochondria in cancer progression/metastasis include alteration of glycolysis, regulation of ROS and suppression of intrinsic apoptosis. This mini-review explains the specific mitochondrial characteristics during cancer metastasis with past and recent findings. It may contribute to understanding mitochondria-related mechanisms of cancer metastasis.


Subject(s)
Apoptosis , Energy Metabolism , Mitochondria/metabolism , Neoplasms/metabolism , Reactive Oxygen Species/metabolism , Animals , Humans , Mitochondria/pathology , Neoplasm Metastasis , Neoplasms/pathology
14.
Article in English | MEDLINE | ID: mdl-22841743

ABSTRACT

Endoplasmic reticulum (ER) stress is associated with various human diseases. Phenylbutyric acid (PBA) is a well-known chemical chaperone that regulates ER stress. The main objective of this study was to develop a simple, rapid, and sensitive method for the simultaneous determination of phenylbutyric acid and its metabolite, phenylacetic acid (PAA). A LC-MS/MS analysis using negative electrospray ionization was used. Samples were analyzed by multiple reaction monitoring (MRM) in 15 min of total run time, using d11-PBA and d7-PAA as internal standards. The limit of quantification was 1 µg/g for tissue and 0.8 µg/mL for plasma. Recoveries for plasma and tissues were higher than 81% for both PBA and PAA. The inter-day and intra-day accuracy and precision were within ±15%. We then further successfully validated this method by applying it to determine the tissue distribution of PBA and its metabolite PAA after i.p. injection of PBA at a dose of 500 mg/kg in mice. The maximum concentrations of PBA and PAA in plasma and tissues were seen at 15 min and 45 min, respectively. The PBA plasma concentration was 15-fold higher than the concentration in the kidney, whereas the PAA plasma concentration was 6-fold higher than the concentration in the liver. The area under the curve decreased in the order of plasma > kidney > liver > heart > muscle > lung for PBA and plasma > liver > kidney > heart > muscle > lung for PAA. The tissue to plasma ratio ranged from 0.007 to 0.063 for PBA and 0.016 to 0.109 for PAA. In summary, the LC-ESI-MS method developed in this study is simple, sensitive and reliable.


Subject(s)
Chromatography, Liquid/methods , Phenylacetates/analysis , Phenylbutyrates/analysis , Tandem Mass Spectrometry/methods , Animals , Kidney/chemistry , Kidney/metabolism , Least-Squares Analysis , Liver/chemistry , Liver/metabolism , Mice , Phenylacetates/blood , Phenylacetates/pharmacokinetics , Phenylbutyrates/blood , Phenylbutyrates/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Tissue Distribution
15.
BMC Complement Altern Med ; 11: 120, 2011 Nov 28.
Article in English | MEDLINE | ID: mdl-22118263

ABSTRACT

BACKGROUND: Salvia miltiorrhiza (SM) has long been used as a traditional oriental medicine for cardiovascular disease. Accumulating evidence also indicates that SM has anti-osteoporotic effects. This study was conducted to examine the SM-induced anti-osteoporotic effect and its possible mechanisms with various doses of SM. METHODS: We studied Sprague-Dawley female rats aged 12 weeks, divided into six groups: sham-operated control (SHAM), OVX rats supplemented with SM (1, 3, 10 and 30 mg/kg) orally for 8 weeks. At the end of the experiment, blood samples were collected and biochemistry analysis was performed. Specimens from both tibia and liver were processed for light microscopic examination. DEXA and µ-CT analyses of the tibia were also performed. RESULTS: SM treatment significantly ameliorated the decrease in BMD and trabecular bone mass according to DEXA and trabecular bone architecture analysis of trabecular bone structural parameters by µ-CT scanning. In serum biochemical analysis, SM decreased the released TRAP-5b, an osteoclast activation marker and oxidative stress parameters including MDA and NO induced by OVX. CONCLUSIONS: The preventive effect of SM was presumably due to its anti-oxidative stress partly via modulation of osteoclast maturation and number. In current study, SM appears to be a promising osteoporosis therapeutic natural product.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Density/drug effects , Osteoporosis, Postmenopausal/drug therapy , Oxidative Stress/drug effects , Phytotherapy , Plant Extracts/therapeutic use , Salvia miltiorrhiza , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Bone Density Conservation Agents/pharmacology , Female , Humans , Malondialdehyde/blood , Nitric Oxide/blood , Osteoclasts/drug effects , Osteoporosis, Postmenopausal/diagnostic imaging , Osteoporosis, Postmenopausal/prevention & control , Ovariectomy , Plant Extracts/pharmacology , Radiography , Rats , Rats, Sprague-Dawley , Tibia/anatomy & histology , Tibia/drug effects , Tibia/metabolism
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