TDx System Research Articles

Therapeutic monitoring of anti-seizure medications in low- and middle-income countries: a systematic review

Background The treatment gap for epilepsy is large in low- and middle-income countries (LMICs) and the effectiveness and safety of the available anti-seizure medication (ASMs) is not fully understood. We systematically reviewed available evidence on therapeutic drug monitoring (TDM) of ASM in LMIC. Methods We searched four main databases (PubMed, Psych-Info, CINAHL and Embase) up to 31st December 2020, with eligible articles screened using a PRISMA checklist and a set of exclusion and inclusion criteria. Full texts were examined to evaluate the extent and practice of TDM in LMICs. Analyses were performed using Stata 13 and descriptive statistics were used to pool median distribution of TDM across studies. Results Of the 6,309 articles identified in the initial search, 65 (1.0%) met the eligibility criteria. TDM of ASMs was mostly done to assess toxicity (42.8%), but rarely to monitor adherence (9.0%). TDM differed by economic status and infrastructural status with majority of the studies coming from Europe (53.8%) and upper-middle-income countries (87.6%). First generation ASMs (82.3%) were more likely to be monitored than second generation ASMs (17.6%) and carbamazepine was the most frequently monitored drug. Fluorescence Polarization Immunoassay (FPIA) was the most common technique used for TDM (41.5%) followed by High-Performance Liquid Chromatography (HPLC) (16.9%). In addition, FPIA was the cheapest method of TDM based on approximated costs ($1000, TDx system). Assay validation and quality control were reported variably, and reference ranges used during TDM of ASMs were relatively uniform. Conclusions TDM is mostly done to evaluate ASM toxicity, but rarely for other reasons such as evaluating adherence or assessing clinical efficacy. There is a need for more investment in comprehensive and targeted TDM in LMICs when initiating treatment, switching therapies, adding or removing ASM and evaluating treatment response and safety of both first generation and second generation ASMs.

Difluorenoheteroles: topological control of π conjugation in diradicaloids and mixed-valence radical ions.

Two families of difluorenoheterole diradicaloids were synthesized, featuring isomeric ring systems with distinct conjugation topologies. The two types of difluorenoheteroles contain, respectively, a Chichibabin-like motif (CH) and a newly introduced heteroatom-linked triphenylmethyl dyad (TD-X). Combined experimental and theoretical investigations show that the TD-X systems have reduced quinoidal character but the interaction between formal spin centers is sufficiently strong to ensure a singlet ground state. The singlet-triplet energy gaps in the TD-X difluorenoheteroles are strongly affected by the heterocyclic ring, with values of -4.3 and -0.7 kcal mol-1 determined for the pyrrole- and thiophene-containing analogues, respectively. In cyclic voltammetry experiments, the TD-X systems show diminished energy gaps and superior reversibility in comparison with their CH counterparts. The radical anions and cations obtained from these diradicaloids show extremely red-shifted bands, occasionally with λ max > 3500 nm. Computational studies show that some of these ions adopt distonic structures and may be characterized as class-II mixed-valence species.

Therapeutic monitoring of anti-seizure medications in low- and middle-income countries: a systematic review

Background: The treatment gap for epilepsy is large in low- and middle-income countries (LMICs) and the effectiveness and safety of the available anti-seizure medication (ASMs) is not fully understood. We conducted a systematic review to evaluate the extent of therapeutic drug monitoring (TDM) of ASM in LMIC, including purposes and methods used during monitoring. Methods: A search was conducted on four main databases (PubMed, Psych-Info, CINAHL and Embase), with eligible articles screened using a PRISMA checklist and a set of exclusion and inclusion criteria. Full texts were examined to evaluate the extent and practice of TDM in LMICs. Descriptive statistics were used to pool median distribution of TDM across studies. Results: Of the 6,309 articles identified in the initial search, 65 (1.0%) met the eligibility criteria. TDM of ASMs was mostly done to assess toxicity (42.8%), but rarely to monitor adherence (9.0%). TDM differed by economic status and infrastructural status with majority of the studies coming from Europe (53.8%) and upper-middle-income countries (87.6%). First generation ASMs (82.3%) were more likely to be monitored than second generation ASMs (17.6%) and carbamazepine was the most frequently monitored drug. Fluorescence Polarization Immunoassay (FPIA) was the most common technique used for TDM (41.5%) followed by High-Performance Liquid Chromatography (HPLC) (16.9%). In addition, FPIA was the cheapest method of TDM based on approximated costs ($1000, TDx system). Assay validation and quality control were reported variably, and reference ranges used during TDM of ASMs were relatively uniform. Conclusions: TDM is mostly done to evaluate ASM toxicity, but rarely for other reasons such as evaluating adherence or assessing clinical efficacy. There is a need for more investment in comprehensive TDM in LMICs that incorporates dose titration of ASM using pharmacokinetics and pharmacodynamics modelling, for both first generation and second generation ASMs.

