Neuroprotective properties of valproate

Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

Neuropharmacology and Drug Interactions in Clinical Practice

Summary: Absorption, distribution, and clearance are key pharmacokinetic principles. These parameters can be highly variable among patients and among compounds, and are factors that must be considered in the wide variability in response to medications. Current antiepileptic drugs (AEDs) present many challenges in their administration. However, understanding and utilizing pharmacokinetic principles can assist the clinician in the appropriate optimization of AEds.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

Effect of Zonisamide (CI-912) on a Synaptic System Model

The effect of the experimental antiepileptic drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide, ZNS) on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs. Intravenous administration of 10-40 mg/kg ZNS significantly depresses descending excitatory mechanisms, as well as segmental and descending inhibitory mechanisms, but has only a minor effect on segmental excitatory mechanisms. This spectrum of activity is similar to that of valproate, and suggests that ZNS should also be a broad-spectrum antiepileptic drug. In agreement with our experimental observations, it has been found that ZNS is effective against complex partial, generalized tonic clonic, and myoclonic seizures. The antiepileptic profile of ZNS in conventional screening tests resembles that of carbamazepine (CBZ) and phenytoin. However, CBZ exacerbates rather than prevents myoclonic seizures. Our experimental model thus provides a more accurate prediction of ZNS's clinical spectrum of activity. The relationship of these findings to the mechanism of action of antiepileptic drugs is discussed.     

Effect of Vigabatrin on the Electroencephalogram in Rats

Vigabatrin (gamma-vinyl GABA; GVG) is a new antiepileptic drug (AED) that increases the level of the inhibitory transmitter, gamma-aminobutyric acid (GABA) in the brain. We evaluated the effect of GVG on the EEG of normal rats. GVG was administered intraperitoneally (i.p.) at a dose of 100 mg/kg once a day for 12 days. EEG was recorded at baseline, on the fourth day, at the end of the 12-day GVG period and 10 days after discontinuation of GVG. GVG increased the amplitude of delta (1-4 Hz) and theta (4-8 Hz) frequency bands and resulted in slowing of the peak frequency (Fp) and mean frequency (Fm) in both the frontal and occipital cortex, especially during waking-immobility. EEG changes normalized within 10 days after the last GVG injections. The results suggest that a relationship may exist between the EEG changes and increase in GABA levels with GVG.     

Effects of Carbamazepine on Murine Humoral and Cellular Immune Responses

Summary: Oral administration of carbamazepine (CBZ)(15, 10, or 5 mg/kg) to mice significantly decreased both humoral and cellular immune responses evaluated by enumeration of direct and indirect plaque-forming spleen cells (PFC) and delayed–type hypersensitivity reaction (DTH) against sheep red blood cells (SRBC) as compared with those observed in normal control animals. Moreover, spleen T cells obtained from CBZ–treated donor mice were capable of decreasing both PFC and DTH responses of normal spleen cells transferred into lethally irradiated recipient animals. The immunodepressor effect of CBZ was observed even though administration of CBZ induced augmentation of spleen cellularity.     

Electrochemistry of Anticonvulsants: Electron Transfer as a Possible Mode of Action

Reduction potentials were determined for various anticonvulsants, including progabide, SL 75.102, CGS 9896, pyridazines, zonisamide, 1,2,3-triazoles, and copper complexes. The values generally were in the range of about -0.1 to -0.6 V for the protonated drugs and the metal complexes. Reduction potentials provide information on the feasibility of electron transfer (ET) in vivo. If the value is relatively positive (greater than about -0.6 V), the agent can act catalytically as an electron acceptor from an appropriate cellular donor. A concomitant favorable influence on abnormal neuronal processes associated with epilepsy could occur. We describe ET as a possible mode of action of anticonvulsants as well as some antiepileptic agents with no electrochemical data based on this hypothetical ET approach.     

Anticonvulsant Activities of 4–Bromobenzaldehyde Semicarbazone

Summary: Some of the properties of 4–bromobenzalde-hyde semicarbazone (compound IV), a prototype molecule of a new class of anticonvulsants, aryl semicarbazones, are described. Compound IV demonstrated activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) tests in mice, with low neurotoxicity. When given orally to rats, it displayed high potency in the MES test and very low neurotoxicity, resulting in a high protective index (PI). Compound IV displayed no proconvulsant properties, and development of rapid tolerance was not noted. When administered intraperitoneally (i.p.) at doses of 100, 300, or 600 mg/kg to rats, compound IV had no effect on levels of γ-aminobu-tyric acid (GABA) or on GABA-T activity in whole brain. When tested in vitro, compound IV had no effect on rat brain GABA-T at a drug concentration of 100 μM. Although the activities of certain drug-metabolizing enzymes were increased after oral administration of compound IV to rats, these effects were less prominent than those of phenytoin (PHT) and carbamazepine (CBZ). The principal mode of action of compound IV does not appear to be an interaction with the GABA_A receptor complex, and other mechanisms, involving excitatory amino acid neurotransmission, will have to be considered in future investigations of the anticonvulsant activity of this compound.     

空管药物疗法治疗牙髓病和根尖周病疗效观察

用ＳＭＴＤ复合药物对牙髓病和根尖周病实施空管药物疗法。７８例１０３颗获得完整随访资料患牙经两年观察，９２．２％治愈率。文章介绍了治疗方法，讨论了空管药物疗法的愈合机理、优点、失败原因及其预防措施。