Spring and parachute approach for piroxicam dissolution; its phenomenological model on the thermodynamics of irreversible processes.

Even though the spring and parachute approach for poorly water-soluble drug candidates effectively improves their dissolution curves with eutectic mixtures, deep eutectic solvents, solid dispersion polymers, and solid solutions, we cannot consider that its enabling factor in these pharmaceutical modifications was enough to be clarified. Based on our previous study that oxybuprocaine acts as a role of parachute generator for piroxicam, the present study explored a small-molecule parachute generator and found that propranolol, a ß-adrenergic-blocking drug, has a parachute effect on the supersaturated state of piroxicam. In addition, changing the concentration of tetracaine and dibucaine to 10 mM and 2.5 mM also showed a parachute effect. These parachute generators control piroxicam's dissolved state kinetically by making the supersaturated state of piroxicam a steady state. However, as the piroxicam anhydrous crystals diminished and the piroxicam monohydrate crystals grew due to Ostwald ripening, it led to attenuating the supersaturated state. This finding advances the elucidation of the mechanism of the parachute effect of polymers.

Chemotherapy combined with immune checkpoint inhibitors may overcome the detrimental effect of high neutrophil-to-lymphocyte ratio prior to treatment in esophageal cancer patients.

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for esophageal cancer (EC). Although ICIs enable long-term survival in some patients, the efficacy of ICIs varies widely among patients. Therefore, predictive biomarkers are necessary for identifying patients who are most likely to benefit from ICIs to improve the efficacy of the treatment. We retrospectively analyzed the outcomes of combination therapy, including nivolumab plus ipilimumab or chemotherapy plus anti-programmed cell death 1 (PD-1) antibodies in our institute to identify biomarkers. Methods: Twenty-seven patients received nivolumab plus ipilimumab, and thirty-six patients received chemotherapy plus anti-PD-1 antibodies were included in this study. We analyzed patient characteristics, efficacy, and safety. Multivariable analysis of biomarkers evaluated the correlation among overall survival (OS), progression-free survival (PFS), and the following variables: body mass index, performance status, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein level, and albumin level before treatment. Results: In multivariable analysis, albumin level was significantly correlated with PFS in the cisplatin plus 5-fluorouracil (CF) plus pembrolizumab group. NLR and albumin level were significantly correlated with OS in the nivolumab plus ipilimumab group. Other variables, including PS, BMI, and CRP did not correlate with any of the outcomes. Conclusions: High NLR in EC patients prior to treatment was significantly less effective for ICIs. In chemotherapy combined with ICIs, NLR before the treatment was not associated with treatment efficacy, suggesting combination chemotherapy may be beneficial for EC patients with high NLR. NLR may be an indicator of immunocompetence in anti-tumor immunity and a convenient predictive biomarker for selecting appropriate treatments including ICIs.

How Does the Powder Mixture of Ibuprofen and Caffeine Attenuate the Solubility of Ibuprofen? Comparative Study for the Xanthine Derivatives to Recognize Their Intermolecular Interactions Using Fourier-Transform Infrared (FTIR) Spectra, Differential Scanning Calorimetry (DSC), and X-ray Powder Diffractometry (XRPD).

Molecular interactions between active pharmaceutical ingredients (APIs) and xanthine (XAT) derivatives were analyzed using singular value decomposition (SVD). XAT derivatives were mixed with equimolar amounts of ibuprofen (IBP) and diclofenac (DCF), and their dissolution behaviors were measured using high-performance liquid chromatography. The solubility of IBP decreased in mixtures with caffeine (CFN) and theophylline (TPH), whereas that of DCF increased in mixtures with CFN and TPH. No significant differences were observed between the mixtures of theobromine (TBR) or XAT with IBP and DCF. Mixtures with various molar ratios were analyzed using differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy to further explore these interactions. The results were subjected to SVD. This analysis provides valuable insights into the differences in interaction strength and predicted interaction sites between XAT derivatives and APIs based on the combinations that form mixtures. The results also showed the impact of the XAT derivatives on the dissolution behavior of IBP and DCF. Although IBP and DCF were found to form intermolecular interactions with CFN and TPH, these effects resulted in a reduction of the solubility of IBP and an increase in the solubility of DCF. The current approach has the potential to predict various interactions that may occur in different combinations, thereby contributing to a better understanding of the impact of health supplements on pharmaceuticals.

