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At least 595 records · Page 33Linked to original sources
PubMed2003

Optimization of the separation of organic explosives by capillary electrophoresis with artificial neural networks.

The separation of 12 explosives by capillary electrophoresis was optimized with the aid of artificial neural networks (ANNs). The selectivity of the separation was manipulated by varying the concentration of sodium dodecyl sulfate (SDS) and the pH of the electrolyte, while maintaining the buffer concentration at 10 mM borate. The concentration of SDS and the electrolyte pH were used as input variables and the mobility of the explosives were used as output variables for the ANN. In total, eight experiments were performed based on a factorial design to train a variety of artificial neural network architectures. A further three experiments were required to train ANN architectures to adequately model the experimental space. A product resolution response surface was constructed based on the predicted mobilities of the best performing ANN. This response surface pointed to two optima; pH 9.0-9.1 and 60-65 mM SDS, and pH 8.4-8.6 and 50-60 mM SDS. Separation of all 12 explosives was achieved at the second optimum. The separation was further improved by changing the capillary to an extended cell detection window and reducing the diameter of the capillary from 75 microm to 50 microm. This provided a more efficient separation without compromising detection sensitivity.

Aniline Compounds↗
PubMedDate not supplied

[The influence of cytaphate on the status of oxidative metabolism in rats with diabetic nephropathy].

The antioxidant effect of cytaphate (0,0-dimethyl-N-cytisinyl phosphate) has been studied in outbred white rats with alloxan-induced insulin-dependent diabetes mellitus. The content of malonic dialdehyde, diene conjugates, ketodienes, middle-weight molecules, primary and secondary products of lipid peroxidation (LPO), and Schiff bases and the activity of catalase, glutathione peroxidase, and adenosine deaminase in erytrocytes have been evaluated. The state of oxidative protein modification, the content of malonic dialdehyde and diene conjugates, and the superoxide-anion production in the blood plasma have been determined. In the blood of animals with model diabetes, the LPO and oxidative protein modification processes were intensified and the level of superoxide anion production was increased. The administration of cytaphate led to a decrease of the LPO intensity and oxidative protein modification and to normalization of the level of superoxide anion production and the activity of enzymes involved in the antioxidant protection system.

Animals↗
PubMed1991

Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors.

A family of genes has been identified that encodes subunits of nicotinic acetylcholine receptors (nAChRs) and is expressed in the nervous system. Functional neuronal nAChRs can be expressed in Xenopus oocytes by injection of RNA encoding 1 of 2 different beta-subunits (beta 2, beta 4) in pairwise combination with RNA encoding 1 of 3 different alpha-subunits (alpha 2, alpha 3, alpha 4). We examined the sensitivity of these 6 different alpha- beta-subunit combinations to the nicotinic agonists ACh, nicotine, cytisine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP). Each subunit combination displayed a distinct pattern of sensitivity to these 4 agonists. The alpha 2 beta 2 combination was 5-fold more sensitive to nicotine than to acetylcholine, while the alpha 3 beta 2 combination was 17-fold less sensitive to nicotine than to ACh, and the alpha 3 beta 4 combination was equally sensitive to both nicotine and ACh. nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 2 were 14-100-fold less sensitive to cytisine than to ACh. In contrast, nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 4 were 3-17-fold more sensitive to cytisine than to ACh. The alpha 2 beta 2, alpha 3 beta 2, and alpha 3 beta 4 combinations were each equally sensitive to DMPP and ACh, while the alpha 2 beta 4, alpha 4 beta 2, and alpha 4 beta 4 combinations were 4-24-fold less sensitive to DMPP than to ACh. We also demonstrated that these differences are neither a consequence of variation in the relative amounts of RNA injected nor an artifact of oocyte expression. The oocyte system can accurately express ligand-gated ion channels because mouse muscle nAChRs expressed in oocytes display pharmacological properties similar to those reported for these receptors expressed on BC3H-1 cells. We conclude that both the alpha- and the beta-subunits contribute to the pharmacological characteristics of neuronal nAChRs.

Acetylcholine↗
PubMed1992

A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment.

