Rational design and development of a stable liquid formulation of riluzole and its pharmacokinetic evaluation after oral and IV administrations in rats.

Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed. Riluzole was solubilized using water miscible organic solvents, namely, polyethylene glycol 400, propylene glycol and glycerin. A Central Composite Design (CCD) approach was used to develop an optimum co-solvent composition that can solubilize the entire 50 mg dose of riluzole in 5 ml. A three-factor five-level design was employed to investigate the effects of composition of co-solvents on riluzole solubility. The selected optimum formulation consists of 15% v/v PEG 400, 20% v/v propylene glycol and 10% v/v glycerin, with riluzole concentration of 10 mg/ml. The optimum composition was assessed for stability at different temperatures. Satisfactory stability was obtained at room temperature and 4 °C (t90 of 17 and 35 months, respectively). The optimum formulation of riluzole was suitable for both oral and intravenous administrations. Single dose pharmacokinetic studies of the optimum formulation by oral and IV routes were evaluated in rats, using commercially available Rilutek® tablets as a reference. The co-solvent formulation was well tolerated both orally and intravenously. In comparison to the commercial tablet, the co-solvent formulation had a faster rate of absorption and more sustained plasma levels with a significantly longer elimination half-life. Higher concentrations of riluzole in brain and spinal cord were achieved from co-solvent formulation as compared to tablet. The riluzole solution formulation is stable and offers advantages of ease of administration, consistent dosing, rapid onset and longer duration of action, better availability at site of action which can be extremely beneficial for the therapy in SCI patients.

Assessing Propylene Glycol Toxicity in Alcohol Withdrawal Patients Receiving Intravenous Benzodiazepines: A One-Compartment Pharmacokinetic Model.

BACKGROUND AND OBJECTIVES: While some case reports indicate that high doses of propylene glycol (PG) may result in metabolic acidosis, there has been no large-scale study that evaluated the risk of metabolic acidosis in patients receiving PG-containing benzodiazepines for acute alcohol withdrawal. This study was undertaken to evaluate the potential toxicity of PG in patients with acute alcohol withdrawal treated with intermittent intravenous bolus doses of diazepam and/or lorazepam. METHODS: This is a retrospective case study using data collected from 18 randomly selected patients receiving one or both of these medications per a modified Clinical Institute Withdrawal Assessment for Alcohol (CIWA) Class 3 protocol. Plasma levels of PG were estimated using a one-compartment pharmacokinetic model. RESULTS: Only two patients had an elevated anion gap compared to their baseline value with one also experiencing a significant increase in serum creatinine. No increases in serum osmolarity were noted. Analysis showed that the benzodiazepine dose received was a good predictor of the estimated PG concentration (r = 0.6), but was poorly correlated with the anion gap. No significant correlation was found with the creatinine clearance or serum creatinine. Patients receiving several daily doses were at higher risk of developing an anion gap (r = 0.33), but the estimated maximum PG concentration did not correlate with the anion gap or serum concentration. CONCLUSION: It does not appear that intermittent bolus administration of intravenous benzodiazepines for alcohol withdrawal influenced renal function or anion gap regardless of number of administered doses, amount of PG received, or the estimated PG concentration.

Transdermal Delivery of Compounds with Different Lipophilicity and Molecular Weight from W/O Microemulsions Analyzed by UPLC-QTOF/ MS and LC-MS/MS.

OBJECTIVE: The aim of this study was to develop a novel W/O microemulsion for a natural extract of Wen-Luo-Tong (WLT) containing mainly icariin, hydroxysafflor yellow A (HSYA) and gallic acid to be applied to skin as a potential treatment for peripheral neuropathy. METHODS: The oil phase was selected on the basis of affinity with the surfactant and co-surfactant. Pseudo-ternary diagrams were constructed to optimize microemulsions and finally stability studies were performed on the selected formulations. Droplet sizes were analyzed by using a zetasizer and were found to be within the desired range. Selected microemulsions with acceptable viscosities, containing 5%, 8% and 10% of water extract solution, were used for in vitro skin penetration studies using Franz diffusion cells and excised rat skin. New LC-MS/MS and UPLC-Q-TOF/MS methods were employed for quantitative and qualitative analysis. RESULTS: The optimized formulation (ME-4) consisting of 10% (w/w) water extract solution, 60% isopropyl myristate, 30%(w/w) Smix: Propylene glycol (5:2) significantly increased the cumulative permeated amounts of HSYA, icariin and gallic acid compared with the water extract solution controls. CONCLUSION: This novel formulation also increased the number of components penetrating rat skin. Ten components were detected in the Franz cell receptor solution using a UPLC-Q-TOF/MS system after the application of formulation ME-4 for 24h on the skin in vitro. However, only one component was detected after applying the control. Therefore, the microemulsion ME-4 was selected for future in vivo pharmacodynamic studies.

