Lipid-altering efficacy and safety of ezetimibe/simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study)

DEFF Research Database (Denmark)

Robinson, Jennifer G; Ballantyne, Christie M; Grundy, Scott M

2009-01-01

the lipid-lowering efficacy of ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 or 20 mg, and ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg in 1,128 patients with hypercholesterolemia and the metabolic syndrome. The primary end point was the percentage of change from baseline in low......, apolipoprotein B, and lipid/lipoprotein ratios resulted with ezetimibe/simvastatin compared with atorvastatin at all specified dose comparisons (p .../simvastatin than with atorvastatin at all dose comparisons (p atorvastatin 10 mg (p atorvastatin 40 mg (p

COMPARATIVE EFFICACY AND SAFETY OF HYPOLIPIDEMIC THERAPY WITH GENERIC AND ORIGINAL MEDICINAL PRODUCTS OF SIMVASTATIN

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E. I. Tarlovskaya

2011-01-01

Full Text Available Aim. To compare efficacy , safety and pharmacoeconomical characteristics of generic and original medicinal products of simvastatin in achievement of cholesterol and low density lipoprotein target levels. Material and methods. 38 patients with arterial hypertension accompanied by type 2 diabetes with dyslipidemia were included into the study. They had no clinically obvious ischemic heart disease and did not receive hypolipidemic pharmacotherapy for a month before the study start. The patients were randomized into group A or group B. Patients of group A (n=18 received original simvastatin, patients of group B (n=20 received generic simvastatin. Initial simvastatin dose was 20 mg daily. Lipid plasma profile, liver enzymes, creatine phosphokinase were evaluated every 4 weeks. Cost-effectiveness ratio was calculated. Results. 11 patients (61% in group A and only 5 patients (25% in group B (χ2=5.05; р<0.05 achieved cholesterol target level with simvastatin in dose of 20 mg daily in 3 months of the treatment. Creatine phosphokinase blood level did not increase significantly. Achievement of cholesterol target level cost 814 and 952 RUB per patient in groups A and B, respectively , in 1 month of simvastatin treatment. These costs were 643 and 417 RUB per patient in groups A and B, respectively , in 3 months of treatment. Conclusion. The original simvastatin in comparison with generic one has advantages in hypolipidemic effect. Safety profile is similar for both medications. Original simvastatin therapy has lower cost than this for generic simvastatin therapy in achievement of cholesterol target level in 1 month of treatment. In 3 months the cost of treatment per patient is 227 RUB higher for original medication in comparison with this for generic medication.

Simvastatin Treatment Improves Survival in a Murine Model of Burn Sepsis

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Beffa, David C; Fischman, Alan J.; Fagan, Shawn P.; Hamrahi, Victoria F.; Kaneki, Masao; Yu, Yong-Ming; Tompkins, Ronald G.; Carter, Edward A.

2014-01-01

Infection is the most common and most serious complication of a major burn injury related to burn size. Despite improvements in antimicrobial therapies sepsis still accounts for 50–60% of deaths in burn patients. Given the acute onset and unpredictable nature of sepsis, primary prevention was rarely attempted in its management. However, recent studies have demonstrated that statin treatment can decrease mortality is a murine model of sepsis by preservation of cardiac function and reversal of inflammatory alterations. In addition, it has been shown that treatment with statins is associated with reduced incidence of sepsis in human patients. In the current study groups of CD1 male mice (n=12) were anesthetized and subjected to a dorsal 30% TBSA scald burn injury. Starting 2 hours post burn, the animals were divided into a treatment group receiving 0.2 µ/g simvastatin or a sham group receiving placebo. Simvastatin and placebo were administered by intraperitoneal injection with two dosing regimens; once daily and every 12 hours. On Post burn day 7 cecal ligation and puncture with a 21-gauge needle was performed under ketamine/xylazine anesthesia and the two different dosing schedules were continued. A simvastatin dose dependant improvement in survival was observed in the burn sepsis model. PMID:21145172

Compound list: simvastatin [Open TG-GATEs

Lifescience Database Archive (English)

Full Text Available simvastatin SST 00117 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/...in_vitro/simvastatin.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_...vitro/simvastatin.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/...Liver/Single/simvastatin.Rat.in_vivo.Liver.Single.zip ftp://ftp.biosciencedbc.jp/

Simvastatin inhibits Candida albicans biofilm in vitro.

Science.gov (United States)

Liu, Geoffrey; Vellucci, Vincent F; Kyc, Stephanie; Hostetter, Margaret K

2009-12-01

By inhibiting the conversion of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate, statins impair cholesterol metabolism in humans. We reasoned that statins might similarly interfere with the biosynthesis of ergosterol, the major sterol of the yeast cell membrane. As assessed by spectrophotometric and microscopic analysis, significant inhibition of biofilm production was noted after 16-h incubation with 1, 2.5, and 5 muM simvastatin, concentrations that did not affect growth, adhesion, or hyphal formation by C. albicans in vitro. Higher concentrations (10, 20, and 25 muM simvastatin) inhibited biofilm by >90% but also impaired growth. Addition of exogenous ergosterol (90 muM) overcame the effects of 1 and 2.5 muM simvastatin, suggesting that at least one mechanism of inhibition is interference with ergosterol biosynthesis. Clinical isolates from blood, skin, and mucosal surfaces produced biofilms; biofilms from bloodstream isolates were similarly inhibited by simvastatin. In the absence of fungicidal activity, simvastatin's interruption of a critical step in an essential metabolic pathway, highly conserved from yeast to man, has unexpected effects on biofilm production by a eukaryotic pathogen.

Pomegranate juice does not affect the disposition of simvastatin in healthy subjects.

Science.gov (United States)

Park, Soo-Jin; Yeo, Chang-Woo; Shim, Eon-Jeong; Kim, Hyunmi; Liu, Kwang-Hyeon; Shin, Jae-Gook; Shon, Ji-Hong

2016-08-01

Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity.

In vitro synergism of simvastatin and fluconazole against Candida species

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Everardo Albuquerque Menezes

2012-08-01

Full Text Available Systemic fungal infections are responsible for high mortality rates. Several species of fungi may be involved, but Candida spp. is the most prevalent. Simvastatin is used to lower cholesterol and also exhibits antifungal action. The aim of this study was to evaluate the synergistic action of simvastatin with fluconazole against strains of Candida spp. Susceptibility testing was performed according to protocol M27-A3, by broth microdilution method and the synergistic effect of simvastatin and fluconazole was calculated based on FICI (Fractional Inhibitory Concentration Index. Eleven strains were evaluated, and simvastatin showed a synergistic effect with fluconazole against 10 (91% of the Candida spp. strains tested. Simvastatin may be a valuable drug in the treatment of systemic infections caused by Candida spp.

Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells

International Nuclear Information System (INIS)

Kim, Yong Chan; Song, Seok Bean; Lee, Mi Hee; Kang, Kwang Il; Lee, Hayyoung; Paik, Sang-Gi; Kim, Kyoon Eon; Kim, Young Sang

2006-01-01

Macrophages participate in several inflammatory pathologies such as sepsis and arthritis. We examined the effect of simvastatin on the LPS-induced proinflammatory macrophage RAW264.7 cells. Co-treatment of LPS and a non-toxic dose of simvastatin induced cell death in RAW264.7 cells. The cell death was accompanied by disruption of mitochondrial membrane potential (MMP), genomic DNA fragmentation, and caspase-3 activation. Surprisingly, despite caspase-dependent apoptotic cascade being completely blocked by Z-VAD-fmk, a pan-caspase inhibitor, the cell death was only partially repressed. In the presence of Z-VAD-fmk, DNA fragmentation was blocked, but DNA condensation, disruption of MMP, and nuclear translocation of apoptosis inducing factor were obvious. The cell death by simvastatin and LPS was effectively decreased by both the FPP and GGPP treatments as well as mevalonate. Our findings indicate that simvastatin triggers the cell death of LPS-treated RAW264.7 cells through both caspase-dependent and -independent apoptotic pathways, suggesting a novel mechanism of statins for the severe inflammatory disease therapy

Pleiotropic effects of simvastatin in physically trained ovariectomized rats

International Nuclear Information System (INIS)

Bernardes, N.; Brito, J.O.; Fernandes, T.G.; Llesuy, S.F.; Irigoyen, M.C.; Belló-Klein, A.; De Angelis, K.

2013-01-01

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats

Pleiotropic effects of simvastatin in physically trained ovariectomized rats

Energy Technology Data Exchange (ETDEWEB)

Bernardes, N. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil); Unidade de Hipertensão, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Brito, J.O. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil); Fernandes, T.G. [Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universdade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Llesuy, S.F. [University of Buenos Aires, Buenos Aires (Argentina); Irigoyen, M.C. [Unidade de Hipertensão, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Belló-Klein, A. [Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universdade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); De Angelis, K. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil)

2013-05-24

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats.

Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway.

Science.gov (United States)

Chen, Ya-Juan; Chen, Peng; Wang, Hai-Xia; Wang, Tao; Chen, Lei; Wang, Xun; Sun, Bei-Bei; Liu, Dai-Shun; Xu, Dan; An, Jing; Wen, Fu-Qiang

2010-06-01

Airway mucus overproduction is a cardinal feature of airway inflammatory diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. Since the small G-protein Ras is known to modulate cellular functions in the lung, we sought to investigate whether the Ras inhibitor simvastatin could attenuate acrolein-induced mucin production in rat airways. Rats were exposed to acrolein for 12 days, after first being pretreated intragastrically for 24 h with either simvastatin alone or simvastatin in combination with mevalonate, which prevents the isoprenylation needed for Ras activation. Lung tissue was analyzed for extracellular signal-regulated kinase (ERK) activity, goblet cell metaplasia and mucin production. To analyze the effect of simvastatin on mucin production in more detail, acrolein-exposed human airway epithelial NCI-H292 cells were pretreated with simvastatin alone or together with mevalonate. Culture medium was collected to detect mucin secretion, and cell lysates were examined for Ras-GTPase activity and epidermal growth factor receptor (EGFR)/ERK phosphorylation. In vivo, simvastatin treatment dose-dependently suppressed acrolein-induced goblet cell hyperplasia and metaplasia in bronchial epithelium and inhibited ERK phosphorylation in rat lung homogenates. Moreover, simvastatin inhibited Muc5AC mucin synthesis at both the mRNA and protein levels in the lung. In vitro, simvastatin pretreatment attenuated the acrolein-induced significant increase in MUC5AC mucin expression, Ras-GTPase activity and EGFR/ERK phosphorylation. These inhibitory effects of simvastatin were neutralized by mevalonate administration both in vitro and in vivo. Our results suggest that simvastatin may attenuate acrolein-induced mucin protein synthesis in the airway and airway inflammation, possibly by blocking ERK activation mediated by Ras protein isoprenylation. Thus, the evidence from the experiment suggests that human trials are warranted to determine the potential

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice.

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Panos Ziros

Full Text Available Fibroblast growth factor 21 (Fgf21 is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole

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Patel C

2011-06-01

Full Text Available Chirag G Patel, Li Li, Suzette Girgis, David M Kornhauser, Ernest U Frevert, David W BoultonBristol-Myers Squibb, Princeton, NJ, USABackground: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin, antihypertensives (eg, diltiazem, nifedipine, verapamil, and antifungals (eg, ketoconazole are metabolized by and/or inhibit the cytochrome P450 (CYP 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.Objective: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate, diltiazem (moderate inhibitor, and ketoconazole (strong inhibitor on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.Methods: Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.Results: Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.Conclusion: Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically

Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

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Lenarczyk, Marek; Su, Jidong; Haworth, Steven T; Komorowski, Richard; Fish, Brian L; Migrino, Raymond Q; Harmann, Leanne; Hopewell, John W; Kronenberg, Amy; Patel, Shailendra; Moulder, John E; Baker, John E

2015-06-01

The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

Analysis of Simvastatin using a Simple and Fast High Performance ...

African Journals Online (AJOL)

performance liquid chromatography (RP-HPLC) analytical method for the lipid lowering drug, simvastatin, and to apply the developed method to study the solubility of the drug in various ..... Takano T, Abe S, Hata S. A selected ion monitoring.

Analysis of Simvastatin using a Simple and Fast High Performance ...

African Journals Online (AJOL)

simvastatin, and to apply the developed method to study the solubility of the ... samples. Results: The developed HPLC method showed good linearity (R2 = 0.9958 ± 0.0040. ... EXPERIMENTAL ... from the true value served as the measure of.

Effect of Simvastatin, Coenzyme Q10, Resveratrol, Acetylcysteine and Acetylcarnitine on Mitochondrial Respiration.

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Fišar, Z; Hroudová, J; Singh, N; Kopřivová, A; Macečková, D

2016-01-01

Some therapeutic and/or adverse effects of drugs may be related to their effects on mitochondrial function. The effects of simvastatin, resveratrol, coenzyme Q10, acetylcysteine, and acetylcarnitine on Complex I-, Complex II-, or Complex IV-linked respiratory rate were determined in isolated brain mitochondria. The protective effects of these biologically active compounds on the calcium-induced decrease of the respiratory rate were also studied. We observed a significant inhibitory effect of simvastatin on mitochondrial respiration (IC50 = 24.0 μM for Complex I-linked respiration, IC50 = 31.3 μM for Complex II-linked respiration, and IC50 = 42.9 μM for Complex IV-linked respiration); the inhibitory effect of resveratrol was found at very high concentrations (IC50 = 162 μM for Complex I-linked respiration, IC50 = 564 μM for Complex II-linked respiration, and IC50 = 1454 μM for Complex IV-linked respiration). Concentrations required for effective simvastatin- or resveratrol-induced inhibition of mitochondrial respiration were found much higher than concentrations achieved under standard dosing of these drugs. Acetylcysteine and acetylcarnitine did not affect the oxygen consumption rate of mitochondria. Coenzyme Q10 induced an increase of Complex I-linked respiration. The increase of free calcium ions induced partial inhibition of the Complex I+II-linked mitochondrial respiration, and all tested drugs counteracted this inhibition. None of the tested drugs showed mitochondrial toxicity (characterized by respiratory rate inhibition) at drug concentrations achieved at therapeutic drug intake. Resveratrol, simvastatin, and acetylcarnitine had the greatest neuroprotective potential (characterized by protective effects against calcium-induced reduction of the respiratory rate).

Pharmacokinetic and bioavailability studies of commercially available simvastatin tablets in healthy and moderately hyperlipidaemic human subjects

International Nuclear Information System (INIS)

Ahmed, M.; Qamar-uz-Zaman, M.; Madni, A.; Usman, M.; Atif, M.; Akhtar, N.; Murtaza, G.

2011-01-01

Simvastatin, an analogue of Lovostatin, is a HMG.CoA reductase inhibitor. It is widely used in the treatment of hyperlipidaemia and coronary heart disease (CHD) with low incidence of myopathy and rhabdomyolysis. As these diseases may alter the pharmacokinetics of drugs, the present study was aimed to elaborate the variation in the pharmacokinetics and bioavailability of simvastatin in local healthy and moderately hyperlipidaemic population. Open, single dose and parallel design was applied to study. A total of 36 male volunteers were used for healthy and moderately hyperlipidaemic groups (n 18 for each) in this study on the basis of screening procedures, body chemistry and physical examination. Simvastatin 40 mg tablets (Saista 40, Bosch, Pakistan) were administered to over-night fasted volunteers. Blood samples were collected before dosing (zero time) and at regular intervals of time. The plasma samples were processed through a liquid-liquid extraction procedure and assayed by using HPLC consisting reversed phase C/sub 18/ column (ZORBAX, 4.6 x 150 mm, 5 mu m), UV detector set at 238 nm. The mobile phase consisted of the mixture of 0.025 M sodium dihydrogen phosphate (pH 4.5): acetonitrile (35: 65, v/v) which was pumped at a flow rate of 1.5 mL.min/sup -1/. The retention time of simvastatin was 7.5 minutes. The plasma drug concentration-time profiles of both groups were found significantly (P 0.05) difference between the values of following pharmacokinetic parameters in healthy and hyperlipidaemic volunteers i.e. C/sub max/, t/sub max/, AUC/sub 0-fi), AUMC/sub 0-enfinity), MRT, t/sub 1/2/, Cl/sub t /and K/sub e/. This study confirmed no significant (P > 0.05) difference in pharmacokinetics and bioavailability parameters after the administration of a single oral dose of 40 mg simvastatin (cholesterol lowering drug) to healthy and moderately hyperlipidaemic volunteers. (author)

Two-year efficacy and safety of Simvastatin 80 mg in familial hypercholesterolemia (The examination of probands and relatives in statin studies with familial hypercholesterolemia [ExPRESS FH])

NARCIS (Netherlands)

de Sauvage Nolting, Pernette R. W.; Buirma, Rudolf J. A.; Hutten, Barbara A.; Kastelein, John J. P.

2002-01-01

High-dose (80 mg) simvastatin is efficacious in both reducing low-density lipoprotein cholesterol (-48%) and triglyceride (-26%) levels and in elevating high-density lipoprotein cholesterol (+ 13%) levels in a large cohort of patients with familial hypercholesterolemia. No tachyphylaxis was seen

Effect of Simvastatin Prodrug on Experimental Periodontitis.

Science.gov (United States)

Bradley, Aaron D; Zhang, Yijia; Jia, Zhenshan; Zhao, Gang; Wang, Xiaobei; Pranke, Laura; Schmid, Marian J; Wang, Dong; Reinhardt, Richard A

2016-05-01

Local application of statins has shown potential in preventing and regenerating bone loss associated with experimental periodontitis. This study evaluates the effect of a novel simvastatin (SIM) prodrug (capable of delivering high doses to periodontitis inflammatory lesion and cells) on experimental periodontitis bone loss and inflammation. Forty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis between maxillary first and second molars (M1-M2). Equal groups were treated with three weekly doses of: 1) prodrug carrier alone (mPEG); 2) 0.5 mg SIM dose equivalent in carrier (SIM/SIM-mPEG); 3) 1.0 mg SIM/SIM-mPEG; 4) 1.5 mg SIM/SIM-mPEG; or 5) ligature alone. Contralateral molars served as unmanipulated controls. Four weeks after initiation of periodontitis, animals were euthanized, the M1-M2 interproximal was evaluated with microcomputed tomography and histology, and data were analyzed with one-way analysis of variance. Ligature alone caused a mean bone loss of 1.01 ± 0.06 mm from the cemento-enamel junction, whereas all doses of SIM/SIM-mPEG reduced bone loss, especially 1.5 mg SIM/SIM-mPEG (0.68 ± 0.05 mm, P periodontitis bone loss and inflammation in rats.

Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events

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Gandhi SK

2012-01-01

% of simulations relative to atorvastatin or simvastatin 40 mg. Sensitivity analyses indicated the findings to be robust.Conclusion: Rosuvastatin 20 mg is cost-effective over a lifetime horizon compared with generic simvastatin or atorvastatin 40 mg in patients at high cardiovascular risk in Sweden.Keywords: cardiovascular disease, cost-benefit analysis, cost-effectiveness, rosuvastatin, simvastatin, atorvastatin, generic, high risk

Is it Simvastatin harmful in children? A case report

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Mara Pisani

2014-09-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common liver disease in children living in Western countries. Hyperlipidemia, obesity and insulin resistance are common components of the metabolic syndrome, which is frequently associated with NAFLD. Since patients with NAFLD are at high risk to develop cardiovascular disease (CVD, statins are frequently prescribed to patients with NAFLD and hyperlipidemia. The 3-Hydroxy-3-methyl-coenzyme A reductase (HMG-CoA reductase is the rate limiting enzyme in cholesterol biosynthesis. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Under treatment with simvastatin, an improvement of enzymatic antioxidant parameters has been described in subjects with hypercholesterolemia. The safety and effectivity of statins in pediatric patients with NAFLD or non-alcoholic steatohepatitis (NASH, and their effect on hepatic fat infiltration or the extent of hepatic fibrosis are not known. Also, no evidences of the effects of a non therapeutic ingestion of this drug on the glutathione homeostasis and in children have been reported. We describe the case of a obese 4-year-old girl in whom an accidental overdose of simvastatin led to decrease levels of glutathione in blood with increase of the GSSG/GSH ratio. No adverse reactions were registered. All laboratory test were normal during the follow up. Only a 35% decrease of Glutathione was observed  such as a possible mechanism of mithocondrial toxicity and depletion of the glutathione pool after the intake of excessive dose of HMG-CoA reductase inhibitors.  Further  RCTs are needed in order to establish the safety and efficacy to use of statin for pediatric NAFLD or NASH.

Effects of simvastatin on CAT-1-mediated arginine transport and NO level under high glucose conditions in conditionally immortalized rat inner blood-retinal barrier cell lines (TR-iBRB).

Science.gov (United States)

Tun, Temdara; Kang, Young-Sook

2017-05-01

Hyperglycemia causes the breakdown of the blood-retinal barrier by impairing endothelial nitric oxide synthase (eNOS) function. Statins have many pleiotropic effects such as improving endothelial barrier permeability and increasing eNOS mRNA stability. The objective of this study was to determine effect of simvastatin on l-arginine transport and NO production under high-glucose conditions in conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB). Changes in l-arginine transport uptake and, expression levels of cationic amino acid transporter 1 (CAT-1) and eNOS mRNA were investigated after pre-treatment with simvastatin and NOS inhibitors (l-NMMA and l-NAME) under high-glucose conditions using TR-iBRB, an in vitro model of iBRB. The NO level released from TR-iBRB cells was examined using Griess reagents. Under high glucose conditions, [ 3 H]l-arginine uptake was decreased in TR-iBRB cells. Simvastatin pretreatment elevated [ 3 H]l-arginine uptake, the expression levels of CAT-1 and eNOS mRNA, and NO production under high-glucose conditions. Moreover, the co-treatment with simvastatin and NOS inhibitors reduced [ 3 H]l-arginine uptake compared to pretreatment with simvastatin alone. Our results suggest that, in the presence of high-glucose levels, increased l-arginine uptake due to simvastatin treatment was associated with increased CAT-1 and eNOS mRNA levels, leading to higher NO production in TR-iBRB cells. Thus, simvastatin might be a good modulator for diabetic retinopathy therapy by increasing of the l-arginine uptake and improving endothelial function in retinal capillary endothelial cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Bacteriostatic effect of simvastatin on selected oral streptococci in vitro

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Eugene J Whitaker

2017-01-01

Full Text Available Context and Objective: Simvastatin is a widely used cholesterol-lowering drug, which has been found to have a number of pleiotropic effects. The aim of this study was to evaluate the antimicrobial effectiveness of simvastatin against selected oral streptococci as determined by the minimum inhibitory concentration (MIC. Methods: Streptococcus mutans, Streptococcus sanguis, Streptococcus anginosus, and Streptococcus salivarius were the test microorganisms. The serial dilution method was used to determine the MIC of simvastatin against these organisms. The MIC was defined as the lowest concentration of simvastatin that completely inhibited growth of the test organisms. Results: The data indicate that simvastatin inhibits the growth of the test organisms, with MIC's ranging from 7.8 to 15.6 μg/ml. Conclusions: Simvastatin has MIC's against the selected bacteria that compare favorably with reported values for topical agents such as essential oil, chlorhexidine gluconate, and triclosan. The levels of simvastatin required to inhibit bacterial growth of oral bacteria exceed the reported levels of the drug found in plasma or crevicular fluid of patients who are treated with this cholesterol-lowering drug. However, clinical studies are warranted to investigate the potential use of simvastatin as a novel antiplaque agent that could be used in local drug delivery to the oral cavity of those patients who are prescribed this cholesterol-lowering drug.

Preparation of Simvastatin Hydrogel through Arginine Addition for Drug Delivery System

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Rosyida Niswati Fathmah

2018-01-01

Full Text Available Simvastatin is a lipid lowering agent which has been used recently as drug delivery system for stimulating bone regeneration. Because of low therapeutic efficacy and bioavailability, it is necessary to deliver simvastatin by local administration e.g. by hydrogel system. However, simvastatin has very poor solubility which restricts to prepare hydrogel formulation. The aim of this study is to improve solubility of simvastatin with arginine as co-solvent for developing a controlled released drug delivery system by loading simvastatin into gelatin hydrogel. The solubility study was performed by addition of an excess mass of simvastatin into the specified molar solutions of the arginine. All conical flasks were placed in a mechanical water bath shaker at the temperature of 25, 40, and 50 °C and shaken for a maximum period of 72 hours. The drug concentration was analyzed by UV/Visible spectroscopy at 238 nm. The hydrogel was prepared by a dehydrothermal method. The results showed that simvastatin solubility increases with increasing arginine concentrations and temperature. Characterizations showed a successful preparation of simvastatin-loaded gelatin hydrogel. The arginine simvastatin hydrogel and the gelatin hydrogel (as a blank exhibited a comparable swelling index (ca. 6.5. Furthermore, microparticles of the material show a narrow particle size distribution in the range between 150-250 μm.

Simvastatin enhances bone morphogenetic protein receptor type II expression

International Nuclear Information System (INIS)

Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N.

2006-01-01

Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function

Simvastatin-induced nocturnal leg pain disappears with pravastatin substitution

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Stojaković Nataša

2013-01-01

Full Text Available Introduction. Statins have similar side effects that do not always occur at the same rate among the various statins. We present a case of simvastatin-induced muscle toxicity that disappeared when pravastatin was substituted for the original drug. Case Outline. A 74-year-old male, a nonsmoker, complained of severe nocturnal leg cramps. The patient also complained that similar painful cramping occurred when he walked rapidly or jogged. Because some components of his lipid panel exceeded the ‘desirable’ range, and as he had a history of myocardial infarction, his family physician prescribed simvastatin (40 mg/day. The patient had taken this medication for the past eight years. The painful nocturnal episodes started two years ago and affected either one or the other leg. Four months ago we discontinued his simvastatin and prescribed pravastatin (80 mg/day. At a follow-up visit six weeks later, the patient reported that his leg pains at night and the pain experienced after brisk walking had disappeared. Four months after the substitution of pravastatin for simvastatin, the patient reported that his complete lack of symptoms had continued. Conclusion. These painful muscle cramps were probably caused by an inadequate vascular supply to the calf and foot muscles. Perhaps a combination of advanced age and atherosclerotic changes created a predisposition for the simvastatin-induced leg cramps. Pravastatin differs from simvastatin in several ways. It is not metabolized by cytochrome P450 (CYP 3A4 oxidases, and thus is not influenced by CYP 3A4 inhibitors like simvastatin. Also, simvastatin is associated with single-nucleotide polymorphisms located within the SLCO1B1 gene on the chromosome 12 and established myopathy, while pravastatin lacks this association. These differences may contribute to increased tolerance to pravastatin in this particular case.

Simvastatin-lnduced nocturnal leg pain disappears with pravastatin substitution.

Science.gov (United States)

Stojaković, Natasa; Igić, Rajko

2013-01-01

Statins have similar side effects that do not always occur at the same rate among the various statins. We present a case of simvastatin-induced muscle toxicity that disappeared when pravastatin was substituted for the original drug. A 74-year-old male, a nonsmoker, complained of severe nocturnal leg cramps. The patient also complained that similar painful cramping occurred when he walked rapidly or jogged. Because some components of his lipid panel exceeded the'desirable' range, and as he had a history of myocardial infarction, his family physician prescribed simvastatin (40 mg/day). The patient had taken this medication for the past eight years. The painful nocturnal episodes started two years ago and affected either one or the other leg. Four months ago we discontinued his simvastatin and prescribed pravastatin (80 mg/day). At a follow-up visit six weeks later, the patient reported that his leg pains at night and the pain experienced after brisk walking had disappeared. Four months after the substitution of pravastatin for simvastatin, the patient reported that his complete lack of symptoms had continued. These painful muscle cramps were probably caused by an inadequate vascular supply to the calf and foot muscles. Perhaps a combination of advanced age and atherosclerotic changes created a predisposition for the simvastatin-induced leg cramps. Pravastatin differs from simvastatin in several ways.l It is not metabolized by cytochrome P450 (CYP) 3A4 oxidases, and thus is not influenced by CYP 3A4 inhibitors like simvastatin. Also, simvastatin is associated with single-nucleotide polymorphisms located within the SLCO1B1 gene on the chromosome 12 and established myopathy, while pravastatin lacks this association. These differences may contribute to increased tolerance to pravastatin in this particular case.

Effect of Simvastatin on Arterial Stiffness in Patients with Statin Myalgia

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Kevin D. Ballard

2015-01-01

Full Text Available Statins reduce arterial stiffness but are also associated with mild muscle complaints. It is unclear whether individuals with muscle symptoms experience the same vascular benefit or whether statins affect striated and smooth muscle cells differently. We examined the effect of simvastatin treatment on arterial stiffness in patients who did versus those who did not exhibit muscle symptoms. Patients with a history of statin-related muscle complaints (n=115 completed an 8 wk randomized, double-blind, cross-over trial of daily simvastatin 20 mg and placebo. Serum lipids and pulse wave velocity (PWV were assessed before and after each treatment. Muscle symptoms with daily simvastatin treatment were reported by 38 patients (33%. Compared to baseline, central PWV decreased (P=0.01 following simvastatin treatment but not placebo (drug ∗ time interaction: P=0.047. Changes in central PWV with simvastatin treatment were not influenced by myalgia status or time on simvastatin (P≥0.15. Change in central PWV after simvastatin treatment was inversely correlated with age (r=-0.207, P=0.030, suggesting that advancing age is associated with enhanced statin-mediated arterial destiffening. In patients with a history of statin-related muscle complaints, the development of myalgia with short-term simvastatin treatment did not attenuate the improvement in arterial stiffness.

Simvastatin Exposure and Rotator Cuff Repair in a Rat Model.

Science.gov (United States)

Deren, Matthew E; Ehteshami, John R; Dines, Joshua S; Drakos, Mark C; Behrens, Steve B; Doty, Stephen; Coleman, Struan H

2017-03-01

Simvastatin is a common medication prescribed for hypercholesterolemia that accelerates local bone formation. It is unclear whether simvastatin can accelerate healing at the tendon-bone interface after rotator cuff repair. This study was conducted to investigate whether local and systemic administration of simvastatin increased tendon-bone healing of the rotator cuff as detected by maximum load to failure in a controlled animal-based model. Supraspinatus tendon repair was performed on 120 Sprague-Dawley rats. Sixty rats had a polylactic acid membrane overlying the repair site. Of these, 30 contained simvastatin and 30 did not contain medication. Sixty rats underwent repair without a polylactic acid membrane. Of these, 30 received oral simvastatin (25 mg/kg/d) and 30 received a regular diet. At 4 weeks, 5 rats from each group were killed for histologic analysis. At 8 weeks, 5 rats from each group were killed for histologic analysis and the remaining 20 rats were killed for biomechanical analysis. One rat that received oral simvastatin died of muscle necrosis. Average maximum load to failure was 35.2±6.2 N for those receiving oral simvastatin, 36.8±9.0 N for oral control subjects, 39.5±12.8 N for those receiving local simvastatin, and 39.1±9.3 N for control subjects with a polylactic acid membrane. No statistically significant differences were found between any of the 4 groups (P>.05). Qualitative histologic findings showed that all groups showed increased collagen formation and organization at 8 weeks compared with 4 weeks, with no differences between the 4 groups at each time point. The use of systemic and local simvastatin offered no benefit over control groups. [Orthopedics. 2017; 40(2):e288-e292.]. Copyright 2016, SLACK Incorporated.

Quality Enhancement by Inclusion Complex Formation of Simvastatin Tablets

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Emőke Rédai

2013-08-01

Full Text Available Introduction: Simvastatin is an inhibitor of hydroxy-methyl-glutaryl-coenzyme A reductase, used in the treatment of hypercholesterolemia. To enhance its bioavailability by inclusion complexation, as host molecule randommethyl-β-cyclodextrin had been used. After evaluating the complexes we chose the kneading product in 1:2 molar ratio for incorporation of 10 mg simvastatin tablets. Materials and methods: We prepared homogenous mixtures of the inclusion complex and some excipients. The tablets were prepared by direct compression. The tablets were evaluated in regard to: weight uniformity, thickness, diameter, hardness, friability, disintegration and dissolution profile. Results: Weights are in the range of 196-208 mg, diameter 6.83-6.86 mm, height 3.86-4.01 mm, hardness 78.3-113.1 N, friability 0.75- 1.19 %, disintegration above 15 minutes. The dissolved amounts of simvastatin from the tablets are higher compared to the dissolution of pure simvastatin, but lower than the dissolution of the complex itself. Excipients, like disintegrants and lubricants greatly influence the dissolution properties of the tablets. Conclusions: According to our results, tablets containing inclusion complex of simvastatin exhibit better solubility, according to the dissolved amount of simvastatin, than pure drug alone. Proper physical parameters of the tablets are obtained by application of 5 % Primellose

Simvastatin and oxidative stress in humans

DEFF Research Database (Denmark)

Rasmussen, Sanne Tofte; Andersen, Jon Thor Trærup; Nielsen, Torben Kjær

2016-01-01

in mitochondrial respiratory complexes I and II and might thereby reduce the formation of reactive oxygen species, which have been implicated in the pathogenesis of arteriosclerosis. Therefore, we hypothesized that simvastatin may reduce oxidative stress in humans in vivo. We conducted a randomized, double......-blinded, placebo-controlled study in which subjects were treated with either 40 mg of simvastatin or placebo for 14 days. The endpoints were six biomarkers for oxidative stress, which represent intracellular oxidative stress to nucleic acids, lipid peroxidation and plasma antioxidants, that were measured in urine.......1% in the placebo group for DNA oxidation and 7.3% in the simvastatin group compared to 3.4% in the placebo group. The differences in biomarkers related to plasma were not statistically significant between the treatments groups, with the exception of total vitamin E levels, which, as expected, were reduced...

The influence of Simvastatin and Korargin on the clinical course of coronary heart disease, body weight and distribution of adipose tissue in patients with type 2 diabetes mellitus.

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E. A. Pogrebniak

2013-06-01

Full Text Available Diabetes mellitus (DM is one of the most influential risk factors for the development of cardiovascular diseases. Incidence of coronary heart diseases (CHD and acute myocardial infarction in diabetic patients is much higher than in people without diabetes. Type 2 DM affects other risk factors of CHD due to the fact that, as a rule, it is accompanied by obesity, hypertension, hypertriglyceridemia and decrease of high density lipoproteins. Purpose of the investigation – to improve the efficiency of treatment of patients with CHD with type 2 DM based on the effect of Simvastatin and Korargin on it’s clinical course, body weight and the distribution of adipose tissue. Materials and methods of the investigation. The study involved 175 patients with CHD aged from 34 to 87, mean age was 61,0 ± 8,0 years, among whom there were 96 (54,9% men and 79 (45,1% women. All surveyed received conventional treatment. Depending on supplementary prescriptions patients were divided into eight groups: 1 group - 22 patients with CHD who were prescribed Simvastatin, 2 group - 20 patients with CHD who were prescribed Korargin, 3 group - 20 patients with coronary artery disease who were prescribed simultaneously both Simvastatin and Korarhin, 4 group - 20 patients with CHD with type 2 diabetes treated with Simvastatin, 5 group - 23 patients with CHD with type 2 diabetes who took Korargin, 6 group - 27 patients with CHD with type 2 diabetes, who were prescribed both Simvastatin and Korargin in addition to conventional treatments, 7 group - 20 patients with CHD who received only conventional treatments, 8 group - 23 patients with coronary artery disease combined with type 2 diabetes who received only conventional treatments. Simvastatin ("Vazostat-Health" FC "Health", Kharkiv was administered at a daily dose of 20 mg at night during 6 months, Korargin (JSC "Engineer", Uman - 0,1 g of L-arginine hydrochloride with 0.1 g of inosine – was administered at a dose of 3

ARTERIAL STIFFNESS PARAMETERS IN PATIENTS WITH MODERATE/HIGH CARDIOVASCULAR RISK DURING LISINOPRIL AND SIMVASTATIN TREATMENT

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V. N. Isakova

2016-01-01

Full Text Available Aim. To evaluate parameters of arterial stiffness by non-invasive arteriography in patients with moderate/high cardiovascular risk receiving lisinopril and simvastatin.Material and methods. 20 patients (aged 50-55 y.o. with arterial hypertension of the 1st degree and dislipidemia are included in the study. All patients had pulse wave velocity (PWV ≥ 10 m/s and/or the corrected index of pulse wave augmentation (AI × 80 ≥ -10% according to non-invasive arteriography data; and moderate-high cardiovascular risk (≥ 3%. Patients received therapy with lisinopril and simvastatin. Blood pressure (BP levels and lipid profiles were assessed before therapy and in 1, 2, 6 and 12 month of the observation. Non-invasive arteriography was performed before therapy and in 2, 6 and 12 months later.Results. BP target levels were reached within 1 month of treatment as well as improvement of lipid profile was reached within 2 months in majority of the patients. Reference PWV and AI were reached in 85,7% of patients within one year of treatment.Conclusion. Arterial stiffness parameters help to evaluate cardiovascular risk changes accurately as the results of treatment.

Histological Study on the Protective Effect of Simvastatin on the Retinal Changes Induced by High-Fat Diet in Mice

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Fayza Ezz Ahmad

2017-09-01

Full Text Available Background: High-fat diet (HFD feeding is an important model to study the changes induced by insulin resistance, Type 2 diabetes mellitus and obesity including retinopathy. Vascular endothelial growth factor (VEGF and p53 have been implicated in the development of retinopathy. Objectives: The aim of his study was to analyze histological retinal changes in a high-fat atherogenic mouse model and to evaluate the possible protective effect of simvastatin on these changes including its effects on the expression of VEGF and p53. Materials and Methods: A total of 27 mice (6 weeks old were divided into 3 study groups according to their diet and treatment given; Group I - normal balanced diet-fed mice, Group II - HFD-fed mice, and Group III - HFD-fed mice treated with simvastatin daily for 30 weeks. All mice were followed up for 30 weeks. At the end of the study at 36 weeks of age, eye tissues were collected and retinal sections were examined using light microscopy. Comparison of the thickness of retinal layers in the three groups was carried out. The localization of VEGF in the retina was determined by immunohistochemical analysis, and apoptotic cell death was assessed using the p53. Results: In the HFD-fed mice, there was an increase in the retinal thickness associated with presence of wide intercellular spaces in the outer nuclear layer. Many cells in the inner nuclear layer showed cytoplasmic vacuolations. Expression of VEGF was significantly increased in the retinal ganglion cell layers and nuclear cell layers. Elevated p53 reaction was demonstrated within the inner retina. The histological changes were significantly improved in the simvastatin treated group. Conclusions: HFD-induced structural changes in the retinal layers and simultaneous upregulation of VEGF and p53. Administration of simvastatin improved these retinal alterations. [J Interdiscip Histopathol 2017; 5(3.000: 83-91

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

International Nuclear Information System (INIS)

Ribeiro, Rodrigo Antonini; Duncan, Bruce Bartholow; Ziegelmann, Patricia Klarmann; Stella, Steffan Frosi; Vieira, Jose Luiz da Costa; Restelatto, Luciane Maria Fabian; Polanczyk, Carisi Anne

2015-01-01

Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

Energy Technology Data Exchange (ETDEWEB)

Ribeiro, Rodrigo Antonini, E-mail: rodrigo.ribeiro@htanalyze.com [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Duncan, Bruce Bartholow [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Ziegelmann, Patricia Klarmann [Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Departamento de Estatística da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Stella, Steffan Frosi [Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Vieira, Jose Luiz da Costa [Instituto de Cardiologia / Fundação Universitária de Cardiologia, Porto Alegre, RS (Brazil); Restelatto, Luciane Maria Fabian [Serviço de Medicina Interna do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS (Brazil); Polanczyk, Carisi Anne [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)

2015-01-15

Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil.

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

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Stefan Bergt, MD

2017-04-01

Full Text Available Summary: Cardiac arrest (CA followed by cardiopulmonary resuscitation (CPR is associated with high mortality and poor neurological outcome. We compared the effects of pravastatin and simvastatin on survival and neurofunction in a murine model of CA/CPR. Pravastatin, a hydrophilic statin, increased survival and neurofunction during a 28-day follow-up period. This therapy was associated with improved pulmonary function, reduced pulmonary edema, and increased endothelial cell function in vitro. In contrast, lipophilic simvastatin did not modulate survival but increased pulmonary edema and impaired endothelial cell function. Although pravastatin may display a therapeutic option for post-CA syndrome, the application of simvastatin may require re-evaluation. Key Words: cardiac arrest, endothelial cell function, ischemia and reperfusion injury, pravastatin, resuscitation, simvastatin

Localised controlled release of simvastatin from porous chitosan–gelatin scaffolds engrafted with simvastatin loaded PLGA-microparticles for bone tissue engineering application

Energy Technology Data Exchange (ETDEWEB)

Gentile, Piergiorgio [Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin (Italy); School of Clinical Dentistry, University of Sheffield, 19 Claremont Crescent, Sheffield (United Kingdom); Nandagiri, Vijay Kumar [Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin (Italy); School of Pharmacy, Royal College of Surgeons in Ireland, 123, St. Stephen Green, Dublin 2 (Ireland); Daly, Jacqueline [Division of Biology, Department of Anatomy, Royal College of Surgeons in Ireland, 123, St. Stephen Green, Dublin 2 (Ireland); Chiono, Valeria; Mattu, Clara; Tonda-Turo, Chiara; Ciardelli, Gianluca [Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin (Italy); Ramtoola, Zebunnissa, E-mail: zramtoola@rcsi.ie [School of Pharmacy, Royal College of Surgeons in Ireland, 123, St. Stephen Green, Dublin 2 (Ireland)

2016-02-01

Localised controlled release of simvastatin from porous freeze-dried chitosan–gelatin (CH–G) scaffolds was investigated by incorporating simvastatin loaded poly-(DL-lactide-co-glycolide) acid (PLGA) microparticles (MSIMs) into the scaffolds. MSIMs at 10% w/w simvastatin loading were prepared using a single emulsion-solvent evaporation method. The MSIM optimal amount to be incorporated into the scaffolds was selected by analysing the effect of embedding increasing amounts of blank PLGA microparticles (BL-MPs) on the scaffold physical properties and on the in vitro cell viability using a clonal human osteoblastic cell line (hFOB). Increasing the BL-MP content from 0% to 33.3% w/w showed a significant decrease in swelling degree (from 1245 ± 56% to 570 ± 35%). Scaffold pore size and distribution changed significantly as a function of BL-MP loading. Compressive modulus of scaffolds increased with increasing BL-MP amount up to 16.6% w/w (23.0 ± 1.0 kPa). No significant difference in cell viability was observed with increasing BL-MP loading. Based on these results, a content of 16.6% w/w MSIM particles was incorporated successfully in CH–G scaffolds, showing a controlled localised release of simvastatin able to influence the hFOB cell proliferation and the osteoblastic differentiation after 11 days. - Highlights: • Simvastatin loaded PLGA microparticle engrafted porous CH–G scaffolds were produced. • The microparticle optimal amount to be incorporated into the scaffolds was studied. • Physical properties of scaffolds changed as a function of microparticle loading. • The level of simvastatin released enhanced cell proliferation and mineralisation.

Localised controlled release of simvastatin from porous chitosan–gelatin scaffolds engrafted with simvastatin loaded PLGA-microparticles for bone tissue engineering application

International Nuclear Information System (INIS)

Gentile, Piergiorgio; Nandagiri, Vijay Kumar; Daly, Jacqueline; Chiono, Valeria; Mattu, Clara; Tonda-Turo, Chiara; Ciardelli, Gianluca; Ramtoola, Zebunnissa

2016-01-01

Localised controlled release of simvastatin from porous freeze-dried chitosan–gelatin (CH–G) scaffolds was investigated by incorporating simvastatin loaded poly-(DL-lactide-co-glycolide) acid (PLGA) microparticles (MSIMs) into the scaffolds. MSIMs at 10% w/w simvastatin loading were prepared using a single emulsion-solvent evaporation method. The MSIM optimal amount to be incorporated into the scaffolds was selected by analysing the effect of embedding increasing amounts of blank PLGA microparticles (BL-MPs) on the scaffold physical properties and on the in vitro cell viability using a clonal human osteoblastic cell line (hFOB). Increasing the BL-MP content from 0% to 33.3% w/w showed a significant decrease in swelling degree (from 1245 ± 56% to 570 ± 35%). Scaffold pore size and distribution changed significantly as a function of BL-MP loading. Compressive modulus of scaffolds increased with increasing BL-MP amount up to 16.6% w/w (23.0 ± 1.0 kPa). No significant difference in cell viability was observed with increasing BL-MP loading. Based on these results, a content of 16.6% w/w MSIM particles was incorporated successfully in CH–G scaffolds, showing a controlled localised release of simvastatin able to influence the hFOB cell proliferation and the osteoblastic differentiation after 11 days. - Highlights: • Simvastatin loaded PLGA microparticle engrafted porous CH–G scaffolds were produced. • The microparticle optimal amount to be incorporated into the scaffolds was studied. • Physical properties of scaffolds changed as a function of microparticle loading. • The level of simvastatin released enhanced cell proliferation and mineralisation.

Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy.

Science.gov (United States)

Davis, Benjamin B; Zeki, Amir A; Bratt, Jennifer M; Wang, Lei; Filosto, Simone; Walby, William F; Kenyon, Nicholas J; Goldkorn, Tzipora; Schelegle, Edward S; Pinkerton, Kent E

2013-08-01

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death. The statin drugs may have therapeutic potential in respiratory diseases such as COPD, but whether they prevent bronchial epithelial injury is unknown. We hypothesised that simvastatin attenuates acute tobacco smoke-induced neutrophilic lung inflammation and airway epithelial injury. Spontaneously hypertensive rats were given simvastatin (20 mg·kg(-1) i.p.) daily for either 7 days prior to tobacco smoke exposure and during 3 days of smoke exposure, or only during tobacco smoke exposure. Pretreatment with simvastatin prior to and continued throughout smoke exposure reduced the total influx of leukocytes, neutrophils and macrophages into the lung and airways. Simvastatin attenuated tobacco smoke-induced cellular infiltration into lung parenchymal and airway subepithelial and interstitial spaces. 1 week of simvastatin pretreatment almost completely prevented smoke-induced denudation of the airway epithelial layer, while simvastatin given only concurrently with the smoke exposure had no effect. Simvastatin may be a novel adjunctive therapy for smoke-induced lung diseases, such as COPD. Given the need for statin pretreatment there may be a critical process of conditioning that is necessary for statins' anti-inflammatory effects. Future work is needed to elucidate the mechanisms of this statin protective effect.

Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation

Directory of Open Access Journals (Sweden)

Hou Ssu-Yu

2010-06-01

Full Text Available Abstract Background 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA reductase inhibitors (statins have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved. Methods The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin. Results Simvastatin (20-50 μM exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin. Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2 formation, and phospholipase C (PLCγ2, protein kinase C (PKC, and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP phosphorylation, and endothelial nitric oxide synthase (eNOS expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation. Conclusion The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP

Simvastatin-induced cardiac autonomic control improvement in fructose-fed female rats

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Renata Juliana da Silva

2011-01-01

Full Text Available OBJECTIVE: Because autonomic dysfunction has been found to lead to cardiometabolic disorders and because studies have reported that simvastatin treatment has neuroprotective effects, the objective of the present study was to investigate the effects of simvastatin treatment on cardiovascular and autonomic changes in fructose-fed female rats. METHODS: Female Wistar rats were divided into three groups: controls (n=8, fructose (n=8, and fructose+ simvastatin (n=8. Fructose overload was induced by supplementing the drinking water with fructose (100 mg/L, 18 wks. Simvastatin treatment (5 mg/kg/day for 2 wks was performed by gavage. The arterial pressure was recorded using a data acquisition system. Autonomic control was evaluated by pharmacological blockade. RESULTS: Fructose overload induced an increase in the fasting blood glucose and triglyceride levels and insulin resistance. The constant rate of glucose disappearance during the insulin intolerance test was reduced in the fructose group (3.4+ 0.32%/min relative to that in the control group (4.4+ 0.29%/min. Fructose+simvastatin rats exhibited increased insulin sensitivity (5.4+0.66%/min. The fructose and fructose+simvastatin groups demonstrated an increase in the mean arterial pressure compared with controls rats (fructose: 124+2 mmHg and fructose+simvastatin: 126 + 3 mmHg vs. controls: 112 + 2 mmHg. The sympathetic effect was enhanced in the fructose group (73 + 7 bpm compared with that in the control (48 + 7 bpm and fructose+simvastatin groups (31+8 bpm. The vagal effect was increased in fructose+simvastatin animals (84 + 7 bpm compared with that in control (49 + 9 bpm and fructose animals (46+5 bpm. CONCLUSION: Simvastatin treatment improved insulin sensitivity and cardiac autonomic control in an experimental model of metabolic syndrome in female rats. These effects were independent of the improvements in the classical plasma lipid profile and of reductions in arterial pressure. These results

Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression

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Santos T

2012-10-01

Full Text Available Tainaê Santos,1 Monaliza Marizete Baungratz,1 Suellen Priscila Haskel,2 Daniela Delwing de Lima,3 Júlia Niehues da Cruz,4 Débora Delwing Dal Magro,5 José Geraldo Pereira da Cruz51Department of Medicine, 2Department of Physiotherapy, Regional University of Blumenau, Santa Catarina, Brazil; 3Department of Pharmacy, University of Joinville Region, Santa Catarina, Brazil; 4Department of Medicine, University of the Extreme South of Santa Catarina, Santa Catarina, Brazil; 5Department of Natural Sciences, Regional University of Blumenau, Santa Catarina, BrazilAbstract: Simvastatin inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and is widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of simvastatin extend to the central nervous system. The effects of simvastatin combined with fluoxetine provide an exciting and potential paradigm to decreased anxiety and depression. Thus, the present paper investigates the possibility of synergistic interactions between simvastatin and fluoxetine in models of anxiety and depression. We investigated the effects of subchronically administered simvastatin (1 or 10 mg/kg/day combined with fluoxetine (2 or 10 mg/kg at 24, 5, and 1 hour on adult rats before conducting behavioral tests. The results indicate that simvastatin and/or fluoxetine treatment reduces anxiety-like behaviors in the elevated plus-maze and open-field tests. Our results showed that simvastatin and/or fluoxetine induced a significant increase in the swimming activity during the forced swimming test (antidepressant effect, with a concomitant increase in climbing time in simvastatin-treated animals only (noradrenergic activation. We hypothesize that anxiolytic and antidepressant effects of simvastatin and/or fluoxetine produce their behavioral effects through similar mechanisms and provide

IGF-1 prevents simvastatin-induced myotoxicity in C2C12 myotubes.

