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PubMed2004

The solubility of ethane, propane, and carbon dioxide in aqueous solutions of sodium cumene sulfonate.

Measurements have been made to determine the solubilities of ethane, C2H6, propane, C3H8, and carbon dioxide, CO2, in aqueous solutions of sodium cumene sulfonate (NaCS) at 25 degrees C. The solubilities measured for each gas satisfy Henry's law at all concentrations of NaCS. The solubilities of C2H6 and C3H8 exhibit quite similar behavior with respect to added NaCS. The solubilities of these two gases are very low in pure water and are found to be nearly independent of NaCS concentration over a concentration range of 0-0.4 mol NaCS/kg H2O. At intermediate concentrations of NaCS, the solubilities of C2H6 and C3H8 exhibit a gradual increase with added NaCS concentrations ranging from 0.4 to 2.0 mol NaCS/kg H2O. At NaCS concentrations greater than 2.0 mol NaCS/kg H2O, the solubilities of these two gases increase with added NaCS in an approximately linear manner, with the solubility of C3H8 increasing more rapidly than that for C2H6 (by a factor of approximately 2.5). CO2 is much more soluble in pure water than the hydrocarbon gases and exhibits markedly different behavior with respect to added NaCS. The solubility of CO2 decreases with added NaCS over a concentration range of 0-0.9 mol NaCS/kg H2O, passes through a minimum at a concentration of approximately 1.0 mol NaCS/kg H2O, and then increases with added NaCS at higher NaCS concentrations in a manner similar to that observed with C2H6 and C3H8. The trends in solubility observed for these three gases dissolved in aqueous solutions of NaCS resemble those found previously with aqueous solutions of ordinary surfactants. The solubility data measured for these three gases can be interpreted surprisingly well in terms of the mass-action model for micellization, in which salting-out effects due to monomer salt ions suppress gas solubility at low NaCS concentrations and gas solubilization by small micelles of NaCS acts to enhance gas solubility at the higher NaCS concentrations.

Benzene Derivatives↗

PubMed2001

Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization.

The solubility of seven drugs (nitrofurantoin, chlorothiazide, phenobarbital, prednisolone, griseofulvin, diazepam and piroxicam) in the absence and presence of gelatin was measured, at three different pH values (3.7, 5.0 and 7.0) at 37 degrees C. Drugs studied had different physicochemical properties (log P, pK(a), aqueous solubility) and their solubility in presence of 0.1 and 0.5% (w/v) hydrolyzed (and in some cases common) gelatin was estimated. Results show that the solubility of all drugs is significantly enhanced, especially in the presence of 0.5% gelatin. This gelatin-induced enhancement in drug solubility is higher in the pH in which acidic drugs are less ionized, especially for the less lipophilic acidic drugs (nitrofurantoin, chlorothiazide). In all cases, drug solubility in presence of gelatin is correlated with their aqueous solubility. Therefore, the established relationships between aqueous and gelatin solubility can be employed to derive an estimate of the drug solubility in presence of gelatin once its aqueous solubility is known. With the exception of piroxicam which is highly ionized and phenobarbital which is relatively soluble, there seems to be a tendency for larger gelatin-induced increases in solubility as drug lipophilicity increases or aqueous solubility decreases.

Chemistry, Pharmaceutical↗

PubMed2000

An investigation of the solubility of various compounds in the hydrofluoroalkane propellants and possible model liquid propellants.

The aims of this study were to investigate descriptive parameters that may predict the solubility of compounds in the hydrofluoroalkane (HFA) propellants and to identify a model HFA propellant that is liquid at room temperature and atmospheric pressure. The solubility of 32 and 20 compounds chosen to give a wide range of physicochemical properties in HFA-134a and HFA-227, respectively, was measured. The Fedors solubility parameter and a computed log octanol water partition coefficient (CLOGP) were compared with the compounds' solubility in the HFA propellants. A total of 19 and 15 solutes had finite solubilities for HFA-134a and HFA-227, respectively, although the remaining solutes were miscible in all proportions. There was no apparent relation between solubility in HFA and the Fedors solubility parameter. This was not improved by considering the hydrogen-bonding potential of the compounds. When log solubility versus CLOGP was plotted, there was a linear relation for 16 and 12 of the compounds exhibiting a finite solubility in the HFA propellants, although four solutes (phenols) were displaced to the left of the linear relation. The remaining 3 compounds had much lower solubilities than was predicted from their CLOGPs, possibly as a consequence of their crystallinity (high melting points). Of the putative model propellants investigated (i.e., perfluorohexane (PFH), 1H-perfluorohexane [1H-PFH], and 2,2,2-trifluoroethanol), 1H-PFH was the most promising, with a linear relation between solubility in 1H-PFH and solubility in HFA propellant being observed. The solubilities in 1H-PFH were approximately 11 and 26% of those in HFA-134a and HFA-227.

