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p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The fungicide Iprodione is widely applied in vegetables and raises concern for human health. The A549 human lung carcinoma cell line is a suitable model for assessing the toxicological effects of drugs. The goal of this work was to evaluate the genotoxicity and oxidative stress in the A549 cell line exposed to sublethal concentrations from 3 to 100 µg/mL Iprodione considering LC50 = 243.4 µg/mL Iprodione, as determined by the MTT assay. Generalized Linear Mixed Models (GLMM) were performed to determine the association between the responses NDI, MNi m and MNi b and the explanatory variables. Iprodione and solvent were relativized to the control whereas the concentration was included as numeric variable. ANOVA was used for the comparison of treatments. The coefficients of linear association between the explanatory variables and NDI, and the coefficients of logistic association between explanatory variables and MNi m were not significant. However, these coefficients showed significant association with MNi b only for Iprodione treatment but not for Iprodione concentration, indicating lack of dose-response relationship. Genotoxicity risk assessment indicated that the increase in Iprodione concentrations increased slightly the probability of belonging to the genotoxic category. ANOVA showed significant differences in MNi b , and non-significant differences in NDI and MNi m among treatments. The oxidative stress analysis performed at 3, 12, and 25 μg/mL Iprodione showed a significant and linear increase in SOD, and a significant and linear decrease in GSH and GST. The Dunnett test was significant for GSH at 12 and SOD at 25 μg/mL.

A novel nanocomposite poly(ethylene-co-vinyl acetate) (EVA) film with controlled in vitro release of iprodione (ID) was prepared. Chitosan (CS) was used as the reinforcement which enhances the water and oxygen permeability of films. ID loaded poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) (IPP) micelles were used as the drug carrier which endows the films with antifungal and controlled release ability. IPP micelles with spherical shape and uniform size were obtained, and the maximum encapsulation efficacy (EE) was 91.17 ± 5.03% by well controlling the feeding amount of ID. Incorporation CS could improve the oxygen and moisture permeability of films, and the maximum oxygen permeability (OP) and water vapor transmission rate (WVTR) were 477.84 ± 13.03 cc/(m 2 ·d·0.1 MPa) and 8.60 ± 0.25 g m -2 d -1 , respectively. After loading IPP micelles, the films showed an improved antifungal ability and temperature-sensitive drug release behavior, and were found to enhance the quality of grapes by pre-harvest spraying., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5-membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes-two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD 7.4 , aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins.

Objectives: Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche., Methods: Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1(nu)) mice., Results: Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1(nu)) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo., Conclusions: Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effects., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A creatinine metabolite, 5-hydroxy-1-methylhydantoin (HMH: NZ-419), a hydroxyl radical scavenger, has previously been shown to confer renoprotection by inhibiting the progression of chronic kidney disease in rats. In the current study, we demonstrate that HMH modulates the effects of glucose and bradykinin (BK) in vascular smooth muscle cell (VSMC). HMH a novel anti-oxidant drug completely suppressed the expression of B2-kinin receptors (B2KR) in response to high glucose (25 mM) stimulation in VSMC and was also shown to attenuate the effects of BK on VSMC remodeling. HMH inhibited the BK-induced increase in MAPK phosphorylation and attenuated the increase in connective tissue growth factor (CTGF) protein levels in VSMC. These findings suggest that HMH may confer vascular protection against high glucose concentrations and BK-stimulation to ameliorate vascular injury and remodeling through its anti-oxidant properties.

The distribution of AZD7903 and/or its metabolites was studied in rats following a single p.o. or i.v. dose using quantitative whole-body autoradiography (QWBA). At 5 min after i.v. administration of the ¹⁴C compound, high levels of radioactivity were observed in the fundus of the stomach compared to blood and plasma and the rest of the stomach, indicating an active secretion of ¹⁴C material into the stomach. Also, excretion and pharmacokinetics were studied following p.o. and i.v. dosage in rats. The radioactivity was mainly excreted via feces, and even in i.v. administered bile-duct cannulated (BDC) animals a significant part of radioactivity (26% in males and 57% in females) was recovered in the feces in the form of parent compound and two minor metabolic products. The compound was well absorbed (F% 98 in males and 76 in females), and showed low clearance in plasma (0.14 L/h/kg in males and 0.03 L/h/kg in females) and low-intermediate Vd(ss) (0.7 L/kg). Clear differences in metabolic pathways (qualitative) and rates (quantitative) and consequently in PK parameters between sexes were observed. In summary, the results indicate AZD7903 being substrate for a transporter protein and support the hypothesis that the differences in disposition between sexes are due to differences in metabolic pathways and rates.

