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J W Simpkins

Publications and source records attributed to J W Simpkins.

At least 91 records · Page 5Linked to original sources
PubMed1989

A rapid, sensitive method for the simultaneous quantitation of estradiol and estradiol conjugates in a variety of tissues: assay development and evaluation of the distribution of a brain-enhanced estradiol-chemical delivery system.

A rapid and sensitive method that permits the simultaneous quantitation of estradiol (E2) and the E2 conjugate [estradiol 17-(1,4-dihydrotrigonellinate)] in biological tissues from rats is described. This method development was necessitated by the design of this E2-chemical delivery system (E2-CDS) which permits the predictable metabolism of the E2-CDS to a charged quaternary ion (E2-Q+) and its subsequent hydrolysis to slowly liberate E2. Based upon in vitro determinations of the rates of oxidation of E2-CDS to E2-Q+ and hydrolysis of E2-Q+ to E2, we anticipated that concentrations of E2-Q+ would be several orders of magnitude higher in tissues than E2. Three steps were used to extract and prepare samples for the radioimmunoassay (RIA) of estradiol. The first step is homogenization and extraction of the biological samples with an organic solvent; the second step is the base catalyzed hydrolysis of the E2 conjugate in 1 N NaOH; and the third step utilizes solid-phase extraction (SPE) with C18 reversed-phase columns which provide a means of achieving a rapid and precise extraction and separation of E2. The analysis of plasma samples does not require the initial solvent extraction. All purified E2 samples were then reconstituted in the assay buffer and assayed by RIA for E2. The application of this procedure to the determination of E2-Q+ and E2 in biological materials was assessed for specificity, reliability and recovery in vitro by using tissues and plasma from rats and in vivo evaluations of the distribution of E2 and E2-Q+ were done using rats treated with 1 mg E2-CDS/kg. Our in vitro analyses revealed that E2 and E2-Q+ could be differentially extracted with a high recovery and that both compounds could be specifically and reliably assayed in brain, plasma, anterior pituitary, liver, kidney, lung, heart and adipose tissue. In vivo analyses revealed that following a single i.v. injection of E2-CDS, brain levels of E2 exceeded serum levels by 30-, 41-, and 82-fold while brain levels of E2-Q+ exceeded serum levels by 33-, 70-, and 294-fold at 1, 7 and 14 days, respectively. Collectively, these data indicate that E2-Q+ and E2 can be reliably quantitated in a variety of tissues following the administration of an E2-chemical delivery system.

Animals↗
PubMed1989

Tissue distribution of cocaine in the pregnant rat.

Cocaine hydrochloride was administered by single intraperitoneal (IP) doses to pregnant rats at day 18 or 19 of gestation. Plasma and tissue cocaine and norcocaine concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis of concentration versus time data showed rapid distribution of cocaine and its metabolite to maternal and fetal tissues. The area under the cocaine concentration versus time curve (AUC) in fetus compared to maternal plasma was 3.33. The half-life of cocaine in the maternal plasma and fetus was 46 and 55 minutes, respectively, similar to values reported for cocaine elimination half-life in human plasma. The order of cocaine concentrations was placenta greater than fetal liver greater than maternal heart greater than whole fetus greater than fetal brain greater than maternal brain = maternal plasma. Norcocaine concentrations were usually less than 20% of cocaine concentrations in plasma and tissues. These results support extensive fetal exposure to cocaine following administration to pregnant rodents. Pharmacodynamic studies of cocaine in pregnancy should consider the effects of the drug on the developing fetus.

Animals↗
PubMed1989

Gonadal steroid and chronic morphine treatment do not change the posttranslational processing of beta-endorphin in the rat brain.

