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PubMed1987

Opioid modulation of LH secretion during the oestrous cycle of heifers.

Injections of an opioid agonist (bremazocine) and/or an antagonist (quadazocine) were given to heifers during the luteal or follicular phase of the oestrous cycle. Quadazocine was injected (210 mg/injection) three times at 2-h intervals, and bremazocine was injected (0.45 mg/injection) every 15 min for 6 h. Blood samples were taken every 15 min beginning 6 h before treatments started and continued for 18 h. LH secretion patterns were not affected by quadazocine in the luteal-phase heifers, but quadazocine and bremazocine had marked effects during the follicular phase. Quadazocine increased LH secretion by increasing peak height but not peak frequency. Bremazocine decreased LH secretion through both peak height and frequency. This decrease was of greater magnitude than the increase due to quadazocine. When quadazocine and bremazocine were given together, these effects were cancelled and none of the effects carried over into the bleeding period after treatments stopped. No apparent interruption of follicular maturation was detected since all follicular-phase heifers were detected in oestrus at normal intervals. We conclude that heifers in this experiment did not have an opioid-mediated mechanism for progesterone suppression of LH but that an opioid mechanism for modulating LH does exist during the follicular phase.

Animals↗
PubMed1988

Ovarian steroid hormone involvement in endogenous opioid modulation of LH secretion in mature ewes during the breeding and non-breeding seasons.

The opioid antagonist WIN-44441-3 (WIN-3, Sterling-Winthrop) caused significant increases in LH secretion in ovariectomized ewes treated with progesterone but not in ovariectomized animals treated with oestradiol-17 beta. In the non-breeding season, plasma LH concentrations in ovariectomized ewes without steroid therapy, given oestradiol-17 beta or oestradiol-17 beta and progesterone together were not affected by treatment with WIN-3 on Day 6 after ovariectomy (there was a significant increase in LH as a result of WIN-3 treatment 13 days after ovariectomy in sheep given no steroid therapy). However, WIN-3 treatment of ovariectomized sheep given progesterone resulted in a significant increase in plasma LH. WIN-3 was ineffective when given to intact ewes treated with progesterone during the non-breeding season. With ovariectomized sheep during the breeding season there was again no response to WIN-3 at 6 days after ovariectomy in sheep given oestradiol-17 beta, but significant LH elevations in animals given no steroid, those given progesterone and those given progesterone + oestradiol-17 beta. The lack of an LH response to WIN-3 in ovariectomized sheep treated with oestradiol-17 beta did not result from a reduced pituitary response to GnRH since such animals responded normally to exogenous GnRH treatment. Overall, these results are consistent with the idea that, irrespective of the time of year, progesterone exerts negative feedback upon LH release at least in part through an opioidergic mechanism, whereas oestradiol-17 beta exerts negative feedback through steps unlikely to involve opioids. Progesterone can override the effect of oestradiol-17 beta during the breeding season only. Further, there appears to be a steroid-independent opioid involvement in LH suppression, operating at both times of year.

Animals↗
PubMed1989

Failure of melatonin to influence endogenous opioid effects on LH secretion in the anoestrous ewe.

In May mature seasonally anoestrous ewes were implanted with melatonin which advanced the onset of cycles by about 1 month. The LH response to an opioid antagonist, WIN-3, was determined 5, 15, 25 and 60 days after melatonin implantation, by intravenous administration of WIN-3 (12.5 mg/dose) 4 times at 15-min intervals during both the 1st and the 5th hour of an 8-h treatment period. There was no effect of WIN-3 at 5, 15 and 25 days after melatonin implantation. At 60 days LH concentration and pulse frequency were significantly increased (P less than 0.05 and less than 0.01 respectively) in response to WIN-3 treatment, but only in those animals which had begun reproductive cycles, an effect known to be mediated by the presence of progesterone. We were therefore unable to find evidence to support the hypothesis that the influence of melatonin in advancing the breeding season may be via an opioidergic pathway.

Anestrus↗
PubMed1989

Quantification of opioid-binding sites in the ewe hypothalamus.