Considering the rise of antibiotic resistance, the development of new antibacterial agents with improved biocidal functions is urgently required. In this study, ionic 5,5-dimethylhydantoin (DMH) analogues containing either a quaternary ammonium moiety (2)-4) or a phosphonate functional group (5),-6), were designed and synthesized to investigate the possible enhancing effect of quaternary ammonium moieties on the antibacterial performance of N-chloramines. These ionic DMH analogues were converted to their N-chloramine counterparts either in free form or after being covalently immobilized on a polymer surface via the "click" chemistry method. In the subsequent antimicrobial assessment against multi-drug-resistant Escherichia coli (MDR-E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), chlorinated 2 and 3, the cyclic N-chloramines with a structural cation, exhibited distinctly enhanced biocidal functions in solution and after immobilization on surfaces., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

To study the structure activity relationship (SAR) on the cytotoxic activity and probe the structural requirement for the potent antitumor activity, a series of novel diazaspiro bicyclo hydantoin derivatives were designed and synthesized. Their structures were confirmed by (1)H NMR, LCMS and IR analyses. The antiproliferative effect of these compounds were determined against human leukemia, K562 (chronic myelogenous leukemia) and CEM (T-cell leukemia) cells using trypan blue and MTT assay, and the SAR associated with the position of N-terminal substituents in diazaspiro bicyclo hydantoin have also been discussed. It has been observed that these compounds displayed strong, moderate and weak cytotoxic activities. Interestingly, compounds having electron withdrawing groups at third and fourth position of the phenyl ring displayed selectively cytotoxic activities to both the cell lines tested with IC(50) value lower than 50 muM. In addition, the cytotoxic activities of the compounds 7(a-o) bearing the substituents at N-3 position of diazaspiro bicyclo hydantoin increases in the order alkene > ester > ether and plays an important role in determining their antitumor activities. The position and number of substituents in benzyl group attached to N-8 of diazaspiro bicyclo hydantoin nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.

The majority of prostaglandins (PGs) are known to induce intestinal fluid secretion (enteropooling). In contrast, PGD(2) has been demonstrated to inhibit fluid secretion induced by other PGs. This study was aimed to investigate, by the use of selective agonists/antagonists, which type of PGD(2) receptor mediates this inhibitory effect. The DP1 agonist BW245C dose-dependently inhibited the enteropooling effect of 16,16-dimethyl-PGE(2). This inhibition was counteracted by the DP1 antagonist BWA868C. In contrast, the CRTH2 receptor does not seem to be involved in the anti-enteropooling effect of PGD(2), since the selective agonists 13,14-dihydro-15-keto-PGD(2) and 15(R)-15-methyl-PGD(2) were without effect. Therefore, our results suggest that the inhibitory effect of PGD(2) in the small intestine is mediated via activation of the DP1 receptor., (Copyright 2008 S. Karger AG, Basel.)

This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.

A novel, durable, long lasting, N-halamine siloxane monomer precursor, 5,5'-ethylenebis[5-methyl-3-(3-triethoxysilylpropyl)hydantoin] has been prepared and characterized by (1)H-NMR and FTIR for the purpose of functionalizing the surfaces of various materials. In this work, the precursor N-halamine moiety was attached by siloxane covalent bonding to surfaces of cotton fibers. Simulated laundering tests indicated that the chlorinated N-halamine structure could survive many repeated home launderings. The materials were rendered biocidal after exposure to oxidative halogen solutions, i.e. dilute household bleach. Once chlorinated, these materials were biocidal against Staphylococcus aureus and Escherichia coli. Upon loss of the halogen from either long-term use or consumption by the microbes on the surfaces, they could be simply recharged by further exposure to dilute bleach to regain biocidal activity.

Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling necrosis. It can be induced in a FADD-deficient variant of human Jurkat T cells treated with TNF-alpha. 5-(1H-Indol-3-ylmethyl)-2-thiohydantoins and 5-(1H-indol-3-ylmethyl)hydantoins were found to be potent necroptosis inhibitors (called necrostatins). A SAR study revealed that several positions of the indole were intolerant of substitution, while small substituents at the 7-position resulted in increased inhibitory activity. The hydantoin ring was also quite sensitive to structural modifications. A representative member of this compound class demonstrated moderate pharmacokinetic characteristics and readily entered the central nervous system upon intravenous administration.

1. Prostaglandin D (DP) receptor agonists have been shown to induce hypotension in rat models, possibly via peripheral vasodilation. However, it is not known which tissues and organs are most responsive. 2. In the present study, BW245C, a DP receptor-selective agonist, was administered to Inactin (Sigma, St Louis, MO, USA)-anaesthetized rats. Animals received three serial i.v. infusions (17 min each) of either BW245C (escalating doses of 0.3, 3 and 30 microg/kg; n=6) or vehicle (6% ethanol in normal saline; n=6). Mean arterial pressure (MAP) and heart rate were monitored continuously and regional blood flow was determined by the radionuclide-labelled microsphere method at baseline and at the end of each infusion. 3. It was found that BW245C dose-dependently reduced MAP; blood flow increased in forelimb skeletal muscle and skin, resulting in decreases in the regional vascular resistance (RVR) of skeletal muscle to -6+/-13, -53+/-11 and -68+/-6% of baseline following 0.3, 3 and 30 microg/kg BW245C, respectively (P<0.05 vs vehicle treatment for the two higher doses), and skin to -29+/-8, -55+/-8 (P<0.05) and -30+/-16% of baseline, respectively. Relative to vehicle, blood flow and RVR for brain, heart, lung, liver, stomach and kidney were not significantly affected by BW245C. 4. These results demonstrate that the hypotension resulting from DP receptor activation in the rat is mediated primarily through vasodilation of arterioles of skeletal muscle independent of changes in blood flow to vital organs.

15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ2), which is a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induced apoptosis of several human tumors including gastric, lung, colon, prostate, and breast. However, the role of PPARgamma signals in other types of cancer cells (e.g., leukemia) except solid cancer cells is still unclear. The aim of this study is to evaluate the ability of 15dPGJ2 to modify the proliferation of the human leukemia cell line THP-1. 15dPGJ2 at 5 microM stimulated the proliferation in THP-1 at 24 to 72 h after incubation. In contrast, 15dPGJ2 at concentrations above 10 microM inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2, and Delta12-PGJ2 (DeltaPGJ2), precursors of 15dPGJ2, had similar proliferative effects at lower concentrations, whereas they induced apoptosis at high concentrations. 15dPGJ2 and three precursors failed to induce the differentiation in THP-1 as assessed by using the differentiation marker CD11b. FACScan analysis revealed that PGD2 at 5 microM, PGJ2 at 1 microM, DeltaPGJ2 at 1 microM and 15dPGJ2 at 5 microM all accelerated cell cycle progression in THP-1. Immunoblotting analysis revealed that PGD2 at 5 microM and 15dPGJ2 at 5 microM inhibited the expression of phospho-p38, phospho-MKK3/MKK6, and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p21, and p27 in THP-1. In contrast, PGJ2 at 1 microM and DeltaPGJ2 at 1 microM did not affect their expressions. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 mitogen-activated protein kinase pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of the THP-1 proliferation.

PGD(2) is the major mediator released by mast cells during allergic responses, and it acts through two different receptors, the D prostanoid receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown that PGD(2) inhibits the migration of epidermal Langerhans cells to the skin draining lymph nodes (LNs) and affects the subsequent cutaneous inflammatory reaction. However, the role of PGD(2) in the pulmonary immune response remains unclear. Here, we show that the intratracheal instillation of FITC-OVA together with PGD(2) inhibits the migration of FITC(+) lung DC to draining LNs. This process is mimicked by the DP1 agonist BW245C, but not by the DP2 agonist DK-PGD(2). The ligation of DP1 inhibits the migration of FITC-OVA(+) DCs only temporarily, but still inhibits the proliferation of adoptively transferred, OVA-specific, CFSE-labeled, naive T cells in draining LNs. These T cells produced lower amounts of the T cell cytokines IL-4, IL-10, and IFN-gamma compared with T cells from mice that received FITC-OVA alone. Taken together, our data suggest that the activation of DP receptor by PGD(2) may represent a pathway to control airway DC migration and to limit the activation of T cells in the LNs under steady state conditions, possibly contributing to homeostasis in the lung.

