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PubMed1997

Soluble adhesion molecules in infants and children undergoing cardiopulmonary bypass.

BACKGROUND: The vascular injury and tissue damage after cardiopulmonary bypass (CPB) involves leukocyte-endothelial interactions mediated by cell adhesion molecules. This study was designed to determine the time course of soluble adhesion molecule levels after CPB in infants and children and to determine whether these levels correlated with preoperative variables, intraoperative bypass management, or postoperative course. METHODS AND RESULTS: In 56 patients undergoing CPB (median age 1.0 year, range 2 days to 19 years), plasma concentrations of soluble E-, P-, and L-selection, soluble ICAM-1, and soluble VCAM-1 were measured using sandwich enzyme-linked immunosorbent assays at the following times: at induction of anesthesia, after 15 minutes of CPB, at the end of CPB, and 1, 6, 18, and 42 hours after CPB. Preoperative, intraoperative, and postoperative data were prospectively recorded. All soluble adhesion molecule levels fell markedly at the initiation of CPB as a result of a combination of dilution and bypass circuit uptake. The time course of soluble selectins (P, E, and L), normalized to end of bypass levels, all rose significantly (P<.001) in the initial 6 hours after CPB and then returned to end bypass levels at 42 hours. Soluble ICAM-1 and VCAM rose 63% and 89% in the first 6 hours and remained elevated throughout the 42 hours. Peak soluble P-selectin levels were associated with total support time (P=.04) and preoperative cyanosis (P=.003). Soluble L-selectin levels were inversely associated with longer total support time (P=.002), longer circulatory arrest time (P=.004), longer length of intubation (P=.0009), preoperative cyanosis (P=.002), and younger age at surgery (P=.01). CONCLUSIONS: Soluble adhesion molecules have a characteristic time course in infants and children undergoing CPB. The soluble adhesion molecule levels after CPB change most significantly in patients with the highest potential for vascular injury: younger, cyanotic patients with longer pump times and longer postoperative courses. These data may be useful in the assessment of new therapies.

Adolescent↗

PubMed1999

Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer.

The level of the acute-phase response is a major predictor of survival in patients with advanced pancreatic cancer. This study examines the association between the acute-phase protein response, as determined by serum C-reactive protein, and serum levels of interleukin-6, soluble interleukin-6 receptor and the soluble tumour necrosis factor receptors in patients with pancreatic cancer. Thirty-four blood samples were collected from 13 patients with advanced pancreatic cancer. Samples were also collected from six healthy subjects. Levels of C-reactive protein, interleukin-6, soluble interleukin-6 receptor and soluble tumour necrosis factor receptors 55 and 75 were measured by indirect ELISA. Serum levels of C-reactive protein, interleukin-6 and soluble tumour necrosis factor receptors 55 and 75 were significantly higher in cancer patients than in controls. Levels of serum soluble interleukin-6 receptor were not significantly different between the two groups. In cancer patients, a significant positive association was found between the level of the acute-phase protein response and serum levels of interleukin-6, soluble tumour necrosis factor receptor 55 and soluble tumour necrosis factor receptor 75. No association was found between levels of soluble interleukin-6 receptor and any other factor. There is no significant relationship between the level of soluble interleukin-6 receptor and the acute-phase protein response in vivo and the biological role of soluble interleukin-6 receptor in the chronic inflammatory component of cachexia remains unclear.

Acute-Phase Reaction↗

PubMed2002

Thermodynamic origin of the solubility profile of drugs showing one or two maxima against the polarity of aqueous and nonaqueous mixtures: niflumic acid and caffeine.

