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K S Estes

Publications and source records attributed to K S Estes.

At least 19 recordsLinked to original sources
PubMed1991

Development of aqueous parenteral formulations for carbamazepine through the use of modified cyclodextrins.

The poor aqueous solubility of carbamazepine was dramatically increased via complexation with various chemically modified beta-cyclodextrins and gamma-cyclodextrins. A preparation of carbamazepine and 2-hydroxypropyl-beta-cyclodextrin was found to be stable to steam sterilization and to storage under a variety of conditions. Carbamazepine, when solubilized in this manner, was found to exert potent anticonvulsant effects in various seizure models and the formulation was tolerated in animals at high doses (100 mg/kg carbamazepine and 1200 mg/kg of the cyclodextrin excipient). The onset of anticonvulsant action was rapid and consistent with almost instantaneous in vivo complex dissociation. The low toxicity of 2-hydroxypropyl-beta-cyclodextrin, when administered via the parenteral route, and its ability to enhance the aqueous solubility of carbamazipine highly favor the use of this excipient.

Animals↗
PubMed1991

A redox-based chemical delivery system that enhances estradiol distribution to the brain: disposition studies in the rat.

The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.

Animals↗
PubMed1990

A redox-based system that enhances delivery of estradiol to the brain: pharmacokinetic evaluation in the dog.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

Animals↗
PubMed1990

Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents.

A dihydropyridine in equilibrium with pyridinium salt redox system was applied to effect brain delivery of gamma-aminobutyric acid (GABA) derivatives and analogues. The redox system allows the lipophilic dihydropyridine conjugates to penetrate the blood brain barrier, whereas corresponding oxidized pyridinium forms are retained in the brain for an extended period and rapidly eliminated from the periphery. The most promising compound was the GABA benzyl ester-CDS (1a, Scheme I). It had an ED50 of 15.8 mg/kg (i.v.) in protecting mice against maximal electroconvulsive shock-induced tonic hind-leg extension.

Animals↗
PubMed1988

A dihydropyridine conjugate which generates high and sustained levels of the corresponding pyridinium salt in the brain does not exhibit neurotoxicity in cynomolgus monkeys.

Many drugs can be selectively delivered to the brain by using a dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS). The interaction of these systems with central dopaminergic function was examined in this communication. Castrate female Sprague-Dawley rats when treated with a CDS for estradiol (i.e. 3-hydroxy-17 beta-[( (1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy) estra-1,3,5(10)-triene or E2CDS) exhibit sustained and profound suppression of serum levels of leuteinizing hormone (LH). Treatment of rats with pargyline (80 mg/kg) prior to E2CDS (2 mg/kg) did not mitigate the biological effectiveness of this estrogen indicating at least indirectly that monoamine oxidate (MAO) was not involved in the CDS activation. In a more direct examination, cynomolgus monkeys treated with various repeated doses of E2CDS (cumulative doses of 0.2-40.0 mg/kg) demonstrated neither impaired motor function nor depleted striatal dopamine concentrations. The latter parameter was measured using liquid chromatographic-electrochemical analysis. These experiments support the contention that the CDS is not neurotoxic and further strengthens the strict structure-activity requirements for MPTP-induced neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins.

A dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified beta-cyclodextrins including hydroxyethyl-beta-cyclodextrin (HECD), hydroxypropyl-beta-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DMCD). Complex formation with all of these cyclodextrins resulted in dramatic increases in the water solubility of E2CDS. Studies on the complex of E2CDS and HPCD (E2CDS-CD) indicated that the encapsulated estrogen was approximately four times more stable than the unmanipulated CDS, producing an estimated half-life of degradation of 4 years compared with 1.2 years for the uncomplexed drug at room temperature. The complexation of E2CDS and HPCD also stabilized the dihydronicotinate in solutions containing potassium ferricyanide. This formulation was shown to be equivalent to E2CDS in dimethyl sulfoxide in delivering the oxidized, estradiol precursor (E2Q+) to the brain, and also produced similar biological responses; these included decreased luteinizing hormone (LH) secretion and a decrease in the rate of weight gain in castrated female rats.

