Population Pharmacokinetics of Topiramate in Patients with Epilepsy Using Nonparametric Modeling.

BACKGROUND: Topiramate (TPM) is used for the treatment of various epileptic seizures and the prevention of migraine. This study aimed to develop a population pharmacokinetic model and identify covariates that influence TPM behavior in patients with epilepsy in Kuwait. METHODS: Data were collected retrospectively from 108 patients (2 years old and above) with epilepsy who were treated with oral TPM and 174 TPM blood samples from 3 hospitals in Kuwait from 2009 to 2016. Data were randomly divided into 2 groups for model development and validation. The population pharmacokinetic model was built using the nonparametric modeling algorithm (Pmetrics). The model was evaluated internally through the visual predictive check method and externally using a new data set. RESULTS: A 1-compartment model with first-order elimination fitted the data well. Covariates showing a significant effect on the elimination rate constant were renal function and coadministration of carbamazepine (CBZ). The mean estimated clearance was 2.11 L/h; this was 50% higher for patients coadministered with CBZ. Age and sex were essential covariates for the volume of distribution (V). The visual predictive check of the final model could predict the measured concentrations. External validation further confirmed the favorable predictive performance of the model with low bias and imprecision for predicting the concentration in a particular population. CONCLUSIONS: TPM elimination was increased with CBZ coadministration and was affected by renal function. Meanwhile, age and sex were the main predictors for V. The predictive performance of the final model proved to be valid internally and externally.

Simulations of topiramate dosage recommendations for poor compliance events.

PURPOSE: To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes using Monte Carlo simulations. METHODS: Monte Carlo simulations were performed for various replacement dosing schemes using the parameters from the published population pharmacokinetic models. The lowest percentage of deviation of simulated concentrations outside the reference range of 5-20 mg/L from the compliance scenario for each replacement dosing scheme was used as a criterion for choosing the proper replacement dosing scheme. RESULTS: For the one missed dose, the replacement with an immediate regular dose and a partial dose resulted in the lowest and highest percentages of concentration below 5 mg/L, respectively. While the opposite results were observed for the upper bound of the reference range (20 mg/L). For the two consecutive missed doses, the replacement with one and a half-missed doses resulted in a lower percentage of deviation of concentrations below 5 mg/L from the compliance scenario than the replacement with one regular dose. CONCLUSIONS: For the one missed dose, taking an immediate regular dose might be suitable for patients who require higher TPM levels, while for patients who require lower TPM levels, an immediate partial dose could be used. For the two consecutive missed doses, an immediate one and a half regular dose might be suitable. However, these results were merely based on simulations; thus, they should be used alongside the clinician's justification based on seizure control.

Development and validation of a UPLC-MS/MS method to quantify fructose in serum and urine.

BACKGROUND: The study of the involvement of fructose in the pathogenesis of cardiometabolic disease requires accurate and precise measurements of serum and urinary fructose. The aim of the present study was to develop and validate such a method by Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS). METHODS: Fructose was quantified using hydrophilic interaction UPLC-MS/MS with a labelled internal standard. Serum fructose levels were determined in healthy individuals (n = 3) after a 15-gram oral fructose load. Twenty-four hours urinary fructose levels were determined in individuals consuming low (median: 1.4 g/day, interquartile range [IQR]: 0.9-2.0; n = 10), normal (31 g/day, 23-49; n = 15) and high (70 g/day, 55-84; n = 16) amounts of fructose. RESULTS: The calibration curves showed perfect linearity in water, artificial, serum, and urine matrices (r2 > 0.99). Intra- and inter-day assay variation of serum and urinary fructose ranged from 0.3 to 5.1% with an accuracy of ~98%. Fasting serum fructose levels (5.7 ± 0.6 µmol/L) increased 60 min after a 15-gram oral fructose load (to 150.3 ± 41.7 µmol/L) and returned to normal after 180 min (8.4 ± 0.6 µmol/L). Twenty-four hours urinary fructose levels were significantly lower in low fructose consumers when compared to normal and high fructose consumers (median: 36.1 µmol/24 h, IQR: 26.4-64.2; 142.3 µmol/24 h, 98.8-203.0; and 238.9 µmol/24 h, 127.1-366.1; p = 0.004 and p < 0.001, respectively). CONCLUSION: Fructose concentrations can be measured accurately and precisely with this newly-developed UPLC-MS/MS method. Its robustness makes it suitable for assessing the value of fructose in clinical studies.