Opioid-binding sites were quantified in the ewe hypothalamus using [3H]diprenorphine ([3H]DIP) as the radioligand. [3H]DIP binding to hypothalamic membrane preparations was stereospecific, saturable with respect to [3H]DIP concentration, and linear with hypothalamic membrane protein content. Scatchard analysis revealed a single class of binding sites. There were no significant differences in binding site concentration or binding affinity in hypothalami from intact ewes during the breeding and non-breeding seasons, or from long-term ovariectomized ewes with and without oestradiol treatment during the breeding season. Thus, whilst ovarian steroid hormones are known to modify LH responses to opioids and their antagonists in the ewe in vivo, they do not appear to do this by modulating the numbers of hypothalamic opioid-binding sites.

Animals↗
PubMed2004

Enhancing the attenuation of explosives in surface soils at military facilities: sorption-desorption isotherms.

The primary objective of the present study was to develop inexpensive soil amendments that can be applied to enhance the adsorption of energetic compounds on military training ranges, thus limiting the potential for these compounds to migrate to groundwater. Adsorption and desorption isotherms were determined for 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine with a wide variety of natural and man-made adsorbents, including wheat straw, sawdust, peat moss, ground rubber tires, and clays. Among the various adsorbents tested, peat moss proved to be the most effective sorbent for the three explosives. The adsorption coefficients (Kd(s)) for TNT and RDX with peat (310 and 87 L/kg, respectively) were at least two orders of magnitude higher than that determined for adsorption of these energetics with two surface soils. The adsorption-desorption isotherms for the explosives showed considerable hysteresis (Kd(s) < Kd(d)) with some of the solid adsorbents, suggesting that the sorption process is not readily reversible but, rather, that some fraction of the adsorbed contaminant is either irreversibly bound or present as a slowly desorbed fraction. The data indicate that the application of specific adsorbents to soils at military impact ranges may significantly improve the protection of local groundwater resources.

Adsorption↗
PubMed2004

Enhancing the attenuation of explosives in surface soils at military facilities: combined sorption and biodegradation.

This research evaluated soil amendments designed to enhance the adsorption and biodegradation of explosives at military training facilities, thus minimizing their potential for transport to subsurface environments. Several carbon cosubstrates were tested in soil slurries for their ability to stimulate the biodegradation of 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (royal demolition exposive [RDX]), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (high-melting explosive [HMX]) by indigenous soil microorganisms. Crude soybean oil and molasses stimulated mineralization of RDX (30-40%) and HMX (approximately 10%). The TNT was not significantly mineralized in any of the treatments, but high-performance liquid chromatography (HPLC) analysis indicated extensive transformation of TNT to amino-containing compounds. The biodegradation of explosives was then examined in unsaturated soil microcosms amended with crude soybean oil and molasses combined with sphagnum peat moss and sawdust. Minimal TNT mineralization was observed, and HMX mineralization was only observed with molasses addition. In contrast, RDX mineralization was extensive in microcosms amended with soybean oil or molasses. The presence of peat moss decreased soybean oil-stimulated RDX mineralization by approximately 5%, but resulted in about 5% greater RDX mineralization compared with molasses only. Sawdust markedly decreased mineralization regardless of cosubstrate type. Mass balance results indicated that the formation of bound residues likely was occurring, especially for TNT. These results indicate that the application of inexpensive adsorbents and cosubstrates to soils may significantly improve the protection of groundwater resources underlying live fire ranges.

Adsorption↗
PubMed2005

Reductive transformation of hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and methylenedinitramine with elemental iron.

Reductive (pre)treatment with elemental iron is a potentially useful method for degrading nitramine explosives in water and soil. In the present study, we examined the kinetics, products, and mechanisms of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) degradation with elemental iron. Both RDX and HMX were transformed with iron to formaldehyde, NH4+, N2O, and soluble products. The yields of formaldehyde were relatively constant (71% +/- 5%), whereas the yields of NH4+ and N2O varied, depending on the nitramine and the mechanism. The reactions most likely were controlled by a surface process rather than by external mass transfer. Methylenedinitramine (MDNA) was an intermediate of both RDX and HMX and was transformed quantitatively to formaldehyde with iron. However, product distributions and kinetic modeling results suggest that MDNA represented a minor reaction path and accounted for only 30% of the RDX reacted and 14% of the formaldehyde produced. Additional experiments showed that RDX reduction with elemental iron could be mediated by graphite and Fe2+ sorbed to magnetite, as demonstrated previously for nitroaromatics and nitrate esters. Methylenedinitramine was degraded primarily through reduction in the presence of elemental iron, because its hydrolysis was slow compared to its reactions with elemental iron and surface-bound Fe2+. Our results show that in a cast iron-water system, RDX may be transformed via multiple mechanisms involving different reaction paths and reaction sites.

