PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Hydantoins”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

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↗
PubMed1992

Effect of L-penicillamine hydantoin, an analogue of glutathione, on rat liver glutathione peroxidase, reductase and transferase reactions.

In soluble fractions prepared from rat liver homogenates, L-penicillamine hydantoin appeared to be, on the basis of SH consumption measurements, a substrate for glutathione peroxidase but not transferase reactions. When glutathione is incubated with rat liver soluble proteins in the presence of penicillamine hydantoin, formation of oxidized glutathione is inhibited. Calculations from Lineweaver-Burk plots point out that inhibition by L-penicillamine hydantoin of the peroxide-dependent oxidations of glutathione is mixed, since both apparent Km and Vmax values are modified. Preincubation of rat liver soluble proteins with L-penicillamine hydantoin led to a progressive inactivation of glutathione peroxidase. The kinetics of this inactivation process with respect to time and inactivator concentration were studied. Inclusion in the preincubation mixture of SH-containing molecules such as dithiothreitol, L-cysteine or glutathione protected the enzyme against inactivation. However, none of these molecules and neither hydantoin, Triton X-100, phenol, nor dialysis could reverse the enzyme from inactivated to activated form. Mitochondrial glutathione peroxidase was inhibited and inactivated by L-penicillamine hydantoin to the same extent as its cytosolic counterpart. Modifications by penicillamine hydantoin of various subcellular markers enzymes (lactate dehydrogenase, N-acetyl beta-glucosaminidase, arylsulfatase C, butyryl-CoA dehydrogenase, lauryl-CoA and glycolate oxidases) were of weak amplitude consisting of either inhibition, inactivation or stimulation.

Animals↗
PubMed1992

Purification and characterization of the hydantoin racemase of Pseudomonas sp. strain NS671 expressed in Escherichia coli.

The hydantoin racemase gene of Pseudomonas sp. strain NS671 had been cloned and expressed in Escherichia coli. Hydantoin racemase was purified from the cell extract of the E. coli strain by phenyl-Sepharose, DEAE-Sephacel, and Sephadex G-200 chromatographies. The purified enzyme had an apparent molecular mass of 32 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. By gel filtration, a molecular mass of about 190 kDa was found, suggesting that the native enzyme is a hexamer. The optimal conditions for hydantoin racemase activity were pH 9.5 and a temperature of 45 degrees C. The enzyme activity was slightly stimulated by the addition of not only Mn2+ or Co2+ but also metal-chelating agents, indicating that the enzyme is not a metalloenzyme. On the other hand, Cu2+ and Zn2+ strongly inhibited the enzyme activity. Kinetic studies showed substrate inhibition, and the Vmax values for D- and L-5-(2-methylthioethyl)hydantoin were 35.2 and 79.0 mumol/min/mg of protein, respectively. The purified enzyme did not racemize 5-isopropylhydantoin, whereas the cells of E. coli expressing the enzyme are capable of racemizing it. After incubation of the purified enzyme with 5-isopropylhydantoin, the enzyme no longer showed 5-(2-methylthioethyl)hydantoin-racemizing activity. However, in the presence of 5-(2-methylthioethyl)hydantoin, the purified enzyme racemized 5-isopropylhydantoin completely, suggesting that 5-(2-methylthioethyl)hydantoin protects the enzyme from inactivation by 5-isopropylhydratoin. Thus, we examined the protective effect of various compounds and found that divalent-sulfur-containing compounds (R-S-R' and R-SH) have this protective effect.

Cloning, Molecular↗
PubMed1979

[Fetal hydantoin syndrome in siblings].

The two children of an epileptic woman who underwent therapy with hydantoin during both pregnancies showed the characteristic findings of the fetal hydantoin syndrome: growth retardation, microcephaly, mental retardation, and a distinct hysmorphic pattern. Both exhibited a ridged metopic suture, hypertelorism, a short nose with a broad base, hypoplasia of the distal phalanges and nails of the toes, and inguinal hernias. In addition the 18-month-old girl exhibited epicanthal folds, strabismus, ptosis, and a small ventricular septal defect; she had been exposed in utero to 300 mg mesantoin daily. Her 6 1/2-year-old brother was more severely retarded, lacking speech and presenting with infantile autism. During pregnancy the mother had taken 400 mg mesantoin daily. About half of the offspring of epileptic women treated with hydantoin during pregnancy are mentally retarded, and 11% exhibit in addition the pattern of dysmorphic findings known as the fetal hydantoin syndrome. Hydantoin should therefore be strictly avoided in epileptic women of child-bearing age unless safe contraceptive measures are taken. In the event of pregnancy, therapeutic abortion should be considered if hydantoin therapy must be maintained.

