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PubMed2004

Structure transition in myosin association with the change of concentration: solubility equilibrium under specified KCl and pH condition.

We observed, for the first time, the elementary process for the ordered self-assembly formation of myosin in solution. It was realized exclusively under the specific condition of 200 mM KCl, 5 mM phosphate buffer, pH 7.08, at 15-20 degrees C, which is called the transition-generating condition (TGC). Described more in detail: pure myosin extracted from rabbit skeletal muscle exhibited the structural transition in its association form only when the myosin concentration c was changed under TGC. The myosin solubility was saturated in both edges of the total myosin concentration c > 10.0 mg/mL (solubility region II) and c < or = 0.25 mg/mL (solubility region I). In the intermediate region, the association structure of myosin changed stepwise with decreasing c. The steps were classified into four regions: region I (c < or = 0.25 mg/mL), II (0.25 < or = c < or = 0.50 mg/mL), III (0.50 < or = c < or = 5.0 mg/mL), and IV (c > 5.0 mg/mL). In each region except II, the plot of the relative soluble myosin concentration c(aq)/c against c(-1) gave a straight line of different slopes, certifying that myosin constructs self-assemblies by the closed association mechanism and that the self-assembly takes dual structures in each region. In region II, a drastic transition occurred in the self-assembled dual structures. Here, a highly associated (insoluble) giant assembly would break into soluble assemblies composed of several myosin molecules. The solubility region I originates a driving force for this structural transition. The basic binding unit of the self-assembly would be a parallel myosin-dimer constructed by the intermolecular axial staggers of 14.3 and 43 nm, as is observed by X-ray diffraction for the thick filament assembly or light meromyosin paracrystals. Myosin could take a single rod-like chain form only in an extremely low concentration region of c < or = c(aq,0) (= 0.053 mg/mL). The association behavior revealed in the present study suggests strongly that the complementary charge cluster and its electrostatic interaction between parallel myosin rods play a crucial role for the ordered self-assembly formation and that the specific electrostatic atmosphere of the solution under TGC is essential to the association mechanism in skeletal muscle myosin, or the thick filament formation of the mammals.

Animals↗

PubMed2005

Combination of Dsb coexpression and an addition of sorbitol markedly enhanced soluble expression of single-chain Fv in Escherichia coli.

Many eukaryotic proteins have been produced successfully in Escherichia coli. However, not every gene can be expressed efficiently in this organism. Most proteins, especially those with multiple disulfide bonds, have been shown to form insoluble protein or inclusion body in E. coli. An inactive form of protein would require an in vitro refolding step to regain biological functions. In this study, we described the system for soluble expression of a single-chain variable fragment (scFv) against hepatocellular carcinoma (Hep27scFv) by coexpressing Dsb protein and enhancing with medium additives. The results revealed that overexpression of DsbABCD protein showed marked effect on the soluble production of Hep27scFv, presumably facilitating correct folding. The optimal condition for soluble scFv expression could be obtained by adding 0.5M sorbitol to the culture medium. The competitive enzyme-linked immunosorbent assay (ELISA) indicated that soluble scFv expressed by our method retains binding activity toward the same epitope on a hepatocellular carcinoma cell line (HCC-S102) recognized by intact antibody (Ab) (Hep27 Mab). Here, we report an effective method for soluble expression of scFv in E. coli by the Dsb coexpression system with the addition of sorbitol medium additive. This method might be applicable for high-yield soluble expression of proteins with multiple disulfide bonds.

Antibodies, Monoclonal↗

PubMed2004

Elevation of the soluble thrombomodulin levels is associated with inflammation after percutaneous coronary interventions.