Animals↗
PubMed1988

A redox system for brain targeted estrogen delivery causes chronic body weight decrease in rats.

The effects of 2 redox based carriers for brain directed delivery of estradiol (CDS-E2) and ethinyl estradiol (CDS-EE) on body weight were examined in rats. A single dose of CDS-E2 (3 mg/kg) decreased weight gain in castrate rats for at least 24 days. The dose response of weight gain and LH suppression were compared 12 days and 12 to 25 after CDS-E2 and CDS-EE, respectively, in ovariectomized (OVX) rats. Weight decrease was detected at a lower dose and was significant for longer after drug treatment than LH decrease. Both compounds were more potent than equimolar estradiol or estradiol valerate in reducing weight gain. Intact rats also showed decreased weight gain but were less sensitive to CDS-E2 compared to OVX rats. The effects appeared to be estrogen specific as carrier-linked testosterone had no effect on weight. The mechanisms of sustained and potent drug effects on weight are being explored.

Animals↗
PubMed1988

Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol.

Studies were undertaken to determine the effects on body weight and food intake of a chemical delivery system which preferentially delivers estradiol (E2) to the brain and there serves as a source for the sustained release of the steroid. We injected intravenously various doses of this estradiol-chemical delivery system (E2-CDS), E2-valerate (E2-VAL) or the dimethyl sulfoxide (DMSO) vehicle to young lean male rats and monitored body weight and 24 hr food intake for 39 days postinjection. E2-VAL caused a transient reduction in food intake and body weight gain. By contrast, a single injection of E2-CDS caused a chronic, dose-dependent reduction in the rate of body weight gain. In these lean rats, the duration of reduced body weight gain was not correlated with the observed transient reduction in food intake. In aged, obese male rats, E2-CDS caused a marked and chronic dose-dependent reduction in body weight. In contrast to lean rats, E2-CDS caused a long-term reduction in food intake in obese rats. To evaluate the importance of the E2-CDS-induced reduction in food intake in the observed persistent weight loss in obese rats, E2-CDS was administered to a group of obese rats and a second group which received the DMSO vehicle was pair-fed an equivalent amount of food daily. The resulting weight loss in both groups was equivalent. These results show that the enhanced delivery of E2 to the brain with the E2-CDS causes sustained reduction in the rate of body weight gain in lean rats and persistent weight loss in obese animals.

Animals↗
PubMed1988

Improved delivery through biological membranes. 32. Synthesis and biological activity of brain-targeted delivery systems for various estradiol derivatives.

Brain-targeted delivery systems based on the dihydropyridine in equilibrium pyridinium salt redox interconversion were synthesized for estradiol, estradiol 3-benzoate, and ethynylestradiol. Initial biological evaluation indicated that while all four compounds synthesized exerted central estrogenic activity as measured by serum LH suppression, only the delivery systems based on the 17-substituted estradiol and ethynylestradiol demonstrated prolonged action (greater than 12 days). The 17-(1-methyl-1,4-dihydronicotinic acid ester) of ethynylestradiol behaved in a similar manner to the previously described estradiol analogue in various assays. Tissue distribution studies in rats showed that administration of the ethynylestradiol derivative resulted in high sustained levels of the corresponding pyridinium salt in the central nervous system (CNS) while blood levels of the oxidized metabolite rapidly fell. The sustained brain levels were associated with a prolonged release of ethynylestradiol. By 24 h, posttreatment, no ethynylestradiol was found by HPLC in the blood while levels of over 20 ng/g of tissue were detected in the CNS. This enhanced central delivery gave a dose- and time-dependent LH suppression, which indicated a three- to fivefold increased potency compared with the corresponding estradiol derivative.

Animals↗
PubMed1988

High-performance liquid chromatographic assay of a central nervous system (CNS)-directed estradiol chemical delivery system and its application after intravenous administration to rats.