The subunit composition and pharmacological regulation of rat neuronal nicotinic cholinergic receptors were assessed. Specific immunoprecipitation was determined in solubilized rat brain homogenates using [3H]cytisine, a high affinity agonist at nicotinic receptors, in conjunction with polyclonal antisera generated against nonhomologous domains of the various subunits comprising this receptor class. In all brain regions tested, only antisera generated against the alpha 4 and beta 2 subunits were able to immunoprecipitate specifically receptors labeled by [3H]cytisine. Thus, these sera were further characterized in order to validate and optimize their use in the immunoprecipitation protocol. Preincubation of solubilized receptors from rat forebrain with antisera generated against the alpha 2, alpha 3, alpha 5, beta 3, or beta 4 subunits did not decrease the amount of precipitable alpha 4 or beta 2 subunit. On the other hand, when either anti-alpha 4 or anti-beta 2 serum was used to immunoprecipitate solubilized receptors from rat forebrain, the supernatants contained little if any remaining receptors that could be specifically precipitated by either antibody. Because these antisera do not cross-react, the data indicate that alpha 4 and beta 2 subunits are associated with each other in at least one neuronal nicotinic receptor subtype that has high affinity for agonists. Moreover, these results imply that all alpha 4 subunits that are labeled by [3H]cystisine are coupled to beta 2 subunits. We also present evidence that the alpha 4/beta 2 subtype characterized in this report is significantly increased in the cortex of rats chronically treated with nicotine.

Alkaloids↗
PubMed1991

SA3443, a novel cyclic disulfide compound, depresses anti-SRBC antibody-forming cell responses in the mouse through inhibition of antigen-presenting cell activities.

(4R)-Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443) is a newly synthesized cyclic disulfide compound which has potential hepatoprotective properties. The effect of SA3443 on the induction of anti-sheep red blood cell (SRBC) plaque (antibody) forming cell (PFC) responses was investigated in vivo and in vitro. SA3443 (approximately 3 mg/kg/day) remarkably decreased the number of anti-SRBC PFC in the spleens of mice immunized with a high dose of SRBC in vivo. The addition of SA3443 (approximately 1 x 10(-7) M) at the initiation of mouse spleen cell cultures in vitro also exerted a significant inhibitory effect on subsequent PFC response to SRBC, and removal of SA3443 after 24 h did not reverse its inhibitory effect. Pre-incubation of isolated adherent spleen cells with SRBC and SA3443 resulted in a similar inhibition of subsequent PFC response, but a pre-incubation of macrophage-depleted cells with SRBC and SA3443 or a pre-incubation of the unseparated spleen cells with SA3443 in the absence of SRBC had no effect. These findings have suggested that SA3443 may depress antibody response through inhibition of macrophage antigen-presenting cell activity.

Adjuvants, Immunologic↗
PubMedDate not supplied

Protective effect of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), a novel cyclic disulfide, on immunologically induced liver injuries in mice.

The effects of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4- carboxylic acid (SA3443), a novel cyclic disulfide, on new immunological liver injury models were investigated. The first liver injury model included a single injection of rabbit anti-basic liver protein antibody into DBA/2 mice. Serum transaminase activities showed a dose-dependent increase 42 hr after the antibody treatment. SA3443 significantly inhibited the elevation of serum transaminase activity and the histopathological changes of the liver in antibody-treated mice at doses of 100 to 300 mg/kg, p.o. The second hepatic failure model was based on an injection of lipopolysaccharide into BALB/c mice which had been previously treated with heat-killed Propionibacterium acnes (P. acnes). SA3443 reduced the lethal acute hepatic failure at doses of 100 to 300 mg/kg. Moreover, a distinct increase in lymphocyte-activating factor activity was detected in the supernatant of the culture medium of the liver macrophage/Kupffer cells isolated from the rat treated with P. acnes. SA3443, at 10(-6) to 10(-4) M, suppressed the release of the lymphocyte-activating factor activity from liver macrophage/Kupffer cells. These results suggest that SA3443 provides considerable protection against immunological liver injuries, and that the efficacy of SA3443 might be partially related to an inhibition of the increase in lymphocyte-activating factor activity.

Alanine Transaminase↗
PubMed1991

[3H]cytisine binding to nicotinic cholinergic receptors in brain.

