Lipophilic Solvents Research Articles

Lack of role for the vanilloid receptor in response to several inspired irritant air pollutants in the C57Bl/6J mouse

Sensory irritants initiate respiratory reflexes by stimulating trigeminal sensory nerves. The vanilloid receptor (TRPV1) is expressed on sensory C fibers. The current experiments were aimed at examining the role of this receptor in mediating responses to several airborne irritants including an acidic (acetic acid), electrophilic (acrolein), and lipophilic solvent (styrene) vapor. Wild-type (C57Bl/6J) and VR1 knockout [B6.129S4-VR1(tm1jul)] mice were exposed to these irritants and breathing pattern responses were assessed by plethysmographic techniques; both wild-type and knockout animals responded similarly to the irritants. The TRPV1 antagonist iodoresiniferatoxin was also without effect on the responses to the irritants. Thus, in the C57Bl/6J mouse the TRPV1 receptor does not appear to play a major role in the stimulation of nasal trigeminal central reflex responses by these irritant air pollutants.

Chiral Bis(amino alcohol)oxalamide Gelators—Gelation Properties and Supramolecular Organization: Racemate versus Pure Enantiomer Gelation

Four new chiral bis(amino alcohol)oxalamides (1-4: amino alcohol=leucinol, valinol, phenylglycinol, and phenylalaninol, respectively) have been prepared as low-molecular-weight organic gelators. Their gelation properties towards various organic solvents and mixtures were determined and these were then compared to related bis(amino acid) oxalamide gelators. Spectroscopic (FTIR, (1)H NMR) and X-ray diffraction studies revealed that the primary organization motif of (S,S)-1 and racemate 1 (rac-1) in lipophilic solvents involved the formation of inverse bilayers. The X-ray crystal structure of (S,S)-1 also shows this type of bilayer organization. The crystal structure of rac-2 reveals meso bilayers of hydrogen-bonded aggregates. Within the bilayers formed, the gelator molecules are connected by cooperative hydrogen bonding between oxalamide units and OH groups, while the interbilayer interactions are realized through lipophilic interactions between the iBu groups of leucinol. Oxalamide meso-1 lacks any gelation ability and crystallizes in monolayers. In dichloromethane rac-1 forms an unstable gel; this is prone to crystallization as a result of the formation of symmetrical meso bilayers. In contrast, in aromatic solvents rac-1 forms stable gels; this indicates that enantiomeric bilayers are formed. Oxalamide rac-1 is capable of gelling a volume of toluene three times larger than (S,S)-1. A tranmission electron microscopy investigation of rac-1 and (S,S)-1 toluene gels reveals the presence of thinner fibers in the former gel, and, hence, a more compact network that is capable of immobilizing a larger volume of the solvent. The self-assembly of these types of gelator molecules into bilayers and subsequent formation of fibrous aggregates can be explained by considering the strength and direction of aggregate forces (supramolecular vectors) in three-dimensional space.

On the water content of the solvent/monoolein/water sponge (L3) phase

The water content of the solvent/monoolein/water sponge phase depends on the lipophilicity of the solvent used. The relatively lipophilic solvent 2-methyl-2,4-pentanediol (MPD) gives a sponge phase at about 60 wt.% water compared with 30 wt.% for the sponge phase formed with polyethylene glycol (Mw≈400, PEG 400). A reasonably good correlation is found between the water content of the sponge phase and the octanol/water partition coefficient for the solvent. The water content of the PEG 400 sponge phase increases considerably (to about 50 wt.%) by adding up to 3 wt.% of ionic compounds such as SDS, CTAB and salts of amphiphilic drugs. Nonionic detergents show less effect on increasing the water content, whereas membrane lipids such as lecithins and cholesterol show unchanged or even decreasing effect on the water content of the sponge phase.

Isolation of lipid raft-associated proteolipids.