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Bonifacio, Annalisa; Sanvee, Gerda M; Brecht, Karin; Kratschmar, Denise V; Odermatt, Alex; Bouitbir, Jamal; Krähenbühl, Stephan

2017-05-01

Statins are generally well tolerated, but treatment with these drugs may be associated with myopathy. The mechanisms of statin-associated myopathy are not completely understood. Statins inhibit AKT phosphorylation by an unclear mechanism, whereas insulin-like growth factor (IGF-1) activates the IGF-1/AKT signaling pathway and promotes muscle growth. The aims of the study were to investigate mechanisms of impaired AKT phosphorylation by simvastatin and to assess effects of IGF-1 on simvastatin-induced myotoxicity in C2C12 myotubes. C2C12 mouse myotubes were exposed to 10 μM simvastatin and/or 10 ng/mL IGF-1 for 18 h. Simvastatin inhibited the IGF-1/AKT signaling pathway, resulting in increased breakdown of myofibrillar proteins, impaired protein synthesis and increased apoptosis. Simvastatin inhibited AKT S473 phosphorylation, indicating reduced activity of mTORC2. In addition, simvastatin impaired stimulation of AKT T308 phosphorylation by IGF-1, indicating reduced activation of the IGF-1R/PI3K pathway by IGF-1. Nevertheless, simvastatin-induced myotoxicity could be at least partially prevented by IGF-1. The protective effects of IGF-1 were mediated by activation of the IGF-1R/AKT signaling cascade. Treatment with IGF-1 also suppressed muscle atrophy markers, restored protein synthesis and inhibited apoptosis. These results were confirmed by normalization of myotube morphology and protein content of C2C12 cells exposed to simvastatin and treated with IGF-1. In conclusion, impaired activity of AKT can be explained by reduced function of mTORC2 and of the IGF-1R/PI3K pathway. IGF-1 can prevent simvastatin-associated cytotoxicity and metabolic effects on C2C12 cells. The study gives insight into mechanisms of simvastatin-associated myotoxicity and provides potential targets for therapeutic intervention.

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

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Rodrigo Antonini Ribeiro

2015-01-01

Full Text Available Background: Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. Objective: To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS perspective. Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg, intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg, high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$. A willingness-to-pay (WTP threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770 was applied. Results: Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Conclusions: Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil.

Are the beneficial cardiovascular effects of simvastatin and metformin also associated with a hormone-dependent mechanism improving insulin sensitivity?

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C. Bulcão

Full Text Available In addition to lipid-lowering and cardiovascular protective actions, statins may have beneficial effects on insulin sensitivity. The objective of the present study was to evaluate the effect of simvastatin therapy on insulin resistance and on leptin, adiponectin, and C-reactive protein (CRP levels, as compared to metformin, in overweight pre-diabetic subjects. Forty-one subjects with BMI >25 kg/m² and impaired fasting glucose or impaired glucose tolerance were randomized to take simvastatin, 20 mg/day (N = 20 or metformin, 1.7 g/day (N = 21 for 16 weeks. Blood samples for the determination of metabolic, hormonal, and inflammatory parameters were obtained at baseline and after each treatment. After metformin therapy, significant reductions in mean BMI and waist circumference were observed, and after simvastatin treatment LDL and triglyceride levels were significantly reduced. Insulin resistance determined by the homeostasis model assessment decreased only with metformin. Independently of the type of medication, a significant decrease in CRP levels was detected from baseline to the end of the study. CRP showed a mean reduction of 0.12 ± 0.04 mg/dL (P = 0.002 over time. No change in leptin or adiponectin levels was induced by any therapy. The data suggest that a low dose of simvastatin does not affect insulin resistance in overweight pre-diabetic subjects and has no effect on leptin or adiponectin levels. Further studies including a larger sample size, higher doses of statins, and a placebo control group are necessary to confirm the present data.

Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.

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Li, Ge; Mayer, Cynthia L; Morelli, Daniel; Millard, Steven P; Raskind, Wendy H; Petrie, Eric C; Cherrier, Monique; Fagan, Anne M; Raskind, Murray A; Peskind, Elaine R

2017-09-19

To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ 42 , total tau, and p-tau 181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ 42 , total tau, and p-tau 181 , respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau 181 ( p = 0.003), where greater decreases from baseline in CSF p-tau 181 concentrations were associated with higher baseline LDL level for the simvastatin group. Simvastatin-related reductions in CSF p-tau 181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia. © 2017 American Academy of Neurology.

Use of Simvastatin and Risk of Acute Pancreatitis: A Nationwide Case-Control Study in Taiwan.

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Lin, Chih-Ming; Liao, Kuan-Fu; Lin, Cheng-Li; Lai, Shih-Wei

2017-07-01

The correlation between simvastatin use and acute pancreatitis is explored. A case-control study was conducted to analyze claim data from the Taiwan National Health Insurance Program. The case group comprising a total of 3882 subjects aged 20 to 84 years with their first acute pancreatitis episode occurring between 1998 and 2011 formed the case group, against 3790 randomly selected controls matched for sex, age, comorbidities, and index year of acute pancreatitis diagnosis. Recent use of simvastatin was defined as subjects whose last remaining simvastatin tablet was noted ≤7 days before the date of acute pancreatitis diagnosis. Remote use of simvastatin was defined as subjects whose last remaining 1 tablet for simvastatin was noted >7 days before the date of acute pancreatitis diagnosis. Never use of simvastatin was defined as subjects who had never been prescribed simvastatin. A multivariable unconditional logistic regression model was used to estimate the odds ratio and 95%CI to explore the correlation between simvastatin use and acute pancreatitis. After adjustment for confounders, multivariable logistic regression analysis revealed that the adjusted odds ratio of acute pancreatitis was 1.3 for subjects with recent use of simvastatin (95%CI 1.02, 1.73), when compared with those with never use of simvastatin. The crude odds ratio decreased to 1.1 for those with remote use of simvastatin (95%CI 0.93, 1.34) but without statistical significance. Recent use of simvastatin is associated with acute pancreatitis. Clinicians should consider the possibility of simvastatin-associated acute pancreatitis for patients presenting for acute pancreatitis without known cause. © 2017, The American College of Clinical Pharmacology.

Determination of Prazosin and Simvastatin in Landfill Leachate using Liquid Chromatography-Time of Flight-Mass Spectrometry

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Zainab Haider Mussa; Zainab Haider Mussa; Fouad Fadhil Al-Qaim; Fouad Fadhil Al-Qaim; Md Pauzi Abdullah; Mohamed Rozali Othman

2016-01-01

Human pharmaceuticals have been shown to occur in considerably high amounts in sewage treatment plant (STP) effluents and surface waters. So far there is no data available on the occurrence of prazosin and simvastatin in leachate sample in Malaysia. Thus, this study is the first report to analysis of prazosin and simvastatin in leachate samples by using solid phase extraction-liquid chromatography-time of flight-mass spectrometry (SPE-LC-TOF-MS). The proposed method included isolation and reconstitute procedure. The linearity range was achieved at 1.5-3000 μg/ L and 0.8-125 μg/ L for prazosin and simvstatin, respectively with a determination coefficient (R 2 ) > 0.99. The limit of quantification (LOQ) for prazosin and simvastatin was calculated at 2.1 and 0.5 ng/ L in deionised water (DIW), meanwhile it was recorded at 3.5 and 2.4 ng/ L for prazosin and simvastatin in effluent sample, respectively. Two pharmaceutical compounds were detected in the leachate samples: prazosin and simvastatin at concentrations levels of 3850 and 415 ng/ L, respectively. (author)

Controlled release of simvastatin from biomimetic β-TCP drug delivery system.

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Joshua Chou

Full Text Available Simvastatin have been shown to induce bone formation and there is currently a urgent need to develop an appropriate delivery system to sustain the release of the drug to increase therapeutic efficacy whilst reducing side effects. In this study, a novel drug delivery system for simvastatin by means of hydrothermally converting marine exoskeletons to biocompatible beta-tricalcium phosphate was investigated. Furthermore, the release of simvastatin was controlled by the addition of an outer apatite coating layer. The samples were characterized by x-ray diffraction analysis, fourier transform infrared spectroscopy, scanning electron microscopy and mass spectroscopy confirming the conversion process. The in-vitro dissolution of key chemical compositional elements and the release of simvastatin were measured in simulated body fluid solution showing controlled release with reduction of approximately 25% compared with un-coated samples. This study shows the potential applications of marine structures as a drug delivery system for simvastatin.

COMPARISON OF EFFICACY AND TOLERABILITY OF ORIGINAL AND GENERIC DRUGS OF SIMVASTATIN IN PATIENTS WITH HYPERLIPIDAEMIA AND HIGH RISK OF ISCHEMIC HEART DISEASE COMPLICATIONS

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S. N. Tolpygina

2008-01-01

Full Text Available Aim. To assess efficacy and safety of generic simvastatin, Simvahexal, in comparison with original drug of simvastatin, Zocor, in patients with hyperlipidaemia in short-term study.Material and methods. 30 patients (19 men and 11 women, 64,0±1,8 y.o. with low density lipoprotein (LDL cholesterol ≥3,0 mmol/l and high cardiovascular risk were involved into the study. During 5 weeks before study including patients kept the hypolipidaemic diet and did not receive any hypolipidaemic drug. 28 patients completed study, 2 patients drop out: one patient because of nettle rash on Zocor therapy, another one – because of personal reason. Efficacy was assessed by dynamic of lipid profile and a number of patients who reached target level of LDL cholesterol (<3 mmol/l. Safety was assessed by side effect rate registration. Patients were randomized in 2 groups (G1 and G2: G1 patients (n=15 received Zocor 20 mg/day during 6 weeks, G2 patients (n=15 – Simvahexal 20 mg/day. After 6 weeks of therapy G1 patients were switched from Zocor to Simvahexal, G2 patients did not change their therapy. Simvahexal dose was increased to 30 mg/day, if the target level of LDL cholesterol had not been reached after first 6 weeks of therapy.Results. After switching therapy from Zocor to Simvahexal 11 patients increased the dose to 30 mg/day, 3 patients kept the dose of 20 mg/day, 1 patient drop out. At the beginning of the study 15 patients received Simvahexal 20 mg/day, after 6 weeks the dose was increased to 30 mg/day in 8 patients, 7 patients kept the dose of 20 mg/day. After 6 weeks of therapy with Zocor 20 mg/day levels of the total cholesterol (TC and LDL cholesterol reduced on 25,2% and 33,6% (p<0,001, respectively. Next 6 weeks of therapy with Simvahexal in the average dose of 27,7 mg/day this reduction reached to 30,9% and 39,9% (p<0,001, respectively. After 6 weeks of therapy with Simvahexal 20mg/day levels of the TC and LDL cholesterol reduced on 28,2%and 38%(p<0

[The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin].

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Savica, V; Bellinghieri, G; Lamanna, F

1992-01-01

Previous studies had determined the role played by L-carnitine and simvastatin in the treatment of altered lipidemia in dialyzed patients with chronic uremia. The authors carried out a study on the above substances either singly or together administered to the same patients with chronic uremia in hemodialysis. This study was aimed at demonstrating the possible synergic normolipidemic action of both substances in comparison with their single administration, because their different mechanism of action could be metabolically enhanced. The obtained results demonstrated that the therapeutic association proposed is preferable to the use of the single substances. Moreover, a higher and more rapid normolipidemic effect was obtained after using L-carnitina associated with simvastatin with respect to the separated substances.

Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern

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Eliasson, Pernilla; Svensson, Rene B; Giannopoulos, Antonis

2017-01-01

simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days....... The maximum force and stiffness were reduced by both statins after 7 days (patorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (p

Simvastatin effects on skeletal muscle

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Larsen, Steen; Stride, Nis; Hey-Mogensen, Martin

2013-01-01

Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9)....

A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease

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Bell, K.L.; Galasko, D.; Galvin, J.E.; Thomas, R.G.; van Dyck, C.H.; Aisen, P.S.

2011-01-01

Background: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. Objective: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. Methods: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale–cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. Results: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. Conclusion: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Classification of evidence: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. PMID:21795660

Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice.

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Miranda, Hugo F; Noriega, Viviana; Olavarria, Loreto; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

2011-12-01

Statins, belonging to a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleiotropic properties, such as anti-inflammatory action. The purpose of this study was to evaluate the antinociceptive and anti-inflammatory effects of simvastatin in five models of nociceptive behaviour. Oral gavage administration of simvastatin induced a dose-dependent inhibition of nociception for 1 day in the acetic acid writhing (ED(50) = 5.59 ± 0.07), tail-flick (ED(50) = 112.96 ± 8.00), hot-plate (ED(50) = 134.87 ± 2.20), formalin hind paw (ED(50) = 19.86 ± 1.12 in phase I and 23.30 ± 2.05 in phase II) and orofacial formalin (ED(50) = 5.54 ± 2.74 in phase I and 11.48 ± 1.88 in phase II) tests. However, after 3 days, the values were in the acetic acid writhing (ED(50) = 6.14 ± 0.51), tail-flick (ED(50) = 154 ± 8.88), hot-plate (ED(50) = 136.14 ± 2.94), formalin hind paw (ED(50) = 15.93 ± 0.42 in phase I and 17.10 ± 1.80 in phase II) and orofacial formalin (ED(50) = 6.79 ± 0.66 in phase I and 5.80 ± 1.49 in phase II) tests. This study demonstrated the antinociceptive and anti-inflammatory activities of simvastatin in five models of tonic or phasic pain. These actions seem to be related to the inhibition of cytokine and prostanoid release and stimulation of nitric oxide synthesis. A possible clinical role of simvastatin could be related to the potentially beneficial effects in the neuropathic pain, and by their pleiotropic properties, they could play a clinical role in anti-inflammatory disease. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

Preparation and characterization of simvastatin/DMβCD complex and its pharmacokinetics in rats

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Gu Fugen

2018-06-01

Full Text Available Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several β-cyclodextrin (βCD derivatives such as HPβCD, SBEβCD and DMβCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each βCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above βCD derivatives DMβCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMβCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC, Fourier-transform infrared spectroscopy (FT-IR and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMβCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax and the time to reach it (tmax were 21.86 μg mL−1 and 1.4 h for the drug complex, 8.25 μg mL−1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01 between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.

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Chan, Dennis; Binks, Sophie; Nicholas, Jennifer M; Frost, Chris; Cardoso, M Jorge; Ourselin, Sebastien; Wilkie, David; Nicholas, Richard; Chataway, Jeremy

2017-08-01

In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6-7·8; pmultiple sclerosis treatment trials. The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a

The efficiency of dyslipidemia control in real clinical practice and the possibilities of its correction in patients with coronary heart disease and diabetes mellitus in the long -term use of simvastatin

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F. Yu. Valikulova

2014-07-01

Full Text Available Objective: To show the efficiency of dyslipidemia control in patients with coronary heart disease (CHD and diabetes mellitus (DM in real outpatient clinical practice and the possibilities of its correction in the long-term use of simvastatin (simvastatin forte 40 mg in one of theNizhny Novgorod polyclinics.Subjects and methods. The efficiency of lipid profile control was analyzed in a sample from the entire dispensary group of patients with DM (n = 713. Patients at highest cardiovascular risk were selected from the dispensary group and included into a group of CHD and DM. There were a total of 461 (64.7 % such patients. Forty-three patients were identified in this group, who were matched for baseline systolic and diastolic blood pressures, age, gender, and DM duration and were found to have significant hypercholesterolemia. Simvastatin forte 40 mg wasprescribed to these patients at their outpatient visit. During a year, the patient made 6 visits to his/her physician (5 visits at 6-werk intervals and the sixth visit by the end of the follow-up year. The dose of simvastatin was unchanged throughout the study.Results.In the entire dispensary group, 64.7 % of the patients had a concurrence of CHD and DM. This group of patients was at high risk for dyslipidemia. In this group, 2.8 % had a total cholesterol (TC level of ≤ 3.5 mmol/l; 4.7 % had a low-density lipoprotein cholesterol (LDL-C level of < 1.8 mmol/l. The total lipid profile was analyzed in only 6.3% of the patients from the entire dispensary group. 28.6 % of the patients with type 1 DM and 21.3% of those with CHD and type 2 DM took statins. Fifty-two week therapy with simvastatin forte 40 mg showed its high efficiency in real practice in decreasing the levels of atherogenic lipids and lipoproteins: TC by 27.6 % (p < 0.001, LDL-C by 36.9 % (p < 0.001, and triglycerides by 34.3 % (p < 0.001 with antiatherogenic high-density lipoprotein cholesterol elevation by 15.2 % (p < 0

Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts

International Nuclear Information System (INIS)

Copaja, Miguel; Venegas, Daniel; Aranguiz, Pablo; Canales, Jimena; Vivar, Raul; Catalan, Mabel; Olmedo, Ivonne; Rodriguez, Andrea E.; Chiong, Mario; Leyton, Lisette; Lavandero, Sergio; Diaz-Araya, Guillermo

2011-01-01

Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types. Methods: Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10 μM) up to 72 h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively. Results: Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras. Conclusion: Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin-induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues. - Research Highlights: → Simvastatin decreases CF and CMF viability independent of cholesterol synthesis. → Simvastatin induces CF and CMF apoptosis in a caspase-dependent manner being CMF more resistant

Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.

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Marsha C Lampi

Full Text Available Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.

Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X-Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions.

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Li, Zhan; Tian, Longlong; Liu, Jianli; Qi, Wei; Wu, Qiang; Wang, Haijing; Ali, Mohammad Chand; Wu, Wangsuo; Qiu, Hongdeng

2017-09-01

Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (≈24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (≈0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Single-step production of the simvastatin precursor monacolin J by engineering of an industrial strain of Aspergillus terreus.

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Huang, Xuenian; Liang, Yajing; Yang, Yong; Lu, Xuefeng

2017-07-01

Monacolin J is a key precursor for the synthesis of simvastatin (Zocor), an important drug for treating hypercholesterolemia. Industrially, monacolin J is manufactured through alkaline hydrolysis of lovastatin, a fungal polyketide produced by Aspergillus terreus. Multistep chemical processes for the conversion of lovastatin to simvastatin are laborious, cost expensive and environmentally unfriendly. A biocatalysis process for monacolin J conversion to simvastatin has been developed. However, direct bioproduction of monacolin J has not yet been achieved. Here, we identified a lovastatin hydrolase from Penicillium chrysogenum, which displays a 232-fold higher catalytic efficiency for the in vitro hydrolysis of lovastatin compared to a previously patented hydrolase, but no activity for simvastatin. Furthermore, we showed that an industrial A. terreus strain heterologously expressing this lovastatin hydrolase can produce monacolin J through single-step fermentation with high efficiency, approximately 95% of the biosynthesized lovastatin was hydrolyzed to monacolin J. Our results demonstrate a simple and green technical route for the production of monacolin J, which makes complete bioproduction of the cholesterol-lowering drug simvastatin feasible and promising. Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear.

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Davis, Max E; Korn, Michael A; Gumucio, Jonathan P; Harning, Julie A; Saripalli, Anjali L; Bedi, Asheesh; Mendias, Christopher L

2015-02-01

Chronic rotator cuff tears are a common source of shoulder pain and disability, and patients with chronic cuff tears often have substantial weakness, fibrosis, inflammation, and fat accumulation. Identifying therapies to prevent the development of these pathologic processes will likely have a positive impact on clinical outcomes. Simvastatin is a drug with demonstrated anti-inflammatory and antifibrotic effects in many tissues but had not previously been studied in the context of rotator cuff tears. We hypothesized that after the induction of a massive supraspinatus tear, simvastatin would protect muscles from a loss of force production and fibrosis. We measured changes in muscle fiber contractility, histology, and biochemical markers of fibrosis and fatty infiltration in rats that received a full-thickness supraspinatus tear and were treated with either carrier alone or simvastatin. Compared with vehicle-treated controls, simvastatin did not have an appreciable effect on muscle fiber size, but treatment did increase muscle fiber specific force by 20%. Simvastatin also reduced collagen accumulation by 50% but did not affect triglyceride content of muscles. Several favorable changes in the expression of genes and other markers of inflammation, fibrosis, and regeneration were also observed. Simvastatin partially protected muscles from the weakness that occurs as a result of chronic rotator cuff tear. Fibrosis was also markedly reduced in simvastatin-treated animals. Whereas further studies are necessary, statin medication could potentially help improve outcomes for patients with rotator cuff tears. Copyright © 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease

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Than, Khoi D.; Rahman, Shayan U.; Wang, Lin; Khan, Adam; Kyere, Kwaku A.; Than, Tracey T.; Miyata, Yoshinari; Park, Yoon-Shin; La Marca, Frank; Kim, Hyungjin M.; Zhang, Huina; Park, Paul; Lin, Chia-Ying

2014-01-01

BACKGROUND CONTEXT A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein-2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to up-regulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. PURPOSE To develop a novel conservative treatment for DDD and related discogenic back pain. STUDY DESIGN/SETTING Laboratory investigation. METHODS Disc injury was induced in 272 rats via 21-gauge needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the MRI index (number of pixels multiplied by corresponding image densities) was determined. Histologically, disc spaces were read by 3 blinded scorers employing a previously described histological grading scale. Genetically, nuclei pulposi were harvested and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. This project was supported by Grant No. R01 AR056649 from NIAMS/NIH. There are no other financial conflicts of interest to report. RESULTS Radiologically, discs treated with 5 mg/mL simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks post-treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL simvastatin in hydrogel demonstrated improved grades in comparison to discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. CONCLUSIONS Degenerate discs treated with 5 mg/mL simvastatin in a hydrogel carrier demonstrated

Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats

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Campos-Martorell M

2016-06-01

Full Text Available Mireia Campos-Martorell,1 Mary Cano-Sarabia,2 Alba Simats,1 Mar Hernández-Guillamon,1 Anna Rosell,1 Daniel Maspoch,2,3 Joan Montaner1,4 1Neurovascular Research Laboratory, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, 2Catalan Institute of Nanoscience and Nanotechnology (ICN2, CSIC and The Barcelona Institute of Science and Technology, Universitat Autònoma de Barcelona, Barcelona, 3Institució Catalana de Recerca i Estudis Avançats (ICREA, 4Neurovascular Unit, Department of Neurology, Universitat Autònoma de Barcelona, Hospital Vall d’Hebron, Barcelona, Spain Background and aims: Although the beneficial effects of statins on stroke have been widely demonstrated both in experimental studies and in clinical trials, the aim of this study is to prepare and characterize a new liposomal delivery system that encapsulates simvastatin to improve its delivery into the brain. Materials and methods: In order to select the optimal liposome lipid composition with the highest capacity to reach the brain, male Wistar rats were submitted to sham or transitory middle cerebral arterial occlusion (MCAOt surgery and treated (intravenous [IV] with fluorescent-labeled liposomes with different net surface charges. Ninety minutes after the administration of liposomes, the brain, blood, liver, lungs, spleen, and kidneys were evaluated ex vivo using the Xenogen IVIS® Spectrum imaging system to detect the load of fluorescent liposomes. In a second substudy, simvastatin was assessed upon reaching the brain, comparing free and encapsulated simvastatin (IV administration. For this purpose, simvastatin levels in brain homogenates from sham or MCAOt rats at 2 hours or 4 hours after receiving the treatment were detected through ultra-high-protein liquid chromatography. Results: Whereas positively charged liposomes were not detected in brain or plasma 90 minutes after their administration, neutral and negatively charged liposomes

[Simvastatin therapy and effect on hiperlipidemia and vascular status in nephrotic children with sustained dyslipidemia].

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Ksiazek, Joanna; Niemirska, Anna; Lipka, Maria; Wierzbicka, Aldona; Syczewska, Małgorzata; Grenda, Ryszard

2009-03-01

Dyslipidemia is common in nephrotic children and persistent lipid abnormalities are risk factor of late vascular complications. The aim of the study was evaluation of efficacy and safety of 12-months simvastatin therapy in nephrotic children with lipid profile abnormalities present despite clinical remission lasting for at least 8 weeks, including ultrasonographic assessment of carotid and femoral arteries. Overall 52 children (40 steroid-dependent and 12 steroid-resistant) were initially introduced to the study and 29 of them were treated with simvastatin. Normalisation of lipid profile was achieved in 19/29 (65.5%) and improvement in 9/29 (31%). Significant reduction in total cholesterol (p 2.0) was small. Increased cIMT was seen at baseline in 4 patients and in 5 after simvastatin treatment, however average and Z-score values in children under simvastatin treatment have decreased. Increased fIMT values were seen at baseline in 2 and in one case after simvastatin treatment. Tolerance of simvastation was very good in all cases but one. Simvastatin therapy was effective and safe in nephrotic non-proteinuric children with abnormal lipid profile. Fair estimation of impact of the 12-months simvastatin therapy on vascular status was not available due to limited number of children with significantly increased IMT at baseline.

Inhibitory effect of the combination therapy of simvastatin and pinocembrin on atherosclerosis in apoE-deficient mice

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Sang Hui

2012-12-01

Full Text Available Abstract The present study was performed to investigate the effects of the combination therapy of pinocembrin and simvastatin on the atherosclerotic lesions development in the ApoE−/− mice. Methods Eight-week-old male ApoE−/− mice were fed high fat diet (HFD and treated with simvastatin (10 mg/kg per day, pinocembrin (20 mg/kg per day, or the combination therapy (simvastatin 5 mg/kg per day and pinocembrin 20 mg/kg per day for 14 weeks. The serum lipid levels, nitric oxide (NO, endothelin (ET, superoxide dismutase (SOD and malondialdehyde (MDA were determined with spectrophotometric measurement and ELISA assay. Vascular endothelial growth factor (VEGF in serum and aortic root was detected. En face analyses of atherosclerotic lesion in whole aorta and aortic root sections were performed with plaque staining using oil red O. Results The combination treatment with simvastatin and pinocembrin resulted in significantly decreased levels of serum total cholesterol, triglycerides and low-density lipoprotein cholesterol, augmented NO levels and SOD activity, inhibited ET and VEGF expression. Immunohistochemistry of aortic valve sections revealed that the combination therapy also suppressed the expression of VEGF induced by HFD. In addition, HFD-induced arterial wall lipid disposition displayed by oil red O staining was reduced significantly in aortic root and whole aorta en face in the combination administrated mice. The effect of the combination was superior to simvastatin alone. Conclusion The combination of simvastatin and pinocembrin synergistically inhibited atherosclerotic lesion development in ApoE−/− mice with hyperlipidemia, which is partially dependent on the protective of vascular endothelium.

Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

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Goc, Anna; Kochuparambil, Samith T; Al-Husein, Belal; Al-Azayzih, Ahmad; Mohammad, Shuaib; Somanath, Payaningal R

2012-01-01

Recent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood. Effect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin. Data indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5. Our study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent

Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.

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Junqiang Yan

Full Text Available BACKGROUND: In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD. This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. METHODOLOGY/PRINCIPAL FINDINGS: Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area, amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9, and TNF-a (tumour necrosis factor-alpha. CONCLUSIONS/SIGNIFICANCE: Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings

Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil

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VanPuijenbroek, EP; DuBufVereijken, PWG; Spooren, PFMJ; VanDoormaal, JJ

1996-01-01

The occurrence of rhabdomyolysis is one of the rare side-effects of the cholesterol-lowering agent simvastatin. During the use of lovastatin, an agent related to simvastatin, the risk of this side-effect might be increased when cyclosporin or gemfibrozil are used concomitantly. It is possible that

Effects of simvastatin treatment on serum adiponectin concentrations in patients with dislipidemia.

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Moezzi, Atefeh; Parizadeh, Seyyed Mohammad Reza; Tavallaie, Shima; Mazidi, Mohsen; Afzali, Fariba; Adab, Afrouz; Ferns, Gordon; Ghayour Mobarhan, Majid

2014-08-01

Adiponectin is an adipose tissue-derived protein with anti-inflammatory properties. Statins are a class of cholesterol-lowering drugs, widely used for treatment of cardiovascular diseases. In the current study, we aimed to assess the effects of simvastatin on serum levels of adiponectin in patients with dyslipidemia, recruited from Ghaem Hospital, Mashhad, Iran. A total of 102 patients with dyslipidemia were treated with simvastatin or placebo during a double-blind, cross-over, placebo-controlled trial. The adiponectin levels were measured before and after each treatment period. Seventy seven participants completed the study. There was a significant reduction in serum total cholesterol (approxmately 21%), low density lipoprotein-cholesterol (LDL-C) (approxmately 28%), and triglycerides (approxmately 11%), after four weeks of treatment with simvastatin (P < 0.001). No significant change in serum adiponectin concentrations was observed after treatment with simvastatin. This may be because of the relatively short duration of treatment and longer treatment duration may be necessary to investigation in future studies.

Enhancement of Autophagy by Simvastatin through Inhibition of Rac1-mTOR Signaling Pathway in Coronary Arterial Myocytes

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Yu-Miao Wei

2013-06-01

Full Text Available Background/Aims: In addition to their action of lowering blood cholesterol levels, statins modulate biological characteristics and functions of arterial myocytes such as viability, proliferation, apoptosis, survival and contraction. The present study tested whether simvastatin, as a prototype statin, enhances autophagy in coronary arterial myocytes (CAMs to thereby exert their beneficial effects in atherosclerosis. Methods and Results: Using flow cytometry, we demonstrated that simvastatin significantly increased the autophagsome formation in CAMs. Western blot analysis confirmed that simvastatin significantly increased protein expression of typical autophagy markers LC3B and Beclin1 in these CAMs. Confocal microscopy further demonstrated that simvastatin increased fusion of autophagosomes with lysosomes, which was blocked by autophagy inhibitor 3-methyladenine or silencing of Atg7 genes. Simvastatin reduced mammalian target of rapamycin (mTOR activity, which was reversed by Rac1-GTPase overexpression and the mTOR agonist phosphatidic acid. Moreover, both Rac1-GTPase overexpression and activation of mTOR by phosphatidic acid drastically blocked simvastatin-induced autophagosome formation in CAMs. Interestingly, simvastatin increased protein expression of a contractile phenotype marker calponin in CAMs, which was blocked by autophagy inhibitor 3-methyladenine. Simvastatin markedly reduced proliferation of CAMs under both control and proatherogenic stimulation. However, this inhibitory effect of simvastatin on CAM proliferation was blocked by by autophagy inhibitor 3-methyladenine or silencing of Atg7 genes. Lastly, animal experiments demonstrated that simvastatin increased protein expression of LC3B and calponin in mouse coronary arteries. Conclusion: Our results indicate that simvastatin inhibits the Rac1-mTOR pathway and thereby increases autophagy in CAMs which may stabilize CAMs in the contractile phenotype to prevent proliferation and growth

Effect of simvastatin on MMPs and TIMPs in cigarette smoke-induced rat COPD model

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Sun J

2017-02-01

Full Text Available Jiawei Sun,1,* Jie Bao,2,* Yanan Shi,3 Bin Zhang,4 Lindong Yuan,5 Junhong Li,1 Lihai Zhang,1 Mo Sun,6 Ling Zhang,2 Wuzhuang Sun1 1Department of Respiratory Medicine, First Hospital of Hebei Medical University, 2Department of Respiratory Medicine, Chest Hospital of Hebei Province, 3Maternal and Child Health Care Center of Hebei Province, 4Department of Emergency, First Hospital of Hebei Medical University, Shijiazhuang, 5Department of Respiratory Medicine, People’s Hospital of Liaocheng, Liaocheng, 6Hebei Medical University, Shijiazhuang, People’s Republic of China *These authors contributed equally to this work Background: Proteases may play an important role in the development of chronic obstructive pulmonary disease and emphysema in response to cigarette smoke exposure (CSE. The current study was designed to investigate the expression of matrix metalloproteinase (MMP-8, MMP-9, MMP-12, tissue inhibitor of MMP (TIMP-1, and TIMP-4 in rat lung tissues in response to CSE, and assessed the effect of simvastatin in regulating expression of MMPs and TIMPs.Methods: Thirty normal Sprague Dawley (SD rats were divided into control (n=10, CSE (n=10, and CSE plus simvastatin (n=10 groups. Animals were whole-body exposed to the cigarette smoke in the box for 1 hour each time, twice a day, 5 days a week for 16 weeks. Animals of CSE + simvastatin group were intra-gastrically administered simvastatin at a dose of 5 mg/kg/day followed by CSE. Bronchoalveolar lavage fluid was harvested for inflammatory cell count and lung tissues were stained for morphologic examination. Expression of mRNA and protein level of MMP-8, MMP-9, MMP-12, TIMP-1, and TIMP-4 was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry, respectively.Results: CSE resulted in a significant increase of mean linear intercept (MLI: 34.6±2.0 µm and bronchial wall thickness and diameter (BWT/D, 0.250±0.062 compared to control (MLI: 24.0±1.7 µm, BWT

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

International Nuclear Information System (INIS)

Wang Junru; Boerma, Marjan; Fu Qiang; Kulkarni, Ashwini; Fink, Louis M.; Hauer-Jensen, Martin

2007-01-01

Purpose: Microvascular injury plays a key role in normal tissue radiation responses. Statins, in addition to their lipid-lowering effects, have vasculoprotective properties that may counteract some effects of radiation on normal tissues. We examined whether administration of simvastatin ameliorates intestinal radiation injury, and whether the effect depends on protein C activation. Methods and Materials: Rats received localized, fractionated small bowel irradiation. The animals were fed either regular chow or chow containing simvastatin from 2 weeks before irradiation until termination of the experiment. Groups of rats were euthanized at 2 weeks and 26 weeks for assessment of early and delayed radiation injury by quantitative histology, morphometry, and quantitative immunohistochemistry. Dependency on protein C activation was examined in thrombomodulin (TM) mutant mice with deficient ability to activate protein C. Results: Simvastatin administration was associated with lower radiation injury scores (p < 0.0001), improved mucosal preservation (p = 0.0009), and reduced thickening of the intestinal wall and subserosa (p = 0.008 and p = 0.004), neutrophil infiltration (p = 0.04), and accumulation of collagen I (p = 0.0003). The effect of simvastatin was consistently more pronounced for delayed than for early injury. Surprisingly, simvastatin reduced intestinal radiation injury in TM mutant mice, indicating that the enteroprotective effect of simvastatin after localized irradiation is unrelated to protein C activation. Conclusions: Simvastatin ameliorates the intestinal radiation response. The radioprotective effect of simvastatin after localized small bowel irradiation does not appear to be related to protein C activation. Statins should undergo clinical testing as a strategy to minimize side effects of radiation on the intestine and other normal tissues

Theoretical and experimental study of fenofibrate and simvastatin

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Nicolás Vázquez, Inés; Rodríguez-Núñez, Jesús Rubén; Peña-Caballero, Vicente; Ruvalcaba, Rene Miranda; Aceves-Hernandez, Juan Manuel

2017-12-01

Fenofibrate, an oral fibrate lipid lowering agent, and simvastatin, which reduces plasma levels of low-density lipoprotein cholesterol, are active pharmaceutical ingredients (APIs), currently in the market. We characterized these APIs by thermal analysis and conducted X-ray powder diffraction techniques. Studies should be carried out in the formulation stage before the final composition of a polypill may be established. Thus, it was found in thermochemical studies that both compounds present no chemical interactions in an equimolar mixture of solid samples at room temperature. Theoretical studies were employed to determine possible interactions between fenofibrate and simvastatin. A very weak intramolecular hydrogen bond is formed between the hydroxyl group (O5H5) of the simvastatin with chlorine and carbonyl group (C11O4, C1O2) of the fenofibrate molecule. These weak energy hydrogen bonds have no effect on the chemical stability of the compounds studied. The results were obtained using Density Functional Theory methods; particularly the BPE1BPE and B3LYP functional and 6-31++G** basis set. The values of energy show good approximation when are compared with similar calculations previously reported. Infrared spectra of monomers and dimers were obtained via theoretical calculations.

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

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Almukhtar, H.; Garle, M.J.; Smith, P.A.; Roberts, R.E.

2016-01-01

Statins induce acute vasorelaxation which may contribute to the overall benefits of statins in the treatment of cardiovascular disease. The mechanism underlying this relaxation is unknown. As statins have been shown to alter mitochondrial function, in this study we investigated the role of mitochondria in the relaxation to simvastatin. Relaxation of porcine coronary artery segments by statins was measured using isolated tissue baths. Mitochondrial activity was determined by measuring changes in rhodamine 123 fluorescence. Changes in intracellular calcium levels were determined in freshly isolated smooth muscle cells with Fluo-4 using standard epifluorescent imaging techniques. Simvastatin, but not pravastatin, produced a slow relaxation of the coronary artery, which was independent of the endothelium. The relaxation was attenuated by the mitochondrial complex I inhibitor rotenone (10 μM) and the complex III inhibitor myxothiazol (10 μM), or a combination of the two. The complex III inhibitor antimycin A (10 μM) produced a similar time-dependent relaxation of the porcine coronary artery, which was attenuated by rotenone. Changes in rhodamine 123 fluorescence showed that simvastatin (10 μM) depolarized the membrane potential of mitochondria in both isolated mitochondria and intact blood vessels. Simvastatin and antimycin A both inhibited calcium-induced contractions in isolated blood vessels and calcium influx in smooth muscle cells and this inhibition was prevented by rotenone. In conclusion, simvastatin produces an endothelium-independent relaxation of the porcine coronary artery which is dependent, in part, upon effects on the mitochondria. The effects on the mitochondria may lead to a reduction in calcium influx and hence relaxation of the blood vessel. - Highlights: • Simvastatin produces a relaxation of the porcine coronary artery. • This relaxation is inhibited by mitochondrial complex inhibitors. • Simvastatin alters mitochondrial membrane potential

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

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Almukhtar, H.; Garle, M.J.; Smith, P.A.; Roberts, R.E., E-mail: richard.roberts@nottingham.ac.uk

2016-08-15

Statins induce acute vasorelaxation which may contribute to the overall benefits of statins in the treatment of cardiovascular disease. The mechanism underlying this relaxation is unknown. As statins have been shown to alter mitochondrial function, in this study we investigated the role of mitochondria in the relaxation to simvastatin. Relaxation of porcine coronary artery segments by statins was measured using isolated tissue baths. Mitochondrial activity was determined by measuring changes in rhodamine 123 fluorescence. Changes in intracellular calcium levels were determined in freshly isolated smooth muscle cells with Fluo-4 using standard epifluorescent imaging techniques. Simvastatin, but not pravastatin, produced a slow relaxation of the coronary artery, which was independent of the endothelium. The relaxation was attenuated by the mitochondrial complex I inhibitor rotenone (10 μM) and the complex III inhibitor myxothiazol (10 μM), or a combination of the two. The complex III inhibitor antimycin A (10 μM) produced a similar time-dependent relaxation of the porcine coronary artery, which was attenuated by rotenone. Changes in rhodamine 123 fluorescence showed that simvastatin (10 μM) depolarized the membrane potential of mitochondria in both isolated mitochondria and intact blood vessels. Simvastatin and antimycin A both inhibited calcium-induced contractions in isolated blood vessels and calcium influx in smooth muscle cells and this inhibition was prevented by rotenone. In conclusion, simvastatin produces an endothelium-independent relaxation of the porcine coronary artery which is dependent, in part, upon effects on the mitochondria. The effects on the mitochondria may lead to a reduction in calcium influx and hence relaxation of the blood vessel. - Highlights: • Simvastatin produces a relaxation of the porcine coronary artery. • This relaxation is inhibited by mitochondrial complex inhibitors. • Simvastatin alters mitochondrial membrane potential

Modulatory Role of Simvastatin against Aluminium Chloride-Induced Behavioural and Biochemical Changes in Rats

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Madhavan Nampoothiri

2015-01-01

Full Text Available Objectives. Aluminium, a neurotoxic agent in humans, has been implicated in the pathogenesis of neurodegenerative disorders. In this study, we examined the behavioral and biochemical effects of aluminium in rats with special emphasis on memory centres, namely, hippocampus and frontal cortex. Further, the effect of simvastatin treatment on aluminium intoxication was evaluated. Methods. Rats were exposed to aluminium chloride (AlCl3 for 60 days. Simvastatin (10 mg/kg/p.o. and rivastigmine (1 mg/kg/p.o. were administered daily prior to AlCl3. Behavioral parameters were assessed using Morris water maze test and actophotometer followed by biochemical investigations, namely, acetylcholinesterase (AChE activity, TNF-α level, antioxidant enzymes (GSH, catalase, lipid peroxidation, and nitrite level in hippocampus and frontal cortex. Triglycerides, total cholesterol, LDL, and HDL levels in serum were also determined. Key Findings. Simvastatin treatment improved cognitive function and locomotor activity in rats. Simvastatin reversed hyperlipidemia and significantly rectified the deleterious effect of AlCl3 on AChE activity. Further, in hippocampus and frontal cortex, aluminium-induced elevation in nitrite and TNF-α and reduction in antioxidant enzymes were inhibited by simvastatin. Conclusion. To conclude, the present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin.

Effects of Simvastatin Treatment on Serum Adiponectin Concentrations in Patients With Dislipidemia

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Moezzi, Atefeh; Parizadeh, Seyyed Mohammad Reza; Tavallaie, Shima; Mazidi, Mohsen; Afzali, Fariba; Adab, Afrouz; Ferns, Gordon; Ghayour Mobarhan, Majid

2014-01-01

Background: Adiponectin is an adipose tissue-derived protein with anti-inflammatory properties. Statins are a class of cholesterol-lowering drugs, widely used for treatment of cardiovascular diseases. Objectives: In the current study, we aimed to assess the effects of simvastatin on serum levels of adiponectin in patients with dyslipidemia, recruited from Ghaem Hospital, Mashhad, Iran. Materials and Methods: A total of 102 patients with dyslipidemia were treated with simvastatin or placebo during a double-blind, cross-over, placebo-controlled trial. The adiponectin levels were measured before and after each treatment period. Seventy seven participants completed the study. Results: There was a significant reduction in serum total cholesterol (approxmately 21%), low density lipoprotein-cholesterol (LDL-C) (approxmately 28%), and triglycerides (approxmately 11%), after four weeks of treatment with simvastatin (P < 0.001). Conclusions: No significant change in serum adiponectin concentrations was observed after treatment with simvastatin. This may be because of the relatively short duration of treatment and longer treatment duration may be necessary to investigation in future studies. PMID:25389496

Augmented simvastatin cytotoxicity using optimized lipid nanocapsules: a potential for breast cancer treatment.

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Safwat, Sally; Hathout, Rania M; Ishak, Rania A; Mortada, Nahed D

2017-03-01

We noticed paucity in exploiting solutol-based lipid nanocapsules in statins formulations though they carry all favorable properties that are needed for cancer passive targeting such as their small particle size, stealth properties, ability to highly accommodate lipophilic drugs, good internalization and P-gp pump inhibition. The aim of this study was to design and optimize new simvastatin drug delivery systems; lipid nanocapsules intended for administration through the intravenous route as potential treatment for breast cancer. Optimized nanocapsules were prepared by the phase-inversion method according to a D-optimal mixture design, characterized and assessed for their cytotoxicity. Three successful models for particle size, polydispersity index (PDI) and percentage of drug released after 48 h were generated. The prepared lipid nanocapsules acquired spherical and homogenous morphology, good stability and tolerance to sterilization. The obtained release profiles demonstrated desired sustained release pattern. Furthermore, testing selected formulations on human breast cancer adenocarcinoma cells showed augmented cytotoxicity of simvastatin reaching low IC50 values as 1.4 ± 0.02 μg/ml compared to the pure drug. The proposed lipid nanocapsules pose promising candidates as simvastatin carriers intended for the targeting of breast cancer.

Local delivery of controlled-release simvastatin to improve the biocompatibility of polyethylene terephthalate artificial ligaments for reconstruction of the anterior cruciate ligament

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Zhang P

2016-01-01

Full Text Available Peng Zhang,1,* Fei Han,2,* Yunxia Li,1 Jiwu Chen,1 Tianwu Chen,1 Yunlong Zhi,1 Jia Jiang,1 Chao Lin,2 Shiyi Chen,1 Peng Zhao2 1Department of Sports Medicine, Huashan Hospital, Fudan University, 2Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, School of Medicine, Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: The Ligament Advanced Reinforcement System has recently been widely used as the primary graft of choice in anterior cruciate ligament (ACL reconstruction. But the biological graft–bone healing still remains a problem. Previous studies have shown that simvastatin (SIM stimulates bone formation. The objective of this study was to investigate whether surface coating with collagen containing low-dose SIM microsphere could enhance the surface biocompatibility of polyethylene terephthalate (PET artificial ligaments to accelerate graft-to-bone healing. The in vitro studies demonstrated that bone marrow stromal cells on the collagen-coated PET scaffolds (COL/PET and simvastatin/collagen-coated PET scaffolds (SIM/COL/PET proliferated vigorously. Compared with the PET group and the COL/PET group, SIM could induce bone marrow stromal cells’ osteoblastic differentiation, high alkaline phosphatase activity, more mineralization deposition, and more expression of osteoblast-related genes, such as osteocalcin, runt-related transcription factor 2, bone morphogenetic protein-2, and vascular endothelial growth factor, in the SIM/COL/PET group. In vivo, rabbits received ACL reconstruction with different scaffolds. Histological analysis demonstrated that graft–bone healing was significantly greater with angiogenesis and osteogenesis in the SIM/COL/PET group than the other groups. In addition, biomechanical testing at the eighth week demonstrated a significant increase in the ultimate failure load and stiffness in the SIM/COL/PET group. The low dose of SIM

Inhibitory effects of simvastatin on oxidative stress of patients with type 2 diabetes mellitus

International Nuclear Information System (INIS)

Su Ying; Liu Xiaomin; Wang Yueying; Sun Yanming; Luan Ying

2008-01-01

To study the effects of simvastatin on oxidative stress and blood lipid metabolism of patients with type 2 diabetes mellitus, 168 diabetic patients were randomly divided into simvastatin group and placebo group. The serum levels of SOD and MDA, as well as the lipid profile in patients were observed before and after 12 weeks treatment, respectively. The results showed that the serum levels of SOD in diabetic patients before treatment were significantly lower, and whereas level of MDA was higher than that of controls (P 0.05). The serum levels of HDL-C in patients after treatment with simvastatin were higher, and while the serum levels of TG, TC, LDL-C and VLDL-C were significantly lower than that of before the treatment (P 0.05). Therefore, the simvastatin could significantly inhibit oxidative stress provoked by hyperglycemia and had beneficial effects on the lipid homeostasis of diabetic patients. (authors)

The effect of simvastatin on inflammation level and carotid artery plaque in patients with diabetes and hyperlipidaemia

International Nuclear Information System (INIS)

Tang Zhuangfei; Zou Yan

2011-01-01

Objective: To investigate the effect of simvastatin on inflammation level and carotid artery plaque in those patients with diabetes and hyperlipidaemia. Methods: A total of 120 patients with type 2 diabetes, accompanying with hyperlipidaemia were orally administered with 20 mg simvastatin each night for 12 weeks to control blood glucose. The changes of their blood lipid, hs-CRP, TNF-α and carotid artery plaque were observed. Results: After simvastatin administration,the serum total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) decreased significantly compared to that before treatment (P 0.05). The level of high sensitivity C-reactive protein(hs-CRP), tumor necrosis factor-α (TNF-α) descended markedly in patients after treatment versus before treatment (P<0.05 or P<0.01). The carotid artery plaque area, thickness and amounts all improved significantly after treatment (P<0.05 or P<0.01). Conclusion: Simvastatin can reduce the level of serum TC, TG and LDL-C in those patients with diabetes and hyperlipidaemia uniquely, but also diminish the inflammation level by regulating the levels of hs-CRP, TNF-α, thus reversing the occurrence, development of carotid artery plaque, lowering the long-term cerebrocardiovascular complications, and improving patients' prognosis. (authors)

Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: A possible role in statin-induced hepatotoxicity?

International Nuclear Information System (INIS)

Tavintharan, S.; Ong, C.N.; Jeyaseelan, K.; Sivakumar, M.; Lim, S.C.; Sum, C.F.

2007-01-01

Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ 10 ). In HepG2 cells, simvastatin decreased mitochondrial CoQ 10 levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ 10 , reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ 10 deficiency plays an important role in statin-induced hepatopathy, and that CoQ 10 supplementation protects HepG2 cells from this complication

Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

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Camargo, L.M.; França, C.N.; Izar, M.C.; Bianco, H.T.; Lins, L.S.; Barbosa, S.P.; Pinheiro, L.F.; Fonseca, F.A.H. [Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Medicina, São Paulo, SP, Brasil, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil)

2014-04-15

It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1Simvastatin/ezetimibe diphosphate did not change platelet aggregation, the amount of circulating endothelial and platelet microparticles, or endothelial progenitor cells. Cardiovascular protection following therapy with simvastatin/ezetimibe seems restricted to lipid changes and improvement of endothelial function not affecting the release of microparticles, mobilization of endothelial progenitor cells or decreased platelet aggregation.

Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

International Nuclear Information System (INIS)

Camargo, L.M.; França, C.N.; Izar, M.C.; Bianco, H.T.; Lins, L.S.; Barbosa, S.P.; Pinheiro, L.F.; Fonseca, F.A.H.

2014-01-01

It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1Simvastatin/ezetimibe diphosphate did not change platelet aggregation, the amount of circulating endothelial and platelet microparticles, or endothelial progenitor cells. Cardiovascular protection following therapy with simvastatin/ezetimibe seems restricted to lipid changes and improvement of endothelial function not affecting the release of microparticles, mobilization of endothelial progenitor cells or decreased platelet aggregation

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells

International Nuclear Information System (INIS)

Glynn, Sharon A; O'Sullivan, Dermot; Eustace, Alex J; Clynes, Martin; O'Donovan, Norma

2008-01-01

A number of recent studies have suggested that cancer incidence rates may be lower in patients receiving statin treatment for hypercholesterolemia. We examined the effects of statin drugs on in vitro proliferation, migration and invasion of melanoma cells. The ability of lovastatin, mevastatin and simvastatin to inhibit the melanoma cell proliferation was examined using cytotoxicity and apoptosis assays. Effects on cell migration and invasion were assessed using transwell invasion and migration chambers. Hypothesis testing was performed using 1-way ANOVA, and Student's t-test. Lovastatin, mevastatin and simvastatin inhibited the growth, cell migration and invasion of HT144, M14 and SK-MEL-28 melanoma cells. The concentrations required to inhibit proliferation of melanoma cells (0.8–2.1 μM) have previously been achieved in a phase I clinical trial of lovastatin in patients with solid tumours, (45 mg/kg/day resulted in peak plasma concentrations of approximately 3.9 μM). Our results suggest that statin treatment is unlikely to prevent melanoma development at standard doses. However, higher doses of statins may have a role to play in adjuvant therapy by inhibiting growth and invasion of melanoma cells

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

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Ning Wang

2018-03-01

Full Text Available Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND 7 and neural stem cells (NSCs were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ and subgranular zone (SGZ of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

Protective effects of simvastatin on coronary artery function in swine with acute infection

DEFF Research Database (Denmark)

Liuba, Petru; Pesonen, Erkki; Forslid, Anders

2006-01-01

cholesterol) between the groups (p>0.2). CONCLUSION:: Acute infection is associated with impairment of the muscarinic and kinin-related reactivity of coronary circulation. These functional abnormalities are in part prevented by simvastatin through mechanisms unrelated to lipid lowering......BACKGROUND:: The risk for coronary events may rise during acute infection. Perturbation in coronary endothelial function emerges as one important link. We investigated whether simvastatin could protect the coronary arterial function from the adverse effects of acute infection in swine. METHODS......:: Coronary endothelium-dependent and -independent vasomotor responses were assessed by Doppler velocimetry in 12 Chlamydia pneumoniae-infected and 6 sham-infected swine 2 weeks after intratracheal inoculation. Half of animals from the infection group were pre-treated with simvastatin (80mg daily), while...

Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor.

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Lim, Taekyu; Lee, Inkyoung; Kim, Jungmin; Kang, Won Ki

2015-10-01

We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

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Lim, Taekyu [Division of Hematology-Oncology, Department of Internal Medicine, VHS Medical Center, Seoul (Korea, Republic of); Lee, Inkyoung [Biomedical Research Institute, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jungmin [Changduk Girls' High School, Seoul (Korea, Republic of); Kang, Won Ki, E-mail: wonki.kang@samsung.com [Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2015-10-01

Purpose: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Methods and Materials: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. Results: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. Conclusion: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

Protective effect of coenzyme Q10 in simvastatin and gemfibrozil induced rhabdomyolysis in rats.

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Farswan, Mamta; Rathod, S P; Upaganlawar, A B; Semwal, Arvind

2005-10-01

Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis. Increase in the level of reduced glutathione, superoxide dismutase, catalase and decrease in the level of lipid peroxidation and serum parameters after administration of antioxidant CoQ10 (10 mg/kg.ip) proved the protective effect of CoQ10 in rhabdomyolysis.

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I

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Graziela Vieira

2017-09-01

Full Text Available Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP was induced by ischemia and reperfusion (IR injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs activator] and bradykinin (BK stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2. Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron. Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.

Simvastatin-nicotinamide co-crystal: design, preparation and ...

African Journals Online (AJOL)

Purpose: To improve the solubility of simvastatin (SV) by co-crystallization using nicotinamide (Nic) as co-crystal agent (co-former). Methods: In silico molecular modeling of Nic counter to SV were investigated using Auto Dock 4.2. Cocrystal of Nic-SV was obtained by solvent evaporation (SE) using an equimolar ratio of Nic ...

Effect of the Combination of Ezetimibe and Simvastatin on Gluconeogenesis and Oxygen Consumption in the Rat Liver.

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Bracht, Lívia; Caparroz-Assef, Silvana Martins; Bracht, Adelar; Bersani-Amado, Ciomar Aparecida

2016-06-01

The aim of this work was to investigate the effects of chronic treatment with the combination of ezetimibe and simvastatin on gluconeogenesis in rat liver. Rats were treated daily for 28 days with the combination of ezetimibe and simvastatin (10/40 mg/kg) by oral gavage. To measure gluconeogenesis and the associated pathways, isolated perfused rat liver was used. In addition, subcellular fractions, such as microsomes and mitochondria, were used for complementary measures of enzymatic activities. Treatment with the combination of simvastatin and ezetimibe resulted in a decrease in gluconeogenesis from pyruvate (-62%). Basal oxygen consumption of the treated animals was higher (+22%) than that of the control rats, but the resulting oxygen consumption that occurred after pyruvate infusion was 43% lower in animals treated with the combination of simvastatin and ezetimibe. Oxygen consumption in the livers from treated animals was completely inhibited by cyanide (electron transport chain inhibitor), but not by proadifen (cytochrome P450 inhibitor). Chronic treatment with ezetimibe/simvastatin decreased the activity of the key enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase by 59% and 45%, respectively, which is probably the major reason for the decreased gluconeogenesis seen in ezetimibe-/simvastatin-treated rats. It is also possible that part of the effect of this combination on gluconeogenesis and on the oxygen consumption is related to the impairment of mitochondrial energy transduction. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

[Effect of simvastatin on inducing endothelial progenitor cells homing and promoting bone defect repair].

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Song, Quansheng; Wang, Lingying; Zhu, Jinglin; Han, Xiaoguang; Li, Xu; Yang, Yanlin; Sun, Yan; Song, Chunli

2010-09-01

To investigate the effect of simvastatin on inducing endothelial progenitor cells (EPCs) homing and promoting bone defect repair, and to explore the mechanism of local implanting simvastatin in promoting bone formation. Simvastatin (50 mg) compounded with polylactic acid (PLA, 200 mg) or only PLA (200 mg) was dissolved in acetone (1 mL) to prepare implanted materials (Simvastatin-PLA material, PLA material). EPCs were harvested from bone marrow of 2 male rabbits and cultured with M199; after identified by immunohistochemistry, the cell suspension of EPCs at the 3rd generation (2 x 10(6) cells/mL) was prepared and transplanted into 12 female rabbits through auricular veins (2 mL). After 3 days, the models of cranial defect with 15 cm diameter were made in the 12 female rabbits. And the defects were repaired with Simvastatin-PLA materials (experimental group, n=6) and PLA materials (control group, n=6), respectively. The bone repair was observed after 8 weeks of operation by gross appearance, X-ray film, and histology; gelatin-ink perfusion and HE staining were used to show the new vessels formation in the defect. Fluorescence in situ hybridization (FISH) was performed to show the EPCs homing at the defect site. All experimental animals of 2 groups survived to the end of the experiment. After 8 weeks in experimental group, new bone formation was observed in the bone defect by gross and histology, and an irregular, hyperdense shadow by X-ray film; no similar changes were observed in control group. FISH showed that the male EPC containing Y chromosome was found in the wall of new vessels in the defect of experimental group, while no male EPC containing Y chromosome was found in control group. The percentage of new bone formation in defect area was 91.63% +/- 4.07% in experimental group and 59.45% +/- 5.43% in control group, showing significant difference (P < 0.05). Simvastatin can promote bone defect repair, and its mechanism is probably associated with inducing EPCs

Protective effects of l-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin.

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Costa, Rute A P; Fernandes, Mariana P; de Souza-Pinto, Nadja C; Vercesi, Aníbal E

2013-02-15

Mitochondrial oxidative stress followed by membrane permeability transition (MPT) has been considered as a possible mechanism for statins cytotoxicity. Statins use has been associated with reduced risk of cancer incidence, especially prostate cancer. Here we investigated the pathways leading to simvastatin-induced prostate cancer cell death as well as the mechanisms of cell death protection by l-carnitine or piracetam. These compounds are known to prevent and/or protect against cell death mediated by oxidative mitochondrial damage induced by a variety of conditions, either in vivo or in vitro. The results provide evidence that simvastatin induced MPT and cell necrosis were sensitive to either l-carnitine or piracetam in a dose-dependent fashion and mediated by additive mechanisms. When combined, l-carnitine and piracetam acted at concentrations significantly lower than they act individually. These results shed new light into both the cytotoxic mechanisms of statins and the mechanisms underlying the protection against MPT and cell death by the compounds l-carnitine and piracetam. Copyright © 2013 Elsevier B.V. All rights reserved.

Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial.

Science.gov (United States)

Pollo-Flores, Priscila; Soldan, Mônica; Santos, Ubiratan Cassano; Kunz, Danielle Gobbi; Mattos, Denise Espindola; da Silva, Alexandre Cerqueira; Marchiori, Roberta Cabral; Rezende, Guilherme Ferreira da Motta

2015-11-01

Pleiotropic effects of statins decrease intrahepatic resistance and portal hypertension. We evaluated the effects of simvastatin on hepatic venous pressure gradient (HVPG) and azygos vein blood flow in cirrhotic patients. A 3-month prospective, randomized, triple-blind trial with simvastatin (40 mg/day) vs. placebo was conducted in patients with cirrhotic portal hypertension. HVPG and azygos blood flow, measured by colour Doppler endoscopic ultrasound, were assessed before and after treatment. The primary endpoint was a decrease in the HVPG of at least 20% from baseline or to ≤12 mmHg after the treatment. 34 patients were prospectively enrolled, and 24 completed the protocol. In the simvastatin group 6/11 patients (55%) presented a clinically relevant decrease in the HVPG; no decrease was observed in the placebo group (p=0.036). Patients with medium/large oesophageal varices and previous variceal bleeding had a higher response rate to simvastatin. HVPG and azygos blood flow values were not correlated. No significant adverse events occurred. Simvastatin lowers portal pressure and may even improve liver function. The haemodynamic effect appears to be more evident in patients with severe portal hypertension. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A network meta-analysis on randomized trials focusing on the preventive effect of statins on contrast-induced nephropathy

DEFF Research Database (Denmark)

Peruzzi, Mariangela; De Luca, Leonardo; Thomsen, Henrik S

2014-01-01

-analysis. Randomized trials focusing on statins were searched and pooled with random-effect odds ratios. A total of 14 trials (6,160 patients) were included, focusing on atorvastatin (high/low dose), rosuvastatin (high dose), simvastatin (high/low dose), and placebo or no statin therapy before contrast administration....... The risk of contrast-induced nephropathy was reduced by atorvastatin high dose and rosuvastatin high dose, with no difference between these two agents. Results for atorvastatin low dose and simvastatin (high/low dose) in comparison to placebo were inconclusive. Atorvastatin and rosuvastatin administered...

Evaluation of the effects of subgingival injection of Simvastatin on space re-opening after orthodontic space closure in adults

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Arezoo Jahanbin

2016-03-01

Full Text Available Background. This clinical trial evaluated the effect of Simvastatin on space re-opening after orthodontic space closure and its effect on the gingival index (GI and clinical attachment loss (CAL. Methods. 16 females, 25‒40 years old, with spaces between anterior mandibular teeth due to chronic periodontitis were participated in this study. The patients were randomly divided into control and experimental groups. In the experimental group, 1.2% Simvastatin gel and in the control group, 0.9% sodium chloride as a placebo was injected into the pocket depth of the six anterior teeth. The amount of space reopening, GI and CAL were measured. Results. No serious complications were observed during interventions and follow-up periods. Space re-opening was significantly reduced in patients receiving Simvastatin (P < 0.001. Moreover, GI reduction was significantly greater in Sim-vastatin group compared to the control group (P < 0.001. However, CAL did not demonstrate a significant difference between the groups. Conclusion. Simvastatin may decrease space re-opening after orthodontic space closure in human anterior teeth.

Application of mixture experimental design to simvastatin apparent solubility predictions in the microemulsifion formed by self-microemulsifying.

Science.gov (United States)

Meng, Jian; Zheng, Liangyuan

2007-09-01

Self-microemulsifying drug delivery systems (SMEDDS) are useful to improve the bioavailability of poorly water-soluble drugs by increasing their apparent solubility through solubilization. However, very few studies, to date, have systematically examined the level of drug apparent solubility in o/w microemulsion formed by self-microemulsifying. In this study, a mixture experimental design was used to simulate the influence of the compositions on simvastatin apparent solubility quantitatively through an empirical model. The reduced cubic polynomial equation successfully modeled the evolution of simvastatin apparent solubility. The results were presented using an analysis of response surface showing a scale of possible simvastatin apparent solubility between 0.0024 ~ 29.0 mg/mL. Moreover, this technique showed that simvastatin apparent solubility was mainly influenced by microemulsion concentration and, suggested that the drug would precipitate in the gastrointestinal tract due to dilution by gastrointestinal fluids. Furthermore, the model would help us design the formulation to maximize the drug apparent solubility and avoid precipitation of the drug.

RED ROSELLA TEA AND AVOCADO AS SIMVASTATIN THERAPY SUPPORT REDUCE TOTAL CHOLESTEROL

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Budi Artini

2017-06-01

Full Text Available Introduction: Hypercholesterolemia is a condition characterized by high levels of total cholesterol in the blood. Many studies have proven that steeping tea rosella and flesh of an avocado can reduce total cholesterol levels. This study was conducted to determine the effectiveness of therapy companion rosella tea and  avocado in lowering total cholesterol levels in hypercholesterolemia clients. Method: This type of research is a quasi-experimental study with pre-post test control group design. The population study was a client with hypercholesterolemia in the working area of menganti health centers. First sample group consisted of nine respondents received the drug Simvastatin 10 mg and rosella tea consumed as much as 2 g 1x / day. The second group consisted of nine respondents received the drug Simvastatin 10 mg and avocado meat weighing 330 grams were consumed 1x / day. The control group consisted of 11 respondents have a drug Simvastatin 10 mg oral 1x daily at night before bed. All groups examined total cholesterol levels before treatment and after treatment on day 15. Result: The results of one-way ANOVA test showed a significant difference between before and after treatment in the first group (p=0,001 and second group (p= 0,005, and there is no significant difference before and after treatment in the control group (p= 0,248. The difference between the three groups showed p= 0.025. Conclusion: The conclusion of this study is giving rosella tea and avocado has the same effectiveness in lowering total cholesterol levels so that health workers can suggest the use of rosella tea and avocado as a companion therapy to reduce total cholesterol level.

The Remarkable Beneficial Effect of Adding Oral Simvastatin to ...

African Journals Online (AJOL)

Psoriasis is a common chronic inflammatory disease with unpredictable prognosis. Given the immunomodulatory effects of statins, the present study was conducted to determine whether the addition of orally administered simvastatin to the topical betamethasone, a standard antipsoriatic treatment, can produce a more ...

Biofunctionalization of Titanium Granules with Simvastatin for Improving Osteogenic Activity and Antibacterial Properties (Ex Vivo Study).

Science.gov (United States)

Karaji, Zahra Gorgin; Houshmand, Behzad; Abbasi, Shahsanam; Shafiei, Sara; Faghihi, Shahab

Titanium-based biomaterials present good biocompatibility, while their osseointegration and antibacterial properties need to be improved. This study aimed to enhance the bone-bonding ability of titanium-based granules, which are intended to be used as bone graft. The titanium granules were anodized in ethylene glycol-based electrolyte and subsequently annealed to be loaded separately with simvastatin. The samples were then inspected with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) for drug loading. The release of simvastatin from titanium granule samples was measured after soaking samples in phosphate-buffered saline (PBS) for 30 days using ultraviolet-visible (UV/Vis) spectroscopy. The alkaline phosphatase (ALP) activity of MG63 osteosarcoma-loaded samples was measured, and microbroth dilution assay was performed to evaluate the antibacterial potential of drug-loaded and nonloaded titanium granule samples for bacterial growth. The results expressed the gradual and constant release of simvastatin within the duration of the examination. ALP of the samples showed improved activity of anodized and annealed granules, while the antibacterial test illustrated no significant improvement in their bactericidal effects. However, the simvastatin-loaded samples showed an improved antibacterial effect compared with nonloaded samples. It is assumed that anodizing, annealing, and subsequent simvastatin loading of titanium granules could be used as surface modification to improve osseointegration and restrain bacterial growth and adhesion. It is fair to believe that the results of this study could be used to treat titanium granules as bone graft substitute materials for dental and orthopedic applications.

The influence of milling on the dissolution performance of simvastatin

DEFF Research Database (Denmark)

Zimper, Ulrike; Aaltonen, Jaakko; Krauel-Goellner, Karen

2012-01-01

properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors......, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed...... by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were...

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

Energy Technology Data Exchange (ETDEWEB)

Smiderle, Lisiane [Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Lima, Luciana O.; Hutz, Mara Helena [Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Sand, Cézar Roberto Van der; Sand, Luiz Carlos Van der; Ferreira, Maria Elvira Wagner; Pires, Renan Canibal [Centro de Diagnóstico Cardiológico, Porto Alegre, RS (Brazil); Almeida, Silvana; Fiegenbaum, Marilu [Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil)

2014-07-15

Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

International Nuclear Information System (INIS)

Smiderle, Lisiane; Lima, Luciana O.; Hutz, Mara Helena; Sand, Cézar Roberto Van der; Sand, Luiz Carlos Van der; Ferreira, Maria Elvira Wagner; Pires, Renan Canibal; Almeida, Silvana; Fiegenbaum, Marilu

2014-01-01

Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations

Directed Evolution and Structural Characterization of a Simvastatin Synthase

Energy Technology Data Exchange (ETDEWEB)

Gao, Xue; Xie, Xinkai; Pashkov, Inna; Sawaya, Michael R.; Laidman, Janel; Zhang, Wenjun; Cacho, Ralph; Yeates, Todd O.; Tang, Yi; UCLA

2010-02-02

Enzymes from natural product biosynthetic pathways are attractive candidates for creating tailored biocatalysts to produce semisynthetic pharmaceutical compounds. LovD is an acyltransferase that converts the inactive monacolin J acid (MJA) into the cholesterol-lowering lovastatin. LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic {alpha}-dimethylbutyryl thioester, albeit with suboptimal properties as a biocatalyst. Here we used directed evolution to improve the properties of LovD toward semisynthesis of simvastatin. Mutants with improved catalytic efficiency, solubility, and thermal stability were obtained, with the best mutant displaying an {approx}11-fold increase in an Escherichia coli-based biocatalytic platform. To understand the structural basis of LovD enzymology, seven X-ray crystal structures were determined, including the parent LovD, an improved mutant G5, and G5 cocrystallized with ligands. Comparisons between the structures reveal that beneficial mutations stabilize the structure of G5 in a more compact conformation that is favorable for catalysis.

Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature.

Science.gov (United States)

Lopez, Jose Luis; Tayek, John A

2016-01-01

Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 μg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole

Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene–polypropylene block copolymer for maximized disintegration and dissolution

Science.gov (United States)

Balata, Gehan F; Zidan, Ahmad S; Abourehab, Mohamad AS; Essa, Ebtessam A

2016-01-01

The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene–polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT’s porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin. PMID:27757012

Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene-polypropylene block copolymer for maximized disintegration and dissolution.

Science.gov (United States)

Balata, Gehan F; Zidan, Ahmad S; Abourehab, Mohamad As; Essa, Ebtessam A

2016-01-01

The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene-polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 3 2 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT's porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

Science.gov (United States)

Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

2015-10-13

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene–polypropylene block copolymer for maximized disintegration and dissolution

Directory of Open Access Journals (Sweden)

Balata GF

2016-10-01

Full Text Available Gehan F Balata,1,2 Ahmad S Zidan,2 Mohamad AS Abourehab,1,3 Ebtessam A Essa4 1Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, 3Department of Pharmaceutics, Faculty of Pharmacy, El-Minia University, El-Minia, 4Department of Pharmaceutics, Faculty of Pharmacy, Tanta University, Tanta, Egypt Abstract: The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs with an optimized disintegration and dissolution characteristics. Polyoxyethylene–polypropylene block copolymer (poloxamer 188 was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs. Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT’s porosity and to fasten disintegration rather than swelling action by

The effects of simvastatin or interferon-α on infectivity of human norovirus using a gnotobiotic pig model for the study of antivirals.

Directory of Open Access Journals (Sweden)

Kwonil Jung

Full Text Available The lack of an animal model for human norovirus (HuNoV has hindered the development of therapeutic strategies. This study demonstrated that a commonly used cholesterol-lowering statin medication, simvastatin, which increases HuNoV replication in an in vitro replicon system, also enhances HuNoV infectivity in the gnotobiotic (Gn pig model. In contrast, oral treatment with interferon (IFN-α reduces HuNoV infectivity. Young piglets, all with A or H1 histo-blood group antigens on enterocytes, were treated orally with 8 mg/kg/day of simvastatin; 5 days later, the pigs were inoculated orally with a GII.4 HuNoV (HS194/2009/US strain and then treated with simvastatin for 5 more days. Simvastatin induced significantly earlier onset and longer duration of HuNoV fecal shedding in treated pigs, frequently with higher fecal viral titers. Simvastatin impaired poly (I:C-induced IFN-α expression in macrophages or dendritic cells, possibly due to lowered toll-like receptor (TLR 3 expression; however, the mechanisms were not related to interferon regulatory factor 3 or nuclear factor kappa B signaling pathway. Thus, the enhanced, earlier infectivity of HuNoV in simvastatin-treated pigs coincided with the inhibitory effect of simvastatin on innate immunity. In contrast to the increased HuNoV shedding that simvastatin induced, viral shedding during the treatment period was reduced or curtailed in the HuNoV-inoculated pigs pre-treated/treated with human IFN-α. Our findings are the first to indicate that IFN-α has potential as antiviral therapy against HuNoV. Based on these intriguing and novel findings using the Gn pig model, we confirmed that HuNoV infectivity is altered by treatment with simvastatin or IFN-α. Collectively, these findings indicate that Gn pigs are a useful model to test immunomodulators or efficacy of antivirals against HuNoV.

Valutazione economica dello studio IDEAL

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Enrica Menditto

2007-10-01

Full Text Available Introduction: the IDEAL (“High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction” study was carried out to compare intensive lowering of low-density lipoprotein (LDL-cholesterol using the highest recommended dose of atorvastatin 80 mg with simvastatin 40 mg. Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of simvastatin in reducing major coronary events in patients with a history of acute myocardial infarction (AMI. Methods: the analysis is based on clinical outcome data from the IDEAL study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die versus usual-dose of simvastatin (20 mg/die in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2006. Effects were measured in terms of mortality and morbidity reduction (number of deaths, life years gained and frequency of hospitalizations. We considered an observation period of 4.8 years. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. We also conducted a threshold analysis. Results: the cost of simvastatin or atorvastatin therapy over the 4.8 years period amounted to approximately 2.3 millions euro and 2.6 millions euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to simvastatin and the overall cost of care per 1,000 patients over 4.8 years of follow-up was estimated at 4.3 millions euro in the simvastatin and 4,18 millions euro in the atorvastatin group, resulting into a cost saving of 121,518 euro that is 2.8% of total costs occurred in the simvastatin group. Discussion: this study is the first economic

Limited Sampling Strategy for the Prediction of Area Under the Curve (AUC) of Statins: Reliability of a Single Time Point for AUC Prediction for Pravastatin and Simvastatin.

Science.gov (United States)

Srinivas, N R

2016-02-01

Statins are widely prescribed medicines and are also available in fixed dose combinations with other drugs to treat several chronic ailments. Given the safety issues associated with statins it may be important to assess feasibility of a single time concentration strategy for prediction of exposure (area under the curve; AUC). The peak concentration (Cmax) was used to establish relationship with AUC separately for pravastatin and simvastatin using published pharmacokinetic data. The regression equations generated for statins were used to predict the AUC values from various literature references. The fold difference of the observed divided by predicted values along with correlation coefficient (r) were used to judge the feasibility of the single time point approach. Both pravastatin and simvastatin showed excellent correlation of Cmax vs. AUC values with r value ≥ 0.9638 (pAUC predictions and >81% of the predicted values were in a narrower range of >0.75-fold but AUC values showed excellent correlation for pravastatin (r=0.9708, n=115; pAUC predictions. On the basis of the present work, it is feasible to develop a single concentration time point strategy that coincides with Cmax occurrence for both pravastatin and simvastatin from a therapeutic drug monitoring perspective. © Georg Thieme Verlag KG Stuttgart · New York.

Simvastatin Attenuates the Oxidative Stress, Endothelial Thrombogenicity and the Inducibility of Atrial Fibrillation in a Rat Model of Ischemic Heart Failure

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Kyoung-Im Cho

2014-08-01

Full Text Available Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF, and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI-induced heart failure (HF rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group and underwent echocardiography, AF induction studies and left atrial (LA fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (INCX, sarcoplasmic reticulum calcium ATPase (SERCA, endothelial nitric oxide synthase (eNOS and induced nitric oxide synthase (iNOS were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham, which were significantly reduced by simvastatin (p < 0.05 vs. MI. The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, INCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes.

Determination of the antibacterial activity of simvastatin against periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans: An in vitro study

Directory of Open Access Journals (Sweden)

Shilpa Emani

2014-01-01

Full Text Available Context and Objective: Statin treatment, apart from its hypolipidemic action has proven its antimicrobial activity by improving the survival rate of patients with severe systemic bacterial infections. Periodontitis is an inflammatory disorder of tooth supporting structures caused by a group of specific microorganisms. The objective of the present study was to determine the antimicrobial activity of pure simvastatin drug against the primary periodontal pathogens. Materials and Methods: Minimum inhibitory concentration (MIC was determined against Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans using serial dilution method. Results: MIC of simvastatin against P. gingivalis was 2 μg/ml and A. actinomycetemcomitans was found to be <1 μg/ml which requires further dilutions to determine the exact value. Conclusions: Data suggests a potent antimicrobial activity of simvastatin against both A. actinomycetemcomitans and P gingivalis. Hence simvastatin can be prescribed as a dual action drug in patients with both hyperlipidemia and periodontal disease.

Simvastatin Inhibits IL-5-Induced Chemotaxis and CCR3 Expression of HL-60-Derived and Human Primary Eosinophils.

Science.gov (United States)

Fu, Chia-Hsiang; Tsai, Wan-Chun; Lee, Ta-Jen; Huang, Chi-Che; Chang, Po-Hung; Su Pang, Jong-Hwei

2016-01-01

IL-5-induced chemotaxis of eosinophils is an important feature of allergic airway inflammatory diseases. Simvastatin, a lipid lowering agent, has been shown to exhibit anti-inflammatory and anti-allergic effects. Our aim was to investigate the effect of simvastatin on IL-5-induced eosinophil chemotaxis and its regulatory mechanisms. Eosinophils were derived by treating HL-60 clone 15 (HC15) cells with butyric acid (BA) in an alkaline condition or through direct isolation from human peripheral blood. The expressions of CC chemokine receptor 3 (CCR3) and interleukin (IL)-5 receptors (IL5Rα and β) were analyzed using RT/real-time PCR. The granular proteins were stained using fast green. Eotaxin-induced chemotaxis was measured using a transwell migration assay. CCR3 protein expression was revealed by immunocytochemistry. An animal model of allergic rhinitis was established by challenging Sprague-Dawley® rats repeatedly with ovalbumin. Butyric acid significantly increased the expression of IL5Rα and IL5Rβ, CCR3 and granular proteins in HC15 cells, indicating the maturation of eosinophils (BA-E cells). IL-5 further enhanced the CCR3 expression at both the mRNA and protein levels and the eotaxin-induced chemotaxis of BA-E cells. Simvastatin inhibited the effects of IL-5 on BA-E cells, but not in the presence of mevalonate. Similar results were also exhibited in human primary eosinophils. In vivo animal studies further confirmed that oral simvastatin could significantly suppress the infiltration of eosinophils into turbinate tissues of allergic rats. Therefore, simvastatin was demonstrated to inhibit IL-5-induced CCR3 expression and chemotaxis of eosinophils mediated via the mevalonate pathway. We confirmed that simvastatin also reduced eosinophilic infiltration in allergic rhinitis.

Simvastatin as an Adjunct to Conventional Therapy of Non-infectious Uveitis: A Randomized, Open-Label Pilot Study.

Science.gov (United States)

Shirinsky, Ivan V; Biryukova, Anastasia A; Shirinsky, Valery S

2017-12-01

Statins have been shown to reduce ocular inflammation in animal models of uveitis and to prevent development of uveitis in observational studies. There have been no experimental human studies evaluating statins' efficacy and safety in uveitis. In this study, we aimed to investigate efficacy and safety of simvastatin in patients with uveitis. For this single-center, open-label, randomized study, we enrolled patients with acute non-infectious uveitis. The patients were randomized to receive 40 mg simvastatin per day for 2 months in addition to conventional treatment or conventional treatment alone. The studied outcomes were the rate of steroid-sparing control of ocular inflammation, measures of ocular inflammation, intraocular pressure, and visual acuity. Fifty patients were enrolled in the study. Twenty-five patients were randomly assigned to receive simvastatin with conventional treatment and 25 to conventional treatment alone. Simvastatin was associated with significantly higher rates of steroid-sparing ocular inflammation control, decrease in anterior chamber inflammation, and improvement in visual acuity. The treatment was well tolerated, no serious adverse effects were observed. Our findings suggest that statins may have therapeutic potential in uveitis. These results need to be confirmed in double-blind, randomized, controlled studies.

The effects of membrane cholesterol and simvastatin on red blood cell deformability and ATP release.

Science.gov (United States)

Forsyth, Alison M; Braunmüller, Susanne; Wan, Jiandi; Franke, Thomas; Stone, Howard A

2012-05-01

It is known that deformation of red blood cells (RBCs) is linked to ATP release from the cells. Further, membrane cholesterol has been shown to alter properties of the cell membrane such as fluidity and bending stiffness. Membrane cholesterol content is increased in some cardiovascular diseases, for example, in individuals with acute coronary syndromes and chronic stable angina, and therefore, because of the potential clinical relevance, we investigated the influence of altered RBC membrane cholesterol levels on ATP release. Because of the correlation between statins and reduced membrane cholesterol in vivo, we also investigated the effects of simvastatin on RBC deformation and ATP release. We found that reducing membrane cholesterol increases cell deformability and ATP release. We also found that simvastatin increases deformability by acting directly on the membrane in the absence of the liver, and that ATP release was increased for cells with enriched cholesterol after treatment with simvastatin. Copyright © 2012 Elsevier Inc. All rights reserved.

Myopati hos en patient i behandling med simvastatin og fluconazol

DEFF Research Database (Denmark)

Pedersen, Jens Kristian; Lydolph, Magnus Christian; Somnier, Finn

2016-01-01

A 69-year-old female was admitted due to progressive loss of muscle strength following addition of fluconazole to long-term simvastatin treatment. Rhabdomyolysis was suspected and both drugs were discontinued. Forced diuresis was initiated together with a short course of prednisolone. After 21...

Simvastatin affects cell motility and actin cytoskeleton distribution of microglia

NARCIS (Netherlands)

Kuipers, HF; Rappert, Angelika A.C.; Mommaas, AM; Van Haastert, ES; Van der Valk, P; Boddeke, HWGM; Biber, KPH; Van den Elsen, PJ

2006-01-01

Statin treatment is proposed to be a new potential therapy for multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. The effects of statin treatment on brain cells, however, are hardly understood. We therefore evaluated the effects of simvastatin treatment on

Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells.

Science.gov (United States)

Sanfelice, Raquel Arruda; da Silva, Suelen Santos; Bosqui, Larissa Rodrigues; Miranda-Sapla, Milena Menegazzo; Barbosa, Bellisa Freitas; Silva, Rafaela José; Ferro, Eloísa A Vieira; Panagio, Luciano Aparecido; Navarro, Italmar Teodorico; Bordignon, Juliano; Conchon-Costa, Ivete; Pavanelli, Wander Rogerio; Almeida, Ricardo Sergio; Costa, Idessania Nazareth

2017-03-01

The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs. Some studies suggest the use of statins, which inhibit cholesterol synthesis in humans and also the initial processes of isoprenoid biosynthesis in the parasite. Thus, the objective of this study was to evaluate the activity of the statins pravastatin and simvastatin in HeLa cells infected in vitro with the RH strain of T. gondii. HeLa cells (1×10 5 ) were infected with T. gondii tachyzoites (5×10 5 ) following two different treatment protocols. In the first protocol, T. gondii tachyzoites were pretreated with pravastatin (50 and 100μg/mL) and simvastatin (1.56 and 3.125μg/mL) for 30min prior to infection. In the second, HeLa cells were first infected (5×10 5 ) with tachyzoites and subsequently treated with pravastatin and simvastatin for 24h at the concentrations noted above. Initially, we evaluated the cytotoxicity of drugs by the MTT assay, number of tachyzoites adhered to cells, number of infected cells, and viability of tachyzoites by trypan blue exclusion. The supernatant of the cell cultures was collected post-treatment for determination of the pattern of Th1/Th2/Th17 cytokines by cytometric bead array. There was no cytotoxicity to HeLa cells with 50 and 100μg/mL pravastatin and 1.56 and 3.125μg/mL simvastatin. There was no change in the viability of tachyzoites that received pretreatment. Regarding the pre- and post-treatment of the cells with pravastatin and simvastatin alone, there was a reduction in adhesion, invasion and proliferation of cells to T. gondii. As for the production of cytokines, we found that IL-6 and IL-17 were significantly reduced in cells infected with T. gondii and treated with pravastatin and simvastatin, when compared to control. Based on these results, we can infer that pravastatin and simvastatin alone possess antiproliferative effects on tachyzoites forms

Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin

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Mangravite, Lara M.; Medina, Marisa Wong; Cui, Jinrui; Pressman, Sheila; Smith, Joshua D.; Rieder, Mark J.; Guo, Xiuqing; Nickerson, Deborah A.; Rotter, Jerome I.; Krauss, Ronald M.

2010-01-01

Objectives Although statins are efficacious for lowering LDL-cholesterol (LDLC), there is wide inter-individual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability. Methods and Results Haplotypes in the LDLR 3′-untranslated region (3UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics (CAP) trial (335 African-Americans and 609European-Americans). LDLR haplotype 5 (L5)was associated with smaller simvastatin-induced reductions in LDLC, total cholesterol, non-HDL cholesterol, and apolipoprotein B (P=0.0002–0.03)in African-Americans, but not European-Americans. The combined presence of L5 and previously described HMGCR haplotypes in African-Americans was associated with significantly attenuated apoB reduction(−22.4±1.5% N=89) both compared to noncarriers (−30.6±1.5% N=78, P=0.0001) and to carriers of either individual haplotype (−28.2±1.1% N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of LDLR surface expression using lymphoblast cell lines (P=0.03). Conclusions We have identified a common LDLR 3UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by increased prevalence of these combined haplotypes in African-Americans. PMID:20413733

Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin

DEFF Research Database (Denmark)

Zhang, Fang; Aaltonen, Jaakko; Tian, Fang

2009-01-01

This study investigated the factors influencing the stability of amorphous simvastatin. Quench-cooled amorphous simvastatin in two particle size ranges, 150-180 microm (QC-big) and ... compared to the crystalline form. The rank of solubility was found to be QC-big=QC-small>CM>crystalline. For the physical stability, the highest crystallization rate was observed for CM, and the slowest rate was detected for QC-big, with an intermediate rate occurring for QC-small. QC exhibited lower...

Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis

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Mouchrek Júnior JCE

2017-05-01

Full Text Available José Carlos Elias Mouchrek Júnior,1 Cristina Gomes Macedo,2 Henrique Ballassini Abdalla,2 Ana Karina Saba,1 Lucas Novaes Teixeira,1 Adriana Quinzeiro e Silva Mouchrek,3 Marcelo Henrique Napimoga,1 Juliana Trindade Clemente-Napimoga,1 Alvaro Henrique Borges,4 Mateus Rodrigues Tonetto,4 Shelon Cristina Souza Pinto,5 Matheus Coelho Bandeca,3 Elizabeth Ferreira Martinez1 1Laboratory of Cell and Molecular Biology, São Leopoldo Mandic Institute and Research Center, Campinas, 2Physiological Sciences, Piracicaba Dental School, University of Campinas, Campinas, São Paulo, 3Department of Dentistry, CEUMA University, São Luis, Maranhão, 4Department of Integrated Dental Science, University of Cuiaba, Cuiabá, Mato Grosso, 5Department of Dentistry, Ponta Grossa State University, Ponta Grossa, Paraná, Brazil Purpose: The aim of this study was to evaluate the effect of simvastatin on the synthesis of cytokines TNF-α and IL-10 and metalloproteinase (MMPs 2 and 9 in a rat model of ligature-induced periodontitis.Materials and methods: Twenty Wistar rats were used, and a cotton ligature was place in a subgingival position encircling the entire cervix of the first molar of the left (ipsilateral side of the mandible. The right (contralateral side of the mandible had no ligature placed and was used as control. After the ligature placement, animals were randomly assigned to two experimental groups (n=10: 1 rats with ligature + vehicle (saline; 10 mL/kg; orally and 2 rats with ligature + simvastatin (25 mg/kg; orally. After 14 days of treatment, the animals were euthanized by anesthetic overdose and the gingival tissue was removed and homogenized in appropriate buffer. MMP-2 and -9 release as well as the IL-10 and TNF-α levels were detected by enzyme-linked immunosorbent assay. Statistical comparison was performed by unpaired Student’s t-test, with p<0.05 representing significance.Results: No differences were observed for TNF-α production between the

Does simvastatin stimulate bone formation in vivo?

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Chorev Michael

2003-04-01

Full Text Available Abstract Background Statins, potent compounds that inhibit cholesterol synthesis in the liver have been reported to induce bone formation, both in tissue culture and in rats and mice. To re-examine potential anabolic effects of statins on bone formation, we compared the activity of simvastatin (SVS to the known anabolic effects of PTH in an established model of ovariectomized (OVX Swiss-Webster mice. Methods Mice were ovariectomized at 12 weeks of age (T0, remained untreated for 5 weeks to allow development of osteopenia (T5, followed by treatment for 8 weeks (T13. Whole, trabecular and cortical femoral bone was analyzed by micro-computed tomography (micro CT. Liquid chromatography/mass spectrometry (LC/MS was used to detect the presence of SVS and its active metabolite, simvastatin β-hydroxy acid (SVS-OH in the mouse serum. Results Trabecular BV/TV at T13 was 4.2 fold higher in animals treated with PTH (80 micro-g/kg/day compared to the OVX-vehicle treated group (p in vivo study. Conclusions While PTH demonstrated the expected anabolic effect on bone, SVS failed to stimulate bone formation, despite our verification by LC/MS of the active SVS-OH metabolite in mouse serum. While statins have clear effects on bone formation in vitro, the formulation of existing 'liver-targeted' statins requires further refinement for efficacy in vivo.

Sitagliptin/Simvastatin: a first combination tablet to treat type 2 diabetes and hypercholesterolemia – a review of its characteristics

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Ramadan WH

2015-02-01

Full Text Available Wijdan H Ramadan, Wissam K Kabbara Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon Background: The purpose of this study was to review the current literature and information on the combination product Juvisync™ (sitagliptin + simvastatin, which was approved by the US Food and Drug Administration in October 2011. Methods: PubMed (2001–2014 was searched for primary and review articles on sitagliptin, simvastatin, or the combination product. Drug manufacturing data and product labeling were also used. Studies of simvastatin, sitagliptin, or the combination were screened and analyzed to include relevant and recent papers. Selected English language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results: When compared with glipizide as add-on therapy to metformin, sitagliptin was noninferior but had lower rates of hypoglycemia and weight gain. In addition, when compared with insulin glargine, sitagliptin was less effective in decreasing glycosylated hemoglobin, but was associated with significantly lower rates of hypoglycemia. Further, trials have shown a beneficial effect of using statins in patients with diabetes mellitus with regard to decreasing cardiovascular risk, regardless of baseline lipid levels or the presence of a cardiac disease. Both medications have also demonstrated an acceptable side effect profile. However, caution is needed when coadministering with any drug that may increase simvastatin levels to reduce the risk of myopathy and rhabdomyolysis. Conclusion: Juvisync should be used in patients requiring both sitagliptin and simvastatin. Both agents have shown good efficacy and acceptable safety profiles. Sitagliptin is a good option for diabetic patients to improve glycemic control with a lower risk of hypoglycemia and weight gain. Keywords: simvastatin, sitagliptin, Juvisync™, diabetes mellitus, hypercholesterolemia

The Nuclear Orphan Receptor NR4A1 is Involved in the Apoptotic Pathway Induced by LPS and Simvastatin in RAW 264.7 Macrophages.

Science.gov (United States)

Kim, Yong Chan; Song, Seok Bean; Lee, Sang Kyu; Park, Sang Min; Kim, Young Sang

2014-04-01

Macrophage death plays a role in several physiological and inflammatory pathologies such as sepsis and arthritis. In our previous work, we showed that simvastatin triggers cell death in LPS-activated RAW 264.7 mouse macrophage cells through both caspase-dependent and independent apoptotic pathways. Here, we show that the nuclear orphan receptor NR4A1 is involved in a caspase-independent apoptotic process induced by LPS and simvastatin. Simvastatin-induced NR4A1 expression in RAW 264.7 macrophages and ectopic expression of a dominant-negative mutant form of NR4A1 effectively suppressed both DNA fragmentation and the disruption of mitochondrial membrane potential (MMP) during LPS- and simvastatin-induced apoptosis. Furthermore, apoptosis was accompanied by Bcl-2-associated X protein (Bax) translocation to the mitochondria. Our findings suggest that NR4A1 expression and mitochondrial translocation of Bax are related to simvastatin-induced apoptosis in LPS-activated RAW 264.7 macrophages.

Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling?

Science.gov (United States)

Zeki, Amir A.; Bratt, Jennifer M.; Rabowsky, Michelle; Last, Jerold A.; Kenyon, Nicholas J.

2010-01-01

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings. PMID:21078495

Effect of simvastatin and ezetimibe on suPAR levels and outcomes

DEFF Research Database (Denmark)

Hodges, Gethin W; Bang, Casper N; Forman, Julie L

2018-01-01

-lowering therapy also lowers suPAR levels is unknown. METHODS: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using...... and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677)....... cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). RESULTS: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%-11.5%) in the placebo group, but only by 4.1% (1.9%-6.2%) in the group with lipid...

Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction.

Science.gov (United States)

Atilano-Roque, Amandla; Joy, Melanie S

2017-12-01

Human organic anion transporting polypeptide 3A1 (OATP3A1) is predominately expressed in the heart. The ability of OATP3A1 to transport statins into cardiomyocytes is unknown, although other OATPs are known to mediate the uptake of statin drugs in liver. The pleiotropic effects and uptake of simvastatin acid were analyzed in primary human cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. Treatment with simvastatin acid reduced indoxyl sulfate-mediated reactive oxygen species and modulated OATP3A1 expression in cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. We observed a pH-dependent effect on OATP3A1 uptake, with more efficient simvastatin acid uptake at pH5.5 in HEK293 cells transfected with the OATP3A1 gene. The Michaelis-Menten constant (K m ) for simvastatin acid uptake by OATP3A1 was 0.017±0.002μM and the V max was 0.995±0.027fmol/min/10 5 cells. Uptake of simvastatin acid was significantly increased by known (benzylpenicillin and estrone-3-sulfate) and potential (indoxyl sulfate and cyclosporine) substrates of OATP3A1. In conclusion, the presence of OATP3A1 in cardiomyocytes suggests that this transporter may modulate the exposure of cardiac tissue to simvastatin acid due to its enrichment in cardiomyocytes. Increases in uptake of simvastatin acid by OATP3A1 when combined with OATP substrates suggest the potential for drug-drug interactions that could influence clinical outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy

DEFF Research Database (Denmark)

Hommel, E; Andersen, P; Gall, M A

1992-01-01

The aim of this study was to assess the effect of simvastatin on plasma lipoproteins and renal function in hypercholesterolaemic Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Twenty-six hypercholesterolaemic (total cholesterol greater than or equal to 5.5 mmol/l) Type 1...

A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.

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Reijo Laaksonen

Full Text Available BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg, atorvastatin (40 mg, or placebo. PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05, while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1 in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.

Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation

International Nuclear Information System (INIS)

Dombrecht, E.J.; De Tollenaere, C.B.; Aerts, K.; Cos, P.; Schuerwegh, A.J.; Bridts, C.H.; Van Offel, J.F.; Ebo, D.G.; Stevens, W.J.; De Clerck, L.S.

2006-01-01

The objective of this study was to evaluate the effect of bisphosphonates (BPs) and simvastatin on chondrocyte lipid peroxidation. For this purpose, a flow cytometrical method using C11-BODIPY 581/591 was developed to detect hydroperoxide-induced lipid peroxidation in chondrocytes. Tertiary butylhydroperoxide (t-BHP) induced a time and concentration dependent increase in chondrocyte lipid peroxidation. Addition of a Fe 2+ /EDTA complex to t-BHP or hydrogen peroxide (H 2 O 2 ) clearly enhanced lipid peroxidation. The lipophilic simvastatin demonstrated a small inhibition in the chondrocyte lipid peroxidation. None of three tested BPs (clodronate, pamidronate, and risedronate) had an effect on chondrocyte lipid peroxidation induced by t-BHP. However, when Fe 2+ /EDTA complex was added to t-BHP or H 2 O 2 , BPs inhibited the lipid peroxidation process varying from 25% to 58%. This study demonstrates that BPs have antioxidant properties as iron chelators, thereby inhibiting the chondrocyte lipid peroxidation. These findings add evidence to the therapeutic potential of bisphosphonates and statins in rheumatoid arthritis

Action of lovastatin, simvastatin, and pravastatin on sterol synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle

NARCIS (Netherlands)

Vliet, A.K. van; Nègre-Arrariou, P.; Thiel, G.C.F. van; Bolhuis, P.A.; Cohen, L.H.

1996-01-01

Lovastatin, simvastatin, and pravastatin are fairly strong inhibitors of sterol synthesis in human myoblasts in culture. Lovastatin and simvastatin have IC50 values of 19 ± 6 nM and 4.0 ± 2.3 nM, respectively. Pravastatin is a weaker inhibitor of sterol synthesis (IC50 value of 110 ± 38 nM). Through

Sitagliptin/Simvastatin: a first combination tablet to treat type 2 diabetes and hypercholesterolemia – a review of its characteristics

Science.gov (United States)

Ramadan, Wijdan H; Kabbara, Wissam K

2015-01-01

Background The purpose of this study was to review the current literature and information on the combination product Juvisync™ (sitagliptin + simvastatin), which was approved by the US Food and Drug Administration in October 2011. Methods PubMed (2001–2014) was searched for primary and review articles on sitagliptin, simvastatin, or the combination product. Drug manufacturing data and product labeling were also used. Studies of simvastatin, sitagliptin, or the combination were screened and analyzed to include relevant and recent papers. Selected English language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results When compared with glipizide as add-on therapy to metformin, sitagliptin was noninferior but had lower rates of hypoglycemia and weight gain. In addition, when compared with insulin glargine, sitagliptin was less effective in decreasing glycosylated hemoglobin, but was associated with significantly lower rates of hypoglycemia. Further, trials have shown a beneficial effect of using statins in patients with diabetes mellitus with regard to decreasing cardiovascular risk, regardless of baseline lipid levels or the presence of a cardiac disease. Both medications have also demonstrated an acceptable side effect profile. However, caution is needed when coadministering with any drug that may increase simvastatin levels to reduce the risk of myopathy and rhabdomyolysis. Conclusion Juvisync should be used in patients requiring both sitagliptin and simvastatin. Both agents have shown good efficacy and acceptable safety profiles. Sitagliptin is a good option for diabetic patients to improve glycemic control with a lower risk of hypoglycemia and weight gain. PMID:25709467

Poly(3-hydroxybutyrate) and Eudragit E microparticles: a release system to enhance the aqueous solubility of felodipine and simvastatin

International Nuclear Information System (INIS)

Bazzo, Giovana C.; Pezzini, Bianca R.; Zetola, Melissa; Wagner, Theodoro M.; Caetano, Daniela B.; Boch, Maura; Schmucker, Iara C.; Schucko, Sacha K.

2009-01-01

Poor water-soluble drugs are a problem for the development of oral solid dosage forms, since it has great potential for low bioavailability. Thus, release systems that promote the increase of aqueous solubility of these drugs are advantageous. This study aimed to evaluate the feasibility of incorporation of felodipine and simvastatin in polymeric microparticles, to improve the aqueous solubility of the drugs. Microparticles of poly(3-hydroxybutyrate) [PHB] and Eudragit E was prepared by emulsion - solvent evaporation technique and characterized as to morphology and encapsulation efficiency of the drugs. Particles with spherical shapes and high levels of drug encapsulated were obtained. There was a significant increase in aqueous solubility of felodipine and simvastatin after its incorporation into the polymeric microparticles. X-ray diffraction analysis showed the conversion of both drugs to amorphous form, which may have contributed to increased the solubility. (author)

The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose.

