Phenytoin Research Articles

Effects of classic antiseizure drugs on seizure activity and anxiety-like behavior in adult zebrafish

The zebrafish is extensively used as a model organism for studying several disorders of the central nervous system (CNS), including epilepsy. Some antiseizure drugs (ASDs) have been shown to produce discrepant results in larvae and adults zebrafish, therefore, their anticonvulsant efficacy in subsequent stages of the pentylenetetrazole (PTZ)-induced seizures should be more precisely characterized. The purpose of this study was to investigate behavioral effects of five classic ASDs: valproate (VPA), phenytoin (PHT), carbamazepine (CBZ), diazepam (DZP), and phenobarbital (PB) administered intraperitoneally (i.p.) in the PTZ-induced seizure test in adult zebrafish. We determined the time of maximal effect and the dose-response relationship of the studied ASDs. Furthermore, we assessed changes in the locomotor activity and the anxiety-like behavior in the color preference test. Moreover, drug concentrations in zebrafish homogenates were examined. VPA, DZP, and PB significantly increased the seizure latency at three subsequent stages of seizures (SI–SIII). PHT produced the anticonvulsant-like effect at SI and SII, while CBZ was effective at SII and SIII. Only DZP decreased zebrafish locomotor activity. A strong anxiolytic-like effect was observed after administration of PHT and PB. A weak anxiolytic-like effect occurred after treatment with VPA and DZP. The HPLC analysis showed the average concentrations of the studied ASDs in the fish body during the maximum anticonvulsant activity of each drug. Our results confirm the advantages of using zebrafish with the mature CNS over larval models and its utility to investigate some neuropharmacological properties of the tested drugs.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats

Ethnopharmacological relevanceCentella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. Aim of the studyThe present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. Materials and methodsWistar rats (175–200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. ResultsThe VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. ConclusionThe results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Phenytoin–levetiracetam adjunctive treatment-induced neurotoxicity and deregulation of cholinergic neurotransmission with evidence of neurocognitive impairment in male Wistar rats

ABSTRACT Introduction The effects of chronic administration of phenytoin (PHT), levetiracetam (LEV), and PHT + LEV adjunctive treatments were examined on the cognitive functions of male rats. Methods Twenty-eight male Wistar rats (150–180 g) were randomized into 4 groups (N = 7). Groups I–IV received daily intraperitoneal administration of normal saline (0.2 ml), therapeutic doses of PHT (50 mg/kg), LEV (50 mg/kg) or sub-therapeutic dose of PHT (25 mg/kg) and LEV (25 mg/kg) combination, respectively, for 28 days. Thereafter, the animals were subjected to behavioral assessment and evaluation of the activities of acetylcholinesterase, lipid peroxidation, and lastly the morphological evaluation of the brain. Data were analyzed using descriptive and inferential statistics. The results were presented as mean ± SEM in graphs or tables, while the level of significance was taken at p < 0.05. Results Working & spatial memory, exploratory activities, and motor-coordination indices were significantly (p = 0.0099) impaired with a reduction in the frontal lobe and hippocampal weight following PHT and PHT + LEV adjunctive treatments. The frontal lobe and hippocampal activities of acetylcholinesterase increased significantly (p = 0.0437) following PHT and PHT + LEV adjunctive treatment. The concentrations of malondialdehyde increased significantly (p = 0.0473) in PHT, LEV, and PHT + LEV compared with the control. There was disorganization in the histoarchitectural profile with chromatolysis, hyalinization, and neural vacuolation in the pre-frontal cortex, hippocampus, and cerebellar tissue, especially in the PHT + LEV treated rats. Conclusion Impairment of cognitive functions following PHT and PHT + LEV adjunctive treatments may be attributable to the deregulation of cholinergic transmission and neurotoxicity.

Intranasal delivery of phenytoin-loaded nanoparticles to the brain suppresses pentylenetetrazol-induced generalized tonic clonic seizures in an epilepsy mouse model.

