PubMed Health⌕ Search

Biomedical subjects

E Pop

Publications and source records attributed to E Pop.

At least 37 records · Page 2Linked to original sources
PubMed1995

Efficacy of a 3-substituted versus 17-substituted chemical delivery system for estradiol brain targeting.

Brain-targeted delivery of estrogens has been achieved by a chemical delivery system (CDS) in which a molecular targetor (1-methyl-1,4-dihydronicotinate) was attached to the 17-alcohol of estradiol. Optimization of this effect was attempted with the isomeric 3-phenol ester. Estradiol 3-nicotinate was prepared with nicotinic anhydride, which selectively acylated the phenol position. Methylation and reduction gave estradiol 3-(1-methyl-1,4-dihydronicotinate) of the 3-E2-CDS. Theoretical and electrochemical investigation indicated that the 3-E2-CDS was more stable to oxidation than was the prototype 17-ester (17-E2-CDS). Systemic administration of the 17-E2-CDS produced high levels of the corresponding quaternary salt in the brain of rats, which disappeared with an estimated half-life of > 2 days, but 3-E2-CDS dosing resulted in no significant quaternary salt trapping. Pharmacological activity was potent and sustained after 17-E2-CDS dosing but transient after 3-E2-CDS administration. Thus, the 3-E2-CDS reduced the rate of weight gain in male rats but to a lesser extent and for a shorter duration than did the 17-E2-CDS. Similar effects were seen on pituitary hypertrophy, reduction in serum androgen concentrations, and involution of prostate and seminal vesicles. The results of these studies suggest that placement of the targeting ester at the phenol position increases dihydropyridine stability but, at the same time, reduces brain sequestration.

Animals↗
PubMed1995

Tissue distribution of LY231617, an antioxidant with neuroprotectant activity, in the rat.

The tissue distribution of a butylated phenol antioxidant, LY231617, which has been shown to exert potent neuroprotection action was examined. Preliminary pharmacokinetic examination suggests that LY231617 was eliminated in a biphasic fashion after iv administration to the rat with a distribution half-life of 5 min and an elimination half-life of close to 2.5 h. The volume of distribution of the compound was large (7.4 L), consistent with its lipophilic structure. Dosing paradigms that have historically resulted in pharmacologically relevant activity were examined and were found to generate brain tissue levels of LY231617 of approximately 45 micrograms/g.

Animals↗
PubMed1995

Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1994

Effect of molecular manipulation on the estrogenic activity of a brain-targeting estradiol chemical delivery system.

The structural parameters important for biological efficacy of an estradiol chemical delivery system (CDS), a brain-targeting approach based on redox trapping, were examined by molecular manipulation of a prototype derivative, estradiol 17-(1-methyl-1, 4-dihydronicotinate) (E2-CDS). Seven E2-CDS analogs in which the N-methyl substituent was altered were prepared including N-substituted short and medium straight chain alkyl, short branched chain alkyl, and aralkyl derivatives. Chemical and in vitro testing indicated that the most stable derivative was the N-benzyl E2-CDS. The analogs were tested in an intact male rat model to assess various central estrogenic manifestations including the rate of body weight gain, serum E2 and testosterone concentrations, and seminal vesicle, prostate and pituitary weight changes. Results indicated that all prepared CDS derivatives exerted some degree of central estrogenization with the most potent compounds being the parent E2-CDS and its ethyl homologue. Importantly, while the ethyl E2-CDS was equipotent to E2-CDS in various biological assays, it did not significantly elevate serum E2 compared to vehicle control at day 14.

Animals↗
PubMed1994

Enhanced delivery of ganciclovir to the brain through the use of redox targeting.

Enhanced delivery of ganciclovir to the brain was demonstrated by a redox-based chemical delivery system. A ganciclovir monoester in which a 1-methyl-1,4-dihydronicotinate was covalently attached to one of the hydroxymethyl functions was prepared. The stability of the ganciclovir chemical delivery system (DHPG-CDS) was evaluated in aqueous buffers and organ homogenates. In vivo distribution studies in the rat indicated that while ganciclovir poorly penetrated into the central nervous system and was rapidly eliminated, DHPG-CDS provided for therapeutically relevant (2.7 microM) and sustained levels of the parent compound through 6 h. An analysis of the area under the concentration curve indicated that the chemical delivery system delivered five times more ganciclovir than that of the parent drug. The high levels in the brain and reduced levels in the blood gave a brain-to-blood drug concentration ratio of 2.54 for ganciclovir when delivered by the chemical delivery system, compared to a ratio of 0.063 when the parent drug was administered. These data suggest that DHPG-CDS could be a useful adjunct for the treatment of cytomegalovirus encephalitis.

