Narrative Review of Topiramate: Clinical Uses and Pharmacological Considerations.

Due to the diverse mechanisms of action of antiseizure drugs, there has been a rise in prescriptions of these drugs for non-epileptic pathologies. One drug that is now being used for a variety of conditions is topiramate. This is a narrative review that used PubMed, Google Scholar, MEDLINE, and ScienceDirect to review literature on the clinical and pharmacologic properties of topiramate. Topiramate is a commonly prescribed second-generation antiseizure drug. The drug works through multiple pathways to prevent seizures. In this regard, topiramate blocks sodium and calcium voltage-gated channels, inhibits glutamate receptors, enhances gamma-aminobutyric acid (GABA) receptors, and inhibits carbonic anhydrase. Topiramate is approved by the Food and Drug Administration (FDA) for epilepsy treatment and migraine prophylaxis. Topiramate in combination with phentermine is also FDA-approved for weight loss in patients with a body mass index (BMI) > 30. The current target dosing for topiramate monotherapy is 400 mg/day and 100 mg/day to treat epilepsy and migraines, respectively. Commonly reported side effects include paresthesia, confusion, fatigue, dizziness, and change in taste. More uncommon and serious adverse effects can include acute glaucoma, metabolic acidosis, nephrolithiasis, hepatotoxicity, and teratogenicity. Related to a broad side effect profile, physicians prescribing this drug should routinely monitor for side effects and/or toxicity. The present investigation reviews various anti-seizure medications before summarizing indications of topiramate, off-label uses, pharmacodynamics, pharmacokinetics, adverse effects, and drug-drug interactions.

Development and Validation of an Analytical Method for Quantitation of Alpha-Pinene Oxide in Rodent Blood and Mammary Glands by GC-MS.

Alpha-pinene is a monoterpene found in the oil of coniferous trees and has a wide variety of applications. Alpha-pinene oxide (APO) is a potential reactive metabolite of alpha-pinene in rodents. The objective of this work is to validate a gas chromatography-mass spectrometry method to quantitate APO in rat and mouse blood and mammary glands in support of studies investigating the toxicity and toxicokinetic behavior of alpha-pinene. The method was validated in male Sprague Dawley rat blood over the concentration range of 5-250 ng/mL. Matrix standard curves were linear (r ≥ 0.99), and accuracy (percent relative error, %RE) was ≤±15% for standards at all levels. Intra- and interday precision (percent relative standard deviation, %RSD) and accuracy (%RE) were evaluated at three concentration levels (10, 50 and 200 ng/mL) and were ≤6.3% and ≤±5.4%, respectively. The limit of detection, determined from the SD of the limit of quantitation (5 ng/mL), was 1.06 ng/mL. Standards as high as 25,000 ng/mL could be accurately quantified after diluting to the validated range (%RE ≤ ±7.1%; %RSD ≤ 5.8%). APO was stable in rat blood for at least 70 days in frozen storage (-80°C). APO could accurately be quantified in male and female Hsd:Sprague Dawley® SD® rat and B6C3F1 mouse blood (mean %RE ≤ ±5.3%; %RSD ≤ 7.8%) and female B6C3F1 and Sprague Dawley rat mammary glands (mean %RE ≤ ±14.6%; %RSD ≤ 8.1%) using a primary matrix standard curve. These results demonstrate that the method is suitable for the analysis of APO in rodent blood and mammary glands generated from toxicokinetic and toxicology studies.

Development and Validation of an Analytical Method for Quantitation of Alpha-pinene in Rodent Blood and Mammary Gland by Headspace GC-MS.

