Altered stereoselectivity of cocaine and bupivacaine isomers in normal and batrachotoxin-modified Na+ channels

The inhibitory effects of local anesthetics (LAs) of cocaine and bupivacaine optical isomers on Na+ currents were studied in clonal GH3 cells under whole-cell patch clamp conditions. At holding potential of -100 mV, all four isomers inhibited peak Na+ currents when the cell was stimulated infrequently. The dose-response curves of this tonic block of peak Na+ currents by (-)/(+) cocaine and (-)/(+) bupivacaine were well fitted by the Langmuir isotherm, suggesting that one LA isomer blocked one Na+ channel. Each pair of isomers showed no greater than a twofold difference in stereoselectivity toward Na+ channels. Additional block of Na+ currents occurred when the cell was stimulated at 2 Hz. This use-dependent block was also observed in all four isomers, which again displayed little stereoselectivity. The voltage dependence of the use-dependent block produced by cocaine isomers did not overlap with the activation of Na+ channels but did overlap with the steady-state inactivation (h infinity), indicating that cocaine can bind directly to the inactivated state of Na+ channels before channel opening. In comparison, the peak batrachotoxin (BTX)-modified Na+ currents were little inhibited by cocaine and bupivacaine isomers. However, the maintained BTX-modified Na+ currents were highly sensitive toward the (-) form of cocaine and bupivacaine isomers during a prolonged depolarization. As a result, a profound time-dependent block of BTX-modified Na+ currents was evident in the presence of these LA isomers. The estimated values of the equilibrium dissociation constant (KD in micromolar) at +50 mV were 35.8, 661, 7.0, and 222 for (-)/(+) cocaine and (-)/(+) bupivacaine, respectively. Although chloramine-T (CT) also modified the fast inactivation of Na+ channels and gave rise to a maintained Na+ current during a prolonged depolarization, LA isomers showed no greater stereoselectivity in blocking this maintained current than in blocking the normal transient Na+ current. We conclude that (a) cocaine and bupivacaine isomers exhibit only weak stereoselectivity toward the LA receptor in normal and CT-treated Na+ channels, (b) BTX drastically modifies the configuration of the LA binding site so that the LA stereoselectivity of the open Na+ channels is altered by an order of magnitude, and (c) the (-) forms of cocaine and bupivacaine interact strongly with the open state of BTX-modified Na+ channels but only weakly, if at all, with the closed state. The last finding may explain why most LA drugs were reported to be less effective toward BTX-modified Na+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute stress may induce ovulation in women

Background  

This study aims to gather information either supporting or rejecting the hypothesis that acute stress may induce ovulation in women. The formulation of this hypothesis is based on 2 facts: 1) estrogen-primed postmenopausal or ovariectomized women display an adrenal-progesterone-induced ovulatory-like luteinizing hormone (LH) surge in response to exogenous adrenocorticotropic hormone (ACTH) administration; and 2) women display multiple follicular waves during an interovulatory interval, and likely during pregnancy and lactation. Thus, acute stress may induce ovulation in women displaying appropriate serum levels of estradiol and one or more follicles large enough to respond to a non-midcycle LH surge.     

Enantioselective detoxication of optical isomers of glycidyl ethers

The detoxication of the enantiomers of glycidyl 4-nitrophenyl ether (GNPE), (?)-(R)- and (+)-(S)-GNPE, and glycidyl 1-naphthyl ether (GNE), (?)-(R)- and (+)-(S)-GNE, by rat liver glutathione transferase and epoxide hydrolase was studied. Enantioselectivity was observed with both enzymes favoring the (R)-isomers as determined by the formation of conjugate, diol, and remaining substrate measured by HPLC. Enantiomers of GNE were detoxified by cytosolic epoxide hydrolase but those of GNPE were not. Substantial nonenzymatically formed conjugates of enantiomers of GNPE were detected showing (S)-GNPE the more reactive of the pair. © 1993 Wiley-Liss, Inc.     