BACKGROUND: Thrombomodulin (TM) is an endothelial cell surface thrombin-binding protein with anticoagulation ability by thrombin-mediated activation of protein C. An increase of plasma soluble TM level is reported to be associated with severity and worse outcome of coronary artery disease. HYPOTHESIS: This prospective study investigated the relation of the elevated levels of plasma soluble TM and inflammatory and myonecrotic markers in patients undergoing percutaneous coronary intervention (PCI). METHODS: Plasma levels of soluble TM, C-reactive protein (CRP), and creatine kinase and its MB isoenzyme were measured before and after PCI in 100 patients undergoing PCIs. RESULTS: Peak TM levels after PCIs were significantly higher than baseline (3.39 +/- 1.63 vs. 2.90 +/- 1.57 ng/ml, p < 0.001). The peak TM levels after PCIs correlated significantly with the peak CRP and MB levels, and the maximal inflation duration (r = 0.423, p < 0.001; r = 0.212, p = 0.034; r = 0.307, p= 0.002, respectively). CONCLUSIONS: Soluble TM levels increase significantly after PCI. The elevation of the soluble TM after PCI shows better correlation with inflammation than myocardial injury, indicating an endothelial origin. Measurement of soluble TM could be useful and calls for further studies on the prognostic effects of this marker in this clinical condition.

Aged↗

PubMed1988

Activation of rat complement by soluble and insoluble rat IgA immune complexes.

The ability of rat monoclonal IgA, specific for 2,4-dinitrophenyl (DNA), to activate the complement (C) system of the rat was investigated using aggregated IgA or IgA immune complexes (IC). IgA was coated onto a solid phase, and tested for its capacity to bind C3 upon incubation at 37 degrees C in normal rat serum (NRS) in the presence of Mg-EGTA. Binding of C3 was observed dependent on the dose of dimeric (d-), polymeric (p-) and secretory IgA tested. In contrast, little C3 fixation was observed in this system with monomeric (m-) rat IgA or with mouse m- and d-IgA (MOPC315). Soluble and insoluble rat IgA IC were prepared using dinitrophenylated rat serum albumin (DNP8RSA) as antigen (Ag), and assessed for C activation. It was shown that insoluble IC (immune precipitates; IP) containing m-, d- or pIgA of rat origin activate the alternative pathway of rat C, as demonstrated by their capacity to induce C consumption in NRS in the presence of Mg-EGTA. When p- and m-IgA IP were compared for their capacity to activate C, it was found that p-IgA activated C four times as efficiently as m-IgA IP (at 2 mg/ml). Soluble rat IgA IC were prepared in an excess of DNP8RSA, fractionated by gel filtration on Sepharose 6B, and analyzed for C activation and antibody (Ab)/Ag ratio. In contrast to m-IgA IP, soluble m-IgA did not activate C. On the other hand soluble d-IgA IC activated C dependent on their concentration and size: at a concentration of 0.1 mg/ml high-molecular weight d-IgA IC with a high Ab/Ag ratio were four times as efficient as low-molecular weight IC with a low Ab/Ag ratio, and twice as efficient as IP prepared at equivalence. To demonstrate the induction by IgA of the assembly of the terminal membrane attack complex, trinitrophenyl (TNP)-conjugated rat red blood cells (TNP-RRBC) coated with d- or p-IgA were shown to be lysed in NRS in the presence of Mg-EGTA. No lysis of m-IgA-coated TNP-RRBC was observed. The results in this study demonstrate that both soluble and insoluble rat IgA IC activate the alternative pathway of homologous rat C. Alternative pathway activation by soluble rate IgA IC is dependent on the size of the IC. The degree of polymerization of the IgA Ab itself also influences C activation.

Animals↗

PubMed1984

Prereplicative changes in the soluble calmodulin of isoproterenol-activated rat parotid glands.

Cells of rat parotid glands were maximally stimulated to initiate DNA synthesis by injecting into the animal a single dose of 25 to 150 mg of isoproterenol/kg of body weight. During the 18- to 21-hr prereplicative period following injection of the highest dose of the drug, there were two predominant and transient redistributions of calmodulin from the bound to the soluble form, which tripled the level of soluble calmodulin at 3 hr and again at 18 hr just before the initiation of DNA synthesis. A small (50%) increase in total calmodulin was observed only during the early (3-h) prereplicative surge of soluble calmodulin. The late, pre-DNA-synthetic surge of soluble calmodulin and the initiation of DNA synthesis were both prevented in rats that lacked their parathyroid-thyroid gland complex and had been hypocalcemic for 48 or 72 hr. Unlike the effect of high doses of isoproterenol, low doses (e.g., 25 mg/kg body weight) of the beta-adrenergic drug could maximally stimulate DNA synthetic activity without the later pre-DNA-synthetic surge of soluble calmodulin, suggesting that any apparent correlation between the level of calmodulin and DNA synthesis may be spurious and that an actual increase in the level of soluble calmodulin just before the onset of DNA synthesis was not a prerequisite for DNA synthetic activity in parotid cells.