The present study examines whether two treatments known to induce refractoriness to exogenous morphine produce this desensitization through a change in the posttranslational processing of brain beta-endorphin (beta-End). The first experiment examined whether an ovarian steroid regimen which produces a transient desensitization of brain opiate receptor mechanisms alters beta-End processing in the preoptic area (POA), medial basal hypothalamus (MBH), and brainstem (BS). The second experiment monitored the effects of morphine pellet treatment, known to produce morphine dependency, on immunoreactive beta-End forms in the hypothalamus and periaquaductal gray area of the midbrain (PAG). The individual molecular forms of beta-End were separated using ion exchange chromatography and collection fractions were quantitated for beta-End immunoreactivity by RIA. The results show that regional differences occur in the posttranslational processing of beta-End. In the hypothalamus, MBH and POA, beta-End-(1-31) and its non-acetylated C-terminal cleavage products, beta-End-(1-27) and beta-End-(1-16) were the predominant forms of beta-End. The PAG pools produced a beta-End peptide elution profile similar to the hypothalamus, although small amounts of N-acetyl-beta-End-(1-31) were also identified. The BS exhibited the least posttranslational processing of beta-End; beta-End-(1-31) was the primary product with smaller amounts of beta-End-(1-27) and beta-End-(1-26) observed. However, neither ovarian steroid treatment nor chronic morphine produced any changes in posttranslational processing of beta-End or in total beta-End concentration in any of the brain regions examined in these experiments. These data indicate that the refractoriness or tolerance to exogenous morphine associated with steroid or chronic morphine treatment cannot be explained by alterations in the biological activity of beta-End resulting from the differential regulation of its posttranslational processing products.

Animals↗
PubMed1989

Effects of a brain-enhanced chemical delivery system for estradiol on body weight and food intake in intact and ovariectomized rats.

Studies were undertaken to determine the effects on body weight of a brain-enhanced chemical delivery system for estradiol. This estradiol-chemical delivery system (E2-CDS) has a long half-life in the brain, where it slowly releases estradiol but is quickly cleared from peripheral tissues. We administered, by a single iv injection, E2-CDS (0.2, 1.0, or 5.0 mg/kg), equimolar doses of another 17-hydroxy-substituted estrogen, estradiol valerate (E2-VAL), or the dimethyl sulfoxide (DMSO) vehicle to female rats. Daily food intake and body weight was determined for 24 days thereafter. E2-CDS caused an initial dose-dependent suppression in body weight for up to 8 days and a suppression in food intake for up to 4 days. In response to E2-VAL, the initial declines in body weight and food intake were lower in magnitude, were shorter in duration, and showed no dose dependency. Following this period of weight loss, E2-CDS-treated rats gained weight at a rate greater than that of the DMSO controls, and at the 0.2- and 1.0-mg/kg doses, body weights achieved were greater than control levels. To determine the role of the ovaries on this biphasic response to E2-CDS, long-term ovariectomized rats were treated with E2-CDS (1.0 mg/kg) or the vehicle and parameters of body weight regulation were determined for 25 days. Ovariectomized rats responded to E2-CDS with a prompt and sustained decrease in body weight which did not recover over the 25-day course of the study. The body-weight loss in ovariectomized rats was associated with a marked reduction in food intake for 8 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Evidence for prolonged suppression of stress-induced release of adrenocorticotropic hormone and corticosterone with a brain-enhanced dexamethasone-redox delivery system.

We have developed a redox system for brain-enhanced delivery of dexamethasone based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Dexamethasone, when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces its rate of exit from the brain. The aim of the study was to evaluate the capacity of a dexamethasone-chemical delivery system (DX-CDS) and dexamethasone (DEX) to suppress stress-induced elevations of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Adult male Sprague-Dawley (CD) rats were administered either DX-CDS (10 mg/kg), an equimolar dose of DEX or the drug vehicle (2-hydroxypropyl-beta-cyclodextrin) by a single tail vein injection. Rats then received either no stress or a restraint stress for a 5- or 15-min duration on days 1, 3, 5 or 7 after drug administration and trunk blood was rapidly collected. To assess peripheral effects of DX-CDS and DEX, 1 ml of blood was removed via orbital puncture and evaluated for total and differential leukocyte counts in a separate group of animals. Both DX-CDS and DEX were effective on day 1 in suppressing, by greater than 95%, ACTH secretion induced by a 5-min stress. However, DX-CDS was effective through day 5 (44% suppression) while DEX was not effective after 24 h. When 15 min of stress was applied, DX-CDS effected a significant ACTH suppression through 7 days while DEX was effective for only 3 days. DX-CDS was effective through day 7 (55%) in suppressing CORT after a 15-min stress while DEX was effective for 3 days only.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1988

Chronic morphine and testosterone treatment: effects on norepinephrine and serotonin metabolism and gonadotropin secretion in male rats.