Short-term High Fructose Intake Reprograms the Transcriptional Clock Rhythm of the Murine Extraorbital Lacrimal Gland.

Purpose: To determine whether high fructose intake (HFI) influences the daily transcriptional clock rhythms of murine extraorbital lacrimal glands (ELGs). Methods: Timed ELGs were collected from two groups of C57BL/6J mice subjected to a 12-hour light/12-hour dark (LD) cycle for 10 days; the first group received water-only feeding and the second received water with 15% fructose. Total RNA was extracted and subjected to RNA sequencing. A JTK_CYCLE algorithm and computational software were used to determine the periodicity, rhythmicity, and amplitude of the cycling transcripts. The rhythmic transcripts from different conditions were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: HFI feeding caused massive remodeling of the preexisting rhythmic genes in the normal control (NC)-fed ELGs. The induced transcripts in HFI-fed mice resulted in a profound reorganization of the coordinated transcriptional oscillations and KEGG pathways. Moreover, HFI feeding significantly altered the distribution of the KEGG pathways over an LD in the ELGs. Finally, we found that the ELGs have a robust core clock machinery and HFI feeding altered amplitude and the peak phase of clock gene transcriptional oscillation in ELGs. Conclusions: Short-term HFI reprograms the daily transcriptomic oscillation of murine ELGs. This information may deepen our understanding of the outcomes of lacrimal glands altered by nutritional challenge.

Effects of fructose-containing sweeteners on fructose intestinal, hepatic, and oral bioavailability in dual-catheterized rats.

OBJECTIVE: Fructose is commonplace in Western diets and is consumed primarily through added sugars as sucrose or high fructose corn syrup. High consumption of fructose has been linked to the development of metabolic disorders, such as cardiovascular diseases. The majority of the harmful effects of fructose can be traced to its uncontrolled and rapid metabolism, primarily within the liver. It has been speculated that the formulation of fructose-containing sweeteners can have varying impacts on its adverse effects. Unfortunately, there is limited data supporting this hypothesis. The objective of this study was to examine the impact of different fructose-containing sweeteners on the intestinal, hepatic, and oral bioavailability of fructose. METHODS: Portal and femoral vein catheters were surgically implanted in male Wistar rats. Animals were gavaged with a 1 g/kg carbohydrate solution consisting of fructose, 45% glucose/55% fructose, sucrose, glucose, or water. Blood samples were then collected from the portal and systemic circulation. Fructose levels were measured and pharmacokinetic parameters were calculated. RESULTS: Compared to animals that were gavaged with 45% glucose/55% fructose or sucrose, fructose-gavaged animals had a 40% greater fructose area under the curve and a 15% greater change in maximum fructose concentration in the portal circulation. In the systemic circulation of fructose-gavaged animals, the fructose area under the curve was 17% and 24% higher and the change in the maximum fructose concentration was 15% and 30% higher than the animals that received 45% glucose/55% fructose or sucrose, respectively. After the oral administration of fructose, 45% glucose/55% fructose, and sucrose, the bioavailability of fructose was as follows: intestinal availability was 0.62, 0.53 and 0.57; hepatic availability was 0.33, 0.45 and 0.45; and oral bioavailability was 0.19, 0.23 and 0.24, respectively. CONCLUSIONS: Our studies show that the co-ingestion of glucose did not enhance fructose absorption, rather, it decreased fructose metabolism in the liver. The intestinal, hepatic, and oral bioavailability of fructose was similar between 45% glucose/55% fructose and sucrose.

Copper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.

High-Fructose Corn-Syrup-Sweetened Beverage Intake Increases 5-Hour Breast Milk Fructose Concentrations in Lactating Women.

