Constructing of predictive model for the surgical effect of patients with cleft lip and palate.

OBJECTIVE: To explore effective factors of surgical effect for patients with cleft lip and palate, and to construct the predictive model of surgical effect, which provide reference for improving the effect of cleft lip and palate surgery. METHODS: This study has been ethically reviewed and approved by the Medical Ethics Committee of Guiyang Stomatological Hospital before the study began.A total of 997 cases of cleft lip and palate surgical treatment in Guiyang Stomatological Hospital from 2015 to 2020 were collected. Logistic regression analysis was used to analyze the factors influencing the surgical outcome, and a score system was established by assigning values to the influencing factors using the nomogram. Data of 110 patients were verified, and decision curve analysis was used to evaluate the predicted results. RESULTS: Logistic regression analysis showed that the number of surgeries, surgical methods, breast milk, prenatal examination, nutrition during pregnancy and labor intensity during pregnancy were independent risk factors for poor surgical results (all P<0.05). The predictive model was built by including the number of surgeries, surgical methods, breast milk, prenatal examination, nutrition and labor intensity during pregnancy into the predictive scoring system. The critical value was 273, the area under ROC curve (AUC) was 0.733(95%CI:0.704~0.76), the sensitivity was 89.57%, and the specificity was 48.14%.When the external validation data of 110 patients were brought into the score, the AUC of poor diagnostic value reached 74.5%, P<0.05, which was close to the modeling accuracy of 73.3%. CONCLUSION: This study constructed a predictive model of surgical effect for patients with cleft lip and palate, which can be used for the clinical prediction of cleft lip and palate patients in Guizhou Province.

Correlation between the systemic clearance of drugs and their food effects in humans.

CONTEXT: Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC(0-∞)) of a drug when compared with fasted state drug administration and no effect when coadministration of food causes no change in AUC(0-∞). In general, low solubility drugs exhibit positive food effects due to improved solubility in fed state administration. But, certain high-solubility and high-permeability drugs that undergo extensive presystemic metabolism exhibit positive food effects because of the increased splanchnic hepatic blood flow in the fed state presumably causing a fraction of drug to bypass first-pass metabolism during absorption. OBJECTIVE: In this study, systemic clearance (Cl) of structurally diverse high-permeability and high-solubility drugs was correlated to their food effects to explore whether drugs undergoing low clearance exhibited no food effects and drugs undergoing high clearance exhibited positive food effects. METHODS: Six drugs exhibiting positive food effects and nine drugs exhibiting no food effects (for comparison) were selected for linear regression analysis. RESULTS: Regression analysis of the selected drugs indicated that percent food effects correlated linearly to Cl and fitted the equation: percent food effects = 0.9163 × Cl - 6.4789. The R(2), p-value and power of the regression model were >0.88, 0.9999, respectively indicating the direct correlation between Cl and food effects of the selected model drugs; other statistical tests validated the model. CONCLUSION: The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects.

Satellite-based survey of extreme methane emissions in the Permian basin.

Industrial emissions play a major role in the global methane budget. The Permian basin is thought to be responsible for almost half of the methane emissions from all U.S. oil- and gas-producing regions, but little is known about individual contributors, a prerequisite for mitigation. We use a new class of satellite measurements acquired during several days in 2019 and 2020 to perform the first regional-scale and high-resolution survey of methane sources in the Permian. We find an unexpectedly large number of extreme point sources (37 plumes with emission rates >500 kg hour-1), which account for a range between 31 and 53% of the estimated emissions in the sampled area. Our analysis reveals that new facilities are major emitters in the area, often due to inefficient flaring operations (20% of detections). These results put current practices into question and are relevant to guide emission reduction efforts.

Dehydration behavior and structural characterization of the GW275919X monohydrate.

GW275919X, a central muscle relaxant for the treatment of lower back pain, exists in a monohydrate. Knowledge of the solid state dehydration behavior and the crystal structure is essential for determining its relative physical stability. Thermal analysis and hot-stage powder X-ray diffraction were used to study the solid state phase transformation during the dehydration process. Crystal structure was determined by single crystal X-ray analysis. Molecular modeling with Cerius(2) software was used to visualize the hydrate crystal structure and to construct the molecular packing and hydrogen bond diagram. Morphology prediction was performed using the BFDH calculation. Crystallographic data: monoclinic, space group, P21/c, a (Angstrom)=14.3734, b (Angstrom)=5.0336, c (Angstrom)=15.4633 and beta=105.11 degrees. Water molecules in the hydrate crystal of GW275919X are involved in the hydrogen bonds and these hydrogen bonds contribute to the coherence of the crystal structure. The longest dimension of the predicted morphology is in the b-direction, which would correspond to the needle axis of the experimental crystals.

Solid state characterization of an neuromuscular blocking agent--GW280430A.

GW280430A is an ultrashort-acting neuromuscular blocking agent and is targeted for muscle relaxation as part of the intubation surgical procedure. The objective of this work was to perform solid state characterization on GW280430A and to evaluate the relationship between water content and glass transition temperature (Tg). GW280430A was characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction (PXRD), microscopy and moisture sorption. The effect of water content on the Tg of GW280430A was evaluated by equilibrating the material over saturated salt solutions at a range of relative humidities (6.4-72.6%) and determining the Tg by DSC using hermetically sealed aluminum pans. GW280430A undergoes dehydration at 40 degrees C, glass transition at 130 degrees C and decomposition at 190 degrees C by differential scanning calorimetry. By PXRD and moisture sorption, GW280430A is an amorphous material and deliquesces at about 70% RH at room temperature. Water acts as a potent plasticizer for GW280430A and the Tg decreases significantly as the water content increases. No measurable decomposition of GW280430A was observed after 4 weeks at 40 degrees C/75% RH.