The effects of sustained-release implants of morphine (M) and/or testosterone (T) on serum gonadotropin levels and norepinephrine (NE) and serotonin (5-HT) metabolism in brain regions were examined. While 4 days of M or 5 mm [corrected] T treatment were without significant effect, the combination dramatically decreased circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Castration increased NE content of the mediobasal hypothalamus (MBH), and although M, 5 mm [corrected] T, or their combination significantly reduced NE levels in the MBH, they remained elevated compared to intact or 30 mm [corrected] T-treated rats. Further, in the MBH no differences in normetanephrine (NME) levels, nor in NME:NE ratios, nor 5-HT metabolism were evident. In the preoptic area-anterior hypothalamus, NE or 5-HT metabolism were not altered by castration and M and/or T. These results show that M and T interact to suppress LH and FSH release in the apparent absence of any appreciable effect on hypothalamic monoamines.

Animals↗
PubMed1988

Evidence for suppression of serum LH without elevation in serum estradiol or prolactin with a brain-enhanced redox delivery system for estradiol.

We developed a redox system for brain-enhanced delivery of estradiol based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Estradiol (E2), when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces the rate of exit of the estradiol-carrier complex from the brain. Subsequent hydrolysis of the carrier provides sustained production of estradiol in the brain. The aim of the study was to evaluate the effects of single vs. multiple injections of the estradiol-chemical delivery system (E2-CDS) on both central and peripheral estrogen-responsive tissues. Ovariectomized Sprague-Dawley rats received an intravenous injection of E2-CDS at 10, 33, 100 or 333 micrograms/kg BW or the drug vehicle, dimethyl sulfoxide (DMSO; 0.5 ml/kg) every 2 days for 7 injections (2 weeks) or a single injection only at 2 days before sacrifice. With a single injection, E2-CDS did not affect serum luteinizing hormone (LH) levels at the 10 micrograms/kg dose but caused a dose-dependent reduction in serum LH of 39-52% at the dose range of 33 to 333 micrograms/kg. By contrast, multiple injections of E2-CDS caused a 32 to 76% reduction in serum LH levels at doses ranging from 10 micrograms/kg to 333 micrograms/kg. Additionally, multiple doses of E2-CDs caused a dose-dependent reduction in body weight at the 10 and 33 micrograms/kg doses with the higher doses causing no further weight reduction. For both single and multiple dosage groups, serum E2 levels remained unchanged after doses of E2-CDS of 10 and 33 micrograms/kg, then increased to 21 pg/ml for the single dosage group and to 23 pg/ml for the multiple dosage group at the 100 micrograms/kg dose, and to 59 pg/ml for singly-injected rats and 60 pg/ml for multiply-injected rats at the 333 micrograms/kg dose. Serum prolactin concentrations were closely correlated with serum E2 levels for both the single and multiple dose groups. These data reveal that a single or multiple doses of E2-CDS can reduce serum LH levels without elevating serum E2 or prolactin concentrations, supporting the concept of brain-enhanced delivery of estradiol with an estradiol chemical delivery system.

Adrenal Glands↗
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

Chronic morphine and testosterone treatment. Effects on sexual behavior and dopamine metabolism in male rats.