This study determined the effects of consuming a high-fructose corn syrup (HFCS)-sweetened beverage on breast milk fructose, glucose, and lactose concentrations in lactating women. At six weeks postpartum, lactating mothers (n = 41) were randomized to a crossover study to consume a commercially available HFCS-sweetened beverage or artificially sweetened control beverage. At each session, mothers pumped a complete breast milk expression every hour for six consecutive hours. The baseline fasting concentrations of breast milk fructose, glucose, and lactose were 5.0 ± 1.3 µg/mL, 0.6 ± 0.3 mg/mL, and 6.8 ± 1.6 g/dL, respectively. The changes over time in breast milk sugars were significant only for fructose (treatment × time, p < 0.01). Post hoc comparisons showed the HFCS-sweetened beverage vs. control beverage increased breast milk fructose at 120 min (8.8 ± 2.1 vs. 5.3 ± 1.9 µg/mL), 180 min (9.4 ± 1.9 vs. 5.2 ± 2.2 µg/mL), 240 min (7.8 ± 1.7 vs. 5.1 ± 1.9 µg/mL), and 300 min (6.9 ± 1.4 vs. 4.9 ± 1.9 µg/mL) (all p < 0.05). The mean incremental area under the curve for breast milk fructose was also different between treatments (14.7 ± 1.2 vs. -2.60 ± 1.2 µg/mL × 360 min, p < 0.01). There was no treatment × time interaction for breast milk glucose or lactose. Our data suggest that the consumption of an HFCS-sweetened beverage increased breast milk fructose concentrations, which remained elevated up to five hours post-consumption.

Influence of Renal Function on Pharmacokinetics of Antiepileptic Drugs Metabolized by CYP3A4 in a Patient With Renal Impairment.

BACKGROUND: Several studies have demonstrated that renal impairment not only decreases renal clearance but also hepatic clearance of medications that are CYP3A4 substrates. We evaluated the influence of renal function on the pharmacokinetics of antiepileptic drugs metabolized by CYP3A4. METHODS: We retrospectively calculated the concentration/dose ratio (CD ratio) for topiramate and clobazam in an epilepsy patient with renal impairment. In addition, we determined the CD ratio of perampanel in 17 patients with normal renal function and compared it with that in the patient with renal impairment. RESULTS: A patient with frontal lobe epilepsy and mild renal impairment [creatinine clearance (CCr): 67.7 mL/min] was taking phenytoin and 3 CYP3A4 substrates (topiramate, clobazam, and perampanel). With progression of renal impairment (CCr: 28.1 mL/min), the CD ratios of topiramate and clobazam increased by about 2-fold. The mean CD ratio of perampanel was 1740 ± 966 ng·mL·mg·kg in the 17 patients with normal renal function using phenytoin. By contrast, the CD ratio of perampanel was markedly higher (range: 5327-9113 ng·mL·mg·kg) in the patient with renal impairment (CCr: <20 mL/min). CONCLUSIONS: These findings suggest that dose adjustment based on therapeutic drug monitoring is probably necessary when topiramate, clobazam, or perampanel is prescribed for patients with moderate-to-severe renal impairment.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Insights into the Hexose Liver Metabolism-Glucose versus Fructose.

High-fructose intake in healthy men is associated with characteristics of metabolic syndrome. Extensive knowledge exists about the differences between hepatic fructose and glucose metabolism and fructose-specific mechanisms favoring the development of metabolic disturbances. Nevertheless, the causal relationship between fructose consumption and metabolic alterations is still debated. Multiple effects of fructose on hepatic metabolism are attributed to the fact that the liver represents the major sink of fructose. Fructose, as a lipogenic substrate and potent inducer of lipogenic enzyme expression, enhances fatty acid synthesis. Consequently, increased hepatic diacylglycerols (DAG) are thought to directly interfere with insulin signaling. However, independently of this effect, fructose may also counteract insulin-mediated effects on liver metabolism by a range of mechanisms. It may drive gluconeogenesis not only as a gluconeogenic substrate, but also as a potent inducer of carbohydrate responsive element binding protein (ChREBP), which induces the expression of lipogenic enzymes as well as gluconeogenic enzymes. It remains a challenge to determine the relative contributions of the impact of fructose on hepatic transcriptome, proteome and allosterome changes and consequently on the regulation of plasma glucose metabolism/homeostasis. Mathematical models exist modeling hepatic glucose metabolism. Future models should not only consider the hepatic adjustments of enzyme abundances and activities in response to changing plasma glucose and insulin/glucagon concentrations, but also to varying fructose concentrations for defining the role of fructose in the hepatic control of plasma glucose homeostasis.

Chromatographic determination of zonisamide, topiramate and sulpiride in plasma by a fluorescent 'turn-on' chemosensor.

