Citrate and recurrent idiopathic calcium urolithiasis

Summary In idiopathic recurrent calcium urolithiasis (RCU) in men (n=37) the metabolic effects of oral tripotassium citrate (PC) were investigated in a longitudinal field study. The patients were either normo- (n=22) or hypocitraturic (n=15). Laboratory examinations were performed before, and after 3, 6, and more than 12 months of medication. Acceptance of PC was poor, mainly because of the salty taste of the tablet preparation chosen, and a number of participants dropped out of the study. In the remaining participants, compliance was acceptable when evaluated on the basis of urinary potassium and undesired side effects did not occur. In the short term (up to 3 months), PC evoked compensated metabolic alkalosis (pH and citrate in urine increased; blood gases remained normal), a drop in urinary calcium, together with increasing oxaluria, hydroxyapatite supersaturation, and calcium phosphate crystalluria. In the long term (>12 months) PC urinary pH and citrate dissociated, in that pH returned to pretreatment baseline values, whereas citrate stayed at high levels. In normocitraturics but not in hypocitraturics, urinary urea and sodium in creased with PC. Hypocitraturics appeared to be less sensitive to the effects of PC, as reflected by the relatively small rise in urinary pH and citrate, and they maintained higher mean levels of indicators of bone metabolism (osteocalcin, alkaline phosphatase, hydroxyproline) despite continuous administration of PC. It was concluded that although the PC tablet preparation was effective it may not be an ideal anti-stone drug treatment in the long term and that, especially in hypocitraturiecs, the intrinsic metabolic defect of RCU may not be sufficiently well controlled.     

Two types of quasi-liquid layers on ice crystals are formed kinetically

Surfaces of ice are covered with thin liquid water layers, called quasi-liquid layers (QLLs), even below their melting point (0 °C), which govern a wide variety of phenomena in nature. We recently found that two types of QLL phases appear that exhibit different morphologies (droplets and thin layers) [Sazaki G. et al. (2012) Proc Natl Acad Sci USA 109(4):1052−1055]. However, revealing the thermodynamic stabilities of QLLs remains a longstanding elusive problem. Here we show that both types of QLLs are metastable phases that appear only if the water vapor pressure is higher than a certain critical supersaturation. We directly visualized the QLLs on ice crystal surfaces by advanced optical microscopy, which can detect 0.37-nm-thick elementary steps on ice crystal surfaces. At a certain fixed temperature, as the water vapor pressure decreased, thin-layer QLLs first disappeared, and then droplet QLLs vanished next, although elementary steps of ice crystals were still growing. These results clearly demonstrate that both types of QLLs are kinetically formed, not by the melting of ice surfaces, but by the deposition of supersaturated water vapor on ice surfaces. To our knowledge, this is the first experimental evidence that supersaturation of water vapor plays a crucially important role in the formation of QLLs.Ice is one of the most abundant materials on Earth, and its surfaces are covered with thin liquid water layers even below their melting point (0 °C) (1–4). Such thin liquid water layers are called “quasi-liquid layers” (QLLs). Because QLLs govern the surface properties of ice just below the melting point, it is well acknowledged that surface melting of ice governs a wide variety of phenomena, such as electrification of thunderclouds (4, 5), regelation (4, 6), frost heave (4, 7), conservation of foods, ice skating (1, 8), preparation of a snowman (1), and growth of ice crystals (2, 4). Therefore, it is essential to understand the surface melting of ice crystals at the molecular level.After Michael Faraday proposed the existence of QLLs in 1842 (1), many studies experimentally confirmed the formation of QLLs by various methods (

难溶性中药成分在过饱和体系下晶体成核和生长行为研究

目的研究难溶性中药成分在过饱和体系中的晶体成核和生长行为,为难溶性中药成分过饱和给药系统的设计奠定基础。方法通过反溶剂法制备载药过饱和体系,选择紫外-可见光谱法监测晶体成核和晶体生长过程,分别测定6种成分在较低过饱和度(S=5)和较高过饱和度(S=20)时的晶体成核诱导时间(tind)和晶体生长速度,利用偏振光显微镜(PLMC)、X射线衍射(XRD)、差示扫描量热仪(DSC)对沉淀进行表征。结果穿心莲内酯、延胡索乙素、丹皮酚、银杏内酯B、高饱和度的水飞蓟宾与姜黄素的成核诱导时间tind1 h,低过饱和度的水飞蓟宾与姜黄素的成核诱导时间tind1 h;穿心莲内酯与延胡索乙素在晶体生长过程中表现出负斜率,而水飞蓟宾、丹皮酚、姜黄素与银杏内酯B在则表现出正斜率。结论穿心莲内酯与延胡索乙素属于快速成核-快速晶体生长分子(I类);丹皮酚、银杏内酯B、较高过饱和度的水飞蓟宾与姜黄素属于快速成核-缓慢晶体生长分子(II类)、较低过饱和度的水飞蓟宾与姜黄素属于缓慢成核-缓慢晶体生长分子(IV类)。     