Alpha-pinene (AP), produced by pine trees and other plants, is the main component of turpentine and is used as a fragrance and flavor ingredient. Exposure occurs via use of personal care and household cleaning products and in the lumber industry. Despite widespread exposure, toxicity data for AP are limited. The objective of this work was to develop and validate a method to quantitate AP in rodent blood and mammary glands, in support of toxicokinetic and toxicology studies of AP. The method uses 100 µL of blood or ~100 mg of mammary gland with analysis by headspace gas chromatography-mass spectrometry. The samples are diluted with internal standard (2H3-AP, IS) and sealed in headspace vials; mammary glands are homogenized within the vial. The vials are equilibrated briefly at 60°C before a headspace sample is analyzed. The method was validated in Sprague Dawley rat blood over the range 5-500 ng/mL and mammary gland over the range 100-5000 ng/g. The method was linear (r ≥0.99), accurate (mean relative error (RE) ≤±13.4%) and precise (relative standard deviation (RSD) ≤7.1%) in both matrices. Recoveries incorporating IS were ≥88.7% at all concentrations in both tissues. Standards as high as 1500 ng/mL in blood and 20,000 ng/g in mammary gland could be analyzed using lower injection volume or extrapolating the calibration curve beyond the upper limit of quantitation (mean %RE ≤±18.7; %RSD ≤2.2). Loss of AP occurred during overnight autosampler storage as well as frozen storage in as few as 15 days, but incorporation of IS prior to storage corrected for the loss such that calculated concentrations were within 84.7-117% of day 0 concentrations following frozen storage up to ≥32 days in both matrices. Matrix evaluation was performed in Hsd:Sprague Dawley®SD® rat and B6C3F1 mouse blood and mammary glands (mean %RE ≤±9.2; %RSD ≤4.3). These data demonstrate that the method is suitable for determination of AP in rodent blood and mammary glands.

Analysis of Nicotine and Non-nicotine Tobacco Constituents in Aqueous Smoke/Aerosol Extracts by UHPLC and Ultraperformance Convergence Chromatography-Tandem Mass Spectrometry.

The non-nicotine constituents of tobacco may alter the reinforcing effects of nicotine, but the quantitative and qualitative profiles of these chemicals in tobacco products such as electronic cigarettes (e-cigarettes), cigars, and waterpipe tobacco are not well characterized. The objective of this work was to develop and validate analytical methods to utilize saline both as an extraction solvent for smoke condensates from cigarettes, little cigars, and waterpipe tobacco and aerosols from e-cigarettes and as a delivery vehicle of nicotine and non-nicotine constitents for nonclinical pharmacological studies. Ultrahigh-performance liquid chromatography was used to analyze nicotine and acetaldehyde, and a novel ultraperformance convergence chromatography-tandem mass spectrometry method was developed to analyze anabasine, anatabine, cotinine, myosmine, nornicotine, harmane, and norharmane. Linearity was confirmed for each standard curve with correlation coefficients (r) ≥ 0.99, and relative errors (RE) for the standards were ≤±10% over the calibration ranges. Method validation was performed by preparing triplicate samples in saline to mimic the composition and concentration of each analyte in the smoke or aerosol condensate and were used to determine method accuracy and precision. Relative standard deviation values were ≤15% and mean RE ≤15% for each analyte at each concentration level. Selectivity of the methods was demonstrated by the absence of peaks in blank vehicle or diluent samples. Storage stability was assessed over ∼45 days. Precision (%RSD ≤ 13) and recovery (percent of day 0 ≥ 80%) indicated that the saline formulations of all four products could be considered stable for up to ∼45 days at 4-8 °C. Therefore, the use of saline both as an extraction solvent and as a delivery vehicle adds versatility and improved performance in the study of the pharmacological effects of constituents from mainstream smoke and aerosols generated from cigarettes, little cigars, waterpipes, and e-cigarettes.

Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice.

Tg.AC mice develop epidermal papillomas in response to treatment with dermally applied nongenotoxic and complete carcinogens. The persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a multi-site rodent carcinogen and tumor promoter that induces the formation of papillomas in Tg.AC mice. To examine the dose-response relationship and compare dermal and oral routes of exposure for TCDD-induced skin papillomas, female Tg.AC mice were exposed dermally to average daily doses of 0, 2.1, 7.3, 15, 33, 52, 71, 152, and 326 ng TCDD/kg/day or 0, 75, 321, and 893 ng TCDD/kg body weight by gavage for 26 weeks. The incidence of cutaneous papillomas was increased in a dose-dependent manner, and tumors developed earlier with higher exposure to TCDD regardless of route of administration. Increased incidences of cutaneous squamous cell carcinomas were observed in mice exposed to dermal (> or =52 ng/kg) and oral (893 ng/kg) TCDD. Higher gavage doses than dermal exposure doses were required to induce papillomas and squamous cell carcinomas. Despite a linear correlation between administered dose and terminal skin concentrations, the incidence of tumor formation was lower in the gavage study than in the dermal study with respect to mean terminal skin TCDD concentrations. These studies demonstrate that, although Tg.AC mice are less responsive to TCDD by gavage than by dermal exposure, the induction of skin neoplasms is a response to systemic exposure and not solely a local response at the site of dermal application. Differences in response between the routes of exposure may reflect pharmacokinetic differences in the delivery of TCDD to the skin over the duration of the study.