The effects of sustained delivery of morphine and/or testosterone (T) on male rat copulatory behavior, penile reflexes and dopaminergic metabolism in selected brain regions were examined. Castration was followed by (1) a decrease in the number of male rats exhibiting intromissive and ejaculatory behavior in mating tests, (2) decreased erections in ex copula tests, and (3) increases in dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations in the mediobasal hypothalamus (MBH) and the preoptic area-anterior hypothalamus (POA-AH). The decreased incidence of copulatory behavior and penile reflexes seen after castration was effectively prevented by a 4-day treatment with 5-mm T-containing Silastic capsules. Chronic morphine implants, conversely, accentuated the castration-induced decrements in copulatory behavior and prevented the 5-mm-T-induced facilitation, but did not alter the number of animals displaying erection (although the number of erections displayed by testosterone-treated rats was reduced) in ex copula tests. Treatment of castrated rats with 5 mm T, but not morphine alone, nor the combination of 5 mm T plus morphine, significantly reduced dopamine and DOPAC levels in the MBH. In the POA-AH, 5 mm T was without effect, whereas morphine, alone or in combination with 5 mm T, reduced the levels of dopamine and DOPAC. These data suggest that (1) the decline in sexual behavior induced by chronic morphine is primarily due to a failure of sexual arousal, and not of erectile ability, and (2) although the decline in sexual activity seen after castration is associated with alterations in dopaminergic metabolism, the effects of morphine and testosterone on sexual activity are opposite and dissociated from alterations in dopaminergic metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Alterations in brain opiate receptor mechanisms on proestrous afternoon.

We have previously observed that gonadal steroid treatments, which stimulate a proestrous-like LH surge is ovariectomized rats, cause a marked reduction in the responsiveness to opiates of a variety of CNS processes. The present study was undertaken to determine if a similar decline in opiate responses is associated with the endogenous steroid-induced LH surge on the afternoon of proestrous. Rats were evaluated for thermic, nociceptive, behavioral and LH secretory responses to morphine sulfate on diestrous I afternoon (DiPM) and proestrous morning (ProAM), times at which LH secretion is low, as well as on proestrous afternoon (ProPM) during the preovulatory LH surge. While on DiPM and ProAM, morphine caused a 33-45% reduction in serum LH levels at doses as low as 5 mg/kg b.w., in ProPM rats doses as high as 10 mg/kg did not affect LH secretion. Similarly, ProAM rats showed a prompt and sustained analgesic response to morphine, but ProPM rats showed a delayed response of shorter duration. DiPM rats showed an acute response intermediate to that of ProAM and ProPM animals. While DiPM and proAM rats exhibited the expected hypothermic response to a high dose of morphine (15 mg/kg), ProPM rats showed no decline in core body temperature, but exhibited a delayed hyperthermic response to the opiate. DiPM and ProAM rats showed a dose-dependent decline in locomotor behavior in response to morphine. In contrast, ProPM rats, which exhibited a significantly elevated basal locomotor activity, failed to show a reduction in locomotion after morphine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Desensitization of brain opiate receptor mechanisms by gonadal steroid treatments that stimulate luteinizing hormone secretion.

We studied the effects of two ovarian steroid treatments that induce proestrous-like surges in LH secretion on responsiveness to morphine sulfate (MS), as measured by induced hypothermic, antinociceptive, behavioral, and LH secretory changes. Ovariectomized rats received no steroids (OVX), 7.5 micrograms estradiol benzoate 2 days before the experiment (EB), or EB and then 5 mg progesterone 48 h later (EBP). MS administration coincided with the steroid-induced LH hypersecretion that occurs in the EB and EBP rats at 1530-1630 h. Serum LH concentrations were determined 30 min after administration of MS. In OVX and EB rats, MS caused a dose-dependent decrease in serum LH, but even 20 mg/kg MS did not alter serum LH during the EBP-induced LH surge. Brain-mediated morphine-induced analgesia was evaluated in the three steroid treatment groups from measurement of latency to pawlick on a hot plate. EB and EBP rats were less responsive than OVX rats to MS-induced antinociception. EB and EBP rats were also less responsive than OVX animals to the spinal cord-mediated analgesia due to MS, as calculated by tail-flick latency. MS-induced hypothermia revealed a responsiveness order of OVX greater than EB greater than EBP. Whereas MS caused a dose-dependent reduction in locomotor activity in OVX and EB rats, EBP rats showed marked hyperactivity at low MS doses and were less responsive to the suppression of locomotor activity at higher doses. These marked steroid-induced changes in MS responsiveness could not be explained by altered pharmacokinetic disposition of morphine. These data indicate that treatment with EBP, which stimulates a preovulatory-like LH surge, decreases the ability of MS to induce hypothermic, antinociceptive, and behavioral responses and abolishes its capacity to suppress LH release. These effects of gonadal steroids were not observed before the LH surge, which suggests that this surge is linked to the decline in MS sensitivity. Further, the diminished response to MS appears to be a function of the magnitude of the LH surge.

