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Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example.
Berthelsen, R, Sjögren, E, Jacobsen, J, Kristensen, J, Holm, R, Abrahamsson, B, Müllertz, A
International journal of pharmaceutics. 2014;(1-2):356-65
Abstract
The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media.
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Exopolysaccharides and antimicrobial biosurfactants produced by Paenibacillus macerans TKU029.
Liang, TW, Wu, CC, Cheng, WT, Chen, YC, Wang, CL, Wang, IL, Wang, SL
Applied biochemistry and biotechnology. 2014;(2):933-50
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Abstract
Paenibacillus macerans TKU029 can produce exopolysaccharides (EPSs; 3.46 g/L) and a biosurfactant (1.78 g/L) in a medium with 2 % (w/v) squid pen powder as the sole carbon/nitrogen source. The biosurfactant can reduce the surface tension of water from 72.30 to 35.34 mN/m at a concentration of 2.76 g/L and reach an emulsification index of 56 % after a 24-h reaction with machine oil. This biosurfactant is stable at 121 °C for 20 min, over a pH range from 3 to 11, and in <5 % salt solutions. It also shows significant antimicrobial activity, which remains active after treatment at 121 °C and at pH values from 4 to 10, against Escherichia coli BCRC13086, Staphylococcus aureus BCRC10780, Fusarium oxysporum BCRC32121 and Aspergillus fumigatus BCRC30099. Furthermore, human skin shows from 37.3 to 44.3 % hydration after being treated with TKU029 EPSs for 180 min. These results imply that EPSs and the biosurfactant from this strain have potential in cosmetics, for removal of oil contamination, and as antimicrobial agents.
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Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo-controlled study.
Zangaglia, R, Martignoni, E, Glorioso, M, Ossola, M, Riboldazzi, G, Calandrella, D, Brunetti, G, Pacchetti, C
Movement disorders : official journal of the Movement Disorder Society. 2007;(9):1239-44
Abstract
Chronic constipation is the most frequent symptom of autonomic system involvement in Parkinson's disease (PD). Quite often the symptom is severe and impairs patients' quality of life. The objective of this study is to determine the efficacy and safety of an isosmotic macrogol solution for the treatment of constipation in PD patients, in a double-blind, placebo-controlled study. A total of 57 PD patients with constipation were randomly assigned to receive an isosmotic macrogol electrolyte solution (MC-ES; 29 patients) or placebo (28 patients) for 8 weeks. Treatment efficacy was defined as complete relief of the symptom or a marked improvement of two of the following indicators: stool frequency, straining, stool consistency, use of rectal laxatives as a rescue therapy. The responder rates were significantly higher in the MC-ES group both at the first (4 weeks; P < 0.0003) and at the final evaluation (8 weeks; P < 0.0012). The frequency of bowel movements (P < 0.002) and stool consistency (P < 0.006) were significantly changed in the MC-ES group compared to the placebo group. At the final evaluation, a rectal laxative was used by 2 (12.5%) patients on placebo, whereas no use was recorded in the MC-ES group. Responder rate for straining showed a favorable trend in patients treated with macrogol versus placebo. Unified Parkinson's Disease Rating Scale Part III and Parkinson's Disease Questionnaire (PDQ-39) did not show any significant modification in either group during the 8-week treatment period. The results of this placebo-controlled study show the efficacy of MC-ES in the treatment of constipation in PD. MC-ES was well-tolerated and did not affect the course of PD.
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A randomized, multicenter study comparing the safety and efficacy of sodium phosphate tablets with 2L polyethylene glycol solution plus bisacodyl tablets for colon cleansing.
