Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine-Topiramate to Prevent Exposure During Pregnancy.

BACKGROUND: The U.S. Food and Drug Administration approved phentermine-topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. OBJECTIVE: To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine-topiramate compared with topiramate or other antiobesity medications (AOMs). DESIGN: Retrospective cohort study. SETTING: Nationwide health insurance claims database. PARTICIPANTS: Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. MEASUREMENTS: Patients initiated use of phentermine-topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion-naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. RESULTS: A total of 156 280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine-topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine-topiramate versus topiramate. Both outcomes were similarly lower for phentermine-topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine-topiramate users. LIMITATIONS: Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. CONCLUSION: Prenatal exposure seemed to be significantly lower among phentermine-topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. PRIMARY FUNDING SOURCE: None.

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

INTRODUCTION: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

Impact of sugars and sugar taxation on body weight control: A comprehensive literature review.

OBJECTIVE: To conduct a comprehensive literature review in the field of added-sugar consumption on weight gain including the effect of fructose-containing caloric sweeteners and sugar taxation. METHODS: A search of three databases was conducted in the time period from the inception of the databases to August 2015. Sensitive search strategies were used in order to retrieve systematic reviews (SR) of fructose, sucrose, or sugar-sweetened beverages (SSBs) on weight gain and metabolic adverse effects, conducted on humans and written in English, Spanish, or French. In addition, a review about SSB taxation and weight outcomes was conducted. RESULTS: The search yielded 24 SRs about SSBs and obesity, 23 SRs on fructose or SSBs and metabolic adverse effects, and 24 studies about SSB taxation and weight control. CONCLUSIONS: The majority of SRs, especially the most recent ones, with the highest quality and without any disclosed conflict of interest, suggested that the consumption of SSBs is a risk factor for obesity. The effect of fructose-containing caloric sweeteners, on weight gain is mediated by overconsumption of beverages with these sweeteners, leading to an extra provision of energy intake. The tax tool alone on added sugars appears insufficient to curb the obesity epidemic, but it needs to be included in a multicomponent structural strategy.

Balancing risk and benefit in heavy drinkers treated with topiramate: implications for personalized care.

BACKGROUND: Despite topiramate's ability to reduce heavy drinking, its adverse effects may limit its clinical utility. METHOD: To evaluate the risks and benefits of topiramate, we reanalyzed data from a completed trial of the medication in 138 heavy drinkers whose goal was to reduce their drinking to safe levels. We used the number of patients who had no heavy drinking days during the last 4 weeks of treatment to calculate topiramate's number needed to treat (NNT). To balance the risks and benefits of topiramate, we adjusted the NNT using 2 different levels of adverse event severity: moderate or greater (NNT-AEmod+) and severe or greater (NNT-AEsev+). This measure helps to guide the clinical use of topiramate in heavy drinkers by incorporating both its beneficial and adverse effects in a single measure. Because a polymorphism (rs2832407) in the gene encoding a kainate receptor subunit appears to moderate topiramate's effects in heavy drinkers, we repeated the analyses based on rs2832407 genotype (C-homozygote vs A-allele carrier) in the European American subsample (n = 122). RESULTS: Overall, the NNT for topiramate was 5.29, the NNT-AEmod+ was 7.52, and the NNT-AEsev+ was 6.12. Among European Americans with the rs2832407*CC genotype, the NNT was 2.28, the NNT-AEmod+ was 2.63, and the NNT-AEsev+ was 2.56. In contrast, for rs2832407*A-allele carriers, the NNT was 180.00, the NNT-AEmod+ was 322.16, and the NNT-AEsev+ was 217.45. CONCLUSIONS: In this sample of heavy drinkers, topiramate had a clinically important treatment effect that was most evident in European Americans with the rs2832407*CC genotype. In that group, in particular, it had a robust treatment effect, even when adjusted for adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00626925.