Developing the complex system in Korea: the case study of TDX and CDMA telecom system

This paper describes and analyses the successful development and commercialisation of Korean TDX telephone switching technologies and CDMA wireless systems, which were initiated as a national R&D project. We introduce the concept of Complex Product System (CoPS) to identify and describe (a) factors for the successful development of CoPS, such as TDX and CDMA, in Korea, (b) features specific to the development of CoPS in Newly Industrialised Economies (NIE) and finally (c) how the characteristics of Korean innovation system interact with the innovation system of telecommunication systems. We suggest that (1) the capabilities for integration of such agents as, public research institute, manufacturers and users play an important role in achieving successful commercialisation, (2) the development of CDMA systems was made possible by technological path dependency. Finally, we discuss the implications for NIEs that are involved in developing CoPS, pointing out the importance of project planning and managerial capability, coevolution of institutions and technology, as well as the interaction between large-scale and local R&D.

The co-evolution of technology and institution in the Korean information and communications industry

The Korean IT industry has shown distinct patterns in learning mechanisms and organisational configuration throughout its entry into advanced information technology. Innovation systems in the area of information technology have also evolved along with technological capability, thereby changing the focus of technological strategies and the role of public institutions. It is found that distinctive patterns of learning and diffusion mechanisms in the case of DRAMs, TDX, and CDMA systems represent successful catch-up situations in Korea as presented in this paper. This paper characterises the stylised facts of the Korean innovation system in the IT sector and traces how technology and institutions coevolved throughout the development process. The transition from technology-using to technology-generating is not an automatic process. Cumulative learning in both technology and organisation is a critical factor to upgrade technological capabilities. The main policy implication of the paper is that it is important to design the corresponding organisational and institutional arrangement in accordance with the changing need of technological upgrading.

Influence of testing system and sample diluents on cyclosporine analysis

目的 比较TDX系统与AXSYM系统检测环孢素的结果,评估不同样品稀释液对超过线性范围的标本进行稀释后对检测结果的影响.方法在TDX和AXSYM系统上检测100例不同浓度的临床标本,对比检测结果.用全血、蛋白磷酸缓冲液、自制样品稀释液和0点定标液对50例超过AXSYM线性范围的临床标本进行稀释,对比检测结果. 结果 TDX系统与AXSYM系统检测环孢素的结果相差显著,按不同浓度范围对两系统检测结果求出了换算公式.以全血、蛋白磷酸缓冲液作为样品稀释液和以0点定标液作为稀释液的标本检测结果有统计学意义,自制样品稀释液和0点定标液检测结果之间无统计学意义.结论 TDX与AXSYM系统检测环孢素结果间的换算公式有助于临床了解方法改变后检测结果的差异,自制样品稀释液可取代0点定标液用于样品稀释。

P-60: Thin-beam Directional X'tallization Method for SOP and OLED Application

We propose a Thin-beam Directional X' tallization (TDX) method, based on a high power, high repetition rate XeF excimer laser source and special optics, to produce a long, narrow (∼ 5 micron) beam with sharp edge slope. We present experimental results from a prototype TDX system that demonstrates very uniform directional laterally grown poly-Si films without any grain boundary protrusions.

Effect of vigabatrin on the pharmacokinetics of carbamazepine.

To evaluate a possible interaction between vigabatrin and carbamazepine in epileptic patients. Steady-state serum concentrations of carbamazepine with and without vigabatrin were compared. The study group consisted of 15 patients (eight females, seven males, and mean age 31 +/- 12 years), with refractory partial epilepsy. They received vigabatrin as add-on therapy. Patients received carbamazepine monotherapy for at least 6 months and the carbamazepine-vigabatrin combination for at least 3 months. Blood samples were obtained in the morning, before the first daily dose and the carbamazepine plasma concentrations were analysed by fluorescence polarization immunoassay (TDx System). No statistically significant differences were found in mean carbamazepine daily dose. Mean trough concentrations were 7.9 +/- 1.4 microg/mL with carbamazepine alone, and 6.5 +/- 2.0 microg/mL with carbamazepine-vigabatrin association (P < 0.03). The mean values of pharmacokinetic parameters were: level/dose ratio (L/D) = 0.59 +/- 0.20 vs. 0.45 +/- 0.15 (P < 0.05) and plasma clearance (Cl) = 78.5 +/- 25.8 vs. 105.8 +/- 38.9 mL/h/kg (P < 0.05), with carbamazepine alone and carbamazepine-vigabatrin combination, respectively. Vigabatrin produced a statistically significant increase in the plasma clearance of carbamazepine when the two drugs were given simultaneously.