Animals↗

PubMed2002

A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs.

The highly lipid soluble, free-base form of halofantrine (Hf base; approximately 50 mg/mL in triglyceride lipids), a highly lipophilic (calculated log P approximately 8.5) antimalarial, has recently been shown to undergo significant intestinal lymphatic transport (54% of administered dose) after postprandial administration to dogs. In contrast, the clinically available hydrochloride salt of Hf (Hf small middle dot HCl), was not considered to be a likely substrate for lymphatic transport because its solubility in long-chain triglyceride lipids is low (< 1 mg/mL). This paper reports the lymphatic transport of Hf after postprandial administration of Hf.HCl, which was surprisingly high at 47% of the administered dose, and not significantly different from that of Hf base. It was postulated that partial conversion of solubilized Hf.HCl to the highly lipid soluble Hf base within the intestinal lumen might account for the extensive lymphatic transport. However, as Hf is a tertiary amine with an expected pK(a) of > 10, at gastrointestinal pH, the fraction of Hf present as the free base form is likely to be extremely low. Physicochemical studies exploring the solubility and pK(a) of Hf suggest that Hf.HCl was extensively solubilized following fed administration. When solubilized in representative fed state mixed micellar solutions, its apparent pK(a) was 6.92 and considerably lower than anticipated for a tertiary amine. It appears that the extensive lymphatic transport of Hf observed after postprandial administration of Hf.HCl was likely to be due to the conversion of solubilized Hf.HCl to the free base. Therefore, in addition to indicators such as log P and triglyceride solubility, factors such as drug solubilization in representative fed state intestinal conditions and the possible conversion to the un-ionized form should be considered when predicting the potential lymphatic transport of salts of poorly water soluble acids and bases.

Animals↗

PubMed2002

Solubility prediction in supercritical CO(2) using minimum number of experiments.

The correlation ability and solubility prediction in supercritical carbon dioxide of a proposed equation were studied. The work involved the solubilities of nicotinic acid and p-acetoxyacetanilide in supercritical carbon dioxide using a dynamic flow solubility system at 35-75 degrees C and 100-200 bar. The generated experimental solubility data together with 21 data sets collected from the literature were used to evaluate the correlation ability of available empirical equations. The average absolute relative deviations (AARD) for the empirical equations are 12.6-24.8%. The prediction capability of the modified empirical relationship was studied with six experimental data points as a training set. Then, solubility at other temperatures and pressures were predicted. The AARD between predicted solubilities and observed values is 17%.

Acetanilides↗

PubMed2003

Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-beta, beta-carotene-4,4'-dione) by Captisol (sulfobutyl ether beta-cyclodextrin).

Carotenoids are the most widely distributed natural pigments, with over 600 individual compounds identified and characterized from natural sources. A few are commercially important molecules, having found utility as additions to animal feed in the aquaculture, poultry, and swine feed industries. The majority are lipophilic molecules with near zero inherent aqueous solubility. Many different methods have been developed to make the carotenoids "water dispersible," as true water solubility has not been described. Astaxanthin (3,3'-dihydroxy-beta, beta-carotene-4,4'-dione) is a commercially important oxygenated carotenoid that has gained wide acceptance as a feed additive in the $50 billion salmon and trout aquaculture industry. Recently, interest in the human health applications of astaxanthin has increased, with astaxanthin receiving approval as a dietary supplement in several countries, including the United States. Moving astaxanthin into a pharmaceutical application will require a chemical delivery system that overcomes the problems with parenteral administration of a highly lipophilic, low molecular weight compound. In the current study, the ability of sulfobutyl ether beta-cyclodextrin (sodium), as the Captisol(R) brand, to increase the aqueous water solubility of crystalline astaxanthin was evaluated. Complexation of crystalline astaxanthin with Captisol increased the apparent water solubility of crystalline astaxanthin approximately 71-fold, to a concentration in the 2 microg/mL range. It is unlikely that this increase in solubility will result in a pharmaceutically acceptable chemical delivery system for humans. However, the increased aqueous solubility of crystalline astaxanthin to the range achieved in the current study will likely find utility in the introduction of crystalline astaxanthin into mammalian cell culture systems that have previously been dependent upon liposomes, or toxic organic solvents, for the introduction of carotenoids into aqueous solution.