Long-Term Outcomes of Carbon Dioxide Insufflation in Thoracoscopic Esophagectomy After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Thoracoscopic esophagectomy (TE) with carbon dioxide (CO2) insufflation is increasingly performed for esophageal cancer; however, there is limited evidence of the long-term outcomes of CO2 insufflation on postoperative survival. OBJECTIVES: We investigated the long-term outcomes of TE with or without CO2 insufflation. METHODS: We enrolled 182 patients who underwent TE for esophageal cancer between January 2003 and October 2013 and categorized them into two groups: with and without CO2 insufflation. The primary endpoint was five-year overall survival (5y-OS). Secondary endpoints included long-term outcomes, such as five-year relapse-free survival (5y-RFS) and five-year cancer-specific survival (5y-CSS), and short-term outcomes, such as surgical and non-surgical complications and reoperation within 30 days. RESULTS: Follow-up until death or the five-year postoperative period was 98.9% (median follow-up duration was six years in survivors). After adjusting for age, sex, and yield pathologic tumor, node, and metastasis (TNM) stage, we found no significant differences in 5y-OS (HR 1.12, 95% CI 0.66-1.91), 5y-RFS (HR 1.12, 95% CI 0.67-1.83), or 5y-CSS rates (HR 1.00, 95% CI 0.57-1.75). For short-term outcomes, significant intergroup differences in operation time (p=0.02), blood loss (p<0.001), postoperative length of stay (p<0.001), and incidence of atelectasis (p=0.004) were observed. The results of the sensitivity analysis were similar to the main results. CONCLUSIONS: In thoracoscopic procedures, CO2 insufflation significantly improved short-term outcomes, and it appears that the recurrence risk of esophageal cancer may not impact the long-term prognosis. While the influence of CO2 insufflation in thoracoscopic esophageal surgery remains unclear, our study suggests that the long-term prognosis is not compromised in other thoracic surgeries.

Maximum Efficacy of Immune Checkpoint Inhibitors Occurs in Esophageal Cancer Patients With a Low Neutrophil-to-Lymphocyte Ratio and Good Performance Status Prior to Treatment.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, few patients achieve long-term survival, and some patients develop serious immune-related adverse events (irAEs). Reliable predictive biomarkers of efficacy and safety need to be established in order to improve efficacy. We retrospectively analyzed the outcomes of nivolumab monotherapy on EC at Showa University, Department of Medicine, to identify biomarkers and characteristics of patients who benefit from ICI monotherapy. PATIENTS AND METHODS: Eighty-six patients with EC who received nivolumab monotherapy were included in the present study. Patient characteristics, efficacy, and safety were analyzed. A multivariable analysis evaluated the correlation among overall survival (OS), progression-free survival (PFS), best overall response (BOR), irAEs, and the following variables: sex, age, performance status (PS), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP) level, albumin level, and body-mass index before treatment. RESULTS: Median PFS was 3.1 months, and median OS was 9.0 months. In multivariable analysis, pretreatment PS, NLR, and sex were significantly correlated with OS and PFS. NLR <3.3 predicted longer survival (median OS 17.5 vs. 6.4 months for NLR ≥3.3; p<0.001). Median OS was 10.6 months for PS 0-1 and 1.3 months for PS 2-3 (p<0.001). NLR remained significantly predictive in the PS 0-1 group. The development of irAEs was significantly associated with increased OS and PFS. CONCLUSION: Patients with low NLR and good PS before treatment may maximize the benefits of ICIs. A low NLR may be an indicator of higher immunocompetence for anti-tumor immunity, suggesting that NLR may be a convenient predictive biomarker in daily practice.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer.

The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.