Aerosol Propellants↗

PubMed2001

Prediction of volatile anaesthetic solubility in blood and priming fluids for extracorporeal circulation.

Volatile anaesthetics are often used during cardiopulmonary bypass (CPB). To understand the kinetics of inhaled anaesthetics during CPB, anaesthetists should understand changes in blood solubility caused by fluid use. We set out to predict the solubility of three volatile anaesthetics, desflurane, isoflurane and halothane, during CPB by determining: (i) their solubility in fresh whole blood and eight CPB priming fluids at 37 degrees C; (ii) the effect of temperature on the solubility of these anaesthetics in lactated Ringer's, gelofusin, banked blood and plasma; (iii) their solubility in different mixtures of these four priming fluids at different temperatures; and (iv) their estimated and actual solubility in blood during hypothermic CPB. We calculated solubility using a concept of volume fraction partition coefficient and compared estimated and measured solubilities. For the three anaesthetics tested, solubilities are in the order: fresh whole blood approximately = plasma > banked blood > normal saline approximately = lactated Ringer's approximately = gelofusin approximately = Haemaccel approximately = hydroxyethyl starch > mannitol. The solubilities of the anaesthetics in all priming fluids increased logarithmically at lower temperatures (P<0.05). The volume-fraction estimates of the partition coefficients were within approximately +/-20% of the measured values for all values of solubility. The corresponding estimates of solubility for CPB blood samples were between -36% and +24% of the measured values. During normothermic CPB, blood solubility of volatile anaesthetics would be unchanged when using plasma, slightly reduced when using banked blood and markedly reduced when using crystalloids and colloids.

Anesthetics, Inhalation↗

PubMed2005

How to find soluble proteins: a comprehensive analysis of alpha/beta hydrolases for recombinant expression in E. coli.

BACKGROUND: In screening of libraries derived by expression cloning, expression of active proteins in E. coli can be limited by formation of inclusion bodies. In these cases it would be desirable to enrich gene libraries for coding sequences with soluble gene products in E. coli and thus to improve the efficiency of screening. Previously Wilkinson and Harrison showed that solubility can be predicted from amino acid composition (Biotechnology 1991, 9(5):443-448). We have applied this analysis to members of the alpha/beta hydrolase fold family to predict their solubility in E. coli. alpha/beta hydrolases are a highly diverse family with more than 1800 proteins which have been grouped into homologous families and superfamilies. RESULTS: The predicted solubility in E. coli depends on hydrolase size, phylogenetic origin of the host organism, the homologous family and the superfamily, to which the hydrolase belongs. In general small hydrolases are predicted to be more soluble than large hydrolases, and eukaryotic hydrolases are predicted to be less soluble in E. coli than prokaryotic ones. However, combining phylogenetic origin and size leads to more complex conclusions. Hydrolases from prokaryotic, fungal and metazoan origin are predicted to be most soluble if they are of small, medium and large size, respectively. We observed large variations of predicted solubility between hydrolases from different homologous families and from different taxa. CONCLUSION: A comprehensive analysis of all alpha/beta hydrolase sequences allows more efficient screenings for new soluble alpha/beta hydrolases by the use of libraries which contain more soluble gene products. Screening of hydrolases from families whose members are hard to express as soluble proteins in E. coli should first be done in coding sequences of organisms from phylogenetic groups with the highest average of predicted solubility for proteins of this family. The tools developed here can be used to identify attractive target genes for expression using protein sequences published in databases. This analysis also directs the design of degenerate, family-specific primers to amplify new members from homologous families or superfamilies with a high probability of soluble alpha/beta hydrolases.

Animals↗

PubMed1987

A soluble interleukin 2 receptor produced by a normal alloreactive human T cell clone binds interleukin 2 with low affinity.

