China
Africa
Explore chapters and articles related to this topic
Mephenytoin
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Since MHT is comparable to PHT in terms of efficacy, the decision to use MHT often depends on the difference of their adverse effects. Dose-related adverse effects (the production of ataxia or mental dulling) tend to be significantly less prominent with MHT (2). Because of this MHT can frequently be substituted for PHT when the latter has proven inappropriate in specific patients because of the dose-related adverse effects. Some patients do report sleepiness at “therapeutic” levels of MHT/nirvanol, but this adverse effect is qualitatively very different from what is experienced by patients taking PHT. On some occasions, therefore, it is appropriate to use smaller doses of both agents to achieve a “combined hydantoin level” (the sum of the total MHT and PHT levels) that is effective (20 to 40 pg/ml) (2). This is one of the rare instances in usage of antiepileptic agents where the addition of the same primary antiepileptic effect by the use of more than one drug is valuable.
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
During pregnancy, phenytoin can produce fetal hydantoin syndrome characterized by hypoplastic phalanges, cleft palate, hare lip, and microcephaly. Intake of phenytoin during pregnancy and presence of maternal epoxide (EPHX1) genotypes 113*H and 139*R are linked with increased risk of fetal hydantoin syndrome (Medscape, 1994–2018).
Medications That May Be Useful in the Management of Patients with Chronic Intractable Pain
Published in Michael S. Margoles, Richard Weiner, Chronic PAIN, 2019
The primary site of action of the hydantoins appears to be the motor cortex, where the spread of abnormal electrical activity is inhibited. Possibly by promoting sodium efflux from neurons, hydantoins tend to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient.
Challenges in the development of next-generation antibiotics: opportunities of small molecules mimicking mode of action of host-defense peptides
Published in Expert Opinion on Therapeutic Patents, 2020
Minghui Wang, Timothy Odom, Jianfeng Cai
Other small molecules being explored in preclinical phase are also quite meaningful [9]. Teng et al. reported a series of small antibacterial compounds based on the acylated reduced amide scaffold, which has excellent broad-spectrum bactericidal activity [5]. They built their HDPs mimics through systematically adjusting cationic parts such as amino or guanidino group, and hydrophobic portion including adamantyl group, phenyl group, biphenyl group, and naphthyl group. The best compound (Figure 1(c)) showed good and rapid bactericidal activity against both Gram-positive and Gram-negative strains with high selectivity. Su et al. greatly improved the antibacterial activity of hydantoin derivates through combining the hydantoin core and the characteristics of HDPs (Figure 1(d)), which exhibited much better activity than nitrofurantoin. They applied a panel of alkyl lipid tail as hydrophobic domain and used versatile short alkyl chains or bulky groups to modify the hydantoin core [10].
Quantitative structure–activity relationship models for compounds with anticonvulsant activity
Published in Expert Opinion on Drug Discovery, 2019
Carolina L. Bellera, Alan Talevi
Over the years, Brown and coworkers have implemented a series of 3D QSAR campaigns focused on neuronal voltage-gated sodium channel, using the CoMFA approximation. In the first of them [65], they used a series of fourteen 5-phenylhydantoin analogues as training sample and in vitro sodium channel binding activity as a dependent variable. The model derived from such training data was used to accurately predict the activity of a small 7-compound test set including hydantoin analogues and carbamazepine. The CoMFA steric and electrostatic maps described two general features that enhanced binding to the sodium channel: a preferred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. The model was used to design the structurally novel R-hydroxy-R-phenylamide, which was evaluated on the sodium channel revealing an IC50 in the low micromolar range (predicted IC50 = 9 µM, actual IC50 = 9 µM!), which is, in fact, more potent than phenytoin itself. This novel compound also served to propose that the intact hydantoin ring is not necessary for efficient binding to the correspondent binding site.
Aldose reductase inhibitors: 2013-present
Published in Expert Opinion on Therapeutic Patents, 2019
Luca Quattrini, Concettina La Motta
Products that appeared to be promising during in vitro studies or in trials with animal models often failed to proceed any further showing uncertain results in clinical trials with humans. Their failure was often due to the emergence of adverse side effects: the clinical development of sorbinil (1, Figure 3), the progenitor of the hydantoin-based inhibitors, was discontinued because of hypersensitivity reactions related to the presence of hydantoin ring [17]. Tolrestat (2, Figure 3), the key representative of the carboxylic acid inhibitors class, displayed severe liver toxicity [18], and the same was also true for the parent acid zopolrestat (6, Figure 3) [19]. In addition, a significant number of compounds under investigation showed limited clinical efficacy, often caused by an inappropriate dosing schedule of the inhibitor or by an unfitting pharmacokinetic tethered with its absorption, distribution, metabolism, and excretion properties. The observed difficulties led to a general and understandable decrease of scientific interest on this enzyme and its inhibitors, which dragged out till the beginning of the 2000s (Figure 2).