Using singular value decomposition to analyze drug/ß-cyclodextrin mixtures: insights from X-ray powder diffraction patterns.

The article discusses the use of mathematical models and linear algebra to understand the crystalline structures and interconversion pathways of drug complexes with ß-cyclodextrin (ß-CD). It involved the preparation and analysis of mixtures of indomethacin, diclofenac, famotidine, and cimetidine with ß-CD using techniques such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and proton nuclear magnetic resonance (1H-NMR). Singular value decomposition (SVD) analysis is used to identify the presence of different polymorphs in the mixtures of these drugs and ß-CD, determine interconversion pathways, and distinguish between different forms. In general, linear algebra or artificial intelligence (AI) is used to approximate the contribution of distinguishable entities to various phenomena. We expected linear algebra to completely reveal all eight entities present in the diffractogram dataset. However, after performing the SVD procedure, we found that only six independent basis functions were extracted, and the entities of the INM α-form and the CIM B-form were not included. It is considered that this is due to that data processing is limited to revealing only six or seven independent factors, as it is a small world. The authors caution that these may not always reproduce or approach reality in complicated real-world situations.

Effect of Cyclodextrin Complex Formation on Solubility Changes of Each Drug Due to Intermolecular Interactions between Acidic NSAIDs and Basic H2 Blockers.

One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of ß-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for ß-CD. Furthermore, the addition of high concentrations of ß-CD to the DIC-FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that ß-CD synergistically improves the solubility of drugs in drug-drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug-drug interactions, such as FAM-DIC. This indicates that ß-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.

Propionic Acid Groups and Multiple Aromatic Rings Induce Binding of Ketoprofen and Naproxen to the Hydrophobic Core of Bovine Serum Albumin.

Ketoprofen (KP), which causes photosensitivity by interacting with serum albumin (SA), and three drugs, ibuprofen (IBP), naproxen (NPX), and diazepam (DZP), which share the same binding site, were investigated for their interaction with bovine SA (BSA). For KP, DZP, and IBP, where drug-concentration-dependent quenching of BSA-intrinsic fluorescence was observed, a modified Stern-Volmer plot showed that dynamic quenching was dominant for KP and static quenching was dominant for DZP and IBP. However, this alone cannot be compared with NPX. Therefore, by performing singular value decomposition (SVD) fluorescence spectroscopy, we were able to find the behavior of the drug-concentration-dependent Langmuir-type principal component vectors. KSVD obtained by the Langmuir equation showed a high correlation with the static extinction constant V. Therefore, KSVD indicates the association constant of the drug with BSA and it was found that NPX and IBP had higher values than KP. Finally, in the analysis of the temperature factors of amino acid residues in each drug-binding region and Trp residues, KP and NPX significantly reduced these temperature factors whereas DZP and IBP hardly changed them. This result is consistent with the dynamic and static quenching dominance in the total quenching mechanism. Summarizing the results so far, it was shown that penetration into the hydrophobic core inside BSA can be achieved not only by one of the multiple aromatic rings and propionic acid groups but also by the joint effect of both. In this study, SVD enabled us to extract information on drug adsorption to BSA from fluorescence spectra. Furthermore, the application of SVD is expected to make it possible to perform fluorescence analysis for drug binding to proteins without being limited by the fluorescence properties of the drug.

Thoracoscopic esophageal drainage for tracheal compression due to mucocele after esophagogastric bypass: a case report.

