Luc Lambs

Metal ion-tetracycline interactions in biological fluids. Part 8. Potentiometric and spectroscopic studies on the formation of Ca(II) and Mg(II) complexes with 4-dedimethylamino-tetracycline and 6-desoxy-6-demethyl-tetracycline.

Effects of metal ion-tetracycline (TC) interactions on both gastrointestinal absorption and pharmacological activity of these drugs are well documented. In particular, recent simulation studies based on newly determined complex stability constants have drawn attention to the potential influence of Ca2+ and Mg2+ ions on the bioavailability of various TC derivatives in blood plasma. Contrary to previous thoughts, it was demonstrated in these studies that the fraction of antibiotic not bound to proteins almost exclusively occurs as calcium and magnesium complexes. Among this fraction, predominant binuclear species are electrically charged, and as such cannot passively diffuse through cell membranes. It was thus postulated that the partial blocking of one of the potential coordination sites of the TC molecule, which would favor the formation of neutral mononuclear complexes, should result in a better tissue penetration of the drug. Such correlations were recently established for specific derivatives. Before possible modifications of the TC molecule can be envisaged, it is necessary that all the chelating sites involved in the relevant complexes be properly assigned. As tetracyclines are very complex ligands, the present paper first deals with the coordination of calcium and magnesium with two simpler parent substances, i.e., 4-dedimethylamino-tetracycline (DTC) and 6-desoxy-6-demethyl-tetracycline (DSC). After the quantitative investigation of the proton and metal complex equilibria involved, UV and circular dichroism spectroscopies are used to study the corresponding structural aspects. In DTC complexes, the BCD ring system acts as the exclusive coordination site for both metals. For DSC, however, the N4 atom plays a leading role in the metal binding and would be the only donor involved in 1:1 species; in ML2 complexes, the second ligand is thought to bind through the BCD ring system.

Metal ion-tetracycline interactions in biological fluids. 2. potentiometric study of magnesium complexes with tetracycline, oxytetracycline, doxycycline, and minocycline, and discussion of their possible influence on the bioavailability of these antibiotics in blood plasma

The formation constants of the various complexes formed by magnesium with four tetracycline derivatives, namely, tetracycline itself, oxytetracycline, doxycycline, and minocycline, were determined by potentiometry over large pH ranges under experimental conditions pertaining to blood plasma (37 degrees C, NaCl 0.15 mol dm-3). The results were used, together with those previously obtained on the complexation of these tetracyclines with proton and calcium, to assess the influence of the two alkali earth metal ions on the bioavailability of these drugs in blood plasma. Accordingly, simulations of the distribution of the four tetracyclines into their different proton and metal complex species were calculated. The distributions confirm that, in combination with the protein-bound fraction of the tetracyclines, the metal-bound fraction represents more than 99% of these drugs in plasma, the extent of their free fraction commonly being less than 1%.

Metal ion-tetracycline interactions in biological fluids. Part 3. Formation of mixed-metal ternary complexes of tetracycline, oxytetracycline, doxycycline and minocycline with calcium and magnesium, and their involvement in the bioavailability of these antibiotics in blood plasma

The equilibria of the complexes formed separately by calcium and magnesium with tetracycline, oxytetracycline, doxycycline and minocycline were studied in the previous parts of this series. Computer simulations run on this occasion showed that the stoichiometry of these species do actually condition the bioavailability of the antibiotics in blood plasma during treatment, the fraction of free base being quite negligible with regard to the metal-bound one.The present paper completes this study with the investigation of the mixed-metal complexes given rise to by calcium and magnesium with the same antibiotics. Such ternary species have been proved to exist for tetracycline, oxytetracycline, and minocycline. Their involvement in the plasma distribution of these drugs is discussed, in relation with the potential abilities of the four tetracyclines to diffuse from plasma into tissue membranes.

