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Toluene is a volatile hydrocarbon with solvent applications in several industries. Acute neurological effects in workers exposed to toluene have been reported in various publications. To inform the basis for a toluene Short Term Exposure Limit (STEL), studies of toluene-exposed workers were modeled using customized exposure scenarios within an existing physiologically-based pharmacokinetic (PBPK) model to simulate blood concentrations during individual studies. Maximum simulated blood concentration ranged from 0.3 to 1.7 (mean = 0.74 mg/L, median = 0.73, upper 95th percentile = 1.07) at the studies identified No Observed Adverse Effect Concentration (NOAEC). Maximum simulated blood concentration ranged from 0.7 to 4.1 mg/L (mean = 1.81, median = 1.63, lower 95th percentile = 0.92) at the studies identified Lowest Observed Adverse Effect Concentration (LOAEC). The maximum blood concentration for a 100 ppm STEL-like simulation was 0.4 mg/L, at the lower end of the NOAEC range and below the 95th percentile of the LOAEC. Therefore, it appears that a STEL <100 ppm would be unnecessary to protect workers due to peak occupational exposures to toluene., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martijn Rooseboom is employed by Shell including stock ownership but was totally free to design and conduct the research and express his own scientific opinion without any obligation to either Shell or CEFIC. He is a member of the Dutch Expert Committee on Occupational Safety (DECOS) of the Health Council of the Netherlands. Colin M. North is an employee of BASF Corporation and owns shares of publicly traded companies involved in the manufacture, use, or sale of toluene. Neslihan Aygun Kocabas is an employee of TotalEnergies and owns shares of a publicly traded company involved in the manufacture, use, or sale of toluene. Nicholas Synhaeve is an employee of ExxonMobil Petroleum & Chemical BV, Machelen, Belgium, involved in the manufacture, use, or sale of toluene. Richard James Radcliffe is an employee of Penman Consulting Ltd (Wantage UK), who manage and provide scientific support to the Lower Olefins and Aromatics (LOA) REACH Consortium, which includes toluene registrants in the EU. Lawrence Segal is a freelance contractor to Penman Consulting BVBA (Brussels Belgium), who manage and provide scientific support to the Lower Olefins and Aromatics (LOA) REACH Consortium, which includes toluene registrants in the EU. He is a member of the Workplace Environmental Exposure Level (WEEL) Committee., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Climatic conditions raise new concerns about the potential impact of heat on the absorption and kinetics of certain chemicals. The impact of 3 temperatures (21, 25 and 30 °C WBGT) on the toxicokinetics of toluene and acetone was therefore evaluated in five human subjects during controlled exposures in an inhalation chamber. Biological samples were collected and analyzed by GC-MS/MS. Increases between 4 and 85 % were observed for solvents concentrations in blood (30 vs 21 °C) while decreases in urine samples for acetone and o-cresol were measured at the end of the exposure period (4 h). Mean blood concentrations at 4 h are well correlated with temperature. Results suggest an increased absorption and/or a decreased elimination of volatile chemicals in the presence of heat. Higher increases of blood chemical concentrations were observed in heavier individuals. Further studies should include physiologically based toxicokinetic models to help in better understanding the mechanisms involved and their respective contribution., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (x e ) was validated using the Van 't Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy Δ sol H°, entropy Δ sol S°, and Gibbs free energy Δ sol G°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10 -1 ) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10 -5 ) was for pure water at 293.2 K. An apparent thermodynamic analysis based on x e gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of Δ sol H° and Δ sol G°. Interestingly, Δ sol G° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of Δ sol G° and Δ sol S° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.

Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)-loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD˃SIM-PLC˃SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.

Lymph node (LN) metastasis is thought to account for 20-30% of deaths from head and neck cancer. The lymphatic drug delivery system (LDDS) is a new technology that enables the injection of drugs into a sentinel LN (SLN) during the early stage of tumor metastasis to treat the SLN and secondary metastatic LNs. However, the optimal physicochemical properties of the solvent used to carry the drug have not been determined. Here, we show that the osmotic pressure and viscosity of the solvent influenced the antitumor effect of cisplatin (CDDP) in a mouse model of LN metastasis. Tumor cells were inoculated into the proper axillary LN (PALN), and the LDDS was used to inject CDDP solution into the subiliac LN (SiLN) to treat the tumor cells in the downstream PALN. CDDP dissolved in saline had no therapeutic effects in the PALN after it was injected into the SiLN using the LDDS or into the tail vein (as a control). However, CDDP solution with an osmotic pressure of ~ 1,900 kPa and a viscosity of ~ 12 mPa⋅s suppressed tumor growth in the PALN after it was injected into the SiLN using the LDDS. The high osmotic pressure dilated the lymphatic vessels and sinuses to enhance drug flow in the PALN, and the high viscosity increased the retention of CDDP in the PALN. Our results demonstrate that optimizing the osmotic pressure and viscosity of the solvent can enhance the effects of CDDP, and possibly other anticancer drugs, after administration using the LDDS., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: This was a single-institution, single-dose, single-arm phase 1 study in healthy adult males to evaluate the safety and absorption of dimethyl sulfoxide (DMSO) from the bladder into the body when KRP-116D (a 50% w/w DMSO solution) was intravesically administered and allowed to remain in the bladder for 15 minutes., Methods: Six healthy adult males were enrolled in this study. KRP-116D (50 mL) was instilled directly into the bladder via a catheter where it was allowed to remain for 15 minutes under lidocaine anesthesia in accordance with the usage of RIMSO-50 (50% w/w DMSO solution) approved in the USA. The residual DMSO solution in the bladder was collected 15 minutes after instillation. The concentrations of DMSO in the plasma and the recovered solution were analyzed by a validated high-performance liquid chromatography (HPLC) method. The concentration in the residual DMSO solution was multiplied by the solution volume and divided by the dosage to calculate the recovery rate of DMSO., Results: Plasma DMSO was detected in one of six subjects, and in the remaining five subjects DMSO was not detected (<19.6 μg/mL). The recovery rate of DMSO from the bladder was 60.7% to 93.7%. The only drug-related adverse event was breath odor (garlic-like breath) observed in four of six subjects (66.7%)., Conclusion: Absorption of DMSO from the bladder was low (16.3%), and the systemic exposure was limited. Most of the DMSO was recovered from the bladder. KRP-116D 50 mL was well tolerated and safe., (© 2019 The Authors. LUTS: Lower Urinary Tract Symptoms published by John Wiley & Sons Australia, Ltd.)

Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (~0.5% for TEGME and ~1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute central nervous system (CNS) depression is the most sensitive toxicological effect associated with aliphatic hydrocarbon exposure. No observed effect levels for the CNS effects of aliphatic constituents decrease with increasing carbon number to C10 (Lammers et al., 2011; McKee et al., 2011), whereas constituents with carbon numbers > C10 do not produce CNS effects at maximally attainable vapor concentrations (Nilsen et al., 1988). Accordingly, as n-decane appeared to be the "worst case" for acute CNS effects among aliphatic hydrocarbon solvent constituents, experimental studies were conducted to more precisely define the no effect level. Rats were exposed for 8 h to n-decane, either constantly at 3000 mg/m 3 or at higher levels using a discontinuous exposure protocol to assess the influence of fluctuating exposures. Neurobehavioral testing methods including visual discrimination performance and motor activity were used to assess performance, and concentrations of n-decane in blood and brain were measured to obtain pharmacokinetic data. No statistically significant differences were observed in the neurobehavioral tests, establishing 3000 mg/m 3 as the no effect level for CNS effects in rats. These data support the recommended guidance value of 1050 mg/m 3 for C9-C15 aliphatic hydrocarbons for use in calculating occupational exposure levels for complex hydrocarbon solvents and provide empirical evidence that advice from the ACGIH ® that within a working day there should be no more than 3 fluctuations, not longer than 15 min and not exceeding 3 times the Threshold Limit Value (TLV ® ), is reasonable for this group of substances., (Copyright © 2019 Elsevier Inc. All rights reserved.)

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Trichloroethylene (TCE) is a persistent environmental contaminant that causes male reproductive toxicity. We investigated whether transient increases in TCE exposure modulated male reproductive toxicity by exposing rats via daily oral to repeated gavage exposures (1000 mg/kg/day) and through drinking water (0.6% TCE) for 14 weeks. The gavage route resulted in reversible reduction of epididymis weight, and reduced body weight that persisted for up to 12-weeks after cessation of exposure. Physiologically-based pharmacokinetic modeling predicted that the gavage route results in higher C max and AUC exposure of TCE compared to drinking water exposure, explaining the observed differences in toxicity between dosing regimens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The manufacture of personalised medicines where specific combinations of active pharmaceutical ingredients (APIs) and their dose within a tablet would be adjusted to the needs of individual patients, would require new manufacturing approaches compared to the established practice. In the case of low-dose formulations, the required precision of API content might not be achievable by traditional unit operations such as solid powder blending. The aim of the present work was to explore an alternative approach, based on the concept of pre-formulated placebo tablets containing mesoporous silica particles capable of absorbing APIs in the form of solutions, which can be precisely dosed at arbitrarily low quantities. The precision of the liquid dosing system has been validated; it was shown that the mechanical properties of the tablets were satisfactory even after multiple impregnation-drying cycles and that pharmacopoeia specifications on content uniformity could be met. Using model APIs, the spatial distribution of the API within the tablet after impregnation was investigated and shown to depend on the number and order of the impregnation-drying cycles. It was found that when an API was loaded to the tablet in a single step, a different dissolution profile was obtained compared to the same quantity dosed in multiple smaller steps. Overall, the approach of loading multiple API to a pre-formulated tablet at defined quantities using drop-on-demand liquid dosing was found to be feasible from the dose uniformity point of view. Further research should focus on potential API interactions and storage stability of tablets manufactured in this way.