Effect of a Low Surface Tension Vehicle on the Dentinal Tubule Penetration of Calcium Hydroxide and Triple Antibiotic Paste.

INTRODUCTION: The purpose of this study was to evaluate dentinal tubule penetration (DTP) of calcium hydroxide (CH) and triple antibiotic paste (TAP) when performed with distilled water (DW) or a low surface tension liquid (ie, propylene glycol [PG]). METHODS: Root apices of 40 single-rooted premolars were removed to obtain 14-mm roots in length. Root canals were enlarged to simulate immature teeth. After smear layer removal, the roots were randomly divided into 4 groups (n = 10) according to the root canal medicaments and the vehicles used: group 1:TAP + DW, group 2: TAP + PG, group 3: CH + DW, and group 4:CH + PG. Root canal medicaments were labeled with 0.1% rhodamine and applied into the canals using a Lentulo spiral. Specimens were molded into acrylic blocks, and 1-mm-thick sections were obtained from the middle third of each root. Specimens were mounted onto glass slides and scanned under a confocal laser scanning microscope. DTP depth, percentage, and area were measured using imaging software. Kruskal-Wallis and Mann-Whitney U tests were used for statistical analysis. The level of significance was set at P < .05. RESULTS: No significant difference was found among the experimental groups in terms of both percentage and depth of DTP (P > .05). CH had a lower penetration area compared with TAP regardless of the vehicle used (P < .05). CONCLUSIONS: A low surface tension vehicle did not alter the penetration of CH and TAP.

Direct estimation of the permeation of topical excipients through artificial membranes and human skin with non-invasive Terahertz time-domain techniques.

BACKGROUND: Drug permeation through skin, or a synthetic membrane, from locally acting pharmaceutical products can be influenced by the permeation behaviour of pharmaceutical excipients. OBJECTIVE: Terahertz time-domain technology is investigated as a non-invasive method for a direct and accurate measurement of excipients permeation through synthetic membranes or human skin. METHODS: A series of in-vitro release and skin permeation experiments of liquid excipients (e.g. propylene glycol and polyethylene glycol 400) has been conducted with vertical diffusion cells. The permeation profiles of excipients through different synthetic membranes or skin were obtained using Terahertz pulses providing a direct measurement. Corresponding permeation flux and permeability coefficient values were calculated based on temporal changes of the terahertz pulses. RESULTS: The influence of different experimental conditions, such as the polarity of the membrane and the viscosity of the permeant, was assessed in release experiments. Specific transmembrane flux values of those excipients were directly calculated with statistical differences between cases. Finally, an attempt to estimate the skin permeation of propylene glycol with this technique was also achieved. All these permeation results were likely comparable to those obtained by other authors with usual analytical techniques. CONCLUSION: Terahertz time-domain technology is shown to be a suitable technique for an accurate and non-destructive measurement of the permeation of liquid substances through different synthetic membranes or even human skin.

Confocal Raman microscopic investigation of the effectiveness of penetration enhancers for procaine delivery to the skin.

A methodology that employs confocal Raman microscopy (CRM) on ex vivo skin samples is proposed for the investigation of drug content and distribution in the skin. To this end, the influence of the penetration enhancers propylene glycol and polyoxyethylene-23-lauryl ether on the penetration and permeation of procaine as a model substance was investigated. The drug content of skin samples that had been incubated with semisolid formulations containing one of these enhancers was examined after skin segmentation. The experiments showed that propylene glycol did not affect the procaine content that was delivered to the skin, whereas polyoxyethylene-23-lauryl ether led to higher procaine contents and deeper penetration. Neither substance was found to influence the permeation rate of procaine. It is thereby shown that CRM can provide additional information on drug penetration and permeation. Furthermore, the method was found to enhance the depth from which Raman spectra can be collected and to improve the depth resolution compared to previously proposed methods.

Low but inducible contribution of renal elimination to clearance of propylene glycol in preterm and term neonates.