AbstractThe term proteolipid (PL) was coined more than 50 yr ago by Folch and Lees (1) to designate a complex protein fraction present in brain myelin that is coextracted with cell lipids using organic solvents. Subsequently, equivalent fractions were isolated from various sources, from bacteria to mammalian cells. This indicated that the existence of proteins with physical-chemical characteristics similar to those extracted from brain myelin is a general biochemical scenario. PLs are operationally defined as membrane proteins displaying unusual lipid-like properties that make them to partition into lipophilic solvents (2). Although no clear-cut distinction was originally made between PLs and lipoproteins (1), today it is evident that proteolipids constitute a different protein group from that of lipoproteins, as the latter term designates water-soluble complexes composed of proteins and lipids (e.g., high-[HDL] and low-[LDL] density lipoproteins).KeywordsLipid RaftCoomassie Blue StainingRaft MembraneOrganic Solvent ExtractApical TransportThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Hydrogen bonded molecular assemblies in crystals and gels of chiral bis(amino alcohol) oxalamides

The research of supramolecular organisation of organic molecules into nano-or micro-dimensional assemblies is of high relevance for design of new materials for versatile applications and for understanding of the organisation of matter in general. Macroscopic manifestation of self-aggregation can result in ordered gels which include entraped solvent molecules. It is recognised that gelation is based on self � assembly of gelators in solution, leading to supramolecular arrays of specific non-covalent interactions: hydrogen bonds, van der Waals interactions and metal coordination. It is a chalenge to predict gelation on the basis of the constitutional and conformational characteristics of an organic molecule and the properties of the liquid to be gelled. Recently we have shown that chiral bis(amino acid) oxalamides represent a rare group of gelators capable to gel water and various lipophilic organic solvents (Makarevic et al., Chem. Eur. J. 2001, 7, 3328), whereas our new results are related to chiral bis(leucinol)oxalamides exhibiting gelating properties. The crystal structures of both, SS- and rac-bis(leucinol)oxalamide reveal two-dimensional hydrogen bonded networks through oxalamide and alcohol functionalities. X-ray powder diffraction was used to identify an appearance of crystalline phases in gels and xerogels of enantiomeric and racemic samples. In all cases the monoclinic crystalline phase identical to the crystals of SS-enantiomer was found. The high gelating properties of racemic compound might be related by van der Waals interactions between enantiomeric fibres of oposite chirality, whereas molecular organisation in fibres is governed by hydrogen bonds.

Porcentagens de saponinas e taninos em vinte e oito cultivares de alfafa (Medicago sativa L.) em duas épocas de corte - Botucatu - SP

O objetivo do estudo foi determinar os conteúdos de saponinas, taninos e a solubilidade da proteína (SP) de 28 cultivares de alfafa: Crioula, Monarca, BR 4, Alto Great, MH 4, SW 9210 A, 5929, BR 1, EL Grande, 5715, MH 15, Valley Plus, BR 2, Rio, SW 8210, Maricopa, ICI 990, 5888, P 30, Alfa-200, WL 516, SW 8112 A, BR 3, Florida 77, Araucana, Falcon, Semit 921 e Sutter. O material analisado foi obtido do 10º e 14º corte, respectivamente; em 08/12/97 e 16/04/98, de um experimento desenvolvido na Faculdade de Medicina Veterinária e Zootecnia, UNESP, Botucatu. Amostras de cada cultivar foram colhidas, pesadas e secas em estufa a 52ºC. As saponinas foram extraídas com solvente hidrofílico e lipofílico e o conteúdo foi calculado pela equação y=0,8121x-1,4759, R² = 1,00. A extração dos taninos totais e condensados foi efetuada por meio de ultra-som (12 min), sendo os taninos totais determinados pela equação: y=44,978 + 0,5644 com R²=0,9977 e os condensados, multiplicando-se a absorbância por 78,26 dividido pelo teor de matéria seca. A SP foi determinada pelo método de KOH, de acordo com a seguinte fórmula: SP (%) = proteína solúvel x 100/proteína bruta da amostra. Os teores de saponinas, taninos totais e condensados e a solubilidade da proteína não diferiram (P>0,05) entre as cultivares. Houve efeito (P<0,05) da época de corte apenas sobre o teor de taninos totais. Os teores médios de saponinas de 1,00% aliados à baixa solubilidade média da proteína bruta (34,11%) não se constituem em fatores limitantes para uso dos cultivares de alfafa estudadas.