The purpose of this work was to investigate the origin of the different solubility profiles of drugs against the polarity of solvent mixtures with a common cosolvent. Niflumic acid and caffeine where chosen as model drugs. The solubilities were measured at five or six temperatures in aqueous (ethanol-water) and nonaqueous (ethyl acetate-ethanol) mixtures. The enthalpies of solution were obtained at the harmonic mean of the experimental temperature. Solid phase changes were analyzed using differential scanning calorimetry and thermomicroscopy. A single solubility maximum was obtained for niflumic acid against the solubility parameter of both mixtures that is not related to solid phase changes. In contrast, caffeine displays two maxima and anhydrous-hydrate transition occurs at the solubility peak in the amphiprotic mixture. The apparent enthalpies of solution of both drugs show endothermic maxima against solvent composition that are related to hydrophobic hydration. A general explanation for the cosolvent action in aqueous mixtures is proposed. The dominant mechanism shifts from entropy to enthalpy at a certain cosolvent ratio dependent on the hydrophobicity and the solubility parameter of the drug. Niflumic acid and caffeine show enthalpy-entropy compensation in ethanol-water, and this relationship is demonstrated for the first time in nonaqueous mixtures. The results support that enthalpy-entropy compensation is a general effect for the solubility of drugs in solvent mixtures. The shape of the solubility curves is correlated with the compensation plots. The solubility peaks separate different enthalpy-entropy relationships that also differentiate the solubility behavior of the hydrate and the anhydrous forms of caffeine.

Algorithms↗

PubMed2005

Trends in solubility of polymorphs.

Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on solubility or dissolution of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on solubility? A large number of literature reports on solubility or dissolution of polymorphs were reviewed and the data were analyzed for trends in solubility ratio of polymorphs. The general trend reveals that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. A similar trend is also observed for anhydrate/hydrate solubility ratios, although anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to estimate the ratio of solubilities of polymorphs from thermal data. The trend in estimated solubility ratio shows good agreement with the one observed with experimentally determined solubility values.

Algorithms↗

PubMed1996

Soluble acid invertase determines the hexose-to-sucrose ratio in cold-stored potato tubers.

Cold storage of potato (Solanum tuberosum L.) tubers is known to cause accumulation of reducing sugars. Hexose accumulation has been shown to be cultivar-dependent and proposed to be the result of sucrose hydrolysis via invertase. To study whether hexose accumulation is indeed related to the amount of invertase activities, two different approaches were used: (i) neutral and acidic invertase activities as well as soluble sugars were measured in cold-stored tubers of 24 potato cultivars differing in the cold-induced accumulation of reducing sugars and (ii) antisense potato plants with reduced soluble acid invertase activities were created and the soluble sugar accumulation in cold-stored tubers was studied. The cold-induced hexose accumulation in tubers from the different potato cultivars varied strongly (up to eightfold). Large differences were also detected with respect to soluble acid (50-fold) and neutral (5-fold) invertase activities among the different cultivars. Although there was almost no correlation between the total amount of invertase activity and the accumulation of reducing sugars there was a striking correlation between the hexose/sucrose ratio and the extractable soluble invertase activity. To exclude the possibility that other cultivar-specific features could account for the obtained results, the antisense approach was used to decrease the amount of soluble acid invertase activity in a uniform genetic background. To this end the cDNA of a cold-inducible soluble acid invertase (EMBL nucleic-acid database accession no. X70368) was cloned from the cultivar Desirée, and transgenic potato plants were created expressing this cDNA in the antisense orientation under control of the constitutive 35S cauliflower mosaic virus promotor. Analysis of the harvested and cold-stored tubers showed that inhibition of the soluble acid invertase activity leads to a decreased hexose and an increased sucrose content compared with controls. As was already found for the different potato cultivars the hexose/sucrose ratio decreased with decreasing invertase activities but the total amount of soluble sugars did not significantly change. From these data we conclude that invertases do not control the total amount of soluble sugars in cold-stored potato tubers but are involved in the regulation of the ratio of hexose to sucrose.

Cold Temperature↗

PubMed2002

Faecal elastase-1 and fat-soluble vitamin profiles in patients with cystic fibrosis in Western Norway.