A redox-based chemical delivery system for estradiol (E2-CDS) has been shown capable of sustained and brain-selective delivery of estradiol (E2). A reversed-phase high-performance liquid chromatographic (HPLC) method is presented for the analysis of E2-CDS and its oxidized quaternary metabolite (E2-Quat) in biological fluids or tissues. The assay utilized a precolumn enrichment technique and detects plasma levels down to 10 ng/ml E2-Quat and 20 ng/ml E2-CDS. Sample preparation is rapid and simple. Samples are homogenized with acetonitrile, then centrifuged, and the supernatant is directly injected into the HPLC system. A water delivering pump injects the sample on a precolumn where the drug is concentrated. The mobile phase backflushes the retained compound onto the analytical column. At the same time, another sample can be injected onto a second precolumn. This alternating precolumn sample enrichment technique allows the injection of large volumes, up to 1800 microliters. Plasma and tissue samples of rats collected after i.v. administration of a single 15-mg/kg E2-CDS dose were analyzed for E2-CDS and E2-Quat by this procedure. The results show sustained brain levels of E2-Quat and prolonged half-life in brain compared to six peripheral tissues measured. These data support the concept of brain-targeted delivery using redox carrier systems of this type.

Animals↗
PubMed1987

A novel redox system for CNS-directed delivery of estradiol causes sustained LH suppression in castrate rats.

A series of 4 studies was conducted to examine the estrogen-like activity of a chemical delivery system (CDS) coupled to estradiol (E2). The CDS is based on a redox system, analogous to the NAD+ in equilibrium NADH coenzyme system and has previously been shown capable of sustained and site specific drug delivery to the central nervous system. The ability of CDS-E2 to suppress luteinizing hormone (LH) in gonadectomized rats was examined as an index of sustained estrogen action. A single dose of CDS-E2 resulted in significantly decreased LH serum levels in castrate rats through at least 24 days while an equimolar dose of E2 resulted in only transient LH decrease. Serum E2 levels were not different between the treatment groups, indicating that peripheral estrogen could not readily explain sustained hormone activity. A dose-response relationship was observed 12 days post-drug treatment in all monitored estrogen activities which showed CDS-E2 is more potent compared to equimolar E2. Further, LH suppression was significantly greater compared to ovariectomized rats treated with equimolar estradiol valerate, while anterior pituitary weights were not different between groups. Together with our previous data, these studies show that CDS-E2 exerts sustained estrogen-like activity which cannot be readily attributed to circulating E2 levels. These findings are consistent with a sustained, brain directed delivery of estrogen.

Animals↗
PubMed1984

Age-related alterations in dopamine and norepinephrine activity within microdissected brain regions of ovariectomized Long Evans rats.

The ability of several stimuli which augment central catecholamine (CA) neuronal activity to reinitiate estrous cycles in old constant estrous (CE) rats suggests CA neuronal function is impaired with advanced age. We examined the effects of age on dopamine (DA) and norepinephrine (NE) levels and turnover rates within microdissected brain regions of previously normally cycling young (3-4 months old) and middle-aged (10 months old) and CE old (20-22 months old) Long Evans 2 weeks after ovariectomy. Steady-state DA concentrations were significantly decreased in old compared to young rats in the nucleus accumbens (34%), anterior hypothalamic nucleus (54%, NHA ), neurointermediate pituitary lobe (51%, NIL) and median eminence (74%, ME). The rate constant of DA loss, an estimate of neuronal activity, decreased in old versus young rats only in the preoptic area suprachiasmatica (60%, POAs ) and NHA (60%) and was unchanged or augmented in the 7 other regions. In contrast, a decline in DA turnover rate of 29-67% was observed in 6 of 9 regions in middle-aged rats and 45-81% in 5 of 9 regions in old rats. Steady-state NE concentrations similarly were significantly decreased in old versus young rats in the POAs (54%), medial forebrain bundle (44%), nucleus suprachiasmatica (49%) and ME (59%). The rate constant of NE loss progressively decreased with increasing age only in the POAs and was unchanged or augmented in other regions. Turnover rate of NE was decreased from 21 to 98% in 4 of 8 regions from old animals. A strong positive correlation was noted between the rate constant of NE (but not DA) loss measured in young rats and the magnitude of the age-related depletion in NE concentrations within specific brain regions. Collectively these data indicate that with increasing age: CA neuronal function is differentially altered in nuclei located along the preoptico-tuberal pathway; substantial declines in both DA and NE concentrations are the primary contributor to the reduced amine turnover noted in several of these regions; and the observed age-related alterations in CA turnover may contribute to impaired LH response and the persistent hyperprolactinemia in old CE rats.