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.

Improvement of metabolic disorders by M16209 (1-(3-bromobenzofuran-2-ylsulfonyl)hydantoin), an antidiabetic agent, was studied in genetically obese Zucker fa/fa rats and C57BL/6J ob/ob mice. In fa/fa rats oral administration of M16209 (30 and 100 mg/kg/day) for 7 days dose dependently improved hyperinsulinemia without affecting body weight. Oral glucose loading (2 g glucose/kg body weight) after 10 days of administration to fa/fa rats revealed that M16209 significantly improved glucose tolerance both 30 and 60 min after glucose loading, but did not affect preload serum glucose levels. At one day after 13 days of administration of M16209, the serum levels of triglyceride, total cholesterol and free fatty acid were clearly lower in treated fa/fa rats than those in untreated rats. In C57BL/6J ob/ob mice, M16209 given for 28 days at doses of 30 and 100 mg/kg/day improved hyperinsulinemia, hyperglycemia and hypercholesterolemia without affecting body weight. In a hyperinsulinemic euglycemic clamp study in fa/fa rats, administration of M16209 for 7 days at a dose of 100 mg/kg/day significantly normalized the decreased metabolic clearance rate but did not show any effect on the augmented hepatic glucose output. These findings demonstrate that improvement of metabolic disorders in genetically obese rodents by M16209 is due to amelioration of insulin resistance in peripheral tissues.

Blood-retinal barrier (BRB) and blood-aqueous barrier (BAB) permeability were assessed by various methods to clarify conflicting reports on whether blood-retinal barrier permeability changes occur in diabetic and galactose-fed rats and to assess the potential role of aldose reductase in this process. Different molecular weight probes were utilized in rats fed for 7-11 months either a normal diet or a diet containing 50% galactose with/without the aldose reductase inhibitor AI1576 or Ponalrestat. BRB and BAB were assessed through radiolabelled sucrose permeability studies in eyes where the anterior segment was frozen during dissection compared to eyes where the anterior segments were not frozen and by quantitative autoradiography. In addition, histological studies using Evans Blue dye, microperoxidase and horseradish peroxidase were conducted. In untreated galactose-fed rats a 4-fold increase in the mean permeability surface area product (PA) to sucrose at the BRB was observed when the aqueous humor was not frozen during retinal dissection. However, no increase in the mean PA to sucrose was observed when the aqueous humor of similar eyes was frozen during dissection. Similarly, no retinal vessel permeability increase was observed by either quantitative autoradiography of [3H]-sucrose after 15 minutes of circulation or histological studies with microperoxidase, horseradish peroxidase or Evans Blue dye. Examination of the BAB revealed an increase in the permeability of iris vessels but not the ciliary body in galactose-fed rats which was reduced by treatment with the aldose reductase inhibitor AI1576. These data indicate that while BRB permeability is not increased in galactose-fed rats, BRB permeability measurements with isotopes are subject to possible contamination from the aqueous humor in untreated galactose-fed rats, which can result in false observations of increased BRB permeability.

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague-Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CLT) values of the two enantiomers were similar, but the intrinsic clearance (Cl(int)) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (Vss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in Vss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC50 values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC50 values in diabetic rats.