Assessment of the quality of harms reporting in non-randomised studies and randomised controlled studies of topiramate for the treatment of epilepsy using CONSORT criteria.

PURPOSE: Treatment decisions should be informed by high quality evidence of both the potential benefit and harms of treatment alternatives. Randomised controlled trials (RCTs) provide the best evidence regarding benefits; however information relating to serious, rare and long-term harms is usually available only from non-randomised studies (NRSs). The aim of this study was to use a checklist based on the CONSORT (Consolidating Standards for Reporting Trials) extension for harms recommendations to assess the quality of reporting of harms data in both NRSs and RCTs of antiepileptic drugs, using studies of topiramate as an example. RESULTS: Seventy-eight studies were included from an online search of seven databases. Harms data was extracted from each study using a 25-point checklist. The mean number of items met was 11.5 (SD 2.96) per study. Commercially funded studies met on average 12.7 items and non-commercially funded studies met 10.08 (p value < 0.001). RCTs met on average 13.0 items and NRSs met 10.8 (p = 0.001). Multi-centre studies and commercially funded studies met significantly more items than single centre and non-commercially funded studies respectively. There was no significant difference in the mean number of items met by studies that had included adult vs. child participants, or studies published pre- vs. post-CONSORT extension for harms in 2004. CONCLUSIONS: Reporting of harms is significantly better in RCTs than in NRSs of TPM, but is suboptimal overall and has not improved since the publication of CONSORT extension for harms in 2004. There is a need to improve the reporting of harms in order to better inform treatment decisions.

Effect of dietary blueberry pomace on selected metabolic factors associated with high fructose feeding in growing Sprague-Dawley rats.

An experiment was conducted to study the protective effect of feeding extruded and unextruded blueberry pomace (BBP) on selected metabolic parameters associated with metabolic syndrome in a model of high fructose (HF)-fed growing Sprague-Dawley rats. Treatments were as follows: (1) control (modified AIN-based diet); (2) HF diet (AIN diet with 58% fructose); (3) HF diet with 1.5% unextruded BBP; (4) HF diet with 1.5% extruded BBP; (5) HF diet with 3% unextruded BBP; and (6) HF diet with 3% extruded BBP. Compared with the control, HF feeding increased fasting plasma insulin and fasting and postprandial plasma triglycerides as well as homeostatic scores of insulin resistance and ß-cell function, but not weight gain, diet intake and efficiency, abdominal fat, oral glucose tolerance, and fasting and postprandial plasma glucose, cholesterol, and leptin levels. Inclusion of unextruded or extruded BBP was effective in minimizing or ameliorating the fructose-induced metabolic anomalies, except postprandial plasma triglycerides, especially at 3% of the diet. In addition, unextruded or extruded BBP at 3% of the diet was also able to reduce plasma cholesterol and abdominal fat relative to the HF control, which may impart additional health benefits. Compared with the control, inclusion of unextruded or extruded BBP at both 1.5% and 3% resulted in lower total fat weight, and animals fed a diet supplemented with 3% unextruded BBP in fasting state or 3% unextruded BBP in fed state had lower leptin levels than the control. This is the first study demonstrating the beneficial effects of feeding blueberry pomace on health.

Sweet potato-based complementary food for infants in low-income countries.