Coupled CH4 production and oxidation support CO2 supersaturation in a tropical flood pulse lake (Tonle Sap Lake,Cambodia)

Carbon dioxide (CO₂) supersaturation in lakes and rivers worldwide is commonly attributed to terrestrial–aquatic transfers of organic and inorganic carbon (C) and subsequent, in situ aerobic respiration. Methane (CH₄) production and oxidation also contribute CO₂ to freshwaters, yet this remains largely unquantified. Flood pulse lakes and rivers in the tropics are hypothesized to receive large inputs of dissolved CO₂ and CH₄ from floodplains characterized by hypoxia and reducing conditions. We measured stable C isotopes of CO₂ and CH₄, aerobic respiration, and CH₄ production and oxidation during two flood stages in Tonle Sap Lake (Cambodia) to determine whether dissolved CO₂ in this tropical flood pulse ecosystem has a methanogenic origin. Mean CO₂ supersaturation of 11,000 ± 9,000 μatm could not be explained by aerobic respiration alone. ¹³C depletion of dissolved CO₂ relative to other sources of organic and inorganic C, together with corresponding ¹³C enrichment of CH₄, suggested extensive CH₄ oxidation. A stable isotope-mixing model shows that the oxidation of ¹³C depleted CH₄ to CO₂ contributes between 47 and 67% of dissolved CO₂ in Tonle Sap Lake. ¹³C depletion of dissolved CO₂ was correlated to independently measured rates of CH₄ production and oxidation within the water column and underlying lake sediments. However, mass balance indicates that most of this CH₄ production and oxidation occurs elsewhere, within inundated soils and other floodplain habitats. Seasonal inundation of floodplains is a common feature of tropical freshwaters, where high reported CO₂ supersaturation and atmospheric emissions may be explained in part by coupled CH₄ production and oxidation.

