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Biomedical subjects

E Shek

Publications and source records attributed to E Shek.

At least 19 recordsLinked to original sources
PubMed2000

Hyperhomocyst(e)inemia induces multiorgan damage.

Hyperhomocyst(e)inemia has been associated with the development of hypertension, stroke, and cardiovascular, cerebral/neuronal, renal, and liver diseases. To test the hypothesis that homocyst(e)ine plays an integrated role in multiorgan injury in hypertension, we employed: (1) spontaneously hypertensive rats (SHR) in which endogenous homocyst(e)ine levels are moderately high (18.1 +/- ().5 microM); (2) control age- and sex-matched Wistar Kyoto (WKY) rats in which homocyst(e)ine levels are normal (3.7 +/- 0.3 microM). To create the pathophysiological condition of hyperhomocyst(e)inemia, 20 mg/day homocyst(e)ine was administered for 12 weeks in (3) SHR (SHR-H) and in (4) WKY (WKY-H) rats. (5) Endogenous homocyst(e)ine levels were reduced slightly but not significantly from 18.1 +/- 0.5 microM to 12.5 +/- 0.7 microM in SHR by folic acid administration (SHR-F). Plasma and tissue levels of homocyst(e)ine were determined by HPLC and spectrophotometric methods. Plasma and sympathetic ganglion (neuronal) matrix metalloproteinase (MMP) activity was measured by zymography. Activity of neuronal MMP was increased in hyperhomocyst(e)inemic rats as compared with controls. Mean arterial pressure (mmHg) was 95 +/- 5, 126 +/- 8,157 +/- 10, 188 +/- 5, and 165 +/- 12 in WKY, WKY-H, SHR, SHR-H, and SHR-F, respectively. Urinary protein (mg/day) was 0.11 +/- 0.03, 0.88 +/- 0.22, 0.47 +/- 0.10, 0.89 +/- 0.21, and 0.81 +/- 0.21 in WKY, WKY-H. SHR, SHR-H, and SHR-F, respectively, as measured by the Bio-Rad dye binding assay. The relationships between increased arterial pressure, plasma homocyst(e)ine, and urinary protein were delineated. Plasma and neuronal creatinine phosphokinase (CK) isoenzymes were measured by agarose gel electrophoresis. All three CK isoenzymes, i.e., MM, MB, and BB, specific for skeletal, cardiac, and nerve tissue, respectively, were induced following 12 weeks' hyperhomocyst(e)inemia, suggesting multiorgan injury by homocyst(e)ine. Homocyst(e)ine induces endocardial endothelial cell (capillary) apoptosis and may reduce capillary cell density. Structural damage to aorta, myocardium, kidney, and renalureter was analyzed by histology. Results suggested an integrated physiological role of homocyst(e)ine in injury to the endothelial/epithelial cell lining in the respective organs.

Animals↗
PubMed1998

Prodrug esters of the indolocarbazole CEP-751 (KT-6587).

Prodrug esters of the indolocarbazole CEP-751 (KT-6587) were prepared with the goal of identifying water soluble, stable but cleavable forms for intravenous dosing. A dipeptide proform Lys-beta-Ala (16, CEP-2563/KT-8391) was identified for advancement to clinical trials.

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↗
PubMed1989

Brain-specific chemical delivery systems for beta-lactam antibiotics. Synthesis and properties of some dihydropyridine and dihydroiosquinoline derivatives of benzylpenicillin.

Six chemical delivery systems (CDS) were synthesized for benzylpenicillin in order to improve its transport across the blood-brain barrier. The CDS's were based on a dihydropyridine----quaternary pyridinium ion redox system, analogous to the naturally occurring NADH----NAD+ system. Two different types of CDS's were prepared: benzylpenicillin esters of diols in which the other hydroxyl group is esterified by dihydrotrigonelline and benzylpenicillin esters of amino alcohols in which the amine group is acylated by dihydrotrigonelline, or by 1,2-dihydro-2-methyl-4-isoquinolinecarboxylic acid. Lipophilicities of the CDS's were proved to be much higher than those of benzylpenicillin by using Rm values as lipophilicity indexes. Upon oxidation, all of the CDS's gave the quaternary ion forms. Kinetic studies in buffer (pH profiles) indicated that the quaternary salts released benzylpenicillin in pH range of 5-9 via hydrolysis. The CDS's in acidic media yielded as the major reaction product 6-hydroxy-1,4,5,6-tetrahydropyridines as a result of water addition, while in basic conditions benzylpenicillin was released. The water addition reaction was dependent on the CDS's structure, being more prevalent in the case of the "amide-esters". The dihydroisoquinoline CDS was rather stable in the pH range 5-8.