Pharmaceutical development and manufacturing of a parenteral formulation of a novel antitumor agent, VNP40101M.

The objective of this study was to develop and manufacture a stable parenteral formulation for Phase I clinical trials of VNP40101M (1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(2-methylamino)carbonyl] hydrazine), a novel antitumor agent. The solubility and stability of the drug was determined. Solubility studies suggested that VNP40101M exhibited poor aqueous solubility but showed appreciable solubility in nonaqueous solvents. The aqueous solubility of the drug could not be increased by adjusting the pH. At a pH above 7, base-catalyzed decomposition of VNP40101M occurred. The low octanol-water partition coefficient of 0.75 suggested poor solubility in lipophilic solvents. Based on these preformulation observations, a parenteral formulation containing 10 mg/mL of VNP40101M was prepared in a solvent system consisting of 30% ethyl alcohol and 70% polyethylene glycol-300 (PEG-300). To minimize base-catalyzed hydrolytic degradation, citric acid at 0.6% concentration was included to acidify the formulation. Rubber closures, filter membranes, and liquid transfer tubing were selected on the basis of compatibility studies and absence of loss of drug due to adsorption of these components. The formulation was subjected to accelerated stability studies and dilution studies with large volume parenteral (LVP) solutions, normal saline, and 5% dextrose injection (D5W). The results of the dilution study indicated that the formulation could be diluted in these solutions up to 2 mg/mL for 8 hours without drug precipitation and degradation. Accelerated stability studies suggested that the product should be kept at 2 degrees C to 8 degrees C for long-term storage. The developed formulation was successfully scaled up and manufactured for use in clinical trials.

Neoral (Cyclosporin microemulsion preconcentrate): pharmacokinetics, pharmacodynamics and its improved clinical outcome

Sandimmun displays considerable inter- and intra-patient variability because its absorption is bile-dependent and affected by concomitant intake of food. Neoral is a microemulsion preconcentrate; a microemulsion is a mixture of the lipophilic active substance with accurately balanced amounts of lipophilic solvent, hydrophilic solvent and surfactant. As the result of advanced microemulsion technique, Neoral has more consistent and improved absorption characteristics. Cyclosporin (cyclosporin A) has been used as an immunosuppressive agent. The major pharmacodynamic action of cyclosporin within T cells is calcineurin inhibition. The complex cyclophilin-cyclosporin competitively binds to the Ca(2+)- and calmodulin-dependent phosphatase calcineurin which then inhibits downstream dephosphorylation and activation of NFAT(transcription factor). The greatest calcineurin inhibition is seen 1-2 h after administration of Neoral in parallel to the highest blood concentration. Variability in cyclosporin exposure was also identified as a risk factor for acute rejection in organ transplant recipients. "Absorption profiling" provides a more accurate prediction of drug exposure and leads to less acute rejection and toxicity. The evolution of Neoral monitoring strategies from trough level to absorption profile will raise the standard of performance of Neoral, resulting in clinical benefits for transplant patients.

Selectivity in microemulsion electrokinetic chromatography

Microemulsion electrokinetic chromatography (MEEKC) is a most promising separation technique providing good selectivity and high separation efficiency of anionic, cationic as well as neutral solutes. In MEEKC lipophilic organic solvents dispersed as tiny droplets in an aqueous buffer by the use of surfactants provide a pseudo-stationary phase to which the solutes may have an affinity either to the surface or they may even partition into the droplets. When the droplets are charged, typically negatively, they will migrate opposite to the electroosmotic flow and hence separation of neutral solutes may take place. In the present paper focus has been set on how to change selectivity in MEEKC. Changes in the nature of surfactant as well as in pH have been shown to be powerful tools in changing the selectivity. The type of lipophilic organic phase is of less importance for the separation of fairly lipophilic solutes. Also changes in the temperature surrounding the capillary may alter the selectivity.