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)

Racemic ethotoin (1000 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times for 120 h following the dose. Ethotoin was quantified enantio-selectively in plasma using a novel chiral column HPLC procedure. One of the enantiomers of the chiral metabolite, 5-phenylhydantoin, was also quantified in the HPLC method. The Cmax and AUC0-infinity values for (+)-(S)-ethotoin were significantly greater than those for (-)-(R)-ethotoin (ratio of mean AUC0-infinity values 0.88), but the elimination half-lives of the isomers were virtually identical [12.35 +/- 5.15 h for (-)-(R)-ethotoin; 12.28 +/- 5.34 h for (+)-(S)-ethotoin]. Parameters derived from AUC0-infinity (Cl0/F and V(area)/F) also differed slightly between the isomers. The data were interpreted as indicating a small difference in the absorption of the two isomers; it seemed unlikely, in terms of the identical elimination rates, that their metabolic profiles would differ greatly. The 5-phenylhydantoin was eliminated with a significantly longer half-life (18.69 +/- 6.11 h) than that of ethotoin. Enantioselectivity in the pharmacokinetics of ethotoin is therefore a minor issue.

[3H]-FCE 22716 and [3H]-FCE 24220 were given both orally and intravenously to the rat. Radioactivity was mainly eliminated by the faecal route after oral administration in both cases. After intravenous administration, renal excretion was twice the faecal one in the case of FCE 22716, whereas for FCE 24220 the two routes were equal. In urine FCE 22716 was eliminated almost completely unchanged after both oral and intravenous administration. FCE 24220 was extensively reduced to FCE 22716 after oral administration, whereas after intravenous treatment, this reduction, although important, was not complete.

A sensitive and selective gas chromatographic-electron-capture assay was developed for the determination of the aldose reductase inhibitor imirestat in lens and plasma. The method involves solid-phase extraction of drug and internal standard from the plasma specimen or lens sample homogenate using "Baker"-10 SPE extraction columns followed by derivatization with pentafluorobenzyl bromide and further purification. Derivatives of drug and internal standard were separated on a fused-silica capillary column and analyzed using a 63Ni electron-capture detector. The limit of detection was 2.5 ng per lens or ml of plasma. The method was used to evaluate the pharmacokinetics of imirestat in human subjects and to quantitate imirestat in animal lens tissue following topical ocular administration.

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of imirestat following topical ocular administration were evaluated in a series of studies in rabbits and dogs. Following single topical doses to both albino and pigmented rabbits, imirestat was subject to rapid uptake into the cornea followed by an initial rapid decline and then very slow elimination, with a t1/2 of approximately 130 hr. Drug was rapidly absorbed into aqueous humor, with concentrations declining to nondetectable levels by 12 hr. Imirestat was retained in the lens following topical dosing similar to that in cornea, with an apparent elimination t1/2 of 140 hr. Vitreous humor concentrations of drug were detectable for up to 72 hr after dosing. There was no apparent difference in the disposition of the drug between albino and pigmented rabbits. Bioavailability following topical dosing increased with dose, although not in a linear fashion. Formulation pH did not have an appreciable effect on ocular bioavailability. There was detectable systemic absorption following topical dosing, with plasma concentrations in rabbit being 50 to 75% of that observed following an equivalent intravenous dose. However, drug levels in the dosed eyes were significantly higher than in contralateral undosed eyes. Multiple dosing of imirestat for 6 weeks resulted in accumulation of drug in rabbit lens. Concentrations were higher in lens cortex than lens nucleus, with the time course for accumulation being different for the two. Our data suggest that imirestat penetrates into ocular tissue following topical dosing and is retained in lens and cornea, potential sites of action for the drug.

Normal eight month old beagle dogs were fed a diet of 30% galactose for a period of two weeks. One group of dogs was untreated while three other groups were orally dosed with 0.25, 1.0, and 5.0 mg/kg of the aldose reductase inhibitor (ARI), AL01576. No visible changes were observed in the lens but glutathione (GSH) and inositol were depleted while dulcitol was elevated. These biochemical changes closely parallel those found in the (two week) streptozotocin induced diabetic rat. In contrast with the diabetic rat model, retina and nerve inositol was not found to differ from normal in spite of significant dulcitol accumulation. Plasma AL01576 was found to be inversely correlated with lens dulcitol concentration. When plasma AL0P1576 concentration was greater than 1 microgram/mL (5 mg/kg), there was a 95% reduction in dulcitol concentration (relative to untreated), while concentrations of 0.2 to 0.2 mg/mL (1 mg/kg) of AL01576 resulted in a dulcitol reduction of at least 70%. Retina and nerve dulcitol concentrations of galactosemic dogs were similarly diminished by AL01576 treatment. The dog model exhibits a biochemical profile of change and responsiveness to ARI therapy similar to that observed in hyperglycemic rats. Changes in retina morphology in diabetic and galactosemic dogs has been shown to closely resemble those occurring in human diabetics; these early biochemical events may also parallel.