Adsorption↗
PubMed2005

Survival and reproduction of enchytraeid worms, Oligochaeta, in different soil types amended with energetic cyclic nitramines.

Hexanitrohexaazaisowurtzitane (CL-20), a new polycyclic polynitramine, has the same functional nitramine groups (N-NO2) as the widely used energetic chemicals hexahydro-1,3,5-trinitro-1,3,5-triazacyclohexane (royal demolition explosive [RDX]) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (high-melting explosive [HMX]). Potential impacts of CL-20 as an emerging contaminant must be assessed before its use. The effects of CL-20, RDX, or HMX on adult survival and juvenile production by potworms Enchytraeus albidus and Enchytraeus crypticus were studied in three soil types, including Sassafras sandy loam (1.2% organic matter [OM], 11% clay, pH 5.5), an agricultural soil (42% OM, 1% clay, pH 8.2), and a composite agricultural-forest soil (23% OM, 2% clay, pH 7.9) by using ISO method 16387 (International Standard Organization, Geneva, Switzerland). Results showed that CL-20 was toxic to E. crypticus with median lethal concentration values for adult survival ranging from 0.1 to 0.7 mg/kg dry mass (DM) when using the three tested soils. In addition, CL-20 adversely affected juvenile production by both species in all soils tested, with median effective concentration (EC50) values ranging from 0.08 to 0.62 mg/kg DM. Enchytraeus crypticus and E. albidus were similarly sensitive to CL-20 exposure in the composite agricultural-forest soil, which supported reproduction by both species and enabled comparisons. Correlation analysis showed weak or no relationship overall among the soil properties and reproduction toxicity endpoints. Neither RDX nor HMX affected (p > 0.05) adult survival of either species below 658 and 918 mg/kg DM, respectively, indicating that CL-20 is more toxic to enchytraeids than RDX or HMX. Examination of data shows that CL-20 should be considered as a potential reproductive toxicant to soil invertebrates, and that safeguards should be considered to minimize the potential for release of CL-20 into the environment.

Agriculture↗
PubMedDate not supplied

Remediating munitions-contaminated soil with zerovalent iron and cationic surfactants.

Soils contaminated from military operations often contain mixtures of HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine), and TNT (2,4,6-trinitrotoluene) rather than a single explosive. Differences among explosives in solubility and reactivity make developing a single remediation treatment difficult. When Fe(0) was used to treat a munitions-contaminated soil, we observed high rates of destruction for RDX and TNT (98%) but not HMX. Our objective was to determine if HMX destruction by Fe(0) could be enhanced by increasing HMX solubility by physical (temperature) or chemical (surfactants) means. To determine electron acceptor preference, we treated RDX and HMX with Fe(0) in homogeneous solutions and binary mixtures. Increasing aqueous temperature (20 to 55 degrees C) increased HMX solubility (2 to 22 mg L(-1)) but did not increase destruction by Fe(0) in a contaminated soil slurry that also contained RDX and TNT. Batch experiments using equal molar concentrations of RDX and HMX demonstrated that RDX was preferentially reduced over HMX by Fe(0). By testing various surfactants, we found that the cationic surfactants (HDTMA [hexadecyltrimethylammonium bromide], didecyl, and didodecyl) were most effective in increasing HMX concentration in solution. Didecyl and HDTMA were also found to be highly effective in facilitating the transformation of HMX by Fe(0). Using HDTMA or didecyl solutions (3%, w/v) containing solid-phase HMX, we observed that 100% of the added HMX was transformed by Fe(0) in the didecyl matrix and 60% in the HDTMA matrix. These results indicate that cationic surfactants can increase HMX solubility and facilitate Fe(0)-mediated transformation kinetics but HMX destruction rates will be slowed when RDX is present.