BACKGROUND: Exocrine pancreatic insufficiency is a major clinical manifestation of cystic fibrosis (CF). Almost nine of ten patients develop signs and symptoms of maldigestion and malabsorption, which often deteriorates nutritional status and therefore worsens the prognosis. Human faecal elastase-1 (FE-1) has shown promising results to assess exocrine pancreatic insufficiency, and this test has been used at Haukeland University Hospital since 1996. AIM OF THE STUDY: To evaluate FE-1 values and fat-soluble vitamin profiles in patients with CF and to correlate exocrine pancreatic function as measured as FE-1 to fat-soluble vitamin profiles. Moreover, we wanted to assess if there are differences between fat-soluble vitamin profiles in patients with impaired versus patent exocrine pancreatic function, and thirdly, if fat-soluble vitamin deficiency at diagnosis is effectively treated by supplementation. METHODS: Consecutive analyses (N = 212) of fat-soluble vitamin profiles and 35 analyses of FE-1 were investigated in 35 patients with CF. In 17 out of 35 patients fat-soluble vitamin profiles were also assessed at diagnosis. Results Mean value of FE-1 for all CF patients was 256.9 microg/g faeces (median 24.1 microg/g faeces). CF patients considered to have maldigestion (N=24) showed a mean value of 19.9 microg/g faeces (median 18.7 microg/g faeces), those without pancreas affection had a mean value of 773.9 microg/g faeces (median 728.9 microg/g faeces, p < 0.01). There was no difference in fat-soluble vitamin profiles among patients with or without exocrine pancreatic insufficiency while on appropriate supplementation. Median value for vitamin E in patients with exocrine pancreatic insufficiency at diagnosis was low (3.6 mg/L). Supplementation of pancreatic enzymes and vitamins normalised profiles in this group at follow-up. There was no significant correlation between exocrine pancreatic function as measured as FE-1 and fat-soluble vitamin profiles, neither in patients with impaired nor in those with patent pancreatic function. CONCLUSIONS: Severe degree of exocrine pancreatic insufficiency is common in patients with cystic fibrosis. There was no correlation of faecal elastase-1 levels to fat-soluble vitamin status. Fat-soluble vitamins (A, D, E) given in appropriate dosages combined with pancreatic enzymes ensured normal profiles in our patients with CF and malabsorption. Officially recommended supplementation of vitamin A and D in Norway during infancy and childhood may explain why so few patients had vitamin deficiencies at diagnosis.

Adolescent↗

PubMed1992

Determination of soluble fibrin: a comparison of four different methods.

The determination of soluble fibrin (SF) in plasma was compared using four different methods. The SF-ELISA immunologically measures the concentration of desAA- and desAABB-fibrin while the SF-tPA-test is based on activation of plasminogen by tissue plasminogen activator (tPA) in the presence of fibrin; the SF-PS-turbidimetry assay relies on the protamine sulphate (PS) -induced aggregation of fibrin in plasma whereas the SF-erythrocyte-agglutination-test (SF-EAT) detects soluble fibrin by its aggregation with fibrin monomers attached to test erythrocytes. Soluble fibrin was generated in vitro by addition of thrombin or ancrod to plasma. In these experiments the soluble fibrin values of the four methods correlated well with each other and with the fibrinopeptide A release, especially in ancrod-induced fibrinogen turnover (r greater than 0.93). This high correlation is remarkable, considering the fact that the methods are based on different principles. Detection of thrombin-induced soluble fibrin was more sensitive; differences between ancrod and thrombin action were observed as well, probably due to different forms of soluble fibrin. A delayed increase of SF-PS-turbidimetry values in particular during the thrombin action can be attributed to a lack of detectable aggregation of soluble fibrin at low concentrations due to its solubility in plasma. Subsequently, soluble fibrin was measured in samples from patients. The SF-ELISA and SF-tPA-test were highly sensitive and correlated better than the other methods with each other, but all correlations were less satisfactory compared with the in vitro studies. These weaker correlations might be explained by the heterogeneity of soluble fibrin determined by inter- and intraindividually varying concentrations of fibrinogen and its different derivatives in plasma samples from patients. All methods provided reliable results with differences in sensitivity, specificity and practicality. The SF-tPA-test, SF-PS-turbidimetry, and SF-EAT are practical methods for routine use whereas the SF-ELISA is a highly reliable and by far the most sensitive and specific method thus offering new insights into pathogenesis of fibrinaemia and related diseases.

Enzyme-Linked Immunosorbent Assay↗

PubMed2005

Preparation and important functional properties of water-soluble chitosan produced through Maillard reaction.

