Compounding and quality control of two pediatric topiramate pharmaceutical preparations.

In pediatric wards, topiramate is prescribed as an antiepileptic at non-licensed dosages. Compounding is the best way to obtain topiramate drug adapted to pediatric patients, but this practice requires to control the quality of batches and to manage a stability study to establish a beyond-use-date. With this objective, 6 mg. mL 1 topiramate oral suspension and 9 mg capsules were realized, and our laboratory was mandated for their quality control. Previously described dosing methods did not allow us to determine topiramate content in prescribed preparations. An original HPLC-UV derivatization dosing method of topiramate was validated and was proved to be stability indicating. This derivatization methodology, but also total aerobic microbial count (TAMC) and total combined yeasts and mold count (TYMC) allowed the quality control of topiramate capsules and topiramate suspension. Beyond-use-dates can be attributed with regards to United States Pharmacopoeia recommendations, and a stability study was performed on 6 mg. mL-1 topiramate suspension to confirm empirical data. Topiramate pediatric suspension was found to be stable for two months at +2/+8 °C, one month after opening and one day at ambient temperature.

pH-responsive release system of topiramate transported on silica nanoparticles by melting method.

Incorporating drugs into silica matrices by the melting method can be applied to obtain drug delivery systems because they are governed by electrostatic type interactions, hydrogen bonding and hydrophilic-hydrophobic interactions between the drug and the silica surface. the melting method is an environmentally correct tool since it is free of organic solvent, low cost and with easy execution for the incorporation of drugs in silicas. Drugs delivery systems are very important for improving the treatment of chronic diseases. Topiramate (TPM) is a potent antiepileptic used in high daily doses as it has low bioavailability. In this context, silica nanoparticles (NPS) were used as an inorganic matrix for TPM transport in (in vitro) release studies. The TPM was incorporated into the NPS by hot melt loading employing a new carrier preparation methodology (NPS/TPM) using a thermobalance (by Thermogravimetry-TG) with high temperature control system. The release study using dissolution media simulating gastrointestinal at pH 1.2 (stomach) and 7.4 (intestine), showed that NPS release TPM in a prolonged and pH-responsive manner. The drug was released at intestinal pH ensuring greater absorption, allowing fewer daily doses and less adverse effects. The kinetic study demonstrated the best fit to the zero-order model proving the pH-responsive profile of the developed system.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer's Disease Model Mice, APP/PS1.

Alzheimer's disease (AD) is a neurodegenerative disease that is the main cause of dementia in the elderly. The aggregation of ß-amyloid peptides is one of the characterizing pathological changes of AD. Topiramate is an antiepileptic drug, which in addition, is used in the treatment of many neuropsychiatric disorders. In this study, the therapeutic effects of topiramate were investigated in a transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). Before, during, and after topiramate treatment, behavioral tests were performed. Following a treatment period of 21 days, topiramate significantly ameliorated deficits in nest-constructing capability as well as in social interaction. Thereafter, brain sections of mice were analyzed, and a significant attenuation of microglial activation as well as ß-amyloid deposition was observed in sections from topiramate-treated APP/PS1 mice. Therefore, topiramate could be considered as a promising drug in the treatment of human AD.

Topiramate: Comprehensive profile.

Topiramate, 2,3:4,5-di-O-isopropylidene-ß-d-fructopyranose sulfamate, is a potent antiepileptic drug with a broad spectrum of activity. It is effective in both partial and generalized seizures. Topiramate was also found to have significant efficacy in migraine prevention with considerable reductions in the frequency of migraine headaches. The most common adverse events, which may accompany the use of topiramate, are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease and taste perversion. The weight loss observed with the use of topiramate in obese, epileptic patients, afforded the approval of this drug as an anti-obesity medication. This action is thought to be based on the selective inhibition of mitochondrial carbonic anhydrase isoforms. This profile is prepared to discuss and explain physical characteristics, proprietary and nonproprietary names of topiramate. It also includes methods of preparation, thermal and spectral behavior and methods of analysis. Pharmacokinetics, metabolism, excretion and pharmacology together with its uses and applications are also discussed.

An alternating polarity switching assay for quantification of oxycodone and topiramate: An application of LC-MS/MS method in support to PK/PD study in rodents.

In mass spectrometry, compounds that have different ionization properties experience challenges in simultaneous analysis. In the present paper, the authors proposed a polarity switching (+ve and -ve) LC-MS/MS method to analyze oxycodone and topiramate in a single run. The developed method was validated in the range of 5-1000 ng/mL for oxycodone and 20-5000 ng/mL for topiramate as per the US FDA guidelines. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode to analyze oxycodone and topiramate simultaneously using oxycodone-d6 and topiramate-d12 as internal standards, respectively. Sample preparation was performed in 96-well protein precipitation plates using acetonitrile. Processed samples were analyzed using a C18 column with a gradient mobile phase composed of 10 mm ammonium formate with 0.1% formic acid and acetonitrile. The method was validated for selectivity, specificity, linearity, precision and accuracy, dilution integrity and stability. After validation, this method was successfully applied to quantify oxycodone and topiramate in plasma of concomitantly treated Sprague Dawley (SD) rats.

Sensitive detection of topiramate degradation products by high-performance liquid chromatography/electrospray ionization mass spectrometry using ion-pairing reagents and polarity switching.

RATIONALE: The chromatographic analysis of topiramate and its degradation products is challenging due to the absence of chromophoric moieties in their structures, the wide polarity range of the compounds and their ionization differences. This work proposes two new mass spectrometry approaches for evaluating these analytes. METHODS: Based on the calculated experimental limit of detection (LOD), a highly sensitive high-performance liquid chromatography (HPLC) paired-ion electrospray ionization mass spectrometry (PIESI-MS) method was developed for the determination of topiramate inorganic degradation products. The influence of different solvent systems on the LODs for topiramate and its main degradation products was determined in both positive/negative ionization modes. In addition, a HPLC method to analyze both organic and inorganic degradation products was proposed by mass spectrometry with positive/negative ion switching electrospray ionization. RESULTS: A sensitive HPLC/PIESI-MS method was achieved for the efficient separation of topiramate inorganic degradation products. Both sulfate and sulfamate were detected in the positive selected ion monitoring (SIM) mode with an increased sensitivity compared with the negative SIM mode. The HPLC/ESI-MS analysis with positive/negative ion switching allowed the simultaneous separation and detection of the major degradation products of topiramate in a 10-min run using a single column and a single detector. CONCLUSIONS: Two new alternative MS approaches for analyzing the main degradation products of topiramate were developed. The proposed methods are considered advantageous over the existing methods and can be applied to quality control studies of topiramate.

Improving the carbonic anhydrase inhibition profile of the sulfamoylphenyl pharmacophore by attachment of carbohydrate moieties.

One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated 'the sugar approach'. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C-glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. The inhibition profile of the new glycomimetics was determined against four human (h) CA isozymes, comprising hCAs I and II (cytosolic, ubiquitous isozymes), hCA IV and hCA IX (tumor associated isozyme). Peracetylated and deprotected C-glycosyl sulfamates showed better inhibition selectivity compared to structurally related phenylsulfamates. In this study, deprotected compound 12 was identified as selective inhibitor of hCA IX. These results confirm that attaching carbohydrate moieties to CA sulfamoylphenyl pharmacophore improves its inhibitory activity.