Science.gov (United States)

Krysiak, Robert; Okopien, Bogusław

2013-01-01

This study was designed to investigate whether metformin affects monocyte secretory function in patients with impaired fasting glucose receiving chronic statin therapy. The study included 48 patients with impaired fasting glucose treated for at least three months with simvastatin (40 mg daily). These patients were randomized to either metformin (3 g daily) or placebo, which was administered together with simvastatin for 90 days. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma C-reactive protein levels, which were accompanied by an improvement in insulin sensitivity. The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and metformin. Copyright © 2013 Elsevier Inc. All rights reserved.

EFFECT OF SIMVASTATIN TREATMENT ON BONE MINERAL DENSITY IN HYPERCHOLESTEROLEMIC POSTMENOPAUSAL WOMEN

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Irena Jankovic

2005-04-01

Full Text Available Statins are able to reduce cardiovascular morbidity and mortality mainly through their hypocholesterolemic effect. Beyond the inhibition of cholesterol synthesis, the identification of pleiotropic mechanisms has motivated many studies to evaluate the effects of statin use on bone mineral density (BMD modification.The aim of our study was to evaluate whether simvastatin treatment (20 mg/d could modify BMD in hypercholesterolemic women (n=28 after one-year treatment as compared with a control group treated only with a diet (n=11. The exclusion criteria was current or previous therapy with statins, bisphosphonates and/or estrogens. The following parameters were determined at the beginning and after one year, and those are: total cholesterol, triglycerides, HDL-C and LDL-C (Friedewald equation. The BMD was measured at the lumbar spine by dual energy x-ray absorpiometry (DEXA.In the simvastatin treated group, BMD showed an insignificant 2,812% increase after 12 months, respectively (0,965+0,111 v 0,992+0,110, P>0,05. The group treated only with hypolipidic diet demonstrated a 3,45% decrease in BMD (respectively, 1,042+0,181 v 1.006+0,182; P>0,05 after 12 months. Nevertheless, the comparison of average BMD changes between the two examined groups during one year showed a significant value diference (-0,027+0,037 v 0,036+0,036; P<0,0006.As partly suggested by retrospective or observational data, this longitudinal study indicates that simvastatin treatment achieves a beneficial effect on BMD.

Evaluation of the effects of subgingival injection of Simvastatin on space re-opening after orthodontic space closure in adults.

Science.gov (United States)

Jahanbin, Arezoo; Abtahi, Mostafa; Namdar, Parastoo; Heravi, Farzin; Sadeghi, Fatemeh; Arab, Hamidreza; Shafaee, Hooman

2016-01-01

Background. This clinical trial evaluated the effect of Simvastatin on space re-opening after orthodontic space closure and its effect on the gingival index (GI) and clinical attachment loss (CAL). Methods. 16 females, 25-40 years old, with spaces between anterior mandibular teeth due to chronic periodontitis were participated in this study. The patients were randomly divided into control and experimental groups. In the experimental group, 1.2% Simvastatin gel and in the control group, 0.9% sodium chloride as a placebo was injected into the pocket depth of the six anterior teeth. The amount of space reopening, GI and CAL were measured. Results. No serious complications were observed during interventions and follow-up periods. Space re-opening was significantly reduced in patients receiving Simvastatin (P space re-opening after orthodontic space closure in human anterior teeth.

Observed and predicted reduction of ischemic cardiovascular events in the Simvastatin and Ezetimibe in Aortic Stenosis trial

DEFF Research Database (Denmark)

Holme, Ingar; Boman, Kurt; Brudi, Philippe

2010-01-01

In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, combined ezetimibe (10 mg) and simvastatin (40 mg) decreased low-density lipoprotein cholesterol levels by 50% and ischemic cardiovascular event (ICE) risk by 22% compared to placebo. A larger decrease in ICE risk might have been...... expected for the degree of lipid-lowering observed. This analysis investigated relations between changes in lipoprotein components (LCs), and ICE risk decrease in the SEAS trial in all patients, by severity of aortic stenosis (AS), and compared to results of other clinical trials. A total of 1,570 patients...

Evidence for simvastatin anti-inflammatory actions based on quantitative analyses of NETosis and other inflammation/oxidation markers

Science.gov (United States)

Al-Ghoul, Walid M.; Kim, Margarita S.; Fazal, Nadeem; Azim, Anser C.; Ali, Ashraf

2014-01-01

Simvastatin (SMV) has been shown to exhibit promising anti-inflammatory properties alongside its classic cholesterol lowering action. We tested these emerging effects in a major thermal injury mouse model (3rd degree scald, ~20% TBSA) with previously documented, inflammation-mediated intestinal defects. Neutrophil extracellular traps (NETs) inflammation measurement methods were used alongside classic gut mucosa inflammation and leakiness measurements with exogenous melatonin treatment as a positive control. Our hypothesis is that simvastatin has protective therapeutic effects against early postburn gut mucosa inflammation and leakiness. To test this hypothesis, we compared untreated thermal injury (TI) adult male mice with TI littermates treated with simvastatin (0.2 mg/kg i.p., TI + SMV) immediately following burn injury and two hours before being sacrificed the day after; melatonin-treated (Mel) (1.86 mg/kg i.p., TI + Mel) mice were compared as a positive control. Mice were assessed for the following: (1) tissue oxidation and neutrophil infiltration in terminal ileum mucosa using classic carbonyl, Gr-1, and myeloperoxidase immunohistochemical or biochemical assays, (2) NETosis in terminal ileum and colon mucosa homogenates and peritoneal and fluid blood samples utilizing flow cytometric analyses of the surrogate NETosis biomarkers, picogreen and Gr-1, and (3) transepithelial gut leakiness as measured in terminal ileum and colon with FITC-dextran and transepithelial electrical resistance (TEER). Our results reveal that simvastatin and melatonin exhibit consistently comparable therapeutic protective effects against the following: (1) gut mucosa oxidative stress as revealed in the terminal ileum by markers of protein carbonylation as well as myeloperoxidase (MPO) and Gr-1 infiltration, (2) NETosis as revealed in the gut milieu, peritoneal lavage and plasma utilizing picogreen and Gr-1 flow cytometry and microscopy, and (3) transepithelial gut leakiness as

Effect of Simvastatin collagen graft on wound healing of defective bone

International Nuclear Information System (INIS)

Kang, Jun Ho; Kim, Gyu Tae; Choi, Yong Suk; Lee, Hyeon Woo; Hwang, Eui Hwan

2008-01-01

To observe and evaluate the effects of Simvastatin-induced osteogenesis on the wound healing of defective bone. 64 defective bones were created in the parietal bone of 32 New Zealand White rabbits. The defects were grafted with collagen matrix carriers mixed with Simvastatin solution in the experimental group of 16 rabbits and with collagen matrix carriers mixed with water in the controlled group. The rabbits were terminated at an interval of 3, 5, 7, and 9 days, 2, 4, 6, and 8 weeks after the formation of defective bone. The wound healing was evaluated by soft X-ray radiography. The tissues within defective bones were evaluated through the analysis of flow cytometry for the manifestation of Runx2 and Osteocalcin, and observed histopathologically by using H-E stain and Masson's trichrome stain. Results : 1. In the experimental group, flow cytometry revealed more manifestation of Runx2 at 5, 7, and 9 days and Osteocalcin at 2 weeks than in the controlled groups, but there was few difference in comparison with the controlled group. 2. In the experimental group, flow cytometry revealed considerably more cells and erythrocytes at 5, 7, and 9 days in comparison with the controlled group. 3. In the experimental group, soft x-ray radiography revealed the extended formation of trabeculation at 2, 4, 6, and 8 weeks. 4. Histopathological features of the experimental group showed more fibroblasts and newly formed vessels at 5 and 7 days, and the formation of osteoid tissues at 9 days, and the newly formed trabeculations at 4 and 6 weeks. As the induced osteogenesis by Simvastatin, there was few contrast of the manifestation between Runx2 and Osteocalcin based on the differentiation of osteoblasts. But it was considered that the more formation of cells and erythrocytes depending on newly formed vessels in the experimental group obviously had an effect on the bone regeneration.

Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying

DEFF Research Database (Denmark)

Craye, Goedele; Löbmann, Korbinian; Grohganz, Holger

2015-01-01

In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin-lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co...

Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor

International Nuclear Information System (INIS)

Sekine, Yoshitaka; Furuya, Yosuke; Nishii, Masahiro; Koike, Hidekazu; Matsui, Hiroshi; Suzuki, Kazuhiro

2008-01-01

Recently, statins have been being studied for their proapoptic and antimetastatic effects. However, the exact mechanisms of their anticancer action are still unclear. Dolichyl phosphate is a nonsterol isoprenoid derivative in the mevalonate pathway that affects the expression of the Insulin-like growth factor 1 receptor (IGF-1R). IGF-1R activation is required for prostate cell proliferation; therefore, IGF-1R inhibitory agents may be of preventive and/or therapeutic value. In this study, the effects of simvastatin on IGF-1R signaling in prostate cancer PC-3 cells were examined. Simvastatin suppressed proliferation and induced apoptosis of PC-3, and the expression of IGF-1R was suppressed by simvastatin. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of PC-3. Simvastatin also inhibited IGF-1-induced activation of both ERK and Akt signaling and IGF-1-induced PC-3 cell proliferation. Our results suggest statins are potent inhibitors of the IGF-1/IGF-1R system in prostate cancer cells and may be beneficial in prostate cancer treatment

Effect of Randomized Lipid Lowering With Simvastatin and Ezetimibe on Cataract Development (from the Simvastatin and Ezetimibe in Aortic Stenosis Study)

DEFF Research Database (Denmark)

Bang, Casper N; Greve, Anders M; Dornonville de la Cour, Morten

2015-01-01

Recent American College of Cardiology/American Heart Association guidelines on statin initiation on the basis of total atherosclerotic cardiovascular disease risk argue that the preventive effect of statins on cardiovascular events outweigh the side effects, although this is controversial. Studies...... indicate a possible effect of statin therapy on reducing risk of lens opacities. However, the results are conflicting. The Simvastatin and Ezetimibe in Aortic Stenosis study (NCT00092677) enrolled 1,873 patients with asymptomatic aortic stenosis and no history of diabetes, coronary heart disease, or other...

The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease

DEFF Research Database (Denmark)

Hoglund, K; Thelen, K M; Syversen, S

2005-01-01

During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients...... with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well...... as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found...

Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy

Directory of Open Access Journals (Sweden)

Toth PP

2012-01-01

Full Text Available Peter P Toth1, Kamlesh M Thakker2, Ping Jiang2, Robert J Padley21University of Illinois College of Medicine, Peoria, and CGH Medical Center, Sterling, 2Abbott, Abbott Park, IL, USABackground: The purpose of this research was to compare the effects of niacin extended-release in combination with simvastatin (NER/S versus atorvastatin monotherapy on high-density lipoprotein (HDL particle number and size in patients with hyperlipidemia or dyslipidemia from the SUPREME study.Methods: This was a post hoc analysis of patients (n = 137 who completed the SUPREME study and who had lipid particle number and size measurements at both baseline and at week 12 by nuclear magnetic resonance spectroscopy. Following ≥4 weeks without lipid-modifying therapy (washout period, the patients received NER/S 1000/40 mg/day for 4 weeks followed by NER/S 2000/40 mg/day for 8 weeks, or atorvastatin 40 mg/day for 12 weeks. Median percent changes in HDL particle number and size from baseline to week 12 were compared between the NER/S and atorvastatin treatment groups using the Wilcoxon rank-sum test. Distribution of HDL particle subclasses at week 12 was compared between the treatment groups using the Cochran–Mantel–Haenszel test.Results: Treatment with NER/S resulted in a significantly greater percent reduction in small HDL particle number at week 12 compared with atorvastatin monotherapy (-1.8% versus 4.2%, P = 0.014, and a numerically greater percent increase in large HDL particle number (102.4% versus 39.2%, P = 0.078 compared with atorvastatin monotherapy. A significantly greater percent increase in HDL particle size from baseline at week 12 was observed with NER/S compared with atorvastatin (6.0% versus 1.3%, P < 0.001. NER/S treatment also resulted in a significant shift in HDL particle size from small and medium at baseline to large at week 12 (P < 0.0001.Conclusion: Treatment with NER/S resulted in larger favorable changes in number and size of HDL particle

Simvastatin mitigates functional and structural impairment of lung and right ventricle in a rat model of cigarette smoke-induced COPD.

Science.gov (United States)

Wang, Yajie; Jiang, Xue; Zhang, Lihai; Wang, Lihong; Li, Zhu; Sun, Wuzhuang

2014-01-01

This study is conducted to investigate an effect of simvastatin on cigarette smoke-induced COPD. Rats were exposed to air (control) and cigarette smoke (smoking) in presence and absence of simvastatin. Heart and lung tissues were harvested for histopathologic and morphometric analysis. Body weight of rat, mean liner intercept (MLI), mean alveolar number (MAN), lung function test, mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI) and 5-HTT level in serum and BALF were examined in experimental rats, respectively. Application of simvastatin mitigated peribronchiolar inflammation and pulmonary bullae formed in the smoke-exposed lungs with weight gain as compared to the smoking rats (P reversal of lung function decline (all P reverses lung function decline and attenuates structural impairments of lung and right ventricle possibly through reducing 5-HTT content in the model of COPD.

Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin

NARCIS (Netherlands)

Kanter, C.T.M.M. de; Luin, M. van; Solas, C.; Burger, D.M.; Vrolijk, J.M.

2014-01-01

A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed

Efficacy of adding topical simvastatin to topical calcipotriol on improvement of cutaneous plaque psoriasis

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Fariba Iraji

2014-01-01

Conclusion: This study indicates that topical simvastatin is not associated with significant impacts in the treatment of psoriasis as compared to oral form. This study indicates that psoriasis is a systemic disorder with variable skin manifestations.

Effect of metformin alone compared with metformin plus simvastatin on polycystic ovarian syndrome in Pakistan women

International Nuclear Information System (INIS)

Malik, M.; Tasnim, N.; Mahmud, G.

2018-01-01

To determine the efficacy of metformin alone versus metformin plus simvastatin for treatment of polycystic ovarian syndrome (PCOS). Study Design:Randomized controlled trial. Place and Duration of Study:Maternal and Child Health Centre, Unit II, Pakistan Institute of Medical Sciences (PIMS), from November 2014 to April 2015. Methodology:One hundred and eight patients (108) were randomly divided into metformin group (n=54) and metformin plus simvastatin group (n=54), detailed clinical history, including menstrual details, was taken with thorough examination performed. Baseline ultrasound was performed to evaluate ovarian size and these were considered enlarged with volume >10cc or with >12 follicles in any one ovary. Blood samples were taken at baseline and after three months of therapy to determine the LH/FSH ratio and lipid profile. Efficacy was defined as >15% decrease in the baseline values. Results:The mean age of patients was 28.82 +- 7.18 years. Mean BMI of the patients was 22.41 +-1.55 Kg/m2 . Efficacy was achieved in 66.7% patients with metformin alone, while in 92.6% with combination medication (p=0.001). Conclusion:The combination of metformin plus simvastatin is more efficacious as compared to metformin alone for management of females with PCOS. (author)

Incorporating simvastatin/poloxamer 407 hydrogel into 3D-printed porous Ti6Al4V scaffolds for the promotion of angiogenesis, osseointegration and bone ingrowth.

Science.gov (United States)

Liu, Hao; Li, Wei; Liu, Can; Tan, Jie; Wang, Hong; Hai, Bao; Cai, Hong; Leng, Hui-Jie; Liu, Zhong-Jun; Song, Chun-Li

2016-10-27

Three-dimensional porous titanium alloys printed via electron beam melting have low stiffness similar to that of cortical bone and are promising scaffolds for orthopedic applications. However, the bio-inert nature of titanium alloy is poorly compatible with bone ingrowth. We previously observed that simvastatin/poloxamer 407 thermosensitive hydrogel induces endogenous angiogenic/osteogenic growth factors and promotes angiogenesis and osteogenesis, but the mechanical properties of this hydrogel are poor. The purpose of this study was to construct 3D-printed porous titanium scaffolds (pTi scaffolds) filled with simvastatin/hydrogel and evaluate the effects of this composite on osseointegration, bone ingrowth and neovascularization using a tibial defect rabbit model. Four and eight weeks after implantation, the bone volume, bone mineral density, mineral apposition rate, and push-in maximum force of the pTi scaffolds filled with simvastatin/hydrogel were significantly higher than those without simvastatin (p bone and neovascularization (p bone ingrowth.

Effects of Titanium Surface Microtopography and Simvastatin on Growth and Osteogenic Differentiation of Human Mesenchymal Stem Cells in Estrogen-Deprived Cell Culture.

Science.gov (United States)

Arpornmaeklong, Premjit; Pripatnanont, Prisana; Chookiatsiri, Chonticha; Tangtrakulwanich, Boonsin

This study aimed to investigate the effects of titanium surface topography and simvastatin on growth and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) in estrogen-deprived (ED) cell culture. Human BMSCs were seeded on cell culture plates, smooth-surface titanium (Ti) disks, and sandblasted with large grits and acid etched (SLA)-surface Ti disks; and subsequently cultured in regular (fetal bovine serum [FBS]), ED, and ED-with 100 nM simvastatin (ED-SIM) culture media for 14 to 21 days. Live/dead cell staining, scanning electron microscope examination, and cell viability assay were performed to determine cell attachment, morphology, and growth. Expression levels of osteoblast-associated genes, Runx2 and bone sialoprotein and levels of alkaline phosphatase (ALP) activity, calcium content, and osteocalcin in culture media were measured to determine osteoblastic differentiation. Expression levels of bone morphogenetic protein-2 (BMP-2) were investigated to examine stimulating effects of simvastatin (n = 4 to 5, mean ± SD). In vitro mineralization was verified by calcein staining. Human BMSCs exhibited different attachment and shapes on smooth and SLA titanium surfaces. Estrogen-deprived cell culture decreased cell attachment and growth, particularly on the SLA titanium surface, but cells were able to grow to reach confluence on day 21 in the ED-osteogenic (OS) culture medium. Promoting effects of the SLA titanium surface in ED-OS were significantly decreased. Simvastatin significantly increased osteogenic differentiation of human BMSCs on the SLA titanium surface in the ED-OS medium, and the promoting effects of simvastatin corresponded with the increasing of BMP-2 gene expression on the SLA titanium surface in ED-OS-SIM culture medium. The ED cell culture model provided a well-defined platform for investigating the effects of hormones and growth factors on cells and titanium surface interaction. Titanium, the SLA surface, and simvastatin

Effect of Simvastatin collagen graft on wound healing of defective bone

Energy Technology Data Exchange (ETDEWEB)

Kang, Jun Ho; Kim, Gyu Tae [Department of Oral and Maxillofacial Radiology, School of Dentistry, Kyung Hee University, Seoul (Korea, Republic of); Choi, Yong Suk; Lee, Hyeon Woo; Hwang, Eui Hwan [Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul (Korea, Republic of)

2008-09-15

To observe and evaluate the effects of Simvastatin-induced osteogenesis on the wound healing of defective bone. 64 defective bones were created in the parietal bone of 32 New Zealand White rabbits. The defects were grafted with collagen matrix carriers mixed with Simvastatin solution in the experimental group of 16 rabbits and with collagen matrix carriers mixed with water in the controlled group. The rabbits were terminated at an interval of 3, 5, 7, and 9 days, 2, 4, 6, and 8 weeks after the formation of defective bone. The wound healing was evaluated by soft X-ray radiography. The tissues within defective bones were evaluated through the analysis of flow cytometry for the manifestation of Runx2 and Osteocalcin, and observed histopathologically by using H-E stain and Masson's trichrome stain. Results : 1. In the experimental group, flow cytometry revealed more manifestation of Runx2 at 5, 7, and 9 days and Osteocalcin at 2 weeks than in the controlled groups, but there was few difference in comparison with the controlled group. 2. In the experimental group, flow cytometry revealed considerably more cells and erythrocytes at 5, 7, and 9 days in comparison with the controlled group. 3. In the experimental group, soft x-ray radiography revealed the extended formation of trabeculation at 2, 4, 6, and 8 weeks. 4. Histopathological features of the experimental group showed more fibroblasts and newly formed vessels at 5 and 7 days, and the formation of osteoid tissues at 9 days, and the newly formed trabeculations at 4 and 6 weeks. As the induced osteogenesis by Simvastatin, there was few contrast of the manifestation between Runx2 and Osteocalcin based on the differentiation of osteoblasts. But it was considered that the more formation of cells and erythrocytes depending on newly formed vessels in the experimental group obviously had an effect on the bone regeneration.

Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis.

Science.gov (United States)

To, Minh-Son; Prakash, Shivesh; Poonnoose, Santosh I; Bihari, Shailesh

2018-05-01

The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta-regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). The present meta-regression provides weak evidence for dose-dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs. Copyright © 2018 Elsevier Inc. All rights reserved.

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.

Science.gov (United States)

Baas, Jara M; Krens, Lisanne L; Bos, Monique M; Portielje, Johanneke E A; Batman, Erdogan; van Wezel, Tom; Morreau, Hans; Guchelaar, Henk-Jan; Gelderblom, Hans

2015-09-01

Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.

Simvastatin as add-on therapy to interferon β-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial

DEFF Research Database (Denmark)

Sorensen, Per Soelberg; Lycke, Jan; Erälinna, Juha-Pekka

2011-01-01

Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy.......Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy....

Effects of simvastatin in chronic obstructive pulmonary disease: Results of a pilot, randomized, placebo-controlled clinical trial

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Catalina Balaguer

2016-04-01

Conclusions: Short-term treatment with simvastatin in stable COPD patients did not modify lung function, pulmonary and systemic inflammation, or vascular stiffness, but it changed Epo and uric acid levels.

Simvastatin Does Not Affect Vitamin D Status, but Low Vitamin D Levels Are Associated with Dyslipidemia: Results from a Randomised, Controlled Trial

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Lars Rejnmark

2010-01-01

Full Text Available Objectives. Statin drugs act as inhibitors of the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA reductase enzyme early in the mevalonate pathway, thereby reducing the endogenous cholesterol synthesis. In recent studies, it has been suggested from epidemiological data that statins also may improve vitamin D status, as measured by increased plasma 25-hydroxyvitamin D (25OHD levels. We now report the results from a randomised controlled trial on effects of simvastatin on plasma 25OHD levels. Design and Methods. We randomised 82 healthy postmenopausal women to one year of treatment with either simvastatin 40 mg/d or placebo and performed measurement at baseline and after 26 and 52 weeks of treatment. The study was completed by 77 subjects. Results. Compared with placebo, plasma levels of cholesterol and low-density lipoproteins decreased in response to treatment with simvastatin, but our study showed no effect of simvastatin on vitamin D status. However, plasma levels of triglycerides were inversely associated with tertiles of plasma 25OHD levels and changes in plasma triglycerides levels correlated inversely with seasonal changes in vitamin D status. Conclusion. Our data do not support a pharmacological effect of statins on vitamin D status, but do suggest that vitamin D may influence plasma lipid profile and thus be of importance to cardiovascular health.

Potential of Red Spinach Leaves Ethanolic Extract (Amaranthus tricolor L. as a Complementary Therapy For Hiperlipidemia: Study in Vivo of Histopathologic and Activity of Alanin Aminotransferase (ALT

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Dimas Adhi Pradana

2016-12-01

Full Text Available This study was conducted to determine the potential of ethanolic extract of red spinach leaves (Amaranthus tricolor L. with control quality as a complementary treatment of hyperlipidemic based on histopathology and activity of alanin aminotrasferase (ALT. A total of 24 male Wistar rats were randomized in 6 groups: normal group; positive control group were given the drug simvastatin; negative control group; 1st treatment group was given extract at dose of 400mg/kgBW rat, 2nd group was given extract at dose of 400mg/kgBW rat and simvastatin dose 0.18 mg/kgBW rat; 3rd treatment groups were given extract at dose of 800mg/kgBW rat and simvastatin dose 0.18 mg/kgBW rat. Induction hyperlipidemic using high fat diet and poloxamer. The data obtained were tested normality with the Shapiro-Wilk test. Statistical analysis using Oneway ANOVA and Post-Hoc Tukey HSD to determine the significance of differences between groups for ALT parameter. Result show the use of ethanolic extract of red spinach leaves can reduce fatty liver condition based on decreased level of ALT and liver histopathologic. It is concluded that the ethanolic extract of red spinach leaves dose 400mg/kgBW rat combine with simvastatin can reduce activity of ALT until 31.57 U1-1.

The effect of simvastatin on lipid droplets accumulation in human embryonic kidney cells and pancreatic cancer cells

Czech Academy of Sciences Publication Activity Database

Gbelcová, H.; Sveda, M.; Laubertová, L.; Varga, I.; Vítek, L.; Kolář, M.; Strnad, H.; Zelenka, Jaroslav; Boehmer, D.; Ruml, T.

2013-01-01

Roč. 12, AUG 21 (2013), s. 126 ISSN 1476-511X Institutional support: RVO:67985823 Keywords : simvastatin * lipid droplets * DNA microarray Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.310, year: 2013

[Adverse muscle effects of a podofyllotoxin-containing cytotoxic drug product with simvastatin].

Science.gov (United States)

Kaipiainen-Seppänen, Oili; Savolainen, Elina; Elfving, Pia; Kononoff, Aulikki

2009-01-01

With the ageing population, drug interactions pose an increasing challenge to health professionals. We describe four patients, for whom concurrent administration of a podofyllotoxin-containing cytotoxic drug product and simvastatin caused severe adverse effects on muscles, including muscle pain, soreness or fatigue or weakness, and in some patients also disintegration of muscle tissue, i.e. rhabdomyolysis. The metabolism of both drugs proceeds via the common CYP3A4 enzyme pathway.

Efficacy, safety and tolerability of simvastatin in children with familial hypercholesterolaemia - Rationale, design and baseline characteristics

NARCIS (Netherlands)

de Jongh, S.; Stalenhoef, A. F. H.; Tuohy, M. B.; Mercuri, M.; Bakker, H. D.; Kastelein, J. J. P.

2002-01-01

Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH). Methods: Patients were recruited from nine lipid clinics

Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

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Yu Chih-Chieh

2012-05-01

Full Text Available Abstract Background Reducing low-density lipoprotein cholesterol (LDL-C is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83 to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026 and total cholesterol (20.8% vs 12.2%, p = 0.0003. Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6% vs doubling statin (41.2%, but the difference was not statistically significant (p = 0.1675. The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327

In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696).

Science.gov (United States)

Ayalasomayajula, S; Han, Y; Langenickel, T; Malcolm, K; Zhou, W; Hanna, I; Alexander, N; Natrillo, A; Goswami, B; Hinder, M; Sunkara, G

2016-08-01

Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication. Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing. Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μm, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination. Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect. © 2016 John Wiley & Sons Ltd.

A Comparison of Betamethasone Valerate 0.1% Cream Twice Daily Plus Oral Simvastatin Versus Betamethasone Valerate 0.1% Cream Alone in the Treatment of Vitiligo Patients

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Fariba Iraji

2017-01-01

Full Text Available Background: Vitiligo, a common disorder of depigmentation, is often difficult to treat. Corticosteroids are known to be effective, but with modest results. Although simvastatin has been reported to be effective for immunorelated dermatologic disorders including vitiligo, controlled trials are lacking. This study was conducted to compare the efficacy of topical betamethasone valerate 0.1% cream (as a standard method of treatment for vitiligo versus a combination of betamethasone valerate plus oral simvastatin in the treatment of vitiligo. Materials and Methods: Eighty-eight subjects with symmetric vitiligo who had body surface involvement up to 20% were divided randomly into two groups. Group A were treated with betamethasone valerate 01% cream twice daily and Group B with betamethasone valerate 01% cream twice daily and oral simvastatin 80 mg daily for 12 weeks. Finally, 46 patients completed treatment after 12 weeks in both groups. The results were evaluated by a blind dermatologist using Vitiligo Area Scoring Index (VASI score at baseline, 4th, 8th, and 12th week of treatment. In a similar way, subjective assessment performed by patients based on photo evaluation at the end of the study. Results: Despite a continuous reduction in VASI score in both groups, according to both physician (P = 0.13 and patient (P = 0.374 assessment oral simvastatin was not statistically more effective than conventional treatment of vitiligo. Conclusion: This study indicates that oral simvastatin is not associated with significant impacts in the treatment of vitiligo as compared to other inflammatory dermatologic conditions such as psoriasis. Indeed, other studies should be initiated regarding exact molecular and cellular effects of statins in the treatment of vitiligo.

A Comparison of Betamethasone Valerate 0.1% Cream Twice Daily Plus Oral Simvastatin Versus Betamethasone Valerate 0.1% Cream Alone in the Treatment of Vitiligo Patients.

Science.gov (United States)

Iraji, Fariba; Banihashemi, Seyed Hossin; Faghihi, Gita; Shahmoradi, Zabihollah; Tajmirriahi, Nabet; Jazi, Safoura Bokaie

2017-01-01

Vitiligo, a common disorder of depigmentation, is often difficult to treat. Corticosteroids are known to be effective, but with modest results. Although simvastatin has been reported to be effective for immunorelated dermatologic disorders including vitiligo, controlled trials are lacking. This study was conducted to compare the efficacy of topical betamethasone valerate 0.1% cream (as a standard method of treatment for vitiligo) versus a combination of betamethasone valerate plus oral simvastatin in the treatment of vitiligo. Eighty-eight subjects with symmetric vitiligo who had body surface involvement up to 20% were divided randomly into two groups. Group A were treated with betamethasone valerate 01% cream twice daily and Group B with betamethasone valerate 01% cream twice daily and oral simvastatin 80 mg daily for 12 weeks. Finally, 46 patients completed treatment after 12 weeks in both groups. The results were evaluated by a blind dermatologist using Vitiligo Area Scoring Index (VASI) score at baseline, 4 th , 8 th , and 12 th week of treatment. In a similar way, subjective assessment performed by patients based on photo evaluation at the end of the study. Despite a continuous reduction in VASI score in both groups, according to both physician ( P = 0.13) and patient ( P = 0.374) assessment oral simvastatin was not statistically more effective than conventional treatment of vitiligo. This study indicates that oral simvastatin is not associated with significant impacts in the treatment of vitiligo as compared to other inflammatory dermatologic conditions such as psoriasis. Indeed, other studies should be initiated regarding exact molecular and cellular effects of statins in the treatment of vitiligo.

Gamma dosimetry of high doses

International Nuclear Information System (INIS)

Martinez C, T.; Galvan G, A.; Canizal, G.

1991-01-01

The gamma dosimetry of high doses is problematic in almost all the classic dosemeters either based on the thermoluminescence, electric, chemical properties, etc., because they are saturated to very high dose and they are no longer useful. This work carries out an investigation in the interval of high doses. The solid system of heptahydrate ferrous sulfate, can be used as solid dosemeter of routine for high doses of radiation. The proposed method is simple, cheap and it doesn't require sophisticated spectrophotometers or spectrometers but expensive and not common in some laboratories

Effects of Topic Simvastatin for the Treatment of Chronic Vascular Cutaneous Ulcers: A Pilot Study.

Science.gov (United States)

Raposio, Edoardo; Libondi, Guido; Bertozzi, Nicolò; Grignaffini, Eugenio; Grieco, Michele P

2015-12-01

Recent research suggests that statins might be useful in the process of wound healing, playing a positive immune-modulatory role, improving microvascular function and reducing oxidative stress. The aim of this pilot study was to evaluate the efficacy of topic application of Simvastatin-based cream in the treatment of chronic vascular cutaneous ulcers, comparing this type of treatment to a collagen-based dressing, proven to be effective for ulcer treatment. A total of 20 ulcers were studied in 2 Groups of randomly-chosen patients for a period of one month. In the first Group a 0.5% Simvastatin-based cream was topically administered, while the second Group (control) was treated with an absorbable type I bovine collagen-based medication. Each week, wound healing progress was observed in both Groups, and the ulcers photographed. Wound healing rate was calculated by considering the absolute change in area and by the formula "healing ratio (%) = [(Area 0 - Area t4 )/Area 0 ] × 100," both sets of data being related to the days comprised in the study in order to calculate healing rate per day. Statistical analysis was performed by Student t test. Study endpoint equaling the time-course changes of ulcer areas. At the end of the study, when considering absolute change in area, the experimental Group appeared to heal better and faster than the control Group although differences between the Groups were not statistically significant. Conversely, rates of wound healing in the experimental and control Groups were 46.88% and 64% respectively, revealing statistically significant differences. ( P topic application of a simvastatin-based cream proved to be well- tolerated but not effective in the management of vascular leg ulcers in a 4 week-period.

Olive oil-diet improves the simvastatin effects with respect to sunflower oil-diet in men with increased cardiovascular risk: a preliminary study.

Science.gov (United States)

Sánchez-Muniz, F J; Bastida, S; Gutiérrez-García, O; Carbajal, A

2009-01-01

Concomitant intake of statins together with certain foods may affect their therapeutic effects. The purpose of this preliminary study was to determine the modulating effect of two culinary oils on the hypolipemic effect of statins. Twenty-five men with severe hypercholesterolemia and high estimate cardiovascular risk (> 20% according to the Adult Treatment Panel III of USA National Institutes of Health, ATP-III) were enrolled in an observational follow-up study to test lipoprotein profile changes after ix month 20-mg/d Simvastatin treatment. Thirteen volunteers using sunflower oil as the habitual culinary fat, and 12 using olive oil, were selected by non-probabilistic incidental sampling. Volunteers consent in follow their habitual diets and to maintain diet characteristics throughout the study. Diet was evaluated through the study by three 24-h recalls and a food frequency questionnaire. The energy contribution of fat (P = 0.019) and MUFA (P alcohol (P = 0.005) was higher in the sunflower oil-group. TC/HDL-cholesterol and the ATP-III 10-year risk percent decreased more (P alcohol intakes were adjusted. Data suggest that although Simvastatin is a very effective hypolipemic drug, olive oil-diets in preference to sunflower oil-diets must be consumed in patients with high cardiovascular risk.

Effect of acute and chronic simvastatin treatment on post-ischemic contractile dysfunction in isolated rat heart

Czech Academy of Sciences Publication Activity Database

Szárszoi, Ondrej; Malý, J.; Ošťádal, P.; Netuka, I.; Bešík, J.; Kolář, František; Ošťádal, Bohuslav

2008-01-01

Roč. 57, č. 5 (2008), s. 793-796 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : simvastatin * contractile dysfunction * protection Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.653, year: 2008

Topical simvastatin gel as a novel therapeutic modality for palatal donor site wound healing following free gingival graft procedure.

Science.gov (United States)

Madi, Marwa; Kassem, Abeer

2018-04-01

Autogenous soft-tissue grafting is a commonly used procedure nowadays in dentistry. However, the prolonged healing time needed for the donor site leads to increase the patient's pain and discomfort. Statin has been observed to be beneficial in reducing bacterial burden, improving epithelization and wound healing. The aim of this study was to evaluate intra-oral topical application of simvastatin/chitosan gel (10 mg/mL) over the palatal donor site following free gingival graft (FGG) procedure. Subjects indicated for FGG procedure were divided into four groups. Group I: Simvastatin suspension (S), group II: simvastatin/chitosan gel (SC), group III: chitosan gel (C), group IV: petroleum gel (P). Treatment was applied three times/day for the following 7 days. Wound healing was evaluated at day 3, 7 and 14 post-surgery. A visual analogue scale (VAS) was used to measure the experienced discomfort at 1, 3, 5, 7 and 14 days. Statistical significant reduction in wound-healing scores was observed after 3 and 7 days for group II compared to other groups (p  = .015). A significant reduction was also observed in VAS score for group II compared to other groups at day 1, 3, 5 and 7. Topical application of S/C gel could be used as a novel therapeutic modality that improved healing and reduced pain in the palatal donor site following FGG procedure.

Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-Induced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells.

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Zhang, Guo-Qiang; Tao, Yong-Kang; Bai, Yong-Ping; Yan, Sheng-Tao; Zhao, Shui-Ping

2018-04-20

Oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α-subunit (eIF2α)/CCAAT/enhancer-binding protein homologous protein (CHOP) endoplasmic reticulum (ER) stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were treated with simvastatin (0.1, 0.5, or 2.5 μmol/L) or DEVD-CHO (selective inhibitor of caspase-3, 100 μmol/L) for 1 h before the addition of ox-LDL (100 μg/ml) and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance (ANOVA) followed by post hoc pairwise comparisons using Tukey's tests. A value of P LDL resulted in a significant increase in apoptosis (31.9% vs. 4.9%, P LDL-induced apoptosis (28.0%, 24.7%, and 13.8%, F = 15.039, all P LDL significantly increased the expression of PERK (499.5%, P LDL-induced expression of PERK (407.8%, 339.1%, and 187.5%, F = 10.121, all P LDL-induced expression of PERK (486.4%) and phosphorylation of eIF2α (418.8%). Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment. This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.

The controlled release of simvastatin from TiO{sub 2} nanotubes to promote osteoblast differentiation and inhibit osteoclast resorption

Energy Technology Data Exchange (ETDEWEB)

Lai, Min, E-mail: minlai@jsnu.edu.cn [School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu 221116 (China); Jin, Ziyang; Yang, Xinyi; Wang, Huaying [School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu 221116 (China); Xu, Kui [Biomedical Engineering Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211 (China)

2017-02-28

Highlights: • The TiO{sub 2} nanotube substrates filled with simvastatin were successfully coated using chitosan/gelatin multilayers. • The bio-functionalized substrates display controlled release of simvastatin in a sustained manner. • The bio-functionalized substrates have great potential for improving osteoblast differentiation. • The bio-functionalized substrates effectively inhibit osteoclast differentiation. - Abstract: The aim of this study was to fabricate a novel drug-releasing bioactive platform that has excellent potential for improving osteoblast differentiation and inhibiting osteoclast resorption. TiO{sub 2} nanotubes (TNTs) with an outer diameter of around 70 nm were prepared by an anodization method. TNTs were filled with simvastatin (SV) and then coated using chitosan/gelatin multilayers (TNT-SV-LBL). The successful fabrication of TNT-SV-LBL substrates was confirmed by field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and contact angle measurement, respectively. The in vitro release behavior of simvastatin from TNT-SV-LBL substrates showed a sustained release as compared to the uncoated group. Osteoblasts adhering to TNT-SV-LBL substrates attached well and displayed significantly higher (p < 0.01) cell viability compared with the other substrates. More importantly, osteoblasts grown on TNT-SV-LBL substrates displayed a statistically significant (p < 0.01 or p < 0.05) increase in protein production levels of alkaline phosphatase (ALP), osteocalcin (OC) and mRNA expression of runt related transcription factor 2 (Runx2), ALP, collagen type I (Col I), osteopontin (OPN), OC and osteoprotegerin (OPG) compared to the other groups after 4, 7 and 14 days of culture, respectively. Additionally, multinuclear osteoclastic differentiation of RAW264.7 cells grown on TNT-SV-LBL substrates was inhibited as confirmed by tartrate-resistant acid phosphatase (TRAP) analysis. These

[Rhabdomyolysis secondary to simvastatin and phenofibrate].

Science.gov (United States)

Forcadell-Peris, M J; de Diego-Cabanes, C

2014-01-01

Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest. The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness. Copyright © 2013 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

Simvastatin: structure solution of two new low-temperature phases from synchrotron powder diffraction and ss-NMR

Czech Academy of Sciences Publication Activity Database

Hušák, M.; Kratochvíl, B.; Jegorov, A.; Brus, Jiří; Maixner, J.; Rohlíček, J.

2010-01-01

Roč. 21, č. 3 (2010), s. 511-518 ISSN 1040-0400 R&D Projects: GA AV ČR IAA400500602; GA MŠk 2B08021 Institutional research plan: CEZ:AV0Z40500505 Keywords : crystal structure * simvastatin * powder diffraction Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.727, year: 2010

Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.

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José A Del Campo

Full Text Available Hepatitis C virus (HCV infection has been related to increased risk of development of hepatocellular carcinoma (HCC while metformin (M and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP and phosphatase and tensin homolog (PTEN proteins while M inhibited mammalian target of rapamycin (mTOR and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.

Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRα signalling pathway in oxLDL-loaded macrophages.

Science.gov (United States)

Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S; Yuan, Xinxu; Henderson, Scott C; Dewey, William L; Li, Pin-Lan; Li, Ningjun; Zhang, Fan

2017-02-01

Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression. With simultaneous nile red and filipin staining, analysis of confocal/multi-photon imaging demonstrated that simvastatin markedly attenuated unesterified (free) cholesterol buildup in macrophages loaded with oxidized low-density lipoprotein but had little effect in reducing the sizes of cholesteryl ester-containing lipid droplets; the reduction in free cholesterol was mainly attributed to decreases in lysosome-compartmentalized cholesterol. Functionally, the egression of free cholesterol from lysosomes attenuated pro-inflammatory cytokine secretion. It was determined that the reduction of lysosomal free cholesterol buildup by simvastatin was due to the up-regulation of Niemann-Pick C1 (NPC1), a lysosomal residing cholesterol transporter. Moreover, the enhanced enzymatic production of 7-hydroxycholesterol by cytochrome P450 7A1 and the subsequent activation of liver X receptor α underscored the up-regulation of NPC1. These findings reveal a novel pleiotropic effect of simvastatin in affecting lysosomal cholesterol efflux in macrophages and the associated significance in the treatment of atherosclerosis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Biological dose estimation for accidental supra-high dose gamma-ray exposure

International Nuclear Information System (INIS)

Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

2011-01-01

To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP)

Science.gov (United States)

Beggs, Peter W; Clark, David WJ; Williams, Sheila M; Coulter, David M

1999-01-01

Aims Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use. Methods A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme’s (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy. Results 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs. Conclusions In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin. PMID:10073746

Optimized dose distribution of a high dose rate vaginal cylinder

International Nuclear Information System (INIS)

Li Zuofeng; Liu, Chihray; Palta, Jatinder R.

1998-01-01

Purpose: To present a comparison of optimized dose distributions for a set of high-dose-rate (HDR) vaginal cylinders calculated by a commercial treatment-planning system with benchmark calculations using Monte-Carlo-calculated dosimetry data. Methods and Materials: Optimized dose distributions using both an isotropic and an anisotropic dose calculation model were obtained for a set of HDR vaginal cylinders. Mathematical optimization techniques available in the computer treatment-planning system were used to calculate dwell times and positions. These dose distributions were compared with benchmark calculations with TG43 formalism and using Monte-Carlo-calculated data. The same dwell times and positions were used for a quantitative comparison of dose calculated with three dose models. Results: The isotropic dose calculation model can result in discrepancies as high as 50%. The anisotropic dose calculation model compared better with benchmark calculations. The differences were more significant at the apex of the vaginal cylinder, which is typically used as the prescription point. Conclusion: Dose calculation models available in a computer treatment-planning system must be evaluated carefully to ensure their correct application. It should also be noted that when optimized dose distribution at a distance from the cylinder surface is calculated using an accurate dose calculation model, the vaginal mucosa dose becomes significantly higher, and therefore should be carefully monitored

Comparison of the effects of metformin, flutamide plus oral contraceptives, and simvastatin on the metabolic consequences of polycystic ovary syndrome

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Ferdous Mehrabian

2016-01-01

Full Text Available Background: Polycystic ovary syndrome (PCOS is one of the common endocrine disorders in women of reproductive ages. It is associated with a range of disorders, such as dyslipidemia, hypertension, insulin resistance (IR, compensatory hyperinsulinemia, gestational, and type 2 diabetes, and increased risk of cardiovascular morbidity. There are different treatments available for PCOS. The purpose of this study was to determine and compare the effects of metformin, flutamide plus oral contraceptives (OCs, and simvastatin on the metabolic consequences of PCOS. Materials and Methods: This study was a single-blind clinical trial. The subjects were selected from a group of patient with PCOS and metabolic syndrome, who were referred to the midwifery clinic of Al-Zahra Hospital and Beheshti Hospital, Isfahan, Iran. A total of 111 subjects were randomly assigned to three groups: metformin, flutamide plus OCs, and simvastatin groups. The measurements were performed at baseline and after 6 months of therapy. Paired t-test, analysis of variance (ANOVA, and chi-square test were applied in this study. Results: A total of 102 subjects were analyzed in this study, 34 subjects were allotted in each group. The prevalence of IR was statistically different between three groups (P-value = 0.001. After a 6-month course, metformin showed larger reduction in fasting blood sugar (FBS level (P-value 0.05. Conclusion: Metformin performed better in FBS reduction. Simvastatin had better performance in terms of reducing TG level and waist circumference.

Effect of simvastatin in the autonomic system is dependent on the increased gain/sensitivity of the baroreceptors

Science.gov (United States)

Moreira, Edson D; Mostarda, Cristiano T; Moraes-Silva, Ivana C; Ferreira, Janaina B; dos Santos, Fernando; Lacchini, Silvia; De Angelis, Kátia; Rodrigues, Bruno; Irigoyen, Maria Cláudia

2013-01-01

A number of mechanisms have been proposed to explain the pleiotropic effect of statin therapy to reduce sympathetic outflow in cardiovascular disease. We tested the hypothesis that statin treatment could improve baroreflex gain-sensitivity triggered by morphological adaptations in the mechanoreceptor site, thus reducing sympathetic activity, regardless of arterial pressure (AP) level reduction. Male spontaneously hypertensive rats (SHR) were divided into control (SHR, n = 8) and SHR-simvastatin (5 mg/kg/day, for 7 days) (SHR-S, n = 8). After treatment, AP, baroreflex sensitivity (BRS) in response to AP-induced changes, aortic depressor nerve activity, and spectral analyses of pulse interval (PI) and AP variabilities were performed. Internal and external carotids were prepared for morphoquantitative evaluation. Although AP was similar between groups, sympathetic modulation, represented by the low frequency band of PI (SHR: 6.84 ± 3.19 vs. SHR-S: 2.41 ± 0.96 msec2) and from systolic AP variability (SHR: 3.95 ± 0.36 vs. SHR-S: 2.86 ± 0.18 mmHg2), were reduced in treated animals. In parallel, simvastatin induced an increase of 26% and 21% in the number of elastic lamellae as well as a decrease of 9% and 25% in the carotid thickness in both, external and internal carotid, respectively. Moreover, improved baroreceptor function (SHR: 0.78 ± 0.03 vs. SHR-S: 1.06 ± 0.04% mv/mmHg) was observed in addition to a 115% increase in aortic depressor nerve activity in SHR-S rats. Therefore, our data suggest that the reduction of sympathetic outflow in hypertension by simvastatin treatment may be triggered by structural changes in the carotid arteries and increased BRS in response to an improvement of the baroreceptors discharge and consequently of the afferent pathway of the baroreflex arch. PMID:24303130

Progress in high-dose radiation dosimetry

International Nuclear Information System (INIS)

Ettinger, K.V.; Nam, J.W.; McLaughlin, W.L.; Chadwick, K.H.

1981-01-01

The last decade has witnessed a deluge of new high-dose dosimetry techniques and expanded applications of methods developed earlier. Many of the principal systems are calibrated by means of calorimetry, although production of heat is not always the final radiation effect of interest. Reference systems also include a number of chemical dose meters: ferrous sulphate, ferrous-cupric sulphate, and ceric sulphate acidic aqueous solutions. Requirements for stable and reliable transfer dose meters have led to further developments of several important high-dose systems: amino acids and saccharides analysed by ESR or lyoluminescence, thermoluminescent materials, radiochromic dyes and plastics, ceric-cerous solutions analysed by potentiometry, and ethanol-chlorobenzene solutions analysed by high-frequency oscillometry. A number of other prospective dose meters are also treated in this review. In addition, an IAEA programme of high-dose standardization and intercomparison for industrial radiation processing is described. (author)

Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin

NARCIS (Netherlands)

Brunham, L. R.; Lansberg, P. J.; Zhang, L.; Miao, F.; Carter, C.; Hovingh, G. K.; Visscher, H.; Jukema, J. W.; Stalenhoef, A. F.; Ross, C. J. D.; Carleton, B. C.; Kastelein, J. J. P.; Hayden, M. R.

2012-01-01

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was

Efficacy and safety of statin therapy in children with familial hypercholesterolemia - A randomized, double-blind, placebo-controlled trial with simvastatin

NARCIS (Netherlands)

de Jongh, Saskia; Ose, Leiv; Szamosi, Tamás; Gagné, Claude; Lambert, M.; Scott, Russell; Perron, P.; Dobbelaere, Dries; Saborio, M.; Tuohy, Mary B.; Stepanavage, Michael; Sapre, Aditi; Gumbiner, Barry; Mercuri, Michele; van Trotsenburg, A. S. Paul; Bakker, Henk D.; Kastelein, John J. P.

2002-01-01

Background-A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous

[Rhabdomyolysis and severe hepatotoxicity due to a drug-drug interaction between ritonavir and simvastatin. Could we use the most cost-effective statin in all human immunodeficiency virus-infected patients?].

