Disposition kinetics of ML-1035 sulfoxide enantiomers and the prochiral sulfide in rats

ML-1035, 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration-time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono-N-desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enantioners, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enantiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction. © 1993 Wiley-Liss, Inc.     

Chemical agents that inhibit pollen development: effects of the phenyl-cinnoline carboxylates SC-1058 and SC-1271 on the ultrastructure of developing wheat anthers (Triticum aestivum L. var Yecora rojò)

Summary Phenylcinnoline carboxylate compounds SC-1058 and SC-1271 cause complete male sterility in wheat when applied at suitable dosages at the pre-meiotic stage of anther development. Anthers from treated and untreated plants were compared using light and electron microscopy from the pre-meiotic stage through the formation of nearly mature pollen. Overall anther development is gradually slowed in treated plants and pollen development is generally arrested in the late prevacuolate or early vacuolate microspore stage, although the first pollen mitosis does sometimes occur. The sporopollenin-containing exine walls are thinner, and show abnormally developed foot and tectum layers with sparse connecting baculi. Microspore cytoplasm degenerates and the cells eventually collapse. At the early, prevacuolate, free microspore stage treated tapetal cells hypertrophy, expanding into the locule. They contain abnormally large vacuoles that appear to form from the fusion of secretory vesicles, and some vacuoles contain electrondense deposits. The sporopollenin-containing orbicular wall and Ubisch bodies are retarded in their development and are structurally deformed. Acetolysis of whole anthers and of thick sections shows that the sporopollen-in-containing structures of treated materials are greatly reduced in thickness and are less rigid than in the control. We conclude that application of these compounds causes interference with the secretory function of tapetal cells which supplies sporopollenin cell-wall polymers to the exine of the microspores and to the tapetal orbicular wall and associated Ubisch bodies. Interference with the tapetal secretion of other nutrients required for microspore development is strongly suggested.     

Antibiofilm Activity of Invasive Plants against Candida albicans: Focus on Baccharis halimifolia Essential Oil and Its Compounds

The extracts of five invasive plants were investigated for antifungal and antibiofilm activities against Candida albicans, C. glabrata, C. krusei, and C. parapsilosis. The antifungal activity was evaluated using the microdilution assay and the antibiofilm effect by measurement of the metabolic activity. Ethanol and ethanol-water extracts of Reynoutria japonica leaves inhibited 50 % of planktonic cells at 250 μg mL⁻¹ and 15.6 μg mL⁻¹, respectively. Ethanol and ethanol-water extracts of Baccharis halimifolia inhibited >75 % of the mature biofilm of C. albicans at 500 μg mL⁻¹. The essential oil (EO) of B. halimifolia leaves was the most active (50 % inhibition (IC₅₀) at 4 and 74 μg mL⁻¹against the maturation phase and 24 h old-biofilms of C. albicans, respectively). Oxygenated sesquiterpenes were the primary contents in this EO (62.02 %), with β-caryophyllene oxide as the major component (37 %). Aromadendrene oxide-(2), β-caryophyllene oxide, and (±)-β-pinene displayed significant activities against the maturation phase (IC₅₀=9–310 μ mol l⁻¹) and preformed 24 h-biofilm (IC₅₀=38–630 μ mol l⁻¹) of C. albicans with very low cytotoxicity for the first two compounds. C. albicans remained the most susceptible species to this EO and its components. This study highlighted for the first time the antibiofilm potential of B. halimifolia, its EO and some of its components.     

Cyclic peptides and depsipeptides from cyanobacteria: A review

An elaborate array of structurally-novel and biologically-active cyclic peptides and depsipeptides are found in blue-green algae (cyanobacteria). Several of these compounds possess structures that are similar to those of natural products from marine invertebrates. Most of these cyclic peptides and depsipeptides, such as the microcystins and the lyngbyatoxins, will probably only be useful as biochemical research tools. A few, however, have the potential for development into useful commercial products. For example, cryptophycin-1, a novel inhibitor of microtubule assembly fromNostoc sp GSV 224, shows impressive activity against a broad spectrum of solid tumors implanted in mice, including multidrug-resistant ones, and majusculamide C, a microfilament-depolymerizing agent fromLyngbya majuscula, shows potent fungicidal activity and may have use in the treatment of resistant fungal-induced diseases of domestic plants and agricultural crops.     

Interaction of influenza virus proteins with planar bilayer lipid membranes II. Effects of rimantadine and amantadine

The dependence of the surface potential difference (ΔU), transversal elasticity module (E₁) and membrane conductivity (G₀) on the concentrations of the antiviral drugs, rimantadine and amantadine was studied in the planar bilayer lipid membrane system. The method used was based on independent measurements of the second and third harmonics of the membrane capacitance current. The binding constants of bilayer lipid membranes obtained from the drug adsorption isotherms were 2.1 · 10⁵ M^?1 and 1.3 · 10⁴ M^?1 for rimantadine and amantadine, respectively. The changes in G₀ took place only after drug adsorption saturation had been achieved. The influence of rimantadine and amantadine on the interaction of bilayer lipid membranes with matrix protein from influenza virus was also investigated. The presence of 70 μg/ml rimantadine in the bathing solution resulted in an increase in the concentration of M-protein at which the adsorption and conductance changes were observed. The effects of amantadine were similar to those of rimantadine but required a higher critical concentration of amantadine. The results obtained suggest that the antiviral properties of rimantadine and amantadine may be related to the interaction of these drugs with the cell membrane, which can affect virus penetration into the cell as well as maturation of the viral particle at the cell membrane.     