In this work we describe the preparation and characterization of lecithin-chitosan nanoparticles (L10Ci+), and investigate their ability to deliver the anti-epileptic drug phenytoin (PHT) to mouse brain following intranasal (IN) administration. L10Ci+ were retained in the nasal cavity compared to PHT in PEG200 solution (PHT/PEG), which suffered immediate nasal drainage. PHT was detected in the brain after 5 min of IN administration reaching a maximum of 11.84 ± 2.31 %ID g-1 after 48 hours. L10Ci+ were associated with a higher brain/plasma ratio (Cb/p) compared to the experimental control comprising free PHT injected via the intraperitoneal route (PHT-IP) across all tested time points. Additionally, L10Ci+ led to lower PHT accumulation in the liver and spleen compared to PHT-IP, which is vital for lowering the systemic side effects of PHT. The relatively high drug targeting efficiency (DTE%) of 315.46% and the drug targeting percentage (DTP%) of 68.29%, combined with the increasing anterior-to-posterior gradient of PHT in the brain confirmed the direct nose-to-brain transport of PHT from L10Ci+. Electroencephalogram (EEG) analysis was used to monitor seizure progression. L10Ci+ resulted in a complete seizure suppression after 4 hours of administration, and this inhibition persisted even with an 8-fold reduction of the encapsulated dose compared to the required PHT-IP dose to achieve a similar inhibitory effect due to systemic loss. The presented findings confirm the possibility of using L10Ci+ as a non-invasive delivery system of PHT for the management of epilepsy using reduced doses of PHT.

Synthesis and Formulation Development of Phenytoin by Inclusion Complexation

Phenytoin is a classical anticonvulsant drug used in the treatment of epilepsy. It is a Biopharmaceutics classification system class II drug that has poor aqueous solubility, which affects dissolution rate. The main objective of this study was to enhance the dissolution rate of phenytoin and formulate the optimized chewable tablet. The phenytoin sodium was chemically synthesized and its solubility was enhanced with inclusion complexation by the kneading method using beta-cyclodextrin. This results in increased solubility of phenytoin sodium from 0.0150 to 0.0171 g/ml and solubility was found to be directly proportional to concentration beta-cyclodextrin. Further, 22 factorial design was used to optimize phenytoin sodium chewable tablet with enhanced solubility. In vitro evaluations were done for all 12 formulations to find out the optimized formulation. We found the significant increase in the percentage of drug release, at the end of 2 h, for formulation B6 (81.66 %) and C12 (92.76 %). Also, the pre-compressional and post-compressional properties of B6 and C12 formulations were found to be within the acceptable rang of chewable tablets. In conclusion, the solubility of phenytoin sodium was enhanced and we successfully developed two (B6 and C12) optimized formulation of phenytoin sodium chewable tablet.

Phenytoin Attenuates Seizure Severity and Hippocampal Derangement than Levetiracetam or Phenytoin-Levetiracetam Adjunctive Treatment in Electrically-Convulsed Mice

This study evaluated the anticonvulsant and neuroprotective efficacy of individual or adjuvant treatment of two different antiepileptic-drugs (AEDs) phenytoin (PHT) and levetiracetam (LEV) against maximal electric shock in mice model. Twenty-five male Albino mice, randomized into five groups (n=5) received treatment as follows: groups 1 and 2 received intraperitoneal (i.p) administration of normal saline (0.1 ml), while groups 3-5 received a therapeutic dose of PHT (50 mg/kg BW) or LEV (50 mg/kg/day BW), or combination of PHT (25 mg/kg) and LEV (25 mg/kg) at sub-therapeutic doses. Thirty minutes later, the mice in groups 2-5 were challenged with maximal electroshock, while various indices of convulsion were determined, while the histomorphological profile of the hippocampus investigated. Data were analyzed using descriptive and inferential statistics with the help of graph pad prism software. The results were presented as mean ± SEM in the graph or table. The level of significance was taken at p<0.05. There was a decrease (p = 0.0001) in the duration of tonic flexion, tonic limb extension, clonic convulsion, stupor, and righting reflex in all the drug-treated groups compared with positive control. Also, the duration of clonic convulsion significantly decreased in the PHT (p = 0.0003) and PHT + LEV treated mice compared with LEV treated. There was significant (p = 0.0001) damage in the neuronal hippocampal tissue of the untreated mice. Funding Information: The authors declared that this research was self-sponsored. Declaration of Interests: The authors declared that this research was conducted in the absence of any commercial or financial relationships that could interpret as potential conflict of interest. Ethics Approval Statement: The experimental protocol was approved by the Health Research Ethics Committee, Institute of Public Health, Obafemi Awolowo University, Ile –Ife which also comply with the ARRIVE guidelines and should be carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments.