AIM: Antiepileptics (AEDs) and antipsychotics are often coprescribed. Interactions between these drugs may affect both efficacy and toxicity. Therefore, drug monitoring is necessary for appropriate dosage adjustments. MATERIALS & METHODS: Specific 'turn-on' chemosensor, 4-chloro-7-nitrobenzofurazan is used for selective and sensitive determination of two AEDs: zonisamide (ZON) and topiramate (TOP) with the antipsychotic sulpiride (SUL) in epileptic patients' plasma followed by reversed-phase-HPLC separation without any interference. RESULTS: Linear behavior was observed in the range of 0.1-3 µg/ml and 0.01-0.5 µg/ml for the AEDs and SUL, respectively, with LOD of 33, 46 and 4 ng/ml and LOQ of 86, 93 and 9 ng/ml for ZON, TOP and SUL, respectively. The proposed method was successfully applied for determination of different pharmacokinetic parameters of ZON and TOP, and for clinical monitoring of the three drugs in healthy volunteers following oral administration. CONCLUSION: The developed method is suitable for the routine therapeutic drug monitoring of these drugs.

Chronic Fructose Ingestion as a Major Health Concern: Is a Sedentary Lifestyle Making It Worse? A Review.

Obesity contributes to metabolic abnormalities such as insulin resistance, dyslipidemia, hypertension, and glucose intolerance, all of which are risk factors associated with metabolic syndrome. The growing prevelance of metabolic syndrome seems to be an end result of our current lifestyle which promotes high caloric, high-fat foods and minimal physical activity, resulting in a state of positive energy balance. Increased adiposity and physical inactivity may represent the beginning of the appearance of these risk factors. Understanding the metabolic and cardiovascular disturbances associated with diet and exercise habits is a crucial step towards reducing the risk factors for metabolic syndrome. Although considerable research has been conducted linking chronic fructose ingestion to the increased prevalence of obesity and metabolic syndrome risk factors, these studies have mainly been performed on animals, and/or in a post-absorptive state. Further, the magnitude of the effect of fructose may depend on other aspects of the diet, including the total amount of carbohydrates and fats in the diet and the overall consumption of meals. Therefore, the overall aim of this review paper is to examine the effects of a diet high in fructose on postprandial lipidemia, inflammatory markers and glucose tolerance, all risk factors for diabetes and cardiovascular disease. Moreover, an objective is to investigate whether increased physical activity can alter such effects.

d-Fructose Modification Enhanced Internalization of Mixed Micelles in Breast Cancer Cells via GLUT5 Transporters.

d-Fructose modified poly(ε-caprolactone)-polyethylene glycol (PCL-PEG-Fru) diblock amphiphile is synthesized via Cu(I)-catalyzed click chemistry, which self-assembles with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) into PCL-PEG-Fru/TPGS mixed micelles (PPF MM). It has been proven that glucose transporter (GLUT)5 is overexpressed in MCF-7 cells other than L929 cells. In this study, PPF MM exhibit a significantly higher uptake efficiency than fructose-free PCL-PEG-N3 /TPGS mixed micelles in both 2D MCF-7 cells and 3D tumor spheroids. Also, the presence of free d-fructose competitively inhibits the internalization of PPF MM in MCF-7 cells other than L929 cells. PPF MM show selective tumor accumulation in MCF-7 breast tumor bearing mice xenografts. Taken together, PPF MM represent a promising nanoscale carrier system to achieve GLUT5-mediated cell specific delivery in cancer therapy.

Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.

BACKGROUND: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. METHODS: Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. RESULTS: A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. CONCLUSIONS: The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

