Ramya Varadarajan

Introduction. Neonatal seizures are commonly attributed to irregular accumulations of high levels of Cl- in neonatal neurons.^1,4,6,7 This leads to difficulty in administering phenobarbital (a GABAergic medication) as a treatment for seizures, as opening of GABA channels leads to neuronal depolarization due to Cl- efflux rather than the expected influx.^2,4,7 Bumetanide has been studied as an adjunct to phenobarbital by blocking NKCCl co-transporters and preventing intracellular Cl- accumulation, but it penetrates poorly into the CNS due to its hydrophilic carboxyl side group.^2,3,8 Recent research has explored derivatives of bumetanide with greater CNS incorporation but similar efficacy.⁸  Methods. To compare the efficacy and safety of phenobarbital and levetiracetam in neonates, a randomized, blinded, controlled phase IIb clinical trial was utilized.³  Bumetanide was compared with several derivatives that achieve greater CNS penetration by using adult rodent models to determine level of drug effectiveness in attenuating seizure activity and associated side effects.^3,5,8  A lipophilic prodrug of bumetanide was analyzed by injecting the drug into adult and neonatal serum to determine rate of metabolism.⁸  Results. 20-40 mg/kg phenobarbital is more effective at attenuating seizure activity in neonates than 40-60 mg/kg levetiracetam, but with more side effects.³  Azosemide and torasemide are diuretic derivatives of bumetanide that also block NKCCl co-transporters but have a longer elimination half-life than bumetanide. They do not achieve greater brain:plasma levels overall.⁵  Bumepamine is a benzylamine derivative that has 16% greater brain tissue binding than bumetanide, but incorporates into brain tissue slowly, increasing the risk of off-target effects.⁴  DIMAEB is a bumetanide prodrug that has higher levels in brain tissue than bumetanide after systemic administration, and neonatal serum is capable of metabolizing DIMAEB to bumetanide at a comparable rate to adult serum, but it is easily taken up into off-target organs.⁸  Conclusions. Studies have found that phenobarbital can be used to treat neonatal seizures, but it is sometimes ineffective due to the irregular Cl- gradient in neonatal neurons.^1,4,6  Variants of bumetanide can be used as an adjunct to phenobarbital; the higher the lipophilicity of these variants, the greater the likelihood of CNS penetration, but with a greater associated risk of organ burden.^4,5,8  Future research should continue developing derivatives of bumetanide that have high CNS incorporation but a low risk of off-target effects.

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