The objective of this research was to improve the solubility of chitosan at neutral or basic pH using the Maillard-type reaction method. To prepare the water-soluble chitosans, various chitosans and saccharides were used under various operating conditions. Biological and physicochemical properties of the chitosan-saccharide derivatives were investigated as well. Results indicated that the solubility of modified chitosan is significantly greater than that of native chitosan, and the chitosan-maltose derivative remained soluble when the pH approached 10. Among chitosan-saccharide derivatives, the solubility of chitosan-fructose derivative was highest at 17.1 g/l. Considering yield, solubility and pH stability, the chitosan-glucosamine derivative was deemed the optimal water-soluble derivative. Compared with the acid-soluble chitosan, the chitosan-glucosamine derivative exhibited high chelating capacity for Zn(2+), Fe(2+) and Cu(2+) ions. Relatively high antibacterial activity against Escherichia coli and Staphylococcus aureus was noted for the chitosan-glucosamine derivative as compared with native chitosan. Results suggest that the water-soluble chitosan produced using the Maillard reaction may be a promising commercial substitute for acid-soluble chitosan.

Anti-Bacterial Agents↗

PubMed2004

Accuracy of calculated pH-dependent aqueous drug solubility.

The aim of the present study was to investigate the extent to which the Henderson-Hasselbalch (HH) relationship can be used to predict the pH-dependent aqueous solubility of cationic drugs. The pH-dependent solubility for 25 amines, carrying a single positive charge, was determined with a small-scale shake flask method. Each sample was prepared as a suspension in 150 mM phosphate buffer. The pH-dependent solubility curves were obtained using at least 10 different pH values. The intrinsic solubility, the solubility at the pKa and the solubility at pH values reflecting the pH of the bulk and acid microclimate in the human small intestine (pH 7.4 and 6.5, respectively) were determined for all compounds. The experimental study revealed a large diversity in slope, from -0.5 (celiprolol) to -8.6 (hydralazine) in the linear pH-dependent solubility interval, which is in sharp contrast to the slope of -1 assumed by the HH equation. In addition, a large variation in the range of solubility between the completely uncharged and completely charged drug species was observed. The range for disopyramide was only 1.1 log units, whereas that for amiodarone was greater than 6.3 log units, pointing at the compound specific response to counter-ion effects. In conclusion, the investigated cationic drugs displayed compound specific pH-dependent solubility profiles, indicating that that the HH equation in many cases will only give rough estimations of the pH-dependent solubility of drugs in divalent buffer systems.

Hydrogen-Ion Concentration↗

PubMed2001

On the role of oil-soluble initiators in the radical polymerization of micellar systems.

Polymerization in micellar systems is a technique which allows the preparation of ultrafine as well as coarse latex particles. This article presents a review of the current literature in the field of radical polymerization of classical monomers in micellar systems initiated by oil-soluble initiators. Besides a short introduction to some of the kinetic aspects of emulsion polymerization initiated by water-soluble initiators, we mainly focus on the kinetics and the mechanism of radical polymerization in o/w and w/o micellar systems initiated by classical oil-soluble initiators. The initiation of emulsion polymerization of an unsaturated monomer (styrene, butyl acrylate,...) by a water-soluble initiator (ammonium peroxodisulfate) is well understood. It starts in the aqueous phase and the initiating radicals enter the monomer-swollen micelle. The formed oligomeric radicals are surface active and increase the colloidal stability of the disperse system. Besides, the charged initiating radicals might experience the energetic barrier when entering the charged particle surface. The locus of initiation with oil-soluble initiators is more complex. It can partition between the aqueous-phase and the oil-phase. Besides, the surface-active oil-soluble initiator can penetrate into the interfacial layer. The dissolved oil-soluble initiator in the monomer droplet can experience the cage effect. The small fraction of the oil-soluble initiator dissolved in the aqueous phase takes part in the formation of radicals. The oligomeric radicals formed are uncharged and therefore, they do not experience the energetic barrier when entering the polymer particles. We summarize and discuss the experimental data of radical polymerization of monomers initiated by oil-soluble initiators in terms of partitioning an initiator among the different domains of the multiphase system. The inhibitor approach is used to model the formation of radicals and their history during the polymerization. The nature of the interfacial layer and the type of oil-soluble initiator including the surface active ones are related to the kinetic and colloidal parameters. The emulsifier type and reaction conditions in the polymerization are summarized and discussed.

Emulsions↗

PubMed1999

Differential subcellular localization of endogenous and transfected soluble epoxide hydrolase in mammalian cells: evidence for isozyme variants.

