Vigabatrin for tuberous sclerosis complex.
ABSTRACT Vigabatrin (VGB) was found to be an effective anti-epileptic drug to reduce infantile spasms in about 50% of patients and it has been found most effective in infantile spasms due to tuberous sclerosis (TSC) in which up to 95% of infants had complete cessation of their spasms. VGB was synthesized to enhance inhibitory gamma-aminobutyric acidergic (GABAergic) transmission by elevating GABA levels via irreversible inhibition of GABA transaminase. The mechanism underlying the particular efficacy of VGB in TSC is still unknown. However, its efficacy suggests that epileptogenesis in TSC may be related to an impairment of GABAergic transmission. VGB should be considered as the first line monotheraphy for the treatment of infantile spasms in infants with confirmed diagnosis of TSC. The efficacy of VGB treatment can be assessed in less than 10 days, but usually a few days treatment with a dose of about 100 mg/kg/day stops infantile spasms. The cessation of the spasms is associated with a marked improvement of behaviour and mental development. Unfortunately, it has become clear that the use of VGB is associated with a late appearance of visual-field defects in up to 50% of patients. Currently the minimum duration and doses of VGB treatment that can produce side effects are unknown. The feasibility of using short treatment periods (2-3 months) should be investigated.
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ABSTRACT: A series of [(η5-C5H5)Ru(DMPP)2L]PF6 complexes, DMPP = 1-phenyl-3,4-dimethylphosphole, L = CH3CN, Ph3P, PhS(O)2CHCH2, (CH3)2NC(O)CHCH2, PhNC, CO and (CH3O)3P, was found to undergo sunlight initiated [2 + 2] photodimerization of the coordinated phospholes only when L is a good π-acceptor ligand. These [2 + 2] dimerizations are accompanied by [4 + 2] dimerizations. The ratio of the [2 + 2] to [4 + 2] cycloaddition products is a function of the steric bulk of L. The nature of the photoexcited state has been probed by electron absorption and emission spectroscopy. The electron absorption spectra show high ɛ bands in the near UV region that are attributed to DMPP π → π* transitions. The emission spectral lifetimes are a function of L and their magnitude at 77 K (about 0.2 to 2.0 μs), together with large Stokes shifts, is indicative of phosphorescence from a triplet excited state. It is postulated that this triplet excited state undergoes cycloaddition by way of a biradical intermediate. The complexes have been characterized by elemental analyses, infrared, electronic, and 1H, 1H31P, 13C1H and 31P1H NMR spectroscopy and cyclic voltammetry. The structure of (η5-C5H5)Ru(DMPP)2[2 + 2](CO)PF6 was confirmed by X-ray crystallography. The complex cation possesses a non-crystallographic mirror plane, the two RuP distances (2.282(1) and 2.281(2) Å) are equivalent and the cyclobutane ring has a long (1.607(8) Å) and a short (1.550(8) Å) CC bond.Journal of Organometallic Chemistry 02/1997; 529(s 1–2):395–408. · 2.30 Impact Factor
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ABSTRACT: Background Tuberous Sclerosis Complex is a genetic multi-system disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mTOR, a key player in control of cellular growth and protein synthesis. The most frequent neurologic symptoms are seizures, which occur in up to 90% of patients and are often intractable, followed by autism spectrum disorders, intellectual disability, ADHD and sleep problems. Conventional treatment has frequently proven insufficient for neurologic and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation, and recent mechanism-based treatment approaches. Methods We performed a literature review to identify ongoing therapeutical challenges and novel strategies. Results To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Animal studies have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using MR diffusion tensor imaging and EEG support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors. Conclusions Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutical approach.Pediatric Neurology 01/2013; · 1.50 Impact Factor
- Epilepsy & Seizure 01/2008; 1(1):1-10.