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Pradip Datta - One of the best experts on this subject based on the ideXlab platform.
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analytic performance evaluation of a new turbidimetric immunoassay for Phenytoin on the advia 1650 analyzer effect of Phenytoin metabolite and analogue
Therapeutic Drug Monitoring, 2005Co-Authors: Pradip Datta, Deven Scurlock, Amitava DasguptaAbstract:Phenytoin is an anticonvulsant that requires therapeutic drug monitoring. Recently, Bayer HealthCare, Diagnostics Division released a turbidimetric immunoassay of Phenytoin on the ADVIA 1650 analyzer. We evaluated the analytic performance of this assay by comparing values obtained in 52 patients receiving Phenytoin using this new assay with the values obtained by using a widely used fluorescence polarization immunoassay (FPIA). The new turbidimetric immunoassay for Phenytoin showed the following imprecision with the low, medium, and high controls: total CV of 5.2% (mean 4.81 microg/mL), 3.7% (mean 16.24 microg/mL), and 4.1% (mean 22.65 microg/mL), respectively. The detection limit of the assay was 0.79 microg/mL, and the assay was linear up to a Phenytoin concentration of 46.1 microg/mL. The assay showed excellent dilution recovery and recovery of spiked samples (mean recovery 101.4% and 94.4%, respectively). We observed an excellent correlation between the values obtained by the FPIA (x-axis) assay and the new turbidimetric (y-axis) assay (y=1.06 x-0.61, r=0.98, n=52). We also determined the cross-reactivity of 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), a major metabolite of Phenytoin, and of oxaprozine, an analogue with a similar chemical structure to Phenytoin, in both Phenytoin assays. Both assays showed almost no cross-reactivity to oxaprozine and only small (5%-8%) cross-reactivity to HPPH. We also found that the turbidimetric assay was free from interference at least up to 1200 mg/dL of hemolysis, 30 mg/dL of free bilirubin, 34.5 mg/dL of conjugated bilirubin, and 750 mg/dL of triglyceride (Intralipid). When a drug-free serum was followed by a serum sample containing 38.5 microg/mL of Phenytoin, no sample probe carryover effect was observed. We conclude that the new turbidimetric assay can be used for routine monitoring of Phenytoin in clinical laboratories.
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mathematical models to calculate fosPhenytoin concentrations in the presence of Phenytoin using Phenytoin immunoassays and alkaline phosphatase
American Journal of Clinical Pathology, 2000Co-Authors: Everly Carol Handy, Pradip DattaAbstract:Under certain circumstances, it is necessary to measure both fosPhenytoin and Phenytoin concentrations. We describe equations by which fosPhenytoin concentrations can be calculated accurately by using Phenytoin immunoassays. We supplemented aliquots of drug-free serum with fosPhenytoin and measured the Phenytoin equivalent concentrations (reading a) using fluorescence polarization immunoassay and a chemiluminescent assay. Then 10 µL of alkaline phosphatase (ALP) solution was added to the specimen, and after incubation for 5 minutes at room temperature, total Phenytoin concentration was measured (reading b). ALP completely converts fosPhenytoin to Phenytoin in 5 minutes. Therefore, the delta reading (b – a) represents increased observed value due to complete conversion of fosPhenytoin to Phenytoin for a particular fosPhenytoin concentration. By using the x-axis as the delta reading and the y-axis as the target fosPhenytoin concentrations, we observed equations that can be used to calculate the concentration of fosPhenytoin in the presence of Phenytoin. To test the validity of our equations, we prepared 2 serum pools from patients receiving Phenytoin and supplemented them with known concentrations of fosPhenytoin. Then initial (reading a) and final (after addition of ALP and incubation, reading b) concentrations were measured by immunoassay. We can accurately predict fosPhenytoin and Phenytoin concentrations from the delta reading. FosPhenytoin is a phosphate ester prodrug of Phenytoin intended for parenteral administration. The chemical name of fosPhenytoin is 5,5-diphenyl-3-[(phosphooxy)methyl]2,4-imidazolidinedione. FosPhenytoin was developed to overcome certain shortcomings associated with parenteral administration of Phenytoin. Because of poor solubility of Phenytoin sodium at the physiologic pH, intramuscular administration is extremely painful owing to crystallization of Phenytoin at the injection site. 1,2 Moreover, absorption of Phenytoin is slow and erratic. Intravenous administration can be irritating to the vein. 3-6 Rapid intravenous injection can