Several alloreactive human T cell clones derived from a rejected kidney graft were found to produce in their culture supernatants soluble interleukin 2 receptors (IL-2R) upon specific antigenic challenge (irradiated B cell line from the graft's donor). Among them, the 2B11, a high producer clone, was used to purify a soluble IL-2R preparation which was analyzed, in comparison with the high and low affinity cell-surface IL-2R expressed by 2B11 cells, for its parameters of interaction with a set of anti-IL-2R monoclonal antibodies (mAb) and IL-2. This soluble receptor purified by affinity chromatography (anti-IL-2R mAb column) and sodium dodecyl sulfate gel electrophoresis is composed of a single chain of 35,000 to 45,000 Da. Immunoradiometric assays (IRMA) at equilibrium were set up, using pairs of mAb directed against two separate epitopes on the Tac antigen of the human IL-2R, to measure the respective dissociation constant of these mAb for the soluble IL-2R. They were found to be identical to those found on the cell-surface IL-2R. A 1:1 stoichiometry between the two epitopes were found both on the membrane and soluble species. Competition experiments between membrane and soluble IL-2R for binding the mAb allowed the quantitative analysis of the concentration of soluble IL-2R without the need of amino acid analysis on purified material and set up a quantitative IRMA for the human soluble IL-2R (detection limit 5 pM). The affinity of the soluble IL-2R for IL-2 was determined by various techniques including an IRMA using an anti-IL-2R mAb and radiolabeled IL-2. The results obtained led us to conclude that the soluble IL-2R binds IL-2 with a dissociation constant (KD = 30 nM) identical to that found for the binding of IL-2 to low affinity cell-surface IL-2R (Tac antigen). Whereas 2.5% of cell-surface IL-2R expressed 2 days after antigenic stimulation of 2B11 cells were of high affinity for IL-2 (KD = 25 pM), no (less than 0.07%) high affinity binding sites could be detected on the purified soluble IL-2R. This soluble IL-2R therefore likely corresponds to a truncated, extracellular part of the membrane Tac antigen. The amounts of soluble Tac antigen produced by the 2B11 alloreactive human T cell clone did not exceed 1 nM and, as expected from the binding studies, did not affect IL-2-induced T cell proliferation. The physiologic and pathologic implications of our results are discussed.

Antibodies, Monoclonal↗

PubMed2001

Serum soluble Fas in the syndrome of hemolysis, elevated liver enzymes, and low platelets.

OBJECTIVE: To assess whether serum levels of soluble Fas and soluble Fas ligand are altered in the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). METHODS: Serum samples from 22 pregnant women diagnosed with HELLP syndrome were compared with sera from 37 healthy women with noncomplicated singleton pregnancies. Serum levels of soluble Fas and soluble Fas ligands were determined by enzyme immunoassay. Student t, chi(2), Pearson's correlation coefficient, and multiple regression tests were used for statistical analyses. RESULTS: Both soluble Fas and soluble Fas ligand were detected in the sera of normal pregnancies as well as in those with HELLP syndrome. The mean serum level of soluble Fas was significantly higher in women with HELLP syndrome than in healthy gravidas (10.75 +/- 0.93 versus 5.81 +/- 0.37 U/mL, P <.001). However, there was no significant difference in mean serum soluble Fas ligand levels of the two groups (0.60 +/- 0.06 compared with 0.50 +/- 0.22 ng/mL, P =.23). In women with HELLP syndrome, there were no significant correlations between serum levels of soluble Fas or soluble Fas ligand with liver transaminases (aspartate and alanine aminotransferase) and platelet count. CONCLUSION: Serum levels of soluble Fas, but not soluble Fas ligand, are significantly higher in women with HELLP syndrome than healthy gravidas. The source of elevated serum levels of soluble Fas in HELLP syndrome remains to be determined.

Adult↗

PubMed1998

Soluble adhesion molecules in reperfusion during coronary bypass grafting.