Science.gov (United States)

Bastida, Carla; Also, Maria Antonia; Pericas, Juan Manuel; Letang, Emili; Tuset, Montse; Miró, Josep Maria

2014-11-01

Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism. A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented. The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death. Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

N-Acetylneuraminic acid attenuates hypercoagulation on high fat diet-induced hyperlipidemic rats

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Zhang Yida

2015-12-01

Full Text Available Background and objective: N-Acetylneuraminic acid (Neu5Ac, a type of sialic acid, has close links with cholesterol metabolism and is often used as a biomarker in evaluating the risk of cardiovascular diseases. However, most studies on the health implications of Neu5Ac have focused on its effects on the nervous system, while its effects on cardiovascular risk factors have largely been unreported. Thus, the effects of Neu5Ac on coagulation status in high fat diet (HFD-induced hyperlipidemic rats were evaluated in this study. Methods: Sprague Dawley male rats were divided into five different groups and fed with HFD alone, HFD low-dose Neu5Ac, HFD high-dose Neu5Ac, HFD simvastatin (10 mg/kg day, and normal pellet alone. Food was given ad libitum while body weight of rats was measured weekly. After 12 weeks of intervention, rats were sacrificed and serum and tissue samples were collected for biochemistry and gene expression analysis, respectively. Results: The results showed that Neu5Ac could improve lipid metabolism and hyperlipidemia-associated coagulation. Neu5Ac exerted comparable or sometimes better physiological effects than simvastatin, at biochemical and gene expression levels. Conclusions: The data indicated that Neu5Ac prevented HFD-induced hyperlipidemia and associated hypercoagulation in rats through regulation of lipid-related and coagulation-related genes and, by extension, induced metabolite and protein changes. The implications of the present findings are that Neu5Ac may be used to prevent coagulation-related cardiovascular events in hyperlipidemic conditions. These findings are worth studying further.

Intracranial meningiomas after high-dose irradiation

International Nuclear Information System (INIS)

Soffer, D.; Gomori, J.M.; Siegal, T.; Shalit, M.N.

1989-01-01

Three patients who presented with intracranial meningiomas 12, 15, and 20 years, respectively, after therapeutic high-dose irradiation of a primary brain tumor are described. Analysis of these cases and similar documented cases suggests that meningiomas after high-dose irradiation constitute a recognizable entity. Patients with such tumors received radiation therapy at a young age (mean age, 9.4 years). After a latent period of 2 to 47 years (mean, 19.8 years) they developed meningiomas at the site of irradiation, at a much younger age than patients with ''spontaneous'' meningiomas. Similar to the situation with meningiomas after low-dose irradiation, a relatively high proportion of meningiomas induced by high-dose irradiation tend to be malignant and biologically aggressive. A very young age at the time of irradiation seems to predispose to the induction of malignant meningiomas, rather than benign tumors. These unusual features provide indirect evidence that high-dose radiation may play a role in the pathogenesis of meningiomas.41 references

High-dose irradiation of food

International Nuclear Information System (INIS)

Diehl, J.F.

1999-01-01

Studies performed on behalf of the International Project on Food Irradiation in the period from 1971 until 1980 resulted in the concluding statement that ''.the irradiation of any food commodity up to an overall average dose of 10 kGy presents no toxicological hazard; hence, toxicological testing of foods so treated is no longer required.'' Since then, licenses for food irradiation have been restricted to this maximum dose in any country applying this technology. Further testing programmes have been carried out investigating the wholesomeness or hazards of high-dose irradiation, but there has been little demand so far by the food industry for licensing of high-dose irradiation, as there is only a small range of products whose irradiation at higher doses offers advantages for given, intended use. These include eg. spices, dried herbs, meat products in flexible pouch packagings for astronauts, or patients with immune deficiencies. (orig./CB) [de

Influence of Statins locally applied from orthopedic implants on osseous integration

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Pauly Stephan

2012-10-01

Full Text Available Abstract Background Simvastatin increases the expression of bone morphogenetic protein 2 (BMP-2 in osteoblasts, therefore it is important to investigate the influence of statins on bone formation, fracture healing and implant integration. The aim of the present study was to investigate the effect of Simvastatin, locally applied from intramedullary coated and bioactive implants, on bone integration using biomechanical and histomorphometrical analyses. Methods Eighty rats received retrograde nailing of the femur with titanium implants: uncoated vs. polymer-only (poly(D,L-lactide vs. polymer plus drug coated (either Simvastatin low- or high dosed; “SIM low/ high”. Femurs were harvested after 56 days for radiographic and histomorphometric or biomechanical analysis (push-out. Results Radiographic analysis revealed no pathological findings for animals of the control and SIM low dose group. However, n=2/10 animals of the SIM high group showed osteolysis next to the implant without evidence of bacterial infection determined by microbiological analysis. Biomechanical results showed a significant decrease in fixation strength for SIM high coated implants vs. the control groups (uncoated and PDLLA. Histomorphometry revealed a significantly reduced total as well as direct bone/implant contact for SIM high- implants vs. controls (uncoated and PDLLA-groups. Total contact was reduced for SIM low vs. uncoated controls. Significantly reduced new bone formation was measured around SIM high coated implants vs. both control groups. Conclusions This animal study suggests impaired implant integration with local application of Simvastatin from intramedullary titanium implants after 8 weeks when compared to uncoated or carrier-only coated controls.

The effect of simvastatin on lipid droplets accumulation in human embryonic kidney cells and pancreatic cancer cells

Czech Academy of Sciences Publication Activity Database

Gbelcová, H.; Sveda, M.; Laubertová, L.; Varga, I.; Vítek, L.; Kolář, Michal; Strnad, Hynek; Zelenka, J.; Boehmer, D.; Ruml, T.

2013-01-01

Roč. 12, 21.8.2013 (2013), s. 126 ISSN 1476-511X R&D Projects: GA MZd(CZ) NT13112 Grant - others:GA MŠk(CZ) EE2.3.30.0060 Program:EE Institutional support: RVO:68378050 Keywords : simvastatin * lipid droplets * DNA microarray * Nile red * pancreatic cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.310, year: 2013

''Low dose'' and/or ''high dose'' in radiation protection: A need to setting criteria for dose classification

International Nuclear Information System (INIS)

Sohrabi, M.

1997-01-01

The ''low dose'' and/or ''high dose'' of ionizing radiation are common terms widely used in radiation applications, radiation protection and radiobiology, and natural radiation environment. Reading the title, the papers of this interesting and highly important conference and the related literature, one can simply raise the question; ''What are the levels and/or criteria for defining a low dose or a high dose of ionizing radiation?''. This is due to the fact that the criteria for these terms and for dose levels between these two extreme quantities have not yet been set, so that the terms relatively lower doses or higher doses are usually applied. Therefore, setting criteria for classification of radiation doses in the above mentioned areas seems a vital need. The author while realizing the existing problems to achieve this important task, has made efforts in this paper to justify this need and has proposed some criteria, in particular for the classification of natural radiation areas, based on a system of dose limitation. (author)

Amino acids as co-amorphous excipients for simvastatin and glibenclamide

DEFF Research Database (Denmark)

Laitinen, Riikka; Löbmann, Korbinian; Grohganz, Holger

2014-01-01

to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co......-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine, and threonine was investigated. Solid-state characterization with X-ray powder diffraction, differential scanning calorimetry, and Fourier...... in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to that of the pure amorphous drug...

Dose-reduction techniques for high-dose worker groups in nuclear power plants

International Nuclear Information System (INIS)

Khan, T.A.; Baum, J.W.; Dionne, B.J.

1991-03-01

This report summarizes the main findings of a study of the extent of radiation dose received by special work groups in the nuclear power industry. Work groups which chronically get large doses were investigated, using information provided by the industry. The tasks that give high doses to these work groups were examined and techniques described that were found to be particularly successful in reducing dose. Quantitative information on the extent of radiation doses to various work groups shows that significant numbers of workers in several critical groups receive doses greater than 1 and even 2 rem per year, particularly contract personnel and workers at BWR-type plants. The number of radiation workers whose lifetime dose is greater than their age is much less. Although the techniques presented would go some way in reducing dose, it is likely that a sizeable reduction to the high-dose work groups may require development of new dose-reduction techniques as well as major changes in procedures. 10 refs., 26 tabs

Performance of thermoluminescent materials for high dose dosimetry

International Nuclear Information System (INIS)

Texeira, Maria I.; Cecatti, Sonia G.P.; Caldas, Linda V.E.

2008-01-01

Cases involving high-doses of ionizing radiation are becoming increasingly common.The objective of this work was to characterize thermoluminescent materials for the dosimetry of workers exposed to high doses. Samples of TLD-200, TLD-400 and TLD-800 pellets from Thermo Electron Corporation were studied in gamma high-doses. Dose-response curves were obtained for doses between 100 mGy and 100 Gy. The reproducibility, the lower detection limits and dose-response curves were obtained for all three materials. The different kinds of detectors show usefulness for dosimetry of workers exposed accidentally to high doses. (author)

Fiber optics in high dose radiation fields

International Nuclear Information System (INIS)

Partin, J.K.

1985-01-01

A review of the behavior of state-of-the-art optical fiber waveguides in high dose (greater than or equal to 10 5 rad), steady state radiation fields is presented. The influence on radiation-induced transmission loss due to experimental parameters such as dose rate, total dose, irradiation history, temperature, wavelength, and light intensity, for future work in high dose environments are given

Biochemical Changes in Erythrocytes as a Molecular Marker of Cell Damage during Long-Term Simvastatin Treatment.

Science.gov (United States)

Mikashinovich, Z I; Belousova, E S

2016-08-01

Long-term administration of simvastatin to rats, irrespective of the baseline cholesterol levels, induced biochemical changes in erythrocytes attesting to hypoxic damage (accumulation of lactate and 2,3-diphosphoglycerate), disturbances in ATP-dependent mechanisms of ion homeostasis regulation (decrease in total ATPase and Ca(2+)-ATPase activities), and antioxidant enzymes system imbalance. These changes can be considered as a sensitive indicator and molecular basis of cell damage during long-term administration of statins.

Radiophotoluminescence light scope for high-dose dosimetry

International Nuclear Information System (INIS)

Sato, Fuminobu; Zushi, Naoki; Sakiyama, Tomoki; Kato, Yushi; Murata, Isao; Shimizu, Kikuo; Yamamoto, Takayoshi; Iida, Toshiyuki

2015-01-01

A radiophotoluminescence (RPL) light scope is a remote-sensing technique for measuring in situ the radiation dose in an RPL detector placed at a distance. The RPL light scope is mainly composed of an ultraviolet (UV) pulse laser, telescopic lenses, a photomultiplier tube, and camera modules. In a performance test, some RPL detectors were placed at distances up to 30 m and were illuminated with a pulsed UV laser beam. The photoluminescence responses of the RPL detectors were analyzed using this scope. Their radiation doses were determined from the amplitude of the given component of the photoluminescence responses. The RPL readout could be repeated without fading, and its amplitude exhibited good linearity at a dose ranging from 0.1 to 60 Gy. Furthermore, a two-dimensional distribution of radiation dose was obtained by laser scanning on an RPL detector. It was confirmed that the RPL light scope was a useful remote-sensing tool for high-dose dosimetry. - Highlights: • A radiophotoluminescence (RPL) light scope was developed for high-dose dosimetry. • The RPL light scope has high sensitivity and accuracy in high-dose dosimetry. • Two-dimensional radiation dose distribution was obtained by the RPL light scope.

High-dose dosimetry using natural silicate minerals

International Nuclear Information System (INIS)

Carmo, Lucas S. do; Mendes, Leticia; Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina; Barbosa, Renata F.

2015-01-01

In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

High-dose dosimetry using natural silicate minerals

Energy Technology Data Exchange (ETDEWEB)

Carmo, Lucas S. do; Mendes, Leticia, E-mail: isatiro@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina, E-mail: lacifid@if.usp.br [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Instituto de Fisica. Departamento de Fisica Nuclear; Barbosa, Renata F., E-mail: profcelta@hotmail.com [Universidade Federal de Sao Paulo (UNIFESP), Santos, SP (Brazil). Departamento de Ciencias do Mar

2015-07-01

In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

Simvastatin Attenuates Contrast-Induced Nephropathy through Modulation of Oxidative Stress, Proinflammatory Myeloperoxidase, and Nitric Oxide

Directory of Open Access Journals (Sweden)

Ketab E. Al-Otaibi

2012-01-01

Full Text Available Contrast media- (CM- induced nephropathy is a serious complication of radiodiagnostic procedures. Available data suggests that the development of prophylaxis strategies is limited by poor understanding of pathophysiology of CM-induced nephropathy. Present study was designed to determine the role of oxidative stress, myeloperoxidase, and nitric oxide in the pathogenesis of iohexol model of nephropathy and its modification with simvastatin (SSTN. Adult Sprague Dawley rats were divided into seven groups. After 24 h of water deprivation, all the rats except in control and SSTN-only groups were injected (10 ml/kg with 25% glycerol. After 30 min, SSTN (15, 30, and 60 mg/kg was administered orally, daily for 4 days. Twenty-four hours after the glycerol injection, iohexol was infused (8 ml/kg through femoral vein over a period of 2 min. All the animals were sacrificed on day 5 and blood and kidneys were collected for biochemical and histological studies. The results showed that SSTN dose dependently attenuated CM-induced rise of creatinine, urea, and structural abnormalities suggesting its nephroprotective effect. A significant increase in oxidative stress (increased lipid hydroperoxides and reduced glutathione levels and myeloperoxidase (MPO and decreased nitric oxide in CM group were reversed by SSTN. These findings support the use of SSTN to combat CM-induced nephrotoxicity.

Relative safety profiles of high dose statin regimens

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Carlos Escobar

2008-06-01

Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment

DEFF Research Database (Denmark)

Blyme, Adam; Asferg, Camilla; Nielsen, Olav W

2015-01-01

AIMS: To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). METHODS AND RESULTS: In 1620 SEAS patients, we m...

High dose gamma-ray standard

International Nuclear Information System (INIS)

Macrin, R.; Moraru, R.

1999-01-01

The high gamma-ray doses produced in a gamma irradiator are used, mainly, for radiation processing, i.e. sterilization of medical products, processing of food, modifications of polymers, irradiation of electronic devices, a.s.o. The used absorbed doses depend on the application and cover the range 10 Gy to 100 MGy. The regulations in our country require that the response of the dosimetry systems, used for the irradiation of food and medical products, be calibrated and traceable to the national standards. In order to be sure that the products receive the desired absorbed dose, appropriate dosimetric measurements must be performed, including the calibration of the dosemeters and their traceability to the national standards. The high dose gamma-ray measurements are predominantly based on the use of reference radiochemical dosemeters. Among them the ferrous sulfate can be used as reference dosemeter for low doses (up to 400 Gy) but due to its characteristics it deserves to be considered a standard dosemeter and to be used for transferring the conventional absorbed dose to other chemical dosemeters used for absorbed doses up to 100 MGy. The study of the ferrous sulfate dosemeter consisted in preparing many batches of solution by different operators in quality assurance conditions and in determining for all batches the linearity, the relative intrinsic error, the repeatability and the reproducibility. The principal results are the following: the linear regression coefficient: 0.999, the relative intrinsic error: max.6 %, the repeatability (for P* = 95 %): max.3 %, the reproducibility (P* = 95%): max.5 %. (authors)

Estimation of the transit dose component in high dose rate brachytherapy

International Nuclear Information System (INIS)

Garcia Romero, A.; Millan Cebrian, E.; Lozano Flores, F.J.; Lope Lope, R.; Canellas Anoz, M.

2001-01-01

Current high dose rate brachytherapy (HDR) treatment planning systems usually calculate dose only from source stopping positions (stationary component), but fails to account for the administered dose when the source is moving (dynamic component or transit dose). Numerical values of this transit dose depends upon the source velocity, implant geometry, source activity and prescribed dose. In some HDR treatments using particular geometry the transit dose cannot be ignored because it increases the dose at the prescriptions points and also could increase potential late tissue complications as predicted by the linear quadratic model. International protocols recommend to verify this parameter. The aim of this paper has been to establish a procedure for the transit dose calculation for the Gammamed 12i equipment at the RT Department in the Clinical University Hospital (Zaragoza-Spain). A numeric algorithm was implemented based on a dynamic point approximation for the moving HDR source and the calculated results for the entrance-exit transit dose was compared with TLD measurements made in some discrete points. (author) [es

ELDRS Characterization for a Very High Dose Mission

Science.gov (United States)

Harris, Richard D.; McClure, Steven S.; Rax, Bernard G.; Kenna, Aaron J.; Thorbourn, Dennis O.; Clark, Karla B.; Yan, Tsun-Yee

2010-01-01

Evaluation of bipolar linear parts which may have Enhanced Low Dose Rate Sensitivity (ELDRS) is problematic for missions that have very high dose radiation requirements. The accepted standards for evaluating parts that display ELDRS require testing at a very low dose rate which could be prohibitively long for very high dose missions. In this work, a methodology for ELDRS characterization of bipolar parts for mission doses up to 1 Mrad(Si) is evaluated. The procedure employs an initial dose rate of 0.01 rad(Si)/s to a total dose of 50 krad(Si) and then changes to 0.04 rad(Si)/s to a total dose of 1 Mrad(Si). This procedure appears to work well. No change in rate of degradation with dose has been observed when the dose rate is changed from 0.01 to 0.04 rad(Si)/s. This is taken as an indication that the degradation due to the higher dose rate is equivalent to that at the lower dose rate at the higher dose levels, at least for the parts studied to date. In several cases, significant parameter degradation or functional failure not observed at HDR was observed at fairly high total doses (50 to 250 krad(Si)) at LDR. This behavior calls into question the use of dose rate trend data and enhancement factors to predict LDR performance.

Quality control of 192Ir high dose rate after loading brachytherapy dose veracity

International Nuclear Information System (INIS)

Feng Zhongsu; Xu Xiao; Liu Fen

2008-01-01

Recently, 192 Ir high dose rate (HDR) afterloading are widely used in brachytherapy. The advantage of using HDR systems over low dose rate systems are shorter treatment time and higher fraction dose. To guarantee the veracity of the delivery dose, several quality control methods are deseribed in this work. With these we can improve the position precision, time precision and dose precision of the brachytherapy. (authors)

Combination of calcium sulfate and simvastatin-controlled release microspheres enhances bone repair in critical-sized rat calvarial bone defects

Directory of Open Access Journals (Sweden)

Fu YC

2015-12-01

Full Text Available Yin-Chih Fu,1–4 Yan-Hsiung Wang,1,5 Chung-Hwan Chen,1,3,4 Chih-Kuang Wang,1,6 Gwo-Jaw Wang,1,3,4 Mei-Ling Ho1,3,7,8 1Orthopaedic Research Center, 2Graduate Institute of Medicine, 3Department of Orthopaedics, 4Department of Orthopaedics, College of Medicine, 5School of Dentistry, College of Dental Medicine, 6Department of Medicinal and Applied Chemistry, 7Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, TaiwanAbstract: Most allogenic bone graft substitutes have only osteoconductive properties. Developing new strategies to improve the osteoinductive activity of bone graft substitutes is both critical and practical for clinical application. Previously, we developed novel simvastatin-encapsulating poly(lactic-co-glycolic acid microspheres (SIM/PLGA that slowly release simvastatin and enhance fracture healing. In this study, we combined SIM/PLGA with a rapidly absorbable calcium sulfate (CS bone substitute and studied the effect on bone healing in critical-sized calvarial bone defects in a rat model. The cytotoxicity and cytocompatibility of this combination was tested in vitro using lactate dehydrogenase leakage and a cell attachment assay, respectively. Combination treatment with SIM/PLGA and the CS bone substitute had no cytotoxic effect on bone marrow stem cells. Compared with the control, cell adhesion was substantially enhanced following combination treatment with SIM/PLGA and the CS bone substitute. In vivo, implantation of the combination bone substitute promoted healing of critical-sized calvarial bone defects in rats; furthermore, production of bone morphogenetic protein-2 and neovascularization were enhanced in the area of the defect. In summary, the combination of SIM/PLGA and a CS bone substitute has osteoconductive and osteoinductive properties, indicating that it could be used for regeneration

Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

NARCIS (Netherlands)

Attema-de Jonge, M.E. (Milly Ellen)

2004-01-01

Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability

Physiological and immunological changes following exposure to low versus high-dose ionizing irradiation; comparative analysis with dose rate and cumulative dose

International Nuclear Information System (INIS)

Heesun, Kim; Heewon, Jang; Soungyeon, Song; Shinhye, Oh; Cukcheul, Shin; Meeseon, Jeong; Chasoon, Kim; Kwnaghee, Yang; Seonyoung, Nam; Jiyoung, Kim; Youngwoo, Jin; Changyoung, Cha

2008-01-01

Full text: While high-dose of ionizing radiation is generally harmful and causes damage to living organisms some reports suggest low-dose of radiation may not be as damaging as previously thought. Despite increasing evidence regarding the protective effect of low-dose radiation, no studies have directly compared the exact dose-response pattern by high- and low-dose of radiation exposed at high-and low-dose rate. This study aims to explore the cellular and molecular changes in mice exposed to low- and high-dose of radiation exposed at low- and high-dose rate. When C57BL/6 mice (Female, 6 weeks) were exposed at high-dose rate, 0.8 Gy/min, no significant change on the level of WBC, RBC, or platelets was observed up to total dose of 0.5 Gy. However, 2 Gy of radiation caused dramatic reduction in the level of white blood cells (WBC) and platelets. This reduction was accompanied by increased DNA damage in hematopoietic environments. The reduction of WBC was mainly due to the reduction in the number of CD4+ T cells and CD19+ B cells. CD8+ T cells and NK cells appeared to be relatively resistant to high-dose of radiation. This change was also accompanied by the reduction of T- and B- progenitor cells in the bone marrow. In contrast, no significant changes of the number of CD4+ T, CD8+ T, NK, and B cells were observed in the spleen of mice exposed at low-dose-rate (0.7 m Gy/h or 3.95 mGy/h) for up to 2 Gy, suggesting that low-dose radiation does not alter cellular distribution in the spleen. Nevertheless, mice exposed to low-dose radiation exhibited elevation of VEGF, MCP-1, IL-4, Leptin, IL-3, and Tpo in the peripheral blood and slight increases in MIP-2, RANTES, and IL-2 in the spleen. This suggests that chronic γ-radiation can stimulate immune function without causing damage to the immune components of the body. Taken together, these data indicate hormesis of low-dose radiation, which could be attributed to the stimulation of immune function. Dose rate rather than total

Dose volume assessment of high dose rate 192IR endobronchial implants

International Nuclear Information System (INIS)

Cheng, B. Saw; Korb, Leroy J.; Pawlicki, Todd; Wu, Andrew

1996-01-01

Purpose: To study the dose distributions of high dose rate (HDR) endobronchial implants using the dose nonuniformity ratio (DNR) and three volumetric irradiation indices. Methods and Materials: Multiple implants were configured by allowing a single HDR 192 Ir source to step through a length of 6 cm along an endobronchial catheter. Dwell times were computed to deliver a dose of 5 Gy to points 1 cm away from the catheter axis. Five sets of source configurations, each with different dwell position spacings from 0.5 to 3.0 cm, were evaluated. Three-dimensional (3D) dose distributions were then generated for each source configuration. Differential and cumulative dose-volume curves were generated to quantify the degree of target volume coverage, dose nonuniformity within the target volume, and irradiation of tissues outside the target volume. Evaluation of the implants were made using the DNR and three volumetric irradiation indices. Results: The observed isodose distributions were not able to satisfy all the dose constraints. The ability to optimally satisfy the dose constraints depended on the choice of dwell position spacing and the specification of the dose constraint points. The DNR and irradiation indices suggest that small dwell position spacing does not result in a more homogeneous dose distribution for the implant. This study supports the existence of a relationship between the dwell position spacing and the distance from the catheter axis to the reference dose or dose constraint points. Better dose homogeneity for an implant can be obtained if the spacing of the dwell positions are about twice the distance from the catheter axis to the reference dose or dose constraint points

Braquiterapia de alta taxa de dose no Brasil High-dose rate brachytherapy in Brazil

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Sérgio Carlos Barros Esteves

2004-10-01

Full Text Available A braquiterapia de alta taxa de dose foi introduzida em nosso meio em janeiro de 1991. Desde então, houve uma mudança significativa na abordagem das neoplasias malignas em relação às vantagens do novo método, e também resolução da demanda reprimida de braquiterapia para as neoplasias ginecológicas. Nos primeiros dez anos de atividade, o Brasil tratou, em 31 serviços, 26.436 pacientes com braquiterapia, sendo mais de 50% das pacientes portadoras de neoplasias do colo uterino. Este estudo mostra o número e o perfil de pacientes tratados com esse método e a sua distribuição no território nacional, deixando explícito o benefício da braquiterapia de alta taxa de dose para o Brasil.High-dose rate brachytherapy was first introduced in Brazil in January 1991. Significant changes in the management of malignant neoplasms were observed since utilization of high-dose rate brachytherapy. The high number of gynecological patients awaiting for brachytherapy also decreased during this period. In the first ten years 26,436 patients were treated with high-dose rate brachytherapy. More than 50% of these patients presented neoplasms of the uterine cervix. In this study we present the number and profile of the patients treated with high-dose rate brachytherapy as well as the distribution of these patients in the Brazilian territory, proving the benefit of the use of high-dose rate brachytherapy in Brazil.

The Influence of Milling on the Dissolution Performance of Simvastatin

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Thomas Rades

2010-12-01

Full Text Available Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM and image analysis. Process induced disorder was determined by partial least squares (PLS regression modeling of respective X-ray powder diffractograms (XRPD and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 μm and a process induced disorder of 6.1% (assessed by Raman spectroscopy and 8.4% (assessed by XRPD, at a set optimization limit of < 2 μm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder

Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study.

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Jennifer Settergren

Full Text Available To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23. Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58-0.68. Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78. Mean DDD (SD for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149 compared to patients on statin monotherapy 127 (93, (p<0.001.Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co

Endorectal high dose rate brachytherapy quality assurance

International Nuclear Information System (INIS)

Devic, S.; Vuong, T.; Evans, M.; Podgorsak, E.

2008-01-01

We describe our quality assurance method for preoperative high dose rate (HDR) brachytherapy of endorectal tumours. Reproduction of the treatment planning dose distribution on a daily basis is crucial for treatment success. Due to the cylindrical symmetry, two types of adjustments are necessary: applicator rotation and dose distribution shift along the applicator axis. (author)

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

International Nuclear Information System (INIS)

Martinez, Alvaro A.; Gustafson, Gary; Gonzalez, Jose; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-01-01

Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p<0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p=0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause

Preparation of Emulsifying Wax/GMO Nanoparticles and Evaluation as a Delivery System for Repurposing Simvastatin in Bone Regeneration.

Science.gov (United States)

Eskinazi-Budge, Aaron; Manickavasagam, Dharani; Czech, Tori; Novak, Kimberly; Kunzler, James; Oyewumi, Moses O

2018-05-30

Simvastatin (Sim) is a widely known drug in the treatment of hyperlipidemia that has attracted so much attention in bone regeneration based on its potential osteoanabolic effect. However, repurposing of Sim in bone regeneration will require suitable delivery systems that can negate undesirable off-target/side effects. In this study, we have investigated a new lipid nanoparticle (NP) platform that was fabricated using a binary blend of emulsifying wax (Ewax) and glyceryl monooleate (GMO). Using the binary matrix materials, NPs loaded with Sim (0-500 µg/mL) were prepared and showed an average particle size of about 150 nm. NP size stability was dependent on Sim concentration loaded in NPs. The suitability of NPs prepared with the binary matrix materials in Sim delivery for potential application in bone regeneration was supported by biocompatibility in pre-osteoclastic and pre-osteoblastic cells. Additional data demonstrated that biofunctional Sim was released from NPs that facilitated differentiation of osteoblasts (cells that form bones) while inhibiting differentiation of osteoclasts (cells that resorb bones). The overall work demonstrated the preparation of NPs from Ewax/GMO blends and characterization to ascertain potential suitability in Sim delivery for bone regeneration. Additional studies on osteoblast and osteoclast functions are warranted to fully evaluate the efficacy simvastatin-loaded Ewax/GMO NPs using in-vitro and in-vivo approaches.

Low dose radiation enhance the anti-tumor effect of high dose radiation on human glioma cell U251

International Nuclear Information System (INIS)

Wang Chang; Wang Guanjun; Tan Yehui; Jiang Hongyu; Li Wei

2008-01-01

Objective: To detect the effect on the growth of human glioma cell U251 induced by low dose irradiation and low dose irradiation combined with large dose irradiation. Methods: Human glioma cell line U251 and nude mice carried with human glioma were used. The tumor cells and the mice were treated with low dose, high dose, and low dose combined high dose radiation. Cells growth curve, MTT and flow cytometry were used to detect the proliferation, cell cycle and apoptosis of the cells; and the tumor inhibition rate was used to assess the growth of tumor in vivo. Results: After low dose irradiation, there was no difference between experimental group and control group in cell count, MTT and flow cytometry. Single high dose group and low dose combined high dose group both show significantly the suppressing effect on tumor cells, the apoptosis increased and there was cell cycle blocked in G 2 period, but there was no difference between two groups. In vivo apparent anti-tumor effect in high dose radiation group and the combining group was observed, and that was more significant in the combining group; the prior low dose radiation alleviated the injury of hematological system. There was no difference between single low dose radiation group and control. Conclusions: There is no significant effect on human glioma cell induced by low dose radiation, and low dose radiation could not induce adaptive response. But in vivo experience, low dose radiation could enhance the anti-tumor effect of high dose radiation and alleviated the injury of hematological system. (authors)

Combination of niacin extended-release and simvastatin results in a less atherogenic lipid profile than atorvastatin monotherapy

Directory of Open Access Journals (Sweden)

William Insull Jr

2010-11-01

Full Text Available William Insull Jr1, Peter P Toth2, H Robert Superko3, Roopal B Thakkar4, Scott Krause4, Ping Jiang4, Rhea A Parreno4, Robert J Padley41Baylor College of Medicine and Methodist Hospital, Houston, Texas; 2University of Illinois College of Medicine, Peoria, Illinois; 3Celera, Alameda, California, Mercer University, Atlanta, Georgia; 4Abbott, Abbott Park, Illinois, USAObjective: To compare the effects of combination niacin extended-release + simvastatin (NER/S versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia.Patients and methods: Patients (n = 137 with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4–5 weeks prior to the study received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher’s exact test.Results: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B <80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003. NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022, small LDL (55% versus 45%; P = 0.011, very low-density lipoprotein (VLDL and total chylomicrons (63% versus 39%; P < 0.001, and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007 and VLDL (9.3% versus 0.1%; P < 0.001, compared with atorvastatin.Conclusion: NER/S treatment significantly improved apo A-I levels and the apo

NIST high-dose calibration services

International Nuclear Information System (INIS)

Humphreys, J.C.

1989-01-01

There is a need for the standardization of high-dose measurements used in the radiation-processing industry in order to provide assured traceability to national standards. NIST provides dosimetry calibration services to this industry. One of these services involves administration of known absorbed doses of gamma rays to customer-supplied dosimeters. The dosimeters are packaged to provide electron equilibrium conditions and are irradiated in a standard 60 Co calibration facility; this provides a calibration of that batch of dosimeters. Another service consists of supplying to a customer calibrated transfer dosimeters for irradiation with the customer's radiation source. The irradiated transfer dosimeters are then returned to NIST for analysis; the results are reported to the customer, providing a calibration of the dose rate of the customer's source. (orig.)

Rectal dose assessment in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer

International Nuclear Information System (INIS)

Oliveira, Jetro Pereira de; Batista, Delano Valdivino Santos; Bardella, Lucia Helena; Carvalho, Arnaldo Rangel

2009-01-01

Objective: The present study was aimed at developing a thermoluminescent dosimetric system capable of assessing the doses delivered to the rectum of patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. Materials and methods: LiF:Mg,Ti,Na powder was the thermoluminescent material utilized for evaluating the rectal dose. The powder was divided into small portions (34 mg) which were accommodated in a capillary tube. This tube was placed into a rectal probe that was introduced into the patient's rectum. Results: The doses delivered to the rectum of six patients submitted to high-dose-rate brachytherapy for uterine cervix cancer evaluated by means of thermoluminescent dosimeters presented a good agreement with the planned values based on two orthogonal (anteroposterior and lateral) radiographic images of the patients. Conclusion: The thermoluminescent dosimetric system developed in the present study is simple and easy to be utilized as compared to other rectal dosimetry methods. The system has shown to be effective in the evaluation of rectal doses in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. (author)

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

Science.gov (United States)

Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-06-01

To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Investigation of polymer composite for high dose dosimetry

International Nuclear Information System (INIS)

Pereira, E.L.M.; Batista, A.S.M.; Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H.

2017-01-01

Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO 2 ) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm -1 and 1730 cm -1 can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm -1 and 1730 cm -1 whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

Statistical behavior of high doses in medical radiodiagnosis

International Nuclear Information System (INIS)

Barboza, Adriana Elisa

2014-01-01

This work has as main purpose statistically estimating occupational exposure in medical diagnostic radiology in cases of high doses recorded in 2011 at national level. For statistical survey of this study, doses of 372 IOE's diagnostic radiology in different Brazilian states were evaluated. Data were extracted from the work of monograph (Research Methodology Of High Doses In Medical Radiodiagnostic) that contains the database's information Sector Management doses of IRD/CNEN-RJ, Brazil. The identification of these states allows the Sanitary Surveillance (VISA) responsible, becomes aware of events and work with programs to reduce these events. (author)

Study of teflon pads as high doses dosemeters

International Nuclear Information System (INIS)

Teixeira, Maria Ines; Caldas, Linda V.E.

2013-01-01

The aim of this work is to study the Teflon, which is used as a binder in the manufacture of dosimetric tablets, for the feasibility of this material as high dose dosemeter. In this paper we used the technique of thermally stimulated luminescence (OSL) to characterize the dosimetric properties of Teflon. Teflon samples were exposed to different doses of radiation, using a source of gamma radiation ( 60 Co). It was obtained dose-response curve between 100 Gy to 50 kGy and reproducibility of OSL response. The preliminary results show that Teflon is a useful material to high dose dosimetry

Ionization chamber for high dose measurements

International Nuclear Information System (INIS)

Rodrigues Junior, Ary de Araujo

2005-01-01

Industrial gamma irradiators facilities are designed for processing large amounts of products, which are exposed to large doses of gamma radiation. The irradiation, in industrial scale, is usually carried out in a dynamic form, where the products go through a 60 Co gamma source with activity of TBq to P Bq (k Ci to MCi). The dose is estimated as being directly proportional to the time that the products spend to go through the source. However, in some situations, mainly for research purposes or for validation of customer process following the ISO 11137 requirements, it is required to irradiate small samples in a static position with fractional deliver doses. The samples are put inside the irradiation room at a fixed distance from the source and the dose is usually determined using dosimeters. The dose is only known after the irradiation, by reading the dosimeter. Nevertheless, in the industrial irradiators, usually different kinds of products with different densities go through between the source and the static position samples. So, the dose rate varies in function of the product density. A suitable methodology would be to monitor the samples dose in real time, measuring the dose on line with a radiation detector, which would improve the dose accuracy and avoid the overdose. A cylindrical ionization chamber of 0.9 cm 3 has been developed for high-doses real-time monitoring, during the sample irradiation at a static position in a 60 Co gamma industrial plant. Nitrogen and argon gas at pressure of 10 exp 5 Pa (1 bar) was utilized to fill the ionization chamber, for which an appropriate configuration was determined to be used as a detector for high-dose measurements. To transmit the signal generated in the ionization chamber to the associated electronic and processing unit, a 20 m mineral insulated cable was welded to the ionization chamber. The signal to noise ratio produced by the detector was about 100. The dosimeter system was tested at a category I gamma

Development of computerized dose planning system and applicator for high dose rate remote afterloading irradiation

Energy Technology Data Exchange (ETDEWEB)

Choi, T. J. [Keimyung Univ., Taegu (Korea); Kim, S. W. [Fatima Hospital, Taegu (Korea); Kim, O. B.; Lee, H. J.; Won, C. H. [Keimyung Univ., Taegu (Korea); Yoon, S. M. [Dong-a Univ., Pusan (Korea)

2000-04-01

To design and fabricate of the high dose rate source and applicators which are tandem, ovoids and colpostat for OB/Gyn brachytherapy includes the computerized dose planning system. Designed the high dose rate Ir-192 source with nuclide atomic power irradiation and investigated the dose characteristics of fabricated brachysource. We performed the effect of self-absorption and determining the gamma constant and output factor and determined the apparent activity of designed source. he automated computer planning system provided the 2D distribution and 3D includes analysis programs. Created the high dose rate source Ir-192, 10 Ci(370GBq). The effective attenuation factor from the self-absorption and source wall was examined to 0.55 of the activity of bare source and this factor is useful for determination of the apparent activity and gamma constant 4.69 Rcm{sup 2}/mCi-hr. Fabricated the colpostat was investigated the dose distributions of frontal, axial and sagittal plane in intra-cavitary radiation therapy for cervical cancer. The reduce dose at bladder and rectum area was found about 20 % of original dose. The computerized brachytherapy planning system provides the 2-dimensional isodose and 3-D include the dose-volume histogram(DVH) with graphic-user-interface mode. emoted afterloading device was built for experiment of created Ir-192 source with film dosimetry within {+-}1 mm discrepancy. 34 refs., 25 figs., 11 tabs. (Author)

Pharmacogenetics and Pharmacokinetics in high-dose alkylating chemotherapy

NARCIS (Netherlands)

Ekhart, G.C. (Corine)

2008-01-01

High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation has been developed as a possible curative treatment modality in several solid tumours. A frequently used high-dose regimen in the Netherlands is the CTC regimen, which is a 4-day course of cyclophosphamide,

Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability

NARCIS (Netherlands)

Bredie, S. J.; de Bruin, T. W.; Demacker, P. N.; Kastelein, J. J.; Stalenhoef, A. F.

1995-01-01

We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well-defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction

Establishment and verification of dose-response curve of chromosomal aberrations after exposure to very high dose γ-ray

International Nuclear Information System (INIS)

Chen Ying; Luo Yisheng; Cao Zhenshan; Liu Xiulin

2006-01-01

To estimate accurately biological dose of the victims exposed to high dose, the dose-response curves of chromosome aberration induced by 6-22 Gy 60 Co γ-ray were established. Human peripheral blood in vitro was irradiated, then lymphocytes were concentrated, cultured 52h, 68h and 72h and harvested. The frequencies of dicentrics (multi-centrics) and rings were counted and compared between different culture times. The dose-response curves and equations were established, as well as verified with high dose exposure accidents. The experiment showed that the culture time should be prolonged properly after high dose exposure, and no significant differences were observed between 52-72h culture. The dose-response curve of 6-22 Gy fitted to linear-square model Y=-2.269 + 0.776D - 7.868 x 10 -3 D 2 and is reliable through verification of the accident dose estimations. In this study, the dose-response curve and equation of chromosome dic + r after 6-22 Gy high dose irradiation were established firstly, and exact dose estimation can be achieved according to it. (authors)

Nonlinear model of high-dose implantation

International Nuclear Information System (INIS)

Danilyuk, A.

2001-01-01

The models of high-dose implantation, using the distribution functions, are relatively simple. However, they must take into account the variation of the function of distribution of the implanted ions with increasing dose [1-4]. This variation takes place owing to the fact that the increase of the concentration of the implanted ions results in a change of the properties of the target. High-dose implantation is accompanied by sputtering, volume growth, diffusion, generation of defects, formation of new phases, etc. The variation of the distribution function is determined by many factors and is not known in advance. The variation within the framework of these models [1-4] is taken into account in advance by the introduction of intuitive assumptions on the basis of implicit considerations. Therefore, these attempts should be regarded as incorrect. The model prepared here makes it possible to take into account the sputtering of the target, volume growth and additional declaration on the implanted ions. Without any assumptions in relation to the variation of the distribution function with increasing dose. In our model it is assumed that the type of distribution function for small doses in a pure target substance is the same as in substances with implanted ions. A second assumption relates to the type of the distribution function valid for small doses in the given substances. These functions are determined as a result of a large number of theoretical and experimental investigations and are well-known at the present time. They include the symmetric and nonsymmetric Gauss distribution, the Pearson distribution, and others. We examine implantation with small doses of up to 10 14 - 10 15 cm -2 when the accurately known distribution is valid

High-dose gadolinium-enhanced MRI for diagnosis of meningeal metastases

International Nuclear Information System (INIS)

Kallmes, D.F.; Gray, L.; Glass, J.P.

1998-01-01

We compared high-dose (0.3 mmol/kg) and standard-dose (0.1 mmol/kg) gadolinium-enhanced MRI for diagnosis of meningeal metastases in 12 patients with suspected meningeal metastases. They were imaged with both standard-dose and high-dose gadolinium. All patients with abnormal meningeal enhancement underwent at least one lumbar puncture for cerebrospinal fluid (CSF) cytology, while patients with normal meningeal enhancement were followed clinically. All patients with negative CSF cytology also were followed clinically. A single observer reviewed all the images, with specific attention to the enhancement pattern of the meninges. Abnormal leptomeningeal enhancement was present in three cases, and abnormal pachymeningeal enhancement in three other patients. All of these patients had abnormal CSF analyses. In two of the three cases of abnormal leptomeningeal enhancement the disease was more evident on high-dose than on standard-dose imaging; in one case the abnormal enhancement was visible only on high-dose imaging. In one of the three cases with abnormal pachymeningeal enhancement, the disease was evident prospectively only with high-dose imaging. (orig.)

Investigation of polymer composite for high dose dosimetry

Energy Technology Data Exchange (ETDEWEB)

Pereira, E.L.M.; Batista, A.S.M., E-mail: adriananuclear@yahoo.com.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H. [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

2017-07-01

Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO{sub 2}) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm{sup -1} and 1730 cm{sup -1} can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm{sup -1} and 1730 cm{sup -1} whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

Methodology of high dose research in medical radiodiagnostic

International Nuclear Information System (INIS)

Barboza, Adriana E.; Martins, Cintia P. de S.

2013-01-01

This work has as main purpose to study occupational exposure in diagnostic radiology in medical cases of high doses recorded in 2011 at the national level . These doses were recorded by monitoring individual of the occupationally exposed individuals (OEI's). This monitoring of the doses received by ionizing radiation has as main objective to ensure that the principle of dose limitation is respected. In this study it were evaluated doses of 372 OEI's radiology in different Brazilian states. Doses were extracted from the database of Sector Management Doses of the Institute for Radioprotection and Dosimetry - IRD/CNEN-RJ, Brazil. The information from the database provide reports of doses from several states, which allows to quantify statistically, showing those with the highest doses in four areas: dose greater than or equal to 20 mSv apron and chest and dose greater than or equal to 100 mSv apron and chest. The identification of these states allows the respective Sanitary Surveillance (VISA), be aware of the events and make plans to reduce them. This study clarified the required procedures when there is a record of high dose emphasizing the importance of using protective radiological equipment, dosimeter and provide a safety environment work by maintaining work equipment. Proposes the ongoing training of professionals, emphasizing the relevance of the concepts of radiation protection and the use of the questionnaire with their investigative systematic sequence, which will allow quickly and efficiently the success the investigations

High-dose preoperative radiation for cancer of the rectum: Impact of radiation dose on patterns of failure and survival

International Nuclear Information System (INIS)

Ahmad, N.R.; Mohiuddin, M.; Marks, G.

1993-01-01

A variety of dose-time schedules are currently used for preoperative radiation therapy of rectal cancer. An analysis of patients treated with high-dose preoperative radiation therapy was undertaken to determine the influence of radiation dose on the patterns of failure, survival, and complications. Two hundred seventy-five patients with localized rectal cancer were treated with high-dose preoperative radiation therapy. One hundred fifty-six patients received 45 Gy (low-dose group). Since 1985, 119 patients with clinically unfavorable cancers were given a higher dose, 55 Gy using a shrinking field technique (high-dose group). All patients underwent curative resection. Median follow-up was 66 months in the low-dose group and 28 months in the high-dose group. Patterns of failure, survival, and complications were analyzed as a function of radiation dose. Fourteen percent of the total group developed a local recurrence; 20% in the low-dose group as compared with 6% in the high-dose group. The actuarial local recurrence rate at 5 years was 20% for the low-dose group and 8% for the high-dose group, and approached statistical significance with p = .057. For tethered/fixed tumors the actuarial local recurrence rates at 5 years were 28% and 9%, respectively, with p = .05. Similarly, for low-lying tumors (less than 6 cm from the anorectal junction) the rates were 24% and 9%, respectively, with p = .04. The actuarial rate of distant metastasis was 28% in the low-dose group and 20% in the high-dose group and was not significantly different. Overall actuarial 5-year survival for the total group of patients was 66%. No significant difference in survival was observed between the two groups, despite the higher proportion of unfavorable cancers in the high-dose group. The incidence of complications was 2%, equally distributed between the two groups. High-dose preoperative radiation therapy for rectal cancer results in excellent local control rates. 27 refs., 2 figs., 8 tabs

Acute renal failure in high dose carboplatin chemotherapy

NARCIS (Netherlands)

Frenkel, J.; Kool, G.; de Kraker, J.

1995-01-01

Carboplatin has been reported to cause acute renal failure when administered in high doses to adult patients. We report a 4 1/2-year-old girl who was treated with high-dose carboplatin for metastatic parameningeal embryonal rhabdomyosarcoma. Acute renal failure developed followed by a slow partial

Dose intercomparison studies for standardization of high-dose dosimetry in Viet Nam

International Nuclear Information System (INIS)

Mai Hoang Hoa; Duong Nguyen Dinh; Kojima, T.

1999-01-01

The Irradiation Center of the Vietnam Atomic Energy Commission (IC-VAEC) is planning to establish a traceability system for high-dose dosimetry and to provide high-dose standards as a secondary standard dosimetry laboratory (SSDL) level in Vietnam. For countries which do not have a standard dosimetry laboratory, the participation in the International Dose Assurance Service (IDAS) operated by the International Atomic Energy Agency (IAEA) is the most common means to verify own dosimetry performance with a certain uncertainty. This is, however, only one-direction dose intercomparison with evaluation by IAEA including unknown parameter at participant laboratories. The SSDL level laboratory should have traceability as well as compatibility, ability to evaluate uncertainties of its own dosimetry performance by itself In the present paper, we reviewed our dosimetry performance through two-way dose intercomparison studies and self-evaluation of uncertainty in our dosimetry procedure. The performance of silver dichromate dosimeter as reference transfer dosimeter in IC-VAEC was studied through two-way blind dose intercomparison experiments between the IC-VAEC and JAERI. As another channel of dose intercomparison with IAEA, alanine dosimeters issued by IDAS were simultaneously irradiated with the IC-VAEC dichromate dosimeters at IC-VAEC and analyzed by IAEA. Dose intercomparison between IC-VAEC and JAERI results into a good agreement (better than ±2.5%), and IDAS results also show similar agreement within ±3.0%. The uncertainty was self-estimated on the basis of the JAERI alanine dosimetry, and a preliminary value of about 1.86% at a 68% confidence level is established. The results from these intercomparisons and our estimation of the uncertainty are consistent. We hope that our experience is valuable to other countries which do not have dosimetry standard laboratories and/or are planning to establish them. (author)

High-dose contrast-enhanced MRI in multiple sclerosis

International Nuclear Information System (INIS)

Koudriavtseva, T.; Pozzilli, C.; Di Biasi, C.; Iannilli, M.; Trasimeni, G.; Gasperini, C.; Argentino, C.; Gualdi, G.F.

1996-01-01

Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs

High-dose contrast-enhanced MRI in multiple sclerosis

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Koudriavtseva, T. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Pozzilli, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Di Biasi, C. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Iannilli, M. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Trasimeni, G. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Gasperini, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Argentino, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Gualdi, G.F. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy)

1996-05-01

Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs.

Standardization of high-dose measurement of electron and gamma ray absorbed doses and dose rates

International Nuclear Information System (INIS)

McLaughlin, W.L.

1985-01-01

Intense electron beams and gamma radiation fields are used for sterilizing medical devices, treating municipal wastes, processing industrial goods, controlling parasites and pathogens, and extending the shelf-life of foods. Quality control of such radiation processes depends largely on maintaining measurement quality assurance through sound dosimetry procedures in the research leading to each process, in the commissioning of that process, and in the routine dose monitoring practices. This affords documentation as to whether satisfactory dose uniformity is maintained throughout the product and throughout the process. Therefore, dosimetry at high doses and dose rates must in many radiation processes be standardized carefully, so that 'dosimetry release' of a product is verified. This standardization is initiated through preliminary dosimetry intercomparison studies such as those sponsored recently by the IAEA. This is followed by establishing periodic exercises in traceability to national or international standards of absorbed dose and dose rate. Traceability is achieved by careful selection of dosimetry methods and proven reference dosimeters capable of giving sufficiently accurate and precise 'transfer' dose assessments: (1) they must be calibrated or have well-established radiation-yield indices; (2) their radiation response characteristics must be reproducible and cover the dose range of interest; (3) they must withstand the rigours of back-and-forth mailing between a central standardizing laboratory and radiation processing facilities, without excessive errors arising due to instabilities, dosimeter batch non-uniformities, and environmental and handling stresses. (author)

Radiographic Comparison of Bovine Bone Substitute Alone versus Bovine Bone Substitute and Simvastatin for Human Maxillary Sinus Augmentation

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Amir Ali Reza Rasouli Ghahroudi

2018-01-01

Full Text Available Objectives: The aim of this study was to compare the efficacy of bovine bone substitute (Compact Bone B. ® alone versus bovine bone substitute and simvastatin for human maxillary sinus augmentation.Materials and Methods: This study was conducted on 16 sinuses in eight patients. Radiographic assessments were done preoperatively (T0, immediately (T1 and at nine months after sinus grafting (T2. Alveolar bone height and density were assessed on cone beam computed tomography (CBCT scans using Planmeca Romexis™ Imaging Software 2.2.Results: The change in alveolar bone height and density between T0, T1 and T2 was significant in both groups. Alveolar bone height (h0, h1, h2 and vertical height of the grafted bone (g1, g2 in three lines (anterior, middle and posterior were not significantly different between groups. The grafted bone height shrinkage (% in the anterior, middle and posterior limits of the augmented area were not significantly different between groups. The existing alveolar and grafted bone density increased significantly in both groups between T1 and T2, except for the existing alveolar bone density in the control group. There were no statistically significant differences between the alveolar bone density values obtained in TI and T2 between groups, except for the existing alveolar bone density at T1.Conclusions: This study did not show any significant positive effect for simvastatin in maxillary sinus augmentation based on radiographic examination.

Platelet-rich plasma, plasma rich in growth factors and simvastatin in the regeneration and repair of alveolar bone.

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Rivera, César; Monsalve, Francisco; Salas, Juan; Morán, Andrea; Suazo, Iván

2013-12-01

Platelet preparations promote bone regeneration by inducing cell migration, proliferation and differentiation in the area of the injury, which are essential processes for regeneration. In addition, several studies have indicated that simvastatin (SIMV), widely used for the treatment of hypercholesterolemia, stimulates osteogenesis. The objective of this study was to evaluate the effects of treatment with either platelet-rich plasma (PRP) or plasma rich in growth factors (PRGF) in combination with SIMV in the regeneration and repair of alveolar bone. The jaws of Sprague Dawley rats (n=18) were subjected to rotary instrument-induced bone damage (BD). Animals were divided into six groups: BD/H 2 O (n=3), distilled water without the drug and alveolar bone damage; BD/H 2 O/PRP (n=3), BD and PRP; BD/H 2 O/PRGF (n=3), BD and PRGF; BD/SIMV (n=3), BD and water with SIMV; BD/SIMV/PRP (n=3), BD, PRP and SIMV; and BD/SIMV/PRGF (n=3), BD, PRGF and SIMV. Conventional histological analysis (hematoxylin and eosin staining) revealed that the BD/SIMV group showed indicators for mature bone tissue, while the BD/SIMV/PRP and BD/SIMV/PRGF groups showed the coexistence of indicators for mature and immature bone tissue, with no statistical differences between the platelet preparations. Simvastatin did not improve the effect of platelet-rich plasma and plasma rich in growth factors. It was not possible to determine which platelet preparation produced superior effects.

Update on pediatric resuscitation drugs: high dose, low dose, or no dose at all.

Science.gov (United States)

Sorrentino, Annalise

2005-04-01

Pediatric resuscitation has been a topic of discussion for years. It is difficult to keep abreast of changing recommendations, especially for busy pediatricians who do not regularly use these skills. This review will focus on the most recent guidelines for resuscitation drugs. Three specific questions will be discussed: standard dose versus high-dose epinephrine, amiodarone use, and the future of vasopressin in pediatric resuscitation. The issue of using high-dose epinephrine for cardiopulmonary resuscitation refractory to standard dose epinephrine has been a topic of debate for many years. Recently, a prospective, double-blinded study was performed to help settle the debate. These results will be reviewed and compared with previous studies. Amiodarone is a medication that was added to the pediatric resuscitation algorithms with the most recent recommendations from the American Heart Association in 2000. Its use and safety will also be discussed. Another topic that is resurfacing in resuscitation is the use of vasopressin. Its mechanism and comparisons to other agents will be highlighted, although its use in the pediatric patient has not been thoroughly studied. Pediatric resuscitation is a constantly evolving subject that is on the mind of anyone taking care of sick children. Clinicians are continually searching for the most effective methods to resuscitate children in terms of short- and long-term outcomes. It is important to be familiar with not only the agents being used but also the optimal way to use them.

Retrospective analysis of dose delivery in intra-operative high dose rate brachytherapy

International Nuclear Information System (INIS)

Oh, M.; Avadhani, J.S.; Malhotra, H.K.; Cunningham, B.; Tripp, P.; Jaggernauth, W.; Podgorsak, M.B.

2007-01-01

Background. This study was performed to quantify the inaccuracy in clinical dose delivery due to the incomplete scatter conditions inherent in intra-operative high dose rate (IOHDR) brachytherapy. Methods. Treatment plans of 10 patients previously treated in our facility, which had irregular shapes of treated areas, were used. Treatment geometries reflecting each clinical case were simulated using a phantom assembly with no added build-up on top of the applicator. The treatment planning geometry (full scatter surrounding the applicator) was subsequently simulated for each case by adding bolus on top of the applicator. Results. For geometries representing the clinical IOHDR incomplete scatter environment, measured doses at the 5 mm and 10 mm prescription depths were lower than the corresponding prescribed doses by about 7.7% and 11.1%, respectively. Also, for the two prescription methods, an analysis of the measured dose distributions and their corresponding treatment plans showed average decreases of 1.2 mm and 2.2 mm in depth of prescription dose, respectively. Conclusions. Dosimetric calculations with the assumption of an infinite scatter environment around the applicator and target volume have shown to result in dose delivery errors that significantly decrease the prescription depth for IOHDR treatment.(author)

Fertility of Tall Girls Treated with High-Dose Estrogen, a Dose-Response Relationship

NARCIS (Netherlands)

Hendriks, A. E. J.; Drop, S. L. S.; Laven, J. S. E.; Boot, A. M.

Context: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. Objective: The aim was to study the effect of estrogen dose on fertility outcome of these women. Design/Setting: We conducted a retrospective cohort study of university

Radiation effects of high and low doses

International Nuclear Information System (INIS)

El-Naggar, A.M.

1998-01-01

The extensive proliferation of the uses and applications of atomic and nuclear energy resulted in possible repercussions on human health. The prominent features of the health hazards that may be incurred after exposure to high and low radiation doses are discussed. The physical and biological factors involved in the sequential development of radiation health effects and the different cellular responses to radiation injury are considered. The main criteria and features of radiation effects of high and low doses are comprehensively outlined

High daily doses of benzodiazepines among Quebec seniors: prevalence and correlates

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Moride Yola

2001-11-01

Full Text Available Abstract Background Use of high daily doses of benzodiazepines is generally contraindicated for seniors. While both patient and physician factors may influence the use of high daily doses, previous research on the effect of patient factors has been extremely limited. The objectives of this study were to determine the one year prevalence of use of high daily doses of benzodiazepines, and examine physician and patient correlates of such use among Quebec community-dwelling seniors. Methods Patient information for 1423 community-dwelling Quebec seniors who participated in the Canadian Study of Health and Aging was linked to provincial health insurance administrative data bases containing detailed information on prescriptions received and prescribers. Results The standardized one year period prevalence of use of high daily doses of benzodiazepines was 7.9%. Use of high daily doses was more frequent among younger seniors and those who had reported anxiety during the previous year. Patients without cognitive impairment were more likely to receive high dose prescriptions from general practitioners, while those with cognitive impairment were more likely to receive high dose prescriptions from specialists. Conclusion High dose prescribing appears to be related to both patient and physician factors.

Proximity correction of high-dosed frame with PROXECCO

Science.gov (United States)

Eisenmann, Hans; Waas, Thomas; Hartmann, Hans

1994-05-01

Usefulness of electron beam lithography is strongly related to the efficiency and quality of methods used for proximity correction. This paper addresses the above issue by proposing an extension to the new proximity correction program PROXECCO. The combination of a framing step with PROXECCO produces a pattern with a very high edge accuracy and still allows usage of the fast correction procedure. Making a frame with a higher dose imitates a fine resolution correction where the coarse part is disregarded. So after handling the high resolution effect by means of framing, an additional coarse correction is still needed. Higher doses have a higher contribution to the proximity effect. This additional proximity effect is taken into account with the help of the multi-dose input of PROXECCO. The dose of the frame is variable, depending on the deposited energy coming from backscattering of the proximity. Simulation proves the very high edge accuracy of the applied method.

High-dose buprenorphine: perioperative precautions and management strategies.

Science.gov (United States)

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Impact of catheter reconstruction error on dose distribution in high dose rate intracavitary brachytherapy and evaluation of OAR doses

International Nuclear Information System (INIS)

Thaper, Deepak; Shukla, Arvind; Rathore, Narendra; Oinam, Arun S.

2016-01-01

In high dose rate brachytherapy (HDR-B), current catheter reconstruction protocols are relatively slow and error prone. The purpose of this study is to evaluate the impact of catheter reconstruction error on dose distribution in CT based intracavitary brachytherapy planning and evaluation of its effect on organ at risk (OAR) like bladder, rectum and sigmoid and target volume High risk clinical target volume (HR-CTV)

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

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Júlia Niehues da Cruz

2017-04-01

Full Text Available ABSTRACT Membrane/lipid rafts (MLRs are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins can disable the N-methyl-D-aspartate (NMDA receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

High-temperature absorbed dose measurements in the megagray range

International Nuclear Information System (INIS)

Balian, P.; Ardonceau, J.; Zuppiroli, L.

1988-01-01

Organic conductors of the tetraselenotetracene family have been tested as ''high-temperature'' absorbed dose dosimeters. They were heated up to 120 0 C and irradiated at this temperature with 1-MeV electrons in order to simulate, in a short time, a much longer γ-ray irradiation. The electric resistance increase of the crystal can be considered a good measurement of the absorbed dose in the range 10 6 Gy to a few 10 8 Gy and presumably one order of magnitude more. This dosimeter also permits on-line (in-situ) measurements of the absorbed dose without removing the sensor from the irradiation site. The respective advantages of organic and inorganic dosimeters at these temperature and dose ranges are also discussed. In this connection, we outline new, but negative, results concerning the possible use of silica as a high-temperature, high-dose dosimeter. (author)

Modulation of the Gut Microbiota by Krill Oil in Mice Fed a High-Sugar High-Fat Diet

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Chenyang Lu

2017-05-01

Full Text Available Multiple lines of evidence suggest that the gut microbiota plays vital roles in metabolic diseases such as hyperlipidemia. Previous studies have confirmed that krill oil can alleviate hyperlipidemia, but the underlying mechanism remains unclear. To discern whether krill oil changes the structure of the gut microbiota during the hyperlipidemia treatment, 72 mice were acclimatized with a standard chow diet for 2 weeks and then randomly allocated to receive a standard chow diet (control group, n = 12 or a high-sugar-high-fat (HSHF diet supplemented with a low (100 μg/g·d, HSHF+LD group, n = 12, moderate (200 μg/g·d, HSHF+MD group, n = 12 or high dosage of krill oil (600 μg/g·d, HSHF+HD group, n = 12, simvastatin (HSHF+S group, n = 12 or saline (HSHF group, n = 12 continuously for 12 weeks. The resulting weight gains were attenuated, the liver index and the low-density lipoprotein, total cholesterol and triglyceride concentrations showed a stepwise reduction in the treated groups compared with those of the control group. A dose-dependent modulation of the gut microbiota was observed after treatment with krill oil. Low- and moderate- doses of krill oil increased the similarity between the composition of the HSHF diet-induced gut microbiota and that of the control, whereas the mice fed the high-dose exhibited a unique gut microbiota structure that was different from that of the control and HSHF groups. Sixty-five key operational taxonomic units (OTUs that responded to the krill oil treatment were identified using redundancy analysis, of which 26 OTUs were increased and 39 OTUs were decreased compared with those of the HSHF group. In conclusion, the results obtained in this study suggest that the structural alterations in the gut microbiota induced by krill oil treatment were dose-dependent and associated with the alleviation of hyperlipidemia. Additionally, the high-dose krill oil treatment showed combined effects on the alleviation of

High-dose MeV electron irradiation of Si-SiO2 structures implanted with high doses Si+

Science.gov (United States)

Kaschieva, S.; Angelov, Ch; Dmitriev, S. N.

2018-03-01

The influence was studied of 22-MeV electron irradiation on Si-SiO2 structures implanted with high-fluence Si+ ions. Our earlier works demonstrated that Si redistribution is observed in Si+-ion-implanted Si-SiO2 structures (after MeV electron irradiation) only in the case when ion implantation is carried out with a higher fluence (1016 cm-2). We focused our attention on the interaction of high-dose MeV electron irradiation (6.0×1016 cm-2) with n-Si-SiO2 structures implanted with Si+ ions (fluence 5.4×1016 cm-2 of the same order magnitude). The redistribution of both oxygen and silicon atoms in the implanted Si-SiO2 samples after MeV electron irradiation was studied by Rutherford back-scattering (RBS) spectroscopy in combination with a channeling technique (RBS/C). Our results demonstrated that the redistribution of oxygen and silicon atoms in the implanted samples reaches saturation after these high doses of MeV electron irradiation. The transformation of amorphous SiO2 surface into crystalline Si nanostructures (after MeV electron irradiation) was evidenced by atomic force microscopy (AFM). Silicon nanocrystals are formed on the SiO2 surface after MeV electron irradiation. The shape and number of the Si nanocrystals on the SiO2 surface depend on the MeV electron irradiation, while their size increases with the dose. The mean Si nanocrystals height is 16-20 nm after irradiation with MeV electrons at the dose of 6.0×1016 cm-2.

A novel theory of radiation damage at high doses

International Nuclear Information System (INIS)

Seeger, A.; Stuttgart Univ.

1989-01-01

Deviations of radiation damage (in the case of metals usually monitored by the residual electrical resistivity) from proportionality with the irradiation dose have so far been analysed almost exclusively in terms of extensions of models originally developed for small doses. The present theory considers the opposite limit i.e. the quasi-saturated state. It is argued that at high doses the Lueck-Sizmann effect may result in a self-organization of clusters of vacancies and self-interstitials, forming a heterogeneous froth. Possible structures of this froth and its effect on the electrical resistivity of metals are discussed. The model is shown to account for the dependence of the ''saturation resistivity'' on the nature of the irradiation as well as for several other hitherto poorly explained observations. Among them are the electrical-resistivity variation induced by high-dose irradiation with heavy ions, the amorphization of certain alloys by high-dose electron irradiation, and the occurrence of ordered arrays of stacking-fault tetrahedra after in-situ irradiations in high-voltage electron microscopes. (author)

Radiobiological aspects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation

International Nuclear Information System (INIS)

Turesson, I.

1990-01-01

The biological effects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation in interstitial and intracavitary radiotherapy and total body irradiation are discussed in terms of dose-rate fractionation sensitivity for various tissues. A scaling between dose-rate and fraction size was established for acute and late normal-tissue effects which can serve as a guideline for local treatment in the range of dose rates between 0.02 and 0.005 Gy/min and fraction sizes between 8.5 and 2.5 Gy. This is valid provided cell-cycle progression and proliferation can be ignored. Assuming that the acute and late tissue responses are characterized by α/β values of about 10 and 3 Gy and a mono-exponential repair half-time of about 3 h, the same total doses given with either of the two methods are approximately equivalent. The equivalence for acute and late non-hemopoietic normal tissue damage is 0.02 Gy/min and 8.5 Gy per fraction; 0.01 Gy/min and 5.5 Gy per fraction; and 0.005 Gy/min and 2.5Gy per fraction. A very low dose rate, below 0.005 Gy/min, is thus necessary to simulate high dose-rate radiotherapy with fraction sizes of about 2Gy. The scaling factor is, however, dependent on the repair half-time of the tissue. A review of published data on dose-rate effects for normal tissue response showed a significantly stronger dose-rate dependence for late than for acute effects below 0.02 Gy/min. There was no significant difference in dose-rate dependence between various acute non-hemopoietic effects or between various late effects. The consistent dose-rate dependence, which justifies the use of a general scaling factor between fraction size and dose rate, contrasts with the wide range of values for repair half-time calculated for various normal-tissue effects. This indicates that the model currently used for repair kinetics is not satisfactory. There are also few experimental data in the clinical dose-rate range, below 0.02 Gy/min. It is therefore

Statistical behavior of high doses in medical radiodiagnosis; Comportamento estatistico das altas doses em radiodiagnostico medico

Energy Technology Data Exchange (ETDEWEB)

Barboza, Adriana Elisa, E-mail: adrianaebarboza@gmail.com, E-mail: elisa@bolsista.ird.gov.br [Instituto de Radioprotecao e Dosimetria, (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)

2014-07-01

This work has as main purpose statistically estimating occupational exposure in medical diagnostic radiology in cases of high doses recorded in 2011 at national level. For statistical survey of this study, doses of 372 IOE's diagnostic radiology in different Brazilian states were evaluated. Data were extracted from the work of monograph (Research Methodology Of High Doses In Medical Radiodiagnostic) that contains the database's information Sector Management doses of IRD/CNEN-RJ, Brazil. The identification of these states allows the Sanitary Surveillance (VISA) responsible, becomes aware of events and work with programs to reduce these events. (author)

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

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Ahmed OA

2015-01-01

Full Text Available Osama AA Ahmed,1,2 Khaled M Hosny,1,3 Majid M Al-Sawahli,1,4 Usama A Fahmy11Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt; 4Holding Company for Biological Products & Vaccines (VACSERA, Cairo, EgyptAbstract: The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1, ethanol concentration (X2, and caseinate concentration (X3. The selected dependent variables were mean particle size (Y1, SMV encapsulation efficiency (Y2, and cumulative percentage of drug permeated after 1 hour (Y3. The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability

Effects of low priming dose irradiation on cell cycle arrest of HepG2 cells caused by high dose irradiation

International Nuclear Information System (INIS)

Xia Jingguang; Jin Xiaodong; Chinese Academy of Sciences, Beijing; Li Wenjian; Wang Jufang; Guo Chuanling; Gao Qingxiang

2005-01-01

Human hepatoma cells hepG2 were irradiated twice by 60 Co γ-rays with a priming dose of 5 cGy and a higher dose of 3 Gy performed 4h or 8h after the low dose irradiation. Effects of the priming dose irradiation on cell cycle arrest caused by high dose were examined with flow cytometry. Cells in G 2 /M phase accumulated temporarily after the 5 cGy irradiation, and proliferation of tumor cells was promoted significantly by the low dose irradiation. After the 3 Gy irradiation, G 2 phase arrest occurred, and S phase delayed temporally. In comparison with 3 kGy irradiation only, the priming dose delivered 4h prior to the high dose irradiation facilitated accumulation of hepG2 cells in G 2 /M phase, whereas the priming dose delivered 8h prior to the high dose irradiation helped the cells to overcome G 2 arrest. It was concluded that effects of the priming dose treatment on cell cycle arrest caused by high dose irradiation were dependent on time interval between the two irradiations. (authors)

A clinical comparison of high dose and low dose of Suxamethonium

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RK Yadav

2014-01-01

Full Text Available Background: Suxamethonium having its rapid onset and short duration of action makes this drug unique amongst the neuromuscular blocking drugs described so far. However, use of suxamethonium is associated with a large number of undesirable side effects. Objective: To evaluate clinical effects of high and low dose of suxamethonium and to determine whether lower dose of suxamethonium can be used for any beneficial effects in terms of its various adverse effects e.g. cardiovascular responses, post-operative muscle pains and intraocular pressure. Methods: A total of 100 patients were included in this prospective study. All these patients on preoperative clinical evaluation were assessed to have adequate airway. All the patients were divided in two groups, low dose group (group I and High dose group (group II with 50 patients in each at random. A standard anesthetic technique was adhered to all the patients and following parameters were observed on comparative basis: a. Fasciculation and post operative myalgia. b. Cardiovascular effects, c. Intraocular pressure. Observation: The incidence of post Suxamethonium pain was significantly greater in group II. Increase in heart rate from baseline was significant in both groups. There was no significant difference between the two groups in the diastolic pressure but rise in systolic blood pressure was significant at all assessment times in both groups. This rise from control was statistically significant. Conclusion: Suxamethonium can be used in lower doses (0.5 mg/kg in elective cases without airway compromise. It gives benefits of reduced muscle pains, cardiovascular responses and intraocular hypertension. Journal of College of Medical Sciences-Nepal, 2013, Vol-9, No-2, 1-8 DOI: http://dx.doi.org/10.3126/jcmsn.v9i2.9677

Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline

DEFF Research Database (Denmark)

Kaae, Rikke; Agertoft, Lone; Pedersen, Sören

2004-01-01

OBJECTIVES: To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. METHODS: Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxi...

Dosimetric systems of high dose, dose rate and dose uniformity in food and medical products

International Nuclear Information System (INIS)

Vargas, J.; Vivanco, M.; Castro, E.

2014-08-01

In the Instituto Peruano de Energia Nuclear (IPEN) we use the chemical dosimetry Astm-E-1026 Fricke as a standard dosimetric system of reference and different routine dosimetric systems of high doses, according to the applied doses to obtain the desired effects in the treated products and the doses range determined for each type of dosimeter. Fricke dosimetry is a chemical dosimeter in aqueous solution indicating the absorbed dose by means an increase in absorbance at a specific wavelength. A calibrated spectrophotometer with controlled temperature is used to measure absorbance. The adsorbed dose range should cover from 20 to 400 Gy, the Fricke solution is extremely sensitive to organic impurities, to traces of metal ions, in preparing chemical products of reactive grade must be used and the water purity is very important. Using the referential standard dosimetric system Fricke, was determined to March 5, 2013, using the referential standard dosimetric system Astm-1026 Fricke, were irradiated in triplicate Fricke dosimeters, to 5 irradiation times (20; 30; 40; 50 and 60 seconds) and by linear regression, the dose rate of 5.400648 kGy /h was determined in the central point of the irradiation chamber (irradiator Gamma cell 220 Excel), applying the decay formula, was compared with the obtained results by manufacturers by means the same dosimetric system in the year of its manufacture, being this to the date 5.44691 kGy /h, with an error rate of 0.85. After considering that the dosimetric solution responds to the results, we proceeded to the irradiation of a sample of 200 g of cereal instant food, 2 dosimeters were placed at the lateral ends of the central position to maximum dose and 2 dosimeters in upper and lower ends as minimum dose, they were applied same irradiation times; for statistical analysis, the maximum dose rate was 6.1006 kGy /h and the minimum dose rate of 5.2185 kGy /h; with a dose uniformity of 1.16. In medical material of micro pulverized bone for

A remarkable hematological and molecular response pattern in a patient with polycythemia vera during combination therapy with simvastatin and alendronate

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Anders Lindholm Sørensen

2016-01-01

Full Text Available We report a 57-year old man with polycythemia vera, who had a remarkable hematological and molecular response during treatment with simvastatin and alendronate. The patient was treated with this combination for 56 months, and during this period the patient has been in complete hematological remission. The JAK2-V617F allele burden has dropped from 64% to sustained values below 20%, and follow-up bone marrow biopsies have revealed no change in PV features, without any regular cytoreductive treatment.

Accelerated Irradiations for High Dose Microstructures in Fast Reactor Alloys

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Jiao, Zhijie [Univ. of Michigan, Ann Arbor, MI (United States)

2017-03-31

The objective of this project is to determine the extent to which high dose rate, self-ion irradiation can be used as an accelerated irradiation tool to understand microstructure evolution at high doses and temperatures relevant to advanced fast reactors. We will accomplish the goal by evaluating phase stability and swelling of F-M alloys relevant to SFR systems at very high dose by combining experiment and modeling in an effort to obtain a quantitative description of the processes at high and low damage rates.

Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase II clinical trial with nimesulide, simvastatin and placebo

International Nuclear Information System (INIS)

Lazzeroni, Matteo; Radice, Davide; Bonanni, Bernardo; Guerrieri-Gonzaga, Aliana; Serrano, Davide; Cazzaniga, Massimiliano; Mora, Serena; Casadio, Chiara; Jemos, Costantino; Pizzamiglio, Maria; Cortesi, Laura

2012-01-01

Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up. This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated

Dose conversion coefficients for high-energy photons, electrons, neutrons and protons

International Nuclear Information System (INIS)

Sakamoto, Yukio

2005-01-01

Dose conversion coefficients for photons, electrons and neutrons based on new ICRP recommendations were cited in the ICRP Publication 74, but the energy ranges of these data were limited and there are no data for high energy radiations produced in accelerator facilities. For the purpose of designing the high intensity proton accelerator facilities at JAERI, the dose evaluation code system of high energy radiations based on the HERMES code was developed and the dose conversion coefficients of effective dose were evaluated for photons, neutrons and protons up to 10 GeV, and electrons up to 100 GeV. The dose conversion coefficients of effective dose equivalent were also evaluated using quality factors to consider the consistency between radiation weighting factors and Q-L relationship. The effective dose conversion coefficients obtained in this work were in good agreement with those recently evaluated by using FLUKA code for photons and electrons with all energies, and neutrons and protons below 500 MeV. There were some discrepancy between two data owing to the difference of cross sections in the nuclear reaction models. The dose conversion coefficients of effective dose equivalents for high energy radiations based on Q-L relation in ICRP Publication 60 were evaluated only in this work. The previous comparison between effective dose and effective dose equivalent made it clear that the radiation weighting factors for high energy neutrons and protons were overestimated and the modification was required. (author)

Evaluation of the dose uniformity for double-plane high dose rate interstitial breast implants with the use of dose reference points and dose non-uniformity ratio

International Nuclear Information System (INIS)

MAjor, T.; Polgar, C.; Somogyi, A.; Nemeth, G.

2000-01-01

This study investigated the influence of dwell time optimizations on dose uniformity characterized by dose values in dose points and dose non-uniformity ratio (DNR) and analyzed which implant parameters have influence on the DNR. Double-plane breast implants with catheters arranged in triangular pattern were used for the calculations. At a typical breast implant, dose values in dose reference points inside the target volume and volumes enclosed by given isodose surfaces were calculated and compared for non-optimized and optimized implants. The same 6-cm treatment length was used for the comparisons. Using different optimizations plots of dose non-uniformity ratio as a function of catheter separation, source step size, number of catheters, length of active sections were drawn and the minimum DNR values were determined. Optimization resulted in less variation in dose values over dose points through the whole volume and in the central plane only compared to the non-optimized case. At implant configurations consisting of seven catheters with 15-mm separation, 5-mm source step size and various active lengths adapted according to the type of optimization, the no optimization, geometrical (volume mode) and dose point (on dose points and geometry) optimization resulted in similar treatment volumes, but an increased high dose volume was observed due to the optimization. The dose non-uniformity ratio always had the minimum at average dose over dose normalization points, defined in the midpoints between the catheters through the implant volume. The minimum value of DNR depended on catheter separation, source step size, active length and number of catheters. The optimization had only a small influence on DNR. In addition to the reference points in the central plane only, dose points positioned in the whole implant volume can be used for evaluating the dose uniformity of interstitial implants. The dose optimization increases not only the dose uniformity within the implant but

Neuroprotective potential of high-dose biotin.

Science.gov (United States)

McCarty, Mark F; DiNicolantonio, James J

2017-11-01

A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain

Polybutadiene and Styrene-Butadiene rubbers for high-dose dosimetry

Energy Technology Data Exchange (ETDEWEB)

Oliveira, Lucas N. [Instituto Federal de Educacao, Ciencia e Tecnologia de Goias-IFG,Campus Goiania, Goiania -GO (Brazil); Instituto de Pesquisas Energeticas e Nucleares -IPEN, Sao Paulo-SP (Brazil); Vieira, Silvio L. [Instituto de Fisica, Universidade Federal de Goias-UFG, Campus Samambaia, Goiania-GO (Brazil); Schimidt, Fernando [Instituto Federal de Educacao, Ciencia e Tecnologia de Goias-IFG,Campus Inhumas, Inhumas-GO (Brazil); Antonio, Patricia L.; Caldas, Linda V.E. [Instituto de Pesquisas Energeticas e Nucleares -IPEN, Sao Paulo-SP (Brazil)

2015-07-01

Polybutadiene and Styrene-Butadiene are synthetical rubbers used widely for pneumatic tires manufacturing. In this research, the dosimeter characteristics of those rubbers were studied for application in high-dose dosimetry. The rubber samples were irradiated with doses of 10 Gy up to 10 kGy, using a {sup 60}Co Gamma Cell-220 system (dose rate of 1.089 kGy/h) and their readings were taken on a Fourier Transform Infrared Spectroscopy-FTIR system (model Frontier/Perkin Elmer). The ratios of two absorbance peaks were taken for each kind of rubber spectrum, Polybutadiene (1306/1130 cm{sup -1}) and Styrene-Butadiene (1449/1306 cm{sup -1}). The ratio calculated was used as the response to the irradiation, and is not uniform across the sample. From the results, it can be concluded for both rubbers: a) the dose-response curves may be useful for high-dose dosimetry (greater than 250 Gy); b) their response for reproducibility presented standard deviations lower than 2.5%; c) the relative sensitivity was higher for Styrene-Butadiene (1.86 kGy{sup -1}) than for Polybutadiene (1.81 kGy{sup -1}), d) for doses of 10 kGy to 200 kGy, there was no variation in the dosimetric response. Both types of rubber samples showed usefulness as high-dose dosimeters. (authors)

Assessments for high dose radionuclide therapy treatment planning

International Nuclear Information System (INIS)

Fisher, D.R.

2003-01-01

Advances in the biotechnology of cell specific targeting of cancer and the increased number of clinical trials involving treatment of cancer patients with radiolabelled antibodies, peptides, and similar delivery vehicles have led to an increase in the number of high dose radionuclide therapy procedures. Optimised radionuclide therapy for cancer treatment is based on the concept of absorbed dose to the dose limiting normal organ or tissue. The limiting normal tissue is often the red marrow, but it may sometimes be the lungs, liver, intestinal tract, or kidneys. Appropriate treatment planning requires assessment of radiation dose to several internal organs and tissues, and usually involves biodistribution studies in the patient using a tracer amount of radionuclide bound to the targeting agent and imaged at sequential timepoints using a planar gamma camera. Time-activity curves are developed from the imaging data for the major organ tissues of concern, for the whole body and sometimes for selected tumours. Patient specific factors often require that dose estimates be customised for each patient. In the United States, the Food and Drug Administration regulates the experimental use of investigational new drugs and requires 'reasonable calculation of radiation absorbed dose to the whole body and to critical organs' using the methods prescribed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Review of high dose studies shows that some are conducted with minimal dosimetry, that the marrow dose is difficult to establish and is subject to large uncertainties. Despite the general availability of software, internal dosimetry methods often seem to be inconsistent from one clinical centre to another. (author)

HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

International Nuclear Information System (INIS)

Al-Haidari, Amr A.; Syk, Ingvar; Thorlacius, Henrik

2014-01-01

Highlights: • Simvastatin blocked CCL17-induced and CCR4-dependent RhoA activation in HT29 cells. • CCL17/CCR4-mediated migration of colon cancer cells was antagonised by simvastatin. • Cell migration recovered by adding Mevalonate and geranylgeranyl pyrophosphate. • Targeting HMG-CoA reductase might be useful to inhibit colon cancer metastasis. - Abstract: Background: Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects. Aim: The aim of this study was to examine the effect of simvastatin on colon cancer cell migration. Methods: Migration assays were performed to evaluate CCL17-induced colon cancer cell (HT-29) chemotaxis. In vitro tumor growth and apoptosis were assessed using a proliferation assay and annexin V assay, respectively. Active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using a G-LISA assay. Results: We found that simvastatin dose-dependently decreased CCL17-induced colon cancer cell migration. Simvastatin had no effect on colon cancer cell proliferation or apoptosis. Inhibition of beta chemokine receptor 4, CCR4, reduced CCL17-evoked activation of RhoA in colon cancer cells. Moreover, administration of mevalonate reversed the inhibitory effect of simvastatin on CCL17-induced colon cancer cell migration. Interestingly, co-incubation with geranylgeranyl pyrophosphate (GGPP) antagonized the inhibitory impact of simvastatin on colon cancer cell migration triggered by CCL17. Moreover, we observed that simvastatin decreased CCL17-induced activation of RhoA in colon cancer cells. Administration of mevalonate and GGPP reversed the inhibitory effect of simvastatin on CCL17-provoked RhoA activation in colon cancer cells. Conclusions: Taken together, our findings show for the first time that HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via

Effect of 1.2% of simvastatin gel as a local drug delivery system on Gingival Crevicular Fluid interleukin-6 & interleukin-8 levels in non surgical treatment of chronic periodontitis patients.

Science.gov (United States)

Gunjiganur Vemanaradhya, Gayathri; Emani, Shilpa; Mehta, Dhoom Singh; Bhandari, Shilpy

2017-10-01

The present study was carried out to evaluate the effect of 1.2% simvastatin gel as local drug delivery (LDD) system on Gingival Crevicular Fluid (GCF) Interleukin -6 (IL-6) and Interleukin-8 (IL-8) levels in chronic periodontitis patients, in addition to scaling and root planing (SRP). A total of 46 chronic periodontitis patients were equally divided into two groups. Group I patients were treated by SRP; Group II patients were treated by SRP followed by LDD of 1.2% simvastatin (SMV) gel. Plaque index (PI), Gingival index(GI), Sulcus Bleeding Index (SBI), Probing pocket depth (PPD) and Relative clinical attachment level (CAL) were recorded & GCF samples were collected at baseline (0day) and at 45th day from both the groups. The collected GCF samples were analysed for IL-6 and IL-8 levels with enzyme-linked immunosorbent assay (ELISA). Both the groups showed significant reduction in all the clinical parameters scores and IL-6 and IL-8 levels after non-surgical periodontal therapy (SRP for group I/SRP+1.2% SMV gel for group II) in contrast to baseline values. However, a greater reduction was observed in group II. A non-significant positive correlation was observed between clinical parameters and IL-6 and IL-8 levels except at baseline, a significant correlation was observed between PPD &IL 6 levels in group II. In adjunct to SRP, 1.2% Simvastatin gel acts as an effective local drug delivery agent for the management of chronic periodontitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and tolerability of high doses of glucocorticoides

Directory of Open Access Journals (Sweden)

Rakić Branislava D.

2016-01-01

Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

Dose conversion coefficients for high-energy photons, electrons, neutrons and protons

CERN Document Server

Sakamoto, Y; Sato, O; Tanaka, S I; Tsuda, S; Yamaguchi, Y; Yoshizawa, N

2003-01-01

In the International Commission on Radiological Protection (ICRP) 1990 Recommendations, radiation weighting factors were introduced in the place of quality factors, the tissue weighting factors were revised, and effective doses and equivalent doses of each tissues and organs were defined as the protection quantities. Dose conversion coefficients for photons, electrons and neutrons based on new ICRP recommendations were cited in the ICRP Publication 74, but the energy ranges of theses data were limited and there are no data for high energy radiations produced in accelerator facilities. For the purpose of designing the high intensity proton accelerator facilities at JAERI, the dose evaluation code system of high energy radiations based on the HERMES code was developed and the dose conversion coefficients of effective dose were evaluated for photons, neutrons and protons up to 10 GeV, and electrons up to 100 GeV. The dose conversion coefficients of effective dose equivalent were also evaluated using quality fact...

High-dose secondary calibration laboratory accreditation program

Energy Technology Data Exchange (ETDEWEB)

Humphreys, J.C. [National Institute of Standards and Technology, Gaithersburg, MD (United States)

1993-12-31

There is a need for high-dose secondary calibration laboratories to serve the multi-billion dollar radiation processing industry. This need is driven by the desires of industry for less costly calibrations and faster calibration-cycle response time. Services needed include calibration irradiations of routine processing dosimeters and the supply of reference standard transfer dosimeters for irradiation in the production processing facility. In order to provide measurement quality assurance and to demonstrate consistency with national standards, the high-dose secondary laboratories would be accredited by means of an expansion of an existing National Voluntary Laboratory Accreditation Program. A laboratory performance criteria document is under development to implement the new program.

High-dose secondary calibration laboratory accreditation program

International Nuclear Information System (INIS)

Humphreys, J.C.

1993-01-01

There is a need for high-dose secondary calibration laboratories to serve the multi-billion dollar radiation processing industry. This need is driven by the desires of industry for less costly calibrations and faster calibration-cycle response time. Services needed include calibration irradiations of routine processing dosimeters and the supply of reference standard transfer dosimeters for irradiation in the production processing facility. In order to provide measurement quality assurance and to demonstrate consistency with national standards, the high-dose secondary laboratories would be accredited by means of an expansion of an existing National Voluntary Laboratory Accreditation Program. A laboratory performance criteria document is under development to implement the new program

Relevance of high-dose chemotherapy in solid tumours

NARCIS (Netherlands)

Nieboer, P; de Vries, EGE; Mulder, NH; van der Graaf, WTA

Drug resistance is a major problem in the treatment of solid tumours. Based on a steep dose-response relationship for especially alkylating agents on tumour cell survival, high-dose chemotherapy was considered of interest for the treatment of solid tumours. Results of phase 1 and 2 studies with

High-dose erythropoietin for tissue protection

DEFF Research Database (Denmark)

Lund, Anton; Lundby, Carsten; Olsen, Niels Vidiendal

2014-01-01

BACKGROUND: The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction....... Experimental studies have been favourable, but the clinical efficacy has yet to be validated. MATERIALS AND METHODS: We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of r...... no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality. CONCLUSIONS: Evidence is sparse to support a tissue-protective benefit of r...

Investigation of PBAT dosimetric properties for high gamma dose dosimetry

International Nuclear Information System (INIS)

Cunha, Elisete L.; Schimitberger, Thiago

2017-01-01

Poly(butylene adipate-co-terephthalate) (PBAT) is an aliphatic-aromatic copolyester which is biodegradable. It is a non-photoluminescent copolyester that becomes photoluminescent after previous exposure to gamma doses higher than 100 kGy. After the previous high energy irradiation, the material shows the highest photo-stimulated luminescence emission when excited with a LED source at wavelengths ranging from 370 to 405 nm. In this work we investigated the enhancement of the photoluminescence (PL) and dosimetric properties of PBAT, after exposure to high doses of gamma radiation ranging from 50 to 4,000 kGy. In this investigation we demonstrate that increasing the PBAT film thickness by 100 μm enhances the PL output by 3.5 times, when irradiated with 500 kGy. Also, besides the already known color green brightness, the PL intensity can also be used for high dose dosimetry purposes for doses ranging from 50 to 750 kGy. The FTIR analysis has demonstrated that the there is a linear relationship between peak intensity and dose for doses ranging from 100 and 2,000 kGy for the absorbance peaks at 3,241 cm -1 and 3271 cm -1 , with linear correlation coefficients of 0.9981 and 0.9992, respectively. The results indicate that PBAT has great potential for applications in bio-imaging devices and high gamma dose dosimetry. (author)

Investigation of PBAT dosimetric properties for high gamma dose dosimetry

Energy Technology Data Exchange (ETDEWEB)

Cunha, Elisete L.; Schimitberger, Thiago, E-mail: elisete.cunha@cdtn.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Engenharia Nuclear; Oliveira, Cristiana M.; Faria, Luiz O., E-mail: farialo@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

2017-07-01

Poly(butylene adipate-co-terephthalate) (PBAT) is an aliphatic-aromatic copolyester which is biodegradable. It is a non-photoluminescent copolyester that becomes photoluminescent after previous exposure to gamma doses higher than 100 kGy. After the previous high energy irradiation, the material shows the highest photo-stimulated luminescence emission when excited with a LED source at wavelengths ranging from 370 to 405 nm. In this work we investigated the enhancement of the photoluminescence (PL) and dosimetric properties of PBAT, after exposure to high doses of gamma radiation ranging from 50 to 4,000 kGy. In this investigation we demonstrate that increasing the PBAT film thickness by 100 μm enhances the PL output by 3.5 times, when irradiated with 500 kGy. Also, besides the already known color green brightness, the PL intensity can also be used for high dose dosimetry purposes for doses ranging from 50 to 750 kGy. The FTIR analysis has demonstrated that the there is a linear relationship between peak intensity and dose for doses ranging from 100 and 2,000 kGy for the absorbance peaks at 3,241 cm{sup -1} and 3271 cm{sup -1}, with linear correlation coefficients of 0.9981 and 0.9992, respectively. The results indicate that PBAT has great potential for applications in bio-imaging devices and high gamma dose dosimetry. (author)

Methodology of high dose research in medical radiodiagnostic; Metodologia de investigacao de doses elevadas em radiodiagnostico medico

Energy Technology Data Exchange (ETDEWEB)

Barboza, Adriana E.; Martins, Cintia P. de S., E-mail: ird@ird.gov.br [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)

2013-11-01

This work has as main purpose to study occupational exposure in diagnostic radiology in medical cases of high doses recorded in 2011 at the national level . These doses were recorded by monitoring individual of the occupationally exposed individuals (OEI's). This monitoring of the doses received by ionizing radiation has as main objective to ensure that the principle of dose limitation is respected. In this study it were evaluated doses of 372 OEI's radiology in different Brazilian states. Doses were extracted from the database of Sector Management Doses of the Institute for Radioprotection and Dosimetry - IRD/CNEN-RJ, Brazil. The information from the database provide reports of doses from several states, which allows to quantify statistically, showing those with the highest doses in four areas: dose greater than or equal to 20 mSv apron and chest and dose greater than or equal to 100 mSv apron and chest. The identification of these states allows the respective Sanitary Surveillance (VISA), be aware of the events and make plans to reduce them. This study clarified the required procedures when there is a record of high dose emphasizing the importance of using protective radiological equipment, dosimeter and provide a safety environment work by maintaining work equipment. Proposes the ongoing training of professionals, emphasizing the relevance of the concepts of radiation protection and the use of the questionnaire with their investigative systematic sequence, which will allow quickly and efficiently the success the investigations.

Dual Incorporation of the in vitro Data (IC50) and in vivo (Cmax) Data for the Prediction of Area Under the Curve (AUC) for Statins using Regression Models Developed for Either Pravastatin or Simvastatin.

Science.gov (United States)

Srinivas, N R

2016-08-01

Linear regression models utilizing a single time point (Cmax) has been reported for pravastatin and simvastatin. A new model was developed for the prediction of AUC of statins that utilized the slopes of the above 2 models, with pharmacokinetic (Cmax) and a pharmacodynamic (IC50 value) components for the statins. The prediction of AUCs for various statins (pravastatin, atorvastatin, simvastatin and rosuvastatin) was carried out using the newly developed dual pharmacokinetic and pharmacodynamic model. Generally, the AUC predictions were contained within 0.5 to 2-fold difference of the observed AUC suggesting utility of the new models. The root mean square error predictions wereAUC for statins. Such a new concept as described in the work may have utility in both drug discovery and development stages. © Georg Thieme Verlag KG Stuttgart · New York.

Structural insight into the physical stability of amorphous Simvastatin dispersed in pHPMA: enhanced dynamics and local clustering as evidenced by solid-state NMR and Raman spectroscopy

Czech Academy of Sciences Publication Activity Database

Urbanová, Martina; Šturcová, Adriana; Kredatusová, Jana; Brus, Jiří

2015-01-01

Roč. 478, č. 2 (2015), s. 464-475 ISSN 0378-5173 R&D Projects: GA ČR(CZ) GA14-03636S; GA MŠk(CZ) LD14010 Grant - others:European Commission(XE) COST Action MP1202 HINT Institutional support: RVO:61389013 Keywords : solid dispersions * simvastatin * pharmaceuticals Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.994, year: 2015

A plant stanol yogurt drink alone or combined with a low-dose statin lowers serum triacylglycerol and non-HDL cholesterol in metabolic syndrome patients

NARCIS (Netherlands)

Plat, Jogchum; Brufau, Gemma; Dallinga-Thie, Geesje M.; Dasselaar, Margreet; Mensink, Ronald P.

2009-01-01

We evaluated the effects of 2 commonly available strategies (plant stanol ester drink and 10 mg simvastatin) on coronary heart disease (CHD) risk variables in participants with metabolic syndrome. Metabolic syndrome patients are at increased risk to develop CHD, partly due to high triacylglycerol

An evaluation of high-dose jobs for ALARA improvement

International Nuclear Information System (INIS)

Mun, J. H.; Kim, H. S.

1997-01-01

It is well known that about 70 percent of occupational dose have incurred from maintenance jobs at outage period. To reduce occupational dose, first, the high-dose jobs at the outage period should be identified and evaluated. For this, the database program is used, which contains the ORE data of reference plants, Kori Units 3 and 4. As a result, it is found that the jobs related to steam generator are the highest dose jobs in terms of collective ORE dose. From the analysis of the job procedures of those jobs, the ALARA improvements are also derived

Teflon pastille use in high dose dosimetry; Utilizacao de pastilhas de teflon em dosimetria de doses altas

Energy Technology Data Exchange (ETDEWEB)

Teixeira, Maria Ines [Associacao Educacional Nove de Julho (UNINOVE), Sao Paulo, SP (Brazil); Caldas, Linda V.E., E-mail: miteixeira@ipen.b, E-mail: lcaldas@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2011-10-26

This paper study the Teflon, which is used as aglomerant in the confection of dosimetric pastilles, for the viabilization of this material as high dose dosimeter. This paper used the OSL technique for the characterization of dosimetric properties of Teflon. The doses-response curve has been obtained for {sup 60}Co radiation between 100 Gy and 50 kGy, and the OSL answer reproducibility. The preliminary results shown that the Teflon is a material which can be used for high dose dosimetry

measurement of high dose radiation using yellow perspex dosimeter

International Nuclear Information System (INIS)

Thamrin, M Thoyib; Sofyan, Hasnel

1996-01-01

Measurement of high dose radiation using yellow perspex dosemeter has been carried out. Dose range used was between 0.1 to 3.0 kGy. Measurement of dose rate against Fricke dosemeter as a standard dose meter From the irradiation of Fricke dosemeter with time variation of 3,6,9,12,15 and 18 minute, it was obtained average dose rate of 955.57 Gy/hour, linear equation of dose was Y= 2.333+15.776 X with its correlation factor r = 0.9999. Measurement result using yellow perspex show that correlation between net optical density and radiation dose was not linear with its equation was ODc exp. [Bo + In(dose).Bi] Value of Bo = -0.215 and Bi=0.5020. From the experiment it was suggested that routine dosimeter (yellow perspex) should be calibrated formerly against standard dosemeters

Diagnosis of cerebral metastases by means of standard doses of Gadobutrol versus a high-dose protocol. Intraindividual evaluation of a phase-II high-dose study

International Nuclear Information System (INIS)

Vogl, T.J.; Friebe, C.E.; Balzer, T.; Mack, M.G.; Steiner, S.; Schedel, H.; Pegios, W.; Lanksch, W.; Banzer, D.; Felix, R.

1995-01-01

In a clinical phase-II study 20 patients who had been diagnosed as having brain metastases with CT or MRT were studied prospectively with Gadobutrol, a new nonionic, low osmolality contrast agent. Each patient received an initial injection of 0.1 mmol/kg body weight and an additional dose of 0.2 mmol/kg Gadobutrol 10 min later. Spinecho images were obtained before and after the two applications of Gadobutrol. Dynamic scanning (Turbo-FLASH) was performed for 3 min after each injection of the contrast agent. Both quantitative and qualitative data were intraindividually evaluated. The primary tumor was a bronchial carcinoma in 11 cases; in 9 other cases there were different primary tumors. Forty-eight hours after the use of Gadobutrol there were no adverse signs in the clinical examination, vital signs or blood and urine chemistry. Statistical analysis (Friedman test and Wilcoxon test) of the C/N ratios between tumor and white matter, percentage enhancement, and visual assessment rating revealed statistically significant superiority of high-dose Gadobutrol injection in comparison to the standard dose. The percentage enhancement increased on average from 104% after 0.1 mmol/kg to 162% after 0.3 mmol/kg Gadobutrol. Qualitative delineation and contrast of the lesions increased significantly. The use of high-dose Gadobutrol improved the detection of 36 additional lesions in 6 patients. (orig./VHE) [de

High-resolution CT of the lung in asbestos-exposed subjects. Comparison of low-dose and high-dose HRCT

International Nuclear Information System (INIS)

Majurin, M.L.; Varpula, M.; Kurki, T.; Pakkala, L.

1994-01-01

The lowest possible mAs settings for high-resolution CT (HRCT) were studied on 45 individuals with suspected asbestos-related lung disease. All patients were investigated with 5 to 6 high-dose HRCT images (120 kVp/160 mA/2 s) at 3-cm intervals. At a selected level 4 additional low-dose images were obtained on each patient with lower mAs settings (100 mA/2 s, 80 mA/2 s, 60 mA/2 s, 30 mA/2 s). Thirty-seven subjects out of 45 had HRCT lesions compatible with asbestosis. HRCT images obtained with as low as 60 mA/2 s settings clearly showed pleural tractions and thickenings, parenchymal bands, honeycombing and subpleural curvilinear shadows, whereas in the evaluation of subpleural short lines and ground glass findings 80 mA/2 s were required. The lowest setting, 30 mA/2 s, was sufficient only in detecting and evaluating pleural tractions and thickenings. We conclude that 160 mAs yield good quality HRCT images, with substantial decrease of radiation dose, for the evaluation of asbestos-related lesions. (orig.)

The clinical pharmacology of alkylating agents in high-dose chemotherapy

NARCIS (Netherlands)

Huitema, A. D.; Smits, K. D.; Mathôt, R. A.; Schellens, J. H.; Rodenhuis, S.; Beijnen, J. H.