Cytisine, a ganglionic agonist, competes with high affinity for brain nicotinic cholinergic receptors labeled by any of several nicotinic 3H-agonist ligands. Here we have examined the binding of [3H]cytisine in rat brain homogenates. [3H]Cytisine binds with high affinity (Kd less than 1 nM), and specific binding represented 60-90% of total binding at all concentrations examined up to 15 nM. The nicotinic cholinergic agonists nicotine, acetylcholine, and carbachol compete with high affinity for [3H]cytisine binding sites, whereas among nicotinic receptor antagonists only dihydro-beta-erythroidine competes with high affinity (in the nanomolar range). Comparison of binding in several brain regions showed that [3H]cytisine binding is higher in the thalamus, striatum, and cortex than in the hippocampus, cerebellum, or hypothalamus. The pharmacology and brain regional distribution of [3H]cytisine binding sites are those predicted for neuronal nicotinic receptor agonist recognition sites. The high affinity and low nonspecific binding of [3H]cytisine should make it a very useful ligand for studying neuronal nicotinic receptors.

Acetylcholine↗
PubMed1990

Naloxone benzoylhydrazone (NalBzoH) analgesia.

Naloxone benzoylhydrazone (NalBzoH) is a novel mixed agonist/antagonist. Against mu agonists, NalBzoH is a potent antagonist with a prolonged duration of action corresponding to its extremely slow rate of dissociation from mu receptors in binding assays. In the present studies, NalBzoH also antagonized mu analgesia, reversing both mu 1 and mu 2 analgesia independently elicited by intracerebroventricular or intrathecal [D-Ala2,MePhe4,-Gly(ol)5]enkephalin injections. It also antagonized kappa 1 analgesia elicited by U50,488H, and delta analgesia produced by intrathecal [D-Pen2,D-Pen5]enkephalin. Yet, at higher doses, NalBzoH alone produced analgesia in the tail-flick, hot plate and writhing assays. Neither the mu-selective antagonist beta-funaltrexamine, the delta-selective antagonist naltrindole, nor the kappa 1-selective antagonist norbinaltorphimine reversed NalBzoH analgesia in the tail-flick test. Analgesia observed with systemically administered NalBzoH was reversed easily by the antagonist WIN44,441 when it was given intracerebroventricularly, but not intrathecally. These observations confirm the opioid nature of NalBzoH analgesia and imply a supraspinal mechanism of action. In contrast, intrathecal, but not intracerebroventricular WIN44,441 reversed analgesia from systemic U50,488H quite potently. Thus, NalBzoH antagonizes mu, delta and kappa 1 actions while retaining its ability to elicit analgesia through a novel and distinct supraspinal kappa 3 system.

Analgesia↗
PubMed1989

[Studies on the alkaloids of radix Sophorae Tonkinensis].

Six alkaloids were isolated from Radix Sophorae Tonkinensis. On the basis of spectrometric analysis and physico-chemical constants they were identified as (I) (+)-matrine, (II) (-)-cytisine, (III) (+)-matrine N-oxide, (IV)(+)-sophocarpine N-oxide, (V)(+)-sophoramine and (VI) (+)-sophoranol respectively. (II), (IV), (V) and (VI) were isolated for the first time from Radix Sophorae Tonkinensis.

Alkaloids↗
PubMed1989

Pharmacological characterization of supersensitivity to naltrexone in squirrel monkeys.

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.

Animals↗
PubMed1989

Reinforcing effect of alfentanil is mediated by mu opioid receptors: apparent pA2 analysis.

Apparent pA2 analysis was used to determine whether the short-duration opioid agonist, alfentanil, acts at mu receptors in the positive reinforcement of operant behavior in the rhesus monkey. In test sessions a red light signaled the availability of alfentanil injections. If a monkey pressed a response lever 30 times, a specific dose of alfentanil was injected i.v., and the red light was extinguished for 10 min. This cycle could be repeated for up to 130 min, the maximum length of a session. Between successive test sessions at least three maintenance sessions were held; in these sessions injections of 0.32 mg/kg/injection of codeine were made available. The dose of alfentanil was changed from one test session to the next, and dose-dependent changes in rates of responding resulted. Rates reached 3.05 responses/sec at 0.010 mg/kg/injection, the highest dose tested. The opioid antagonist, quadazocine, produced dose-dependent, parallel shifts to the right in the alfentanil dose-response curve. In Schild Plot analysis the regression line fit to the antagonism data had a slope of -1.1; the apparent pA2 value for quadazocine was 7.6. This value was close to apparent pA2 values obtained with mu agonists in studies of other behavioral effects of opioids, but distinct from values obtained with kappa agonists in those studies. Thus, it is likely that mu receptors mediate the positive reinforcing effect of alfentanil.