Animals↗
PubMed1993

An AM1 molecular orbital study of alpha-D-glucopyranose and beta-maltose: evaluation and implications.

Chemical reactivity and other characteristics of alpha-D-glucopyranose and beta-maltose were evaluated within a semiempirical molecular orbital (AM1) framework. Theoretically generated structures compared well to those determined by X-ray crystallographic techniques. Calculations suggested that the secondary hydroxy functions (OH-2 and OH-3) of the mono- and di-saccharides were more acidic than the primary alcohol (OH-6), which is consistent with experimental findings. In addition, the enhanced reactivity of the OH-3 locus, which is observed upon OH-2 alkylation of the object sugars, was rationalized in terms of increased OH-3 acidity. The chemical behavior of the monomers examined may be insightful in explaining the reactivity of glucopyranose polymers.

Carbohydrate Conformation↗
PubMed1993

The effect of dihydronicotinate N-substitution on the brain-targeting efficacy of a zidovudine chemical delivery system.

Enhanced brain delivery of zidovudine (AZT) has been demonstrated using a redox-based chemical delivery system (CDS). Optimization of the prototype AZT-CDS (5'-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]-3'-azido-3'-deoxy thymidine ) was investigated by manipulation of the N-methyl group present on the dihydronicotinate portion of the molecule and examining the release of AZT in vivo in a rat model. Of the five compounds examined, all produced higher brain levels and lower blood levels of AZT than did AZT itself. In comparing the novel AZT-CDS analogues to the N-methyl benchmark, the N-propyl system proved to be the most efficient of the compounds tested.

Animals↗
PubMed1992

Chemical systems for delivery of antiepileptic drugs to the central nervous system.

The chemical delivery system (CDS) approach, a recently developed procedure conceived to enhance the specific central nervous system (CNS) uptake of drugs, has been applied to several antiepileptic agents. CDSs based on dihydropyridine<-->pyridinium salt type redox targetors, reversibly linked to the drug, were designed, synthesized and tested for some traditional (phenytoin, valproate) and potential (stiripentol) antiepileptic drugs, as well as some compounds (GABA, adenosine) with important roles in epileptogenesis. Physicochemical, in vitro stability, in vivo tissue distribution, activity and toxicity studies were performed for the new derivatives. The results of these investigations indicated that selected CDSs possessed properties required for delivering the drugs to the CNS. In vivo experiments indicated improved brain uptake and enhanced pharmacologic activity in some of the examined cases. On the other hand, no toxic side effects were registered during the studies. Properly developed CDSs could enhance the therapeutic indexes of the anticonvulsant drugs.

Animals↗
PubMed1991

Redox derivatives of tranylcypromine: syntheses, properties, and monoamine oxidase inhibitor activity of some chemical delivery systems.

Several brain-targeting chemical delivery systems (CDS) based on a dihydropyridine----pyridinium salt type redox system were synthesized for the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). The dihydronicotinate moiety was chemically attached to the amino group of TCP by either an amide or substituted carbamate linkages. Physicochemical studies of the new derivatives, including chromatographic Rm determinations, were performed. Only the substituted carbamate-type derivatives manifested an increased lipophilicity relative to the parent compound. In vitro oxidation stability studies were also performed on selected derivatives using a ferricyanide-mediated method. Results of this assay showed that the dihydropyridine-type derivatives oxidized to the respective quaternary salt forms with stabilities which empirically correlated with other effective CDSs. Preliminary in vivo studies performed in rats indicated that some of the new derivatives exerted significant biological activity.

Animals↗
PubMed1991

Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-beta-cyclodextrin.

A dihydropyridine----pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl-beta-cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720-940 M-1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1990

Antihypertensive activity of redox derivatives of tryptophan.