BACKGROUND: Esophagogastric bypass is performed for esophageal strictures. Mucus retention, known as mucocele, sometimes occurs at the stricture oral side of the remnant esophagus. It is often asymptomatic and is expected to be naturally decompressed, but it may cause respiratory failure depending on the case. Herein, we report a case in which we successfully performed thoracoscopic esophageal drainage as emergency airway management due to tracheal compression by a mucocele after esophagogastric bypass for unresectable esophageal cancer with esophagobronchial fistula. CASE PRESENTATION: A 56-year-old man underwent esophageal bypass surgery for an unresectable esophageal carcinoma with an esophagobronchial fistula following chemotherapy and radiation therapy. Nine months after bypass surgery, he experienced severe dyspnea due to tracheal compression caused by mucus retention on the oral side of the esophageal tumor. We planned thoracoscopic surgery for mucus retention drainage through the right thoracic cavity to secure the airway as an emergency procedure under general anesthesia. Intubation can be performed safely by guiding bronchoscopy in the semi-supine position. Upper esophageal dilation was observed on the cranial side of the azygos arch. We dissected the mediastinal pleura of the upper thoracic esophagus and exposed its wall. A 12-Fr silicone drain was placed in the esophagus through the right chest wall and 120 ml of white fluid was aspirated. He was discharged 9 days after surgery without complications and resumed treatment with an immune checkpoint inhibitor 23 days after surgery. Thereafter, he continued chemotherapy for esophageal cancer, but died of tumor progression and lung metastasis 35 months after bypass surgery and 25 months after thoracoscopic surgery. CONCLUSIONS: Thoracoscopic esophageal drainage could be performed safely as emergency airway management, shorten the period of discontinuance, and allow cancer treatment to be resumed promptly. We believe that this thoracoscopic procedure is an effective and less invasive method if the percutaneous approach is difficult.

Effects of Local Anesthetics on Liposomal Membranes Determined by Their Inhibitory Activity of Lipid Peroxidation.

In this study, we investigated the effects of drugs on membrane function in which lipid peroxidation was inhibited by the antioxidant Trolox (TRO) in liposomes containing egg yolk lecithin. Local anesthetics (LAs), such as lidocaine (LID) and dibucaine (DIB), were used as model drugs. The effect of LAs on the inhibitory activity of TRO was evaluated by calculating the pI50 from the inhibition constant K calculated by curve fitting. pI50TRO indicates the strength of TRO membrane protective function. pI50LA indicates the strength of LA activity. LAs inhibited lipid peroxidation in a dose-dependent manner and decreased pI50TRO. The effect of DIB on pI50TRO was 1.9 times more than that of LID. This result indicated that LA may improve the fluidity of the membrane, which may facilitate the migration of TRO from the membrane to the liquid phase. As a result, TRO is less likely to suppress lipid peroxidation within the lipid membrane, possibly resulting in a decrease in pI50TRO. The effect of TRO on pI50LA was found to be similar in both, indicating that it did not depend on the type of the model drug. These results suggest that our developed procedure successfully quantified the effects of LAs on lipid membrane functions. We were able to obtain the characteristics of model drugs independent of TRO by simultaneously measuring and analyzing the lipid peroxidation inhibitory activities of TRO and model drugs in liposomes.

Optimization of the stability constants of the ternary system of diclofenac/famotidine/ß-cyclodextrin by nonlinear least-squares method using theoretical equations.

This study aimed to establish a new method for determining the stability constants of drug/ß-cyclodextrin (ß-CD) complexes when multiple drugs interacting with each other coexist in the solution of complexation. The basic drug famotidine (FAM) and the acidic drug diclofenac (DIC) were used as model drugs, their solubility decreasing owing to their mutual interaction. The dissolution of both FAM and DIC was characterized by AL-type phase solubility diagrams in the presence of the other's 1:1 complex with ß-CD. When the stability constant was calculated from the slope of the phase solubility diagram using the conventional phase solubility diagram method, it was modified in the presence of the other drug. However, by performing optimization calculations that considered the interactions between the drug/ß-CD complex and the drug, drug/ß-CD complexes, and drugs, we were able to accurately calculate the stability constant of DIC/ß-CD and FAM/ß-CD complexes even in the presence of FAM and DIC, respectively. The results of the solubility profile indicated that various molecular species, which are attributed to drug-drug and drug/ß-CD interactions, interfere with the values of the dissolution rate constants and saturated concentration in the solubility profiles.

Interaction mode of hydroxypropyl-ß-cyclodextrin with vaccine adjuvant components Tween 80 and Triton X-100 revealed by fluorescence increasing-quenching analysis.