BACKGROUND: Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates. METHODS: The pharmacokinetic analysis of PG was performed in NONMEM 6.2. on the basis of PG concentrations in plasma and/or urine samples for a total of 69 (pre)term neonates (birth weight 630-3980 g, gestational age 24-41 weeks, postnatal age 1-29 days) who received PG coadministered with intravenous paracetamol (5-10 mg/kg per 6 hours), phenobarbital (5 mg·kg(-1)·d(-1)), or both. To capture the time-dependent trend in the renal excretion of PG, different models based on time after the first dose, urine volume, and creatinine amount in urine were tested. RESULTS: A one-compartment model parameterized in terms of renal clearance, hepatic clearance, and volume of distribution was found to adequately describe the observations in both plasma and urine. After the first dose was administered, the renal elimination of PG was 15% of total clearance, which increased over time to 25% at 24 hours after the first dose of PG. This increase was best described using a hyperbolic function based on time after the first dose. CONCLUSIONS: Renal elimination of PG in (pre)term neonates is low, particularly compared with the reported percentage of 45% in adults, but it may increase with time after the first dose of PG. To study whether this increase is caused by an autoinduced increase in the renal secretion or a reduction of tubular reabsorption of PG, further research is needed.

Fit of fluxes of sunscreens and other compounds from propylene glycol:water (30:70) through human skin and silicone membrane to the Roberts-Sloan equation: the effect of polar vehicle (or water) solubility.

It would be useful to develop a surrogate for animal skin, which could be use to predict flux through human skin. The fluxes (and physicochemical properties) of sunscreens and other compounds from propylene glycol (PG):water (AQ), 30:70, through human skin have previously been reported. We measured the fluxes of several of those sunscreens and other compounds from PG:AQ, 30:70, through silicone membrane and fit both sets of data to the Roberts-Sloan (RS) equation to determine any similarities. For both sets of data, the fluxes were directly dependent on their solubilities in a lipid solvent [octanol (OCT), in this case] and in a polar solvent (PG:AQ, 30:70, or AQ in this case) and inversely on their molecular weights. The fit of the experimental (EXP) fluxes through human skin in vivo to RS was excellent: r² = 0.92 if the vehicle (VEH) PG:AQ, 30:70 was the polar solvent (RS¹) or r² = 0.97 if water was the polar solvent (RS²). The fit of the EXP fluxes through silicone membrane to RS was good: r² = 0.80 if the VEH PG:AQ, 30:70, was the polar solvent (RS¹) or r² = 0.81 if water was the polar solvent (RS²). The correlations between their EXP fluxes through human skin in vivo and their EXP fluxes through silicone membrane were good (r² = 0.85). In addition, the correlation between EXP fluxes from PG:AQ, 30:70, through human skin in vivo and their fluxes calculated from the coefficients of the fit of solubilities, molecular weights and fluxes from water through silicone membranes from a previous n = 22 database to RS was even better (r² = 0.94). These results suggest that flux through human skin can be calculated from flux through a silicone membrane.

Developmental pharmacokinetics of propylene glycol in preterm and term neonates.

AIM: Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS: A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24-40 weeks). RESULTS: In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL(i) = 0.0849 × {(bBW/2720)(1.69) × (PNA/3)(0.201)}). Volume of distribution scaled allometrically with current bodyweight (V(i) = 0.967 × {(BW/2720)(1.45)}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33-144 and 28-218 mg l(-1) (peak) and 19-109 and 6-112 mg l(-1) (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION: A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.

Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics.

Propylene glycol is an aliphatic alcohol that functions as a skin conditioning agent, viscosity decreasing agent, solvent, and fragrance ingredient in cosmetics. Tripropylene glycol functions as a humectant, antioxidant, and emulsion stabilizer. Polypropylene glycols (PPGs), including PPG-3, PPG-7, PPG-9, PPG-12, PPG-13, PPG-15, PPG-16, PPG-17, PPG-20, PPG-26, PPG-30, PPG-33, PPG-34, PPG-51, PPG-52, and PPG-69, function primarily as skin conditioning agents, with some solvent use. The majority of the safety and toxicity information presented is for propylene glycol (PG). Propylene glycol is generally nontoxic and is noncarcinogenic. Clinical studies demonstrated an absence of dermal sensitization at use concentrations, although concerns about irritation remained. The CIR Expert Panel determined that the available information support the safety of tripropylene glycol as well as all the PPGs. The Expert Panel concluded that PG, tripropylene glycol, and PPGs ≥3 are safe as used in cosmetic formulations when formulated to be nonirritating.