Relationship between blood/air partition coefficients of lipophilic organic solvents and blood triglyceride levels

The blood/air partition coefficient is one of the important parameters for understanding the pharmacokinetics of organic solvents. In conventional pharmacokinetic models, the partition coefficient has been used as a constant value for each solvent. However, blood triglyceride content varies according to a diet, and the variation may affect the partition coefficient of lipophilic organic solvents. In this study, the relationship between the blood/air partition coefficient of lipophilic organic solvents and plasma triglyceride concentrations was clarified. Corn oil (4.0 ml/kg) was administered orally to male Wistar rats, and blood samples were collected 3 h after the administration, when the plasma triglyceride level reached a peak. Control rats received the same amount of distilled water via the same route. The blood/air partition coefficients of five types of lipophilic solvents ( m-xylene, trichloroethylene, 1,1,1-trichloroethane, chloroform and carbon tetrachloride) were determined in these two groups of blood samples. The hematological and biochemical parameters were also examined in the same blood samples. Although the mean plasma triglyceride level in the oil group increased about 3.3 times compared with that in the control group, the increase in the blood/air partition coefficients of the five lipophilic solvents was relatively low (approximately 1.2–1.5 times). We concluded that the diet has no significant effect on the blood/air partition coefficients of organic solvents, and the value can be used as a constant parameter for each solvent in a physiological simulation model.

Synthesis and characterization of novel polyaryloxydiphenylsilane derived from 2,2?- dimethyl-biphenyl-4,4?-diol

A novel polyaryloxydiphenylsilane was synthesized successfully by solution polycondensation of 2,2′-dimethyl-biphenyl-4,4′-diol with diphenyldichlorosilane and the catalyst triethylamine in toluene at 80 °C. Polymers with a relatively high inherent viscosity and yield were obtained when the reactions were carried out in aromatic and lipophilic solvents. The novel polyaryloxydiphenylsilane was soluble in chlorinated aliphatic hydrocarbons such as methylene chloride and chloroform as well as in polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide and also in some common organic solvents such as benzene and toluene. However, it was insoluble in both aliphatic hydrocarbons as well as in alcoholic solvents. The polyaryloxydiphenylsilane began losing weight around 400 °C under a nitrogen atmosphere, and the 10% weight-loss temperature was 473 °C. The glass-transition temperature of the polyaryloxydiphenylsilane was 102 °C. The glass transition could be lowered by the copolymerization technique with 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane as an aromatic diol comonomer. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4591–4595, 1999

The Solubility of Some Azafullerene Derivatives

Several fulleroaziridines, azafulleroids and chiral cage-opened ketolactams were synthesized from alkyl azides and C60. Their solubility in various solvents was evaluated by HPLC. It depends both on the starting azide and the linker group. Moreover, the formation of two sp3 carbons (entries 2) and then of carbonyl derivatives (entries 3) induces a decrease of the polarizability of the C60 moiety and an enhancement of the solubility in lipophilic solvents.

Search for pharmacological leads from tropical rainforest plants

Abstract

Colony formation in Scenedesmus: grazer-mediated release and chemical features of the infochemical

In the unicellularly growing green alga Scenedesmus acutus, the formation of many-celled coenobia may be induced by an infochemical released by the grazer Daphnia magna. We used a stand- ardized bioassay to obtain information about the release of the infochemical by actively feeding D.magna and its chemical nature. The infochemical could not be extracted from the alga or the grazer by aqueous or more lipophilic solvents. When the release of coenobia-inducing activity by actively feeding D.magna was investigated as a function of the individual's body mass, no increase with increasing individual body mass was observed, indicating that the chemical cue originates from zooplankton's non-digestive metabolism rather than from digestion of alga by the grazer. The info- chemical released by D.magna can be characterized as an olefinic low-molecular-weight carboxylic acid. Hydroxy and amino groups can be excluded as moieties of the infochemical essential for biological activity. We present a method to concentrate the infochemical from Daphnia incubation water using lipophilic solid-phase extraction. Subsequent separation by reversed-phase HPLC yielded only one active fraction.