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use of alkaline phosphatase to correct the underestimation of fosPhenytoin concentration in serum measured by Phenytoin immunoassays
American Journal of Clinical Pathology, 1999Co-Authors: E F Warne, Pradip DattaAbstract:The pharmacologic activity of fosPhenytoin, a new phosphate ester pro-drug of Phenytoin, is due to in vivo conversion to Phenytoin. FosPhenytoin concentrations cannot be accurately estimated by Phenytoin immunoassays (fluorescence polarization and chemiluminescence) owing to the nonlinear relation between fosPhenytoin concentration and the observed cross-reactivity. The problem of slow conversion of fosPhenytoin to Phenytoin in serum in vitro can be circumvented by rapidly converting fosPhenytoin to Phenytoin in vitro by alkaline phosphatase. Drug-free serum, heparin, EDTA, or citrated plasma were supplemented with 2 concentrations of fosPhenytoin. Then to 1-mL aliquots of specimen, no enzyme (control), 10 microL, or 25 microL of enzyme solution was added. The specimens were incubated, and Phenytoin concentrations were measured by fluorescence polarization and chemiluminescent assays. In the absence of enzyme, we observed little conversion of fosPhenytoin to Phenytoin, but in the presence of only 10 microL of enzyme, the conversion of fosPhenytoin to Phenytoin was complete in 5 minutes. We also observed complete conversion of fosPhenytoin to Phenytoin by alkaline phosphatase in heparin, EDTA, and citrated plasma. If clinically indicated, the Phenytoin concentration can be measured before and after addition of enzyme to roughly estimate the rate of conversion.
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cross reactivity of fosPhenytoin in four Phenytoin immunoassays
Clinical Chemistry, 1998Co-Authors: Pradip DattaAbstract:FosPhenytoin, 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidine-dione disodium salt (Cerebyx®; ParkeDavis), is a phosphorylated form of the anticonvulsant drug Phenytoin. FosPhenytoin itself has no pharmacological activity but is dephosphorylated in vivo by phosphorylases to the active drug, Phenytoin. The elimination half-life of fosPhenytoin in plasma is 8–15 min in healthy subjects (1)(2). FosPhenytoin can be used for parenteral or intramuscular administration, where its superior aqueous solubility results in less severe side effects than does Phenytoin (2)(3). Few data, however, are available on the interference of fosPhenytoin in Phenytoin immunoassays, which are currently the most common method used to monitor patients’ Phenytoin concentrations. In an abstract (4), Kugler et al. reported that the TDx® Phenytoin assay (Abbott Labs.) was interfered with by fosPhenytoin. We report here the results of detailed cross-reactivity studies for fosPhenytoin in four Phenytoin im-munoassays: ACS:180® Automated Chemiluminescence System (Chiron Diagnostics), TDx Phenytoin and Phenytoin II, and AxSym® Phenytoin II …
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oxaprozin and 5 p hydroxyphenyl 5 phenylhydantoin interference in Phenytoin immunoassays
Clinical Chemistry, 1997Co-Authors: Pradip DattaAbstract:Rainey et al. (1) recently published their studies on metabolite and matrix interference in Abbott TDx® Phenytoin (TDx) and Phenytoin-II (TDxII) assays (Abbott Labs., Abbott Park, IL). They report that TDx Phenytoin, which uses a polyclonal antibody, demonstrates a substantial positive bias in patients with renal insufficiency because of the assay’s high (15.9%) cross-reactivity to the major metabolites of Phenytoin, 5-( p -hydroxyphenyl)-5-phenylhydantoin (HPPH) and its glucuronide ester (HPPG) (2). They also report that the TDxII assay, which uses a monoclonal antibody, has high (∼50%) cross-reactivity to a nonsteroidal anti-inflammatory drug, oxaprozin (Daypro®) (1). During a recent study, a patient taking oxaprozin demonstrated discrepancy between Phenytoin values by the TDxII, which gave the result in the toxic range, and that by Chiron Diagnostics’ …
Amitava Dasgupta - One of the best experts on this subject based on the ideXlab platform.