The essential amino acid, tryptophan, has been shown to lower blood pressure in rats when administered orally or intravenously. In order to potentially enhance this action, a brain-targeting chemical delivery system (CDS) approach was applied to this compound. The CDS is based on a dihydropyridine----pyridinium ion redox system, chemically analogous to the naturally occurring NADH----NAD+ system. The dihydropyridine moiety containing carrier is chemically attached to the amino group by an amide-type bonding while the carboxylic acid functionality is esterified to various alcohols. Physicochemical studies of the new derivatives were performed. The determined chromatographic Rm values indicate an increased lipophilicity for the CDSs compared to the parent compound. Oxidation stability studies performed on selected compounds using a ferricyanide-mediated method showed that the CDSs are oxidized to the respective quaternary salt forms. Activity studies performed in deoxycorticosterone acetate induced hypertensive rats, demonstrated that the delivery system for tryptophan reduced blood pressure more efficiently for a longer time than did the parent compound.

Animals↗
PubMed1990

Application of a brain-targeting chemical delivery system to 9-amino-1,2,3,4-tetrahydroacridine.

Several chemical delivery systems (CDS) were synthesized for the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroacridine (THA). The derivatives prepared were substituted with a 1,4-dihydropyridine in equilibrium pyridinium salt redox system at the amino functionality. These compounds were synthesized by acylation of the 9 amino group of THA with nicotinic anhydride under forced conditions, followed by a selective N-alkylation of the pyridine ring and regioselective reduction of the resulting quaternary salts. Lipophilicity parameters indicated increased lipophilic indices for various CDS's compared to the THA. Oxidation studies showed that dihydronicotinamides readily converted to the quaternary salt, both chemically and enzymatically. The transport forms of THA were also shown not to interact with acetylcholinesterase in vivo. In vivo distribution studies in the rat indicated that high and sustained levels of the pyridinium quaternary ion derivative were present in the central nervous system (CNS). In addition, THA was produced in the CNS from the quaternary salt precursor in low concentrations, indicating a slow but sustained release. The CDS for THA were found to be less acutely toxic than THA.

Aminoacridines↗
PubMed1990

Novel central nervous system targeted semisynthetic penicillins.

A novel series of semisynthetic penicillins was designed and synthesized. The compounds have as an integral part of the molecule a pyridinium <--> dihydropyridine redox system as a substituent at the 6-position. Esters of the dihydropyridine (pro-prodrug) forms of the drugs were expected, because of their pronounced lipophilic character, to easily penetrate biological membranes, including the blood-brain barrier, and to give rise to esters of polar pyridinium ions (prodrug) (via enzymic oxidation of the dihydropyridine moiety). The resulting ions were expected to be rapidly excreted from the periphery, but to be "locked" in the central nervous system; subsequent enzymic cleavage of the ester function was expected to release the free acid-pyridinium salts (drug) in the central nervous system in a sustained manner. The design approach, synthesis, study of some important physicochemical properties, stability determinations and preliminary in vivo distribution and potency evaluations of the novel drugs are described.

Animals↗
PubMed1990

Brain and CSF specific chemical delivery systems for beta-lactam antibiotics. Study of two dihydropyridine derivatives of benzylpenicillin in rabbits and dogs.

Following previous studies in rats, the ability of two chemical delivery systems (CDSs) to deliver benzyl penicillin (1) to the central nervous system of rabbits and dogs was investigated. One of the systems (3) was a diester of methylene diol, and the other (5) a diester of ethylene 1,2-diol; in both, one hydroxyl group of the diol was esterified by the 3-carboxylic acid group of benzylpenicillin, and the other by the carboxy group of an N-methyldihydropyridine (dihydrotrigonelline). The basis of the system is the ability of the dihydropyridine components to undergo oxidation to quaternary pyridinium salts (2 from 3, and 4 from 5). In vitro relative stability studies were first performed in 10% rabbit brain homogenate, rabbit CSF and dog CSF. The results showed that the CDSs (3 and 5) were more stable than the corresponding quaternary salts (2 and 4). Hydrolysis of 2 and 3 resulted in the release of 1, whereas hydrolysis of 4 and 5 released both 1 and the hydroxyethyl ester (6) of 1. In vivo distribution studies were performed in rabbits and dogs. After i.v. administration of equimolar doses of 1 or the CDSs, levels of 1 in brain and CSF were substantially higher and more prolonged in the cases of the CDSs than in the case of 1 itself. Brain levels of 1 were lower following administration of 5, as compared with 3, due to the release of the intermediate compound, the hydroxyethyl ester (6) of 1, which was not hydrolyzed efficiently to 1 in rabbit or dog brain. The substantially increased and prolonged penicillin levels following administration of the CDSs arise as the result of improved penetration of the lipophilic CDSs across the blood-brain barrier, and a "lock-in" effect of the corresponding quaternary salts generated in situ.