BACKGROUND: In low-income countries, most infants are given cereal-based complementary foods prepared at the household level. Such foods are high in phytate, which limits the bioavailability of nutrients, including iron, calcium, zinc, and in some cases proteins, which are crucial to the development of infants. OBJECTIVE: To compare the levels of macronutrients (protein, fat, and carbohydrate), gross energy, and fructose in sweet potato-based (denoted ComFa) formulations and enriched Weanimix (dehulled maize-dehulled soybean-groundnut blend with fish powder and sugar incorporated). The phytate level was also compared. METHODS: A composite flour of sweet potato and soybeans containing fish powder was processed by oven toasting as a home-based complementary food. Another blend containing skim milk powder was processed by extrusion cooking or roller drying as industrial-based prototypes. The macronutrient composition and the levels of fructose and phytate were determined in the ComFa formulations and enriched Weanimix. RESULTS: The ComFa formulations and the enriched Weanimix met the stipulated values in the Codex Alimentarius Commission standard for energy (400 kcal/100 g), protein (15 g/100 g), and fat (10 to 25 g/100 g) for complementary food, with the exception of the industrial-based ComFa formulations, which satisfied 83% of the protein requirement (15 g/100 g). The ComFa formulations had a quarter of the phytate level of enriched Weanimix. The fructose level in the sweet potato-based complementary foods was more than five times that in enriched Weanimix. CONCLUSIONS: The sweet potato-based formulations were superior to enriched Weanimix as complementary foods for infants in low-income countries, based on the fructose (which makes the porridge naturally sweet) and phytate levels.

Long-term assessment of topiramate for epilepsy: an open-label, single-arm, multicentre, prospective study in a naturalistic setting.

BACKGROUND AND OBJECTIVE: Most patients with epilepsy require long-term medical therapy. Newer antiepileptic drugs (AEDs) appear to be overall similarly effective to older agents but may be better tolerated. However, most of the clinical data available for newer AEDs derive from a number of short-term studies. The objective of this study was to explore long-term outcomes in patients with epilepsy treated with topiramate in routine clinical practice. METHODS: This was an open-label, multicentre, optional follow-up monotherapy study that included adolescents and adults with epilepsy who completed two similarly designed 28- or 30-week studies and agreed to participate for an additional 52 weeks. Seizure types and frequency, topiramate dose, vital signs and treatment-emergent adverse events (TEAEs) after 12, 26, 39 and 52 weeks were documented. Post hoc analyses to explore differences between males and females were conducted. RESULTS: 114 patients (49.0% women, mean ± SD age 43 ± 17.5 years) with a mean ± SD disease duration of 61 ± 118 months (men 54 ± 96 vs women 68 ± 138 months) were followed up for a median of 18.5 months. Seventy-eight percent of patients completed the study. Reasons for premature discontinuation were: loss to follow-up (10.5%), TEAE (5.3%), lack of efficacy (2.6%), non-adherence (0.9%) and other reasons (4.4%). Seizure frequency per 4 weeks decreased from a mean ± SD 5.0 ± 28.3 at baseline to 0.6 ± 2.1 during the whole observation period. Fifty-four patients (52.9%) were seizure free during the whole observation period. In addition, 69 of 95 patients (72.6%) whose topiramate therapy was stable within a range of ±50 mg/day for a period of at least 12 months (maintenance phase) were seizure free while treated with a median topiramate dose of 100 mg/day. The most frequently reported TEAEs were paraesthesias (13.2% of patients), dizziness (7.0%) and seizure-related events (7.0%). No significant differences between males and females were found for treatment response or retention. CONCLUSION: Topiramate is an effective and well tolerated long-term treatment option for adolescents and adults with epilepsy.

Polyphenol-rich strawberry pomace reduces serum and liver lipids and alters gastrointestinal metabolite formation in fructose-fed rats.

This study compared the effects of supplementation with a polyphenol-rich pomace from strawberry (US) and a strawberry pomace without most of these compounds (PS) on gastrointestinal, blood, and tissue biomarkers in rats fed diets differing in carbohydrate contents for 4 wk. The diets were: corn starch (group CS), high fructose (60% by weight; group F), starch with 7.7% of either US or PS (groups CS+US and CS+PS, respectively), and high fructose with 7.7% of either US or PS (groups F+US and F+PS, respectively). An interaction (P < 0.05) was observed between diet type and strawberry preparation, showing that upon fructose feeding, US had a greater effect than PS on lowering serum insulin, liver total cholesterol, and conjugated dienes. Additionally, the F+US group had lower serum FFA than the F+PS group (P < 0.05). The extraction of polyphenols diminished the physiological effect associated with strawberry intake, suggesting that the fiber component of the pomace was also active in reducing metabolic complications following fructose feeding to rats.

Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.

OBJECTIVE: Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors. METHODS: For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII). RESULTS: Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing. CONCLUSION: The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients.

Assessment of endothelial function and blood metabolite status following acute ingestion of a fructose-containing beverage.

AIM: Fructose intake has increased concurrent with sugar intake and this increase has been implicated in contributing to the development of metabolic syndrome risk factors. Recent evidence suggests a role for uric acid (UA) as a potential mediator via suppression of nitric oxide (NO) bioavailability. The aim of this study was to explore this hypothesis by measuring changes in UA concentration and systemic NO bioavailability as well as endothelial function in response to acute ingestion of a glucose-fructose beverage. METHODS: Ten young (26.80 +/- 4.80 years), non-obese (body mass index: 25.1 +/- 2.55 kg m(-2); percent body fat: 13.5 +/- 6.9%) male subjects ingested either a glucose (100 g dextrose in 300 mL) or isocaloric glucose-fructose (glucose : fructose; 45 : 55 g in 300 mL) beverage. Blood was sampled pre- and every 15-min post-ingestion per 90 min and assayed for glucose, lactate, fructose, total nitrate/nitrate, UA and blood lipids. Forearm blood flow and pulse-wave velocity were recorded prior to and at 30 and 45 min time intervals post-ingestion, respectively, while heart rate, systolic and diastolic blood pressure were recorded every 15 min. RESULTS: The glucose-fructose ingestion was associated with a significant (P < 0.05) increase in plasma lactate concentration and altered free fatty acid levels when compared with glucose-only ingestion. However, UA was not significantly different (P = 0.08) between conditions (AUC: -1018 +/- 1675 vs. 2171 +/- 1270 micromol L(-1) per 90 min for glucose and glucose-fructose conditions respectively). Consequently, no significant (P < 0.05) difference in endothelial function or systemic NO bioavailability was observed. CONCLUSION: Acute consumption of a fructose-containing beverage was not associated with significantly altered UA concentration, endothelial function or systemic NO bioavailability.

A pilot study of topiramate dosages for migraine prophylaxis in an Asian population.

Topiramate is known to be efficacious in migraine prophylaxis, but its optimal dose has not been systematically studied in the Asian population. Here, we show that a fixed low dose of topiramate 25 mg/day is efficacious in migraine prophylaxis and also attest to advantages in terms of medication cost savings and more favourable side effect profile.

Clinical assessment of topiramate therapy in patients with migrainous vertigo.

OBJECTIVE: To assess the efficacy of topiramate in reducing both the frequency and the severity of vertigo and headache attacks in patients with migrainous vertigo and to compare 50 and 100 mg/day doses of the drug. METHODS: Thirty patients diagnosed as definite migrainous vertigo were recruited in the study. Vertigo and headache frequency was determined as the monthly number of attacks whereas severity was determined by visual analog scales measured in millimeters from 0 to 100. Patients were randomized to either 50 or 100 mg/day topiramate for 6 months. Vertigo and headache frequency and severity were evaluated at the end of the study period. RESULTS: Number of mothly vertigo attacks decreased significantly in the overall group after treatment (median from 5.5 to 1; P < .01). The same was true for monthly headache attacks (median from 4 to 1; P < .01). A statically significant improvement in vertigo severity was noted (median from 80 to 20 mm; P < .01). Headache severity showed significant improvement as well (median from 60 to 30 mm; P < .01). No statistically significant difference between high- and low-dose groups was present regarding efficacy (P > .05). Four patients in the high-dose group discontinued treatment at the end of the first month because of adverse effects. CONCLUSIONS: In the overall group, topiramate was found to be effective in reducing the frequency and the severity of vertigo and headache attacks. Both doses of the drug were equally efficacious. The 50 mg/day dose seems to be appropriate as higher adverse effects were noted when 100 mg/day was used.