Lipase stereoselectivity and regioselectivity toward three isomers of dicaprin: A kinetic study by the monomolecular film technique

Here we present a kinetic study on the steroselectivity and regioselectivity of 23 purified lipases of animal and microbial origin. This work, concerning a general problem of the mechanism of lipase–substrate molecular recognition, was performed using pure dicaprin isomers: 1,2-sn-dicaprin, 2,3-sn-dicaprin, and 1,3-sn-dicaprin spread as monomolecular films at the air–water interface. The first two isomers are optically active antipodes (enantiomers), forming stable films up to 40 mN m^?1, while the last is a prochiral compound, with a surface pressure of collapse of 32 mN m^?1. To our knowledge, this is the first report on the use of three diglyceride isomers as lipase substrates under identical and controlled physicochemical conditions. The lipases tested display a typical behaviour, characteristic of each enzyme, which allowed us to classify the lipases in groups according to (1) the profiles of enzyme velocity as a function of surface pressure, (2) their preferences for a given diglyceride isomer, quantified using new parameters termed steroselectivity index (S.I.), vicinity index (V.I.), and surface pressure threshold (S.P.T.). The general observation, true for all the enzymes tested, is that the three substrates are well differentiated, and the differentiation is more pronounced at high interfacial energy (low surface pressure). This observation supports our hypothesis that lipase conformational changes, resulting from the enzymesurface interaction, affect the enzymes' specificities. Generally speaking, the stereopreference for either sn-1 or sn-3 position on glycerides is maintained both in the case of di- and tri-glycerides. © 1995 Wiley-Liss, Inc.     

Oxaliplatin may induce cytokine-release syndrome in colorectal cancer patients

INTRODUCTION: Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven anti-tumor activity in colorectal cancer. Moreover, oxaliplatin appears to be relatively well tolerated and easy to handle, even on an outpatient basis. PATIENTS AND METHODS: Five advanced colorectal cancer patients treated with oxaliplatin-based chemotherapy developed, after the end of oxaliplatin infusion, similar idiosyncratic reactions characterized by chills, high fever, hypotension, abdominal pain, nausea and often diarrhoea. Venous blood for IL-6 and TNF-alpha assessment was drawn just after the beginning of the reaction and 15 and 30 minutes later. After drawing the third venous sample, intravenous dexamethasone (8 mg) was administered and the drawing of other two venous samples was performed (180 and 360 minutes after the beginning of the reaction). RESULTS: TNF-alpha and IL-6 serum concentrations significantly decreased after steroid therapy administration. The decrease of TNF-alpha and IL-6 levels went along with the clinical complete regression of symptoms and signs in all the 5 patients. No statistically significant correlation was found between other laboratory parameters and basal cytokine levels or cytokine decrease after steroid therapy. DISCUSSION: Our results clearly show that that idiosyncratic reaction observed in colorectal cancer patients after oxaliplatin infusion may be due to a massive release of cytokines such as TNF-alpha and IL-6. Symptom regression following steroid therapy administration went along with significant decrease of cytokines levels, confirming that TNF-alpha and IL-6 play a role in the pathogenesis of this reaction.     

Antioxidant role of N-acetyl cysteine isomers following high dose irradiation

High dose, acute radiation exposure, as in radiation accidents, induces three clinical syndromes that reflect consequences of oxidative protein, lipid, and DNA damage to tissues such as intestine, lung, and liver. In the present study, we irradiated C57BL/6 mice with 18 Gy whole-body radiation (XRT) and evaluated N-acetyl cysteine (NAC) isomers LNAC and DNAC as potential radioprotectors under conditions that would model the gastrointestinal syndrome. We focused on tissues thought not immediately involved in the gastrointestinal syndrome. Both LNAC and DNAC protected the lung and red blood cells (RBC) from glutathione (GSH) depletion following radiation exposure. However, only LNAC also supplemented the spleen GSH levels following XRT. Protection from increased malondialdehyde (MDA) levels (lung) and increased 8-hydroxy-deoxyguanosine (8-oxo-dG) presence (liver) following XRT was observed with treatment by either isomer of NAC. These results imply that either NAC isomer can act as a radioprotectant against many aspects of oxidative damage; chirality is only important for certain aspects. This pattern would be consistent with direct action of NAC in many radioprotection and repair processes, with a delimited role for NAC in GSH synthesis in some aspects of the problem.     

Successive optical resolution by replacing crystallization of DL-threonine

DL -Threonine [DL -Thr; (2RS,3SR)-2-amino-3-hydroxybutanoic acid] was optically resolved by replacing crystallization using L -serine (L -Ser) and 4-hydroxy-L -proline (L -Hyp) as optically active cosolutes. D -Thr was allowed to crystallize preferentially from racemic aqueous solutions in the presence of these L -α-amino acids. The optical resolution of DL -Thr was more successfully achieved by using L -Ser, whose structure is more similar to that of DL -Thr than L -Hyp, and successively gave D - and L -Thr of 87—92% optical purities. The D - and L -Thr obtained were then recrystallized from water to give optically pure D - and L -Thr. © 1994 Wiley-Liss, Inc.     