The nonionic surfactants Tween 80 (Tw80) and Triton X-100 (TX100), which are used as components of adjuvants, were used with bovine serum albumin (BSA) and hydroxfypropyl-ß-cyclodextrin (HP-ß-CD) as model antigens. The interaction patterns of Tw80 and TX100 with the hydrophobic cores of the model antigens were investigated. The fluorescence of 8-anilinonaphthalene-1-sulfonic acid (ANS), a hydrophobic fluorescent probe, was used to evaluate the effect of surfactants on each model antigen. A Hanes Woolf plot was used to analyze the adsorption of ANS to BSA, and an activator-inhibitor model was used to analyze the concentration-dependent increase and decrease of ANS fluorescence intensity. For BSA, TX100 occupies the ANS binding site inside the BSA hydrophobic core, while Tw80 does not contribute to the ANS binding site in the hydrophobic core. For HP-ß-CD, the ANS concentration required for analyzable fluorescence intensity extended to the range where ANS concentration-dependent quenching was not negligible. Using the activator inhibitor model, we were able to separate the activators and inhibitors of ANS fluorescence and evaluate the affinity of ANS for HP-ß-CD and surfactants. The results obtained showed that TX100 provided a hydrophobic environment to the ANS while being encapsulated by HP-ß-CD, while Tw80 did not interact with HP-ß-CD and provided a hydrophobic environment to the ANS independently of each other. The interpretations obtained were corroborated by the determination of the CMC of TX100 and Tw80, the effect of salt on ANS fluorescence, and 1H-NMR and ROESY. In summary, the results showed that the large hydrophilic head of Tween, composed of sorbitan and PEG chains, floated in the aqueous phase like a balloon, while Triton pierced the hydrophobic core of the antigen like a spear. In both BSA and HP-ß-CD model antigens, TX100 impinged on the hydrophobic core.

Clinical Treatment of Perioperative Disseminated Intravascular Coagulation in Patients Who Underwent Gastrointestinal and Hepato-Biliary-Pancreatic Surgery.

BACKGROUND: It is unclear how effective recombinant thrombomodulin (rTM) treatment is in disseminated intravascular coagulation (DIC) during the perioperative period of gastrointestinal and hepato-biliary-pancreatic surgery. The current study aimed to evaluate the therapeutic outcomes of rTM for perioperative DIC. METHODS: We enrolled 100 consecutive patients diagnosed with perioperative DIC after gastrointestinal surgery, and hepato-biliary-pancreatic including emergency procedures, between January 2012 and May 2021. Patients received routine rTM treatment immediately after DIC diagnosis. Then, the DIC, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated and used for evaluation. The outcomes of rTM treatment and the predictors of survival were evaluated. RESULTS: The causative diseases of DIC were as follows: perforated peritonitis, n = 38; intestinal ischemia, n = 23; intra-abdominal abscess, n = 13; anastomotic leakage, n = 7; pneumonia, n = 7; cholangitis, n = 4; and others, n = 6. The 30-day mortality rate was 18.0%. There were significant differences in the platelet count (13.78 vs 10.41, P = .032) and the SOFA score (5.22 vs 9.89, P<.0001) at the start of DIC treatment between the survivor and non-survivor groups (day 0). The survivor group had a significantly lower DIC score (3.13 vs 4.93, P = .0006) and SOFA score (4.94 vs 12.14, P < .0001) and a higher platelet count (13.50 vs 4.34, P < .0001) than the non-survivor group on day 3. CONCLUSIONS: Comprehensive and systemic treatment is fundamentally essential for DIC, in which rTM may play an important role in the treatment of perioperative DIC.

Saturated adsorption of lidocaine and coal tar dyes onto porous polytetrafluoroethylene.