Adjuvants, Immunologic↗

PubMed2004

Determination of water-soluble acid distribution in poly(lactide-co-glycolide).

Determination of the kinetics of water-soluble degradation products inside poly(lactide-co-glycolide) (PLGA) delivery systems during polymer degradation is important to evaluate the polymer microclimate conditions, particularly microclimate pH changes for optimization of encapsulated drug stability. A pre-derivatization high-performance liquid chromatography (HPLC) method was developed for separation and quantification of water-soluble acid impurities and degradation products in PLGA. Thin PLGA films (approximately 200 microm) were incubated in PBS/0.02% Tween 80, pH 7.4, for 6 weeks. Water-soluble monomers and oligomers were obtained from polymer films after repeated CHCl(3)/H(2)O extraction and then derivatized into bromophenacyl esters. With the common chromophore, the esters were separated and quantified by HPLC with increased ultraviolet (UV) sensitivity at 254 nm. The total amount of water-soluble acids in the extract was validated by potentiometric titration with tetrabutyl ammonium hydroxide. During the first 3 weeks of incubation of PLGA 50:50 (inherent viscosity = 0.63 dL/g), the principal water-soluble acids in the polymer were glycolic, lactic, and lactoyllactic acids, and an unknown oligomer. After 4 weeks of incubation, a large fraction of higher molecular weight oligomers was observed. Pre-derivatization HPLC can be used to accurately measure water-soluble acid distribution, and may be invaluable to examine the degradation behavior of PLGAs, including the underlying mechanism of polymer microclimate pH development.

Acids↗

PubMed2001

Solubility and precipitation of nicotinic acid in supercritical carbon dioxide.

Solubilities of a model compound (nicotinic acid) in pure supercritical carbon dioxide (SC-CO(2)) and SC-CO(2) modified with methanol have been measured in the pressure range of 80-200 bar and between temperatures of 35 and 90 degrees C. On-line ultraviolet detection enabled a simple and relatively fast measurement of very low levels of solubility (10(-7) mol fraction) with good accuracy in pure and modified SC-CO(2). The solute solubility in both pure SC-CO(2) and SC-CO(2) modified with methanol increased with pressure at all investigated temperatures. A retrograde solubility behavior was observed in that, at pressures below 120 bar, a solubility decrease on temperature increase occurred. Solubility data were used to calculate supersaturation values and to define optimum operating conditions to obtain crystalline particles 1-5 microm in diameter using the solution-enhanced dispersion by supercritical fluids (SEDS) process, thereby demonstrating the feasibility of a one-step production process for particulate pharmaceuticals suitable for respiratory drug delivery.

Aluminum↗

PubMed2006

High throughput solubility measurement with automated polarized light microscopy analysis.

As a high throughput solubility assay, the solution-precipitation method using a dimethylsulfoxide (DMSO) sample stock solution (DMSO-SP) has been widely used in drug discovery. However, the solid form of the precipitant has not been investigated. In this study, we investigated the experimental conditions of the DMSO-SP, focusing on the solid form of the precipitant. The final concentration of DMSO was 1% (v/v). The precipitant of more than a half of the model compounds was observed as crystalline by polarized light microscopy analysis. When the incubation time was 20 h and the precipitant was crystalline, the DMSO-SP solubility was similar to the solubility from a powder material (PWD). However, when the incubation time was 10 min and/or the precipitant was not crystalline, the DMSO-SP solubility was higher than the PWD solubility. These results suggested that the information regarding the solid form of the precipitant is important in interpreting the solubility data. In addition, we developed an automated birefringence diagnose system for drug discovery usage.

