A case report on the efficacy of vigabatrin analogue (1 S , 3 S )-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms

Doumlele, Kyra; Conway, Erin; Hedlund, Julie; Tolete, Patricia; Devinsky, Orrin

doi:10.1016/j.ebcr.2016.08.002

Cited by 24 publications

(25 citation statements)

References 14 publications

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“…Of interest, this model predicted a better efficacy‐tolerability profile of CPP‐115, a vigabatrin analogue with higher affinity for GABA aminotransferase and lower risk for retinal toxicity, at significantly lower doses than vigabatrin . Indeed, it was rewarding that a recently published case report of an infant with refractory IS treated with CPP‐115 corroborated these data in the clinical setting …”

Section: Inflammation In Infantile Spasms Epileptogenesis: Recent Promentioning

confidence: 97%

“…21 Indeed, it was rewarding that a recently published case report of an infant with refractory IS treated with CPP-115 corroborated these data in the clinical setting. 22 LPS is known to trigger the release of proinflammatory cytokines and generate further inflammation and gliosis. Indeed, elevated expression of cytokines like interleukin-1b (IL-1b), and tumor necrosis factor a (TNFa) as well as astro-and microgliosis are seen in the perilesional regions of pups treated with the multiple-hit rat model protocol.…”

Section: Inflammation In Infantile Spasmsmentioning

confidence: 99%

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Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

et al. 2017

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Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Here, we discuss the progress on animal models of epilepsies and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler’s murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of pro-inflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both of these inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology- specific therapies for the epilepsies and attendant comorbidities, including the drug resistant forms.

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Section: Inflammation In Infantile Spasms Epileptogenesis: Recent Promentioning

confidence: 97%

Section: Inflammation In Infantile Spasmsmentioning

confidence: 99%

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

et al. 2017

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“…There is need for both the discovery of novel therapeutic candidates as well as the careful reevaluation of various second‐line therapies for which efficacy is uncertain. It is also possible that our current first‐line therapies may be reinvented: There is potential that ACTH fragments or analogues may yield a more favorable balance of efficacy and safety, and that a contemporary VGB analogue (CPP‐115) may exhibit greater potency and safety than VGB itself . It is important to note that with recognition that the cumulative relapse rate approaches 50% among children followed to age 4 years, our patients require therapies that can be initiated in infancy and safely continued for several years to mitigate the risk of relapse.…”

Section: Future Aimsmentioning

confidence: 99%

Treatment of infantile spasms

Hussain

2018

Epilepsia Open

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SummaryThe treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well‐tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long‐term administration. In evaluating any treatment for infantile spasms, the key short‐term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long‐term outcomes are enduring seizure‐freedom and measures of intellectual performance in later childhood and adulthood. First‐line treatment options—namely hormonal therapy and vigabatrin—display moderate to high efficacy but also exhibit substantial side‐effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second‐line therapies supported by less‐compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol—the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.

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“…As expected, phenytoin has no effect on spasms in this model (Ono, Moshe & Galanopoulou 2011). This model has been extensively used for the screening of new potential therapies for IS, including a promising experimental drug CPP-115 (more potent vigabatrin analogue with lower risk for retinal toxicity) (Briggs, Mowrey, Hall & Galanopoulou 2014) which was recently clinically tested in a case report with very similar efficacy (Doumlele, Conway, Hedlund, Tolete & Devinsky 2016). In addition, other new drugs showing efficacy in this model include a drug with broad-spectrum anti-epileptic effect in experimental animal models of seizures (carisbamate) and an mTOR inhibitor rapamycin (Ono, Moshe & Galanopoulou 2011, Raffo, Coppola, Ono, Briggs & Galanopoulou 2011).…”

Section: Does Activation Of the Inflammatory Pathways In The Brainmentioning

confidence: 99%

Inflammation in Epileptic Encephalopathies

Shandra

Moshé

Galanopoulou

2017

Stress and Inflammation in Disorders

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West syndrome (WS) is an infantile epileptic encephalopathy (EE) that manifests with infantile spasms, hypsarrhythmia (in ~60% of infants) and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12–15%) or of unknown origin. The current treatment options include hormonal treatment [adrenocorticotropic hormone (ACTH) and high dose steroids], the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate pro-inflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of West syndrome? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

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A case report on the efficacy of vigabatrin analogue (1 S , 3 S )-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms

Cited by 24 publications

References 14 publications

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

Treatment of infantile spasms

Inflammation in Epileptic Encephalopathies

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