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 (t 90 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar chemicals that are metabolized through oxidation and glutathione conjugation pathways. Both chemicals have been shown to elicit liver and kidney toxicity in rodents and humans; however, TCE has been studied much more extensively in terms of both metabolism and toxicity. Despite their qualitative similarities, quantitative comparison of tissue- and strain-specific metabolism of TCE and PCE has not been performed. To fill this gap, we conducted a comparative toxicokinetic study where equimolar single oral doses of TCE (800 mg/kg) or PCE (1000 mg/kg) were administered to male mice of C57BL/6J, B6C3F1/J, and NZW/LacJ strains. Samples of liver, kidney, serum, brain, and lung were obtained for up to 36 h after dosing. For each tissue, concentrations of parent compounds, as well as their oxidative and glutathione conjugation metabolites were measured and concentration-time profiles constructed. A multi-compartment toxicokinetic model was developed to quantitatively compare TCE and PCE metabolism. As expected, the flux through oxidation metabolism pathway predominated over that through conjugation across all mouse strains examined, it is 1,200-3,800 fold higher for TCE and 26-34 fold higher for PCE. However, the flux through glutathione conjugation, albeit a minor metabolic pathway, was 21-fold higher for PCE as compared to TCE. The degree of inter-strain variability was greatest for oxidative metabolites in TCE-treated and for glutathione conjugation metabolites in PCE-treated mice. This study provides critical data for quantitative comparisons of TCE and PCE metabolism, and may explain the differences in organ-specific toxicity between these structurally similar chemicals., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The objective of this study was to develop agomelatine (AGM) intramuscular sustained release PLA microparticles by using solvent evaporation combined with wet milling technology. The final preparation had a regular and homogeneous particle size of approximately 35 µm, as measured by laser diffraction particle size analysis and scanning electron microscopy (SEM). The drug was confirmed to be within the carrier in an amorphous state through differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD) experiments. Additionally, Fourier transform infrared spectroscopy (FT-IR) analysis was applied to confirm that there was hydrogen bonding between the drug and polymer at the molecular level. In vitro release experiments indicated that the drug could achieve long-term sustained release over the period of one month, with only a 3.07% burst release, due to the involvement of the polymer and removal of drug adsorbed on the surface during the wet grinding process. The dominant release mechanism was considered to be diffusion of the drugs in the initial period. Following this, with the hydrolysis of PLA to form a colloidal viscous layer, drug release is due to the combined effect of diffusion and erosion of the polymer matrix. Additionally, drug release behavior is closely related to the degradation mechanism of the polymer carrier. The results suggest that AGM could be developed as a potential delivery system for long-acting intramuscular administration with extensive application prospects.

Trichloroethylene (TCE) is a chlorinated solvent that has been used widely around the world in the twentieth century for metal degreasing and dry cleaning. Although TCE displays general toxicity and is classified as a human carcinogen, the association between TCE exposure and respiratory disorders are conflicting. In this review we aimed to systematically evaluate the current evidence for the respiratory effects of TCE exposure and the implications for the practicing clinician. There is limited evidence of an increased risk of lung cancer associated with TCE exposure based on animal and human data. However, the effect of other chlorinated solvents and mixed solvent exposure should be further investigated. Limited data are available to support an association between TCE exposure and respiratory tract disorders such as asthma, chronic bronchitis, or rhinitis. The most consistent data is the association of TCE with autoimmune and vascular diseases such as systemic sclerosis and pulmonary veno-occlusive disease. Although recent data are reassuring regarding the absence of an increased lung cancer risk with TCE exposure, clinicians should be aware of other potential respiratory effects of TCE. In particular, occupational exposure to TCE has been linked to less common conditions such as systemic sclerosis and pulmonary veno-occlusive disease., (Copyright © 2017. Published by Elsevier Ltd.)

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2-20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Deep eutectic solvent (DES), the benign green solvent with uniquely physical properties, has been widely applied in various fields. Our previous study indicated that DES could improve the stability and extraction efficiency of salvianolic acid B (SAB). In this work, with SAB as a model drug, the feasibility of DES as a drug carrier for oral preparation was investigated by evaluating the influence of DES on the pharmacokinetics of SAB and the toxicity of DES. Acute oral toxicity test illustrated that choline chloride-glycerol (ChCl-GL, molar ratio 1:2) was non-toxic with the median lethal dose of 7733mg/kg. To comparison the difference of pharmacokinetics between SAB dissolved in ChCl-GL (1:2) and in water, a rapid and sensitive ultra-performance liquid chromatography coupled with mass spectrum was established to determine SAB and its metabolites in rat plasma. The method validation was also tested for the specificity, linearity (r 2 >0.9980 over two orders of magnitude), precision (intra-day relative standard deviation (RSD)<2.73% and inter-day RSD<7.72%), extraction recovery (70.96-80.78%) and stability under three different situations. Compared to water, the pharmacokinetic parameters clarified that ChCl-GL (1:2) could promote the absorption of SAB, the peak concentration (C max ) of 0.308±0.020mg/L was slightly higher than 0.277±0.024mg/L (SAB dissolved in water), and the peak time (T max ) was significantly decreased from 30min (SAB dissolved in water) to 20min. There was no significant difference on the metabolites between SAB dissolved in ChCl-GL (1:2) and in water. This is the first report on the pharmacokinetic study of DES as a candidate of drug carrier, and the results provide a meaningful basis for the application of DES in pharmaceutical preparation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Acetonitrile (ACN) is a solvent rapidly absorbed through lungs and intestinal tract, and is slowly metabolized to cyanide (CN) by enzymatic processes mediated by CYP2E1., Objective: To describe the clinical and laboratory evolution, ACN elimination half-life, and its presence in breast milk in a nursing mother who attempted suicide., Case Details: A 25-year-old 2-month nursing mother ingested an estimated dose of 2.1 g/kg of ACN. Blood and urine samples were collected 24 h later for ACN, CN and thiocyanate analysis, and 12.5 g sodium thiosulfate i.v. in 1-h infusion was started and repeated every 24 h for 4 days. ACN results showed 200 mg/L in blood and 235 mg/L in urine. ACN analysis in the breast milk at Day 6 showed level of 21 mg/L compared to 27 mg/L in blood collected at the same time, suggesting a possible relationship of 1.3:1.0 ratio. An elimination half-life of 40.4 h was calculated, compared to 32 and 36 h showed in other studies., Discussion: The clinical management must involve the use of CN antidotes for more than 24 h depending on the symptoms and blood levels of ACN. Furthermore, our data showed the possible existence of a close relationship between plasma and breast milk levels.