Acción antibacteriana de pastas de hidróxido de calcio frente a Enterococcus faecalis / Antibacterial effciacy by calcium hydroxide pastes on Enterococcus faecalis

Objetivo. Se evaluó in vitro la actividad antibacteriana de pastas de Ca (OH)2 frente a Enterococcus faecalis. Material y método. Las pasta usadas fueron: 1-Ca(OH)2 con solución salina, 2-Ca(OH)2 con clorhexidina (CHX) 0,2% y 3-Ca (OH)2 con propilenglicol. Se trabajó con 6 tubs experimentales y un tubo control de crecimiento bacteriano y se realizó una curva de muerte, evaluándolas a diferentes tiempos 0,1,2 y 5 horas y 1, 7 y 14 días. Los datos se analizaron con ANOVA. Resultados y conclusiones. Ca (OH)2 con CHX 0,2% produjo inhibición total de Enterococcus faecalis a la hora de permanencia en contacto con el microorganismo, manteniéndose este efecto durante los 14 días. La pasta de Ca (OH)2 con propilenglico inhibió al microorganismo durante la 1º hora, sin evidenciarse diferencias con la pasta 2 (p>0,05), manteniéndose este efecto durante 5 horas, luego hubo recrecimiento bacteriano. La pasta de Ca(OH=2 con solución salina inhibió al Enterococcus faecalis a partir del día 1 hasta el día 14 (AU)

Objective. The aim of this study was to evaluate the antimicrobial effects of calcium hydroxide pastes on Enterococcus faecalis. Material and methods. The pastes evaluated were: 1-calcium hydroxide with saline solution, 2-calcium hydroxide with chlorhexidine (CHX) 0,2% and 3-calcium hydroxide with propileneglicol. Six experimental tubes and one control tube were prepared and incubated for 0, 1, 2, 5 hours, 1, 7 and 14 days. The curves death were made. The data was analyzed with ANOVA test. Results and Conclusions. Ca (OH)2 with CHX 0,2% paste inhibited Enterococcus faecalis at 1 hour and maintained this effect over 14 days. Ca(OH)2, with propileneglicol had inhibitory effect at 1 hour, showing no significant difference with paste 2 (p>0,05). Paste 3 maintained inhibitory action for 5 hours, then microorganism grow again. Ca(OH)2 with saline solution paste inhibit Enterococcus faecalis after 1 day of contact. This effect continue to 14th day. Ca(OH)2 with CHX 0,2% and Ca(OH)2 with propileneglicol pastes were effective in 1 hour time (p<0,05). Only the pastes 1 and 2 maintained inhibitory action for 14 days (AU)

The propylene glycol research project to illustrate the feasibility and difficulties to study toxicokinetics in neonates.

This paper aims to describe our propylene glycol (PG) research project to illustrate the feasibility and the difficulties encountered to perform excipient studies in neonates. PG is frequently co-administered excipient. PG accumulation potentially results in hyperosmolarity, lactic acidosis or hepato-renal toxicity in adults, reflecting issues related to pharmacokinetics (PKs) and -dynamics (PDs). Consequently, similar observations in neonates are urgently needed. Since newborns display 'physiological' impaired hepatic and renal elimination capacity, description of PG PK in neonates is warranted. The PG PD was assessed based on indicators of renal, hepatic and metabolic (in)tolerance earlier reported in adults and relating to osmolar changes. Based on the PK and PD data collected in neonates, we suggest that there is a lower limit of PG tolerance in neonates. In addition to preliminary data on PG disposition and tolerance in neonates, we mainly focus on the limitations of the current observations and the difficulties encountered during this PG project to further illustrate the specific setting of neonatal research.

Analytical optimal controls for the state constrained addition and removal of cryoprotective agents.

Cryobiology is a field with enormous scientific, financial, and even cultural impact. Successful cryopreservation of cells and tissues depends on the equilibration of these materials with high concentrations of permeating chemicals (CPAs) such as glycerol or 1,2 propylene glycol. Because cells and tissues are exposed to highly anisosmotic conditions, the resulting gradients cause large volume fluctuations that have been shown to damage cells and tissues. On the other hand, there is evidence that toxicity to these high levels of chemicals is time dependent, and therefore it is ideal to minimize exposure time as well. Because solute and solvent flux is governed by a system of ordinary differential equations, CPA addition and removal from cells is an ideal context for the application of optimal control theory. Recently, we presented a mathematical synthesis of the optimal controls for the ODE system commonly used in cryobiology in the absence of state constraints and showed that controls defined by this synthesis were optimal. Here we define the appropriate model, analytically extend the previous theory to one encompassing state constraints, and as an example apply this to the critical and clinically important cell type of human oocytes, where current methodologies are either difficult to implement or have very limited success rates. We show that an enormous increase in equilibration efficiency can be achieved under the new protocols when compared to classic protocols, potentially allowing a greatly increased survival rate for human oocytes and pointing to a direction for the cryopreservation of many other cell types.