Falsely low vancomycin results using the Abbott TDx.

Vancomycin is a glycopeptide antibiotic that is used to treat serious infections. When present in toxic concentrations, vancomycin can cause renal damage and hearing loss, 1 so therapeutic monitoring of the drug is advocated, particularly in the presence of renal impairment. Auores- cence polarization assay using the Abbott TDx (Abbott Laboratories, Abbott Park IL, USA) is still a common method of measuring vancomy- cin, although many laboratories have switched to an updated method employing a monoclonal antibody (Vancomycin II) on the Abbott AxSYM. In the process of making this change in our laboratory, we conducted comparison studies of vancomycin results from the two instruments and found marked discrepancies in plasma samples that had very high concentra- tions of conjugated bilirubin. We then carried out spiking experiments to determine which method was giving the incorrect results. METHODS AND RESULTS The Abbott TDx and AxSYM systems were used to measure vancomycin concentrations in 28 plasma samples obtained from patients with total bilirubin concentrations of less than

Vancomycin assay performance in patients with acute renal failure.

Fluorescence polarization immunoassays (FPIA) have been reported to overestimate vancomycin serum concentrations compared to high-performance liquid chromatography (HPLC) or enzyme multiplied immunoassay technique (EMIT) in patients with chronic renal disease. The assay manufacturer has modified the FPIA to remedy this overestimation. The purpose of this study was to compare the assay performance of two FPIAs to EMIT in acute renal failure patients receiving vancomycin and continuous venovenous hemofiltration. Open-label trial. Intensive care unit in a university affiliated hospital. 15 serum and ultrafiltrate samples were obtained from 14 critically ill patients (mean +/- SD; 57 +/- 12 years; 8 males/6 females). Vancomycin concentrations were determined by a polyclonal FPIA (pFPIA) performed on the TDx system, a monoclonal FPIA (mFPIA) performed on the AxSYM system and EMIT. The coefficient of variation for all assays was < 5%. The mean difference +/- SDd between mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: -0.08 +/- 1.55 and 1.24 +/- 2.11 mg/l, respectively. The limits of agreement between the mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: -3.18 to 3.03 and -2.99 to 5.46 mg/l, respectively. Our data demonstrate that the manufacturer's changes to the pFPIA have reduced overestimation. The mFPIA appears to be an acceptable assay for measuring vancomycin serum concentrations in acute renal failure patients and does not significantly overestimate these concentrations.

Difficulties in the assay of liposomal amikacin (MiKasome) in serum.

Antibiotic-free human serum was spiked with known concentrations of liposomal amikacin and assayed on the Abbott TDx System, using polarization fluoroimmuno assay (PFIA) kits from Abbott Laboratories, Oxis and Sigma. Although all three kits gave a linear response, the Abbott and Oxis kits showed very low recovery (<21%) with only the Sigma kit giving near 100% recovery. Heating samples at 56 degrees C for 30 min improved recovery with the Abbott and Oxis kits (75-80% of target value), but decreased recovery with the Sigma kit (85% of target value). The loss of amikacin from liposomal amikacin, as measured using the Sigma kit, was related to both temperature and duration of heating, reaching a maximal loss of 21% after 1 h at 60 degrees C.

Intraocular penetration of gentamicin after once-daily aminoglycoside dosing.

Intraocular concentrations-particularly intravitreal concentrations-after systemic administration of gentamicin are poor. Once-daily aminoglycoside dosing of intravenous gentamicin achieves peak serum levels up to five times higher than conventional dosing. Whether these increased serum levels of gentamicin improve the aqueous or vitreous concentrations in humans has not been determined. The authors sought to determine if the intraocular penetration of gentamicin would be improved using this method. Patients undergoing vitrectomy procedures were administered intravenous gentamicin in a dose of 7 mg/kg approximately 1 hour before surgery. An adjustment in dosing was made for anyone more than 20% over his or her ideal body weight. Aqueous, vitreous, and serum samples were collected before any intraocular surgical manipulation. The samples were analyzed by fluorescence polarization immunoassay (TDx system). The average single gentamicin dose was 498 mg (range, 360-700 mg). The aqueous, vitreous, and serum levels averaged 1.14 microg/mL, 0.41 microg/mL, and 22.07 microg/mL, respectively. No correlation between serum level concentrations and time of administration was found for the aqueous and vitreous levels in this study. Although the average peak serum level of gentamicin was five times higher than previously reported, the vitreous levels averaged only 1.5 times higher. The blood-retinal barrier is difficult to penetrate even when higher serum levels are achieved. Due to its poor ocular penetration, gentamicin may not be among the best drugs for prophylaxis of penetrating eye injuries, surgical prophylaxis, or treatment of endophthalmitis.