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.

Solvents are commonly used in pharmaceutical and cosmetic formulations and sanitary products and cleansers. The uptake of solvent into the skin may change the molecular organization of skin lipids and proteins, which may in turn alter the protective skin barrier function. We herein examine the molecular effects of 10 different solvents on the outermost layer of skin, the stratum corneum (SC), using polarization transfer solid-state NMR on natural abundance 13 C in intact SC. With this approach it is possible to characterize the molecular dynamics of solvent molecules when present inside intact SC and to simultaneously monitor the effects caused by the added solvent on SC lipids and protein components. All solvents investigated cause an increased fluidity of SC lipids, with the most prominent effects shown for the apolar hydrocarbon solvents and 2-propanol. However, no solvent other than water shows the ability to fluidize amino acids in the keratin filaments. The solvent molecules themselves show reduced molecular mobility when incorporated in the SC matrix. Changes in the molecular properties of the SC, and in particular alternation in the balance between solid and fluid SC components, may have significant influences on the macroscopic SC barrier properties as well as mechanical properties of the skin. Deepened understanding of molecular effects of foreign compounds in SC fluidity can therefore have strong impact on the development of skin products in pharmaceutical, cosmetic, and sanitary applications., Competing Interests: The authors declare no conflict of interest.

The present investigation was undertaken to determine the distribution of 1,2-dichloropropane (DCP) in the blood, liver, kidney, lung, and abdominal fat of rats after oral administration. Male rats were orally administered 62 or 125 mg/kg body weight doses of DCP dissolved in corn oil by gavage, and the concentrations in the blood and tissues were measured. The DCP concentration in the abdominal fat was much greater than in the blood and other tissues. Twenty-four-hr after oral administration, DCP could still be detected in the blood and abdominal fat in the 62-mg/kg group, and in the blood, liver, kidney, lung, and abdominal fat in the 125-mg/kg group. Our results are valuable data pertaining to the pharmacokinetics of DCP and to human health risk assessment of oral exposure to DCP.

Methanol is a common toxicant in the United States, especially from automotive products. Its kinetics have been described previously and typically involve little urinary excretion. We present a case of prolonged methanol half-life in a patient with chronic kidney disease. An 80-year-old male with a baseline glomerular filtration rate of 24 mL·min·1.73 m was transferred to our facility after unintentional methanol ingestion. The original facility had treated him with an oral ethanol load; upon arrival to our facility, he was immediately loaded with fomepizole. His initial serum methanol concentration was 66.1 mg/dL. After a risk/benefit discussion, we decided not to perform hemodialysis on the patient and he was treated with fomepizole and supportive care. After 6 days as an inpatient, the patient's methanol level had declined to 22 mg/dL, fomepizole was discontinued, and the patient was able to be discharged without apparent complications. Based on the exponential best fit line for the patient's methanol concentrations, his methanol half-life during fomepizole treatment was approximately 70 hours, significantly longer than the 30-50 hours typically reported. The reasons for this difference are unclear. This report is limited by being a single case. Further study on the kinetics of methanol in the setting of chronic kidney disease is needed.

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To preliminarily develop a surfactant-free, polymeric solid dispersion (PSD) of paclitaxel suitable for oral administration., Methods: A co-solvent quench method was applied to screen the proper polymer matrix of the PSD which were prepared in a liquid system using a quasi-emulsion solvent diffusion method (QESDM). Three dissolution experiments and two in vivo tests in rats were used to explain the differences among the formulations., Results: The theoretical solubility ratio of amorphous/crystalline PTX was 92.6 (37 °C). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was chosen as the polymer carrier of the PSD and a porous silicon dioxide [called white carbon black (WCB)] was selectable to be used to further adjust the dissolution rate. The absolute oral bioavailability (AOB, 20 mg/kg) of the three formulas [HPMCAS/paclitaxel/WCB = 4/1/0 (F1), 8/1/0 (F2) and 4/1/4 (F3), w/w/w] were 11.8, 13.6 and 25.6%, respectively. The AOB of F3 is nearly seven times higher than that (3.8%) of paclitaxel material (a control). The advantage of higher HPMCAS/paclitaxel ratio of F2 in a dissolution test was not reflected in the first in vivo test due to the relatively higher dose of polymer which could not be effectively dissolved under the limitation of intestinal environment. This was deduced from the dissolution tests and was finally validated when the oral dose of PTX (and thus polymer) was reduced. The relevant AOBs (10 mg/kg) were 10.4, 20.8 and 19.6%, respectively., Conclusion: The PSD is a promising formulation strategy and the QESDM is a practical preparation method to implement such formulation design.

The main object of the self-emulsifying drug-delivery system (SEDDS) is oral bioavailability (BA) enhancement of a poorly water-soluble drug. Low aqueous solubility and low oral BA are major concerns for formulation scientists. As many drugs are lipophilic in nature, their lower solubility and dissolution are major drawbacks for their successful formulation into oral dosage forms. More than 60% of drugs have a lipophilic nature and exhibit poor aqueous solubility. Various strategies are reported in the literature to improve the solubility and enhance BA of lipophilic drugs, including the formation of a cyclodextrin complex, solid dispersions, and micronization. SEDDSs are ideally isotropic mixtures of drug, oil, surfactant, and/or cosurfactant. SEDDSs have gained increasing attention for enhancing oral BA and reducing drug dose. SEDDSs also provide an effective and excellent solution to the various issues related to the formulation of hydrophobic drugs that have limited solubility in gastrointestinal fluid. Our major focus of this review is to highlight the importance of SEDDSs in oral BA enhancement of poorly water-soluble drugs.