Pharmacokinetics and tissue distribution profile of icariin propylene glycol-liposome intraperitoneal injection in mice.

OBJECTIVES: The pharmacokinetics and tissue distribution of icariin propylene glycol-liposome suspension (ICA-PG-liposomes) have been investigated. METHODS: ICA-PG-liposomes or ICA-PG-solution were prepared and intraperitoneally injected to mice. Morphology and size distribution of ICA-PG-liposomes were observed by transmission electron microscopy (TEM) and laser particle sizer. Plasma and tissues were collected at different times after intraperitoneal injection and icariin concentrations were determined by HPLC. KEY FINDINGS: From TEM, ICA-PG-liposomes showed spherical vesicles with a mean particle size of 182.4 nm. The encapsulation efficiency of ICA-PG-liposomes reached 92.6%. Pharmacokinetics of ICA-PG-liposomes displayed the three open compartments model. ICA-PG-liposomes enhanced icariin absorption from the abdominal cavity, prolonged mean retention time (MRT((0-t))), increased area under curve (AUC((0-t))) and maximum concentration in plasma. Compared with ICA-PG-solution, ICA-PG-liposomes resulted in larger amounts of icariin being distributed into spleen (60.38% total icariin), liver (16.68%), lung (6.21%), kidney (4.64%), heart (1.43%) and brain (1.83%). AUC((0-t)) values in most tissues (except lung) of mice administered ICA-PG-liposomes were higher than those administered ICA-PG-solution, while Clearance in most tissues (except brain and lung) decreased. The MRT((0-t)) values of ICA-PG-liposomes in all tissues and half lives of most tissues (except brain) were prolonged. From Targeted efficiency and relative uptake data, the spleen was the target tissue of the ICA-PG-liposomes. CONCLUSIONS: ICA-PG-liposomes changed the pharmacokinetic behaviour and enhanced icariin distribution in tissues. With nanometer size, high encapsulation efficiency and improved pharmacokinetics, ICA-PG-liposomes might be developed as promising carriers for icariin injection.

Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs.

Aerosolized propylene glycol (PG) was generated as log-normally distributed particulate clouds in different concentrations using a novel capillary aerosol generator (CAG) and evaluated in a battery of non-clinical studies intended to assess its potential inhalation and systemic toxicity in 2 species before ICH-compliant "first-time-in-man" studies. Exposures were nose-only in rats, and via face mask with oropharyngeal tube in dogs. The CAG-generated PG aerosol had a mass median aerodynamic diameter (MMAD) of 2.29µm, with a 1.56 geometric standard deviation (GSD) in the rat studies, and a MMAD of 1.34µm (1.45 GSD) in the dog studies, consistent with expected particle size exposures in man. International Congress on Harmonization (ICH) Guidelines were followed, which recommend preliminary non-clinical safety studies using the vehicle and device (CAG-PG) prior to the first human exposure including safety pharmacology, pharmacokinetic (PK) studies, single dose toxicity studies, and repeated dose toxicity studies in two species. In the rat, the only biologically relevant findings included clinical signs of ocular and nasal irritation indicated by minor bleeding around the eyes and nose, and minimal laryngeal squamous metaplasia. This finding is commonly observed in inhalation studies in the rat, and likely related to the unique sensitivity of the tissue, as well as the circuitous airflow pathway through the larynx which increases particle deposition. In the female Beagle dog, treatment-related decreases in hemoglobin, red blood cells and hematocrit were observed in the two highest exposure groups, equivalent to approximately 18 and 60mg/kg/day. In male dogs from the high dose group, similar small decreases, albeit, non-statistically significant decreases were observed in these hematological markers as well. PK studies in rats and dogs showed that the absorption of PG following pulmonary inhalation exposure occurs rapidly, and equilibrium between lung tissue and plasma is achieved quickly. With daily inhalations of PG aerosols, there is evidence of minor tissue accumulation of PG in each species. Inhalation exposure to CAG-generated PG aerosols achieved PG concentrations in the systemic circulation that were similar to those attained via the oral route. Systemic elimination of PG appears to be saturable, presumably via hepatic metabolism. PG elimination in the high dose groups for both species showed terminal plasma and lung concentration-time profiles suggesting a zero-order elimination process. There was no apparent tissue toxicity of the lung, liver and kidney in these studies. Under the conditions of these studies, the NOEL for the rat was determined to be 20mg/kg/day for the 28-day study. In the Beagle dog, the NOEL was approximately 6.05mg/kg/day for the 28-day study. Overall, these studies allowed us to conclude that PG aerosol generated with the capillary aerosol generator could be administered safely in man, with an adequate margin of safety needed to conduct "first-time-in-man" human exposure studies.