Johanson, JF, Popp, JW, Cohen, LB, Lottes, SR, Forbes, WP, Walker, K, Carter, E, Zhang, B, Rose, M
The American journal of gastroenterology. 2007;(10):2238-46
Abstract
OBJECTIVE The safety and efficacy of NaP tablets have not been compared with 2L PEG lavage solution. A multicenter, investigator-blinded study was conducted to compare the colon-cleansing efficacy of a new NaP tablet formulation with that of 2L PEG solution plus bisacodyl tablets in adults undergoing colonoscopy. METHODS A total of 481 patients were randomized to receive either 32 tablets (48 g) of NaP or 2L PEG solution plus 4 (20 mg) bisacodyl tablets. Quality of colon cleansing was assessed using a 4-point scale (1 = excellent, 2 = good, 3 = fair, and 4 = inadequate), and the primary efficacy end point was mean overall colon-cleansing score. Safety assessments included recording of adverse events and changes in biochemical tests and vital signs. RESULTS A total of 411 patients were included in the efficacy analysis. The mean overall and ascending colon-cleansing scores for NaP tablets were significantly better than PEG plus bisacodyl (overall 1.5 vs 1.8, ascending 1.4 vs 1.8, P < 0.0001 for both). Patients treated with NaP tablets experienced significantly fewer adverse events (66%vs 82%, P= 0.0003) and gastrointestinal symptoms (64%vs 79%, P= 0.0001) compared with patients receiving PEG plus bisacodyl. Patients receiving NaP tablets were significantly less likely to experience abdominal distention, abdominal pain, and vomiting than patients receiving PEG plus bisacodyl (P < 0.0012). Transient fluctuations in laboratory parameters were observed in both treatment groups; however, the fluctuations were more common and of greater magnitude in the NaP group particularly in phosphorous, sodium, and potassium. CONCLUSION The colon-cleansing efficacy of the new 32-tablet NaP dosing regimen in this study was found to be significantly better than the 2L PEG solution plus bisacodyl tablets regimen. The 32-tablet NaP dosing regimen was associated with fewer adverse events. As expected electrolyte shifts were more common and of greater magnitude in the NaP group compared with the PEG plus bisacodyl group; however, both treatment groups demonstrated significant changes in electrolytes and creatinine.
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Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulphate.
Jakasa, I, Verberk, MM, Bunge, AL, Kruse, J, Kezic, S
Experimental dermatology. 2006;(10):801-7
Abstract
In this in vivo human study we assessed the influence of skin damage by sodium lauryl sulphate (SLS) on percutaneous penetration of polyethylene glycols (PEGs) of different molecular weights (MW). Percutaneous penetration of PEGs was determined using tape stripping of the stratum corneum (SC). The forearm skin of volunteers was pretreated with 5% w/w SLS for 4 h, and 24 h later patches with PEGs were applied for 6 h. The penetration parameters were deduced by data regression to Fick's law for unsteady-state diffusion. The trans-epidermal water loss (TEWL) increased after SLS treatment from 6.3 +/- 2.1 to 17.9 +/- 8.7 g/m(2)/h. The diffusion coefficient for all PEGs was increased in the SLS-damaged skin. The increase was smaller for higher MW. In addition, the partition coefficient of PEGs between SC and water was larger in the SLS-compromised skin and showed a tendency to increase with MW. The permeability coefficient decreased gradually with increasing MW of PEGs in both control and SLS-compromised skin. SLS caused a threefold increase in the permeability coefficient for all MWs ranging in control skin from 0.34 to 0.70 x 10(-5) cm/h and in the SLS-compromised skin from 1.20 to 2.09 x 10(-5) cm/h for MW of 590-282 Da. The results of this study show the deleterious effect of SLS on the skin barrier for hydrophilic PEGs. A defective skin barrier will facilitate absorption of other chemicals and local skin effects.
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Sequential application of cold and sodium lauryl sulphate decreases irritation and barrier disruption in vivo in humans.
Fluhr, JW, Bornkessel, A, Akengin, A, Fuchs, S, Norgauer, J, Kleesz, P, Grieshaber, R, Elsner, P
The British journal of dermatology. 2005;(4):702-8
Abstract
BACKGROUND Irritant contact dermatitis (ICD) is one of the most frequent types of occupational dermatitis. Different factors are involved in the development of contact dermatitis. In the food-processing industry, the combined exposure to different irritants may be involved in the development of ICD. Few data have been published regarding the irritant potential of sodium lauryl sulphate (SLS) in combination with cold. OBJECTIVES The present study was intended to analyse whether cold exposure and low skin temperature influence the development of ICD. METHODS Twenty (part I) and 12 (part II) healthy volunteers were exposed twice daily for 4 days to SLS alone, different low temperatures alone (4 degrees C six times for 90 s with an interval of 20 s or 15 degrees C for 10 min) or a combination of cold and SLS (19.6 microL SLS 1% cm(-2), part I; or 52.6 microL SLS 0.5% cm(-2), part II) using the tandem repetitive irritation test. Irritant cutaneous reactions were measured by noninvasive biophysical methods with transepidermal water loss as a parameter for permeability barrier function and skin colour reflectance together with visual scoring as parameters for inflammatory reactions. RESULTS Cold alone caused no significant skin reaction compared with untreated control. Exposure to SLS alone and SLS together with cold (independent of the applied temperature of 4 or 15 degrees C) twice daily induced a clear irritant reaction and barrier disturbance. Reactions did not differ whether SLS was applied before or after cold. Furthermore, 'tandem application' of cold and SLS diminished the barrier disruption and irritant reaction compared with SLS alone. CONCLUSIONS We conclude that the application of cold may have a protective effect on the development of ICD, at least in our short-term model.