Sudden deaths attributed to sniffing trichloroethylene are caused by the abuse of this solvent which produces pleasant inebriating effects with rapid dissipation. In the event of repeated cycles of inhalation, a dangerous and uncontrolled systemic accumulation of trichloroethylene may occur, followed by central nervous system depression, coma and lethal cardiorespiratory arrest. Sometimes death occurs outside the hospital environment, without medical intervention or witnesses and without specific necroscopic signs. Medico legal investigations into sudden sniffing deaths associated with trichloroethylene demand careful analysis of the death scene and related circumstances, a detailed understanding of the deceased's medical history and background of substance abuse and an accurate evaluation of all autopsy and laboratory data, with close cooperation between the judiciary, coroners and toxicologists., (Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Introduction: Oral potassium replacement is still inevitable. To reduce the irritation of the gastric and intestinal mucosa, pellet and matrix based formulations ensuring extended release of potassium chloride are used. The dissolution tests may help to understand the in vivo steps of the release of potassium chloride and the absorption of potassium., Aim: Using dissolution tests extended to 12 hours the authors evaluated potassium chloride release characteristics of pellet and matrix tablet based formulations used for potassium replacement., Method: The tests were performed in line with the CPMP/EWP/QWP/1401/98 guideline at nine time points (0, 1, 2, 3, 4, 5, 7, 9 and 12 hours) in three dissolution media (0.1 M hydrochloric acid, pH 1.2; acetate buffer, pH 4.5; phosphate buffer, pH 6.8)., Results: Similar results were found in all three dissolution media., Conclusions: It is conceivable, that the release of potassium chloride begins already in the stomach (pH = 1.2) and at an average speed of gastrointestinal transit - in about 6-7 hours - 80% of the potassium chloride content of both formulations is dissolved by the time of the entrance to the large bowel. It seems likely, that in vivo in the proximal section of the gastrointestinal tract more potassium chloride is dissolved out of the matrix based formulation, than from the pellet based one. Both formulations meet the clinical requirements of the effective potassium chloride release.

Introduction: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen)., Materials and Methods: We assessed the accuracy of the models' predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated., Results: With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52-4.19mg/L with the Bos model, 1.42-4.04mg/L with the Mumtaz model, and 1.81-4.31mg/L with the Jongeneelen model compared to 0.27-5.44mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4-2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels., Conclusions: The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure.

Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of interindividual variability in TCE metabolism and toxicity, especially in the liver. A hypothesis was tested that amounts of oxidative metabolites of TCE in mouse liver are associated with hepatic-specific toxicity. Oral dosing with TCE was conducted in subacute (600 mg/kg/d; 5 d; 7 inbred mouse strains) and subchronic (100 or 400 mg/kg/d; 1, 2, or 4 wk; 2 inbred mouse strains) designs. The quantitative relationship was evaluated between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P-450-mediated oxidation (trichloroacetic acid [TCA], dichloroacetic acid [DCA], and trichloroethanol) and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione] in serum and liver, and various hepatic toxicity phenotypes. In subacute study, interstrain variability in TCE metabolite amounts was observed in serum and liver. No marked induction of Cyp2e1 protein levels in liver was detected. Serum and hepatic levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1 but not with degree of induction in hepatocellular proliferation. In subchronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Hepatic protein levels of CYP2E1, ADH, and ALDH2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE.

Ethanol is commonly used as a solvent in injectable formulations of poorly water-soluble drugs. The concentrations of ethanol in such formulations are generally considered reasonably safe. It is long known that ethanol can potentiate central effects of sedatives and tranquillizers, particularly the benzodiazepines, most likely as a result of a synergistic interaction at the GABAA receptor. However, whether this occurs at the low systemic doses of ethanol resulting from its use as solvent in parenteral formulations of benzodiazepines is not known. In the present study we evaluated whether a commercial ethanol-containing aqueous solution of diazepam exerts more potent anti-seizure effects than an aqueous solution of diazepam hydrochloride or an aqueous emulsion of this drug in the intrahippocampal kainate model of temporal lobe epilepsy in mice. Spontaneous epileptic seizures in this model are known to be resistant to major antiepileptic drugs. Administration of the ethanol-containing formulation of diazepam caused an almost complete suppression of seizures. This was not seen when the same dose (5 mg/kg) of diazepam was administered as aqueous solution or emulsion, although all three diazepam formulations resulted in similar drug and metabolite concentrations in plasma. Our data demonstrate that ethanol-containing solutions of diazepam are superior to block difficult-to-treat seizures to other formulations of diazepam. To our knowledge, this has not been demonstrated before and, if this finding can be translated to humans, may have important consequences for emergency treatment of acute seizures, series of seizures, and initial treatment of status epilepticus in patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The poly[La-(Glc-Leu)] copolymer was applied in the present investigation as polymeric carrier to fabricate naltrexone (NTX)-loaded poly[La-(Glc-Leu)] microspheres in the single emulsion solvent evaporation technique for the long-term treatment of alcohol dependence. Newly synthesized poly[La-(Glc-Leu)] copolymer exhibited diminished crystallanity, good biocompatibility and favorable biodegradability to be explored for drug delivery application. Scanning Electron Microscopy study revealed smooth and spherical-shaped NTX-loaded polymeric microspheres with a mean size of 10-90 µm. Influence of various decisive formulation variables such as amount of polymer, stabilizer concentration, homogenization speed, homogenization time, drug loading and organic-to-aqueous phase ratio on particle size, and entrapment efficiency was studied. Differential scanning calorimeter and X-ray diffractometry study confirmed the drug entrapment within polymer matrix into the microsphere environment. In vitro drug release showed the sustained drug release of formulation for the period of 28 d giving biphasic release pattern. Histological examination of NTX-loaded poly[La-(Glc-Leu)] microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that NTX-loaded microspheres were biocompatible. Insignificant increase in the serum creatine phosphokinase level (p < 0.05) as compared with the normal value revealed good muscle compatibility of the poly[La-(Glc-Leu)] microsphere system. Biocompatible nature and sustained drug-release action of poly[La-(Glc-Leu)] microspheres may have potential application in depot therapy.