Lack of ant attendance may induce compensatory plant growth

Three levels in ant–plant protection systems need to be considered to fully understand how these symbiotic systems work. Here we present the effect of Oecophylla smaragdina ants on (1) the arthropod community, (2) herbivory, and (3) plant performance, within a studied mangrove ant–plant protection system. On Rhizophora mucronata trees in Thailand ants successfully colonised ant trees attached with a string to a natural ant tree, whereas they were unable to colonise control trees without this connection. Trees were monitored and arthropods (numbers and composition), leaf damage, leaf turnover and growth rates (stem diameter, tree height and total leaf area) were recorded in two surveys covering a period of 12 months. The number of herbivorous arthropods, but not the number of predators, was significantly lower on ant trees compared to control trees. Likewise, the amount of leaf damage inflicted by the four major groups of herbivores (Chrysomelidae, Tortricidae, Geometridae and Sesarminae) was significantly lower on ant trees compared to control trees and so was the leaf turnover rate. In spite of this, the released herbivore pressure on ant trees did not translate into higher growth rates. In contrast, all growth responses increased more on control trees compared to ant trees. Differences between the two groups were insignificant but leaf area increase was only marginally nonsignificant (P=0.062). The results show that ants remove herbivorous arthropods more efficiently than predators but ant-colonised mangroves do not necessarily benefit from this despite the resulting decrease in herbivory.     

Ligand-configuration-dependent hybrid supramolecular isomers based on the octamolybdate building blocks from one-pot hydrothermal crystallization

Two novel 3-D hybrid supramolecular isomers, namely, α-[Cu₂(ABPT)₂(H₂O)₂(Mo₈O₂₆)]_n (1) and β-[Cu₂(ABPT)₂(H₂O)₂(Mo₈O₂₆)]_n·4nH₂O (2), have been successfully isolated from one-pot hydrothermal crystallization and characterized. Single-crystal X-ray diffractions show that the ABPT ligands in compound 1 taking the transoid-configuration to link distorted octahedral copper centers into 1-D metal-organic chains, which are further interlaced by [Cu₂(γ-Mo₈O₂₆)] inorganic ladder-like chains to generate a 3-D hybrid structure. In 2, the square-pyramidal Cu^II centers are firstly linked by cisoid-ABPT ligands to give 2-D metal-organic coordination layers, which are connected by [δ-Mo₈O₂₆]⁴⁻ clusters into a 3-D hybrid network. Compounds 1 and 2 both can be regarded as 3,4-connected nets based on nonequivalent nodes with (4³.6.8⁶)₂(4².6)₂(4².8⁴) and (4.8²)₂(4.8².10³)₂ topologies, respectively. By careful inspection of the structures of 1 and 2, it is believed that the ligand configuration plays a crucial role for the formation of these two hybrid supramolecular isomers.     

Identification of the optical isomers of the amino acids in Polysphondylium violaceum acrasin

Using optically specific enzymes on the hydrolysate of glorin, we show the structure of natural glorin to be: N-propionyl-γ-L-glutamyl-L-ornithine-δ-lactam ethyl ester     

Anticonvulsant properties of spirohydantoins derived from optical isomers of camphor

Natural camphor exists as thed(+) form but thel(–) form has been synthesized. Replacement of the keto group on carbon 2 of each form with a hydantoin moiety led to only one spirohydantoin derivative. Bothd andl derivatives were synthesized. Both forms and their racemic mixture were tested in vivo for toxicity and behavioral effects in mice. A dose of 100 mg/kg of thed form was not toxic: mice showed normal grooming and exploratory behavior; thel form induced hunched posture, body jerks and myoclonic manifestations followed by quiescence. Thedl form showed intermediate effects. Challenge with the convulsant pentylenetetrazol (Metrazol) 2 hr after treatment with placebo or the camphor spirohydantoins produced seizure manifestations in all controls, in half of the subjects pretreated with thed-camphor derivative, in none of those pretreated with thel derivative and an intermediate response in those pretreated with racemic mixture. Thus, a spirohydantoin moiety added to camphor conferred strong anticonvulsive properties on thel form and modest ones on thed form; thed form did not seem to antagonize thel form.