1-Octanol↗

PubMed1976

Solubility of straight-chain and branched alkyl barbiturates in straight-chain alcohols.

The solubilities of a series of chemically related barbiturates, including some medically useful ones as well as phenobarbital, were determined at 25 degrees in the straight-chain alcohols methanol through butanol. The solubility values are given in both milligrams per milliliter and the mole fraction notation. The solubility in methanol was the highest and decreased nonlinearly for the solubility in 1-butanol. In several cases, mole fraction solubility gave shouldering or peaking as a function of the carbon number of the solvent. This series of barbiturates was broken down into two subsets of straight-chain and branched alkyl barbiturates, and solubility ratios in these subsets were considered.

Alcohols↗

PubMed1976

Solubilities of testosterone propionate and related esters in organic solvents.

The solubility parameters of a range of saturated hydrocarbons were calculated from vapor pressures and heats of vaporization. Solubilities of testosterone propionate were determined in these solvents at 25 degrees and yielded solute solubility parameters which varied from solvent to solvent. The solubility parameter of testosterone propionate was determined by several other methods, and support was found for the previously published figure of 9.5 cal(1/2) cm(-3/2). The geometric mean coefficient (l(12)) in saturated hydrocarbons was found to be a rectilinear function of the branching ratio (r). The mean l(12) of androstanolone and testosterone propionates was used to calculate the solubilities of other esters, giving good agreement with experimental results. IR data, presented as the sum of the shifts of the 3-keto and 17-ester carbonyl stretching frequencies in polar solvents, correlated rectilinearly with the geometric mean coefficients and the plot extrapolated to the l(12) value of n-hexane, calculated from the branching ratio plot. Attempts to predict solubilities of other esters in polar solvents using l(12) values achieved only limited success.

Chemical Phenomena↗

PubMed1976

Nitrofurantoin solubility in aqueous urea and creatinine solutions.

Experiments were carried out to determine the effect of urea and creatinine on the solubility of nitrofurantoin in water at different temperature and pH conditions. The addition of urea to aqueous media increased nitrofurantoin solubility up to a maximum concentration level and then decreased solubility at higher urea concentrations. The amount of urea needed to bring about maximum nitrofurantoin solubility was dependent on temperature and ranged between 1.75 and 2.50%. Spectral studies suggest a possible interaction between urea and nitrofurantoin molecules. Nitrofurantoin solubility increased with an increasing creatinine concentration ranging from 0.05 to 1.6%. Spectral studies indicate a strong interaction between creatinine and nitrofurantoin molecules in solution. The combined effect of urea and creatinine of the solubility of nitrofurantoin could account for the absence of crystalluria with this drug, even though unusually high concentrations in urine have been reported.

Buffers↗

PubMed1978

Solubility of calcium oxalate in 1-alkanols and ethanol--water mixtures.

Solubility profiles for calcium oxalate were determined in pure 1-alkanols and ethanol--water mixtures at 20 degrees. The magnitude of solubility in the aliphatic alcohols was highest in methanol and decreased in a nonlinear fashion as the dielectric constant decreased, going to n-decanol. In ethanol--water mixtures, the solubility increased nonlinearly with water content or increasing dielectric constants. The work factor for these systems was also calculated and, as expected, a "mirror image" to the solubility profiles was evidenced. In the mixed solvent system, a dramatic change in the magnitude of solubility occurred after a dielectric constant value of about 60, indicating ionic association or ion-pairs below this value. The Born relationship of solubility and ionic size was tested in the ethanol--water system, and the ionic size of the divalent species of about 2.27 A agreed with the theoretical ionic size of about 2.4 A. These results indicate that the water number of calcium is 8 or that a monolayer of dipoles surrounds this divalent cationic species.