Metal ion-tetracycline interactions in biological fluids. Part 5. Formation of zinc complexes with tetracycline and some of its derivatives and assessment of their biological significance

A series of studies was previously devoted to the dependence of the bioavailability of various tetracyclines on their coordination with calcium and magnesium ions. Several clinical investigations have also shown zinc to interfere with the gastrointestinal absorption of the drug in humans. On the other hand, the administration of tetracycline to rats was reported to result in the increase of the elimination rate of zinc, which could orginate in zinc-tetracycline interactions in blood plasma.Formation constants for zinc complexes with tetracycline, oxytetracycline, doxycycline, minocycline, chlortetracycline and demethylchlortetracycline were thus determined at 37°C in NaCl 0.15 mol.dm−3 aqueous medium.Computer simulations were then carried out to investigate the drug influence on the distribution of the low-molecular-weight fraction of zinc in human blood plasma. Zinc-tetracycline interactions in the gastrointestinal fluid were also simulated, using clinical data relative to fasting subjects as taken from the literature.No significant effect can be expected from tetracyclines on the distribution of zinc in plasma at the usual therapeutic levels. However, zinc-tetracycline interactions have been found to be determining factors for the bioavailabilities of the metal as well as of the antibiotic in the gastro-intestinal fluid.

Metal ion-tetracycline interactions in biological fluids. Part 7. Quantitative investigation of methacycline complexes with Ca(II), Mg(II), Cu(II) and Zn(II) ions and assessment of their biological significance

Abstract Previous studies based on computer-simulated distributions of several tetracyclines in blood plasma during treatment have revealed that the fraction of drug not bound to proteins almost exclusively occurs in the form of calcium and magnesium complexes. In contrast to former thoughts, it thus appeared that the bioavailability of tetracyclines should primarily depend on the physicochemical properties of the most predominant of these species rather than on those of the free patent molecules. In particular, the possible formation of electrically charged homo- or heterobinuclear complexes with the above two metals at the expense of their neutral diffusible mononuclear homologues should notably reduce the bioavailability of the drug. The substitution of electron-attracting groups at positions 5–7, which tends to weaken the electron density of the phenolic diketone moiety, should help to prevent the formation of such binuclear complexes. This hypothesis recently proved valid for chlortetracycline but not for demethylchlortetracycline. Before future developments involving other possible structural changes can be envisaged, the present paper reports an investigation of the coordination of methacycline with Ca(II), Mg(II), Zn(II) and Cu(II) ions, the influence of the methylene group at C6 being expected to resemble that of the chlorine at position 7. Corresponding results show that the methylene substituent does effectively prevent methacycline from generating binuclear complexes with calcium and magnesium, and its effect on copper and zinc coordination is similar. Potential biological implications are discussed on the basis of pertinent computer simulations.

Mangrove trees growing in a very saline condition but not using seawater

Mangrove trees, which develop along tropical coasts, are known to use saline water uptake. In French Guiana, the high salinity condition is the result of seawater evaporation on mud banks formed from the Amazon sediment flumes. In the back mangrove a few kilometres inland, groundwater, soil water and the xylem sap uptake in the trees remain highly salty, and only very tolerant plants like Avicennia germinans can flourish, whereas the less salt-tolerant Rhizophora mangle is more difficult to find. Curiously, the same Avicennia trees propagate on the seafront. However, stable isotope ratio mass spectrometry (IRMS) measurements and ion analysis (high-performance liquid chromatography (HPLC) and inductively coupled plasma atomic emission (ICP-AES) spectroscopy reveal that the origin of the water in the back mangrove is not seawater. It is freshwater percolating into the sand bars from the inland marshes and rainwater during the wet season that redissolves a marine evaporite and gives a saline groundwater. The absence of barren saltine areas (tanne) in French Guiana could be explained by this freshwater inflow, the aquifer being no longer linked with the ocean.

Metal ion-tetracycline interactions in biological fluids. Part 6. Formation of copper(II) complexes with tetracycline and some of its derivatives and appraisal of their biological significance

Abstract It was previously established by computer simulation that the interactions of tetracyclines with calcium and magnesium play a paramount role in the bioavailability of these antibiotics in blood plasma. More recently, the influence of zinc was found to be insignificant in this biofluid at drug therapeutic levels but clinical data, relative to the gastrointestinal absorption of tetracyclines as well as zinc in the presence of each other, could be interpreted on the basis of the appropriate simulations. The present paper deals first with the experimental determination of the formation constants for the complexes of copper(II) with tetracycline, oxytetracycline, doxycyline, minocycline, chlortetracycline and demethylchlortetracyclin in aqueous NaCl 0.15 mol dm−3 at 37 °C. The data was then used for simulating the distribution of copper and each of these drugs in blood plasma as well as in gastrointestinal fluid. No influence can be expected from copper on the bio- availability of tetracyclines in blood plasma, the reverse also being true. For the therapeutic doses under consideration, copper cannot interfere with gastrointestinal absorption of these antibiotics but the presence of the latter tends to favour copper absorption to a determining extent.