OBJECTIVE: Adhesion of activated leukocytes to the endothelial cells as a result of myocardial ischaemia/reperfusion during open chest coronary artery surgery has been shown to be involved in the development of tissue damage. Activated leukocytes adhere to endothelium via adhesion molecules expressed by both cell types, resulting in the impairment of coronary capillary flow. Upon cell activation, adhesion proteins may be released in the soluble form to circulating blood. The purpose of our study was to verify whether myocardial ischaemia/reperfusion occurring during coronary artery bypass grafting results in release of the soluble adhesion molecules VCAM-1, ICAM-1, E-selectin and L-selectin into the circulation. METHODS: Plasma levels of the soluble adhesion molecules were measured in vein, arterial and coronary sinus blood samples taken from 15 patients undergoing coronary artery bypass grafting (CABG). Blood samples for estimations were collected during the procedure: before aorta cross-clamping, at the beginning of reperfusion and 30 min after reperfusion. Soluble adhesion molecules levels were measured by standard ELISA assays. RESULTS: Mean plasma levels of soluble VCAM-1 in arterial samples increased significantly at the beginning of reperfusion and 30 min after reperfusion. In contrast, soluble L-selectin plasma levels in arterial samples remained unchanged. In coronary sinus samples, levels of soluble ICAM-1 significantly increased 30 min after reperfusion. Moreover, in coronary sinus samples collected 30 min after reperfusion, soluble ICAM-1 levels were significantly higher than in arterial samples obtained at the same time. The mean concentration of soluble E-selectin in samples obtained from coronary sinus decreased significantly 30 min after reperfusion. Moreover, plasma levels of soluble E-selectin in coronary sinus samples obtained 30 min after reperfusion were significantly decreased compared with these observed in arterial samples collected at the same time. CONCLUSIONS: The reperfusion of ischaemic myocardium during CABG results in a significant increase in plasma levels of the soluble endothelial adhesion molecules VCAM-1 and ICAM-1 and significant decrease in soluble E-selectin plasma levels. L-selectin plasma levels during CABG procedure remain unchanged. We propose that the increased plasma concentrations of soluble VCAM-1 and ICAM-1 are a result of endothelial cell activation during ischaemia/reperfusion following bypass surgery.

Aged↗

PubMed2002

Soluble Fas may be a proinflammatory marker after cardiopulmonary bypass in children.

OBJECTIVES: Ischemia-reperfusion injury after cardiopulmonary bypass is known to provoke an inflammatory response, which can be attenuated with steroid pretreatment. Cardiopulmonary bypass is also known to stimulate apoptosis. Induction of the cellular apoptotic cascade occurs via interaction between two membrane receptors: Fas and Fas ligand. Both molecules also exist in soluble forms, whose significance remains undetermined; however, both may have a proinflammatory role. We aimed to document the temporal profile of soluble Fas and soluble Fas ligand after cardiopulmonary bypass and to investigate whether steroid pretreatment alters this response. METHODS: The study was of a non-randomized, non-blinded, prospective nature. Twenty-seven infants were monitored prospectively, of whom 13 received dexamethasone at induction of anesthesia. Soluble Fas, soluble Fas ligand, and interleukin 6 were measured from induction of anesthesia until 24 hours after admission to the intensive care unit. Data on clinical and laboratory variables were also collected at the same time intervals. RESULTS: As expected, dexamethasone pretreatment attenuated interleukin 6 release and the clinical systemic inflammatory response after bypass. Soluble Fas showed a remarkably similar profile to interleukin 6, in terms of temporal release and attenuation with steroids. There was also a correlation between maximum soluble Fas and markers of capillary leak (colloid requirement and drain loss). Conversely, soluble Fas ligand release was unchanged by cardiopulmonary bypass and steroid administration. However, patients with higher soluble Fas ligand levels exhibited a more dramatic drop and delayed recovery in monocyte count, consistent with the role of this molecule in apoptosis. CONCLUSIONS: Release of soluble Fas and soluble Fas ligand follows a markedly different temporal profile after cardiopulmonary bypass. The similarity between soluble Fas and interleukin 6, together with the attenuation of both with steroids, may suggest a role for soluble Fas as a proinflammatory marker.

Anti-Inflammatory Agents↗

PubMed1996

Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients.