2000-01-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is

Radiobiological modelling of dose-gradient effects in low dose rate, high dose rate and pulsed brachytherapy

International Nuclear Information System (INIS)

Armpilia, C; Dale, R G; Sandilos, P; Vlachos, L

2006-01-01

This paper presents a generalization of a previously published methodology which quantified the radiobiological consequences of dose-gradient effects in brachytherapy applications. The methodology uses the linear-quadratic (LQ) formulation to identify an equivalent biologically effective dose (BED eq ) which, if applied uniformly to a specified tissue volume, would produce the same net cell survival as that achieved by a given non-uniform brachytherapy application. Multiplying factors (MFs), which enable the equivalent BED for an enclosed volume to be estimated from the BED calculated at the dose reference surface, have been calculated and tabulated for both spherical and cylindrical geometries. The main types of brachytherapy (high dose rate (HDR), low dose rate (LDR) and pulsed (PB)) have been examined for a range of radiobiological parameters/dimensions. Equivalent BEDs are consistently higher than the BEDs calculated at the reference surface by an amount which depends on the treatment prescription (magnitude of the prescribed dose) at the reference point. MFs are closely related to the numerical BED values, irrespective of how the original BED was attained (e.g., via HDR, LDR or PB). Thus, an average MF can be used for a given prescribed BED as it will be largely independent of the assumed radiobiological parameters (radiosensitivity and α/β) and standardized look-up tables may be applicable to all types of brachytherapy treatment. This analysis opens the way to more systematic approaches for correlating physical and biological effects in several types of brachytherapy and for the improved quantitative assessment and ranking of clinical treatments which involve a brachytherapy component

Calcium carbonate as a possible dosimeter for high irradiation doses

International Nuclear Information System (INIS)

Negron M, A.; Ramos B, S.; Camargo R, C.; Uribe, R. M.; Gomez V, V.; Kobayashi, K.

2014-08-01

The aim of this work is to analyze the interactions of 5 MeV electron beam radiation and a 290 MeV/u Carbon beam with calcium carbonate (powder) at 298 K and at different irradiation doses, for the potential use of calcium carbonate as a high-dose dosimeter. The irradiation doses with the electron beam were from 0.015 to 9 MGy, and with Carbon beam from 1.5 kGy to 8 kGy. High-energy radiation induces the formation of free radicals in solid calcium carbonate that can be detected and measured by electron paramagnetic resonance (EPR). An increase of the EPR response for some of the free radicals produced in the sample was observed as a function of the irradiation dose. The response of one of the radicals decreased with the dose. These measurements are reproducible; the preparation of the sample is simple and inexpensive; and the signal is stable for several months. The response curves show that the dosimeter tends to saturate at 10 MGy. Based on these properties, we propose this chemical compound as a high-dose dosimeter, mainly for electron irradiation. (author)

Calcium carbonate as a possible dosimeter for high irradiation doses

Energy Technology Data Exchange (ETDEWEB)

Negron M, A.; Ramos B, S.; Camargo R, C. [UNAM, Instituto de Ciencias Nucleares, Ciudad Universitaria, 04510 Mexico D. F. (Mexico); Uribe, R. M. [Kent State University, College of Technology, Kent OH (United States); Gomez V, V. [UNAM, Instituto de Quimica, Ciudad Universitaria, 04510 Mexico D. F. (Mexico); Kobayashi, K., E-mail: negron@nucleares.unam.mx [Yokohama National University (Japan)

2014-08-15

The aim of this work is to analyze the interactions of 5 MeV electron beam radiation and a 290 MeV/u Carbon beam with calcium carbonate (powder) at 298 K and at different irradiation doses, for the potential use of calcium carbonate as a high-dose dosimeter. The irradiation doses with the electron beam were from 0.015 to 9 MGy, and with Carbon beam from 1.5 kGy to 8 kGy. High-energy radiation induces the formation of free radicals in solid calcium carbonate that can be detected and measured by electron paramagnetic resonance (EPR). An increase of the EPR response for some of the free radicals produced in the sample was observed as a function of the irradiation dose. The response of one of the radicals decreased with the dose. These measurements are reproducible; the preparation of the sample is simple and inexpensive; and the signal is stable for several months. The response curves show that the dosimeter tends to saturate at 10 MGy. Based on these properties, we propose this chemical compound as a high-dose dosimeter, mainly for electron irradiation. (author)

Calibration of high-dose radiation facilities (Handbook)

International Nuclear Information System (INIS)

Gupta, B.L.; Bhat, R.M.

1986-01-01

In India at present several high intensity radiation sources are used. There are 135 teletheraphy machines and 65 high intensity cobalt-60 sources in the form of gamma chambers (2.5 Ci) and PANBIT (50 Ci). Several food irradiation facilities and a medical sterilization plant ISOMED are also in operation. The application of these high intensity sources involve a wide variation of dose from 10 Gy to 100 kGy. Accurate and reproducible radiation dosimetry is essential in the use of these sources. This handbook is especially compiled for calibration of high-dose radiation facilities. The first few chapters discuss such topics as interaction of radiation with matter, radiation chemistry, radiation processing, commonly used high intensity radiation sources and their special features, radiation units and dosimetry principles. In the chapters which follow, chemical dosimeters are discussed in detail. This discussion covers Fricke dosimeter, FBX dosimeter, ceric sulphate dosimeter, free radical dosimetry, coloured indicators for irrdiation verification. A final chapter is devoted to practical hints to be followed in calibration work. (author)

Plasma Doping - Enabling Technology for High Dose Logic and Memory Applications

International Nuclear Information System (INIS)

Miller, T.; Godet, L.; Papasouliotis, G. D.; Singh, V.

2008-01-01

As logic and memory device dimensions shrink with each generation, there are more high dose implants at lower energies. Examples include dual poly gate (also referred to as counter-doped poly), elevated source drain and contact plug implants. Plasma Doping technology throughput and dopant profile benefits at these ultra high dose and lower energy conditions have been well established [1,2,3]. For the first time a production-worthy plasma doping implanter, the VIISta PLAD tool, has been developed with unique architecture suited for precise and repeatable dopant placement. Critical elements of the architecture include pulsed DC wafer bias, closed-loop dosimetry and a uniform low energy, high density plasma source. In this paper key performance metrics such as dose uniformity, dose repeatability and dopant profile control will be presented that demonstrate the production-worthiness of the VIISta PLAD tool for several high dose applications.

Spectroscopic gamma camera for use in high dose environments

Energy Technology Data Exchange (ETDEWEB)

Ueno, Yuichiro, E-mail: yuichiro.ueno.bv@hitachi.com [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Takahashi, Isao; Ishitsu, Takafumi; Tadokoro, Takahiro; Okada, Koichi; Nagumo, Yasushi [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Fujishima, Yasutake; Kometani, Yutaka [Hitachi Works, Hitachi-GE Nuclear Energy, Ltd., Hitachi-shi, Ibaraki-ken (Japan); Suzuki, Yasuhiko [Measuring Systems Engineering Dept., Hitachi Aloka Medical, Ltd., Ome-shi, Tokyo (Japan); Umegaki, Kikuo [Faculty of Engineering, Hokkaido University, Sapporo-shi, Hokkaido (Japan)

2016-06-21

We developed a pinhole gamma camera to measure distributions of radioactive material contaminants and to identify radionuclides in extraordinarily high dose regions (1000 mSv/h). The developed gamma camera is characterized by: (1) tolerance for high dose rate environments; (2) high spatial and spectral resolution for identifying unknown contaminating sources; and (3) good usability for being carried on a robot and remotely controlled. These are achieved by using a compact pixelated detector module with CdTe semiconductors, efficient shielding, and a fine resolution pinhole collimator. The gamma camera weighs less than 100 kg, and its field of view is an 8 m square in the case of a distance of 10 m and its image is divided into 256 (16×16) pixels. From the laboratory test, we found the energy resolution at the 662 keV photopeak was 2.3% FWHM, which is enough to identify the radionuclides. We found that the count rate per background dose rate was 220 cps h/mSv and the maximum count rate was 300 kcps, so the maximum dose rate of the environment where the gamma camera can be operated was calculated as 1400 mSv/h. We investigated the reactor building of Unit 1 at the Fukushima Dai-ichi Nuclear Power Plant using the gamma camera and could identify the unknown contaminating source in the dose rate environment that was as high as 659 mSv/h.

Analysis of the physico-chemical quality Enalapril and Simvastatin drugs manipulated in magistral pharmacies from Belo Horizonte, MG, Brazil

International Nuclear Information System (INIS)

Gomes, Tatiana Cristina Bomfim

2013-01-01

The increasing expansion of compounding pharmacy associated with several reports on variances in the quality of compounded drugs demonstrates the need for verification of quality, safety and efficacy of these products. In this work, physical and chemical analyzes were performed to evaluate the quality of some capsules manipulated enalapril and simvastatin, acquired in five pharmacies in Belo Horizonte /Brazil. Among the analyzes are pharmacopoeial tests for appearance, identification, determination of weight, content, related compounds and uniformity of dosage units, and was also performed neutron activation analysis for the determination of inorganic impurities in drugs sampled. The results showed that 60% of the samples were unsatisfactory for pharmacopoeial tests. The contents of the capsules sampled for individual testing unit dose uniformity between 0% and 136.2%. This test is important in evaluating the quality, which influences the safety and efficacy of drug treatment, since it allows you to check if the product contains the proper dosage and necessary for successful pharmacotherapy. On the other hand, underdosing can lead to reduced or absent desired therapeutic response, and overdoses can provide an undesirable effects and even toxic. The concentration of inorganic impurities was considered to be relatively small. However, no specific limits for some chemical elements in medicine hamper a better thread. In addition, further studies must be performed to assess chronic exposure to low concentrations of inorganic impurities, since drugs can be continuously used, and other sources of exposure must also be considered in order to evaluate the risk. The problems related to the quality and safety of compounded drugs are still reality in the country and reveal a serious public health problem, especially regarding the lack of uniformity between the unit doses of medications. It is suggested that the competent authorities to sanitary products, propose changes in

Calibration procedure for thermoluminescent dosemeters in water absorbed doses for Iridium-192 high dose rate sources

International Nuclear Information System (INIS)

Reyes Cac, Franky Eduardo

2004-10-01

Thermoluminescent dosimeters are used in brachytherapy services quality assurance programs, with the aim of guaranteeing the correct radiation dose supplied to cancer patients, as well as with the purpose of evaluating new clinical procedures. This work describes a methodology for thermoluminescent dosimeters calibration in terms of absorbed dose to water for 192 Ir high dose rate sources. The reference dose used is measured with an ionization chamber previously calibrated for 192 Ir energy quality, applying the methodology proposed by Toelli. This methodology aims to standardizing the procedure, in a similar form to that used for external radiotherapy. The work evolves the adaptation of the TRS-277 Code of the International Atomic Energy Agency, for small and big cavities, through the introduction for non-uniform experimental factor, for the absorbed dose in the neighborhood of small brachytherapy sources. In order to simulate a water medium around the source during the experimental work, an acrylic phantom was used. It guarantees the reproducibility of the ionization chamber and the thermoluminescent dosimeter's location in relation to the radiation source. The values obtained with the ionization chamber and the thermoluminescent dosimeters, exposed to a 192 Ir high dose rate source, were compared and correction factors for different source-detector distances were determined for the thermoluminescent dosimeters. A numeric function was generated relating the correction factors and the source-detector distance. These correction factors are in fact the thermoluminescent dosimeter calibration factors for the 192 Ir source considered. As a possible application of this calibration methodology for thermoluminescent dosimeters, a practical range of source-detector distances is proposed for quality control of 192 Ir high dose rate sources. (author)

Biological dose estimation and comet analysis of the victims in a high dose 60Co radiation accident

International Nuclear Information System (INIS)

Chen Ying; Liu Xiulin; Luo Yisheng; Li You; Yao Bo

2007-01-01

Objective: To explore the methods of chromosome preparation in human peripheral blood and bone marrow after very high dose exposure and fit the dose-response curve of dicentrics and tings in the range of high doses over 6 Gy for estimating biological dose and detecting DNA damage in the victims of '10.21' accident. Methods: The samples of peripheral blood and bone marrow in 2 victims were collected to prepare chromosome mataphases and dicentrics (multicentrics) + rings were counted. The dose-response curve and equation of human blood irradiated between 6-22 Gy in vitro were established and applied to assess biological dose of 2 victims. In addition, their DNA damages were tested by alkaline single cell gel electrophoresis. Results: The dicentric + ring numbers of 4.47 per cell in victims B's peripheral blood lymphocytes and 9.15 per cell in victim A's bone marrow who had no mitosis in peripheral blood cell. The whole body average doses of victims B and A estimated by 6-22 Gy equation arrived at 9.4 Gy and 19.5 Gy, respectively. The serious DNA damages were expressed by small head and large tail comet figures. Conclusions: The biological doses of 2 victims estimated by 6-22 Gy dose-response curve have reached the levels of extreme grave bone marrow and intestinal ARS, respectively. (authors)

Preservation of Minced Meats by Using Medium and High-doses Irradiation

International Nuclear Information System (INIS)

Hammad, A.A.I.; Swailam, H.M.H.; Taha, S.M.A.

2003-01-01

The effect of medium (2.5-10 kGy) dose irradiation and high(20-70 kGy) dose irradiation on the microbiological, chemical and organoleptic properties of minced meat samples was studied. It was found that irradiation dose of only 5 kGy greatly reduced all microbial counts and completely eliminated all non-spore forming pathogenic bacteria contaminated minced meat samples. Consequently this irradiation dose extended the refrigerated (3 degree ±1) storage life of these products for more than 8 weeks. This irradiation dose almost did not affect the chemical composition, particularly the main amino acids and main fatty acids of minced meat samples. Panelists could not differentiate between irradiated minced meat samples at this dose and unirradiated samples. High doses irradiation, i.e.40 and 70 kGy were sufficient and efficient in sterilization of minced meat samples and in obtaining long-stable minced meat products (Two years) at ambient temperature. These irradiation doses slightly reduced (not more than 7%) aspartic acid, glutamic acid, methionine and lysine of minced meat. It also decreased the relative percentage of total unsaturated fatty acids by not more than 17 % . These high irradiation doses caused loss of C 18:3 and C 20:1

Efficacy and tolerability of high-dose phenobarbital in children with focal seizures.

Science.gov (United States)

Okumura, Akihisa; Nakahara, Eri; Ikeno, Mitsuru; Abe, Shinpei; Igarashi, Ayuko; Nakazawa, Mika; Takasu, Michihiko; Shimizu, Toshiaki

2016-04-01

We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. We reviewed data on children (agedphenobarbital (>5 mg/kg/day to maintain a target serum level >40 μg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ⩾75%. Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 μg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. Oral high-dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Novel high dose rate lip brachytherapy technique to improve dose homogeneity and reduce toxicity by customized mold

International Nuclear Information System (INIS)

Feldman, Jon; Appelbaum, Limor; Sela, Mordechay; Voskoboinik, Ninel; Kadouri, Sarit; Weinberger, Jeffrey; Orion, Itzhak; Meirovitz, Amichay

2014-01-01

The purpose of this study is to describe a novel brachytherapy technique for lip Squamous Cell Carcinoma, utilizing a customized mold with embedded brachytherapy sleeves, which separates the lip from the mandible, and improves dose homogeneity. Seven patients with T2 lip cancer treated with a “sandwich” technique of High Dose Rate (HDR) brachytherapy to the lip, consisting of interstitial catheters and a customized mold with embedded catheters, were reviewed for dosimetry and outcome using 3D planning. Dosimetric comparison was made between the “sandwich” technique to “classic” – interstitial catheters only plan. We compared dose volume histograms for Clinical Tumor Volume (CTV), normal tissue “hot spots” and mandible dose. We are reporting according to the ICRU 58 and calculated the Conformal Index (COIN) to show the advantage of our technique. The seven patients (ages 36–81 years, male) had median follow-up of 47 months. Four patients received Brachytherapy and External Beam Radiation Therapy, 3 patients received brachytherapy alone. All achieved local control, with excellent esthetic and functional results. All patients are disease free. The Customized Mold Sandwich technique (CMS) reduced the high dose region receiving 150% (V150) by an average of 20% (range 1–47%), The low dose region (les then 90% of the prescribed dose) improved by 73% in average by using the CMS technique. The COIN value for the CMS was in average 0.92 as opposed to 0.88 for the interstitial catheter only. All differences (excluding the low dose region) were statistically significant. The CMS technique significantly reduces the high dose volume and increases treatment homogeneity. This may reduce the potential toxicity to the lip and adjacent mandible, and results in excellent tumor control, cosmetic and functionality

Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients.

Science.gov (United States)

Gabardi, Steven; Asipenko, Natalya; Fleming, James; Lor, Kevin; McDevitt-Potter, Lisa; Mohammed, Anisa; Rogers, Christin; Tichy, Eric M; Weng, Renee; Lee, Ruth-Ann

2015-07-01

Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir

Chromosomal Aberrations in Normal and AT Cells Exposed to High Dose of Low Dose Rate Irradiation

Science.gov (United States)

Kawata, T.; Shigematsu, N.; Kawaguchi, O.; Liu, C.; Furusawa, Y.; Hirayama, R.; George, K.; Cucinotta, F.

2011-01-01

Ataxia telangiectasia (A-T) is a human autosomally recessive syndrome characterized by cerebellar ataxia, telangiectases, immune dysfunction, and genomic instability, and high rate of cancer incidence. A-T cell lines are abnormally sensitive to agents that induce DNA double strand breaks, including ionizing radiation. The diverse clinical features in individuals affected by A-T and the complex cellular phenotypes are all linked to the functional inactivation of a single gene (AT mutated). It is well known that cells deficient in ATM show increased yields of both simple and complex chromosomal aberrations after high-dose-rate irradiation, but, less is known on how cells respond to low-dose-rate irradiation. It has been shown that AT cells contain a large number of unrejoined breaks after both low-dose-rate irradiation and high-dose-rate irradiation, however sensitivity for chromosomal aberrations at low-dose-rate are less often studied. To study how AT cells respond to low-dose-rate irradiation, we exposed confluent normal and AT fibroblast cells to up to 3 Gy of gamma-irradiation at a dose rate of 0.5 Gy/day and analyzed chromosomal aberrations in G0 using fusion PCC (Premature Chromosomal Condensation) technique. Giemsa staining showed that 1 Gy induces around 0.36 unrejoined fragments per cell in normal cells and around 1.35 fragments in AT cells, whereas 3Gy induces around 0.65 fragments in normal cells and around 3.3 fragments in AT cells. This result indicates that AT cells can rejoin breaks less effectively in G0 phase of the cell cycle? compared to normal cells. We also analyzed chromosomal exchanges in normal and AT cells after exposure to 3 Gy of low-dose-rate rays using a combination of G0 PCC and FISH techniques. Misrejoining was detected in the AT cells only? When cells irradiated with 3 Gy were subcultured and G2 chromosomal aberrations were analyzed using calyculin-A induced PCC technique, the yield of unrejoined breaks decreased in both normal and AT

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

Science.gov (United States)

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

Science.gov (United States)

Day, Troy; Read, Andrew F.

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. PMID:26820986

High-dose zolpidem dependence - Psychostimulant effects? A case report and literature review

Directory of Open Access Journals (Sweden)

Abhijna Chandan Chattopadhyay

2016-01-01

Full Text Available Zolpidem, an imidazoline nonbenzodiazepine sedative drug, is used widely. Initial reports showed minimal abuse potential. However, multiple reports have appeared of dose escalation and abuse. Subjective effects of high-dose zolpidem are not known. In light of accumulating evidence of abuse potential, we hereby report a case of high-dose dependence and a review of relevant literature. A 33-year-old male presented with 5 years of daily use of 600–1700 mg of zolpidem tartrate. He reported subjective effects of euphoria, intense craving, and inability to stop use. Loss of receptor specificity, pharmacokinetic factors, and different receptor distributions can explain paradoxical stimulatory effects of high-dose zolpidem. Further studies are required to characterize subjective effects of high-dose zolpidem.

Concomitant chemoradiotherapy with high dose rate brachytherapy ...

African Journals Online (AJOL)

Concomitant chemoradiotherapy with high dose rate brachytherapy as a definitive treatment modality for locally advanced cervical cancer. T Refaat, A Elsaid, N Lotfy, K Kiel, W Small Jr, P Nickers, E Lartigau ...

In vivo evaluation of a simvastatin-loaded nanostructured lipid carrier for bone tissue regeneration

International Nuclear Information System (INIS)

Yue, Xinxin; Niu, Mao; Zhang, Te; Wang, Cheng; Wu, Wangxi; Zhang, Qi; Lai, Chunhua; Zhou, Lei; Wang, Zhonglei

2016-01-01

Alveolar bone loss has long been a challenge in clinical dental implant therapy. Simvastatin (SV) has been demonstrated to exert excellent anabolic effects on bone. However, the successful use of SV to increase bone formation in vivo largely depends on the local concentration of SV at the site of action, and there have been continuing efforts to develop an appropriate delivery system. Specifically, nanostructured lipid carrier (NLC) systems have become a popular type of encapsulation carrier system. Therefore, SV-loaded NLCs (SNs) (179.4 nm in diameter) were fabricated in this study, and the osteogenic effect of the SNs was evaluated in a critical-sized rabbit calvarial defect. Our results revealed that the SNs significantly enhanced bone formation in vivo, as evaluated by hematoxylin and eosin (HE) staining, immunohistochemistry, and a fluorescence analysis. Thus, this novel nanostructured carrier system could be a potential encapsulation carrier system for SV in bone regeneration applications. (paper)

Protective effects of Arctium lappa L. root extracts (AREs) on high fat diet induced quail atherosclerosis.

Science.gov (United States)

Wang, Zhi; Li, Ping; Wang, Chenjing; Jiang, Qixiao; Zhang, Lei; Cao, Yu; Zhong, Weizhen; Wang, Chunbo

2016-01-08

This study was designed to evaluate the protective effects of Arctium lappa L. root extracts (AREs) from different extraction methods (aqueous, ethanol, chloroform and flavone) on atherosclerosis. Quails (Coturnix coturnix) were subjected to high fat diet, with or without one of the four different AREs or positive control simvastatin. Blood samples were collected before treatment, after 4.5 weeks or ten weeks to assess lipid profile (Levels of total cholesterol (TC), Triacylglycerol (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL)). After ten weeks, the serum levels of nitric oxide (NO) as well as antioxidant and pro-oxidative status (Levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione peroxidase (GSH-Px)) were measured. Furthermore, aortas were collected after ten weeks treatment, aorta lipid contents (TC, TG and LDL) were assessed, and histology was used to confirm atherosclerotic changes. The results indicated that high fat diet significantly deteriorated lipid profile and antioxidant status in quail serum, while all the extracts significantly reverted the changes similar to simvastatin. Aorta lipid profile assessment revealed similar results. Histology on aortas from quails treated for ten weeks confirmed atherosclerotic changes in high fat diet group, while the extracts significantly alleviated the atherosclerotic changes similar to simvastatin. Among the different extracts, flavones fraction exerted best protective effects. Our data suggest that the protective effects of AREs were medicated via hypolipidemic and anti-oxidant effects. Underlying molecular mechanisms are under investigation.

Radiation exposure for 'caregivers' during high-dose outpatient radioiodine therapy

International Nuclear Information System (INIS)

Marriott, C. J.; Webber, C. E.; Gulenchyn, K. Y.

2007-01-01

On 27 occasions, radiation doses were measured for a family member designated as the 'caregiver' for a patient receiving high-dose radioiodine outpatient therapy for differentiated thyroid carcinoma. For 25 of the administrations, patients received 3.7 GBq of 131 I. Radiation doses for the designated caregivers were monitored on an hourly basis for 1 week using electronic personal dosemeters. The average penetrating dose was 98±64 μSv. The maximum penetrating dose was 283 μSv. Measured dose rate profiles showed that, on average, one-third of the caregiver dose was received during the journey home from hospital. The mean dose rate profile showed rapid clearance of 131 I with three distinct phases. The corresponding clearance half-times were 131 I contaminating the home. (authors)

High-Dose versus Low-Dose Vitamin D Supplementation and Arterial Stiffness among Individuals with Prehypertension and Vitamin D Deficiency

Directory of Open Access Journals (Sweden)

Amanda Zaleski

2015-01-01

Full Text Available Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD. However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. Methods. Participants were randomized to high-dose (4000 IU/d versus low-dose (400 IU/d oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP, carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. Results. There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all p>0.202. High-dose vitamin D decreased augmentation index and pressure by 12.3 ± 5.3% (p=0.047 and 4.0 ± 1.5 mmHg (p=0.02, respectively. However, these decreases in arterial stiffness were not associated with increases in serum 25-hydroxyvitamin D over 6 mo (p=0.425. Conclusion. High-dose vitamin D supplementation appears to lower surrogate measures of arterial stiffness but not indices of central pulse wave velocity. Clinical Trial Registration. This trial is registered with www.clinicaltrials.gov (Unique Identifier: NCT01240512.

High dose calibrations at the Pacific Northwest Laboratory

International Nuclear Information System (INIS)

McDonald, J.C.; Fox, R.A.

1988-10-01

The need is increasing for both high radiation exposures and calibration measurements that provide traceability of such exposures to national standards. The applications of high exposures include: electronic component damage studies, sterilization of medical products and food irradiation. Accurate high exposure measurements are difficult to obtain and cannot, in general, be carried out with a single dose measurement system or technique because of the wide range of doses and the variety of materials involved. This paper describes the dosimetric measurement and calibration techniques used at the Pacific Northwest Laboratory (PNL) that make use of radiochromic dye films, thermoluminescent dosimeters (TLDs), ionization chambers, and calorimetric dosimeters. The methods used to demonstrate the consistency of PNL calibrations with national standards will also be discussed. 4 refs

SU-F-P-19: Fetal Dose Estimate for a High-Dose Fluoroscopy Guided Intervention Using Modern Data Tools

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Moirano, J [University of Washington, Seattle, WA (United States)

2016-06-15

Purpose: An accurate dose estimate is necessary for effective patient management after a fetal exposure. In the case of a high-dose exposure, it is critical to use all resources available in order to make the most accurate assessment of the fetal dose. This work will demonstrate a methodology for accurate fetal dose estimation using tools that have recently become available in many clinics, and show examples of best practices for collecting data and performing the fetal dose calculation. Methods: A fetal dose estimate calculation was performed using modern data collection tools to determine parameters for the calculation. The reference point air kerma as displayed by the fluoroscopic system was checked for accuracy. A cumulative dose incidence map and DICOM header mining were used to determine the displayed reference point air kerma. Corrections for attenuation caused by the patient table and pad were measured and applied in order to determine the peak skin dose. The position and depth of the fetus was determined by ultrasound imaging and consultation with a radiologist. The data collected was used to determine a normalized uterus dose from Monte Carlo simulation data. Fetal dose values from this process were compared to other accepted calculation methods. Results: An accurate high-dose fetal dose estimate was made. Comparison to accepted legacy methods were were within 35% of estimated values. Conclusion: Modern data collection and reporting methods ease the process for estimation of fetal dose from interventional fluoroscopy exposures. Many aspects of the calculation can now be quantified rather than estimated, which should allow for a more accurate estimation of fetal dose.

Comparative study of SOI/Si hybrid substrates fabricated using high-dose and low-dose oxygen implantation

International Nuclear Information System (INIS)

Dong Yemin; Chen Meng; Chen Jing; Wang Xiang; Wang Xi

2004-01-01

Hybrid substrates comprising both silicon-on-insulator (SOI) and bulk Si regions have been fabricated using the technique of patterned separation by implantation of oxygen (SIMOX) with high-dose (1.5 x 10 18 cm -2 ) and low-dose ((1.5-3.5) x 10 17 cm -2 ) oxygen ions, respectively. Cross-sectional transmission electron microscopy (XTEM) was employed to examine the microstructures of the resulting materials. Experimental results indicate that the SOI/Si hybrid substrate fabricated using high-dose SIMOX is of inferior quality with very large surface height step and heavily damaged transitions between the SOI and bulk regions. However, the quality of the SOI/Si hybrid substrate is enhanced dramatically by reducing the implant dose. The defect density in transitions is reduced considerably. Moreover, the expected surface height difference does not exist and the surface is exceptionally flat. The possible mechanisms responsible for the improvements in quality are discussed

Effects of low dose gamma radiation on the early growth of red pepper and the resistance to subsquent high dose of radiation

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Kim, J. S.; Baek, M. H.; Kim, D. H.; Lee, Y. K. [KAERI, Taejon (Korea, Republic of); Lee, Y. B. [Chungnam National Univ., Taejon (Korea, Republic of)

2001-05-01

Red pepper (capsicum annuum L. cv. Jokwang and cv. Johong) seeds were irradiated with the dose of 0{approx}50 Gy to investigated the effect of the low dose gamma radiation on the early growth and resistance to subsequent high dose of radiation. The effect of the low dose gamma radiation on the early growth and resistance to subsequenct high dose of radiation were enhanced in Johong cultivar but not in Jokwang cultivar. Germination rate and early growth of Johong cultivar were noticeably increased at 4 Gy-, 8 Gy- and 20 Gy irradiation group. Resistance to subsequent high dose of radiation of Johong cultivar were increased at almost all of the low dose irradiation group. Especially it was highest at 4 Gy irradiation group. The carotenoid contents and enzyme activity on the resistance to subsequent high dose of radiation of Johong cultivar were increased at the 4 Gy and 8 Gy irradiation group.

Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

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Aline Correa de Carvalho

2013-01-01

Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

Transperineal high-dose-rate interstitial radiation therapy in the management of gynecologic malignancies

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Itami, Jun; Hara, Ryuseke; Kozuka, Takuyou; Yamashita, Hideomi; Nakajima, Kaori; Shibata, Kouji; Abe, Yoshihisa; Fuse, Masashi; Ito, Masashi [International Medical Center of Japan, Tokyo (Japan). Dept. of Radiation Therapy and Oncology

2003-11-01

Background: High-dose-rate interstitial radiation therapy is a newly introduced modality, and its role in the management of gynecologic malignancies remains to be studied. Clinical experience in high-dose-rate interstitial radiation therapy was retrospectively investigated. Patients and Methods: Eight patients with primary and nine with recurrent gynecologic malignancies underwent high-dose-rate interstitial radiation therapy with/without external-beam irradiation. Fractional dose of the high-dose-rate interstitial radiation therapy ranged between 4 and 6 Gy with total doses of 15-54 Gy. Interstitial irradiation was performed twice daily with an interval of > 6 h. Results: 2-year local control rate was 75% for primary treatment and 47% for treatment of recurrence (p = 0.46). Maximum tumor size had a statistically significant impact on local control (p < 0.002). Grade 2 and 4 late complications were seen in five patients, and the incidence was significantly higher in patients with a larger volume enclosed by the prescribed fractional dose of high-dose-rate interstitial radiation therapy. The incidence of grade 2 and 4 complications at 18 months was 78% and 0% with a volume > 100 cm{sup 3} and {<=} 100 cm{sup 3}, respectively (p < 0.04). Conclusion: Although high-dose-rate interstitial radiation therapy is a promising modality, it must be applied cautiously to patients with bulky tumors because of the high incidence of serious complications. (orig.)

Stock selection of high-dose-irradiation-resistant materials for filter press under high-dose irradiation operation

International Nuclear Information System (INIS)

Ishiyama, Shintaro; Minami, Mamoru; Hara, Kouji; Yamashita, Manabu

2015-01-01

In a volume reduction process for the decontamination of contained soil, the performance degradation of a filter press is expected owing to material deterioration under high-dose irradiation. Eleven-stock selection of candidate materials including polymers, fibers and rubbers for the filter press was conducted to achieve a high performance of volume reduction of contaminated soil and the following results were derived. Crude rubber and nylon were selected as prime candidates for packing, diaphragm and filter plate materials. Polyethylene was also selected as a prime candidate for the filter cloth material. (author)

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

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Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Effective dose calculation in CT using high sensitivity TLDs

International Nuclear Information System (INIS)

Brady, Z.; Johnston, P.N.

2010-01-01

Full text: To determine the effective dose for common paediatric CT examinations using thermoluminescence dosimetry (TLD) mea surements. High sensitivity TLD chips (LiF:Mg,Cu,P, TLD-IOOH, Thermo Fisher Scientific, Waltham, MA) were calibrated on a linac at an energy of 6 MY. A calibration was also performed on a superricial X-ray unit at a kilovoltage energy to validate the megavoltage cali bration for the purpose of measuring doses in the diagnostic energy range. The dose variation across large organs was assessed and a methodology for TLD placement in a 10 year old anthropomorphic phantom developed. Effective dose was calculated from the TLD measured absorbed doses for typical CT examinations after correcting for the TLD energy response and taking into account differences in the mass energy absorption coefficients for different tissues and organs. Results Using new tissue weighting factors recommended in ICRP Publication 103, the effective dose for a CT brain examination on a 10 year old was 1.6 millisieverts (mSv), 4.9 mSv for a CT chest exa ination and 4.7 mSv for a CT abdomen/pelvis examination. These values are lower for the CT brain examination, higher for the CT chest examination and approximately the same for the CT abdomen/ pelvis examination when compared with effective doses calculated using ICRP Publication 60 tissue weighting factors. Conclusions High sensitivity TLDs calibrated with a radiotherapy linac are useful for measuring dose in the diagnostic energy range and overcome limitations of output reproducibility and uniformity asso ciated with traditional TLD calibration on CT scanners or beam quality matched diagnostic X-ray units.

HIGH-DOSE RATE BRACHYTHERAPY IN CARCINOMA CERVIX STAGE IIIB

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Sathya Maruthavanan

2016-07-01

Full Text Available INTRODUCTION Radiotherapy is the standard treatment in locally advanced (IIB-IVA and early inoperable cases. The current standard of practice with curable intent is concurrent chemoradiation in which intracavitary brachytherapy is an integral component of radiotherapy. This study aims at assessing the efficacy of HDR ICBT (High-dose rate intracavitary brachytherapy in terms local response, normal tissue reactions, and feasibility. METHODS AND MATERIALS A total of 20 patients of stage IIIB cancer of the uterine cervix were enrolled in the study and were planned to receive concurrent chemotherapy weekly along with EBRT (external beam radiotherapy to a dose of 50 Gy/25 Fr. Suitability for ICBT was assessed at 40 Gy/20 Fr. 6/20 patients were suitable at 40 Gy and received HDR ICBT with a dose of 5.5 Gy to point A in 4 sessions (5.5 Gy/4 Fr. The remaining 14/20 patients completed 50 Gy and received HDR ICBT with a dose of 6 Gy to point A in 3 sessions (6 Gy/3 Fr. RESULTS A total of 66 intracavitary applications were done and only one application required dose modification due to high bladder dose, the pelvic control rate was 85% (17/20. 10% (2/20 had stable disease and 5% (1/20 had progressive disease at one year of follow up. When toxicity was considered only 15% developed grade I and grade II rectal complications. Patient compliance and acceptability was 100%. Patients were very comfortable with the short treatment time as compared with patients on LDR ICBT (low-dose rate intracavitary brachytherapy treatment interviewed during the same period. CONCLUSION This study proves that HDR brachytherapy is efficacious and feasible in carcinoma of cervix stage IIIB. It also proves that good dose distribution can be achieved with HDR intracavitary facility by the use of dose optimization. The short treatment time in HDR ICBT makes it possible to maintain this optimised dose distribution throughout the treatment providing a gain in the therapeutic ratio and

Effect of onion flavonoids on colorectal cancer with hyperlipidemia: an in vivo study

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He Y

2014-01-01

Full Text Available Yongshan He,1,* Heiying Jin,1,* Wei Gong,2,* Chunxia Zhang,1 Acheng Zhou1 1National Center of Colorectal Surgery, Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China; 2Department of Surgery, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin, People's Republic of China *These authors contributed equally to this work Objectives: This study aims to find the effect of onion's extraction on the colorectal cancer with hyperlipidemia. Method: We established a hyperlipidemia-subcutaneously heterotopic colorectal cancer orthotopic transplant model and fed mice a high fat diet and performing transplantation. Animal models were treated with capecitabine and/or simvastatin and low-, middle-, high- dose of onion's extraction and both tumor growth rate and blood lipid levels were monitored. Results: We found that colorectal cancer in onion's extraction groups was significantly inhibited, and the effect of high dose of onion's extraction was equivalent to capecitabine. Onion's extraction effectively decreased levels of apoB and TC. Conclusion: Our study established a hyperlipidemia colon tumor model involving subcutaneous colon translocation and orthotopic transplantation, this model was an ideal research model for mutual influence of hyperlipidemia and colorectal cancer. Onion's extraction could inhibit the proliferation of colorectal cancer; the function of the high-dose of onion's extraction was fairly to capecitabine, which provided a new direction in protecting and treating colorectal cancer. Keywords: colorectal cancer, hyperlipidemia, onion flavonoids, capecitabine, simvastatin

High dose per fraction dosimetry of small fields with Gafchromic EBT2 film

International Nuclear Information System (INIS)

Hardcastle, Nicholas; Basavatia, Amar; Bayliss, Adam; Tome, Wolfgang A.

2011-01-01

Purpose: Small field dosimetry is prone to uncertainties due to the lack of electronic equilibrium and the use of the correct detector size relative to the field size measured. It also exhibits higher sensitivity to setup errors as well as large variation in output with field size and shape. Radiochromic film is an attractive method for reference dosimetry in small fields due to its ability to provide 2D dose measurements while having minimal impact on the dose distribution. Gafchromic EBT2 has a dose range of up to 40 Gy; therefore, it could potentially be useful for high dose reference dosimetry with high spatial resolution. This is a requirement in stereotactic radiosurgery deliveries, which deliver high doses per fraction to small targets. Methods: Targets of 4 mm and 12 mm diameters were treated to a minimum peripheral dose of 21 Gy prescribed to 80% of the maximum dose in one fraction. Target doses were measured with EBT2 film (both targets) and an ion chamber (12 mm target only). Measured doses were compared with planned dose distributions using profiles through the target and minimum peripheral dose coverage. Results: The measured target doses and isodose coverage agreed with the planned dose within ±1 standard deviation of three measurements, which were 2.13% and 2.5% for the 4 mm and 12 mm targets, respectively. Conclusions: EBT2 film is a feasible dosimeter for high dose per fraction reference 2D dosimetry.

Acinetobacter Prosthetic Joint Infection Treated with Debridement and High-Dose Tigecycline.

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Vila, Andrea; Pagella, Hugo; Amadio, Claudio; Leiva, Alejandro

2016-12-01

Prosthesis retention is not recommended for multidrug-resistant Acinetobacter prosthetic joint infection due to its high failure rate. Nevertheless, replacing the prosthesis implies high morbidity and prolonged hospitalization. Although tigecycline is not approved for the treatment of prosthetic joint infection due to multidrug resistant Acinetobacter baumannii, its appropriate use may preclude prosthesis exchange. Since the area under the curve divided by the minimum inhibitory concentration is the best pharmacodynamic predictor of its efficacy, we used tigecycline at high dose, in order to optimize its efficacy and achieve implant retention in 3 patients who refused prosthesis exchange. All patients with prosthetic joint infections treated at our Institution are prospectively registered in a database. Three patients with early prosthetic joint infection of total hip arthroplasty due to multidrug resistant A. baumannii were treated with debridement, antibiotics and implant retention, using a high maintenance dose of tigecycline (100 mg every 12 hours). The cases were retrospectively reviewed. All patients signed informed consent for receiving off-label use of tigecycline. Tigecycline was well tolerated, allowing its administration at high maintenance dose for a median of 40 days (range 30-60). Two patients were then switched to minocycline at standard doses for a median of 3.3 months in order to complete treatment. Currently, none of the patients showed relapse. Increasing the dose of tigecycline could be considered as a means to better attain pharmacodynamic targets in patients with severe or difficult-to-treat infections. Tigecycline at high maintenance dose might be useful when retention of the implant is attempted for treatment for prosthetic joint infections due to multidrug resistant Acinetobacter. Although this approach might be promising, off-label use of tigecycline should be interpreted cautiously until prospective data are available. Tigecycline is

The Comparison of Two Types of Treatment (High Dose and Low Dose IVIG in Children with GBS in Mofid Hospital

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Parvaneh Karim-Zadeh

2003-12-01

Full Text Available Objective: Acute inflammatory demyelinating peripheral neuropathy (Guillain-Barre-Syndrome is by far the most common cause of immune–mediated peripheral nerve disease in children and with the near disappearance of poliomyelitis, is responsible for the great majority of cases of acute flaccid paralysis. Several controlled studies have done with corticosteroids, plasma pheresis and IVIG in pediatric patients. IVIG treatment can be done in two types of treatment: 1- High dose that means 1gr/kg/day for 2 days. 2- Low dose that means 400mg/kg/day for 5 days. Several studies in other countries have shown faster rate of recovery in patients who received total dose of IVIG in 2 days as opposed to 5 days. Materials & Methods: Because we have not any study about this two types of treatment in IRAN we decided to comparison this two types of IVIG treatment. So the patients that referred to Mofid children hospital for weakness and we diagnosed GBS (with history, physical examination, laboratories and EMG-NCV are divided in two groups: 1- High dose IVIG treatment (experimental group. 2- Low dose IVIG treatment (control group Then the results evaluated. Results: Our findings included that in high dose IVIG therapy we have faster rate of recovery and the Hospital stay is shorter than low dose IVIG-therapy. Also in this type of treatment “because the patients cure faster” , so complications are decreased in them. In the group of high dose IVIG therapy, lower and upper extremities weakness decreased in time. Conclusion: We did not receive any relationship between side effects of drugs and the type of treatment. The relationship between high dose IVIG therapy and drug side effects was not significant.

High-dose Sulbactam Treatment for Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant

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In Beom Jeong

2016-11-01

Full Text Available Background Several antibiotics can be used to treat ventilator-associated pneumonia caused by carbapenem-resistant A. baumannii (CRAB-VAP including high-dose sulbactam. However, the effectiveness of high-dose sulbactam therapy is not well known. We report our experience with high-dose sulbactam for treatment of CRAB-VAP. Methods Medical records of patients with CRAB-VAP who were given high-dose sulbactam between May 2013 and June 2015 were reviewed. Results Fifty-eight patients with CRAB-VAP were treated with high-dose sulbactam. The mean age was 72.0 ± 15.2 years, and the acute physiology and chronic health evaluation II (APACHE II score was 15.1 ± 5.10 at the time of CRAB-VAP diagnosis. Early clinical improvement was observed in 65.5% of patients, and 30-day mortality was 29.3%. Early clinical failure (odds ratio [OR]: 8.720, confidence interval [CI]: 1.346-56.484; p = 0.023 and APACHE II score ≥ 14 at CRAB-VAP diagnosis (OR: 10.934, CI: 1.047-114.148; p = 0.046 were associated with 30-day mortality. Conclusions High-dose sulbactam therapy may be effective for the treatment of CRAB-VAP. However, early clinical failure was observed in 35% of patients and was associated with poor outcome.

Mutational influences of low-dose and high let ionizing radiation in drosophila melanogaster

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Lei, Huang; Fanjun, Kong; Sun, Yeqing

For cosmic environment consists of a varying kinds of radiation particles including high Z and energy ions which was charactered with low-dose and high RBE, it is important to determine the possible biofuctions of high LET radiation on human beings. To analyse the possible effectes of mutational influences of low-dose and high-LET ionizing radiation, wild fruit flies drosophila melanogaster were irradiated by 12C6+ ions in two LET levels (63.3 and 30 keV/µum) with different low doses from 2mGy to 2000mGy (2, 20, 200, 2000mGy) in HIRFL (Heavy ion radiation facility laboratory, lanzhou, China).In the same LET value group, the average polymorphic frequency was elevated along with adding doses of irradation, the frequency in 2000 mGy dose samples was significantly higher than other samples (p<0.01).These results suggest that genomic DNA sequence could be effected by low-dose and high-LET ionizing radiation, the irradiation dose is an important element in genomic mutation frequency origination.

Effects of Berberine on Amelioration of Hyperglycemia and Oxidative Stress in High Glucose and High Fat Diet-Induced Diabetic Hamsters In Vivo

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Cong Liu

2015-01-01

Full Text Available This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet-induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg·kg−1 for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes.

Comparison of therapeutic lipid target achievements among high-risk patients in Oman.

Science.gov (United States)

Al-Waili, Khalid; Al-Zakwani, Ibrahim; Al-Dughaishi, Tamima; Baneerje, Yajnavalka; Al-Sabti, Hilal; Al-Hashmi, Khamis; Farhan, Hatem; Habsi, Khadija Al; Al-Hinai, Ali T; Al-Rasadi, Khalid

2014-05-01

We compared therapeutic lipid target achievements among patients with diabetes or coronary heart disease (CHD) in Oman. A retrospective chart review of 94 patients was conducted at an outpatient clinic in Sultan Qaboos University Hospital, Muscat, Oman. The variables included low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apo B). The overall mean age of the cohort was 59 ± 12 years, 54% were male, 66% were diabetic, 48% hypertensive, 45% had CHD, 94% were on simvastatin, 4% were on fenofibrate, and 2% were on both simvastatin and fenofibrate. Lipid goal attainments of calculated LDL-C (<2.6 mmol/L), apo B (<0.9 g/L), and non-HDL-C (<3.36 mmol/L) were reached in 52%, 39%, and 53% of the patients, respectively. A significant proportion of high-risk patients treated with lipid-lowering agents reach LDL-C but not the apo B treatment targets, suggesting that the use of apo B target values should also be considered.

Global dose to man from proposed NNTRP high altitude nuclear tests

International Nuclear Information System (INIS)

Peterson, K.R.

1975-05-01

Radionuclide measurements from past high altitude nuclear testing have enabled development of a model to estimate surface deposition and doses from 400 kt of fission products injected in winter within the Pacific Test Area at altitudes in excess of 50 km. The largest 30-year average dose to man is about 10 millirem and occurs at 30 0 to 50 0 N latitude. The principal contributor to this dose is external gamma radiation from gross fission products. Individual doses from 90 Sr via the forage-cow-milk pathway and 137 Cs via the pasture-meat pathway are about 1/5 the gross fission product doses. The global 30-year population dose is 3 x 10 7 person-rem, which compares with a 30-year natural background population dose of 1 X 10 10 person-rem. Due in large part to the global distribution of population, over 98 percent of the global person-rem from the proposed high altitude tests is received in the Northern Hemisphere, while about 75 percent of the total population dose occurs within the 30 0 --50 0 N latitude belt. Detonations in summer would decrease the global dose by about a factor of three. (U.S.)

High dose-per-pulse electron beam dosimetry: Usability and dose-rate independence of EBT3 Gafchromic films.

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Jaccard, Maud; Petersson, Kristoffer; Buchillier, Thierry; Germond, Jean-François; Durán, Maria Teresa; Vozenin, Marie-Catherine; Bourhis, Jean; Bochud, François O; Bailat, Claude

2017-02-01

The aim of this study was to assess the suitability of Gafchromic EBT3 films for reference dose measurements in the beam of a prototype high dose-per-pulse linear accelerator (linac), capable of delivering electron beams with a mean dose-rate (Ḋ m ) ranging from 0.07 to 3000 Gy/s and a dose-rate in pulse (Ḋ p ) of up to 8 × 10 6 Gy/s. To do this, we evaluated the overall uncertainties in EBT3 film dosimetry as well as the energy and dose-rate dependence of their response. Our dosimetric system was composed of EBT3 Gafchromic films in combination with a flatbed scanner and was calibrated against an ionization chamber traceable to primary standard. All sources of uncertainties in EBT3 dosimetry were carefully analyzed using irradiations at a clinical radiotherapy linac. Energy dependence was investigated with the same machine by acquiring and comparing calibration curves for three different beam energies (4, 8 and 12 MeV), for doses between 0.25 and 30 Gy. Ḋ m dependence was studied at the clinical linac by changing the pulse repetition frequency (f) of the beam in order to vary Ḋ m between 0.55 and 4.40 Gy/min, while Ḋ p dependence was probed at the prototype machine for Ḋ p ranging from 7 × 10 3 to 8 × 10 6 Gy/s. Ḋ p dependence was first determined by studying the correlation between the dose measured by films and the charge of electrons measured at the exit of the machine by an induction torus. Furthermore, we compared doses from the films to independently calibrated thermo-luminescent dosimeters (TLD) that have been reported as being dose-rate independent up to such high dose-rates. We report that uncertainty below 4% (k = 2) can be achieved in the dose range between 3 and 17 Gy. Results also demonstrated that EBT3 films did not display any detectable energy dependence for electron beam energies between 4 and 12 MeV. No Ḋ m dependence was found either. In addition, we obtained excellent consistency between films and TLDs over the entire Ḋ p

Oval pulsed high-dose dexamethasone for myositis

NARCIS (Netherlands)

Hoogendijk, JE; Wokke, JHJ; de Visser, M

To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Sis patients responded. Side effects

Oral pulsed high-dose dexamethasone for myositis

NARCIS (Netherlands)

van der Meulen, M. F.; Hoogendijk, J. E.; Wokke, J. H.; de Visser, M.

2000-01-01

To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Six patients responded. Side effects

High-dose acetylcysteine in idiopathic pulmonary fibrosis

NARCIS (Netherlands)

Demedts, Maurits; Behr, Juergen; Buhl, Roland; Costabel, Ulrich; Dekhuijzen, Richard; Jansen, Henk M.; MacNee, William; Thomeer, Michiel; Wallaert, Benoit; Laurent, François; Nicholson, Andrew G.; Verbeken, Eric K.; Verschakelen, Johny; Flower, Christopher D. R.; Capron, Frédérique; Petruzzelli, Stefano; de Vuyst, Paul; van den Bosch, Jules M. M.; Rodriguez-Becerra, Eulogio; Corvasce, Giuseppina; Lankhorst, Ida; Sardina, Marco; Montanari, Mauro

2005-01-01

BACKGROUND Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added

Regular self-microstructuring on CR39 using high UV laser dose

International Nuclear Information System (INIS)

Parvin, P.; Refahizadeh, M.; Mortazavi, S.Z.; Silakhori, K.; Mahdiloo, A.; Aghaii, P.