Abnormalities, Multiple↗
PubMed1976

Relationship of molecular structure to in vivo scintigraphic distribution patterns of carbon-11 labeled compounds. 3. (11C)Hydantoins.

The preparation and gamma-scintigraphic evaluation of the in vivo distribution patterns in dogs of a series of structurally related hydantoins labeled with the positron emitting, 20.4 min half-life radionuclide, carbon-11 are described. Carbon-11 labeled HCN was collected in water or aqueous Me2SO containing carrier KCN following cyclotron bombardment of 99% N2-1% H2 gas mixture with 22 MeV protons for 1 hr at 25-35 muA. Five 11C-labeled 5,5-dialkylhydantoins, three [11C]diarylhydantoins, five [11C]-5-alkyl-5-phenylhydantoins, and five [11C]spirohydantoins were prepared by heating generally under pressure, a mixture of 11C-labeled KCN, which was produced by isotopic exchange with carrier KCN, the corresponding aldehyde or ketone, and excess (NH4)2CO3 in aqueous ethanol or Me2SO solvent. The 11C-labeled hydantoins were dissolved in 1-1.5% aqueous NaOH for intravenous administration to dogs. Total synthesis time was 70-106 min and 1-59 mCi of final product was available for conducting serial in vivo imaging for up to 2 hr or more with the gamma-scintillation camera. Carbon-11 activity from all compounds showed initial blood-pool distribution with variable concentration of activity in the brain, lungs, liver, and kidney. All of the 11C-labeled diarylhydantoins, and most having one phenyl substituent, and one having a hexamethylene moiety showed initial accumulation of 11C activity in brain. Carbon-11 labeled 5,5-diphenylhydantoin (dilantin) showed the greastest qualitative accumulation of activity in the brain. Those 11C-labeled hydantoins having a carboxyl substituent showed prominent renal concentration and urinary excretion of activity. Most 11-c-labeled hydantoins showed a progressive homogenous whole body distribution of activity in all cellular tissues of the body. The relatively uniform distribution of activity in cellular tissues and slow excretion from the body support the thesis that the pharmacologic action of the hydantoins is related to physical effects on biomembranes rather than to specific chemical interactions with cell constituents.

Animals↗
PubMed1975

Purinylhydantoins. Facile conversion of the naturally occurring N-(purin-6-ylcarbamoyl)-L-amino acids into 3-pruin-6-ylhydantoins and 3-cyclohexyl-1-(purin-6-ylcarbamoyl)hydantoins.

The naturally occurring N-(purin-6-ylcarbamoyl)-L-threonine (PCT, 1b), N-(purin-6-ylcarbamoyl)glycine (PCG, 1a), and some of their analogs were converted into novel purine derivatives, the purinylhydantoins. The PCT and PCG underwent intramolecular cyclization in the presence of N,N-dicyclohexylcarbodiimide (CDD) to give the 3-purin-6-ylhydantoins (2a-c). The same hydantoins were also obtained when the PCT and PCG were allowed to react through the mixed anhydride formed from cyclohexyl isocyanate or ethyl chloroformate. 1,3-Dicyclohexyl-1-(N-(purin-6-ylcarbamoyl)aminoacyl)ureas 3a and 3c, by-products obtained from the DCC reaction, were rapidly converted in aqueous NaOH to another type of purinylhydantoins, the 3-cyclohexyl-1-(purin-6-ylcarbamoyl)hydantoins 4a and 4b. Compound 4a when heated in base underwent hydrolysis of the hydantoin ring giving biuret N-(cyclohexylcarbamoyl)-N-(purin-6-ylcarbamoyl)glycine (5a) and N-(purin-6-ylcarbamoyl)glycine cyclohexylamide (6a). The characterization of these hydantoins was carried out by uv, nmr, and mass spectrometry. The 3-purin-6-ylhydantoins and 3-cyclohexyl-1-(purin-6-ylcarbamoyl)hydantoins showed growth inhibitory activity in the cultured leukemic cells, while the parent amino acid compounds were inactive.

Amino Acids↗
PubMed1975

[Malignant lymphoma following years of hydantoin treatment for epilepsy].