Metal ion-tetracycline interactions in biological fluids. Part 4. Potential influence of ca2+ and mg2+ ions on the bioavailability of chlortetracycline and demethylchlortetracycline, as expected from their computer-simulated distributions in blood plasma

Abstract Coordination of tetracydines with calcium and magnesium was previously shown to exert a determining effect on the distribution of these antibiotics in blood plasma. In particular, it was clearly established by computer simulation that the free fraction of the drug is quite negligible with respect to its metal-bound fraction. The bioavailabiity of a tetracycline in blood plasma is thus expected to depend directly on the electrical charge of its predominant metal complexes in the biofluid. On account of the metal to ligand ratio corresponding to the usual therapeutic levels, bioavailability is critically sensitive to the property of the antibiotic to give rise to electrically charged binuclear species. The blocking of one of the two potential binding sites of the tetracycline molecule should thus result in a larger percentage of neutral complexes, hence in a better tissue penetration by the drug. The present work is devoted to the investigation of the coordination of 7-chlortetracycline (CTC) and 6-demethyl-7-chlortetracycline (DMC) with calcium and magnesium in blood plasma. The influence of the chloro substituent is discussed with respect to the objective defined above.

Dynamics of the association between a long-lived understory myrmecophyte and its specific associated ants.

Myrmecophytic symbioses are widespread in tropical ecosystems and their diversity makes them useful tools for understanding the origin and evolution of mutualisms. Obligate ant–plants, or myrmecophytes, provide a nesting place, and, often, food to a limited number of plant–ant species. In exchange, plant–ants protect their host plants from herbivores, competitors and pathogens, and can provide them with nutrients. Although most studies to date have highlighted a similar global pattern of interactions in these systems, little is known about the temporal structuring and dynamics of most of these associations. In this study we focused on the association between the understory myrmecophyte Hirtella physophora (Chrysobalanaceae) and its obligate ant partner Allomerus decemarticulatus (Myrmicinae). An examination of the life histories and growth rates of both partners demonstrated that this plant species has a much longer lifespan (up to about 350xa0years) than its associated ant colonies (up to about 21xa0years). The size of the ant colonies and their reproductive success were strongly limited by the available nesting space provided by the host plants. Moreover, the resident ants positively affected the vegetative growth of their host plant, but had a negative effect on its reproduction by reducing the number of flowers and fruits by more than 50%. Altogether our results are important to understanding the evolutionary dynamics of ant–plant symbioses. The highly specialized interaction between long-lived plants and ants with a shorter lifespan produces an asymmetry in the evolutionary rates of the interaction which, in return, can affect the degree to which the interests of the two partners converge.

Isotopic values of the Amazon headwaters in Peru: comparison of the wet upper Río Madre de Dios watershed with the dry Urubamba-Apurimac river system

RATIONALEnThe Amazon River is a huge network of long tributaries, and little is known about the headwaters. Here we present a study of one wet tropical Amazon forest side, and one dry and cold Atiplano plateau, originating from the same cordillera. The aim is to see how this difference affects the water characteristics.nnnMETHODSnDifferent kind of water (spring, lake, river, rainfall) were sampled to determine their stable isotopes ratios (oxygen 18/16 and hydrogen 2/1) by continuous flow isotope ratio mass spectrometry (IRMS). These ratios coupled with chemical analysis enabled us to determine the origin of the water, the evaporation process and the water recycling over the Amazon plain forest and montane cloud forest.nnnRESULTSnOur study shows that the water flowing in the upper Madre de Dios basin comes mainly from the foothill humid forest, with a characteristic water recycling process signature, and not from higher glacier melt. On the contrary, the water flowing in the Altiplano Rivers is mainly from glacier melts, with a high evaporation process. This snow and glacier are fed mainly by Atlantic moisture which transits over the large Amazon forest.nnnCONCLUSIONSnThe Atlantic moisture and its recycling over this huge tropical forest display a progressive isotopic gradient, as a function of distance from the ocean. At the level of the montane cloud forest and on the altiplano, respectively, additional water recycling and evaporation occur, but they are insignificant in the total water discharge.