The method of treatment of acute hematogenic osteomyelitis of long tubular bones in children is described. This method was employed in 31 children, aged from 3 to 14 years, with acute hematogenic osteomyelitis. The complete recovery was noted in 27 cases, in 4--due to late hospitalization and secondary infection the inflammatory process became chronic.

Ethotoin is an anticonvulsant that was considered minimally effective when introduced, but due to its apparent lack of side effects, there has been renewed interest in the drug for use in generalized and psychomotor seizures. We have characterized the pharmacokinetics of ethotoin in children and have found nonlinearity. Seizures were controlled in 16 of 17 patients, and there were no side effects reported. Gingival hyperplasia due to previous phenytoin therapy improved in all cases.

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4-mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of approximately 30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the GI tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Effective prescribing of anticonvulsants requires foreknowledge of baseline pharmacokinetic data. Little such information is available about the hydantoins other than phenytoin, although one of them, mephenytoin, is widely used. Useful pharmacokinetic data should be derived from patients already exposed to anticonvulsants to reflect the induction of hepatic oxidative enzymes. Single-dose studies of mephenytoin (Mesantoin) and ethotoin (Peganone) were performed in adult inpatients on stable regimens of other anticonvulsants. Five patients received mephenytoin, 7 mg per kilogram of body weight. Serial blood sampling was performed rigorously. The time to peak concentration (Tmax) for mephenytoin was 1 hour, with a half-life (T 1/2) of 7 hours; the T 1/2 of its metabolite, 5-ethyl-5-phenylhydantion, was 96 hours. Ethotoin administration was 25 mg per kilogram in 5 patients. Ethotoin Tmax was 2 hours, with a T 1/2 of 5 hours. Saliva accurately represented the unbound fraction for all three agents. Mean salivary levels (as percentage of total levels) were 61% for mephenytoin, 73% for its metabolite, and 54% for ethotoin. The implications for therapy are that following mephenytoin administration, the metabolite 5-ethyl-5-phenylhydantoin will provide anticonvulsant effectiveness, with its long half-life producing stable blood levels on simple dose schedules. Ethotoin, in contrast, has a short half-life and would require divided daily doses to achieve a steady state. This, rather than pharmacological ineffectiveness, limits its usefulness.

A case of possible malignant hyperthermia in a 6-month-old child is presented. Malignant hyperthermia was manifested in this patient by persistent metabolic acidosis in the intraoperative and postoperative periods, by a rapid rise in temperature with concomitant unresponsiveness in the postoperative period, and by a positive caffeine-halothane stimulation test. The malignant hyperthermia occurring in the postoperative period resolved promptly following administration of dantrolene sodium. An unusual aspect of this case is that both of the child's parents had normal CPK values and negative caffeine-halothane stimulation tests.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

The malignant glioma cell line U-87MG was used for 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), aziridinylbenzoquinone (AZQ), cis-diaminodichloroplatinum (II) (cis-DDP), and spirohydantoin mustard (SHM) treatments at 37 degrees and 42 degrees C. With the exception of SHM, all drugs killed a greater proportion of cells at the higher temperature, as assessed by the colony-formation assay. Drug-dose enhancement ratios were 1.6, 2.8, 2, and 1:1 for BCNU, AZQ, cis-DDP, and SHM, respectively. Because methods to heat discrete volumes of brain are now available, we conclude that hyperthermic increase of BCNU, AZQ, and cis-DDP cytotoxicity might have therapeutic application for malignant gliomas.

The pre-anaesthetic administration of dantrolene sodium to individuals at risk from malignant hyperthermia has not yet found an accepted place in human anaesthetic practice, although the effectiveness of dantrolene sodium as a prophylactic drug has been clearly shown in animal studies. In the patient described in this report, no conclusion is drawn about the effectiveness of dantrolene sodium, but attention is drawn to a brief episode of vomiting and diarrhoea some two hours after ingestion of the drug. Modification of the dosage scheme may be advisable.