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validation of a free Phenytoin assay on cobas c501 analyzer using calibrators from cobas integra free Phenytoin assay by comparing its performance with fluorescence polarization immunoassay for free Phenytoin on the tdx analyzer
Journal of Clinical Laboratory Analysis, 2013Co-Authors: Amitava Dasgupta, Bonnette Davis, Loretta ChowAbstract:For many years, fluorescence polarization immunoassay (FPIA) on the TDx analyzer has been used for determination of free Phenytoin concentration. Recently Abbott Laboratories decided to discontinue the TDx analyzer and related assays on this analyzer. Free Phenytoin assay is also available from Roche Diagnostics for application on the Cobas Integra analyzer (fluorescence polarization assay) but not on Cobas c510 analyzer. Free Phenytoin calibrators from the Cobas Integra free Phenytoin assay and the reagents from the KIMSPhenytoin assay were used for the determination of free Phenytoin on the Cobas c501 analyzer. The intra-run and inter-run precisions were both <7.2%. The assay was linear from 0.2 to 4 μg/ml. The free Phenytoin assay on the Cobas c501 was compared with the FPIAassay on the TDx analyzer using sera from 25 patients receiving Phenytoin (Phenytoin concentration between 0.3 and 3.7 μg/ml). The following regression equation was observed: y = 0.9899 x + 0.0408 (r = 0.98, n = 25). In conclusion, the free Phenytoin assay on the Cobas c501 analyzer is a valid alternative to free Phenytoin assay on the TDx analyzer. J. Clin. Lab. Anal. 27:1–4, 2013. © 2012 Wiley Periodicals, Inc.
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analytic performance evaluation of a new turbidimetric immunoassay for Phenytoin on the advia 1650 analyzer effect of Phenytoin metabolite and analogue
Therapeutic Drug Monitoring, 2005Co-Authors: Pradip Datta, Deven Scurlock, Amitava DasguptaAbstract:Phenytoin is an anticonvulsant that requires therapeutic drug monitoring. Recently, Bayer HealthCare, Diagnostics Division released a turbidimetric immunoassay of Phenytoin on the ADVIA 1650 analyzer. We evaluated the analytic performance of this assay by comparing values obtained in 52 patients receiving Phenytoin using this new assay with the values obtained by using a widely used fluorescence polarization immunoassay (FPIA). The new turbidimetric immunoassay for Phenytoin showed the following imprecision with the low, medium, and high controls: total CV of 5.2% (mean 4.81 microg/mL), 3.7% (mean 16.24 microg/mL), and 4.1% (mean 22.65 microg/mL), respectively. The detection limit of the assay was 0.79 microg/mL, and the assay was linear up to a Phenytoin concentration of 46.1 microg/mL. The assay showed excellent dilution recovery and recovery of spiked samples (mean recovery 101.4% and 94.4%, respectively). We observed an excellent correlation between the values obtained by the FPIA (x-axis) assay and the new turbidimetric (y-axis) assay (y=1.06 x-0.61, r=0.98, n=52). We also determined the cross-reactivity of 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), a major metabolite of Phenytoin, and of oxaprozine, an analogue with a similar chemical structure to Phenytoin, in both Phenytoin assays. Both assays showed almost no cross-reactivity to oxaprozine and only small (5%-8%) cross-reactivity to HPPH. We also found that the turbidimetric assay was free from interference at least up to 1200 mg/dL of hemolysis, 30 mg/dL of free bilirubin, 34.5 mg/dL of conjugated bilirubin, and 750 mg/dL of triglyceride (Intralipid). When a drug-free serum was followed by a serum sample containing 38.5 microg/mL of Phenytoin, no sample probe carryover effect was observed. We conclude that the new turbidimetric assay can be used for routine monitoring of Phenytoin in clinical laboratories.