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Polyethylene glycol versus sodium phosphate in bowel cleansing for colonoscopy: a randomized trial.
Huppertz-Hauss, G, Bretthauer, M, Sauar, J, Paulsen, J, Kjellevold, Ø, Majak, B, Hoff, G
Endoscopy. 2005;(6):537-41
Abstract
BACKGROUND AND STUDY AIMS There have been conflicting results regarding the adverse effects of established bowel cleansing regimens. The aim of the present study was to compare the effects of three bowel cleansing regimens on subjective well-being, electrolyte balance, cardiac arrhythmia, and the microscopic post-cleansing appearance of the colonic mucosa. PATIENTS AND METHODS A total of 231 consecutive outpatients were randomly assigned to receive bowel preparation for colonoscopy with either 4 l polyethylene glycol (PEG; group I, n = 76); 2 l PEG plus 10 mg Bisacodyl (group II, n = 71); or 90 ml sodium phosphate (group III, n = 84). After bowel preparation, the participants completed a questionnaire on symptoms. Endoscopists blinded to the regimen used gave scores for the quality of cleansing at endoscopy, ranging from poor (0) to very good (5). Blood samples were taken before and after bowel cleansing, electrocardiographic monitoring was used during colonoscopy, and mucosal biopsy samples were taken in the sigmoid colon. RESULTS Bowel preparation in group II was poorer (mean score 3.26) than in groups I (3.88) and III (4.01); P < 0.001 (II vs. III), P < 0.001 (I vs. II). The frequency of arrhythmias and post-cleansing mucosal inflammation was similar in all three groups. Lower serum potassium and higher serum phosphate concentrations were found in group III in comparison with the other groups ( P < 0.001). CONCLUSIONS No differences were detected regarding the effectiveness and safety of bowel preparation with PEG alone and sodium phosphate in individuals without cardiac, renal, or hepatic failure, despite a significantly stronger alteration of the electrolyte balance with sodium phosphate.
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The influence of body mass index on skin susceptibility to sodium lauryl sulphate.
Löffler, H, Aramaki, JU, Effendy, I
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 2002;(1):19-22
Abstract
BACKGROUND The influence of nutrition on the physiological functions of man is well studied. Numerous diseases can be exacerbated by obesity. However, it has not yet been determined whether body weight and body mass index (BMI), as an indicator of a high body fat store, can influence skin sensitivity. OBJECTIVE This study investigates the correlation between body mass index and the epidermal functions, evaluated by bioengineering methods, before and after an irritant patch test with sodium lauryl sulphate (SLS). METHODS Epidermal functions were evaluated using an evaporimeter, chromameter and laser-Doppler-flowmeter. Patch testing was conducted for 48 h with two different concentrations of SLS (0.25% and 0.5%) on the forearms of healthy volunteers. Measurements were performed 24h after patch removal. RESULTS Obese individuals showed significantly increased transepidermal water loss (TEWL), skin blood flow and skin colour (red) as compared to a control group. However, the degree of skin sensitivity to SLS was not correlated with BMI. CONCLUSION Basal biophysical parameters of the skin are primarily correlated with the BMI. This may be caused by obesity-induced physiological changes, e.g. increased sweat gland activity, high blood pressure and physiological temperature-regulating system. The epidermal barrier function, as evaluated after SLS patch testing is, however, not correlated with a high BMI, indicating a normal skin barrier.
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Inter-relationships of paclitaxel disposition, infusion duration and cremophor EL kinetics in cancer patients.
van Zuylen, L, Gianni, L, Verweij, J, Mross, K, Brouwer, E, Loos, WJ, Sparreboom, A
Anti-cancer drugs. 2000;(5):331-7
Abstract
Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p<0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2=0.733; p=0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations.