• Title/Summary/Keyword: Dose-Area Product

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Validation of LC-MS/MS Method for Determination of Rabeprazole in Human Plasma : Application of Pharmacokinetics Study (인체 혈장중 라베프라졸의 정량을 위한 LC-MS/MS 분석법 검증 및 단일 용량 투여에 의한 약물동태 연구)

  • Tak, Sung-Kwon;Seo, Ji-Hyung;Ryu, Ju-Hee;Choi, Sang-Joon;Lee, Myung-Jae;Kang, Jong-Min;Lee, Jin-Sung;Hong, Seung-Jae;Yim, Sung-Vin;Lee, Kyung-Tae
    • Journal of Pharmaceutical Investigation
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    • v.39 no.1
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    • pp.73-78
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    • 2009
  • A simple LC-MS/MS method of rabeprazole in human plasma was developed and validated. Rabeprazole and Internal standard (I.S), omeprazole, were extracted from human plasma by liquid liquid extraction, chromatographic separation of rabaprazole in plasma was achieved at $45^{\circ}C$ with a Shiseido UG120 $C_{18}$ column and methanol-10 mM ammonium acetate buffer (pH 9.42 with ammonium water), as mobile phase. Rabeprazole produced a protonated precursor ion [$(M+H)^+$] at m/z 360.10 and corresponding product ion at m/z 242.21. Internal standard produced a protonated precursor ion [$(M+H)^+$] at 346.09 and corresponding product ion at m/z 198.09. This method showed linear response over the concentration range of $1{\sim}500\;ng/mL$ with correalation coefficient greater than 0.99. The lower limit of quantitation (LLOQ) using 0.2 mL plasma was 1 ng/mL, which was sensitive enough for pharmacokinetics studies. The method was specific and validated with a limit of quantitation of 1 ng/mL. The intra-day and inter-day precision and accuracy were acceptable for all samples including the LLOQ. The applicability of the method was demonstrated by analysis of plasma after administration of a single 10 mg dose to 36 healthy subject. From the plasma rabeprazole concentration versus time curves, the mean $AUC_t$ (The area under the plasma concentration-time curve from time 0 to 12 hr ) was $691.36{\pm}321.88\;ng{\cdot}hr/mL$, $C_{max}$ (maximum plasma drug concentration) of $353.21{\pm}131.52\;ng/mL$ reached $3.4{\pm}1.1\;hr$ after adiministration. The mean biological half-life of rabeprazole was $1.37{\pm}0.75\;hr$. Based on the results, this simple method could readily be used in pharmacokinetics studies.

Bioequivalence Evaluation of Two Brands of Zolpidem Tartrate 10 mg Tablets(Zanilo and Stilnox) in Healthy Male Volunteers

  • Ryu, Ju-Hee;Lee, Heon-Woo;Lee, Hyun-Su;Kang, Il-Mo;Seo, Ji-Hyung;Kang, Jin-Yang;Lee, Kyung-Tae
    • Journal of Pharmaceutical Investigation
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    • v.36 no.5
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    • pp.343-348
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    • 2006
  • The purpose of the present study was to evaluate the bioequivalence of two zolpidem tartrate tablets, Stilnox tablet(Sanofi-aventis Korea, reference product) and Zanilo tablet(ChoDang Pharm Co., Ltd., Korea, test product), according to the guidelines of Korea Food and Drug Administration(KFDA). After adding an internal standard(cimetropium), 250 ${\mu}L$ plasma samples were extracted using 1.3 mL of ethyl acetate. Extracted compounds were analyzed by HPLC with triple-quadrupole mass spectrometry. This method for determination of zolpidem is proved accurate and reproducible with the limit of quantitation of 1 ng/mL in human plasma. Twenty-four healthy male Korean volunteers received each medicine at the zolpidem tartrate dose of 10 mg in a $2{\times}2$ crossover study. There was one-week washout period between the doses. Plasma concentrations of zolpidem were monitored for over a period of 8 hr after the administration. $AUC_{0-t}$(the area under the plasma concentration-time curve) was calculated by the linear trapezoidal rule. $C_{max}$(maximum plasma drug concentration) and $T_{max}$(time to reach $C_{max}$) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_{0-t}$ and $C_{max}$. No significant sequence effect was found for all of the bio-availability parameters indicating that the crossover design was properly performed. The 90% confidence intervals for the log transformed data were acceptable range of log 0.8 to log 1.25(e.g., log 0.92-log 1.06 for $AUC_{0-t}$, log 0.96-log 1.13 for $C_{max}$). The major parameters, $AUC_{0-t}$ and $C_{max}$ met the criteria of KFDA for bioequivalence indicating that Zanilo tablet is bioequivalent to Stilnox tablet.

Oral Bioavailability for Sub-micron Particle Curcumin (TheracurminCR-033P) and Absorption Rate by Product Composition in Healthy Human Volunteers (서브마이크론 입자 형태 커큐민의 생체 흡수율 및 제품 조성에 따른 흡수율 동등성 연구)

  • Park, Hee Jung;Takahashi, Tsukasa;Ozawa, Hitomi
    • Food Engineering Progress
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    • v.21 no.3
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    • pp.273-279
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    • 2017
  • Curcumin have various health-beneficial properties in numerous studies. However, its bioavailability is low due to its limited intestinal uptake and rapid metabolism. This study aimed to evaluate the pharmacokinetics of newly developed sub-micron particle curcumin with increased water dispersibility (Theracurmin(R) CR-033P). Plasma curcumin levels were measured at 0, 1, 2, 4, 8 h after Theracurmin(R) CR-033P intake using high-performance liquid chromatography. For analyzing pharmacokinetics of Theracurmin(R) CR-033P, eighteen healthy subjects were recruited and received Theracurmin(R) CR-033P at a single oral dose containing curcumin 30 mg. $C_{max}$ was 28.14 ng/ml, and the area under the curve for 8 h was estimated to be 104.36 ng/ml. Based on the area under the plasma concentration (AUC), the bioavailability of sub-micron particle curcumin was higher 22-, 35-, 28-fold than native curcumin in men, women, and all subjects, respectively. For comparing by formulation, seven healthy subjects were recruited and received two type of treatment: (1) existing dosage form 300 mg (contained curcumin 30 mg) ${\times}$ 3 capsule, (2) high dosage form 300 mg (contained curcumin 90 mg) ${\times}$ 1 capsule + placebo 300 mg ${\times}$ 2 capsule. In the cross-over study, there was no significant differences in $C_{max}$ and AUC of plasma curcumin. In conclusion, submicron particle curcumin with increased water dispersibility significantly improved its oral bioavailability and women absorbed curcumin more effectively than men. Different formulation of Theracurmin(R) CR-033P has shown equivalent to the reference in terms of pharmacokinetics.

Glass Dissolution Rates From MCC-1 and Flow-Through Tests

  • Jeong, Seung-Young
    • Proceedings of the Korean Radioactive Waste Society Conference
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    • 2004.06a
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    • pp.257-258
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    • 2004
  • The dose from radionuclides released from high-level radioactive waste (HLW) glasses as they corrode must be taken into account when assessing the performance of a disposal system. In the performance assessment (PA) calculations conducted for the proposed Yucca Mountain, Nevada, disposal system, the release of radionuclides is conservatively assumed to occur at the same rate the glass matrix dissolves. A simple model was developed to calculate the glass dissolution rate of HLW glasses in these PA calculations [1]. For the PA calculations that were conducted for Site Recommendation, it was necessary to identify ranges of parameter values that bounded the dissolution rates of the wide range of HLW glass compositions that will be disposed. The values and ranges of the model parameters for the pH and temperature dependencies were extracted from the results of SPFT, static leach tests, and Soxhlet tests available in the literature. Static leach tests were conducted with a range of glass compositions to measure values for the glass composition parameter. The glass dissolution rate depends on temperature, pH, and the compositions of the glass and solution, The dissolution rate is calculated using Eq. 1: $rate{\;}={\;}k_{o}10^{(ph){\eta})}{\cdot}e^{(-Ea/RT)}{\cdot}(1-Q/K){\;}+{\;}k_{long}$ where $k_{0},\;{\eta}$ and Eaare the parameters for glass composition, pH, $\eta$ and temperature dependence, respectively, and R is the gas constant. The term (1-Q/K) is the affinity term, where Q is the ion activity product of the solution and K is the pseudo-equilibrium constant for the glass. Values of the parameters $k_{0},\;{\eta}\;and\;E_{a}$ are the parameters for glass composition, pH, and temperature dependence, respectively, and R is the gas constant. The term (1-Q/C) is the affinity term, where Q is the ion activity product of the solution and K is the pseudo-equilibrium constant for the glass. Values of the parameters $k_0$, and Ea are determined under test conditions where the value of Q is maintained near zero, so that the value of the affinity term remains near 1. The dissolution rate under conditions in which the value of the affinity term is near 1 is referred to as the forward rate. This is the highest dissolution rate that can occur at a particular pH and temperature. The value of the parameter K is determined from experiments in which the value of the ion activity product approaches the value of K. This results in a decrease in the value of the affinity term and the dissolution rate. The highly dilute solutions required to measure the forward rate and extract values for $k_0$, $\eta$, and Ea can be maintained by conducting dynamic tests in which the test solution is removed from the reaction cell and replaced with fresh solution. In the single-pass flow-through (PFT) test method, this is done by continuously pumping the test solution through the reaction cell. Alternatively, static tests can be conducted with sufficient solution volume that the solution concentrations of dissolved glass components do not increase significantly during the test. Both the SPFT and static tests can ve conducted for a wide range of pH values and temperatures. Both static and SPFt tests have short-comings. the SPFT test requires analysis of several solutions (typically 6-10) at each of several flow rates to determine the glass dissolution rate at each pH and temperature. As will be shown, the rate measured in an SPFt test depends on the solution flow rate. The solutions in static tests will eventually become concentrated enough to affect the dissolution rate. In both the SPFt and static test methods. a compromise is required between the need to minimize the effects of dissolved components on the dissolution rate and the need to attain solution concentrations that are high enough to analyze. In the paper, we compare the results of static leach tests and SPFT tests conducted with simple 5-component glass to confirm the equivalence of SPFT tests and static tests conducted with pH buffer solutions. Tests were conducted over the range pH values that are most relevant for waste glass disssolution in a disposal system. The glass and temperature used in the tests were selected to allow direct comparison with SPFT tests conducted previously. The ability to measure parameter values with more than one test method and an understanding of how the rate measured in each test is affected by various test parameters provides added confidence to the measured values. The dissolution rate of a simple 5-component glass was measured at pH values of 6.2, 8.3, and 9.6 and $70^{\circ}C$ using static tests and single-pass flow-through (SPFT) tests. Similar rates were measured with the two methods. However, the measured rates are about 10X higher than the rates measured previously for a glass having the same composition using an SPFT test method. Differences are attributed to effects of the solution flow rate on the glass dissolution reate and how the specific surface area of crushed glass is estimated. This comparison indicates the need to standardize the SPFT test procedure.

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LOW PERMEABILITY THROUGH THE BLOOD-BRAIN BARRIER OF MORPHINE GLUCURONIDES.

  • Kang, Young-Sook;Ulrich Bickel;Oliver P. Schumacher;Karlheinz Voigt
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1996.04a
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    • pp.246-246
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    • 1996
  • The glucuronide conjugates of morphine have been claimed to exert significant neuropharmacological effects. Morphine-6-glucuronide (M6G) may be a potent opioid agonist in vivo, and morphine-3-glucuronide (M3G) may act as a weak opioid antagonist. The present study addressed the permeability of the blood-brain barrier (BBB) for these metabolites compared to morphine. Tracers were prepared by enzymatic glucuronidation of U-methyl-$^3$H]-morphine. Brain uptake in rats was measured by the internal carotid artery perfusion technique and after i.v. bolus injections. In the perfusion experiments morphine showed a permeability-surface area product (PS) of 3.52${\pm}$0.61 ${\mu}$L min$\^$-1/ g$\^$-1/ Uptake seems to be mediated by passive diffusion and was not saturable by 100 ${\mu}$M morphine in the perfusate. The BBB permeability of [$^3$H]-M3G and [$^3$H]-M6G was too low to be quantified after 5 min of perfusion. Brain uptake of [$^3$H]-M3G and [$^3$H]-M6G 60 min after i.v. bolus injection reached 0.0060${\pm}$0.0003 and 0.0030${\pm}$0.0005% injected dose per g, respectively. From these brain concentrations and from the corresponding plasma concentration - time curves, BBB PS values of 0.14${\pm}$ 0.02 ${\mu}$L min$\^$-1/g$\^$-1/ and 0.11 ${\pm}$ 0.01 ${\mu}$L min$\^$-1/g$\^$-1/, respectively, were calculated. The ratio of BBB PS values is complementary to the analgesic potencies of morphine and M6G after different routes of administration. The low PS of MSG explains, why it is approximate]y equipotent to morphine after systemic injection, although it is about 2 orders of magnitude more potent than morphine after administration directly into the central nervous system.

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Analysis of the ESD and DAP According to the Change of the Cine Imaging Condition of Coronary Angiography and Usefulness of SNR and CNR of the Images: Focusing on the Change of Tube Current (관상동맥 조영술(Coronary Angiography)의 씨네(cine) 촬영조건 변화에 따른 입사표면선량(ESD)과 흡수선량(DAP) 및 영상의 SNR·CNR 유용성 분석: 관전류 변화를 중점으로)

  • Seo, Young Hyun;Song, Jong Nam
    • Journal of the Korean Society of Radiology
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    • v.13 no.3
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    • pp.371-379
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    • 2019
  • The purpose of this study was to investigate the effect of the change in the X-ray condition on the entrance surface dose (ESD) and dose area product (DAP) in the cine imaging of coronary angiography (CAG), and to analyze the usefulness of the condition change on the dose relation and image quality by measuring and analyzing the Signal to Noise Radio (SNR) and Contrast to Nois Ratio (CNR) of the angiographic images taken by the Image J program. Data were collected from 33 patients (24 males and 9 females) who underwent CAG at this hospital from November 2017 to March 2018. In terms of imaging condition and data acquisition, the ESD and DAP of group A with a high tube current of 397.2 mA and group B with a low tube current of 370.7 mA were retrospectively obtained for comparison and analysis. For the SNR and CNR measurement and analysis via Image J, the result values were derived by substituting the obtained data into the formula. The correlations among ESD and DAP according to the change in the imaging condition, SNR, and CNR were analyzed by using the SPSS statistical analysis software. The relationships of groups A and B, having a difference in the imaging condition, mA, with ESD ($A:483.5{\pm}60.1$; $B: 464.4{\pm}39.9$) and DAP ($A:84.3{\pm}10.7$; $B:81.5{\pm}7$) were not statistically significant (p>0.05). In the relationships with SNR and CNR based on Image J, the SNR ($5.451{\pm}0.529$) and CNR ($0.411{\pm}0.0432$) of the images obtained via the left coronary artery (LCA) imaging of group B showed differences of $0.475{\pm}0.096$ and $-0.048{\pm}0.0$, respectively, from the SNR ($4.976{\pm}0.433$) and CNR ($0.459{\pm}0.0431$) of the LCA of group A. However, the differences were not statistically significant (p<0.05). In the SNR and CNR obtained via the right coronary artery (RCA) imaging, the SNR ($4.731{\pm}0.773$) and CNR ($0.354{\pm}0.083$) of group A showed increased values of $1.491{\pm}0.405$ and $0.188{\pm}0.005$, respectively, from the SNR ($3.24{\pm}0.368$) and CNR ($0.166{\pm}0.033$) of group B. Among these, CNR was statistically significant (p<0.05). In the correlation analysis, statistically significant results were shown in SNR (LCA) and CNR (LCA); SNR (RCA) and CNR (RCA); ESD and DAP; ESD and sec; DAP and CNR (RCA); and DAP and sec (p<0.05). As a result of the analyses on the image quality evaluation and usefulness of the dose change, the SNR and CNR were increased in the RCA images of the CAG obtained by increasing the mA. Based on the result that CNR showed a statistically significant difference, it is believed that the contrast in the image quality can be further improved by increasing the mA in RCA imaging.

Comparison of Enalapril Maleate Tablets on Bioavailability and the Time Course of Inhibition of Plasma Angiotensin-Converting Enzyme (Enalapril Maleate 정제의 동등성에 관한 연구 ; 약동학적 성상 및 혈장 ACE 활성도 억제 효과)

  • Jang, In-Jin;Jang, Byung-Soo;Shin, Sang-Goo;Shin, Jae-Gook;Rho, Il-Kun;Lee, Kyeong-Hun;Park, Chan-Woong
    • The Korean Journal of Pharmacology
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    • v.26 no.2
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    • pp.219-226
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    • 1990
  • Enalapril maleate tablets of two different producers were tested for bioequivalence. Enalapril is rapidly metabolized to an active metabolite, enalaprilat which inhibits angiotensin-converting enzyme (ACE). The pharmacokinetics of enalapril maleate and the time course of inhibition of plasma ACE activity after administration of the drugs were studied. Two single doses of 10mg each of enalapril maleate were administered orally to twelve male volunteers in a balanced, randomized, two-way crossover investigation. Plasma enalaprilat concentrations were determined over a 23-hour after the dose by enzyme inhibition assay and enalapril by the same method following in vitro hydrolysis. Urinary recoveries of enalapril and enalaprilat were determined for the calculation of renal clearance. Plasma ACE activity was determined by an enzyme assay. Peak plasma levels of enalapril were observed about 1 hour after the doses, and practically all enalapril had disappeared from plasma within 6 hour. Peak enalapril concentrations of both formulations were almost identical ($Vasotec^{\circledR}$, 61.38 ng/ml; $Beartec^{\circledR}$, 64.27 ng/ml). The values of the pharmacokinetic parameters of enalaprilat computed for $Vasotec^{\circledR}$ and $Beartec^{\circledR}$ tablets are presented in that order; area under the curve=330.63:320.96 $ng{\cdot}hr/ml$; peak concentration=38.63:39.43 ng/ml; time to peak=3.83:4.08 hour; elimination half-life=3.95:3.92 hours. No statistically significant difference was detected when area under the curve and all other parameters were compared. Using criteria of 95% confidence interval for the comparison of these parameters, only the upper limits of area under the curve and time to peak of enalapril were over 120%. All the parameters of enalaprilat were acceptable. Percent inhibition of plasma ACE to plasma enalaprilat concentration showed the sigmoid concentration-inhibition relationship. Time courses of plasma ACE inhibition after the administration of both formulations were quite similar. The formulations were found to be equivalent when compared on the premise that no significant difference was detected when pharmacokientic parameters and inhibition of ACE activity were compared, based on the confidence limits analysis.

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Distribution of Mast cells and Nerves in the Developing Postnatal Submandibular and Sublingual Glands of Rats (생후 발생중인 흰쥐의 턱밑샘 및 혀밑샘에서의 비만세포와 신경의 분포양상)

  • Kim, Jae-Gon;An, Soo-Hyeon;Lee, Young-Su;Baik, Byeong-Ju;Cho, Eui-Sic
    • Journal of the korean academy of Pediatric Dentistry
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    • v.26 no.2
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    • pp.350-364
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    • 1999
  • The distribution of mast cells and nerves were investigated in the submandibular and sublingual glands of postnatal rats, using morphometric, histochemical and immunohistochemical techniques. Mast cells were observed in the submandibular and sublingual glands of postnatal development. Number of mast cells gradually increased in both glands following development. At birth, mast cells were relatively fewer in submandibular gland than those in sublingual gland, and they were mainly distributed in parenchymal tissues. At $2{\sim}4$ weeks, most of the mast cells were observed in the connective tissues, surrounding neurovascular elements, but some mast cells were closely related with the acini of submandibular gland. PGP 9.5 immunoreactive nerve fibers were found in the submandibular and sublingual glands of all developmental age. The nerve fibers were showed in varicose shape, and mainly located in adjacent area of ducts and vascular components of both glands. The number of nerve fibers were increased rapidly until 8 weeks, but they were not increased any more until 24 weeks. Therefore, it is suggested that mast cells and nerve fibers related with each other, and that their interactions may play roles not only in maturation of secretory units but also growth and differentiation of the tubular structures of the rat submandibular and sublingual glands during postnatal development.