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unexpected suppression of free Phenytoin concentration by salicylate in uremic sera due to the presence of inhibitors maldi mass spectrometric determination of molecular weight range of inhibitors
Life Sciences, 1999Co-Authors: David A Biddle, Alice Wells, Amitava DasguptaAbstract:Abstract Salicylate displaces Phenytoin from protein binding leading to an increase in free Phenytoin concentration. We observed unexpected decreases in free Phenytoin concentration in the presence of salicylate. Serum pools containing no Phenytoin or salicylate were supplemented with the same concentrations of Phenytoin. Then to the aliquots of the individual pool, no salicylate (control), 150, 300 and 500 μg ml of salicylate (therapeutic range: 15–300 μg ml ) were added. Specimens were incubated at 37 °C for 2 h and after re-equilibration at room temperature for 20 min, total and free Phenytoin (in the protein free ultrafiltrates) concentrations were measured using fluorescence polarization immunoassay on the TDx/FLX analyzer. We observed an increase in free Phenytoin concentration from 1.91 μg ml (in the absence of salicylate) to 2.39 μg ml in the presence of 500 μg ml salicylate (total Phenytoin: 13.3 μg ml ) in the normal pool. In sharp contrast, the free Phenytoin concentrations decreased from an initial concentration of 3.82 μg ml to 2.52 μg ml in the presence of 500 μg ml of salicylate (total Phenytoin: 13.2 μg ml ) in the uremic pool. We also treated the uremic pool with activated charcoal. In the original uremic pool, the initial free Phenytoin concentration was 3.05 μg ml and the free concentrations then decreased to 2.28 μg ml in the presence of 300 μg ml of salicylate. In contrast, in the charcoal treated pool, the initial free Phenytoin concentration increased from 1.61 μg ml to 3.23 μg ml in the presence of 300 μg ml of salicylate. More interestingly when uremic toxins were extracted back from charcoal with methanol and the dry residue was added to an aliquot of normal serum, the normal serum behaved like a uremic serum and free Phenytoin concentration was significantly decreased in the presence of salicylate. When an aliquot of methanol extract was studied by Matrix-Assisted Laser Desorption lonization Mass Spectrometry (scan up to 10,000), we observed no peak at molecular weight over 551, indicating that these inhibitors are small molecules. We also identified hippuric acid as one of the inhibitors.
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in vitro displacement of Phenytoin from protein binding by nonsteroidal antiinflammatory drugs tolmetin ibuprofen and naproxen in normal and uremic sera
Therapeutic Drug Monitoring, 1996Co-Authors: Amitava Dasgupta, Timothy G TimmermanAbstract:Displacement of Phenytoin (90% bound to albumin) by other highly albumin-bound drugs like salicylate has been well documented. Other widely used nonsteroidal antiinflammatory drugs like tolmetin, ibuprofen, and naproxen are also strongly bound to albumin and can potentially displace Phenytoin. However, Phenytoin-ibuprofen interaction has been poorly studied in the past, and interaction of Phenytoin with tolmetin or naproxen has not been studied before. For normal serum pool (albumin 3.7 g/dl), we observed significant increases in free Phenytoin concentrations only with antiinflammatory drug concentrations at the upper end of therapeutic or above therapeutic concentrations. However, for the uremic pool (albumin 2.9 g/dl), displacement of Phenytoin was significant even at the lower end of therapeutic concentrations of those antiinflammatory drugs. Of the three antiinflammatory drugs we studied, ibuprofen caused the highest displacement of Phenytoin.
A R Kugle - One of the best experts on this subject based on the ideXlab platform.