A diagnostic intoxication tool for clozapine and phenytoin using hybrid micelle liquid chromatography

Micellar liquid chromatography was employed for the quantification and separation of the antidepressant drug clozapine (CLZ) and antiepileptic agent phenytoin (PHY). This mixture was separated using C8 column operating at 40°C using a mobile phase consisting of 0.075 M sodium dodecyl sulphate (SDS), 10% acetonitrile, 0.3% triethylamine (TEA), adjusted to pH 2.5 by 2 M ortho-phosphoric acid and applying a simple gradient program starting with a flow rate of 0.8 mL/min for the first 10 min of analysis applying 220 nm as detection wavelength, followed by raising the flow rate to 1.5 mL/min till end of analysis, adopting UV detection wavelength of 250 nm. The proposed method was used to quantify the concentration of both (CLZ) and (PHY) in rat whole blood whether spiked or in vivo suggesting its utility as a diagnostic tool for intoxication with either drugs in emergency rooms.

Central inhibition prevents the in vivo acute toxicity of harmine in mice.

Harmine is a β-carboline alkaloid that displays antidepressant, antitumor and other pharmacological effects. However, the strong toxic effects limit its clinical application, and should be first considered. To evaluate the in vivo toxicity of harmine and explore intervention strategies against its toxicity. The in vivo toxicity of harmine was assessed from the symptoms, biochemical indices, and cardiovascular effects in mice. The intervention experiments were performed by using anesthetics, central drugs, and peripheral anticholinergics. The acute toxicity of harmine is significantly dose-dependent and the median lethal dose is 26.9 mg/kg in vivo. The typical symptoms include convulsion, tremor, jumping, restlessness, ataxia, opisthotonos, and death; it also changes cardiovascular function. The anesthetics improved the survival rate and abolished the symptoms after harmine poisoning. Two central inhibitors, benzhexol and phenytoin sodium, uniformly improved the survival rates of mice poisoned with harmine. The peripheral anticholinergics didn't show any effects. Harmine exposure leads to central neurological symptoms, cardiovascular effects and even death through direct inhibition of the central AChE activity, where the death primarily comes from central neurological symptoms and is cooperated by the secondary cardiovascular collapse. Central inhibition prevents the acute toxicity of harmine, and especially rapid gaseous anesthetics such as isoflurane, might have potential application in the treatment of harmine poisoning.

Physico-Chemical and Microbiological Study for the Stability of Phenytoin Sodium Extemporaneously Compounded Suspension in Saudi Arabia Hospitals

Epilepsy is a chronic and the fourth most common neurological disorder which affects people of all age groups. Recently research and awareness on epilepsy-related deaths have rapidly grown over the past two decades. Many previous studies are attributed to the guidelines that apprise health care professionals in handling these deaths, but there is a relative scarcity of information accessible for clinicians and pharmacists who are responsible for manufacturing or preparing the extemporaneous anti-epileptic suspensions in the hospitals. Mostly in partial seizures, phenytoin is one of the first-choice drugs. In Saudi Arabian hospitals, the extemporaneous preparation of phenytoin suspension is common, but the hot climatic weather in Saudi Arabia possesses stability problems that should be tackled as the prepared suspension should pass all the stability tests to ensure uniform dosage of the extemporaneous formulation. In the current study, the commercial capsules were used to prepare the oral phenytoin sodium extemporaneous suspension. The physical, chemical and microbiological stability of phenytoin sodium suspension is analyzed at various temperatures.