Endogenous, constitutive soluble epoxide hydrolase in mice 3T3 cells was localized via immunofluorescence microscopy exclusively in peroxisomes, whereas transiently expressed mouse soluble epoxide hydrolase (from clofibrate-treated liver) accumulated only in the cytosol of 3T3 and HeLa cells. When the C-terminal lie of mouse soluble epoxide hydrolase was mutated to generate a prototypic putative type 1 PTS (-SKI to -SKL), the enzyme targeted to peroxisomes. The possibility that soluble epoxide hydrolase-SKI was sorted slowly to peroxiosmes from the cytosol was examined by stably expressing rat soluble epoxide hydrolase-SKI appended to the green fluorescent protein. Green fluorescent protein soluble epoxide hydrolase-SKI was strictly cytosolic, indicating that -SKI was not a temporally inefficient putative type 1 PTS. Import of soluble epoxide hydrolase-SKI into peroxisomes in plant cells revealed that the context of -SKI on soluble epoxide hydrolase was targeting permissible. These results show that the C-terminal -SKI is a non-functional putative type 1 PTS on soluble epoxide hydrolase and suggest the existence of distinct cytosolic and peroxisomal targeting variants of soluble epoxide hydrolase in mouse and rat.

3T3 Cells↗

PubMed1998

Role of adhesion molecule expression and soluble fractions in hepatic resection.

BACKGROUND: Little has so far been documented about the relationship between liver injury and adhesion molecules. The aim of this study is to clarify the role of adhesion molecules in hepatic resection by studying both the expression of such adhesion molecules and the measurement of their soluble fractions in the blood. STUDY DESIGN: To study adhesion molecule expression in the liver, liver biopsies were obtained before and after hepatectomy in 14 patients. Using frozen sections, immunochemical staining for intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was then performed. To study the soluble fractions of adhesion molecules in the hepatic venous blood, the serum soluble fractions of ICAM-1 and VCAM-1 from another 17 patients were measured using an enzyme-linked immunosorbent assay. The plasma levels of polymorphonuclear leukocyte (PMN) elastase were also measured using an enzyme immunoassay. Both the preoperative and postoperative values of the serum soluble fractions of ICAM-1, VCAM-1, and PMN elastase were then compared. The correlation between their values and the perioperative variables was also investigated. RESULTS: Either ICAM-1 or VCAM-1 was stained on the sinusoidal endothelial cells and Kupffer cells or circulating PMNs in the sinusoid. The positive rate of either ICAM-1 or VCAM-1 staining in livers with more than 40 minutes of total ischemic time (80%) was significantly higher than that in livers with less than 40 minutes of total ischemic time (0%; p < 0.05). The incidence of postoperative complications in the ICAM-1 positive staining group tended to be higher than that in the ICAM-1 negative group. Both soluble fractions of ICAM-1 and VCAM-1 in patients with cirrhotic liver disease were also significantly higher than those in patients with a normal liver. The soluble VCAM-1 level in patients with a chronic active hepatitic liver tended to be higher than that in those with a nonactive hepatitic liver. The preoperative level of soluble ICAM-1 correlated with that ofVCAM- 1, PMN elastase, albumin, aspartate aminotransferease (AST), and the indocyanine green dye retention test at 15 minutes (ICG R15), while the preoperative level of VCAM-1 correlated with albumin, the hepaplastin test, AST, and ICG R15. Both the serum soluble ICAM-1 and VCAM-1 levels after hepatectomy were significantly lower than those before hepatectomy. By contrast, the posthepatectomy level of PMN elastase was significantly higher than its prehepatectomy level. The difference between the postoperative and preoperative values of soluble ICAM-1 correlated with the postoperative AST level, postoperative alanine aminotransferase level, and total ischemic time. CONCLUSIONS: Adhesion molecules were expressed in the liver after hepatic resection, and such expression correlated with a total ischemic time during hepatectomy. In addition, judging from the soluble forms of such molecules, these adhesion molecules play an important role in hepatic resection.

Aged↗

PubMed1998

Engineering the isoelectric point of a renal cell carcinoma targeting antibody greatly enhances scFv solubility.