Efficacy of Neoral in the immediate postoperative period in children post-liver transplantation.

Cyclosporine (Sandimmune) is an effective immunosuppressive drug but may be poorly absorbed in the early postoperative period after liver transplantation, exposing the recipient to an increased risk for rejection. Neoral is a new oral formulation of cyclosporine that uses a mixture of surfactant, lipophilic, and hydrophilic solvents to permit microemulsification that leads to potentially better absorption. This oral drug has not been evaluated in children immediately posttransplantation. The aim of this study was to evaluate the pharmacokinetics, bioavailability, and safety of Neoral during the first week post-liver transplantation in children. Twelve children, 8 boys and 4 girls, with a median age of 2.6 years (range, 1 to 8 years) were administered Neoral within 12 hours posttransplantation. Pharmacokinetic profiles were performed over a 12-hour period on each child on days 1, 3, and 5 and twice-daily trough levels were obtained on days 2, 4, 6, and 7. The maximum concentration (Cmax), time to reach Cmax (Tmax), 12-hour trough levels, and area under the curve were calculated, and rejection episodes and adverse events were documented over a 12-week period. Neoral was well absorbed, even on the first postoperative day. After the introduction of enteral feeding, the peak levels increased (Cmax, 655 ng/mL) and were achieved significantly sooner (Tmax, 2 hours). There was no significant difference in drug exposure between days 1, 3, and 5 (P > .05). The incidence of acute rejection was 25% and hypertension was reported in 4 of 12 patients during the first week. Neoral was well absorbed in the early post-liver transplantation period, provided effective immunosuppression, and was not associated with a high incidence of adverse events or toxicity. The introduction of enteral feeding improved absorption.

Formation of Columnar and Lamellar Lyotropic Mesophases by Facial Amphiphiles with Protic and Lipophilic Solvents

The influence of water, formamide, and n-dodecane on the liquid crystalline properties of several rodlike 4,4‘‘-bis(decyloxy)-p-terphenyl derivatives incorporating nonionic hydrophilic groups in a central position was investigated by polarizing microscopy and X-ray scattering. Up to three different rectangular columnar mesophases have been found for molecules with large hydrophilic groups with increasing concentrations of protic solvents. Remarkably only one lattice parameter changes in dependence on the mesophase type and the number of solvent molecules coordinated to the polar groups. We propose that the columns represent ribbons consisting of the rigid terphenyl units, separated laterally by the segregated regions of the hydrophilic groups, whereby the three different columnar mesophases should result from an anisotropic swelling of the polar regions on addition of solvents. Lipophilic solvents (dodecane) destabilize the columnar phases and replace them by smectic layer structures (SA phases).

Preparation of new polyether with oxetane pendant group

A new oxetane-containing polyether was synthesized by polycondensation of bisphenol-AF (BPAF) with 3,3-bis(chloromethyl)oxetane (BCMO) using the phase-transfer catalyzed method. The polycondensation proceeded very smoothly in aromatic solvents, catalyzed by quaternary ammonium or phosphonium salts, such as tetrabutylammonium bromide (TBAB) and tetrabutylphosphonium bromide (TBPB), to afford the polymer with high yield and molecular weight. Further, a polymer with relatively high molecular weight was obtained when the reactions were carried out in aromatic and lipophilic solvents such as benzene and nitrobenzene. The modification of this oxetane-containing polyether was easily achieved by carrying out ring-opening of the oxetane ring by using hydrogen chloride in methylene chloride, which produced a functional polymer containing hydroxyl and chloro groups. The oxetane-containing polyether was observed to be soluble in chlorinated aliphatic hydrocarbons such as methylene chloride and chloroform, as well as polar solvents such as DMSO, DMF, and DMAc, and also some common organic solvents such as benzene and toluene. However, it was insoluble in both aliphatic hydrocarbons as well as alcoholic solvents. The oxetane-containing polyether was observed to start losing weight at around 300°C under nitrogen atmosphere, and 10% weight loss was measured to be 411°C. The glass transition temperature of the oxetane-containing polyether was measured to be 134°C and the wide-angle X-ray diffraction pattern revealed this polymer to be semicrystalline. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 103–107, 1998