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VCUG Studies on the Clinical Usefulness of Aids (VCUG 보조기구의 임상적 유용성에 관한 고찰)

  • Choe, Dea yeon;Kim, Dong hyun
    • Journal of the Korean Society of Radiology
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    • v.9 no.7
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    • pp.529-533
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    • 2015
  • VCUG(Voiding Cystourethrography) study is being performed to check urinary reflex symptom from bladder to ureter or kidney in the method of filling the bladder with radiation opaque contrast agent. However, VCUG study have been performed impersonally, patients have to be naked and open their legs and then void. This method is so impersonal that it is immediately needed to improve the way of testing and crete new aid. Therefore, this study through producing underwear for VCUG, analysis and compares the test time of VCUG, patient radiation dose and patient satisfaction. The target of this study was 79 Male and Female patients who visited genitourinary clinic of PNUYH for their VCUG tests AXIUM Iconos R200(Siemens Medical System : Germany) and self-produced plastic underwears made by vinyl and plasic molding machine were used. The 79 patient were divided into two groups : experiment of patient and comparison group of we patient (using aid) in order to compare, testing time, DAP (dose area product) and patient satisfaction. There was time reduction, from 35.3min of comparison group to 27.8min experimentation group by 7.5min decrease. And comparison group of $4566.6{\mu}Gym^2$(DAP) decreased experimental group (using aid) of $3411.9{\mu}Gym^2$ by $1154.7{\mu}Gym^2$. In the case of patients satisfaction study, anxiety had a drop by 3.45 of comparison group to 2.51 experimentation group by 0.94 decrease. in experimental group. And shame had a drop by 4.02 of comparison group to 3.08 experimentation group by 0.94 increase. in experimental group. Difference of the smooth voiding had a drop by 1.90 of comparison group to 2.84 experimentation group by 0.94 increase. in experimental group. In addition satisfaction had a rise by 1.19 in experimental group. There were also other opinions of uncomfortableness on it and troublesome to wear. VCUG is one of the sensitive care required test. Therefore staff and the aid can give patients such comfortable and the aid can consentive on voiding. As a result test time and DAP can be reduced. It is needed to make testing at more comfortable for patients.

Relation between Ablation Execution Time and Radiation Exposure Effect in the Treatment of Atrial-fibrillation using Cryo-balloon and 3D Radio-frequency Ablation (냉각 풍선 절제술과 3D 고주파 절제술을 이용한 심방세동 치료 시 절제술 시행 시간과 방사선 피폭 영향과의 연관성)

  • Seo, Young-Hyun
    • Journal of the Korean Society of Radiology
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    • v.16 no.4
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    • pp.427-434
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    • 2022
  • Atrial fibrillation treatment includes 3D RFCA and Cryo-balloon ablation. Both procedures have in common that they enter after understanding the structure of the heart using angiography equipment. Therefore, there is a disadvantage that the effect of exposure according to the procedure time can be a threat to both the patient and the operator, so this study aims to confirm the relationship between the total ablation time and the effect of radiation exposure. We used follow-up data (retrospective) from 41 patients who underwent coronary angiography and arrhythmia at the same time from March 2019 to July 2022. The range for total ablation time was based on the recorded data from the start to the end of the total ablation. The end point of 3D RFCA was when the ablation was completed for 4 pulmonary veins, and in the case of Cryo-balloon ablation, the data that succeeded in electrical insulation were included. As a result of analyzing the total ablation time, the time taken for Cryo-balloon ablation was 1037.29±103.66 s, which was 2448.61 s faster than 3D RFCA using 3485.9±405.71 s, and was statistically significant. (p<0.05) As a result of analyzing the total fluoroscopy time, the exposure time for 3D RFCA was 2573.75±239.08 s, which was less by 1717.15 s than the exposure time for Cryo-balloon ablation, 4290.9±420.42 s, and was statistically significant. In the case of total area dose product, 3D RFCA was 59.04±13.1 uGy/m2, which was lower than Cryo-balloon ablation 980.6±658.07 uGy/m2 by 921.56 uGy/m2, which was statistically significant. As the insulation time of the Cryo-balloon ablation is shorter than that of the 3D RFCA, the method using the Cryo-balloon ablation is considered to be effective when the patient's condition is not good and a quick procedure is required. However, in patients with permanent Atrial fibrillation, there is a high probability of structural changes in the heart, so it is considered that 3D RFCA is better than Cryo-balloon ablation, which is difficult to manipulate.