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clinical experience with fosPhenytoin in adults pharmacokinetics safety and efficacy
Journal of Child Neurology, 1998Co-Authors: Lloyd E Knapp, A R KugleAbstract:FosPhenytoin, a prodrug of Phenytoin, is rapidly and completely converted to Phenytoin in adults after intravenous or intramuscular administration and is significantly better tolerated than parenteral Phenytoin. FosPhenytoin is highly plasma-protein bound and, when present in sufficient concentration, will displace Phenytoin from plasma proteins. The clinical utility is that fosPhenytoin may be used to achieve therapeutic Phenytoin concentrations more rapidly than intravenous Phenytoin infused at its maximum recommended rate. In a clinical study of generalized convulsive status epilepticus, fosPhenytoin, with or without benzodiazepine pretreatment, controlled seizures in 76 (93.8%) of 81 patients. In other studies, fosPhenytoin maintained seizure control when substituted for oral Phenytoin and for seizure prophylaxis in neurosurgery and trauma patients. Adverse events associated with fosPhenytoin generally were related to the central nervous system and were similar to those associated with Phenytoin, exce...
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cross reactivity of fosPhenytoin in two human plasma Phenytoin immunoassays
Clinical Chemistry, 1998Co-Authors: A R Kugle, Gerald D. Nordblom, Thomas M Annesley, Jeffrey R Koup, Stephe C OlsoAbstract:The cross-reactivity of fosPhenytoin, a phosphate ester prodrug of Phenytoin, was investigated in the Abbott Phenytoin TDx/TDxFLx fluorescence polarization immunoassay (TDx) and the Behring Diagnostics Phenytoin Emit 2000 enzyme-multiplied immunoassay (Emit). The first part of our study investigating cross-reactivity utilized in vitro correlation of the two immunoassays with a validated and specific Phenytoin HPLC method used to assay plasma samples prepared in several Phenytoin and fosPhenytoin concentration combinations. FosPhenytoin cross-reacted with both immunoassays, but to a greater extent with TDx. In the second part of the study, empirically-derived models that best explained the in vitro data were used to predict "immunoassay-derived" Phenytoin concentrations in plasma samples collected from actual patients after intravenous (i.v.) or intramuscular (i.m.) fosPhenytoin dosing. The greatest degree of Phenytoin concentration overestimation occurred at times when fosPhenytoin concentrations were highest: within 1 to 2 h after i.v. infusion or during the first 2 to 4 h after i.m. injection. It is recommended that Phenytoin concentrations not be monitored using these or other potentially nonspecific immunoanalytical methods for at least 2 h after i.v. fosPhenytoin infusion or 4 h after i.m. fosPhenytoin injection.
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safety and tolerance of multiple doses of intramuscular fosPhenytoin substituted for oral Phenytoin in epilepsy or neurosurgery
JAMA Neurology, 1996Co-Authors: J Wilde, K Campbell, R E Ramsay, William R Garne, John M Pellock, S A Henki, A R KugleAbstract:Background: Safety, tolerability, and pharmacokinetics of fosPhenytoin sodium, a water-soluble Phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosPhenytoin for oral Phenytoin sodium in 240 epileptic or neurosurgical patients taking oral Phenytoin sodium (100-500 mg/d). Methods: Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral Phenytoin at an individualized dose. During treatment, the Phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral Phenytoin; the fosPhenytoin-treated patients received oral placebo and intramuscular fosPhenytoin equimolar to their Phenytoin dose. Results: Both groups had similar types and frequencies of mild to moderate adverse events. FosPhenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosPhenytoin equimolar to a patient's oral Phenytoin dose produced equal or greater plasma Phenytoin concentrations. Conclusions: Dosing adjustments are not required when intramuscular fosPhenytoin is temporarily substituted or oral Phenytoin therapy is resumed. Intramuscular fosPhenytoin is a safe and well-tolerated alternative to oral Phenytoin when oral administration is not feasible.