Aging↗
PubMed1984

Age-related alteration in catecholamine activity within microdissected brain regions of ovariectomized Fischer 344 rats.

The effects of increasing age on catecholamine (CA) metabolism in microdissected brain regions and on serum and pituitary hormone levels were examined in ovariectomized Fischer 344 rats. Young (4 to 5 months old) and middle-aged (9 to 10 months old) normally cycling and old repeated pseudopregnant rats (21-22 months old, PP) were ovariectomized to eliminate the complicating effects of cyclic gonadal steroid fluctuations. CA metabolism was examined 2 weeks later. To determine CA turnover rates, each age-group was subdivided into three groups, which were killed by decapitation 0, 45, or 90 min after administration of alpha-methyl-para-tyrosine (alpha-mpt). Dopamine (DA) and norepinephrine (NE) concentrations were determined in microdissected brain regions by radioenzymatic assay, and turnover rates were estimated. Steady-state concentrations of NE were not altered in middle-aged rats, but NE turnover rates increased in middle-aged rats in five of the six areas examined. While NE concentrations did not change with age in the median eminence (ME), NE turnover rates increased significantly in the two older age groups. These data indicate that the age-related decline in NE concentrations in several ventral diencephalic nuclei is preceded by a period of hyperactivity in noradrenergic neurons. DA concentrations were generally decreased in most areas examined in old versus young rats, with dramatic DA depletions (42-78%) observed in five regions. However, no consistent relationship between DA concentrations and turnover rates was seen either in regions with stable DA levels or in those which showed an age-associated decrease in DA concentrations. In the ME, a 42% decline in DA concentration was associated with an increase in the DA turnover rate in the oldest group of rats. Serum luteinizing hormone (LH) levels were similar in all three age groups of ovariectomized rats, while serum prolactin was elevated four-fold in old compared to younger animals. These data indicate that a complex pattern of regional alterations in CA metabolism accompanies the aging process and these may be related to the pseudopregnant state and hormone secretory capacity of aging Fischer 344 rats.

Age Factors↗
PubMed1983

Cysteamine depletes prolactin in young and old hyperprolactinemic rats.

Studies were undertaken to evaluate the effects of cysteamine on serum and anterior pituitary concentrations of prolactin in hyperprolactinemic female rats. Serum prolactin was elevated in young (4 to 5 months old) rats by implantation of 17 beta-estradiol while 26- to 28-month-old rats were in constant estrus and exhibited an age-related hyperprolactinemia. At 4 h after treatment with cysteamine (90 mg/kg body wt) serum and anterior pituitary prolactin concentrations were reduced in young animals by 98 and 85%, respectively. In old constant-estrous rats, cysteamine reduced serum prolactin by 92% and anterior pituitary prolactin by 82%. In young pseudopregnant rats, cysteamine induced a prompt resumption of estrous cycles. These studies indicate that cysteamine is an effective depletor of serum and pituitary prolactin in hyperprolactinemic rats.

Aging↗
PubMed1982

Normal LHRH neuronal function and hyperprolactinemia in old pseudopregnant Fischer 344 rats.

