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At least 19 recordsLinked to original sources
PubMed1976

Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome.

The fetal hydantoin syndrome is a variable pattern of altered growth and performance which includes unusual facies, distal phalangeal hyoplasia, and other defects occurring in some infants exposed in utero to hydantoins. A prospective study of 35 infants exposed prenatally to this class of anticonvulsants showed that 11% had sufficient features to be classified as having the fetal hydantoin syndrome. An additional 31% displayed some features compatible with the prenatal effects of hydantoins. A case-control study of 104 infants whose mothers received hydantoins during pregnancy supports these conclusions. Reduction of intellectual ability in infants with the fetal hydantoin syndrome is the area of greatest concern. Women being treated with hydantoin anticonvulsants should be told of the nature and magnitude of risks to the developing fetus before considering a pregnancy.

Abnormalities, Drug-Induced↗
PubMed1981

Biopharmaceutical studies on hydantoin derivatives. I. Physico-chemical properties of hydantoin derivatives and their intestinal absorption.

The physico-chemical properties of a series of hydantoin derivatives and their intestinal absorption from solution were studied. The introduction of the benzenesulfonyl group at the 1-position of the hydantoin ring greatly affects the physico-chemical properties: the acid dissociation constants were increased 1000-fold and the partition coefficients were increased 100- to 1000-fold in the chloroform/water system and 10- to 100-fold in the n-octanol/water system. The solubilities of 1-benzenesulfonylhydantoin derivatives increased with increasing pH of the solution at pH more than 5, but the solubilities of the 1- unsubstituted hydantoin derivatives were scarcely dependent on the pH of the solution in the pH 1 to 8 region. The intestinal absorption from solution was found to be caused by the passive transport according to the first-order kinetics. The rate constants of absorption of 1-benzenesulfonylhydantoin derivatives were rather large even under the condition where they were 99% ionized in the solution than that of the corresponding 1-unsubstituted hydantoin derivatives which exist mainly as the unionized from under the same condition. The intestinal absorption from a solution and the partitioning to chloroform produced linear free energy relationships to each other for the 1-benzenesulfonylhydatoin derivatives and for the 1-unsubstituted hydantoin derivatives independently. However when the partition coefficients in the n-octanol/water system were applied, the hydroxyl derivatives were found to deviate from linear relationships. On the basis of the results, a suggestion was made on the in vivo behavior and the bioavailability.

Animals↗
PubMed1982

Biopharmaceutical studies on hydantoin derivatives. II. Pharmacokinetics and bioavailability of hydantoin derivatives in dogs.

Pharmacokinetics and bioavailability for the 1-benzenesulfonylhydantoin derivatives and 1-unsubstituted hydantoin derivatives were evaluated from the plasma concentrations after oral and intravenous administrations to dogs. Apparent volume of distribution of the 1-benzenesulfonylhydantoin derivatives was about 0.25 l/kg, while that of the 1-unsubstituted hydantoin derivatives was about 1.3 l/kg. The result suggests that introduction of the benzenesulfonyl group at 1-position of the hydantoin ring has marked effect on the distribution into the fluids and tissues of the body. Bioavailabilities of sodium 5,5-diphenylhydantoin and sodium 1-benzenesulfonyl-5,5-diphenylhydantoin exceeded those of their corresponding free forms. The results were well explicable in terms of the excellent dissolution behaviours of the salt forms. The bioavailabilities of 5-ethyl-5-phenylhydantoin and 1-benzenesulfonyl-5-ethyl-5-phenylhydantoin were almost perfect. The results suggest that the dissolution rate is a rate-determining step in the bioavailability of the derivatives having two phenyl groups at 5-position of the hydantoin ring, irrespective of the presence of the benzenesulfonyl group at 1-position.

Administration, Oral↗
PubMed2006

Topochemical models for the prediction of voltage-gated sodium channel binding activity of hydantoins and related non-hydantoins.

The relationship of Wiener's topochemical index-a distance based topochemical index, molecular connectivity topochemical index-an adjacency based topochemical index and eccentric connectivity topochemical index-an adjacency-cum-distance based topochemical index with sodium channel binding activity has been investigated. A dataset comprising 50 hydantoins and related non-hydantoins was selected. The dataset was divided equally into training and test sets. The values of the three topochemical indices for all the compounds present in both the training and test sets were computed using an in-house computer program. The resulting data was analyzed and suitable models were developed after identification of the active ranges in the training set. Subsequently, a biological activity was assigned to each compound involved in the training set using these models, which was then compared with the reported sodium channel binding activity. An accuracy of prediction of the order of >99% was observed using the proposed models. Cross-validation of these models using the test set revealed an exceptionally high accuracy of approximately 95%.

Chemistry, Pharmaceutical↗
PubMedDate not supplied

Synthesis and cytotoxicity of platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin and 3-aminocycloheptanespiro-5-hydantoin.

Four new platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin (acpsh) and 3-aminocycloheptanespiro-5-hydantoin (achpsh) were synthesized and characterized by elemental analysis, IR and 1NMR spectra. The spectral analyses indicated a cis-square planar structure of the complexes with ligands coordinated via the NH2 group. The complexes were evaluated for in vitro cytotoxicity in murine erythroleukemia (MEL) cells, clone F4N, using cell-growth and macromolecular synthesis assay. The compounds, with exception of [Pt(NH3)(achpsh)Cl2] (IV), exhibited much lower cytotoxicity than that of cisplatin (DDP). Compound IV was nearly as cytotoxic as DDP. The new complexes exerted low antibacterial activity as assessed by seven bacterial strains.