Azocines↗
PubMed2002

Recent progress in the development of subtype selective nicotinic acetylcholine receptor ligands.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand gated ion channels, which are found at the neuromuscular junction and in the central and peripheral nervous systems. The channels can be assembled from fourteen known subunits. The exact combination and function of all the channels are still not determined but in the CNS certain combinations have been identified which appear to modulate the release of specific neurotransmitters. Non-specific nAChR agonists like nicotine and epibatidine, have been shown to have interesting pharmacology but their clinical value is limited by their undesirable side effects. Selective ligands for different receptor subtypes have been reported and these compounds are probably the best tools for determining the function of the subtypes. The expectation is that some receptor subtype selective nAChR ligands will be clinically useful for the treatment of a broad range of CNS disorders. The development of stable cell lines functionally expressing specific combinations of subunits has greatly improved our understanding of ligand specificity. There have also been advances in the modelling of the ligand binding site, thanks to the discovery of a homologous snail ACh binding protein the X-ray structure of which was determined in 2001. These techniques should lead to rapid advances in the development of truly subtype selective ligands. In this review we describe recent progress in the area and describe the first 1000 fold selective low molecular weight ligands from the AstraZeneca group. We also comment on the first subtype specific channel modulators.

Alkaloids↗
PubMedDate not supplied

Biological denitrification of hydrolysates from octahydro-1,3,5,7 tetranitro-1,3,5,7-tetrazocine.

Alternatives for the destruction of common military explosives, including trinitrotoluene; hexahydro-1,3,5-trinitro-1,3,5-triazine; and octahydro-1,3,5,7 tetranitro-1,3,5,7-tetrazocine (HMX) are being investigated in the post-cold war period. One alternative combines chemical treatment (i.e., base hydrolysis of the explosives) and biological treatment (i.e., denitrification of the hydrolysate). This paper focuses on results of the biological part of the treatment process, during which Hyphomicrobium sp. bacteria were isolated from a seed obtained from a denitrification facility. The bacteria were enriched and maintained on a surrogate waste with methanol as the carbon source. The resulting culture is capable of anoxic growth in waste solutions containing up to 5000 mg/L of nitrite-nitrogen. The culture efficiently denitrifies both surrogate and actual hydrolysate wastes. A substrate inhibition model was used to accurately predict denitrification rates. Comparisons are made between denitrification rates obtained for surrogate versus actual wastes. Denitrification rates were higher when actual waste streams were used. This work demonstrates the feasibility of using Hyphomicrobiun sp. bacteria to treat HMX hydrolysate and presents a model that can be used to design a large-scale system.

Azocines↗
PubMed2004

Comparison of plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis or clinically normal calves.

OBJECTIVE: To compare plasma disposition of alkaloids after lupine challenge in cattle that had given birth to calves with lupine-induced arthrogryposis and cattle that had given birth to clinically normal calves and determine whether the difference in outcome was associated with differences in plasma disposition of anagyrine. ANIMALS: 6 cows that had given birth to calves with arthrogryposis and 6 cows that had given birth to clinically normal calves after being similarly exposed to lupine during pregnancy. PROCEDURES: Dried lupine (2 g/kg) was administered via gavage. Blood samples were collected before and at various time points for 48 hours after lupine administration. Anagyrine, 5,6-dehydrolupanine, and lupanine concentrations in plasma were measured by use of gas chromatography. Plasma alkaloid concentration versus time curves were generated for each alkaloid, and pharmacokinetic parameters were determined for each cow. RESULTS: No significant differences in area under the plasma concentration versus time curve, maximum plasma concentration, time to reach maximum plasma concentration, and mean residence time for the 3 alkaloids were found between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Because no differences were found in plasma disposition of anagyrine following lupine challenge between cattle that had given birth to calves with arthrogryposis and those that had not, our findings do not support the hypothesis that between-cow differences in plasma disposition of anagyrine account for within-herd differences in risk for lupine-induced arthrogryposis.

Alkaloids↗
PubMed2004

The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus pursh) in sheep.