Introduction: Isopropanol is a clear, colorless liquid with a fruity odor and a mild bitter taste. Most commonly found domestically as rubbing alcohol, isopropanol is also found in numerous household and commercial products including cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals., Aim: The aim of this review is to critically review the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning., Methods: OVID MEDLINE and ISI Web of Science were searched to November 2013 using the words "isopropanol", "isopropyl alcohol", "2-propanol", "propan-2-ol", and "rubbing alcohol" combined with the keywords "poisoning", "poison", "toxicity", "ingestion", "adverse effects", "overdose", or "intoxication". These searches identified 232 citations, which were then screened via their abstract to identify relevant articles referring specifically to the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning; 102 were relevant. Further information was obtained from book chapters, relevant news reports, and internet resources. These additional searches produced eight non-duplicate relevant citations., Epidemiology: The majority of isopropanol exposures are unintentional and occur in children less than 6 years of age. Although isopropanol poisoning appears to be a reasonably common occurrence, deaths are rare., Toxicokinetics: Isopropanol is rapidly absorbed following ingestion with peak plasma concentrations occurring within 30 min. It can also be absorbed following inhalation or dermal exposure. Isopropanol is widely distributed with a volume of distribution of 0.45-0.55 L/kg. Isopropanol is metabolized by alcohol dehydrogenase to acetone, acetol and methylglyoxal, propylene glycol, acetate, and formate with conversion of these metabolites to glucose and other products of intermediary metabolism. The elimination of isopropanol is predominantly renal, though some pulmonary excretion of isopropanol and acetone occurs. In one case 20% of the absorbed dose was eliminated unchanged in urine, with the remainder excreted as acetone and metabolites of acetone. The elimination half-life of isopropanol is between 2.5 and 8.0 h, whereas elimination of acetone is slower with a half-life following isopropanol ingestion of between 7.7 and 27 h., Mechanisms of Toxicity: While the exact mechanism of action of isopropanol has not been fully elucidated, brain stem depression is thought to be the predominant mechanism. While the clinical effects are thought to be mostly due to isopropanol, acetone may also contribute., Clinical Features: The major features of severe poisoning are due to CNS and respiratory depression, shock, and circulatory collapse. The most common metabolic effects are an increased osmol (osmolal) gap, ketonemia, and ketonuria. Diagnosis. Poisoning can be diagnosed using the measurement of isopropanol serum concentrations, though these may not be readily available. Diagnosis is therefore more typically made on the basis of the patient's history and clinical presentation. An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis, along with a fruity or sweet odor on the breath and CNS depression support the diagnosis. Management. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Hemodialysis enhances elimination of isopropanol and acetone and should be considered in very severe poisoning., Conclusions: Severe isopropanol poisoning results in CNS and respiratory depression and circulatory collapse. Treatment primarily consists of symptom-directed supportive care. Although hemodialysis increases the elimination of isopropanol and acetone substantially, it should only be considered in severe life-threatening poisonings. Patients usually make a full recovery provided they receive prompt supportive care.

The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE., (© 2013.)

Studies were conducted to determine the anaesthetic/sedative concentrations and durations that would maximise anaesthetic/sedative residue concentrations in rainbow trout (Oncorhynchus mykiss) skin-on fillet tissue. Rainbow trout (167-404 g) were exposed to 50 mg l(-1) AQUI-S(®) 20E (10% active ingredient, eugenol) in 17°C freshwater for durations up to 1440 min, 100 and 250 mg l(-1) AQUI-S(®) 20E for durations up to 240 min, and 500 and 1000 mg l(-1) AQUI-S(®) 20E for durations up to 90 min. Fish exposed to 100 mg l(-1) AQUI-S(®) 20E for durations of 30, 60, 120 and 240 min had the greatest eugenol concentrations in the fillet tissue, 50, 58, 54 and 62 µg g(-1), respectively. All other exposure concentrations and durations resulted in significantly lower eugenol concentrations, i.e. all < 39 µg g(-1).