The risks and costs of multiple-generic substitution of topiramate.

OBJECTIVE: To investigate clinical and economic consequences following generic substitution of one vs multiple generics of topiramate (Topamax; Ortho-McNeil Neurologics, Titusville, NJ). METHODS: Medical and pharmacy claims data of Régie de l'Assurance-Maladie du Québec from January 2006 to October 2007 were used. Patients with epilepsy treated with topiramate were selected. An open-cohort design was used to classify the observation period into periods of brand, single-generic, and multiple-generic use. One-year generic-switch and switchback-to-brand rates were estimated using Kaplan-Meier methodology. Medical resource utilization and costs were compared among the three periods using multivariate regression analysis. RESULTS: In total, 948 patients were observed during 1,105 person-years of brand use, 233 person-years of single-generic use, and 92 person-years of multiple-generic use. A total of 23% of generic users received at least two different generic versions. Compared to brand use, multiple-generic use was associated with higher utilization of other prescription drugs (incidence rate ratio [IRR] = 1.27, 95% confidence interval [CI] = 1.24-1.31), higher hospitalization rates (0.48 vs 0.83 visit/person-year, IRR = 1.65, 95% CI = 1.28-2.13), and longer hospital stays (2.6 vs 3.9 days/person-year, IRR = 1.43, 95% CI = 1.27-1.60), but the effect was less pronounced in single-generic use (hospitalization: IRR = 1.08, 95% CI = 0.88-1.34, length of stay: IRR = 1.12, 95% CI = 1.03-1.23). The risk of head injury or fracture was nearly three times higher (hazard ratio = 2.84, 95% CI = 1.24-6.48) following a generic-to-generic switch compared to brand use. The total annualized health care cost per patient was higher in the multiple-generic than brand periods by C$1,716 (cost ratio = 1.21, p = 0.0420). CONCLUSION: Multiple-generic substitution of topiramate was significantly associated with negative outcomes, such as hospitalizations and injuries, and increased health care costs.

In vitro neutron irradiation of glioma and endothelial cultured cells.

To fully develop its potential boron neutron capture therapy (BNCT) requires the combination of a suitable thermal/epithermal neutron flux together with a selective intake of (10)B-boron nuclei in the target tissue. The latter condition is the most critical to be realized as none of the boron carriers used for experimental or clinical purposes proved at the moment an optimal selectivity for cancer cells compared to normal cells. In addition to complex physical factors, the assessment of the intracellular concentration of boron represent a crucial parameter to predict the dose delivered to the cancer cells during the treatment. Nowadays the dosimetry calculation and then the prediction of the treatment effectiveness are made using Monte Carlo simulations, but some of the model assumption are still uncertain: the radiobiological dose efficacy and the probability of tumour cell survival are crucial parameters that needs a more reliable experimental approach. The aim of this work was to evaluate the differential ability of two cell lines to selectively concentrate the boron-10 administered as di-hydroxyboryl-phenylalanine (BPA)-fructose adduct, and the effect of the differential boron intake on the damage produced by the irradiation with thermal neutrons; the two cell lines were selected to be representative one of normal tissues involved in the active/passive transport of boron carriers, and one of the tumour. Recent in vitro studies demonstrated how BPA is taken by proliferating cells, however the mechanism of BPA uptake and the parameters driving the kinetics of influx and the elimination of BPA are still not clarified. In these preliminary studies we analysed the survival of F98 and human umbilical vein endothelial cells (HUVEC) cells line after irradiation, using different thermal fluencies at the same level of density population and boron concentration in the growing medium prior the irradiation. This is first study performed on endothelium model obtained by a primary human cell line (HUVEC). The perspective application of this work is to develop a model able to foresee the effects produced by different combination of boron influx with a thermal neutron fluencies, applying a standardized radiobiological methodology, and in particular to continue the investigation of the radiobiological effects on the endothelium model as the main tissue involved in the transport of boronated molecules.