Alfentanil↗
PubMedDate not supplied

[The effect of cytisine on mRNA transport in the cytoplasm of eukaryotic cells (plants and animals)].

The action of alkaloid cytisine on protein biosynthesis in eukaryotic cells was studied. It was shown that the alkaloid had no effect on mRNA translation. Cytisine inhibited the release of mRNP particles from rat liver and wheat embryos nuclei. Sedimentation properties and distribution in CsCl gradient of the material extracted from alkaloid-treated nuclei did not differ from control one and were similar to informosomes from animal and plant cells described earlier. The main part of mRNA with sedimentation coefficients 14-18S, capable for translation in the cytoplasm is retained in alkaloid-treated nuclei.

Alkaloids↗
PubMed1987

Nicotine elevates rat plasma ACTH by a central mechanism.

Nicotine is a potent secretagogue for the release of adrenocorticotropin (ACTH) from the anterior pituitary in vivo. However, the location of its action is unknown; knowledge of this is essential for elucidating its mechanism. Our studies show that cytisine, a peripherally acting nicotinic cholinergic agonist, given i.v. at doses equimolar or greater than nicotine, failed to elevate plasma ACTH levels, whereas nicotine (0.01 and 0.03 mg/kg b.wt.) had significant effects. Nicotine (10(-7)-10(-4) M) had no effect on the secretion of beta-endorphin by anterior pituicytes in vitro, nor did it potentiate the action of corticotropin-releasing factor (10(-9) or 10(-8) M). Intracerebroventricular injection of nicotine (1-20 micrograms) significantly elevated ACTH levels. Moreover, ACTH responses to nicotine delivered into the hypothalamic region of the third ventricle were significantly greater than those elicited by injection into the upper region. Additional studies were conducted to determine the earliest age at which nicotine stimulates ACTH. The response to i.p. nicotine (1 or 2 mg/kg b.wt.) was present but diminished during the postnatal period, whereas maximal responses comparable to mature rats were attained by day 15. To establish whether nicotine has a central effect in younger animals, nicotinic antagonists were tested. Hexamethonium (2 mg/kg b.wt.), a peripherally acting antagonist, was ineffective against nicotine (0.025 and 2.0 mg/kg b.wt.), whereas mecamylamine (2 mg/kg b.wt.), inhibitory at both peripheral and central sites, blocked the ACTH response. Thus, whether administered peripherally or centrally, nicotine activates central mechanisms mediating the release of ACTH; it appears that the target(s) for nicotine are within the hypothalamus or brainstem.

Adrenocorticotropic Hormone↗
PubMed1987

Differentiation between mu and kappa receptor-mediated effects in opioid drug discrimination: apparent pA2 analysis.

Apparent pA2 values for the opioid antagonist, quadazocine, were used to characterize differential involvement of mu and kappa opioid receptors in the discriminative stimulus effects of opioid agonists. Rhesus monkeys were trained to discriminate s.c. injections of either codeine or ethylketazocine from sham injections. In tests of drug generalization, morphine, levorphanol and alfentanil all produced dose-dependent increases in codeine-appropriate responding, and ethylketazocine produced dose-dependent increases in ethylketazocine-appropriate responding. Quadazocine antagonized the discriminative stimulus effects of each of the agonists. Apparent pA2 values for quadazocine (and slopes of the regression lines fit to the data in "Schild Plot" analysis) were 7.8 (-1.0) with morphine, 7.7 (-1.4) with levorphanol, 7.9 (-0.92) with alfentanil and 5.7 (-0.93) with ethylketazocine. If regression line slopes were constrained to equal -1, 7.8 was the apparent pA2 value with all agonists except ethylketazocine (5.7). This difference in apparent pA2 values for quadazocine confirms that different receptors (mu and kappa, respectively) mediate the discriminative effects of opioid agonists in codeine- and ethylketazocine-trained rhesus monkeys. Also, when the antagonism data were reanalyzed separately for each individual monkey, apparent pA2 values from individual animals were found to be similar to values from other animals in the same group and to values based on grouped data.

Alfentanil↗