Sodium hypochlorite (NaOCl) is recommended as an endodontic irrigant in view of its broad antimicrobial and tissue dissolution capacities. To enhance its penetration into inaccessible areas of root canals and to improve its overall effect, the addition of surface-active agents has been suggested. The aim of this investigation was to review the effect of the reduction of the surface tension on the performance of NaOCl in endodontics. A search was performed in the Medline electronic database (articles published up to 28 July 2012, in English) with the search terms and combinations as follows: 'sodium hypochlorite AND surface tension or interfacial force or interfacial tension or surface-active agent or amphiphilic agent or surface active agent or surfactant or tenside or detergent'. The purpose of this search was to identify publications that compared NaOCl alone and NaOCl modified with the addition of a surface-active agent in endodontics. A hand search of articles published online ('in-press' and 'early view'), and appearing in the reference list of the articles included, was further performed, using the same search criteria as the electronic search. The search identified 302 publications, of which 11 fulfilled the inclusion/exclusion criteria of the review. The evidence available suggests that surface-active agents improve the penetration of NaOCl in the main canal and have no effect on its pulp tissue dissolution ability. There are, however, insufficient data to enable a sound conclusion to be drawn regarding the effect of modifying NaOCl's surface tension on lubrication, antimicrobial and smear layer or debris removal abilities., (© 2012 International Endodontic Journal.)

Objectives: We evaluated color vision impairment in workers exposed to organic solvents, especially xylene., Methods: Three groups of subjects, comprising 63 workers occupationally exposed to organic solvents, 122 non-exposed workers in the same industry, and 185 subjects from the general population as controls, were evaluated for color vision. Exposure to solvents was indirectly evaluated by measuring the concentration of a urinary metabolite. Color vision was assessed using the Lanthony Desaturated 15-hue (Lanthony D-15) panel., Results: Color confusion index (CCI) values in the exposed group were significantly higher than in the non-exposed workers or the general population, after adjustment for age and education, and significantly correlated with the concentration of methylhippuric acid. Color vision impairments were detected more frequently among the exposed group, and the most common types were type III and complex impairments. The rate of type III impairments was 9.52% in the exposed group, 1.64% in the non-exposed group, and 1.62% in the general population., Conclusion: Our results support the hypothesis that acquired color vision impairments could be induced by exposure to xylene. Testing for color vision impairment is a relatively simple, non-invasive and sensitive diagnostic method for relatively low-level exposures to xylene., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The role of catalase in methanol (MeOH) teratogenesis is unclear. In rodents it both detoxifies reactive oxygen species (ROS) and metabolizes MeOH and its formic acid (FA) metabolite. We treated pregnant mice expressing either high (hCat) or low catalase activity (aCat), or their wild-type (WT) controls, with either MeOH (4g/kg ip) or saline. hCat mice and WTs were similarly susceptible to MeOH-initiated ophthalmic abnormalities and cleft palates. aCat and WT mice appeared resistant, precluding assessment of the developmental impact of catalase deficiency. Catalase activity was respectively increased at least 1.5-fold, and decreased by at least 35%, in hCat and aCat embryos and maternal livers. MeOH and FA pharmacokinetic profiles were similar among hCat, aCat and WT strains. Although the hCat results imply no ROS involvement, embryo culture studies suggest this may be confounded by maternal factors and/or a requirement for higher catalase activity in the hCat mice., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Several risk assessments have been conducted for ethylene glycol (EG). These assessments identified the kidney as the primary target organ for chronic effects. None of these assessments have incorporated the robust database of species-specific toxicokinetic and toxicodynamic studies with EG and its metabolites in defining uncertainty factors used in reference value derivation. Pertinent in vitro and in vivo studies related to one of these metabolites, calcium oxalate, and its role in crystal-induced nephropathy are summarized, and the weight of evidence to establish the mode of action for renal toxicity is reviewed. Previous risk assessments were based on chronic rat studies using a strain of rat that was later determined to be less sensitive to the toxic effects of EG. A recently published 12-month rat study using the more sensitive strain (Wistar) was selected to determine the point of departure for a new risk assessment. This approach incorporated toxicokinetic and toxicodynamic data and used Benchmark Dose methods to calculate a Human Equivalent Dose. Uncertainty factors were chosen, depending on the quality of the studies available, the extent of the database, and scientific judgment. The Reference Dose for long-term repeat oral exposure to EG was determined to be 15 mg/kg bw/d., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Methanol poisoning has become a considerable problem in Iran. Liver can show some features of poisoning after methanol ingestion. Therefore, our concern was to examine liver tissue histopathology in fatal methanol poisoning cases in Iranian population. In this study, 44 cases of fatal methanol poisoning were identified in a year. The histological changes of the liver were reviewed. The most striking features of liver damage by light microscopy were micro-vesicular steatosis, macro-vesicular steatosis, focal hepatocyte necrosis, mild intra-hepatocyte bile stasis, feathery degeneration and hydropic degeneration. Blood and vitreous humor methanol concentrations were examined to confirm the proposed history of methanol poisoning. The majority of cases were men (86.36%). In conclusion, methanol poisoning can cause histological changes in liver tissues. Most importantly in cases with mean blood and vitreous humor methanol levels greater than 127 ± 38.9 mg/dL more than one pathologic features were detected.

The pilot of a light aircraft that crashed after a loss of power was found to have ethanol in the vitreous and the blood, but almost none in the urine. The globes of the eyes were intact, and the body was refrigerated after recovery until the autopsy was performed the following morning. The pilot was described as a "nondrinker," and additional specialized toxicology testing results were inconsistent with ethanol ingestion. The pilot's body was extensively exposed to fuel during the prolonged extraction. Investigation determined that the aircraft had been fueled with gasoline that contained 10% ethanol. Although exposure to automotive fuel has not been previously described as a source of ethanol in postmortem specimens, it may represent a source for the ethanol detected during postmortem toxicology testing in this case, and this finding may be relevant to other cases with similar exposure.