Soil organic matter and structural stability: mechanisms and implications for management

Summary The stability of pores and particles is essential for optimum growth of plants. Two categories of aggregates macro- (> 250 m) and micro- (<250 m) depend on organic matter for stability against disruptive forces caused by rapid wetting. Dispersion of clay particles from microaggregates is promoted by adsorption of complexing organic acids which increase the negative charge on clays. The acids are produced by plants, bacteria and fungi. However, the dispersibility of clay in microaggregates is offset by the binding action of polysaccharides, mainly mucilages produced by bacteria, but also by plant roots and fungal hyphae. The stability of microaggregates is also enhanced by multivalent cations which act as bridges between organic colloids and clays. Macroaggregates are enmeshed by plant roots, both living and decomposing, and are thus sensitive to management, and increase in number when grasses are grown and the soil is not disturbed. Lack of root growth,i.e. fallow, has the opposite effect. Various implications for management of soil structure are discussed.Introductory lecture     

Effects of Muscarinic Agonists and Depolarizing Agents on Inositol Monophosphate Accumulation in the Rabbit Vagus Nerve

The effects of muscarinic agonists and depolarizing agents on inositol phospholipid hydrolysis in the rabbit vagus nerve were assessed by the measurement of [3H]inositol monophosphate production in nerves that had been preincubated with [3H]inositol. After 1 h of drug action, carbachol, oxotremorine, and arecoline increased the inositol monophosphate accumulation, though the maximal increase induced by these agonists differed. Addition of the muscarinic antagonists atropine or pirenzepine shifted the carbachol dose-response curves to the right, without decreasing the carbachol maximal stimulatory effects. The KB for pirenzepine was 35 nM, which is characteristic of muscarinic high-affinity binding sites coupled to phosphoinositide turnover and often associated with the M1 receptor subtype. On the other hand, agents known to depolarize or to increase the intracellular Ca2+ concentration, e.g., elevated extracellular K+, ouabain, Ca2+, and the Ca2+ ionophore A23187, also increased inositol monophosphate accumulation. These effects were not mediated by the release of acetylcholine, as suggested by the fact that they could not be potentiated by the addition of physostigmine nor inhibited by the addition of atropine. The Ca(2+)-channel antagonist Cd2+, also known to inhibit the Na+/Ca2+ exchanger, was able to block the effects of K+ and ouabain, but did not alter those of carbachol. These results suggest that depolarizing agents increase inositol monophosphate accumulation in part through elevation of the intracellular Ca2+ concentration and that muscarinic receptors coupled to phosphoinositide turnover are present along the trunk of the rabbit vagus nerve.     

The effect of re-release of Oryctes rhinoceros baculovirus in the biological control of rhinoceros beetles in Western Samoa

The Rhinoceros Beetle Project in Western Samoa has developed and successfully applied biological methods to control the rhinoceros beetle, a serious pest of coconut palms, by using two specific pathogens, a baculovirus (Family Baculoviridae), and an entomopathogenic fungus, Metarhizium anisopliae. The application of virus particularly has markedly suppressed the beetle population and helped revive the copra industry. The virus disease had established itself in the wild beetle population several years after its introduction at a level between 30 and 50%. At the same time an increase in beetle numbers and damage to palm trees was experienced. Therefore, a continuous release of virus into beetle-infested areas was proposed. It was argued that, considering the relatively high level of “natural” virus incidence, further releases of virus into the population would be futile. In a combined research and control program, virus was again re-released into the wild beetle population which was already virus infected. The results show that through re-release the virus level can be raised and the number of beetles and consequently the damage can be reduced. The techniques of the control methods are described. The virus release is very easy and cheap; it requires no chemicals, no special equipment, and it is particularly recommended in situations where breeding places are inaccessible or other methods such as plantation sanitation are either impossible or economically impractical. Above all, the methods are absolutely safe from the standpoint of environmental protection.     

Entamoeba histolytica and Giardia lamblia: Growth responses to reducing agents

The growth responses of Entamoeba histolytica strains HM-1:IMSS and HK-9 to a variety of reducing agents were tested for one subculture in TYI-S-33 medium, prepared with no cysteine or ascorbic acid. Amoebae did not grow in this medium. Addition of l-ascorbic acid, d- or l-cysteine, or l-cystine each permitted the maximum growth observed. Dithiothreitol supported 68% maximum growth of HK-9 amoebae, but only 12% of HM-1. In contrast, growth of both strains was greatly diminished (0–13% growth) with 11 other compounds tested including glutathione, thiomalic acid, thioglycolic acid, and methionine. The growth responses of Giardia lamblia were similarly tested in TYI-S-33, as well as in TP-S-1 media. If l-cysteine was omitted from either medium, trophozoites did not grow, and eventually lysed. In TYI-S-33 medium, the requirement for l-cysteine was specific, whereas in TP-S-1 medium, other sulfhydryl compounds were partially effective and lower concentrations of l-cysteine satisfied the requirement. Ascorbic acid or l-cystine alone was totally ineffective; however, in combination, 30 to 60% of maximum growth was achieved. Once added to either medium, cysteine was rapidly oxidized. Amino acid analysis of the growth media revealed that the broth components of TP-S-1 medium contained 2.8 mM and TYI-S-33 broth 2.1 mM endogenous levels of cysteine (or half-cystine), with an additional 3 mM contributed by 10% serum.