Binding of dansylamide † derivatives to nucleotides and nucleic acids 1

Dansylamide† has been modified by the introduction of several side chains into the sulfonamide substituent. Compounds with no, or with only one positive charge at the side chains were found not to be useful for association studies with nucleotides or nucleic acids. Relatively high binding constants with moderate base selectivities have been observed with a ligand obtained from dansyl chloride and N,N′-bis(3-aminopropyl)piperazine, which contains two dansyl units and two permanently charged peralkylammonium centers. Interactions of this ligand with double-stranded nucleic acids show a biphasic binding, the first at base pair concentrations below 10–7 M being only detectable by a decrease of fluorescence intensity. The second phase is characterized by increased fluorescence and by wavelength changes similar to effects observed in lipophilic solvents and by affinities of up to 5 × 105 M. At higher concentrations bathochromic shifts and extinction changes in UV spectra of the dye suggest an intercalation mechanism, in line with preliminary circular dichroism studies.

Biodegradable, somatostatin acetate containing microspheres prepared by various aqueous and non-aqueous solvent evaporation methods

Somatostatin, a therapeutic peptide drug, was entrapped within polymeric microspheres made from high molecular weight poly ( d, l-lactide/glycolide) (PLGA) or low molecular weight poly ( d, l-lactide) (PLA) by various modifications of the O/W-solvent evaporation method. The drug was either dispersed as solid (dispersion method), dissolved with the aid of a co-solvent (co-solvent method) or emulsified as an aqueous solution (W/O/W-multiple emulsion method) in the organic polymer solution prior to emulsification into an external aqueous phase. Additionally, a non-aqueous O/O-method was evaluated for the formation of the microspheres. Acceptable encapsulation efficiencies were obtained with all methods, regardless of the physical state of drug and the polymer type. The total volume of organic solvent and the co-solvent content were found to be important preparation factors of the O/W-co-solvent method. A more lipophilic solvent system appeared to favor efficient drug encapsulation. Replacing the widely used but toxic methylene chloride with ethyl acetate resulted in significantly lower drug loadings. The preparation method substantially affected the morphology of the microspheres and the drug release.

Photochemical reactions and phototoxicity of sterols: novel self-perpetuating mechanisms for lipid photooxidation.

Sterols are important lipid components that may contribute to phototoxicity. We have found that phototoxic response in earthworms is related to sterols extractable with lipophilic solvents. The photochemically active compounds in worm lipids are 5,7,9(11),22-ergostatetraen-3 beta-ol (9-DHE) and 5,7,9(11)-cholestartien-3 beta-ol (9-DDHC), respectively. Human skin lipids are known to contain 9-DHE. We have also found 9-DDHC in human skin, which is reported here for the first time. In the presence of an excess of the corresponding 5,7-dienes (ergosterol of 7-dehydrocholesterol), these photoactive sterols constitute a self-regenerating source of singlet molecular oxygen (1O2) during irradiation in vivo or in vitro with UVA (315-400 nm). The quantum yield for photosensitization of 1O2 by 9-DHE was estimated to be 0.09. The 1O2 is scavenged by the dienes and the rate constant for 1O2 quenching by ergosterol was found to be 1.2 x 10(7) M-1 s-1 in methyl t-butyl ether (MTBE). This scavenging ultimately leads to the production of 5,8-endoperoxide and hydrogen peroxide. Photochemically induced superoxide radical was also produced on irradiation of sterol 5,7,9-trienes and trapped with the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The production of singlet oxygen, peroxides and radicals by the sterols may be significant in the cell damaging and tumor promoting action of UVA light on skin.