Blood-Brain Barrier↗
PubMed1989

Brain-specific chemical delivery systems for beta-lactam antibiotics. In vitro and in vivo studies of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin in rats.

Four chemical delivery systems (CDS's) based on a dihydropyridine----quaternary pyridinium salt redox system were used for the brain delivery of benzylpenicillin (BP). CDS's 5 and 9 are diesters of C1 and C2 diols in which one hydroxyl group is esterified by the benzylpenicillin-3-carboxylic group and the other by dihydrotrigonelline. CDS's 13a and 17 are benzylpenicillin esters of amino alcohols in which the amine group is acylated by dihydro-trigonelline (13a) or by 1,2-dihydro-2-methyl-4-isoquinolinecarboxylic acid (17). In vitro relative stability studies showed that both CDS's and quaternary pyridinium salts were quite unstable in rat and rabbit blood or brain but much more stable in dog or human blood. Kinetic studies performed in rat brain homogenate demonstrated the facile enzymatic oxidation of the CDS's to the corresponding quaternary salts. Hydrolysis of the CDS's and the quaternary salts resulted in the release of benzylpenicillin. In biological media CDS 13a also yielded a water addition product, the 6-hydroxy-1,4,5,6-tetrahydropyridine derivative. In vivo distribution studies were carried out in rats. After iv administration of equimolar doses of BP and CDS's, brain benzylpenicillin levels were found to be substantially higher and more prolonged in case of 5 and 9 than of BP itself. However, administration of 13a and 17 resulted in lower brain benzylpenicillin levels due to the water addition reaction and a nonspecific brain delivery, respectively. The remarkable increase of BP levels as well as the prolonged effect after the administration of 5 and 9 is a result of an improved penetration through the blood-brain barrier of the lipophilic CDS's and a "lock-in" effect of the corresponding quaternary salts generated in situ.

Animals↗
PubMed1989

Chemical delivery systems for drugs containing an amino group: synthesis and properties of some pyridine derivatives of desipramine.

Seven chemical delivery systems (CDS) based on a dihydropyridine<-->quaternary pyridinium salt type redox system and analogous to the naturally occurring NADH<-->NAD+ coenzyme system were applied in the case of the antidepressant drug desipramine. The pyridine moiety-containing carriers were linked to the amino function of desipramine either as amides or substituted carbamates. Lipophilic properties were expressed in terms of chromatographic Rm values. Oxidative stability of the dihydropyridine forms of the CDSs were determined in vitro. The amide type derivatives were stable toward hydrolysis in buffers and in biological fluids, whereas the carbamates released the parent drug in a very efficient manner. In a behavioral despair test, the CDSs did not show improved activity when compared to desipramine. In vivo distribution studies of one of the CDS did not show more efficient delivery of the desipramine into the rat brain but did show a prolonged presence at a constant level.

Animals↗
PubMed1987

Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU.

A redox chemical delivery system based on the NADH in equilibrium NAD+ model was applied to an active metabolite (D) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), i.e. CCNU-OH. The 1,4-dihydrotrigonelline ester of CCNU-OH, N-(2-chloro ethyl)-N'-[trans-4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyc lohexyl]- N-nitrosourea (D-CDS) was prepared by a direct hydride transfer reaction of the corresponding pyridinium precursor (D-Q+) with a highly reactive 1-benzyl-1,2-dihydroisonicotinamide. The in vitro kinetics in biological fluids indicated facile oxidative conversion of D-CDS to D-Q+. An in vivo study showed that one intravenous injection to rats of D-CDS resulted in rapid brain accumulation of D-Q+, followed by a sustained release of CCNU-OH, while D-Q+ was rapidly eliminated from systemic circulation. The ratio of brain/blood concentration of D-Q+ was found to increase progressively with time. At an equimolar dose of CCNU-OH, the ratio of brain/blood concentration for CCNU-OH was found to be close to unity.