2014-01-01

The UV laser induced replicas in the form of self-lining microstructures are created by high dose (with high fluence) ArF laser irradiation on CR39. Microstructures as the self-induced contours, in the form of concentric circles, appear when the laser fluence is well above the ablation threshold. It leads to the regular periodic parallel lines, i.e. circles with large radii having spatial separation 100–200 nm and line width 300–600 nm, where the number of shots increases to achieve higher UV doses. The surface wettability is also investigated after laser texturing to exhibit that a notable hydrophilicity takes place at high doses.

High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8

International Nuclear Information System (INIS)

Behr, T.M.; Gotthardt, M.; Schipperm, M.L.; Gratz, S.; Behe, M.P.; Brittinger, G.; Woermann, B.; Becker, W.

2002-01-01

CD20 has been used as target molecule for low-dose as well as high-dose, myeloablative RIT of B-cell NHL. MCL is an especially aggressive, prognostically unfavorable form of B-cell NHL. The aim of this study was to investigate whether high-dose, myeloablative RIT with the 131 I-labeled chimeric anti-CD20 antibody C2B8 (rituxan, Mabthera, Roche) may be therapeutically more effective than conventional low-dose therapy in MCL. A total of twelve patients with chemorefractory or relapsed mantle cell lymphoma were studied so far (all of them having relapsed after high-dose chemotherapy, seven of them combined with 12 Gy TBI). A diagnostic-dosimetric study was performed with 10 mCi of 131 I-C2B8 at a protein dose of 2.5 mg/kg. In case of splenic pooling, the protein dose was increased until a more 'favorable' biodistribution was obtained. Therapy was performed with conventional (30-75 mCi; n=4) or myeloablative activities (261-515 mCi; n=8) of 131 I-C2B8 at the previously optimized protein dose, aiming at whole-body doses of ≤ 0.8 Gy (for low-dose RIT) or lung doses of ≤ 27 Gy (for high-dose RIT). Clinical follow-up was obtained for up to 42 months. Overall, in 11 patients the 2.5 mg/kg protein dose was used, whereas in one patient with marked splenomegaly, 10 mg/kg were necessary to overcome the splenic antigenic sink. In the high-dose patients, non-hematologic toxicity was restricted to mild to moderate nausea, fever, transient bilirubin or liver enzyme elevations. Despite thyroid blocking, 6/8 high-dose (in contrast to 0/4 low-dose) patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. The response rate in the low-dose arm was only 1(PR)/4, whereas 7/8 high-dose patients experienced complete and the remainder a partial remission. 6 high-dose patients are still in CR (one of them relapsed locally at 3 months, one systemically at 26 months after RIT), and 7 are still alive for up to 42+ months. In contrast to low-dose therapy

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

Science.gov (United States)

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2015-07-01

High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

Radiation Parameters of High Dose Rate Iridium -192 Sources

Science.gov (United States)

Podgorsak, Matthew B.

A lack of physical data for high dose rate (HDR) Ir-192 sources has necessitated the use of basic radiation parameters measured with low dose rate (LDR) Ir-192 seeds and ribbons in HDR dosimetry calculations. A rigorous examination of the radiation parameters of several HDR Ir-192 sources has shown that this extension of physical data from LDR to HDR Ir-192 may be inaccurate. Uncertainty in any of the basic radiation parameters used in dosimetry calculations compromises the accuracy of the calculated dose distribution and the subsequent dose delivery. Dose errors of up to 0.3%, 6%, and 2% can result from the use of currently accepted values for the half-life, exposure rate constant, and dose buildup effect, respectively. Since an accuracy of 5% in the delivered dose is essential to prevent severe complications or tumor regrowth, the use of basic physical constants with uncertainties approaching 6% is unacceptable. A systematic evaluation of the pertinent radiation parameters contributes to a reduction in the overall uncertainty in HDR Ir-192 dose delivery. Moreover, the results of the studies described in this thesis contribute significantly to the establishment of standardized numerical values to be used in HDR Ir-192 dosimetry calculations.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

Science.gov (United States)

Benes, Lane B; Bassi, Nikhil S; Davidson, Michael H

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects. Copyright © 2016 Elsevier Inc. All rights reserved.

TL response of citrine samples for high-dose dosimetry

International Nuclear Information System (INIS)

Teixeira, Maria Ines; Caldas, Linda V.E.

2011-01-01

The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the thermoluminescence technique (TL). In this work, the TL properties of citrine samples were studied. They were exposed to different doses of gamma radiation ( 60 Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tectosilicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO 2 ), and it has a lower symmetry and more compact reticulum. The citrine stone samples were powdered, and the selected grains were mixed with Teflon in the proportion 2 (Teflon):1 (Citrine). The mixture was pressed and sintered for production of Citrine -Teflon pellets of 50 mg. The TL emission curve showed two peaks at 160 deg C and 220 deg C. To remove the TL peak (160 deg C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The TL dose-response curve between 50 Gy and 100 kGy, the reproducibility of TL response and the lower detection dose were obtained. The preliminary results show that citrine may be useful for high-dose dosimetry. (author)

Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

Science.gov (United States)

Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L

1999-03-17

Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

Science.gov (United States)

Oberg, Johanna; Verelst, Margareta; Jorde, Rolf; Cashman, Kevin; Grimnes, Guri

2017-10-01

Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D 3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose. Copyright © 2017 Elsevier Ltd. All rights reserved.

Radiation processing and high-dose dosimetry at ANSTO

International Nuclear Information System (INIS)

Gant, G.J.; Saunders, M.; Banos, C.; Mo, L.; Davies, J.; Evans, O.

2001-01-01

The Radiation Technology group at ANSTO is part of the Physics Division and provides services and advice in the areas of gamma irradiation and high-dose dosimetry. ANSTO's irradiation facilities are designed for maximum dose uniformity and provide a precision irradiation service unique in Australia. Radiation Technology makes and sells reference and transfer standard dosimeters which are purchased by users and suppliers of commercial irradiation services in Australia and the Asia-Pacific region. A calibration service is also provided for dosimeters purchased from other suppliers

Safety of high-dose daptomycin in patients with severe renal impairment

Directory of Open Access Journals (Sweden)

Tai CH

2018-03-01

Full Text Available Chih-Hsun Tai,1 Chi-Hao Shao,2 Chen-You Chen,2 Shu-Wen Lin,1–3 Chien-Chih Wu1,2 1Department of Pharmacy, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan Background: Treatment options are limited for infections due to multidrug-resistant Gram-positive pathogens. Daptomycin is a lipopeptide antibiotic with concentration-dependent killing characteristic and dose-dependent post-antibiotic effect. To achieve optimized pharmacodynamic effect, some experts advocated using a high dose of daptomycin (≥9 mg/kg for severe infections. However, the safety of high-dose therapy in patients with renal impairment remains unknown. This study was aimed to evaluate the safety of daptomycin in patients with severe renal impairment. Methods: This was a retrospective study performed by reviewing electronic medical records. Patients with severe renal impairment who were treated with daptomycin in a tertiary teaching hospital between January 1, 2013, and June 30, 2016, were included for evaluation. The incidence rates of creatine kinase (CK elevation between high-dose (≥9 mg/kg and standard-dose (<9 mg/kg groups were compared. Results: Overall, 164 patients met the inclusion criteria, and 114 (69.5% of them were on renal replacement therapy. Vancomycin-resistant enterococci were the most common pathogens (61.3% of the patients with documented pathogens. The treatment success rate was 51.6% in the 91 patients with bacteremia. The average dose of daptomycin was 8.0±2.3 mg/kg, and 37 (22.6% patients received ≥9 mg/kg. CK levels were followed in 108 (65.9% patients. Significantly higher incidence of CK elevation was found in the high-dose group compared with that in the standard-dose group (10.8% vs 1.6%, P<0.05. Moreover

Unusual complication and successful high-dose chemotherapy ...

African Journals Online (AJOL)

... treated with high-dose chemotherapy in our institution, complicated by unusual bilateral renal vein tumour thrombi and tumour lysis syndrome. We believe this unique case highlights the need for early recognition of current and potential complications on staging computed tomography imaging, as well as successful use of ...

Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

Energy Technology Data Exchange (ETDEWEB)

Saunders, W.M.; Char, D.H.; Quivey, J.M.; Castro, J.R.; Chen, G.T.Y.; Collier, J.M.; Cartigny, A.; Blakely, E.A.; Lyman, J.T.; Zink, S.R.

1985-02-01

The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

International Nuclear Information System (INIS)

Saunders, W.M.; Char, D.H.; Quivey, J.M.

1985-01-01

The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons

Low dose rate and high dose rate intracavitary treatment for cervical cancer

International Nuclear Information System (INIS)

Hareyama, Masato; Oouchi, Atsushi; Shidou, Mitsuo

1997-01-01

From 1984 through 1993, 144 previous untreated patients with carcinoma of uterine cervix were treated with either low dose rate 137 Cs therapy (LDR) or high dose rate 60 Co therapy (HDR). The local failure rates for more than 2-years for the primary lesions were 11.8% (8 of 63 patients) for LDR and 18.0% (11 of 61 patients). Rectal complication rates were significantly lower for HDR versus LDR (14.3% VS. 32.8%. p<0.01). Also, bladder complication rates were significantly lower for HDR versus LDR (0% VS. 10.4%, p<0.005). Treatment results in term of local control were equivalent for HDR and LDR treatment. However, the incidence of complications was higher for the LDR group than for the HDR group. (author)

Dimethyl sulfoxyde diethyl fumarate solution for high dose dosimetry

International Nuclear Information System (INIS)

Al-Kassiri, H.; Kattan, M.; Daher, Y.

2007-06-01

Dosimetric characterization of diethyl fumarate DEF in dimethyl sulfoxyde DMSO solution has been studied spectrophotometrically for possible application at high dose radiation dosimetry in the range (0-225 kGy). The absorption spectra of irradiated solution showed broad absorption bands between (325-400 nm) with a shoulder at 332 nm. The absorption increases as the dose is increased. Absorbance at 332 nm were measured and plotted against absorbed dose. Linear relationship and good response were found between absorbed dose and absorbance of 20% DEF concentration in the range (0-225 kGy) at the wave length, and linearity up to 250 kGy of absorbance at 332 nm .Good dose rate independence was observed in the range (14-33 kGy/h). The effect of post irradiation storage in darkness and indirect daylight conditions were not found to influence the absorption up to 700 h after irradiation. The effect of irradiation temperature within the range (0 to 60 centigrade degree) on the dosimetry performance was discussed.(author)

Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying.

Science.gov (United States)

Craye, Goedele; Löbmann, Korbinian; Grohganz, Holger; Rades, Thomas; Laitinen, Riikka

2015-12-03

In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin-lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture upon ball milling. In addition, a spray-dried formulation of SVS without LYS was prepared. Energy-dispersive X-ray spectroscopy (EDS) revealed that SLS coated the SVS and SVS-LYS particles upon spray drying. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that in the spray-dried formulations the remaining crystallinity originated from SLS only. The best dissolution properties and a "spring and parachute" effect were found for SVS spray-dried from a 5% SLS solution without LYS. Despite the presence of at least partially crystalline SLS in the mixtures, all the studied formulations were able to significantly extend the stability of amorphous SVS compared to previous co-amorphous formulations of SVS. The best stability (at least 12 months in dry conditions) was observed when SLS was spray-dried with SVS (and LYS). In conclusion, spray drying of SVS and LYS from aqueous surfactant solutions was able to produce formulations with improved physical stability for amorphous SVS.

Biological effective doses in the intracavitary high dose rate brachytherapy of cervical cancer

Directory of Open Access Journals (Sweden)

Y. Sobita Devi

2011-12-01

Full Text Available Purpose: The aim of this study is to evaluate the decrease of biological equivalent dose and its correlation withlocal/loco-regional control of tumour in the treatment of cervical cancer when the strength of the Ir-192 high dose rate(HDR brachytherapy (BT source is reduced to single, double and triple half life in relation to original strength of10 Ci (~ 4.081 cGy x m2 x h–1. Material and methods: A retrospective study was carried out on 52 cervical cancer patients with stage II and IIItreated with fractionated HDR-BT following external beam radiation therapy (EBRT. International Commission onRadiation Units and Measurement (ICRU points were defined according to ICRU Report 38, using two orthogonal radiographimages taken by Simulator (Simulix HQ. Biologically effective dose (BED was calculated at point A for diffe -rent Ir-192 source strength and its possible correlation with local/loco-regional tumour control was discussed. Result: The increase of treatment time per fraction of dose due to the fall of dose rate especially in HDR-BT of cervicalcancer results in reduction in BED of 2.59%, 7.02% and 13.68% with single, double and triple half life reduction ofsource strength, respectively. The probabilities of disease recurrence (local/loco-regional within 26 months are expectedas 0.12, 0.12, 0.16, 0.39 and 0.80 for source strength of 4.081, 2.041, 1.020, 0.510 and 0.347 cGy x m2 x h–1, respectively.The percentages of dose increase required to maintain the same BED with respect to initial BED were estimated as1.71, 5.00, 11.00 and 15.86 for the dose rate of 24.7, 12.4, 6.2 and 4.2 Gy/hr at point A, respectively. Conclusions: This retrospective study of cervical cancer patients treated with HDR-BT at different Ir-192 sourcestrength shows reduction in disease free survival according to the increase in treatment time duration per fraction.The probable result could be associated with the decrease of biological equivalent dose to point A. Clinical

Improvements in dose calculation accuracy for small off-axis targets in high dose per fraction tomotherapy

Energy Technology Data Exchange (ETDEWEB)

Hardcastle, Nicholas; Bayliss, Adam; Wong, Jeannie Hsiu Ding; Rosenfeld, Anatoly B.; Tome, Wolfgang A. [Department of Human Oncology, University of Wisconsin-Madison, WI, 53792 (United States); Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC 3002 (Australia) and Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW 2522 (Australia); Department of Human Oncology, University of Wisconsin-Madison, WI 53792 (United States); Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW 2522 (Australia) and Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW 2522 (Australia); Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53792 (United States); Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53792 (United States); Einstein Institute of Oncophysics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461 (United States) and Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW 2522 (Australia)

2012-08-15

Purpose: A recent field safety notice from TomoTherapy detailed the underdosing of small, off-axis targets when receiving high doses per fraction. This is due to angular undersampling in the dose calculation gantry angles. This study evaluates a correction method to reduce the underdosing, to be implemented in the current version (v4.1) of the TomoTherapy treatment planning software. Methods: The correction method, termed 'Super Sampling' involved the tripling of the number of gantry angles from which the dose is calculated during optimization and dose calculation. Radiochromic film was used to measure the dose to small targets at various off-axis distances receiving a minimum of 21 Gy in one fraction. Measurements were also performed for single small targets at the center of the Lucy phantom, using radiochromic film and the dose magnifying glass (DMG). Results: Without super sampling, the peak dose deficit increased from 0% to 18% for a 10 mm target and 0% to 30% for a 5 mm target as off-axis target distances increased from 0 to 16.5 cm. When super sampling was turned on, the dose deficit trend was removed and all peak doses were within 5% of the planned dose. For measurements in the Lucy phantom at 9.7 cm off-axis, the positional and dose magnitude accuracy using super sampling was verified using radiochromic film and the DMG. Conclusions: A correction method implemented in the TomoTherapy treatment planning system which triples the angular sampling of the gantry angles used during optimization and dose calculation removes the underdosing for targets as small as 5 mm diameter, up to 16.5 cm off-axis receiving up to 21 Gy.

Improvements in dose calculation accuracy for small off-axis targets in high dose per fraction tomotherapy

International Nuclear Information System (INIS)

Hardcastle, Nicholas; Bayliss, Adam; Wong, Jeannie Hsiu Ding; Rosenfeld, Anatoly B.; Tomé, Wolfgang A.

2012-01-01

Purpose: A recent field safety notice from TomoTherapy detailed the underdosing of small, off-axis targets when receiving high doses per fraction. This is due to angular undersampling in the dose calculation gantry angles. This study evaluates a correction method to reduce the underdosing, to be implemented in the current version (v4.1) of the TomoTherapy treatment planning software. Methods: The correction method, termed “Super Sampling” involved the tripling of the number of gantry angles from which the dose is calculated during optimization and dose calculation. Radiochromic film was used to measure the dose to small targets at various off-axis distances receiving a minimum of 21 Gy in one fraction. Measurements were also performed for single small targets at the center of the Lucy phantom, using radiochromic film and the dose magnifying glass (DMG). Results: Without super sampling, the peak dose deficit increased from 0% to 18% for a 10 mm target and 0% to 30% for a 5 mm target as off-axis target distances increased from 0 to 16.5 cm. When super sampling was turned on, the dose deficit trend was removed and all peak doses were within 5% of the planned dose. For measurements in the Lucy phantom at 9.7 cm off-axis, the positional and dose magnitude accuracy using super sampling was verified using radiochromic film and the DMG. Conclusions: A correction method implemented in the TomoTherapy treatment planning system which triples the angular sampling of the gantry angles used during optimization and dose calculation removes the underdosing for targets as small as 5 mm diameter, up to 16.5 cm off-axis receiving up to 21 Gy.

The influence of high doses of radiation in citrine stones

International Nuclear Information System (INIS)

Teixeira, M. I.; Caldas, L. V. E.

2014-08-01

The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, jasper, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the techniques of optical absorption (Oa), thermoluminescent (Tl), optically stimulated luminescence (OSL) and resonance paramagnetic electron (EPR). In this work, the Tl properties of citrine samples were studied. They were exposed to different doses of gamma radiation ( 60 Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tecto silicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO 2 ), and it has a lower symmetry and more compact reticulum. The Tl emission curve showed two peaks at 160 grades C and 220 grades C. To remove the Tl peak (160 grades C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The Tl dose-response curve between 50 Gy and 100 kGy, the reproducibility of Tl response and the lower detection dose were obtained. The results show that citrine may be useful as high-dose detectors. (Author)

The influence of high doses of radiation in citrine stones

Energy Technology Data Exchange (ETDEWEB)

Teixeira, M. I. [Universidade Nove de Julho - UNINOVE, Rua Vergueiro 235/249, 01504-001 Sao Paulo (Brazil); Caldas, L. V. E., E-mail: miteixeira@ipen.br [Instituto de Pesquisas Energeticas e Nucleares / CNEN, Av. Lineu Prestes 2242, Cidade Universitaria, 05508-000 Sao Paulo (Brazil)

2014-08-15

The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, jasper, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the techniques of optical absorption (Oa), thermoluminescent (Tl), optically stimulated luminescence (OSL) and resonance paramagnetic electron (EPR). In this work, the Tl properties of citrine samples were studied. They were exposed to different doses of gamma radiation ({sup 60}Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tecto silicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO{sub 2}), and it has a lower symmetry and more compact reticulum. The Tl emission curve showed two peaks at 160 grades C and 220 grades C. To remove the Tl peak (160 grades C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The Tl dose-response curve between 50 Gy and 100 kGy, the reproducibility of Tl response and the lower detection dose were obtained. The results show that citrine may be useful as high-dose detectors. (Author)

Review of high-dose intravenous vitamin C as an anticancer agent.

Science.gov (United States)

Wilson, Michelle K; Baguley, Bruce C; Wall, Clare; Jameson, Michael B; Findlay, Michael P

2014-03-01

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial. © 2014 Wiley Publishing Asia Pty Ltd.

Conventional-Dose versus High-Dose Chemotherapy for Relapsed Germ Cell Tumors

Directory of Open Access Journals (Sweden)

Deaglan J. McHugh

2018-01-01

Full Text Available The majority of metastatic germ cell tumors (GCTs are cured with cisplatin-based chemotherapy, but 20–30% of patients will relapse after first-line chemotherapy and require additional salvage strategies. The two major salvage approaches in this scenario are high-dose chemotherapy (HDCT with autologous stem cell transplant (ASCT or conventional-dose chemotherapy (CDCT. Both CDCT and HDCT have curative potential in the management of relapsed/refractory GCT. However, due to a lack of conclusive randomized trials, it remains unknown whether sequential HDCT or CDCT represents the optimal initial salvage approach, with practice varying between tertiary institutions. This represents the most pressing question remaining for defining GCT treatment standards and optimizing outcomes. The authors review prognostic factors in the initial salvage setting as well as the major studies assessing the efficacy of CDCT, HDCT, or both, describing the strengths and weaknesses that formed the rationale behind the ongoing international phase III “TIGER” trial.

Low- and high-dose laser irradiation effects on cell migration and destruction

Science.gov (United States)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

High-dose radioiodine therapy of Graves disease

International Nuclear Information System (INIS)

Solodky, V.; Fomin, D.; Pestritskaya, E.

2015-01-01

Full text of publication follows. Objectives: to estimate the effectiveness and safety of the disease treatment under different modes of applying RIT. Materials and methods: 67 patients with the thyrotoxicosis condition associated with Graves disease were researched. The patients were divided into 2 groups: a control group with 25 people (18 women and 7 men), who underwent a low-dose therapy of 150-500 MBq; and a main group of 42 people (32 women and 10 men), who underwent a high-dose therapy of 550 and 800 MBq. The volume of thyroid prior to the treatment made up 23.8 ± 20 ml in the main group and 30.2 ± 23 ml in the control one. The average age in the high-dose group was 44.6 ±23 years old and in the low-dose -47.2 ± 24 years old. In terms of the hormone level before the RIT, 52% of the main group patients experienced euthyroidism, while 48% - thyrotoxicosis. The corresponding indices in the control group were 42% and 58% respectively. The cessation of the thyreostatic therapy came on 5. to 21. day prior to the treatment, with the average of 14 ±7 days in both groups. The diagnosis of the disease was based on ultrasonography, planar scintigraphy, the hormone level and antibody titer. The performance was assessed through the attainment of hypo-thyrosis and the transition to a substitutive hormonal therapy with L-thyroxine in 6 months or more. The attainment of euthyroidism was seen as a partial effect due to a possibility of relapse. Results: in 6 months a positive result in the form of hypo-thyrosis was achieved for 39 patients in the main group, which accounted for 93%, and 3 patients (7%) experienced euthyroidism. No symptomatic thyrotoxicosis relapses were revealed. In the control group, hypo-thyrosis was achieved by 18 patients, which accounted for 72%; euthyroidism came up to 12%; 4 patients needed a refresher course of RIT, which made up 16% of the group. 93% of the main group patients tolerated the treatment favourably. 3 patients complained of the

Establishment of a dosimetric system for high doses using glasses

International Nuclear Information System (INIS)

Correa Quezada, Valeria de la Asuncion

1997-01-01

A routine dosimetric system was developed using commercial glass samples. The dosimetric characteristics of national and imported samples were studied: batch uniformity, response repeatability, reutilization, absorbed dose response, detection range, response stability as a function of absorbed dose, storage temperature and thermal treatments pre- and post-irradiation, using the optical absorption technique. As an application, the dosimetric system was tested in a flower irradiation process at IPEN. All the obtained results show the usefulness of the proposed system for high dose dosimetry. (author)

Implementation of high-dose chemical dosimetry for industrial facilities

International Nuclear Information System (INIS)

Conceicao, Cirilo Cezar Sant'Anna da

2006-01-01

The purpose of this work is the implementation of methodology for high dose measurements using chemical dosimeters in liquid phase, traceable to the international metrology system, and make available in the country, the standard of high-dose to industrial irradiation facilities and research irradiators, trough the quality program with comparative measurements and direct use of the standard dosimeters in routine. The use of these low cost dosimetry systems in industrial irradiation facilities, assists to the certification requirements and it can reduce the costs with dosimetry for approximately 20% of the total dosimetry costs, using these systems in routine measurements and validation process, largely substituting the imported PMMA dosimeters, among others. (author)

Applichation of the sulphate ceric dosimetric in the high doses range

International Nuclear Information System (INIS)

Prieto Miranda, F.

1991-01-01

The ceric-cerous dosimetric system is one of the system more employed in the high dose dosimetry. The spectrophotometric procedure to measure the ceric-concentration is an usual analityc method to determine the absorbed dose. On the other hand, due at increase employ of the irradiation process control. In this paper is realized the ceric-cerous dosimetric calibration in the dose range of 0,6 - 5 kGy and the application in the irradiation process control to differents absorbed dose values

Absolute and relative dose measurements with Gafchromic trade mark sign EBT film for high energy electron beams with different doses per pulse

International Nuclear Information System (INIS)

Fiandra, Christian; Ragona, Riccardo; Ricardi, Umberto; Anglesio, Silvia; Giglioli, Francesca Romana

2008-01-01

The authors have evaluated the accuracy, in absolute and relative dose measurements, of the Gafchromic trade mark sign EBT film in pulsed high-energy electron beams. Typically, the electron beams used in radiotherapy have a dose-per-pulse value of less than 0.1 mGy/pulse. However, very high dose-per-pulse electron beams are employed in certain linear accelerators dedicated to intraoperatory radiation therapy (IORT). In this study, the absorbed dose measurements with Gafchromic trade mark sign EBT in both low (less than 0.3 mGy per pulse) and high (30 and 70 mGy per pulse) dose-per-pulse electron beams were compared with ferrous sulfate chemical Fricke dosimetry (operated by the Italian Primary Standard Dosimetry Laboratory), a method independent of the dose per pulse. A summary of Gafchromic trade mark sign EBT in relative and absolute beam output determination is reported. This study demonstrates the independence of Gafchromic trade mark sign EBT absorption as a function of dose per pulse at different dose levels. A good agreement (within 3%) was found with Fricke dosimeters for plane-base IORT applicators. Comparison with a diode detector is presented for relative dose measurements, showing acceptable agreement both in the steep dose falloff zone and in the homogeneous dose region. This work also provides experimental values for recombination correction factor (K sat ) of a Roos (plane parallel) ionization chamber calculated on the basis of theoretical models for charge recombination.

High-speed radiation dose calculations for severe accidents using INDOS

International Nuclear Information System (INIS)

Davidson, G.R.; Godin-Jacqmin, L.J.; Raines, J.C.

1992-01-01

The computer code INDOS (in-plant dose) has been developed for the high-speed calculation of in-plant radiation dose rates and doses during and/or due to a severe accident at a nuclear power plant. This paper describes the current capabilities of the code and presents the results of calculations for several severe-accident scenarios. The INDOS code can be run either as a module of MAAP, a code widely used in the nuclear industry for simulating the response of a light water reactor system during severe accidents, or as a stand-alone code using output from an alternative companion code. INDOS calculates gamma dose rates and doses in major plant compartments caused by airborne and deposited fission products released during an accident. The fission product concentrations are determined by the companion code

A comparison of high-dose and low-dose tranexamic acid antifibrinolytic protocols for primary coronary artery bypass surgery

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Stephen M McHugh

2016-01-01

Full Text Available Background and Aims: Tranexamic acid (TA is used for prophylactic antifibrinolysis in coronary artery bypass surgeries to reduce bleeding. We evaluated the efficacy of two different doses of TA for prophylactic antifibrinolysis in patients undergoing primary coronary artery bypass grafting (CABG surgery in this retrospective cohort study at a tertiary care referral centre. Methods: One-hundred eighty-four patients who underwent primary CABG with cardiopulmonary bypass (CPB via sternotomy between January 2009 and June 2011 were evaluated. Pre-operative patient characteristics, intraoperative data, post-operative bleeding, transfusions, organ dysfunction and 30-day mortality were compared between high-dose TA (30 mg/kg loading dose followed by infusion of 15 mg/kg/h until the end of surgery along with 2 mg/kg priming dose in the bypass circuit and low-dose TA (15 mg/kg loading dose followed by infusion of 6 mg/kg/h until the end of surgery along with 1 mg/kg priming dose in the bypass circuit groups. Univariate comparative analysis of all categorical and continuous variables was performed between the two groups by appropriate statistical tests. Linear and logistic regression analyses were performed to control for the effect of confounding on the outcome variables. Results: Chest tube output, perioperative transfusion of blood products and incidence of re-exploration for bleeding did not differ significantly (P> 0.05 between groups. Post-operative complications and 30-day mortality were comparable between the groups. The presence of cardiogenic shock and increased pre-operative creatinine were found to be associated with increased chest tube output on the post-operative day 2 by multivariable linear regression model. Conclusions: Low-dose TA protocol is as effective as high-dose protocol for antifibrinolysis in patients undergoing primary CABG with CPB.

Salvage high-dose-rate interstitial brachytherapy for locally recurrent rectal cancer

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Pellizzon, Antonio Cassio Assis, E-mail: acapellizzon@hcancer.org.br [A.C. Camargo Cancer Center, Sao Paulo, SP (Brazil). Departamento de Radioterapia

2016-05-15

For tumors of the lower third of the rectum, the only safe surgical procedure is abdominal-perineal resection. High-dose-rate interstitial brachytherapy is a promising treatment for local recurrence of previously irradiated lower rectal cancer, due to the extremely high concentrated dose delivered to the tumor and the sparing of normal tissue, when compared with a course of external beam radiation therapy. (author)

Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children.

Science.gov (United States)

Aglipay, Mary; Birken, Catherine S; Parkin, Patricia C; Loeb, Mark B; Thorpe, Kevin; Chen, Yang; Laupacis, Andreas; Mamdani, Muhammad; Macarthur, Colin; Hoch, Jeffrey S; Mazzulli, Tony; Maguire, Jonathon L

2017-07-18

Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months

High dose rate brachytherapy for oral cancer.

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Yamazaki, Hideya; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Furukawa, Souhei; Koizumi, Masahiko; Ogawa, Kazuhiko

2013-01-01

Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer.

Low dose versus high dose anti-snake venom therapy in the treatment of haematotoxic snake bite in South India.

Science.gov (United States)

Joseph, Imanto M; Kuriakose, Cijoy K; Dev, Anand Vimal; Philip, George A

2017-10-01

Most of the studies on the appropriate dose of anti-snake venom (ASV) are from tertiary hospitals and the guidelines are unclear. Our observational study compared the outcomes of two prevalent treatment regimes for haematotoxic snake bite in a secondary care hospital in South India. The time to normalisation of whole blood clotting time, mortality and complications were not different between the groups. The average dose of ASV required in the low and high dose groups were 106 mL and 246 mL, respectively. Consequently, patients who received low dose ASV incurred approximately 50% less expense. Urticarial rashes were also significantly fewer in the low dose group.

Characterization of Radiation Hardened Bipolar Linear Devices for High Total Dose Missions

Science.gov (United States)

McClure, Steven S.; Harris, Richard D.; Rax, Bernard G.; Thorbourn, Dennis O.

2012-01-01

Radiation hardened linear devices are characterized for performance in combined total dose and displacement damage environments for a mission scenario with a high radiation level. Performance at low and high dose rate for both biased and unbiased conditions is compared and the impact to hardness assurance methodology is discussed.

Brachytherapy for early oral tongue cancer. Low dose rate to high dose rate

International Nuclear Information System (INIS)

Yamazaki, Hideya; Inoue, Takehiro; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Inoue, Toshihiko; Furukawa, Souhei; Kakimoto, Naoya

2003-01-01

To examine the compatibility of low dose rate (LDR) with high dose rate (HDR) brachytherapy, we reviewed 399 patients with early oral tongue cancer (T1-2N0M0) treated solely by brachytherapy at Osaka University Hospital between 1967 and 1999. For patients in the LDR group (n=341), the treatment sources consisted of Ir-192 pin for 227 patients (1973-1996; irradiated dose, 61-85 Gy; median, 70 Gy), Ra-226 needle for 113 patients (1967-1986; 55-93 Gy; median, 70 Gy). Ra-226 and Ir-192 were combined for one patient. Ir-192 HDR (microSelectron-HDR) was used for 58 patients in the HDR group (1991-present; 48-60 Gy; median, 60 Gy). LDR implantations were performed via oral and HDR via a submental/submandibular approach. The dose rates at the reference point for the LDR group were 0.30 to 0.8 Gy/h, and for the HDR group 1.0 to 3.4 Gy/min. The patients in the HDR group received a total dose of 48-60 Gy (8-10 fractions) during one week. Two fractions were administered per day (at least a 6-h interval). The 3- and 5-year local control rates for patients in the LDR group were 85% and 80%, respectively, and those in the HDR group were both 84%. HDR brachytherapy showed the same lymph-node control rate as did LDR brachytherapy (67% at 5 years). HDR brachytherapy achieved the same locoregional result as did LDR brachytherapy. A converting factor of 0.86 is applicable for HDR in the treatment of early oral tongue cancer. (author)

Radiation shielding and dose rate distribution for the building of the high dose rate accelerator

International Nuclear Information System (INIS)

Matsuda, Koji; Takagaki, Torao; Nakase, Yoshiaki; Nakai, Yohta.

1984-03-01

A high dose rate electron accelerator was established at Osaka Laboratory for Radiation Chemistry, Takasaki Establishment, JAERI in the fiscal year of 1975. This report shows the fundamental concept for the radiation shielding of the accelerator building and the results of their calculations which were evaluated through the model experiments. After the construction of the building, the leak radiation was measured in order to evaluate the calculating method of radiation shielding. Dose rate distribution of X-rays was also measured in the whole area of the irradiation room as a data base. (author)

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

Science.gov (United States)

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Interaction of 2-Gy Equivalent Dose and Margin Status in Perioperative High-Dose-Rate Brachytherapy

International Nuclear Information System (INIS)

Martinez-Monge, Rafael; Cambeiro, Mauricio; Moreno, Marta; Gaztanaga, Miren; San Julian, Mikel; Alcalde, Juan; Jurado, Matias

2011-01-01

Purpose: To determine patient, tumor, and treatment factors predictive of local control (LC) in a series of patients treated with either perioperative high-dose-rate brachytherapy (PHDRB) alone (Group 1) or with PHDRB combined with external-beam radiotherapy (EBRT) (Group 2). Patient and Methods: Patients (n = 312) enrolled in several PHDRB prospective Phase I-II studies conducted at the Clinica Universidad de Navarra were analyzed. Treatment with PHDRB alone, mainly because of prior irradiation, was used in 126 patients to total doses of 32 Gy/8 b.i.d. or 40 Gy/10 b.i.d. treatments after R0 or R1 resections. Treatment with PHDRB plus EBRT was used in 186 patients to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments after R0 or R1 resections along with 45 Gy of EBRT with or without concomitant chemotherapy. Results: No dose-margin interaction was observed in Group 1 patients. In Group 2 patients there was a significant interaction between margin status and 2-Gy equivalent (Eq2Gy) dose (p = 0.002): (1) patients with negative margins had 9-year LC of 95.7% at Eq2Gy = 62.9Gy; (2) patients with close margins of >1 mm had 9-year LC of 92.4% at Eq2Gy = 72.2Gy, and (3) patients with positive/close <1-mm margins had 9-year LC of 68.0% at Eq2Gy = 72.2Gy. Conclusions: Two-gray equivalent doses ≥70 Gy may compensate the effect of close margins ≥1 mm but do not counterbalance the detrimental effect of unfavorable (positive/close <1 mm) resection margins. No dose-margin interaction is observed in patients treated at lower Eq2Gy doses ≤50 Gy with PHDRB alone.

Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

Science.gov (United States)

Qi, Wei; Gevonden, Martin; Shalev, Arieh

2017-02-01

Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

The usefulness of metal markers for CTV-based dose prescription in high-dose-rate interstitial brachytherapy

International Nuclear Information System (INIS)

Yoshida, Ken; Mitomo, Masanori; Nose, Takayuki; Koizumi, Masahiko; Nishiyama, Kinji; Yoshida, Mineo

2002-01-01

We employ a clinical target volume (CTV)-based dose prescription for high-dose-rate (HDR) interstitial brachytherapy. However, it is not easy to define CTV and organs at risk (OAR) from X-ray film or CT scanning. To solve this problem, we have utilized metal markers since October 1999. Moreover, metal markers can help modify dose prescription. By regulating the doses to the metal markers, refining the dose prescription can easily be achieved. In this research, we investigated the usefulness of the metal markers. Between October 1999 and May 2001, 51 patients were implanted with metal markers at Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC), Osaka National Hospital (ONH) and Sanda City Hospital (SCH). Forty-nine patients (head and neck: 32; pelvis: 11; soft tissue: 3; breast: 3) using metal markers were analyzed. During operation, we implanted 179 metal markers (49 patients) to CTV and 151 markers (26 patients) to OAR. At treatment planning, CTV was reconstructed judging from the metal markers, applicator position and operation records. Generally, we prescribed the tumoricidal dose to an isodose surface that covers CTV. We also planned to limit the doses to OAR lower than certain levels. The maximum normal tissue doses were decided 80%, 150%, 100%, 50% and 200% of the prescribed doses for the rectum, the urethra, the mandible, the skin and the large vessel, respectively. The doses to the metal markers using CTV-based dose prescription were generated. These were compared with the doses theoretically calculated with the Paris system. Treatment results were also investigated. The doses to the 158 metal markers (42 patients) for CTV were higher than ''tumoricidal dose''. In 7 patients, as a result of compromised dose prescription, 9 markers were lower than the tumoricidal dose. The other 12 markers (7%) were excluded from dose evaluation because they were judged as miss-implanted. The doses to the 142 metal markers (24 patients) for OAR were lower

Neutron dose to patients treated with high-energy medical accelerators

International Nuclear Information System (INIS)

McGinley, P.H.

2001-01-01

The neutron dose equivalent received by patients treated with high energy x-ray beams was measured in this research. A total of 13 different medical accelerators were evaluated in terms of the neutron dose equivalent in the patient plane and at the beam center. The neutron dose equivalent at the beam center was found to ranged from 0.02 to 9.4 mSv per Sv of x-ray dose and values from 0.029 to 2.58 mSv per Sv of x-ray were measured in the patient plane. It was concluded that the neutron levels meet the International Electrotechnical Commission standard for the patient plane. It was also concluded that when intensity modulated radiation treatment is conducted the neutron dose equivalent received by the patient will increase by a factor of 2 to 10. (author)

Study of a new glass matrix by thermoluminescent technique for high-dose dosimetry

Energy Technology Data Exchange (ETDEWEB)

Ferreira, Pamela Z.; Carvalho, Gabriel S. Marchiori de; Cunha, Diego M. da; Dantas, Noelio O.; Silva, Anielle C.A.; Neves, Lucio P.; Perini, Ana P., E-mail: anapaula.perini@ufu.br [Universidade Federal de Uberlandia (UFU), MG (Brazil). Instituto de Fisica; Linda, V.E. Caldas [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Carrera, Betzabel N.S.; Watanabe, Shigueo [Universidade de Sao Paulo (IF/USP), Sao Paulo, SP (Brazil). Instituto de Fisica

2016-07-01

The thermoluminescence technique is widely used for both personal and for high-dose dosimetry. In this work, the thermoluminescence technique was utilized to study a new glass matrix, with nominal composition of 20Li{sub 2}CO{sub 3}.10Al{sub 2}O{sub 3}.30BaO.40B{sub 2}O{sub 3} (mol%), irradiated with different doses in a {sup 60}Co source. The glow curves and the dose-response curve were obtained for radiation doses of 10, 50, 100, 200 e 700 Gy. The results showed that this new glass matrix has potential use in high-dose dosimetry. (author)

Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA

International Nuclear Information System (INIS)

Speight, E.L.; Farr, P.M.

1994-01-01

In PUVA treatment of psoriasis, clinical observation suggests that uninvolved skin is more susceptible to PUVA erythema than lesions of psoriasis. If this is the case, then the efficacy of PUVA treatment might be increased by using localized high-dose UVA restricted to lesional skin. We have therefore studied the erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA and, for comparison, the erythemal response to UVB. This study demonstrates that psoriasis may clear rapidly, without burning, using high-dose UVA. Availability of a suitable irradiation apparatus would allow rapid and effective PUVA treatment to be used for localized, resistant disease. (author)

Sustained release of simvastatin from hollow carbonated hydroxyapatite microspheres prepared by aspartic acid and sodium dodecyl sulfate.

Science.gov (United States)

Wang, Ke; Wang, Yinjing; Zhao, Xu; Li, Yi; Yang, Tao; Zhang, Xue; Wu, Xiaoguang

2017-06-01

Hollow carbonated hydroxyapatite (HCHAp) microspheres as simvastatin (SV) sustained-release vehicles were fabricated through a novel and simple one-step biomimetic strategy. Firstly, hollow CaCO 3 microspheres were precipitated through the reaction of CaCl 2 with Na 2 CO 3 in the presence of aspartic acid and sodium dodecyl sulfate. Then, the as-prepared hollow CaCO 3 microspheres were transformed into HCHAp microspheres with a controlled anion-exchange method. The HCHAp microspheres were 3-5μm with a shell thickness of 0.5-1μm and were constructed of short needle nanoparticles. The HCHAp microspheres were then loaded with SV, exhibiting excellent drug-loading capacity and sustained release properties. These results present a new material synthesis strategy for HCHAp microspheres and suggest that the as-prepared HCHAp microspheres are promising for applications in drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Enteric microbiome metabolites correlate with response to simvastatin treatment.

Directory of Open Access Journals (Sweden)

Rima Kaddurah-Daouk

Full Text Available Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP study: Full Range of Response (FR, and Good and Poor Responders (GPR were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP, rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic

Treatment of carcinoma of uterine cervix with high-dose-rate intracavitary irradiation using Ralstron

International Nuclear Information System (INIS)

Suh, C.O.; Kim, G.E.; Loh, J.J.K.

1988-01-01

From May 1979 through December 1981, a total of 530 patients with carcinoma of the uterine cervix were treated with radiation therapy with curative intent. Of the 530 patients, 365 were treated with a high-dose-rate remote-controlled afterloading system (RALS) using a cobalt source, and 165 patients received a low dose rate using a radium source. External pelvic irradiation with a total of 40-50 Gy to the whole pelvis followed by intracavitary radiation (ICR) with a total dose of 30-39 Gy in ten to 13 fractions to point A was the treatment protocol. ICR was given three times a week with a dose of 3 Gy per fraction. Five-year actuarial survival rate with high-dose-rate ICR by stage was as follows: stage I:82.7% (N = 19) stage II:69.6% (N = 184), and stage III:52.2% (N = 156). The above results were comparable with those with conventional low-dose-rate ICR treatment, and late complications were far less. The application of high-dose-rate ICR was technically simple and easily performed on an outpatient basis without anesthesia, and the patients tolerated it very well. Radiation exposure to personnel was virtually none as compared with that of low-dose-rate ICR. Within a given period of time, more patients can be treated with high-dose-rate ICR because of the short treatment time. The authors therefore conclude that high-dose-rate ICR is suitable for a cancer center where a large number of patients are to be treated

Ion exchange resins as high-dose radiation dosimeters

International Nuclear Information System (INIS)

Alian, A.; Dessouki, A.; El-Assay, N.B.

1984-01-01

This paper reports on the possibility of using various types of ion exchange resins as high-dose radiation dosimeters, by analysis of the decrease in exchange capacity with absorbed dose. The resins studied are Sojuzchim-export-Moscow Cation Exchanger KU-2 and Anion Exchanger AV-17 and Merck Cation Exchanger I, and Merck Anion Exchangers II and III. Over the dose range 1 to 100 kGy, the systems show linearity between log absorbed dose and decrease in resin ion exchange capacity. The slope of this response function differs for the different resins, depending on their ionic form and degree of cross-linking. The radiation sensitivity increases in the order KU-2; Exchanger I; AV-17; Exchanger II; Exchanger III. Merck resins with moisture content of 21% showed considerably higher radiation sensitivity than those with 2 to 3% moisture content. The mechanism of radiation-induced denaturing of the ion exchanger resins involves cleavage and decomposition of functional substituents, with crosslinking playing a stabilizing role, with water and its radiolytic products serving to inhibit radical recombination and interfering with the protection cage effect of crosslinking. (author)

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

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Shakespeare TP

2016-05-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Rural Clinical School, Faculty of Medicine, University of New South Wales, Coffs Harbour, NSW, Australia Aim: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods: Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results: In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion: There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. Keywords: radiotherapy, IMRT, dose

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

Science.gov (United States)

Taguchi, Isao; Iimuro, Satoshi; Iwata, Hiroshi; Takashima, Hiroaki; Abe, Mitsuru; Amiya, Eisuke; Ogawa, Takanori; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Miyauchi, Katsumi; Yamazaki, Tsutomu; Ito, Hiroshi; Otsuji, Yutaka; Kimura, Kazuo; Takahashi, Jun; Hirayama, Atsushi; Yokoi, Hiroyoshi; Kitagawa, Kazuo; Urabe, Takao; Okada, Yasushi; Terayama, Yasuo; Toyoda, Kazunori; Nagao, Takehiko; Matsumoto, Masayasu; Ohashi, Yasuo; Kaneko, Tetsuji; Fujita, Retsu; Ohtsu, Hiroshi; Ogawa, Hisao; Daida, Hiroyuki; Shimokawa, Hiroaki; Saito, Yasushi; Kimura, Takeshi; Inoue, Teruo; Matsuzaki, Masunori; Nagai, Ryozo

2018-05-08

Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P Japanese patients with stable coronary artery disease. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730. © 2018 The Authors.

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

Science.gov (United States)

Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

2012-01-01

BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

Dose specification for 192Ir high dose rate brachytherapy in terms of dose-to-water-in-medium and dose-to-medium-in-medium

International Nuclear Information System (INIS)

Fonseca, Gabriel Paiva; Yoriyaz, Hélio; Tedgren, Åsa Carlsson; Nilsson, Josef; Persson, Maria; Reniers, Brigitte; Verhaegen, Frank

2015-01-01

Dose calculation in high dose rate brachytherapy with 192 Ir is usually based on the TG-43U1 protocol where all media are considered to be water. Several dose calculation algorithms have been developed that are capable of handling heterogeneities with two possibilities to report dose: dose-to-medium-in-medium (D m,m ) and dose-to-water-in-medium (D w,m ). The relation between D m,m and D w,m for 192 Ir is the main goal of this study, in particular the dependence of D w,m on the dose calculation approach using either large cavity theory (LCT) or small cavity theory (SCT). A head and neck case was selected due to the presence of media with a large range of atomic numbers relevant to tissues and mass densities such as air, soft tissues and bone interfaces. This case was simulated using a Monte Carlo (MC) code to score: D m,m, D w,m (LCT), mean photon energy and photon fluence. D w,m (SCT) was derived from MC simulations using the ratio between the unrestricted collisional stopping power of the actual medium and water. Differences between D m,m and D w,m (SCT or LCT) can be negligible (<1%) for some tissues e.g. muscle and significant for other tissues with differences of up to 14% for bone. Using SCT or LCT approaches leads to differences between D w,m (SCT) and D w,m (LCT) up to 29% for bone and 36% for teeth. The mean photon energy distribution ranges from 222 keV up to 356 keV. However, results obtained using mean photon energies are not equivalent to the ones obtained using the full, local photon spectrum. This work concludes that it is essential that brachytherapy studies clearly report the dose quantity. It further shows that while differences between D m,m and D w,m (SCT) mainly depend on tissue type, differences between D m,m and D w,m (LCT) are, in addition, significantly dependent on the local photon energy fluence spectrum which varies with distance to implanted sources. (paper)

Rectal dose assessment in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer; Avaliacao da dose no reto em pacientes submetidas a braquiterapia de alta taxa de dose para o tratamento do cancer do colo uterino

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Oliveira, Jetro Pereira de [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Faculdade de Medicina; Rosa, Luiz Antonio Ribeiro da [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)], e-mail: lrosa@ird.gov.br; Batista, Delano Valdivino Santos; Bardella, Lucia Helena [Instituto Nacional de Cancer (INCA), Rio de Janeiro, RJ (Brazil). Unit of Medical Physics; Carvalho, Arnaldo Rangel [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil). Lab. of Thermoluminescent Dosimetry

2009-03-15

Objective: The present study was aimed at developing a thermoluminescent dosimetric system capable of assessing the doses delivered to the rectum of patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. Materials and methods: LiF:Mg,Ti,Na powder was the thermoluminescent material utilized for evaluating the rectal dose. The powder was divided into small portions (34 mg) which were accommodated in a capillary tube. This tube was placed into a rectal probe that was introduced into the patient's rectum. Results: The doses delivered to the rectum of six patients submitted to high-dose-rate brachytherapy for uterine cervix cancer evaluated by means of thermoluminescent dosimeters presented a good agreement with the planned values based on two orthogonal (anteroposterior and lateral) radiographic images of the patients. Conclusion: The thermoluminescent dosimetric system developed in the present study is simple and easy to be utilized as compared to other rectal dosimetry methods. The system has shown to be effective in the evaluation of rectal doses in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. (author)

High dose therapy with autologous stem cell support in malignant disorders

International Nuclear Information System (INIS)

Holte, H.; Kvaloey, S.O.; Engan, T.

1996-01-01

New biomedical knowledge may improve the diagnostic procedures and treatment provided by the Health Services, but at additional cost. In a social democratic health care system, the hospital budgets have no room for expensive, new procedures or treatments, unless these are funded through extra allocation from the central authorities. High dose therapy with autologous stem cell support in malignant disorders is an example of a new and promising, but rather expensive treatment, but its role in cancer therapy has yet to be established. The indications for testing high dose therapy with autologous stem cell support in various malignancies are discussed, with emphasis on the principles for deciding which categories of disease should have priority. The authors suggest some malignant disorder for which high dose therapy with stem cell support should be explored versus conventional treatment in randomized prospective trials. 8 refs., 1 tab

High dose rate brachytherapy for oral cancer

International Nuclear Information System (INIS)

Yamazaki, Hideya; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Koizumi, Masahiko; Ogawa, Kazuhiko; Furukawa, Souhei

2013-01-01

Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer. (author)

The influence of bile salts on the distribution of simvastatin in the octanol/buffer system.

Science.gov (United States)

Đanić, Maja; Pavlović, Nebojša; Stanimirov, Bojan; Vukmirović, Saša; Nikolić, Katarina; Agbaba, Danica; Mikov, Momir

2016-01-01

Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability. LogD values of SVA and SVL with or without bile salts were measured by liquid-liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes. Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results. Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.

Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.