The cases are presented of 4 hydantreated epileptic patients developing malignant lymphomas (1 Hodgkin's lymphoma). The duration of the hydantoin therapy ranged from 7 to 23 years. There was no evidence of an allergic drug reaction, with the exception of slight blood eosinophilia. Prior to the lymphoma one patient exhibited leukopenia and a second thrombocytopenia. Hydantoins were discontinued in 3 cases but the lymphomas never disappeared spontaneously and only once did tumor progression came to a stillstand. Two patients were successfully treated with either chemo- or radiotherapy. Possible correlations between the documented immunosuppressive action of hydantoin derivatives and tumor induction are discussed. Malignant lymphomas may be sequelae of long-term hydantoin therapy and are not always preceded by the well-known reversible hydantoin lymphadenopathy.

Drug Hypersensitivity↗
PubMed1992

Identification and sequencing of a gene encoding a hydantoin racemase from the native plasmid of Pseudomonas sp. strain NS671.

DNA fragments containing the genes involved in the conversion of 5-substituted hydantoins to their corresponding L-amino acids have been cloned from the 172-kb native plasmid (pHN671) of Pseudomonas sp. strain NS671. The largest recombinant plasmid, designated pHPB14, encoded the ability to convert D-5-substituted hydantoins to the corresponding L-amino acids, whereas the smallest one, designated pHPB12, encoded the ability to convert them to their corresponding N-carbamyl-D-amino acids. Restriction analysis suggested that the inserts of both recombinant plasmids are derived from the identical portion in pHN671 and that the insert of pHPB14, compared with that of pHPB12, has an extra 5.3 kb in length. DNA sequencing revealed that pHPB14 contains two additional complete open reading frames, designated ORF5 and hyuE. Analysis of deletion derivatives of pHPB14 indicated that hyuE is required for the ability to produce L-amino acids from the corresponding D-5-substituted hydantoins, but ORF5 is not. Cells of Escherichia coli transformed with a plasmid containing hyuE were capable of racemizing different 5-substituted hydantoins, indicating that hyuE is a gene encoding a hydantoin racemase.

Amino Acid Sequence↗
PubMed1975

Hydantoin immunosuppression and carcinogenesis.

The immunological response of mice submitted to hydantoin treatment was determined. Hydantoin reduced the absolute number of spleen cells in treated animals and did not modify spleen cells reactivity to concanavalin A, although the response to SRBC challenge, as measured by the Jerne plaque-forming cell technique, was significantly decreased. Following these findings, the influence of hydantoin on carcinogenesis was evaluated by using the model of urethane-induced lung adenomas in SWR mice. Treatment with hydantoin significantly reduced the incidence of the induced adenomas. We confirmed that hydantoin modifies the immune response of the host mainly by depressing its humoral function and we have shown that this effect was associated with an inhibitory effect on tumour induction.

Adenoma↗
PubMed1976

IgA deficiency, epilepsy, and hydantoin medication.

Serum-immunoglobulin concentrations were measured in 364 patients with epilepsy. On dividing the patients into those treated with or without hydantoins, and according to possible aetiological factors, a characteristic pattern emerged. Irrespective of the treatment given, the mean values of IgA were significantly reduced in patients in whom constitutional factors were apparent, including those with familial prevalence of seizures. While IgA was rarely found below 0-6 mg/ml, a limit chosen to define IgA deficiency in patients not treated with hydantoins, the IgA level was subnormal in 20-25% of the patients treated with such drugs. In contrast, the mean concentration of IgA was normal and no individual subnormal values were observed in epileptic patients treated with or without hydantoins whose disease was thought to be secondary to traumatic or infectious events or to metabolic disturbances. The data suggest that epilepsy with constitutional characteristics might predispose to low IgA, but that IgA deficiency only occurs when hydantoins are given. Whether this postulated predisposition is relevant to the aetiology or pathogenesis of epilepsy remained unresolved.

Child↗
PubMed1979

Kinetics of carboxymethylation of histidine hydantoin.