Animals↗
PubMed1983

Characterization of spray patterns of inhalation aerosols using thin-layer chromatography.

The spray pattern of an inhalation aerosol was characterized using photography and by observing the impaction pattern on a TLC plate. The aerosol plume was conical in shape, and its cross section increased with increasing distance from the actuator. Three puffs of the aerosol, at a distance of 3 cm between actuator and the TLC plate, produced a spot that had approximately the same diameter as the cross section of the aerosol plume at that distance from the actuator. The TLC technique with these parameters was selected to develop an assay characterizing the spray pattern of an inhalation aerosol because of its specificity, simplicity, and speed.

Aerosols↗
PubMed1980

Simplex search in optimization of capsule formulation.

The simplex method of optimization was applied to a capsule formulation uing the dissolution rate and compaction rate as the desired responses to be optimized. The formulation parameters investigated included the levels of drug, disintegrant, lubricant, and fill weight. Following the successful optimization of the capsule formulation, the accumulated data were fitted to a polynomial regression model to plot response surface maps around the optimum.

Capsules↗
PubMed1980

Determination of ethinylestradiol and norethisterone in an oral contraceptive capsule by reversed-phase high performance liquid chromatography.

A specific and sensitive analytical method is described for the simultaneous determination of ethinylestradiol and norethisterone in a capsule formulation. These steroids, commonly used in oral contraceptives, were extracted from the capsules with acetonitrile and tetrahydrofuran. The steroids were then quantitated with a high performance liquid chromatograph using a ODS reversed-phase column and a ternary solvent system of water, acetonitrile, and tetrahydrofuran as the mobile phase. Several solvent systems for the mobile phase were examined using various C18 columns. The k' values for several steroids are reported, together with column performance parameters. It was found that columns from different manufacturers had significantly different behaviors with respect to separation parameters for these steroids.

Capsules↗
PubMed1976

Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1,6-dihydropyridine-2-carbaldoxime, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride.

A dihydropyridine-pyridine type redox pro-drug system was developed for delivering quaternary pyridinium salts through biological membranes. As a first application, the dihydropyridine derivative of N-methylpyridinium-2-carbaldoxime chloride (2-PAM) was synthesized using a reduction-addition-elimination sequence. The dihydro-2-PAM obtained has all the required properties for an effective transport through lipoidal barriers and it reverts easily back to 2-PAM as a result of a chemical or enzymatic oxidation process.

Biological Transport↗
PubMed1976

Improved delivery through biological membranes. 2. Distribution, excretion, and metabolism of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride.

N-Methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug of 2-PAM, was found to be converted in vivo to 2-PAM, rapidly and quantitatively. The significantly changed properties of the pro-2-PAM resulted in a longer biological half-life and a favorable distribution of 2-PAM formed upon its oxidation. No new metabolite was found when pro-2-PAM was administered intravenously; however, a new metabolic product was formed when the pro-drug was given by oral route.

Administration, Oral↗
PubMed1976

Improved delivery through biological membranes. 3. Delivery of N-methylpyridinium-2-carbaldoxime chloride through the blood-brain barrier in its dihydropyridine pro-drug form.

Administration of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug form of 2-PAM, resulted in an average of 13-fold increase in the amount of 2-PAM delivered into the brain of mice as compared to the administration of 2-PAM. The pro-drug which crossed the BBB resulted in a dramatic increase in the reactivation of AChE blocked by DFP. In vivo studies of the "aging" of the phosphorylated AChE in the brain of mice could also be studied using pro-2-PAM.

Acetylcholinesterase↗
PubMed1975

Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative.

A dihydropyridine-pyridine type redox system was successfully applied for delivering a quaternary pyridinium salt, N-methylpyridinium-2-aldoxime chloride (2-PAM), through the blood-brain barrier. The dihydropyridine derivative of 2-PAM was quickly oxidized to 2-PAM after crossing the blood-brain barrier. As a result of this approach, the brain cholinesterase blocked by organophosphates could be reactivated. The new method should be useful in delivering numerous drugs which are otherwise inaccessible to the brain because of their polar ionic character.

Animals↗