Influence of Ketogenic Diet and Phenytoin Sodium on Isoniazid Induced Epilepsy in Wistar Rats

Abstract: Aim: The current research was set up to estimate the influence of ketogenic diet in combination with phenytoin sodium on isoniazid induced epilepsy in rats. Methods: In this work 30 rats were used with weight range of 150-200gms were selected and divided into five groups. Group -1(Positive control), Group – II (Negative control), Group – III (Standard), Group – IV (Ketogenic diet), Group – V (Ketogenic diet + Standard). The doses of isoniazid, phenytoin sodium, ketogenic diet were selected and the work was executed for a period of 30 days. Results: At the end of the study animals were sacrificed to collect brain for estimating GABA levels in different groups. Results indicated that, there is a notable rise in levels of GABA which helps in reducing seizure latency when the ketogenic diet was added to that of standard drug. Conclusion: The change in levels of GABA when compared to the ketogenic diet alone and standard suggest that ketogenic diet along with standard drug may produce antiepileptic activity by increasing the levels of GABA in isoniazid induced epilepsy in rats. Key words: Epilepsy, Ketone diet, Isoniazid, Phenytoin, GABA.

Association between antiseizure medication use and risk of urinary tract infection: A case–control study

AimThe aim of this study was to analyze the association between antiseizure medication (ASM) and the risk of urinary tract infections (UTI) in patients with epilepsy treated in general practices in Germany. MethodsThis study includes a total of 2201 patients (mean age: 61.4) whose first documented UTI diagnosis occurred between January 2015 and December 2019 (index date) and who were prescribed at least one ASM in 1198 general practices in Germany within one year prior to the index date. Based on a case–control design, the association between predefined criteria and UTI was investigated by matching (1:1) controls without UTI to cases with UTI by sex, age, and codiagnoses. Logistic regression models were used to analyze the association between ASM use and UTI risk. ResultsIn the first regression model, phenytoin (PHT), primidone, carbamazepine (CBZ), and valproate (VPA) were associated with an increased risk of UTI. In the second model, these associations were confirmed with effects per prescription for PHT, primidone, CBZ, and VPA use. Additionally, the effect per prescription was significant for oxcarbazepine (OXC), topiramate, and gabapentin. ConclusionThe study found that PHT, primidone, CBZ, and VPA in particular are associated with an increased risk of infections of the urinary tract. Oxcarbazepine, topiramate, and gabapentin are also associated with increased risk of UTI, albeit to a less significant extent. In general, the immunological and hematological side effects of these molecules may play an important role in the development of UTI under anticonvulsant therapy.

Development and validation of an innovative UPLC method to quantify lacosamide, oxcarbazepine, and lamotrigine in the serum of children with epilepsy in China.

This study has developed and validated a novel UPLC method to quantify lacosamide (LCM), oxcarbazepine (OXC), and lamotrigine (LTG) in children with epilepsy in Xinjiang, China. Phenytoin sodium was used as the internal standard. The mobile phase contained ammonium dihydrogen phosphate solution (10 mmol/L, pH = 4.0) and methanol (55:45, v/v). The flow rate, injection volume, column temperature, and detection wavelength were 0.2 mL/min, 2 μL, 30°C, and 240 nm, respectively. The method was linear within 0.5-40, 2.5-80, and 2.5-40 μg/mL for LCM, 10-hydroxycarbazepine (MHD), and LTG, respectively (r2 ≥ 0.998). The intra- and inter-day precision as measured by the relative standard deviation values was between 1.36 and 4.50, 0.54 and 1.91, and 0.58 and 1.56%. Recovery ranged from 96.58 to 106.22%. All serum samples could be maintained for up to 3 h at ambient temperature, 24 h at 4°C, 30 days at -30°C, and after successive freeze-thaw cycles (24 h per cycle) in the absence of significant degradation.

Formulation of Orally Disintegrating Films as an Amorphous Solid Solution of a Poorly Water-Soluble Drug.