OBJECTIVE: To study the influence of long-term volume therapy with different solutions and continuous administration of pentoxifylline on plasma concentrations of circulating adhesion molecules. DESIGN: Prospective, randomized study. SETTING: A surgical intensive care unit (ICU) of a university hospital. PATIENTS: Forty-two patients with sepsis secondary to major surgery were included. INTERVENTIONS: The patients were randomly separated into three groups. In group 1 (n=14), volume therapy was exclusively carried out with 10% low-molecular-weight hydroxyethyl starch solution. In group 2 (n=14), patients exclusively received 20% human albumin for volume therapy. In group 3 (n=14), volume therapy was not defined and pentoxifylline was continuously given (1.4 mg/kg/hr iv). MEASUREMENTS AND MAIN RESULTS: From arterial blood samples, plasma concentrations of soluble adhesion molecules (endothelial leukocyte adhesion molecule-1 [soluble ELAM-1], intercellular adhesion molecule-1 [soluble ICAM-1], vascular cell adhesion molecule-1 [soluble VCAM-1], and soluble granule membrane protein-140) were serially measured on the day of admission to the ICU ("baseline" value) and during the next 5 days at noon. No significant differences between the three groups were found for macrohemodynamics. Soluble ELAM-1, soluble ICAM-1 and soluble VCAM-1 plasma concentrations were markedly higher than normal values at baseline in all groups. In the hydroxyethyl starch group, soluble ELAM-1 plasma concentration decreased to the normal range, whereas it further increased in the human albumin group and was almost unchanged in the pentoxifylline group. During the study period, soluble ICAM-1 and soluble VCAM-1 plasma concentrations remained unchanged in the hydroxyethyl starch group. However, these concentrations increased in the other groups. Soluble granule membrane protein-140 increased significantly only in the human albumin group (483 +/- 103 to 683 +/- 94 ng/mL). In the hydroxyethal starch-treated patients, Acute Physiology and Chronic Health Evaluation II score decreased significantly (from 24.3 +/- 3.4 at baseline to 17.0 +/- 3.3 at the end the study period). Only PaO2/FIO2 was correlated to plasma concentrations of adhesion molecules. CONCLUSIONS: Sepsis is associated with markedly increased plasma concentrations of adhesion molecules, indicating endothelial activation or damage. By long-term volume therapy with hydroxyethal starch solution, these concentrations remained unchanged or even decreased, whereas in patients in whom human albumin was infused or pentoxifylline was given continuously, plasma concentration of soluble adhesion molecules further increased.

Aged↗

PubMed2003

Soluble thrombomodulin and coronary heart disease.

PURPOSE OF REVIEW: Endothelial thrombomodulin is a major vasoprotective molecule. The membrane thrombomodulin is digested by proteases and the degradation products are detectable in circulating blood. The purpose of this review is to provide recent information regarding the relationship of soluble thrombomodulin with coronary heart disease. RECENT FINDINGS: Results from a population-based, prospective, coronary heart disease, case-cohort study reveal an inverse relationship between plasma soluble thrombomodulin and the relative risk of coronary heart disease. Participants in this study were healthy subjects without acute thrombotic events. They were followed, and coronary heart disease events were ascertained. Individuals with a high level of soluble thrombomodulin are associated with a significant reduction in the relative risk of coronary heart disease events. There is a significant interaction between soluble thrombomodulin and soluble intercellular adhesion molecule-1 in predicting the risk of coronary heart disease events. Individuals with a high soluble thrombomodulin level do not have an increased risk of coronary heart disease, even when soluble intercellular adhesion molecule-1 is at the highest levels. In contrast, at low soluble thrombomodulin levels, soluble intercellular adhesion molecule-1 has a 'dose-dependent' association with coronary heart disease risk. These results suggest an interplay between vasoprotective and pro-inflammatory endothelial molecules. Soluble thrombomodulin and its parent molecule appear to play a predominant role in determinations of the risk of coronary heart disease events. SUMMARY: The soluble thrombomodulin level in plasma is an independent risk factor for coronary heart disease. It is inversely associated with coronary heart disease risk. Combinatorial analysis of soluble thrombomodulin and soluble intercellular adhesion molecule-1 provides a more specific assessment of coronary heart disease risk in middle-aged subjects.

Animals↗

PubMed1999

The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state.