Several species of lupine (Lupinus spp.) are poisonous to livestock, producing death in sheep and "crooked calf disease" in cattle. Range livestock cope with poisonous plants through learned foraging strategies or mechanisms affecting toxicant disposition. When a toxic plant is eaten, toxicant clearance may be influenced by the animal's nutritional and/or physiological status. This research was conducted to determine whether differences in body condition or short-term nutritional supplementation of sheep altered the disposition of lupine alkaloids given as a single oral dose of ground silvery lupine (Lupinus argenteus) seed. Ewes in average body condition (ABC, n = 9) and low body condition (LBC, n = 10) received a single dose of ground lupine seeds including pods (8.5 g/kg BW) via gavage on the first day of the experiment, and were then randomly assigned to one of two nutritional supplement treatments. Blood samples were taken 0 to 60 h after dosing to compare blood alkaloid concentration and to evaluate alkaloid absorption and elimination profiles. Concentrations of total alkaloid and anagyrine, 5,6 dehydrolupanine, lupanine, and alkaloid E were measured in serum. These four alkaloids constituted 78 and 75% of the total alkaloid concentration in serum for LBC vs. ABC groups, respectively. Initial analysis indicated that short-term supplementation had no effect on alkaloid disposition, and supplementation was removed from the statistical model. The highest concentration of total alkaloids was observed 2 h after dosing. Overall, serum total alkaloid and anagyrine levels (area under the curve) were higher (P < 0.01) for sheep in the LBC group. Serum peak concentrations of total alkaloid and anagyrine were higher in LBC vs. ABC groups (P < 0.05). Serum elimination of anagyrine, unknown alkaloid E, and lupanine was decreased in LBC vs. ABC treatments (P < 0.05). These results demonstrate that body condition is important in the disposition of lupine alkaloids; however, further research is needed to determine the potential benefit, if any, that short-term nutritional supplementation might have on alkaloid disposition.

Alkaloids↗
PubMed1991

Induction of cytotoxic cell activities by a novel cyclic disulfide compound, SA3443 in vivo.

(4R)-Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443) is a newly synthesized cyclic disulfide compound which offers potential hepatoprotective properties. The effect of SA3443 on the induction of natural killer (NK) and cytotoxic T lymphocyte (CTL) activities was investigated. NK activity in BALB/c mice splenic cells was investigated using YAC-1 cells as target cells. SA3443, at a dose range of 30-300 mg/kg/day, augmented NK activity significantly when administered orally once daily for 4 days before the assay. Alloantigen-specific CTL activity in splenic cells from BALB/c mice was detected 9 days after sensitization with C57BL/6 mice splenic detected 9 days after sensitization with C57BL/6 mice splenic cells. SA3443, at a dose of 100 mg/kg/day, augmented CTL activity significantly when administered orally, once daily for 4 days beginning after the sensitization and for 2 days before the assay, while a high dose of SA3443, at 300 mg/kg, suppressed CTL activity. From these results, it is thought that SA3443 may assist in the elimination of hepatitis viruses from the liver in patients with chronic active hepatitis, by the activation of NK and/or CTL activities.

Adjuvants, Immunologic↗
PubMedDate not supplied

Electrophysiology: a method to investigate the functional properties of ligand-gated channels.

Ligand-gated channels (LGCs) play a fundamental role in the fast transmission of electrical activity from neuron to neuron and/or to effector cells. Studies of LGCs in isolation have become possible since the identification of genes coding for these membrane proteins together with the establishment of reconstitution techniques in host systems. Methods for electrophysiological investigations of LGCs reconstituted either in the Xenopus oocytes or stably tranfected in cell lines are discussed. Functional studies of reconstituted receptors enable fast determination of LGCs' pharmacological profiles and comparison of their physiological properties. Combination of molecular engineering with physiological measurements allows studies with unpreceeding resolution and it is now possible to examine at the amino-acid level the contribution of some residues in the formation of the ligand-binding site or the ionic channel domains.

Acetylcholine↗
PubMed1999

Activation of peripheral kappa opioid receptors inhibits capsaicin-induced thermal nociception in rhesus monkeys.

8-Methyl-N-vanillyl-6-nonenamide (capsaicin) was locally applied in the tail of rhesus monkeys to evoke a nociceptive response, thermal allodynia, which was manifested as reduced tail-withdrawal latencies in normally innocuous 46 degrees C water. Coadministration of three kappa opioid ligands, U50,488 (3.2-100 microgram), bremazocine (0.1-3.2 microgram), and dynorphin A(1-13) (3.2-100 microgram), with capsaicin in the tail dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by a small dose of an opioid antagonist, quadazocine; (0.32 mg), applied in the tail; however, this dose of quadazocine injected s.c. in the back did not antagonize local U50,488. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied kappa opioid agonists is in the tail. In addition, local nor-binaltorphimine (0.32 mg) and oxilorphan (0.1-10 microgram) antagonist studies raised the possibility of kappa opioid receptor subtypes in the periphery, which indicated that U50,488 produced local antinociception by acting on kappa1 receptors, but bremazocine acted probably on non-kappa1 receptors. These results provide functional evidence that activation of peripheral kappa opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model is a useful tool for evaluating peripherally antinociceptive actions of kappa agonists without central side effects and suggests new approaches for opioid pain management.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