Polytetrafluoroethylene (PTFE) has excellent physical properties and has been used in a wide range of applications in various fields. Adsorption research on PTFE is essential as primary research for the further application of PTFE. We attempted to adsorb coal tar dyes and model drugs such as lidocaine onto PTFE as a guideline to search for medicines that adsorb onto PTFE. Saturation curves were obtained after analyzing the adsorption of coal tar dyes on PTFE using the Hanes-Woolf plot. In addition, we collected multiple cases of ATR-FTIR spectral changes and/or retention depending on TPM derivatives and other adsorbates. Lidocaine matched some coal tar dye for the apparent spectral changes between the adsorbed molecules and its crystalline powder. The apparent spectral changes are blue-shifted, suggesting a hydrophobic interaction between the dyes/lidocaine and porous PTFE. This work provides a promising strategy for further application of PTFE.

Enthalpy-Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem.

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Increased selectivity of sodium deoxycholate to around Tryptophan213 in bovine serum albumin upon micellization as revealed by singular value decomposition for excitation emission matrix.

In the present study, we investigated the effect of bile salts (sodium deoxycholate, NaDC) on the conformation of a globular protein (bovine serum albumin, BSA). The two Tryptophan (Trp) residues of BSA and the fluorescence energy of NaDC are in a three-way relationship, and singular value decomposition (SVD) was used to separate each element in the fluorescence spectra. SVD was used to separate the elements in the fluorescence spectra. SVD showed that NaDC had a particularly large effect on the microenvironment around Trp213 and that micellar NaDC enhanced the selectivity for Trp213. In addition, the Stern-Volmer plots of the warfarin (WAR) specific domain (domain I) and ketoprofen (KP) specific domain (domain II) in the presence and absence of NaDC showed that the effect of NaDC was selective for domain II, where Trp213 is located. These results indicate that NaDC induces a localized and selective conformational change in BSA, and that the selectivity varies depending on the aggregation state of NaDC.

Increased Transumbilical Incision Complication Rates With Laparoscopic Colorectal Resection: A Single-center Propensity Score-matched Cohort Study.

AIM: To evaluate the complication rates and risk factors associated with transumbilical incision (TUI) and comprehensively examine differences according to the procedures using propensity score matching. PATIENTS AND METHODS: The study involved 737 patients who underwent laparoscopic procedures between 2009 and 2017 (Japanese University-Hospital-Medical-Information-Network Clinical Trials Resistry No. 000040653). The occurrences of superficial surgical site infection (SSI) and TUI hernia were analyzed. RESULTS: SSI occurred in 17 patients (2.31%) and hernia occurred in 29 (3.93%). Multivariate analysis revealed that female sex and diabetes mellitus were correlated with incisional hernia. Propensity score-matching analysis was performed to compare those who underwent colorectal resection with those who underwent other resections; the results showed that the former had a significantly higher rate of TUI hernia (p<0.001), as well as a significantly higher incidence of SSI (p=0.004). CONCLUSION: A significant higher incidence of SSI and TUI hernia in laparoscopic colorectal resection was found. The construction of the TUI was feasible with rationality.

Comparative study of the hydrophobic interaction effect of pH and ionic strength on aggregation/emulsification of Congo red and amyloid fibrillation of insulin.

Amyloid fibrillation is provoked by the conformational rearrangement of its source. In our previous study, we claimed that the conformational rearrangement of hen egg white lysozyme requires intermolecular aggregation/packing induced. Our proposed causality of the aggregation and amyloid formation was demonstrated by the quantitative dependence of amyloid fibrillation on pH difference from its isoelectric point (pI) and on the square root of ionic strength in order to reduce the intermolecular repulsion due to the shielding effect of electrolytes (DLVO effect). When Congo red has dianionic form at the pH higher than its pKa, it forms ribbon-like micelle colloids under lower ionic strength, while it loses electrostatic repulsion and aggregates to be emulsified in the octanolic phase under the higher ionic strength. These behaviors of Congo red were resembling to molecular assembly of surfactants. In contrast, the amyloid formation of insulin was proportional to the square root of ionic strength at the pH lower than its isoelectric point. Therefore, the trigger for conformational rearrangement of amyloid fibrillation is predominantly gripped by hydrophobic hydration and an electrostatic shielding effect. We concluded that the both behaviors of Congo red and insulin were derived from a driving force related to the hydrophobic hydration.