Animals↗
PubMed1989

Improved anticonvulsant activity of phenytoin by a redox brain delivery system I: Synthesis and some properties of the dihydropyridine derivatives.

Nine chemical delivery systems (CDSs) were synthesized for the efficient transport of phenytoin (DPH) across the blood-brain barrier. The CDSs were based on a dihydropyridine in equilibrium quaternary pyridinium ion redox system which relies on chemistry similar to the NADH in equilibrium NAD interconversion for activity. The chemical carriers, derivatives of trigonelline, 1-alkylcarboxynicotinamide, 3-pyridylacetic acid, and N-methylpicolinic acid, were esterified with 3-(hydroxymethyl)phenytoin. The CDSs proved to be more lipophilic (5-23 times) than DPH. The 1-alkylcarboxydihydronicotinamide CDSs, excluding the sterically hindered one (11e), were quite unstable in rat tissue homogenates and hydrolyzed to release DPH. In human blood, however, they were found to be much more stable (75 times) toward hydrolysis. All other CDSs were oxidized quantitatively to the corresponding pyridinium ion in rat brain homogenates. These compounds were found to possess the required physicochemical characteristics for delivering DPH into rat brain.

Animals↗
PubMed1989

Improved anticonvulsant activity of phenytoin by a redox brain delivery system. II: Stability in buffers and biological materials.

The stability of nine chemical delivery systems (CDSs) for phenytoin (DPH) was studied in aqueous buffers and in biological materials. The systems were based on a dihydropyridine in equilibrium quaternary pyridinium salt redox pair attached to 3-(hydroxymethyl)phenytoin via an ester linkage. The pyridinium derivatives released DPH in aqueous buffers and their hydrolytic reactivity was consistent with their chemical structure. Although in rat blood and plasma all pyridinium esters hydrolyzed rapidly, there was a wide range in the hydrolysis rates in rat brain homogenate. The sterically hindered 1-alkylcarboxynicotinamide was the least reactive ester (t1/2 = 98.2 min), while the trigonellylglycolate ester was the fastest to hydrolyze enzymatically (t1/2 = 2 min) in rat brain homogenate. In acidic media, the major products of all dihydropyridine esters were the corresponding water adducts, the 6-hydroxy- 1,4,5,6-tetrahydropyridines. These adducts were of no significance in biological materials. After comparison of the relative stability of the corresponding pairs of dihydropyridine and pyridinium ion in brain homogenate and the absolute stability of the various dihydropyridines, two CDSs were chosen for further in vivo evaluations. The CDSs chosen were the dihydrotrigonellinate ester and its 6-methyl derivative.

Animals↗
PubMed1989

Improved anticonvulsant activity of phenytoin by a redox brain delivery system. III: Brain uptake and pharmacological effects.

Phenytoin (DPH) was delivered to the brain by a dihydropyridine in equilibrium pyridinium salt redox system, which was evaluated for anticonvulsant activity. Following iv injection of the lipophilic delivery system of DPH (2) to rats, concentrations of DPH were lower but sustained and, after 30 min, essentially the same as the levels after equimolar administration of DPH. While 2 delivered the same levels of DPH to the brain as DPH did, it was twice as potent as DPH in rats (ED50 was 7.5 mumol/kg for 2 and 14.2 mumol/kg for DPH) and mice (2: 10.5; DPH: 23.9) against maximal electroshock seizures (MES), and seven times more potent in mice (2: 10.0, DPH: 70.6) against maximal pentylenetetrazole seizures (MPS). Moreover, 2 was active against pentylenetetrazole threshold seizures (PTS) in mice and rats (ED50 = 44.1 and 40.5 mumol/kg, respectively), while DPH was ineffective (up to a dose of 79.2 mumol/kg). After evaluation of acute neurological toxicity in rats, 2 was found to possess 1.5 times higher a protective index (for MES) than DPH. It appeared also that while DPH was 2.9 times less sensitive to MPS than to MES, 2 was equally potent to both types of convulsions. Thus, the data indicate that 2 delivered DPH more efficiently to the brain. The better anticonvulsant activity (quantitatively as well as qualitatively) of 2 can be explained on the basis of an improved distribution in the brain due to its higher lipophilicity, and by favorable regional differences in the rates of conversion of 2 to DPH at the convulsing foci.

Animals↗