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the safety tolerability and pharmacokinetics of fosPhenytoin after intramuscular and intravenous administration in neurosurgery patients
Pharmacotherapy, 1996Co-Authors: Adley A Ouche, Claudio Fele, Christine J Dea, David D Michie, Enjami K Tipto, Kenneth R Smith, Ronald E Krame, Yro Young, Uce R Parks, A R KugleAbstract:Study Objective. To evaluate the safety, tolerability, and pharmacokinetic profile of fosPhenytoin, a water-soluble Phenytoin prodrug, after intramuscular and intravenous administration. Design. Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. Setting. Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. Patients. Neurosurgical patients who required anticonvulsant prophylaxis or treatment. Interventions. In the intramuscular study, 118 patients received loading doses ranging from 480–1500 mg Phenytoin equivalents (PE) and daily maintenance doses ranging from 130–1250 mg PE for 3–14 days. In the intravenous study, 88 patients received fosPhenytoin and 28 received Phenytoin sodium for 3–14 days. Mean ± SD loading doses and maintenance doses of intravenous fosPhenytoin and Phenytoin were 1082 ± 299 mg PE and 411 ± 221 mg PE, and 1082 ± 299 mg and 422 ± 197 mg, respectively. Trough Phenytoin concentrations were measured daily in all patients. Measurements and Main Results. Intramuscular fosPhenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosPhenytoin group (6%) than in the Phenytoin group (25%, p<0.05). Reductions in infusion rates were required in 17% and 36% of fosPhenytoin and Phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma Phenytoin concentrations were approximately 10 μg/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosPhenytoin. Trough Phenytoin concentrations were similar between patients receiving intravenous Phenytoin and fosPhenytoin on all study days. Conclusion. FosPhenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic Phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosPhenytoin is significantly better tolerated than intravenous Phenytoin sodium in this patient subset.
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pharmacology and pharmacokinetics of fosPhenytoin
Neurology, 1996Co-Authors: Thomas R Owne, A R Kugle, Michael A EldoAbstract:FosPhenytoin sodium, a phosphate ester prodrug of Phenytoin, was developed as a replacement for parenteral Phenytoin sodium.Unlike Phenytoin, fosPhenytoin is freely soluble in aqueous solutions, including standard IV solutions, and is rapidly absorbed by the IM route. FosPhenytoin is metabolized (conversion half-life of 8 to 15 min) to Phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma Phenytoin concentrations are consistently attained after IM or IV administration of fosPhenytoin loading doses. FosPhenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after IM or IV administration than parenteral Phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosPhenytoin. NEUROLOGY 1996;46(Suppl 1): S3-S7
Kenji Onodera - One of the best experts on this subject based on the ideXlab platform.
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effects of Phenytoin and or vitamin k2 menatetrenone on bone mineral density in the tibiae of growing rats
Life Sciences, 2002Co-Authors: Kenji Onodera, Atsushi Takahashi, Shinobu SakuradaAbstract:In this study, we investigated 1) whether the administration of Phenytoin induced bone loss; and 2) whether menatetrenone could prevent bone loss induced by Phenytoin. For this purpose, we previously developed a procedure to measure the bone mineral density using a conventional X-ray absorptiometry method. A long-termed administration of Phenytoin (20 mg/kg per day for 5 weeks) produced bone loss in the tibiae of growing rats. The values of bone mineral density (BMD) were significantly decreased in the tibial diaphysis and metaphysis in the Phenytoin-treated group. In this period, we measured the serum level of vitamin K-dependent protein, osteocalcin, a marker of bone formation. The serum level of osteocalcin showed a decrease in the Phenytoin-treated group compared with the vehicle-treated group. Combined administration of menatetrenone (30 mg/kg in diet per day) with Phenytoin for 5 weeks prevented the reduction of BMD, and the level of osteocalcin was slightly increased. Thus, it is suggested that long-termed Phenytoin exposure may inhibit bone formation concomitantly with insufficient vitamin K, which, at least in part, contributed to bone loss in rats. Finally, these findings implicated the therapeutic usefulness of menatetrenone on a moderate degree of bone abnormality such as drug-induced osteopenia.