The reaction of the imidazole group of histidine hydantoin with bromoacetate was studied as a model for carboxymethylation of histidine residues in proteins. pK values of 6.4 and 9.1 (25 degrees C) and apparent heats of ionization of 7.8 and 8.7 kcal/mol were determined for the imidazole and hydantoin rings, respectively. At pH values corresponding to the isoelectric points for histidine hydantoin, the rates of carboxymethylation at 12, 25, 37, and 50 degrees C were determined; the modified hydantoins were hydrolyzed to the corresponding histidine derivatives for quantitative amino acid analysis. At pH 7.72 and 25 degrees C, the imidazole tele-N was alkylated (k = 3.9 X 10(-5) M-1 s-1) twice as fast as the pros-N. The monocarboxymethyl derivatives were carboxymethylated at the same rate at the pros-N (k = 2.1 X 10(-5) M-1 s-1) but 3 times faster at the tele-N (k = 11 X 10(-5) M-1 s-1). The enthalpies of activation determined for carboxymethylation of the imidazole ring and its monocarboxymethyl derivatives were similar (15.9 +/- 0.7 kcal/mol). delta S for the four carboxymethylations was -25 +/- 2 eu. The electrostatic component of delta S (delta S es) was calculated from the influence of the dielectric constant on the reaction rate at 25 degrees C. delta S es was slightly negative (-4 +/- 1 eu) for mono- or dicarboxymethylations, indicating some charge separation in the transition state. The nonelectrostatic entropy of activation was -21 +/- 2 eu for all four carboxymethylations.

Acetates↗
PubMed1992

Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors.

The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.

Aldehyde Reductase↗
PubMed1991

Drug-metal interactions: spectroscopic studies of copper hydantoin complexes.

The preparation and spectral properties of copper(II) complexes of two hydantoins are reported. Complexes of the general formula Cu(hyd)2(py)2, where hyd = phenytoin or nirvanol; and py = pyridine were prepared and characterized by infrared and ESR. Spectral data show that the copper atom is bound to the nitrogen atom of the hydantoin anion and to the nitrogen atom of the pyridine molecule to form 2:2:1 hydantoin:pyridine:copper complexes. The ESR data indicate that both complexes have tetragonal symmetry (g11 greater than g perpendicular greater than g e) with the unpaired electron in the d x2-y2 orbital.

Copper↗
PubMed1977

[Development of new antiepileptics. II. Anticonvulsant effect of hydantoin derivatives].

From a series of N-substituted hydantoin derivatives, 1-phenyl-3-(o-chloro-p-sulfonamide-phenyl)-hydantoin was found to exhibit the best anticonvulsant activity against electroshock seizures. This substance showed also a weak activity against pentylenetetrazole seizures, as well as minor analgesic and sedative effects. The toxic effects are negligible; the lethal dose in mice was higher than 5000 mg/kg p.o. The other tested hydantoin derivatives showed much weaker anticonvulsant activities.

Analgesics↗
PubMedDate not supplied

[Effect of hydantoins on urinary excretion of 5-hydroxyindoleacetic acid].

The investigations were carried out in 10 patients with epileptic seizures. The obtained results were compared with those in a control group of 20 healthy subjects. The 24-hour urinary excretion of 5-HIAA efore hydantoinal and on the 1st, 2dn and 3rd days of hydantoinal administration was determined by the method of Udenfried et al. as modified by McFarlane et al. It was found that healthy subjects excreted significantly more 5-HIAA before and after hydantoinal load. Administration of this drug increased significantly the excretion of this metabolite with urine, in healthy subjects but in epileptics it had no significant effect on 5-HIAA level in 24-hour urine.

Adolescent↗
PubMed1979

Ganglioneuroblastoma and fetal hydantoin-alcohol syndromes.

A ganglioneuroblastoma developed in a 35-month-old boy with both the fetal hydantoin and fetal alcohol syndromes. Our case, plus two recent reports in the literature, would very likely establish the relationship between fetal hydantoin syndrome and the development of neural crest tumors. Infants exposed in utero to hydantoins should be closely observed for the development of these tumors.

Abnormalities, Drug-Induced↗
PubMed1978

Ultrastructural studies on hydantoin induced lymphomas in mice.

Ultrastructural studies were done on cells from original tumors and from short time cultures of mouse thymic lymphomas experimentally induced by chronic exposure to diphenyl-hydantoin. The tumors appeared in mouse strains with low (C57Bl) and high (SJL/J) susceptibility to spontaneous lymphoma development and were not observed in a resistant strain (C3Hf). Thymic lymphoma development was usually preceded by increasing lymphoreticular atrophy followed by progressive reticulohistiocytic hyperplasia, and subsequently spread to other tissues. Morphologically the tumor was characterized as a lymphoblastic lymphoma. Abnormal cell changes in the original tumors and cultured cells, and the presence of murine C-type particles in the cultured cells but not in the original tumors, are discussed in relation with the disturbance of immune system and the lymphoma enhancement produced by diphenyl-hydantoin.

Animals↗