BACKGROUND: The murine A6H monoclonal antibody targets a cell surface antigen associated with renal cell carcinoma with high specificity and excellent biodistribution properties. Tumor to blood ratios of > 40:1 have been achieved in clinical studies. OBJECTIVES: In order to generate an antibody engineering system that would allow the construction of improved derivatives for diagnostics and therapeutics, a single-chain Fv antibody (scFv) derived from A6H was constructed. The initial single-chain Fv, constructed with a cysteine residue and hexa-histidine sequence at the C-terminus, displayed a limited solubility of 100 microg/ml at pH 7.4. The low solubility and refolding yield of the original single-chain Fv required that a more soluble variant be designed and constructed. STUDY DESIGN: We hypothesized that lowering the pI of the scFv antibody away from the physiological range would yield a more soluble antibody. A derivative was thus subsequently engineered with five glutamic acid residues followed by the cysteine and hexa-histidine residues. The cysteine was included to provide a conjugation site for future radiolabeling studies. RESULTS: The redesigned A6H single-chain Fv has a predicted pI of 6.1, relative to 7.5 for the native scFv. The redesigned A6H scFv displayed a greatly enhanced solubility of > 15 mg/ml at pH 7.4. Both the original scFv and the redesigned single-chain Fv exhibited a strong tendency to form dimers and soluble high molecular weight aggregates. The monomer and disulfide bonded dimer were separated from the aggregates and complete cell binding isotherms were obtained, demonstrating that the purified A6H scFv retains much of the activity of the parent monoclonal. CONCLUSION: The addition of glutamic acid to the C-terminus of poorly soluble scFv antibodies could provide a straightforward avenue for improving their solubility properties. The increased solubility of the A6H scFv allowed the purification of the monomeric and dimeric species from the soluble aggregated species.

Amino Acid Sequence↗

PubMed2001

Solubility of triazine pesticides in pure and modified subcritical water.

Solubility measurements in pure and modified water serve as a basis for optimizing the subcritical water extraction of target analytes such as food contaminants. The solvent strength of the water is affected by both the system's temperature and the amount and type of cosolvent modifier that is added to the water, which causes a reduction in the dielectric constant of water. In the present work, the solubilities of the triazine pesticides atrazine, cyanazine, and simazine were measured in pure and modified water at temperatures ranging from 50 to 125 degrees C and at a pressure of 50 atm. The solubility data were obtained using a static solubility apparatus with on-line liquid chromatographic (LC) detection. By increasing the temperature of the water, the solubilities of the triazine pesticides increased approximately 3-fold in pure water for each 25 degrees C temperature increment. Cyanazine was 5 times more soluble than atrazine and an order of magnitude more soluble than simazine at 100 degrees C. The solubility of atrazine was also measured in ambient and hot water modified with ethanol and urea. At 100 degrees C, the solubility of atrazine is doubled when the water is modified with urea, and is increased over an order of magnitude when ethanol is used as modifier. The data, therefore, indicate that adding a cosolvent to water in addition to increasing the system temperature increases the solubilities of triazine pesticides in subcritical water. It was further determined that the solutes do not thermally degrade or hydrolyze at the temperatures reported in this study.

Atrazine↗

PubMed2000

What is the true solubility advantage for amorphous pharmaceuticals?

PURPOSE: To evaluate the magnitude of the solubility advantage for amorphous pharmaceutical materials when compared to their crystalline counterparts. METHODS: The thermal properties of several drugs in their amorphous and crystalline states were determined using differential scanning calorimetry. From these properties the solubility advantage for the amorphous form was predicted as a function of temperature using a simple thermodynamic analysis. These predictions were compared to the results of experimental measurements of the aqueous solubilities of the amorphous and crystalline forms of the drugs at several temperatures. RESULTS: By treating each amorphous drug as either an equilibrium supercooled liquid or a pseudo-equilibrium glass, the solubility advantage compared to the most stable crystalline form was predicted to be between 10 and 1,600 fold. The measured solubility advantage was usually considerably less than this, and for one compound studied in detail its temperature dependence was also less than predicted. It was calculated that even for partially amorphous materials the apparent solubility enhancement (theoretical or measured) is likely to influence in-vitro and in-vivo dissolution behavior. CONCLUSIONS: Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simple thermodynamic considerations. This appears to be the result of difficulties in determining the solubility of amorphous materials under true equilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage for amorphous pharmaceuticals, which directly reflects the driving force for their initial dissolution.