Relationship between the uptake of 18F-borono-L-phenylalanine and L-[methyl-11C] methionine in head and neck tumors and normal organs.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the distribution of 4-borono-2-18F-fluoro-phenylalanine (18F-BPA) and L-[methyl-11C] methionine (11C-Met) in normal organs and tumors and to evaluate the usefulness of 11C-Met/PET in screening potential candidates for boron neutron capture therapy (BNCT). MATERIAL METHODS: Seven patients who had at least one histologically confirmed head and neck tumor were included in this study. They underwent both whole-body 18F-BPA-PET/CT and 11C-Met-PET/CT within a span of 6 months. Uptake was evaluated using the maximum standardized uptake value (SUVmax). Regions of interest (ROIs) were placed within the tumors and target organs of brain, thyroid, submandibular gland, lung, liver, esophagus, stomach pancreas, spleen, muscle, and bone marrow. RESULTS: The tumor SUVmax of FBPA and 11C-Met showed strong correlation (r 2 = 0.72, P = 0.015). Although 18F-BPA and 11C-Met showed markedly different uptake in some organs (submandibular gland, liver, heart, stomach pancreas, spleen, and bone marrow), the uptake of 11C-Met was consistently higher than that of 18F-BPA in these cases. CONCLUSION: 11C-Met PET/CT might be used instead of 18F-BPA PET/CT to predict the accumulation of 10B in tumors and to select candidates for BNCT. However, it would not be suitable for evaluating accumulation in some normal organs. Therefore, the 18F-BPA-PET study remains a prerequisite for BNCT. This is the first report of the correlation between 18F-BPA and 11C-Met accumulation.

Adding glucose to food and solutions to enhance fructose absorption is not effective in preventing fructose-induced functional gastrointestinal symptoms: randomised controlled trials in patients with fructose malabsorption.

BACKGROUND: In healthy individuals, the absorption of fructose in excess of glucose in solution is enhanced by the addition of glucose. The present study aimed to assess the effects of glucose addition to fructose or fructans on absorption patterns and genesis of gastrointestinal symptoms in patients with functional bowel disorders. METHODS: Randomised, blinded, cross-over studies were performed in healthy subjects and functional bowel disorder patients with fructose malabsorption. The area-under-the-curve (AUC) was determined for breath hydrogen and symptom responses to: (i) six sugar solutions (fructose in solution) (glucose; sucrose; fructose; fructose + glucose; fructan; fructan + glucose) and (ii) whole foods (fructose in foods) containing fructose in excess of glucose given with and without additional glucose. Intake of fermentable short chain carbohydrates (FODMAPs; fermentable, oligo-, di-, monosaccharides and polyols) was controlled. RESULTS: For the fructose in solution study, in 26 patients with functional bowel disorders, breath hydrogen was reduced after glucose was added to fructose compared to fructose alone [mean (SD) AUC 92 (107) versus 859 (980) ppm 4 h-1 , respectively; P = 0.034). Glucose had no effect on breath hydrogen response to fructans (P = 1.000). The six healthy controls showed breath hydrogen patterns similar to those with functional bowel disorders. No differences in symptoms were experienced with the addition of glucose, except more nausea when glucose was added to fructose (P = 0.049). In the fructose in foods study, glucose addition to whole foods containing fructose in excess of glucose in nine patients with functional bowel disorders and nine healthy controls had no significant effect on breath hydrogen production or symptom response. CONCLUSIONS: The absence of a favourable response on symptoms does not support the concomitant intake of glucose with foods high in either fructose or fructans in patients with functional bowel disorders.

Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring.

BACKGROUND: This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy. METHODS: A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method. RESULTS: Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 µmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002). CONCLUSIONS: Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.

The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate.

OBJECTIVE: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. METHODS: The t1/2z and t1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N=36) of 200mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. RESULTS: As previously reported, mean t1/2z was similar between USL255 (80.2h) and TPM-IR (82.8h); TPM-IR t1/2z was ∼4 times longer than reported in the Topamax label (21h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff (55.7 vs 37.1h for TPM-IR). When t1/2z was calculated from 48 to 336h, values ranged from 28.8 to 82.8h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. SIGNIFICANCE: As expected for the same moiety, t1/2z of USL255 and TPM-IR were similar; however, the longer t1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t1/2z may be less clinically meaningful than t1/2eff, and using t1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens.