Crystal structure and thermal behavior of nedocromil nickel octahydrate.

The hydration behavior of a salt depends on the nature of the cation and the anion and on the molecular packing. A transition metal salt (nickel) of nedocromil was prepared and its crystal structure was elucidated in an attempt to study the influence of the nature of the bivalent cation on the structure, water interactions and molecular packing. Crystal data: nedocromil nickel octahydrate (NNi), orthorhombic, Pca2(1), a=29.5446(1) A, b=25.0444(1) A, c=13.3767(2) A, Z=16. The Ni2+, has octahedral coordination, but the coordination environments of the cations and the bonding environments of the water molecules differ. NNi contains four Ni2+ ions in the asymmetric unit, two of which are each octahedrally coordinated to five water molecules and to a carboxyl oxygen. The two remaining Ni2+ ions are linked in a Ni2(H2O)10(+4) species. Thermal analytical data for NNi show that the water molecules in this hydrate are lost in a single step dehydration, which may be attributed to the fairly continuous water layer in the ac plane of the crystal lattice.

Effect of position isomerism on the formation and physicochemical properties of pharmaceutical co-crystals.

The effect of position isomerism on the co-crystals formation and physicochemical properties was evaluated. Piracetam was used as the model compound. Six position isomers, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acid (DHBA), were used as the co-crystal formers. Co-crystals were prepared on a 1:1 molar ratio by crystallization from acetonitrile. The solid-state properties of co-crystals were characterized using X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR). All co-crystal formers formed co-crystal with piracetam except 2,6-DHBA. This failure was possibly due to steric hindrance of two bulk hydroxyl groups and preference of intra-molecular hydrogen bonding formation between hydroxyl group and carboxylic acid group. The XRD patterns of resulting co-crystal indicated that they are highly crystalline and different than parental compounds. Based on the single crystal data, P_23DHBA is orthorhombic while P_24DHBA, P_34DHBA, and P_35DHB belong to monoclinlic system. The hydrogen bonding network patterns of the co-crystals are also different. DSC data showed that the melting temperatures of resulting co-crystals are all lower than that of the starting materials. The melting point rank order of the co-crystals is: P_24DHBA > P_34DHBA > P_23DHBA > P_25DHBA > P_35DHBA.

Solubilization and solid-state characterization of a poorly soluble 5-alpha reductase inhibitor.

GI197111X is a 5-alpha reductase inhibitor for the treatment of androgenetic alopecia. Equilibrium solubilities of GI197111X were determined in multiple solvents or cosolvents. A polymorph screen was conducted using suspension equilibration and solution recrystallization methods. Single crystals were grown from pyridine/water and crystal structure was determined using a Bruker SMART diffractometer. Crystal structure data were imported into Cerius2 to provide visualization of the crystal structure and calculation of the simulated X-ray powder diffraction (XRPD) pattern. The solubility of GI19711IX was low at 25 degrees C in all vehicles suitable for animal and human dosing. The solubility of 6.4 mg/mL in Capmul MCM made it the only choice for a soft gel dosage form for phase I/II. Solution recrystallization and suspension equilibration of GI197111X have produced only one crystal form. Crystal structure data: orthorhombic P2(1) 2(1) 2(1); a= 10.8960(6) A, b=11.5683(6) A, c=20.9019(11) A; unit cell volume 2634.65(24) A3; Z=4; calculated density= 1.248 g/cc. The molecule has seven chiral centers, and single-crystal analysis eliminated all possible stereo-isomers except the expected conformation or its enantiomer. Hydrogen bonds occur from both carbonyl oxygens to an H-N group. Simulated vacuum-based crystal morphology (habit) calculated using the Bravais-Friedel-Donnay-Harker, Growth Morphology, and Hartman-Perdok modules in Cerius2 was a close match to the morphology observed by light microscopy.

Preformulation studies for an ultrashort-acting neuromuscular blocking agent GW280430A. I. Buffer and cosolvent effects on the solution stability.

GW280430A is an ultrashort-acting neuromuscular blocking agent targeted at muscle relaxation to facilitate surgical intubation. The objective of this work was to study the buffer and cosolvent effects on the solution stability of GW280430A. The buffer catalytic effect was examined in citrate, malate, tartrate, and glycine by measuring the rate of degradation of GW280430A (0.2 mg/mL) at constant pH (3), ionic strength (0.15 M), and various buffer concentrations (0.01-0.05 M). The temperature dependence of the buffer catalytic effect and the degradation of the GW280430A in cosolvent (ethanol, propylene glycol, polyethylene glycol 400, N,N-dimethylacetamide)/water mixtures were studied at 40, 50, and 60 degrees C. The loss of parent drug was monitored by reverse-phase high-performance liquid chromatography. The degradation of GW280430A followed first-order kinetics in all buffer solutions. Significant buffer-catalyzed hydrolysis of GW280430A was observed with citrate, tartrate, and malate buffers, but not in glycine-buffered solutions. The activation energies in all buffered drug solutions ranged from 70 to 80 kJ/mol and decreased with increasing buffer concentration. GW280430A degradation was primarily through ester hydrolysis and followed first-order kinetics in aqueous solutions. In cosolvent/water mixtures, new degradation products were observed, indicating a chemical reaction between GW280430A and cosolvents. The reaction activation energies in the cosolvent/water mixtures ranged from 75 to 85 kJ/mol, with the longest t(0.9) at 5 degrees C equal to approximately 12 months and at 25 degrees C equal to 36 days. Consideration should be given to the incorporation of glycine or a low concentration of citrate, malate, or tartrate buffer in the parenteral formulation development of GW280430A. Cosolvents prolonged the predicted t(0.9) for GW280430A in solution, but the enhancement was not significant enough to pursue a liquidformulation.