ＴＤＸシステムを用いた高齢者における内因性ジゴキシン様反応物質の測定

ＴＤＸシステムを用いた高齢者における内因性ジゴキシン様反応物質の測定

Use of the USDT flow immunosensor for quantitation of benzoylecgonine in urine

The flow immunosensor works on a principle somewhat distinct from other immunoassay systems in that it performs a displacement immunoassay. Antibody-coated matrices are saturated with fluorescently labeled benzoylecgonine (BE), which is released and measured in the presence of BE-containing urine and measured downstream from the matrix. The same antibody matrix can be used for many samples. A flow immunosensor instrument, built by US Drug Testing, Inc., has recently received ‘Premarket Notification’ (510(K)) from the Food and Drug Administration (FDA) to screen urine for the presence of the cocaine metabolite BE. The performance of the flow immunosensor for screening BE in urine was validated by comparison with results of a blind study using the Syva EMIT, the Abbott TDx and gas chromatography-mass spectroscopy (GC-MS). Potentially interfering drugs were also spiked into urine and evaluated using the flow immunosensor. While the FDA approval is for determining whether the BE concentration is above or below the 300 μg/l cutoff recommended by the National Institute of Drug Abuse, we have also shown that the flow immunosensor can be adapted to produce quantitative determinations of the amount of BE in the urine samples. The reliability of the quantitation was confirmed by testing 100 urine samples containing unknown amounts of BE using the flow immunosensor, GC-MS and the Abbott TDx system. Comparison of quantitative data obtained using the immunosensor and GC-MS showed a 97% correlation, compared with a much lower value for data from the TDx and GC-MS.

Cobas Integra: clinical laboratory instrument with continuous and random-access capabilities

The Cobas Integra from Roche Diagnostic Systems is a new clinical laboratory analyzer with continuous and random-access features for routine chemistries, specific proteins, electrolytes, hormones, therapeutic drugs, and drugs of abuse. The system maintains 68 test-specific reagent cassettes on board, along with multiple ion-selective electrodes (ISEs) for electrolyte determinations. This gives the Cobas Integra the capability of analyzing as many as 72 analytes without having to load additional reagents. We describe the basic analyzer configuration and the subsystems for absorbance, fluorescence polarization, and ISE measurements. Performance characteristics for precision, methods comparison, and on-board stability are given for assays representative of the various test groups. The 29 Cobas Integra tests evaluated in the present study show good agreement (r > or = 0.98 and slopes generally 0.90 to 1.12) with the respective methods available on either the Olympus AU5000, Hitachi 911 or 717, Behring BNA, or Abbott TDx systems. Total assay precision (CV) ranged from 0.8% to 8.5%, and calibration curves were stable for as long as 20 weeks. Test throughput, which is dependent on pipetting sequence, was determined to be up to 600 tests per hour without ISE and up to 750 tests per hour with ISE; the time to first result was 2.0-10.0 min.

Enzyme immunoassay, kinetic microparticle immunoassay, radioimmunoassay, and fluorescence polarization immunoassay compared for drugs-of-abuse screening

The newest formulation of the Syva EMIT assay for drugs of abuse, EMIT II, and a new immunoassay, OnLine (Roche), utilizing the kinetic interaction of microparticles in solution (KIMS) methodology, RIA tests, and TDx fluorescence polarization immunoassay (FPIA) procedures were compared for marijuana, cocaine, opiates, and barbiturates. Both EMIT II and OnLine immunoassays were performed with a Hitachi 717 analyzer. Calibration curves, the degree of separation between negative and cutoff calibrators, precision, likelihood of carryover from positive to negative samples, and overall ease and speed of analysis were evaluated. RIA and OnLine detected 99% of gas chromatography/mass spectrometry (GC/MS)-confirmed marijuana samples; TDx, 95%; and EMIT II, 88%. All four immunoassays detected approximately 99% of confirmed cocaine-positive urines. RIA, OnLine, and TDx all detected 100% of opiate-confirmed samples; EMIT II, 97%. Barbiturate assays exhibited the greatest disparity, with OnLine and TDx detecting 100% of confirmed positives; EMIT II, 88%; and RIA, 78%. For a variety of reasons, we prefer the fully automated EMIT II and OnLine assays for high-volume urine testing, in comparison with our laboratory's semiautomated RIA tests and the limited-throughput TDx system. The four immunoassays investigated delivered comparable performance in terms of detection rates for GC/MS-confirmed positives for some drugs but not for others.