Influencia del suplemento con inulina enriquecida con fructooligosacáridos sobre el contenido y la densidad mineral ósea tras el parto y la lactación en ratas / Influence of supplementation with oligofructose-enriched inulin on bone mineral content and density after delivery and lactation in rats

Introducción: la gestación y lactancia están relacionadas con pérdidas temporales en la densidad mineral ósea (DMO) materna. Una suplementación con calcio podría resultar beneficiosa para evitar la pérdida de masa ósea del esqueleto materno. Otros nutrientes como los prebióticos han sido identificados como responsables de un incremento en la absorción de minerales, pudiendo condicionar la mineralización ósea. Objetivo: estudiar el efecto de la suplementación de la dieta materna con el prebiótico inulina enriquecida con oligofructosa, durante la gestación y la lactancia sobre el contenido mineral óseo (CMO) y la DMO al final del periodo de lactancia. Métodos: las ratas gestantes fueron alimentadas con dieta estándar (grupo CC), dieta fortificada en calcio (grupo Ca) o enriquecida con el prebiótico inulina enriquecida con oligofructosa (grupo Pre) hasta el final del periodo de lactancia. Posteriormente se evaluó el CMO y DMO por absorciometría de rayos X (DEXA) y el pH del contenido cecal. Resultados: en términos generales, el grupo Pre presenta los mayores valores absolutos de CMO y DMO de entre los tres grupos, siendo en la tibia significativamente diferentes en los grupos CC y Pre frente al grupo Ca. El pH del contenido cecal del grupo Pre es signifi cativamente inferior al de los grupos CC y Ca. Conclusión: la suplementación con inulina enriquecida con oligofructosa, en condiciones nutricionales no deficientes en calcio, durante la gestación y la lactancia, ejerce una protección del esqueleto materno en las ratas y puede ser considerada como una estrategia nutricional para proteger la masa ósea materna en el periodo perinatal (AU)

Introduction: Pregnancy and lactation are related with temporary decreases in maternal bone mineral density (BMD). Calcium supplementation could be beneficial to prevent bone loss of maternal skeleton. Other nutrients, such as prebiotics have showed to produce an increase of the mineral absorption and therefore affecting bone mineralization. Objective: To study the effect of maternal diet supplementation with prebiotic oligofructose-enriched inulin during gestation and lactation on the maternal bone mineral content (BMC) and BMD at the end of lactation. Methods: Pregnant rats were fed with standard diet (CC group), calcium fortified diet (Ca group) or with prebiotic oligofructose-enriched inulin supplemented diet until the end of the lactation period. At weaning, bone mineral content (BMC) and BMD were determined by dual-energy X-ray absorptiometry and the pH of the cecal content was also determined. Results: In absolute terms, the highest BMD and BMC were found in the Pre group as compared with the other two groups being significant in the tibia when compared Pre group and CC group with Ca group. The pH of the cecal content in the Pre group was also significantly lower as compared with the other two groups. Conclusion: Prebiotic oligofructose-enriched inulin supplementation, in calcium no-deficient conditions, during gestation and lactation exerts a protection on maternal skeleton during pregnancy and lactation in the rats and could be considered as a plausible nutritional option for protecting maternal bone mass during these periods (AU)

HPTLC Method for Estimation of Topiramate in Solubility Studies, Diffusion Studies, Plasma, Brain Homogenate and Pharmaceutical Formulation.

Topiramate, 2,3:4,5-bis-O-(1-methylethylidene)-ß-d-fructopyranose, is an anticonvulsant drug indicated in the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures in adults and children. An economic and rapid high-performance thin-layer chromatographic (HPTLC) method was developed and was validated for the quantitative determination of topiramate in plasma, brain homogenate and pharmaceutical formulation. The simple extraction method was used for the isolation of topiramate from formulation, plasma and brain homogenate samples. HPTLC separation was achieved on an aluminum-backed layer of silica gel 60F254 plates using toluene : acetone (5.0 : 2.0, v/v) as mobile phase. Spots of developed plates were visualized by spraying of reagent [3.0% phenol in the mixture of ethanol : sulfuric acid (95 : 5, v/v)]. Quantitation was achieved by densitometric analysis at 340 nm over the concentration range of 1,000-5,000 ng/spot. The method was found to give compact spot for the drug (Rf: 0.61 ± 0.018). The regression analysis data for the calibration plots showed good relationship with a correlation coefficient of 0.9983. The minimum detectable amount was found to be 165 ng/spot, whereas the limit of quantitation was found to be 500 ng/spot. Statistical analysis of the data showed that the method is precise, accurate, reproducible and selective for the analysis of topiramate. The developed method was successfully employed for the estimation of topiramate in samples of equilibrium solubility study, diffusion study, microemulsion formulation and suspension formulation (developed in-house), rat plasma and rat brain homogenate samples.