Analgesia↗
PubMed1988

Effects of a brain-enhanced chemical delivery system for estradiol on body weight and serum hormones in middle-aged male rats.

We have developed a redox-chemical delivery system for brain-enhanced drug delivery of estradiol based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Estradiol, when combined with the carrier, readily crosses the blood-brain barrier and upon oxidation of the carrier is "locked" in the brain. The aim of this study was to evaluate the effects of the estradiol-chemical delivery system (E2-CDS) on body weight change and associated alterations in the secretion of anterior pituitary hormones in middle-aged, male rats. The data revealed that rats receiving E2-CDS exhibited a significant weight loss by 2 days which continued to day 14, the last observation day. A significant weight difference was observed between E2-CDS and DMSO-treated animals. Serum estradiol levels of rats treated with E2-CDS were elevated 100-fold by day 1 and decreased thereafter and serum prolactin concentrations were doubled by 24 hours and continued to increase to the completion of the experiment. Testosterone levels were markedly suppressed by 24 hours while serum levels of LH, TSH, T3, T4 and GH were not significantly altered. These data indicate that the E2-CDS causes a long-term reduction in body weight and testosterone secretion and that these changes are not mediated by alterations in the secretion of anterior pituitary hormones.

Age Factors↗
PubMed1988

Brain-enhanced delivery of testosterone using a chemical delivery system complexed with 2-hydroxypropyl-beta-cyclodextrin.

Enhanced brain delivery of testosterone was suggested by application of a dihydropyridine in equilibrium pyridinium salt redox system. The drug delivery method is based upon the NAD+ in equilibrium NADH coenzyme system and utilizes the covalent attachment of testosterone to a dihydropyridine-type carrier. Upon administration of two such testosterone chemical delivery systems (T-CDS1 or T-CDS2), serum LH levels were suppressed by 71-87% after 24 hours and maintained through 5 days (28%) with T-CDS1. An equimolar dose of testosterone or testosterone propionate failed to suppress serum LH. Peripheral testosterone target tissues (seminal vesicles and prostate gland) were only slightly stimulated by T-CDS1. Complexation of T-CDS1 with 2-hydroxypropyl-beta-cyclodextrin allowed a lowering of the effective LH-suppressing dose of T-CDS1 from 25 mg/kg to 10 mg/kg, presumably by increasing the solubility of T-CDS1 in the blood. These findings suggest that testosterone can be effectively delivered to the central nervous system (CNS) with minimal peripheral effect, and the delivery of T-CDS1 to the CNS can be improved via complexation with 2-hydroxypropyl-beta-cyclodextrin.

Animals↗
PubMed1988

Evidence for the delivery of narcotic antagonists to the colon as their glucuronide conjugates.

Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered s.c. nalmefene HCl caused a dose-dependent tail skin temperature increase, whereas nalmefene glucuronide was ineffective. Nalmefene precipitated brain-mediated morphine withdrawal at doses as low as 10 micrograms/kg, whereas nalmefene glucuronide was ineffective at doses as high as 1 mg/kg. After p.o. administration of the drugs, naloxone HCl and nalmefene HCl caused diarrhea, withdrawal behavior and tail skin temperature responses by 15 min. In contrast, after p.o. administration of the glucuronide conjugate of either narcotic antagonist, diarrhea was delayed for 75 to 203 min. This latency probably reflects the required transit time to the lower gastrointestinal tract inasmuch as direct colonic administration of either nalmefene or nalmefene glucuronide caused diarrhea within 5 to 8 min. Additionally, the magnitude of brain-mediated withdrawal was smaller and its time of occurrence was delayed and compared to the diarrhea response after p.o. administration of the conjugated forms of the narcotic antagonists. Our calculations indicate that about 0.2 to 0.5% of the dose of the narcotic antagonist administered orally as the glucuronide was absorbed systemically. These results indicate that p.o. administration of the glucuronide conjugates of naloxone and nalmefene results in delivery of the narcotic antagonists to the colon. As such these conjugates may be useful in the prevention or relief of constipation caused by opiate use, without interfering with the central analgesic effects of the narcotics.

Animals↗
PubMed1987

Alpha-adrenergic mediation of the tail skin temperature response to naloxone in morphine-dependent rats.

Studies were undertaken to evaluate the role of central noradrenergic neurons in the tail skin temperature (TST) surge that accompanies morphine withdrawal in the rat. A 5 degrees C increase in TST and a 1-2 degrees C decrease in rectal temperature (Tr) was observed following administration of a dose of naloxone HCl (NAL, 1 mg/kg, s.c.) which precipitated withdrawal in morphine-dependent rats. Intracerebroventricular (i.c.v.) injection of clonidine HCl, a partial alpha 2-adrenergic agonist did not alter TST in morphine-dependent animals. However, clonidine (10 or 50 micrograms/rat, i.c.v.) given 10 min prior to the administration of NAL completely blocked the TST response to the opiate antagonist in the morphine-dependent animals. Although NAL and clonidine reduced Tr to a similar extent in morphine-dependent rats, their effects were not additive when the drugs were administered sequentially. Treatment with the alpha-adrenergic antagonist phentolamine (11.9 or 60 micrograms/rat, i.c.v.) failed to alter TST when administered alone, but the highest dose significantly reduced the TST response to naloxone in the morphine-dependent rat. In addition, phentolamine, at high doses only, moderately reduced Tr, but the alpha-adrenergic antagonist failed to modify the decline in Tr associated with NAL-precipitated morphine withdrawal. Collectively, these data indicate that brain noradrenergic neurons play a role in the TST surge which accompanies NAL-precipitated morphine withdrawal, and that the TST and Tr responses can be dissociated in the morphine-dependent rat.

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↗
PubMed1987

Anxiolytic activity of a brain delivery system for GABA.

We evaluated the anxiolytic property of a brain-specific gamma-aminobutyric acid delivery system (GABA-CDS) in male rats by means of a drink-foot shock conflict procedure. Brain-specific delivery of the active compound was achieved by combination of GABA benzyl ester with an interconvertible dihydropyridine in equilibrium pyridinium salt carrier, which is "locked in" to the brain upon its oxidation. Pharmacokinetic studies revealed that the hydrophilic pyridinium salt form (G-Q+) of the GABA-CDS formed in situ remained in the brain for 12 h but was cleared from the blood and other peripheral tissues by 0.5-4 h. While the lipophilic form (G-DH) of the GABA-CDS caused a marked and sustained anxiolytic response when administered systemically, GABA and the charged pyridinium salt (G-Q+ form) of the GABA-CDS were ineffective. G-DH was injected at either 0, 4, 10 or 25 mg/kg IV in DMSO after rats were water and food deprived. After either 0.5, 2, 4, 8 or 24 h, rats were permitted 10 s of shock-free drinking of 10% sucrose, then given a 35 mA (DC) current through the drinking tube. Drinking time was recorded for 3 min. All doses of G-DH caused a significant increase in anxiolysis over control levels through 8 h. An increase (4 to 7-fold) in anxiolytic activity was observed through the 10 mg/kg dose with the 25 mg/kg dose causing no additional increase. No sedation or analgesia was observed at 2 h with any anxiolytic-producing dose of G-DH. These results suggest that G-DH elicits anxiolysis with minimal sedation, through the local brain action the G-Q+ or subsequent to the release of GABA.

Animals↗