Soluble fibrin detected in clinical plasma samples includes a variety of complexes consisting of fibrin monomer units, fibrinogen, and various proteolytic derivatives of fibrinogen and fibrin. The advantage of measuring soluble fibrin over fibrinopeptide A to detect thrombin action on fibrinogen is the considerably longer half-life of soluble fibrin in the circulation. Soluble fibrin can be detected by a variety of methods, including paracoagulation and precipitation assays, adsorption of fibrin monomer to insolubilized fibrinogen, functional assays based on the cofactor activity of some soluble fibrin compounds in t-PA-induced plasminogen activation, and by using fibrin-specific antibodies. Fibrin-specific antibodies may react with epitopes generated directly by fibrinopeptide A or B release or with epitopes generated by fibrin polymerization. Epitopes dependent on fibrinopeptide A release are often not accessible in native fibrin complexes and require the disaggregation of fibrin compounds to be reactive, whereas epitopes dependent on fibrinopeptide B release or fibrin polymerization are accessible to the monoclonal antibodies in nondenatured fibrin. Since soluble fibrin assays detect different structural or functional properties of soluble fibrin, no common calibrator for all soluble fibrin assays and, often, little correlation between different assay systems in clinical evaluations exist. Clinical applications of soluble fibrin assays include diagnosis and treatment monitoring of intravascular coagulation processes and prethrombotic states, monitoring anticoagulant treatment, and biocompatibility investigations. Some soluble fibrin assays have been demonstrated to be extremely sensitive indicators of acute fibrin formation. For the exclusion of venous thrombosis, D-dimer assays appear to be more sensitive than current soluble fibrin assays, since D-dimer assays detect freshly formed fibrin and proteolytic fragments of particulate clots. Further clinical studies are needed to establish the clinical utility of specific, soluble fibrin assays. The development of rapid, quantitative soluble fibrin assays for clinical routine use should be encouraged.

Acute Disease↗

PubMed2005

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH.

PURPOSE: To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate. METHODS: pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs. RESULTS: pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2-5 is attributed to its higher solubility product (K(sp)) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH(max) (pH of maximum solubility) of approximately 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts. CONCLUSIONS: Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.

Haloperidol↗

PubMed1998

Two distinct forms of soluble MHC class I molecules synthesized by different mechanisms in normal rat cells in vitro.

Rat soluble MHC class I synthesis was studied at both RNA and protein levels to determine whether multiple forms of soluble MHC class I molecules are produced by different mechanisms. RT-PCR and sequencing of MHC class I transcripts identified an alternatively spliced nonclassical MHC class I gene product, lacking both exon 5 and 6, in both spleen and liver. Immunoprecipitation and SDS-PAGE identified two distinct soluble MHC class I proteins in both splenocyte- and hepatocyte-culture supernatants. The 36Kd classical soluble MHC class I protein (RT1.Aa) was precipitated by both allele-specific (MN4.91.6, R3/13, R2/15S) and pan-reactive (OX18) mAbs. The 39Kd non-RT1.A soluble MHC class I protein was precipitated only by OX18. The production of soluble RT1.Aa was inhibited by a metalloproteinase inhibitor, but not by serine/thiol protease inhibitors. None of these protease inhibitors interfered with the soluble non-RT1.A production, suggesting that it might be derived from an alternatively spliced MHC class I transcript. The soluble non-RT1.A was always associated with beta2m. However, soluble RT1.Aa molecule was cleaved in beta2m-free form and was reassociated with beta2m in culture supernatants. Thus two soluble MHC class I molecules, classical (36Kd RT1.Aa) and nonclassical (the alternatively spliced transcript), were produced from rat cells. Alternative splicing led to the nonclassical soluble MHC class I synthesis. Proteolytic cleavage by metalloproteinase led to the classical soluble MHC class I synthesis.

Alleles↗

PubMed2002

Experimental and computational screening models for prediction of aqueous drug solubility.

PURPOSE: To devise experimental and computational models to predict aqueous drug solubility. METHODS: A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. RESULTS: The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/ mL, covering a range of almost seven log10 units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R2 of 0.91 and RMSEtr of 0.61) was devised. CONCLUSIONS: A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.

Chemical Phenomena↗

PubMedDate not supplied

Enhanced solubility of 2,8 dihydroxyadenine (DOA) in human urine.