Maximum transepidermal flux for similar size phenolic compounds is enhanced by solvent uptake into the skin.

In principle, the maximum skin flux of solutes should be unaffected by the vehicle, unless that vehicle affects the skin. We recently showed that the maximum epidermal flux for 10 similarly sized phenolic compounds, with differing lipophilicities was defined by their solubility in the skin. Here, we extend these studies to examine how maximum fluxes are affected by cosolvents reported to enhance skin penetration. We compared in vitro human epidermal permeation and stratum corneum solubility for 10 phenols with similar molecular weights and hydrogen bonding but varying lipophilicity from 60% propylene glycol (PG)/water, 40% PG/water and water vehicles. We also measured solvent uptake into stratum corneum, investigated the changes in the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy of stratum corneum and the multiphoton microscopy (MPM) images of ß-naphthol for the various vehicles. We found that phenolic compounds maximum flux and stratum corneum solubilities generally increased with the percentage of PG in the binary solvent system but that the estimated diffusivities appeared to be vehicle independent. Maximum fluxes were related to vehicle-dependent stratum corneum solubilities. Theses solubilities, in turn, depended on the amount of vehicle absorbed into the stratum corneum and the amount of phenolic compounds dissolved in that absorbed vehicle. ATR-FTIR and MPM studies suggest that the vehicle-induced increased uptake of solutes into the stratum corneum occurred by an increased solubility in intercellular lipids of stratum corneum.

In vivo comparison of the optical clearing efficacy of optical clearing agents in human skin by quantifying permeability using optical coherence tomography.

The objective of this work is to quantify and compare the optical clearing efficacy of glucose, propylene glycol, glycerol solutions through the human skin tissue in vivo by calculating permeability coefficient of three solutions. Currently, the permeability coefficient of agent in tissues was extracted from optical coherence tomography (OCT) amplitude data mainly through the OCT signal slope and the OCT amplitude methods. In this study, we report the OCT attenuation coefficient method which is a relatively novel and rarely reported methodology to measure the permeability coefficient during the optical skin clearing procedure. The permeability coefficients for 40% propylene glycol, glucose and glycerol were (2.74 ± 0.05) × 10(-6) cm s(-1), (1.78 ± 0.04) × 10(-6) cm s(-1) and (1.67 ± 0.04) × 10(-6) cm s(-1), respectively. It could be clearly seen that the permeability coefficient of the 40% propylene glycol solution is higher than that of 40% glucose solution, and the permeability coefficient of the 40% glucose solution is higher than that of the 40% glycerol solution. These indicate 40% propylene glycol solution is more effective than others in the human skin in vivo. We then compare and prove consistency of optical clearing efficacy figured out by three different methods.

Suitability of cryoprotectants and impregnation protocols for embryos of Japanese whiting Sillago japonica.

The purpose of this study was to examine the suitability of cryoprotectant agent (CPA) impregnation protocols for the embryos of Japanese whiting (Sillago japonica), a small-sized, easy-to-rear, and prolific marine fish which may constitute a suitable experimental material for the development of cryopreservation methods for fish embryos. Our immediate goals were to assess the toxicity and permeability of various CPAs to whiting embryos of different developmental stages. Exposure of gastrula, somites, tail elongation, and pre-hatching embryos to 10%, 15%, and 20% solutions of propylene glycol (PG), methanol (MeOH), dimethyl sulfoxide (Me2SO), dimethylformamide (DFA), ethylene glycol (EG), and glycerol (Gly) in artificial sea water (ASW; 33 psu) for 20 min revealed that CPA toxicity for whiting embryos increased in the order of PG

A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients.

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.