Alcohols↗

PubMed1979

Solubility of doxycycline in aqueous solution.

The solubility of doxycyline monohydrate and doxycycline hydrochloride dihydrate was investigated in aqueous solution. The hydrochloride dihydrate salt was isolated and identified from solutions initially containing doxycycline hyclate in water. The pKa' = 3.09 (mu = 0.1 and 25 degrees) for protonation of doxycycline was determined spectrophotometrically. The pH-solubility profiles were determined for doxycycline monohydrate in water and in 1.0 M NaNO3-HNO3 and NaCl-HCl. The pH-solubility profile at 25 degrees for doxycycline in aqueous hydrochloric acid without added salt reached a sharp maximum fo 50 mg/ml at pH 2.16. Added chloride ion strongly suppressed the solubility of the hydrochloride dihydrate salt. The apparent solubility product was not constant but decreased as the concentration of added salt increased. A theoretical model was developed involving dimerization of doxycycline and applied to the experimental data. The dimerization constant, Kd = 24 M-1, and true solubility product, K0sp = 1.8 X 10(-3) M2, were calculated. The effect of concentration on NMR and visible spectra indicated that dimerization resulted from intermolecular hydrogen bonding of the phenolic beta-diketone portion of the molecule.

Doxycycline↗

PubMed1981

Thermochemical investigations of nearly ideal binary solvents. VII: Monomer and dimer models for solubility of benzoic acid in simple binary and ternary solvents.

Solubilities are reported for benzoic acid at 25.0 degrees in binary mixtures of carbon tetrachloride with cyclohexane, n-hexane, or n-heptane and of cyclohexane with n-hexane or n-heptane and in ternary mixtures of carbon tetrachloride-cyclohexane-n-hexane and carbon tetrachloride-cyclohexane-n-heptane. Solubilities also are reported for benzoic acid in some binary solvents at 30.0 degrees and for m-toluic acid in binary mixtures of cyclohexane and n-hexane at 25.0 degrees. The results are compared to the predictions of equations developed previously for solubility in systems of purely nonspecific interactions, with the benzoic acids considered as either monomeric or dimeric molecules in solution. The dimer model gave more accurate predictions, with a maximum deviation of 4.4% between observed and predicted solubilities in all systems studied. Solubility maxima were predicted and observed for benzoic and m-toluic acids in cyclohexane-n-hexane and for benzoic acid in cyclohexane-n-heptane. The application of these solubility relationships to liquid-liquid partition coefficients is discussed.

Benzoates↗

PubMed1982

Metronidazole phosphate--a water-soluble prodrug for parenteral solutions of metronidazole.

To develop a parenteral solution of relatively water-insoluble metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), its phosphate ester was synthesized via two routes. One route utilized 2-cyanoethyl phosphate and the other utilized pyrophosphoryl tetrachloride. The first method used dicyclohexylcarbodiimide as a coupling agent and the cyanoethyl group was removed under mild alkaline conditions. The second method was a one-step procedure in which free acid of metronidazole phosphate was isolated as a crystalline solid. The solubility of metronidazole in various solvents was determined at 25 degrees. From the pH-dependence of its aqueous solubility, the pKa of the conjugate acid of metronidazole was estimated to be 2.62, which agreed well with the pKa values of other nitroimidazoles. Metronidazole phosphate behaved as a zwitterionic compound in an acidic medium with a minimum solubility at pH 2.0. At pH 7, its solubility was approximately 50 times that of metronidazole. The phosphate ester was so soluble at pH higher than 7 that it was difficult to measure the solubility accurately. In human serum, the hydrolysis of metronidazole phosphate followed zero-order kinetics at an initial concentration of 0.25 mg/ml or higher, presumably due to enzyme saturation (0.035 mg/ml/hr at 37 degrees). A reversed-phase HPLC procedure was adopted to monitor the appearance of metronidazole and the disappearance of metronidazole phosphate. Subcutaneous administration of metronidazole phosphate to rats produced a blood level of bioactivity comparable to that observed after administration of metronidazole.

Animals↗