The objective of the present study was to develop an orally disintegrating film (ODF) for a poorly water-soluble drug, phenytoin (PHT), using the cosolvent solubilization technique to achieve the amorphization of the drug, followed by the preparation of ODFs. Eleven formulations were prepared with different polymers, such as polyvinyl alcohol (PVA) and high methoxyl pectin (HMP) by the solvent casting method. The prepared films were subjected to characterization for weight variations, thickness, surface pH, disintegration time and mechanical strength properties. Then, differential scanning calorimetry, X-ray diffraction analysis and the drug release patterns of the selected films were evaluated. Among the prepared formulations, the formulation composed of 1% w/w of PVA, 0.04% w/w of sodium starch glycolate with polyethylene glycol 400, glycerin and water as cosolvents (PVA-S4) showed promising results. The physical appearance and mechanical strength properties were found to be good. The PVA-S4 film was clear and colorless with a smooth surface. The surface pH was found to be around 7.47 and the in vitro disintegration time was around 1.44 min. The drug content of the PVA-S4 film was 100.27%. X-ray diffractometry and thermal analysis confirmed the transition of phenytoin in the PVA-S4 film into a partially amorphous state during film preparation using the cosolvent solubilization approach. The resulting PVA-S4 film showed a higher dissolution rate in comparison to the film without a cosolvent. Overall, this study indicated the influence of cosolvents on enhancing the solubility of a poorly water-soluble drug and its film dissolution.

Various Diseases and Clinical Heterogeneity Are Associated With "Hot Cross Bun".

Objective: To characterize the clinical phenotypes associated with the “hot cross bun” sign (HCBs) on MRI and identify correlations between neuroimaging and clinical characteristics.Methods: Firstly, we screened a cohort of patients with HCBs from our radiologic information system (RIS) in our center. Secondly, we systematically reviewed published cases on HCBs and classified all these cases according to their etiologies. Finally, we characterized all HCBs cases in detail and classified the disease spectra and their clinical heterogeneity.Results: Out of a total of 3,546 patients who were screened, we identified 40 patients with HCBs imaging sign in our cohort; systemic literature review identified 39 cases, which were associated with 14 diseases. In our cohort, inflammation [neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and acute disseminated encephalomyelitis (ADEM)] and toxicants [toxic encephalopathy caused by phenytoin sodium (TEPS)] were some of the underlying etiologies. Published cases by systemic literature review were linked to metabolic abnormality, degeneration, neoplasm, infection, and stroke. We demonstrated that the clinical phenotype, neuroimaging characteristics, and HCBs response to therapy varied greatly depending on underlying etiologies.Conclusion: This is the first to report HCBs spectra in inflammatory and toxication diseases. Our study and systemic literature review demonstrated that the underpinning disease spectrum may be broader than previously recognized.

Incidence rates of severe cutaneous adverse reactions due to antiseizure medication: A nationwide study using health claims data in Korea.

Antiseizure medications (ASMs) can rarely result in severe, sometimes fatal, cutaneous adverse reactions. To date, few studies have reported on the incidence rates (IRs) of severe cutaneous adverse reactions (SCARs) due to ASM use. This study aimed to determine the IRs of SCAR resulting from the use of seven commonly prescribed ASMs, carbamazepine (CBZ), phenytoin (PHT), oxcarbazepine (OXC), lamotrigine (LMT), zonisamide (ZNS), levetiracetam (LVT), and topiramate (TPM), and to compare the associated risks among the drugs. Using a nationwide health claims database, we selected all the patients prescribed with one of the target ASMs. We defined a SCAR case as the first hospitalization with one of three specific codes provided by the International Classification of Diseases, 10th revision (L511, L512, and L27). We then calculated the IR of SCARs according to each target ASM. The IR of SCARs for each ASM was as follows: 870/1000000 person-years (PYs) for CBZ, 5750/1000000 PYs for PHT, 1490/1000000 PYs for OXC, 3860/1000000 PYs for LMT, 1540/1000000 PYs for ZNS, 830/1000000 PYs for LVT, and 400/1000000 PYs for TPM. Concomitant use of antibiotics and nonsteroidal anti-inflammatory drugs significantly increased the risk of SCARs with OXC, LVT, or TPM use. Comorbid skin disease was associated with a significantly higher IR of SCARs from CBZ, PHT, OXC, LMT, or LVT use. This is the first study in Asia to determine the IRs of SCARs for various ASMs and compare the rates across drugs using a large dataset. The results from this study should help clinicians select safer ASMs in practice.