Water solubility of the adenine catabolite 2,8 dihydroxyadenine (DOA) frequently forms the basis for predicting potential DOA crystal formation in human urine following infusion of adenine-fortified blood. Measurements relevant to solubility, ionic dissociation, and supersaturability of DOA in aqueous buffers and human urine at 37 C establish striking quantitative differences in the physico-chemical behavior of DOA in the two media. The basal solubility of DOA is 1.53 +/- 0.04 mg/1 (approximately 9 X 10(-6) M) in water (pH 6.5). DOA is an ampholyte characterized by aqueous thermodynamic macrodissociation constants of pKa1 = 2.6, pKa2 = 8.1, and pKa3 = 11.52. This compound displays pH-dependent solubility, although significant solubility increases beyond basal values do not occur within the physiologic pH range for human urine. Supersaturated aqueous solutions (three to sixteen times basal solubility) can be achieved but are unstable. In contrast, human urine at 37 C exhibits enhanced capacity for solubilizing DOA. In vitro basal solubility is 2.68 +/- 0.84 mg/1 at pH 5.0 and 4.97 +/- 1.49 mg/1 at pH 7.8. The apparent pK 2for DOA in urine of 7.9 to 8.1 is dependent upon urine osmolality. Urine can be supersaturated with Doa in vitro to approximately ten times its basal solubility by adding DOA solubilized in weak base, or by evaporation of a urine-DOA mixture. DOA remains supersaturated in urine for at least 16 hours despite gentle agitation. Little variation in in vitro DOA apparent supersaturation was found among urine samples from four normal individuals (40.38 +/- 3.33 mg/1). A patient receiving oral adenine exhibited urinary DOA solubility in considerable excess (96.0 mg/1) of that predicted from water and from in vitro urine solubility studies. Thus, water solubility of DOA is poorly predictive of in vitro and in vivo DOA solubility in human urine. On the basis of these data, estimates of the load of adenine-fortified blood expected to result in urinary DOA crystal formation may be revised upward.

Adenine↗

PubMed2000

Aqueous solubility of diclofenac diethylamine in the presence of pharmaceutical additives: a comparative study with diclofenac sodium.

Aqueous solubility of diclofenac diethylamine (DDEA), a nonsteroidal anti-inflammatory drug currently formulated as a topical emulgel, was studied in the presence of pharmaceutical additives and compared with diclofenac sodium (DS). Electrolytes at low concentrations exhibited a salting-in effect on DDEA with peak solubility that was attributed to the association of DDEA into micelles, followed by a salting-out effect at higher concentrations, by which structure formation by DDEA molecules increased and precipitation occurred. For DS, which is not capable of forming micelles, the salting-out effect was dominant due to the common ion effect. Cosolvents displayed significant enhancement in solubility of both salts except glycerol, which showed a slight increase in solubility of DDEA and a decrease in solubility of DS due to transformation into the less soluble hydrate form. Ethanol and polyethylene glycol (PEG) 400 cosolvent systems at all concentrations showed positive deviations from the log-linear solubility equation. In the case of propylene glycol (PG) cosolvent systems, negative deviations were observed at low volume fractions of cosolvent, while positive deviations were observed at high volume fractions of cosolvent for DS and DDEA. The parent drug, being less ionizable and highly nonpolar, showed negative deviations up to 90% PG content. Thus, the positive deviations for DS and DDEA could be attributed to the more ionizable carboxylic group and its higher ability for hydrogen bonding at higher fractions of cosolvent. Polyvinylpyrrolidone (PVP) and PEG4000 or PEG6000 enhanced the solubility of DS and DDEA, with PVP exerting higher solubilizing efficiency and DS showing better solubility than DDEA. Solubilities of DS in Tween 80 (T80) and Pluronic F-127 (PF127) aqueous solutions were almost similar, while the solubility of DDEA in the presence of T80 was higher than the solubility in the presence of PF127. DS appeared to be located more in the polyoxyethylene mantle of the micelles, while DDEA was located more in the core of the micelles.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

Solubility of guaifenesin in the presence of common pharmaceutical additives.

The aqueous solubility of guaifenesin, a highly water-soluble drug, in the presence of salts, sugars, and cosolvents was determined at 25 degrees C and 40 degrees C. The solubility of drug at both temperatures was reduced with increasing concentrations of salts and sugars. The extent of reduction in drug solubility was dependent on the type of salts and sugars used. The salting-out coefficient of additives was calculated by plotting log-linear solubility profiles of the drug against the concentrations of the additives. The solubility of guaifenesin, a neutral compound, was found to be higher at lower pH values, which could be due to hydrogen-bonding effects. At 25 degrees C, glycerin, PEG 300, and propylene glycol increased the solubility of drug at low solvent concentrations while the solubility was reduced at high concentrations. At 40 degrees C, the solubility of drug was reduced at all concentrations of cosolvents. The thermodynamic events accompanying the solubility process were discussed to explain the solubility phenomena observed in the presence of additives. The reduced aqueous solubility of guaifenesin in the presence of additives greatly improved the entrapment of drug into controlled-release wax microspheres.

Chemistry, Pharmaceutical↗