The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

Markowitz, Geoffrey J.; Kadam, Shilpa D.; Boothe, Dawn M.; Irving, Natasha D.; Comi, Anne M.

doi:10.1097/wnr.0b013e328338ba18

Cited by 45 publications

(32 citation statements)

References 20 publications

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“…Phenobarbital has been reported to have a half-life of ~16 h in neonatal mice [59], and a range of 9 to 20 h has been reported in adult rats [60]. By contrast, retigabine has a half-life in the range of 2 h; thus levels of phenobarbital in the present study likely remained elevated substantially longer than those of retigabine.…”

Section: Discussionmentioning

confidence: 54%

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Frankel

Medvedeva

Gutherz

et al. 2016

Epilepsy & Behavior

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Anticonvulsant drugs, when given during vulnerable periods of brain development, can have long-lasting consequences on nervous system function. In rats, the second postnatal week approximately corresponds to the late third trimester of gestation/early infancy in humans. Exposure to phenobarbital during this period has been associated with deficits in learning and memory, anxiety-like behavior, and social behavior, among other domains. Phenobarbital is the most common anticonvulsant drug used in neonatology. Several other drugs, such as lamotrigine, phenytoin, and clonazepam have also been reported to trigger behavioral changes. A new generation anticonvulsant drug, retigabine, has not previously been evaluated for long-term effects on behavior. Retigabine acts as an activator of KCNQ channels, a mechanism that is unique among anticonvulsants. Here, we examined the effects retigabine exposure from postnatal day (P)7 to P14 on behavior in adult rats. We compared these effects to those produced by phenobarbital (as a positive control) and saline (as a negative control). Motor behavior was assessed using the open field and rotarod, anxiety-like behavior by the open field, elevated plus maze, and light-dark transition task, and learning/memory by the passive avoidance task; social interactions were assessed in same-treatment pairs and nociceptive sensitivity was assessed via the tail-flick assay. Motor behavior was unaltered by exposure to either drug. We found that retigabine and phenobarbital exposure both induced increased anxiety-like behavior in adult animals. Phenobarbital, but not retigabine exposure impaired learning and memory. These drugs also differed in their effects on social behavior, with retigabine-exposed animals displaying greater social interaction than phenobarbital-exposed animals. These results indicate that neonatal retigabine induces a subset of behavioral alterations previously described for other anticonvulsant drugs, and extend our knowledge of drug-induced behavioral teratogenesis to a new mechanism of anticonvulsant action.

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Section: Discussionmentioning

confidence: 54%

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Frankel

Medvedeva

Gutherz

et al. 2016

Epilepsy & Behavior

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“…These data suggest that higher plasma levels of CZP are necessary to affect motor behavior. While data on the pharmacokinetics of CZP in rats are sparse (Hoogerkamp et al, 1996) showed that the terminal half-life of CZP in adult rats is approximately 1 h. Given that immature organisms eliminate CZP more slowly than adults (Markowitz et al, 2010), we speculate that factors other than the sedative effects of CZP are responsible for the alteration of the HR in P12 animals. Interestingly, home-response impairment was also observed in P23 animals, the oldest group tested.…”

Section: Discussionmentioning

confidence: 72%

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Mikulecká

Šubrt

Stuchlı́k

et al. 2014

Front. Behav. Neurosci.

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Clinical and experimental studies suggest possible risks associated with the repeated administration of benzodiazepines (BZDs) during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP) on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day) was administered from postnatal day (P)7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1) a homing response (HR) test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2) passive avoidance was tested in three trials (at 0, 2 and 24 h intervals) on P12, P15, P18, P25 and P32 rats; (3) within- and between-session habituation was tested in an open field (OF) at P70; and (4) a long-term memory (LTM) version of the Morris water maze (MWM) was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the HR and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test). The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to emotional/motivational responsiveness.

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“…These CSF and serum levels compare well with those reported previously in canine and small animal models. 59−61 We compared this to the dendrimer serum (35 μg/mL) and CSF (0.25 μg/mL) levels (2 h after IV administration of 5 mg/kg of D-FITC as in the biodistribution studies above, Figure 3). Since the dendrimer was administered at a much lower level (20-fold), on an equal mass basis, the dendrimer would have a higher serum level but lower CSF level compared to free VPA.…”

Section: Resultsmentioning

confidence: 99%

Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest

Mishra¹,

Beaty

Lesniak³

et al. 2014

ACS Nano

130

161

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Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.

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The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

Cited by 45 publications

References 20 publications

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest

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