Farmacocinética poblacional de fenitoína en pacientes adultos

La fenitoína (DPH) es un antiepiléptico considerado de primera elección en el tratamiento de las crisis focales y convulsiones tónico-clónicas. DPH presenta elevada unión a proteínas plasmáticas, un comportamiento cinético no lineal dependiente de la dosis, elevada variabilidad cinética interindividual y un estrecho margen terapéutico; estas características aconsejan su monitorización para optimizar su balance eficacia/toxicidad. El objetivo de este trabajo fue la caracterización de la farmacocinética de DPH en población adulta. Concentraciones en estado de equilibrio de DPH procedentes de 215 pacientes adultos fueron utilizadas para desarrollar un modelo farmacocinético poblacional (PopPK) aplicando una metodología de efectos mixtos no lineales con el programa NONMEM v.7.3. La cinética de DPH fue descrita adecuadamente mediante un modelo monocompartimental con absorción de orden cero y cinética de eliminación no lineal ajustada a la ecuación de Michaelis-Menten. Edad, peso, magnitud de dosis y comedicación con ácido valproico han mostrado influencia sobre la velocidad de eliminación de DPH, reduciendo su variabilidad de forma considerable. Se ha obtenido un modelo PopPK preliminar que ha mostrado una adecuada capacidad descriptiva y predictiva en población adulta en un amplio rango de dosis (50-800 mg/día). No obstante, se precisa su aplicación en el contexto clínico para confirmar su validez.

Phenytoin induced Chorea: commonly used antiepileptic drug causing a rare movement disorder

Background: Phenytoin, a commonly prescribed antiepileptic drug, causes side effects like ataxia, tremor, hirsutism, gum hyperplasia, insomnia, confusion, headache and vertigo when used for longer duration. However, chorea is a rarely reported side effect of phenytoin and is completely reversible on stopping treatment. Case presentation: A twenty-one-year-old Indian male patient, who had generalized epilepsy and had been on sodium valproate for 2 years, presented with acute onset chorea four days after starting phenytoin sodium. He had normal serum phenytoin levels. A thorough evaluation was done, which suggested phenytoin as a possible cause of chorea. Phenytoin was withdrawn, resulting in a dramatic subsiding of chorea. A rechallenge with the drug resulted in reappearance of choreiform movements. These disappeared again after drug withdrawal, implicating phenytoin as the possible etiological agent for chorea. Conclusion: Phenytoin rarely induces involuntary movements as an adverse effect. During phenytoin therapy, if a patient develops involuntary movements, phenytoin toxicity should be suspected even with normal drug levels. This is important as drug withdrawal leads to complete symptomatic improvement thereby avoiding extensive workup for other secondary causes.

Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles.

Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship.

Hypothalamic-pituitary-testicular axis derangement following chronic phenytoin-levetiracetam adjunctive treatment in male Wistar rats.

The effects of phenytoin (PHT), levetiracetam (LEV) or their adjunctive treatment on the hypothalamic-pituitary-testicular axis in male Wistar rats were determined. Twenty-eight male rats (150-180g) were randomised into four groups (N=7). Groups I to IV received intraperitoneal treatment of either normal saline (0.2ml i.p) or PHT (50mg/kg i.p) or LEV (50mg/kg) or PHT (25mg/kg) and LEV (25mg/kg) combination for 28days. The organ weight, concentrations of reproductive hormones and semen profile were determined, while the brain, epididymis and testis were preserved in 10% neutral-buffered formalin for the histomorphological study. Data were analysed using descriptive and inferential statistics. The results were presented as mean±SEM in graphs or tables, while the level of significance was taken at p<.05. The semen profile was altered significantly in all the treatment groups. The gonadotrophic releasing hormone, luteinising hormone and testosterone concentration decreased significantly in the PHT- and PHT+LEV-treated groups compared with control. There were various disruptions in the hypothalamus, pituitary and testis of the PHT- and PHT+LEV adjunctive-treated rats. In conclusion, chronic PHT+LEV treatment may pose deleterious effects on the hypothalamic-pituitary-testicular axis than single treatment of either of the two drugs in male rats.