The aim of this paper is to investigate the removal of toluene from gaseous solution through Glycyrrhiza glabra root (GGR) as a waste material. The batch adsorption experiments were conducted at various conditions including contact time, adsorbate concentration, humidity, and temperature. The adsorption capacity was increased by raising the sorbent humidity up to 50 percent. The adsorption of toluene was also increased over contact time by 12 h when the sorbent was saturated. The pseudo-second-order kinetic model and Freundlich model fitted the adsorption data better than other kinetic and isotherm models, respectively. The Dubinin-Radushkevich (D-R) isotherm also showed that the sorption by GGR was physical in nature. The results of the thermodynamic analysis illustrated that the adsorption process is exothermic. GGR as a novel adsorbent has not previously been used for the adsorption of pollutants.

Background: Most of floating systems have an inbuilt limitation of high variability in the gastric retention time, invariably affecting the bioavailability of drug. An oral sustained release system is formulated to increase gastric residence time by a different way like floating., Aim: The objective of present investigation was to prepare hollow microspheres of Rosiglitazone Maleate in order to increase its bioavailability and reduce the dose frequency., Method: Hollow microspheres of Rosiglitazone Maleate were prepared by O/W emulsion-solvent diffusion technique using biodegradable anionic acrylic resin as a polymer. A mixture of dichloromethane and ethanol (1:1) used as solvent system for drug and polymer with water containing polyvinyl alcohol and salt as external aqueous phase., Result: Entrapment efficiency of drug was increased upto 89.71% as a result of salting out effect. The morphology of Eudragit S100 based microspheres in comparison to Ethyl cellulose and hydroxy propyl methyl cellulose (HPMC) was found to be hollow, spherical, and porous which was analysed by scanning electron microscopy. Microspheres were evaluated for micromeritic profile and found satisfactory. The FT-IR spectra confirmed the absence of drug-polymer interaction. The Eudragit S100 based formulation demonstrated favorable in vitro floating and sustained release profile for longer period of time with increased bioavailability. The anionic acrylic resin based microspheres confirmed to have high floating ability >12 h., Conclusion: Entrapment efficiency and bioavailability of Rosiglitazone Maleate loaded microspheres were increased significantly after modification of method. The release mechanism for formulation was diffusion controlled and had followed first order kinetics, as well as physically and chemically stable as per ICH guidelines.

The liver is the main organ responsible for the metabolism of drugs and toxic chemicals, and so is the primary target organ for many organic solvents. Work activities with hepatotoxins exposures are numerous and, moreover, organic solvents are used in various industrial processes. Organic solvents used in different industrial processes may be associated with hepatotoxicity. Several factors contribute to liver toxicity; among these are: species differences, nutritional condition, genetic factors, interaction with medications in use, alcohol abuse and interaction, and age. This review addresses the mechanisms of hepatotoxicity. The main pathogenic mechanisms responsible for functional and organic damage caused by solvents are: inflammation, dysfunction of cytochrome P450, mitochondrial dysfunction and oxidative stress. The health impact of exposure to solvents in the workplace remains an interesting and worrying question for professional health work.

Methanol is a large volume industrial chemical and widely used solvent and fuel additive. Methanol's well known toxicity and use in a wide spectrum of applications has raised long-standing environmental issues over its safety, including its carcinogenicity. Methanol has not been listed as a carcinogen by any regulatory agency; however, there are debates about its carcinogenic potential. Formaldehyde, a metabolite of methanol, has been proposed to be responsible for the carcinogenesis of methanol. Formaldehyde is a known carcinogen and actively targets DNA and protein, causing diverse DNA and protein damage. However, formaldehyde-induced DNA adducts arising from the metabolism of methanol have not been reported previously, largely due to the absence of suitable DNA biomarkers and the inability to differentiate what was due to methanol compared with the substantial background of endogenous formaldehyde. Recently, we developed a unique approach combining highly sensitive liquid chromatography-mass spectrometry methods and exposure to stable isotope labeled chemicals to simultaneously quantify formaldehyde-specific endogenous and exogenous DNA adducts. In this study, rats were exposed daily to 500 or 2000 mg/kg [¹³CD₄]-methanol by gavage for 5 days. Our data demonstrate that labeled formaldehyde arising from [¹³CD₄]-methanol induced hydroxymethyl DNA adducts in multiple tissues in a dose-dependent manner. The results also demonstrated that the number of exogenous DNA adducts was lower than the number of endogenous hydroxymethyl DNA adducts in all tissues of rats administered 500 mg/kg per day for 5 days, a lethal dose to humans, even after incorporating an average factor of 4 for reduced metabolism due to isotope effects of deuterium-labeled methanol into account.

This study evaluated the influence of the penetration coefficient (PC) and ethanol addition on the penetration depth (PD) of experimental infiltrants into proximal caries lesions in primary molars. Caries lesions (n = 45) were randomly treated with 1 of 4 experimental infiltrants (PC63; PC185; PC204; PC391) for 5 min. Lesion depths and PDs were analysed using dual fluorescence confocal microscopy. Lesions were almost completely infiltrated in all groups. Median PDs and percentage penetrations were not significantly different between groups (p > 0.05). When applied for 5 min, all tested infiltrants were able to infiltrate proximal caries in primary molars nearly completely., (Copyright © 2012 S. Karger AG, Basel.)

Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6 minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.