Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats

Svalheim, Sigrid; Taubøll, Erik; Surdova, Kristina; Ormel, Lasse; Dahl, Ellen; Aleksandersen, Mona; McNeilly, Alan S.; Gjerstad, Leif; Ropstad, Erik

doi:10.1016/j.seizure.2007.11.018

Cited by 31 publications

(30 citation statements)

References 29 publications

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“…If a child responded to LEV in the ICU, had no adverse effects noted acutely, and had an indication for additional anticonvulsant therapy, continuing LEV would be a reasonable choice (38). However, recent data have demonstrated that while generally superior to older anticonvulsants in terms of adverse events, newer anticonvulsants are also associated with long-term effects (39) including behavior changes (40, 41) in humans and endocrine (42) and bone growth effects in animals (43). As further data emerge comparing the newer anticonvulsants for long-term use, decisions regarding appropriate anticonvulsants for acute use in an ICU setting and prolonged use in an outpatient setting may need to be separated.…”

Section: Discussionmentioning

confidence: 99%

Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures

Abend

Monk

Licht

et al. 2009

Pediatric Critical Care Medicine

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Objective-Intravenous (IV) levetiracetam (LEV) is approved for use in patients older than 16 years and may be useful in critically ill children, although there is little data available regarding pharmacokinetics. We aim to investigate the safety, an appropriate dosing, and efficacy of IV LEV in critically ill children.Design-We describe a cohort of critically ill children who received IV LEV for status epilepticus, including refractory or nonconvulsive status, or acute repetitive seizures.Results-There were no acute adverse effects noted. Children had temporary cessation of ongoing refractory status epilepticus, termination of ongoing nonconvulsive status epilepticus, cessation of acute repetitive seizures, or reduction in epileptiform discharges with clinical correlate.Conclusions-IV LEV was effective in terminating status epilepticus or acute repetitive seizures and well tolerated in critically ill children. Further study is needed to elucidate the role of IV LEV in critically ill children. Keywordslevetiracetam; status epilepticus; seizure; pediatric Intravenous (IV) levetiracetam (LEV) has been approved for use by the U.S. Food and Drug Administration in patients aged 16 years and older (1), but there is little data available regarding pharmacokinetics, tolerability, or efficacy in younger children. Additionally, LEV has not been approved by the Food and Drug Administration for treatment of acute seizures. LEV is a broadspectrum anticonvulsant and can be administered rapidly as a loading dose over 15 minutes, although adult studies suggest infusion times of 5 minutes are well tolerated (2). Pharmacokinetically, LEV completely avoids hepatic metabolism, which may prove beneficial in complex patients with liver dysfunction or metabolic disorders or those patients at risk for major drug interactions. In comparison with other IV anticonvulsants, LEV has few known adverse effects, including a low risk of sedation, cardiorespiratory depression, or coagulopathy, and thus is potentially useful in critically ill pediatric patients. We present data on a cohort of critically ill children who received IV LEV for status epilepticus or acute repetitive seizures. MethodsThis is a retrospective case series of critically ill children who received IV LEV for status epilepticus or acute repetitive seizures at The Children's Hospital of Philadelphia between For information regarding this article, abend@email.chop.edu. NIH Public Access ResultsTen children were identified who received IV LEV for status epilepticus or acute repetitive seizures in the pediatric ICU (Table 1). The median age was 5 years and range was 0.08-14 years. Loading dose of LEV ranged from 6.5 to 31 mg/kg. Indications for therapy included nonconvulsive status epilepticus refractory to other anticonvulsant medications in three children, nonconvulsive status epilepticus with LEV as the first-line anticonvulsant in two children, acute repetitive seizures in four children (nonconvulsive in two patients, clinical in two patients), and periodic epileptifo...

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Section: Discussionmentioning

confidence: 99%

Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures

Abend

Monk

Licht

et al. 2009

Pediatric Critical Care Medicine

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“…Administration duration of LEV was chosen according to the completion time of spermatogenesis and was in accordance with the guideline OECD 416: Guideline For Testing of Chemicals: Two-Generation Reproduction Toxicity Study [12], and doses of LEV were determined according to previous studies [13–15]. Also, the therapeutic doses of LEV were between 500 mg/day and 3000 mg/day [11] and the doses we have chosen were in accordance with the guidelines extrapolating human doses to animal doses [16].…”

Section: Methodsmentioning

confidence: 99%

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress

et al. 2017

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Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are potential contributors to reproductive toxicity.

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“…Low-dose LEV was found to impair longitudinal skeletal growth and increase the risk of fractures in immature rats [140]. LEV was found to affect serum estradiol levels, suggesting that young and female individuals might be at risk of fractures with long-term use of LEV [141]. However, other reports [142,143] did not observe this effect.…”

Section: New Generation Aedsmentioning

confidence: 99%

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

Fan

Lee

Chang

et al. 2016

IJMS

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Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.

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Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats

Abstract: Our findings indicate a possible effect of LEV on the hypothalamic-pituitary-gonadal (HPG) axis and ovarian morphology in non-epileptic rats. The effects differ from those previously described for other AEDs. Caution must be taken before these results can be applied to humans.

Cited by 31 publications

References 29 publications

Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures

Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

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