Globally, most lakes and rivers are supersaturated with dissolved carbon dioxide (CO₂) relative to the atmosphere, highlighting their outsized role in transferring and transforming terrestrial carbon (C) (1–3). Terrestrial–aquatic transfers of C can include CO₂ dissolved in terrestrial ground and surface waters (3–6), dissolved inorganic carbon (DIC) from carbonate weathering (7, 8), or organic C from various sources that is subsequently respired in lakes and rivers (9, 10). Initially, oceanic export was thought to be the only fate for terrestrial–aquatic transfers of C, but a growing body of research on sediment burial of organic C and CO₂ emissions from freshwaters prompted the “active pipe” revision to this initial set of assumptions (11). Although freshwaters are now recognized as focal points for transferring and transforming C on the landscape, most of this research has been conducted within temperate freshwaters (2, 11, 12). Few studies focus on the mechanisms of CO₂ supersaturation in tropical lakes and rivers, with most conducted in just one watershed, the Amazon (4, 13–15).CO₂ supersaturation within tropical freshwaters is likely influenced by their unique flood pulse hydrology. The canonical flood pulse concept hypothesizes that annual flooding of riparian land will lead to organic C mobilization and respiration (16). Partial pressures of CO₂ (pCO₂) have been measured in excess of 44,000 μatm in the Amazon River (13), 16,000 μatm in the Congo River (17), and 12,000 μatm in the Lukulu River (17). Richey et al. (13), Borges et al. (18), and Zuidgeest et al. (17) have each shown that that riverine pCO₂ scales with the amount of land flooded in these watersheds. Yet it was only recently that Abril and Borges (19) proposed the importance of flooded land to the “active pipe.” These authors differentiate uplands that unidirectionally drain water downhill (via ground and surface water) from floodplains that bidirectionally exchange water with lakes and rivers (19). They conceptualize how floodplains combine high hydrologic connectivity, high rates of primary production, and high rates of respiration to transfer relatively large amounts of C to tropical freshwaters (19).Methanogenesis inevitably results on floodplains after dissolved oxygen (O₂) and other electron acceptors for anaerobic respiration such as iron and sulfate are consumed (16, 19). Horizontal gradients in dissolved O₂ and reducing conditions have been observed extending from the center of lakes and rivers through their floodplains in the Mekong (20, 21), Congo (22), Pantanal (23), and Amazon watersheds (4). CH₄ production and oxidation occur along such redox gradients (4, 16, 19, 23). CH₄ is produced by acetate fermentation (Eq. 1) and carbonate reduction (Eq. 2) within freshwaters (24, 25). CH₄ production coupled with aerobic oxidation results in CO₂ (Eq. 3 and ref. 25), yet no studies have quantified the relative contribution of coupled CH₄ production and oxidation to CO₂ supersaturation within tropical freshwaters.CH3COOH→CO2+CH4,[1]CO2+8H++8e−→CH4+2H2O,[2]CH4+2O2→CO2+2H2O.[3]The relative contribution of coupled CH₄ production and oxidation to CO₂ supersaturation within tropical freshwaters can be traced with stable C isotopes of CO₂ and CH₄. Methanogenesis results in CH₄ that is depleted in ¹³C (δ¹³C = −65 to −50‰ from acetate fermentation and −110 to −60‰ from carbonate reduction) compared to other potential sources of organic and inorganic C (δ¹³C = −37 to −7.7‰; see Materials and Methods) (24–26). The oxidation of this ¹³C-depleted CH₄ results in ¹³C-depleted CO₂ (24–26). At the same time, CH₄ oxidation enriches the ¹³C/¹²C of residual CH₄ as bacteria and archaea preferentially oxidize ¹²C-CH₄ (25). This means that the ¹³C/¹²C of CO₂ and CH₄ can serve as powerful tools to determine the source of CO₂ supersaturation within freshwaters.Tonle Sap Lake (TSL) is Southeast Asia’s largest lake and an understudied flood pulse ecosystem that supports a regionally important fishery (21, 22, 27). Each May through October, monsoonal rains and Himalayan snowmelt increase discharge in the Mekong River and cause one of its tributaries, the Tonle Sap River, to reverse course from southeast to northwest (21). During this course reversal, the Tonle Sap River floods TSL. The TSL flood pulse increases lake volume from 1.6 to 60 km³ and inundates 12,000 km² of floodplain for 3 to 6 mo per year (21, 27). Holtgrieve et al. (22) have shown that aerobic respiration is consistently greater than primary production in TSL (i.e., net heterotrophy), with the expectation of consistent CO₂ supersaturation. But, the partial pressures, C isotopic compositions, and ultimately the source of dissolved CO₂ in TSL remain unquantified.To quantify CO₂ supersaturation and its origins in TSL, we measured the partial pressures of CO₂ and CH₄ and compared their C isotopic composition to other potential sources of organic and inorganic C. We carried out these measurements in distinct lake environments during the high-water and falling-water stages of the flood pulse, hypothesizing that CH₄ production and oxidation on the TSL floodplain would support CO₂ supersaturation during the high-water stage. We found that coupled CH₄ production and oxidation account for a nontrivial proportion of the total dissolved CO₂ in all TSL environments and during both flood stages, showing that anaerobic degradation of organic C at aquatic–terrestrial transitions can support CO₂ supersaturation within tropical freshwaters.     

Enhanced dissolution performance of curcumin with the use of supersaturatable formulations

The goal of this research was to employ formulation strategies to develop supersaturatable formulations for curcumin, a poorly water-soluble drug to improve the in vitro dissolution performance. Self-emulsifying lipid-based formulations and hydrophilic carrier formulations with polymeric precipitation inhibitors were designed to achieve supersaturation upon dilution. In vitro dissolution of curcumin from each formulation was performed, in addition to assessment of the utility of polymers such as polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC) as precipitation inhibitors. For the hydrophilic solvent formulation, it was observed that the presence of 10% w/w polymer results in curcumin concentrations almost 100-fold greater compared to the formulation without the polymer. Incorporation of polymer in the SEDDS formulation results in a supersaturated solution of curcumin with concentrations identical to the theoretical starting dose. The high drug concentrations were sustained for 3?h as compared to the self-emulsifying formulation without the polymer. The low dissolution of curcumin in the neat hydrophilic solvent and self-emulsifying formulation is attributed to the uncontrolled precipitation of the drug upon mixing with the dissolution media, which is a result of formation of an unstable supersaturated solution. Upon relative assessment, the rank order in which the polymers inhibited precipitation was PVP-K30 < PVP-K90 < HPMC.     

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

We developed a simulation method to describe in vitro drug concentration?time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZ_III), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZ_DH). After a certain period, de-supersaturation due to the precipitation of CBZ_DH was observed. In the simulation of this typical dissolution?precipitation profile, the precipitation process of CBZ_DH was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZ_DH were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZ_DH. The dissolution process of CBZ_III was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.