Chemistry, Pharmaceutical↗

PubMed2003

Circulating soluble cytochrome c in liver disease as a marker of apoptosis.

OBJECTIVES: To measure levels of soluble cytochrome c, a clinical marker of apoptosis in patients with liver disease; determine whether soluble cytochrome c is derived from the liver; and correlate soluble cytochrome c level with histology and disease activity. DESIGN: Laboratory research study with comparison group. SETTING: Liver Institute, at the Rabin Medical Center, Israel, and In Vitro Toxicology Laboratory, Canada. SUBJECTS: A total of 108 patients with liver disease and 30 healthy controls. INTERVENTIONS: Paired hepatic and portal vein samples were taken via the transjugular vein in patients after liver biopsy and transjugular intrahepatic portacaval shunt, and bile from patients with external biliary drainage. Soluble cytochrome c was measured with an enzyme-linked immunosorbent assay in peripheral blood. Apoptotic cells in liver tissue were identified by morphological criteria and quantitated with the dUTP nick-end-labelling (TUNEL) assay. MAIN OUTCOME MEASURES: Soluble cytochrome c level by type of liver disease by clinical and histological findings. RESULTS: Soluble cytochrome c concentration (mean 187.1 +/- 219.5 ng x mL(-1)) was significantly higher in patients with liver disease than in controls (39.8 +/- 35.1 ng x mL(-1); P = 0.0001), with highest levels in the primary sclerosing cholangitis group (mean 1041.0 +/- 2844.8 ng x mL(-1); P = 0.001). Cytochrome c levels were correlated with serum bilirubin, alkaline phosphatase, creatinine levels, necroinflammatory score and apoptotic index, but not with serum alanine aminotransferase and synthetic liver function tests. In the 16 paired samples, soluble cytochrome c level was higher in the hepatic (mean 267.9 +/- 297.0 ng x mL(-1)) than the portal vein (mean 169.2 +/- 143.3 ng x mL(-1)), and it was highly detectable in bile (mean 2288.0 +/-4596.0 ng x mL(-1)) (P = 0.001). Untreated patients with chronic viral hepatitis (B and C) had significantly higher levels (mean 282.8 +/-304.3 ng x mL(-1)) than treated patients (77.9 +/- 35.8 ng x mL(-1); P = 0.001). CONCLUSIONS: Soluble cytochrome c levels are increased in different types of liver disease. Soluble cytochrome c is probably derived from the liver and secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble cytochrome c may serve as a serum marker of apoptosis.

Adult↗

PubMedDate not supplied

Mechanistic study of solubility enhancement of nifedipine using vitamin E TPGS or solutol HS-15.

The objective of our study was to find mechanisms responsible for solubility enhancement of nifedipine in solid dispersions of vitamin E TPGS and/or solutol HS-15. Solid dispersions of nifedipine with selected polymers such as vitamin E TPGS, solutol HS-15, PEG(1,000), and lipocol C-10 of varying drug/polymer ratios were prepared by a fusion method. The solubility enhancement was found to be in the order of vitamin E TPGS > solutol HS-15 > lipocol C-10 > PEG(1,000). Lipocol C-10, with a similar hydrophilic-lipophilic value as vitamin E TPGS, showed a comparable retained solubility enhancement during saturation solubility studies but had lower dissolution profile. Overall, vitamin E TPGS showed the best solubility and dissolution performance, while solutol HS-15 and lipocol C-10 demonstrated moderate solubility enhancements. Solid dispersions of vitamin E TPGS as prepared by microfluidization technique initially showed slightly higher solubility compared with samples prepared by fusion method, but eventually it became the same as the study progressed. However, solid dispersion of solutol HS-15 as prepared by microfluidization demonstrated a significant, sustained increased in solubility over its sample when prepared by fusion method. Based on these results, we concluded that enhanced solubility using vitamin E TPGS and solutol HS-15 resulted from a partial conversion of crystalline drug to the amorphous form, increase in wettability of the drug by water soluble polymers, better separation of drug particles, micellar solubilization of drug by high concentrations of surfactant polymers, and interaction between polymer and drug at the molecular level.

Calcium Channel Blockers↗

PubMed1999

The effects of pH and mixed solvent systems on the solubility of oxytetracycline.

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.

Anti-Bacterial Agents↗