Animals↗
PubMed1988

Patch test reactivity to DMDM hydantoin. Relationship to formaldehyde allergy.

The relationship between contact allergy to formaldehyde and positive patch test reactions to DMDM hydantoin was investigated. 35 formaldehyde-allergic patients were patch tested with serial dilutions of formaldehyde (0.1%-0.3%-1.0% aq.) and DM hydantoin (the non-formaldehyde-containing parent compound of DMDM hydantoin). 21 were also patch tested with MDM hydantoin (1 molecule formaldehyde) in serial dilutions: 7 (33%) reacted to 1 or more concentrations. The other 14 were also tested with DMDM hydantoin (2 molecules formaldehyde) in serial dilutions: 8 (57%) reacted to 1 or more concentrations. Patients patch-test-positive to formaldehyde 0.1% and/or 0.3% tended to show more patch test reactivity to (D)MDM hydantoin than those who reacted only to 1%. Aqueous solutions of (D)MDM hydantoin in concentrations as used in cosmetic products therefore contain enough free formaldehyde to cause dermatitis in a patch test system in some formaldehyde-allergic patients: 12 such patients applied a cream containing 1% DMDM hydantoin to the flexor aspect of the lower arm twice daily for 1 week; 4 (33%) developed dermatitis. The use of a cream containing 0.25% DMDM hydantoin in these 4 patients still caused dermatitis in 1 and provoked itching in another. An increase in the use of DMDM hydantoin in cosmetic products will also inevitable increase the risk of cosmetic dermatitis in consumers allergic to formaldehyde.

Cosmetics↗
PubMed1985

Fetal hydantoin syndrome: inhibition of placental folic acid transport as a potential mechanism for fetal growth retardation in the rat.

Maternal hydantoin ingestion during pregnancy results in a well defined clinical entity termed "fetal hydantoin syndrome". The clinical characteristics of this syndrome includes growth retardation, and congenital anomalies. Because folic acid is essential for protein synthesis and growth, and since hydantoin interferes with intestinal transport of folic acid, we postulated that part of the fetal hydantoin syndrome may be due to inhibition of placental folic acid by maternal hydantoin. Therefore, we studied in vivo placental folate transport in a well-established model for fetal hydantoin syndrome in the rat. Our results indicate that maternal hydantoin ingestion, significantly decreased fetal weight and placental and fetal uptake of folate compared to controls. To determine whether maternal hydantoin ingestion has a generalized or specific effect on placental function, we examined placental and fetal zinc transport in the same model. Our results indicate that zinc transport is not altered by hydantoin ingestion. We conclude that maternal hydantoin ingestion results in fetal growth retardation which may be due in part to inhibition of placental folate transport.

Animals↗
PubMed1994

Bicyclic hydantoins with a bridgehead nitrogen. Comparison of anticonvulsant activities with binding to the neuronal voltage-dependent sodium channel.

The anticonvulsant activity of diphenylhydantoin (DPH or phenytoin) is consistent with its actions on the neuronal voltage-dependent sodium channel. To further elucidate the binding requirements for this site, we synthesized several hydantoin analogs and evaluated these in in vitro sodium channel-binding and/or in vivo whole animal anticonvulsant assays. 5-Pentyl-5-phenylhydantoin (8), the most potent binder to the sodium channel in this study, had the same affinity as DPH (IC50 = 40 microM), revealing that one phenyl ring is sufficient for good interactions. Since our previous studies with monophenyl-substituted bicyclic 2,4-oxazolidinediones suggested that N3-alkylation and the conformational constraint of a 5-alkyl substituent over one face of the oxazolidinedione ring improved activity, we synthesized two examples of analogous bicyclic hydantoins. However, the bicyclic hydantoins were much less potent binders to the neuronal voltage-dependent sodium channel than their monocyclic counterparts. The binding activity for the more potent bicyclic hydantoin, 1,8-diaza-9,10-dioxo-7-phenylbicyclo[5.2.1]decane (4) (IC50 = 427 microM), was comparable to that of the ring-opened, N3-methylated monocyclic hydantoin model, 5-butyl-3-methyl-5-phenylhydantoin (9) (IC50 = 285 microM), and these were 8-11 times less potent than the monocyclic model 8, which contains a free imide NH. Furthermore, 5-butyl-5-phenylhydantoin (7; IC50 = 103 microM) was less potent than 8, suggesting that increased log P may enhance binding. Thus, unlike 2,4-oxazolidinediones, N3-alkylation of hydantoins dramatically decreases sodium channel-binding activity. Bicyclic hydantoin 4 was nevertheless a good anti-MES anticonvulsant in mice (ED50 = 86 mg/kg), although this activity likely results from mechanisms other than interactions at the neuronal voltage-dependent sodium channel. Compound 4 was also relatively neurotoxic (TD50 = 124 mg/kg). These results suggest that the binding of hydantoins to the sodium channel may be enhanced by (a) a free imide NH group and (b) an increased log P. Furthermore, 2,4-oxazolidinediones and hydantoins must either orient differently in the same binding site or interact with different sites on the neuronal voltage-dependent sodium channel.

Alkylation↗