Comparison of a RP-HPLC Method with the Therapeutic Drug Monitoring System TDxfor the Determination of Theophylline in Blood Serum

Abstract Blood serum samples of patients undergoing theophylline therapy were analysed in parallel with a new RP-HPLC method and the therapeutic drug monitoring TDx system. Both techniques are accurate, precise, technically easy, rapid, but the results taken by the TDx method are in all cases higher than HPLC. The mean increase is of about 56%.

Comparison of a mechanized version of the ‘König’ reaction and a fluorescence polarization immunoassay for the determination of nicotine metabolites in urine

Smoking can be detected by the determination of cotinine in urine. We compared the performance of an automated modification of the ‘König’ reaction adapted to a centrifugal analyzer with an automated commercial fluorescence polarization immunoassay (TDX system). In the latter assay, cotinine, as the primary metabolite of nicotine, can be measured with high specificity. In contrast, the ‘König’ reaction also detects nicotine metabolites other than cotinine by a group colour reaction. Analysis speed of the ‘König’ reaction was about 66 samples/h with a detection limit 2 S.D. above the mean value of urine samples of non-smokers. Analysis speed of the TDX system was 41 samples/h. The coefficient of variation (C.V.) of both methods in smokers' urine was 8.6% (‘König’ reaction) vs 3.4% (TDX system) in the high range and 16.4% vs 9.5% in the low range. In a controlled, prospective study recruiting 86 cigarette-smoking volunteers, 83.7% were correctly classified as being smokers by both systems, 13.9% were classified as smokers by the ‘König’ reaction only and 2.4% were misclassified as non-smokers by both systems. Thus, the sensitivity of the ‘König’ reaction seems to be higher than in the TDX system (97.6% vs. 83.7%). Of 33 non-smoking individuals, 81.8% were correctly classified as non-smokers by both system, 18.2 were misclassified as smokers by the ‘König’ reaction and no person was misclassified by the fluorescence polarization immunoassay. Thus, the specificity of the TDX system seems to be higher than that of the ‘König’ reaction (100% vs. 81.8%). We conclude that both systems are applicable to detect individuals who smoke regularly by simple urine testing. The higher specificity of the TDX system is outweighted by the sensitivy of the ‘König’ reaction at much lower cost.

Clinical Pharmacokinetics of Theophylline during Co-Treatment with Ticarcillin plus Clavulanic Acid in Patients Suffering from Acute Exacerbation of Chronic Bronchitis

The effect of ticarcillin/clavulanic acid, taken for 7 days as vials containing 1000 mg of ticarcillin and 200 mg of clavulanic acid twice daily intramuscularly, on the steady-state pharmacokinetics of theophylline was studied in 12 patients suffering from acute exacerbation of chronic obstructive pulmonary disease. Initially, patients were treated for four days with theophylline as sustained-release formulation in the amount of 600 mg daily; on the last day, blood samples were taken for theophylline determination. Theophylline concentrations were measured serially for 12 hours by the method of polarized immunofluorescence (Abbott TDx system). Subsequently, while theophylline was continued at the same dosage, each patient received in addition ticarcillin/clavulanic acid vials every 12 hours. After seven days of this combined medication, the serial assays of plasma were repeated at the same time intervals as before. No influence of ticarcillin/clavulanic acid was detectable on the steady-state theophylline pharmacokinetics. It is concluded that both drugs can be administered concomitantly without any dosage adjustment of theophylline.

Free Phenytoin Monitoring in Serum and Saliva of Epileptic Patients in China

Twenty-three serum samples and 13 saliva samples from 14 Chinese epileptic patients treated with phenytoin (DPH) were obtained to study the correlations between total, free serum, and saliva DPH concentrations. The binding of DPH to serum protein was assessed by equilibrium dialysis, and total and free DPH concentrations were analyzed with a domestic fluorescence polarization immunoassay reagent by the TDx system. A strong correlation existed between the total and free concentrations (r = 0.90, n = 20, p < 0.001). The mean value for the DPH free fraction was 11.13 +/- 3.65%. The mean value for the saliva fraction was 9.40 +/- 2.60%. This is the first attempt to monitor free DPH concentrations in serum in Chinese patients.