The relative contributions of LHRH neuronal function and hyperprolactinemia to the maintenance of the repeated pseudopregnant (PP) state in old Fischer 344 rats were examined. LHRH concentrations within 8 microdissected regions of the preoptico-tuberal pathway were not different between normally cycling 4-5 and 10-11 months old rats and PP 22-23 months old rats. LHRH concentrations were significantly decreased in the median eminence and serum LH was increased 2 weeks after ovariectomy in all 3 age groups. Ovariectomy had no significant effect on LHRH concentrations in any of the other brain regions examined in these three age-groups. Serum prolactin levels were elevated 4-fold in old PP rats when compared to younger animals and these old PP rats failed to exhibit the normally observed decline in serum prolactin in response to ovariectomy. Daily treatment for 10 days with the dopamine agonist, CB-154, reinitiated normal ovarian cycles in 7 of 7 old PP rats while vehicle treatment was ineffective in altering the PP state. The data suggest that persistent hyperprolactinemia rather than impaired LH secretory mechanisms is primarily responsible for the PP state in old Fischer 344 rats.

Age Factors↗
PubMed1982

Altered hypothalamic dopamine depletion rate and LHRH content in noncyclic hamsters.

Effect of light deprivation on hypothalamic dopamine (DA) depletion rate and luteinizing hormone releasing hormone (LHRH) content was evaluated in golden hamsters. Hamsters maintained in continuous darkness (CD) became acyclic after about 6 weeks while another group of hamsters maintained vaginal cyclicity under 20 lux light intensity for 14 hours a day. All hamsters were ovariectomized subsequently. Luteinizing hormone releasing hormone levels were significantly higher in the medial basal hypothalamus (MBH) and the serum gonadotropin levels were significantly lower in CD hamsters when compared with 20 lux group. However, gonadotropin release in response to exogenous LHRH was not significantly different in CD or 20 lux group of hamsters. Examination of hypothalamic catecholamine levels one hour after alpha-methyl-p-tyrosine injection indicated that the DA depletion was higher in CD animals. Results indicate that light deprivation probably enhances DA depletion rate in the MBH, suggesting that increased activity in dopaminergic neurons may inhibit the release of MBH LHRH in hamsters kept in continuous darkness.

Animals↗
PubMed1982

Resumption with clonidine of pulsatile LH release following acute norepinephrine depletion in ovariectomized rats.

The effects of adrenergic stimulation on the pulsatile release of LH were investigated in ovariectomized rats with acute depletion of brain norepinephrine (NE) levels. Rats bearing atrial cannula were pretreated with NE synthesis inhibitors, diethyldithiocarbamate (DDC) or bis (4-methyl-1-homopiperanzinyl thiocarbanyl) disulfide (FLA-63) and blood was withdrawn at 15-min intervals beginning 1 h later. DDC and FLA-63 markedly dampened pulsatile LH secretion. Administration of the alpha-adrenergic agonist clonidine (CLON) resulted in immediate LH release and apparent resumption of pulsatile LH secretion. The facilitatory effect of CLON on LH secretion was was more pronounced in FLA-63 than in DDC-pretreated rats. Additional characterization of the pattern of LH secretion in FLA-63-pretreated rats showed that the interval between LH pulses was significantly lengthened after acute NE depletion; however, CLON treatment increased LH pulse frequency to that found in ovariectomized rats. To further investigate the ability of CLON to augment pulsatile LH release, the LH secretory pattern was determined between 2 and 4 h after CLON administration FLA-63-pretreated rats. 8 of 10 rats receiving CLON (0.3 mg/kg) responded with episodic LH release 2-4 h following treatment while saline-treated rats continued to show dampened LH secretory patterns. These studies demonstrate that following acute depletion of NE in ovariectomized rats, a single injection of CLON can enhance both the amplitude and frequency of LH pulses. Further, the data suggest that central noradrenergic neurons exert only a permissive effect on pulsatile LH release and that the pulsatile mechanism may predominately be resident in LHRH neurons.

Animals↗