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Phenytoin induced bone loss and its prevention with alfacalcidol or calcitriol in growing rats
Calcified Tissue International, 2001Co-Authors: Kenji Onodera, Atsushi Takahashi, Hideaki Mayanagi, Hiroyuki Wakabayashi, Junzo Kamei, Hisashi ShinodaAbstract:Studies were carried out to determine the effects and mechanism of action of Phenytoin on the bone metabolism in male rats. Administration of Phenytoin, 20 mg/kg/ day for 5 weeks, did not affect the growth curve. Biochemical data indicated that the serum osteocalcin, a marker of bone formation, was decreased significantly but there were no significant differences in the levels of serum calcium, pyridinoline, 25-hydroxyvitamin D3 (25OHD) and parathyroid hormone (PTH) in the Phenytoin-treated group compared with the vehicle-treated group. The values of bone mineral density (BMD) were decreased in all regions of bones tested (mandibular head, tibial metaphysis, tibial diaphysis, femoral metaphysis, and femoral diaphysis) in the Phenytoin-treated group. In histomorphometric analysis, Phenytoin decreased trabecular bone volume and trabecular thickness, and increased osteoclast numbers per area of bone surface in the secondary trabecular bone of the tibia. Additionally, there was no significant difference in osteoid thickness. Combined administration of either alfacalcidol or calcitriol with Phenytoin for 5 weeks prevented the reduction of BMD induced by Phenytoin. From these findings, it is unlikely that toxic effects on the growth curve caused the decreased BMD induced by Phenytoin. It is also evident that repeated administration of Phenytoin may cause osteopenia which may be due to bone loss by inhibiting bone formation and/or by accelerating bone resorption rather than osteoid accumulation. The bone loss is not rachitic because of the lack of increase in osteoid thickness. Moreover, combined administration of alfacalcidol or calcitriol with Phenytoin showed a preventative effect against bone loss. The bone loss induced by Phenytoin in this study may be a convenient model for further research into the problem of drug-induced osteopenia.
Stephe C Olso - One of the best experts on this subject based on the ideXlab platform.
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Cross-reactivity of fosPhenytoin in two human plasma Phenytoin immunoassays
2015Co-Authors: Stephe C OlsoAbstract:The cross-reactivity of fosPhenytoin, a phosphate ester prodrug of Phenytoin, was investigated in the Abbott Phenytoin TDx®/TDxFLxTM fluorescence polarization immunoassay (TDx) and the Behring Diagnostics phe-nytoin Emit ® 2000 enzyme-multiplied immunoassay (Emit). The first part of our study investigating cross-reactivity utilized in vitro correlation of the two immu-noassays with a validated and specific Phenytoin HPLC method used to assay plasma samples prepared in several Phenytoin and fosPhenytoin concentration com-binations. FosPhenytoin cross-reacted with both immu-noassays, but to a greater extent with TDx. In the second part of the study, empirically-derived models that best explained the in vitro data were used to predict “immu-noassay-derived ” Phenytoin concentrations in plasm
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cross reactivity of fosPhenytoin in two human plasma Phenytoin immunoassays
Clinical Chemistry, 1998Co-Authors: A R Kugle, Gerald D. Nordblom, Thomas M Annesley, Jeffrey R Koup, Stephe C OlsoAbstract:The cross-reactivity of fosPhenytoin, a phosphate ester prodrug of Phenytoin, was investigated in the Abbott Phenytoin TDx/TDxFLx fluorescence polarization immunoassay (TDx) and the Behring Diagnostics Phenytoin Emit 2000 enzyme-multiplied immunoassay (Emit). The first part of our study investigating cross-reactivity utilized in vitro correlation of the two immunoassays with a validated and specific Phenytoin HPLC method used to assay plasma samples prepared in several Phenytoin and fosPhenytoin concentration combinations. FosPhenytoin cross-reacted with both immunoassays, but to a greater extent with TDx. In the second part of the study, empirically-derived models that best explained the in vitro data were used to predict "immunoassay-derived" Phenytoin concentrations in plasma samples collected from actual patients after intravenous (i.v.) or intramuscular (i.m.) fosPhenytoin dosing. The greatest degree of Phenytoin concentration overestimation occurred at times when fosPhenytoin concentrations were highest: within 1 to 2 h after i.v. infusion or during the first 2 to 4 h after i.m. injection. It is recommended that Phenytoin concentrations not be monitored using these or other potentially nonspecific immunoanalytical methods for at least 2 h after i.v. fosPhenytoin infusion or 4 h after i.m. fosPhenytoin injection.
