Mannitol

The applicability of a two-parameter Fickian diffusion model for predicting the skin steady-state permeability based on measurements of the transient transport of permeants across the skin was tested. Using five model permeants possessing different physicochemical properties and pig skin as the model membrane, the skin permeabilities predicted by the two-parameter Fickian diffusion model were compared with the measured skin permeabilities. Results show that the transient skin permeation profiles of the hydrophobic permeants, estradiol, testosterone, and dolichol, across splitthickness pig skin can be modeled adequately by the two-parameter Fickian diffusion model (with constant parameter values), and therefore, that this model can be utilized to shorten the experimental time required to determine the skin permeabilities of these compounds. However, the skin permeabilities of the highly hydrophilic permeants, mannitol and sucrose, predicted by the two-parameter Fickian diffusion model (with constant parameter values) were significantly lower than the experimentally determined values, indicating that the dominant skin pathway of polar permeants within the excised pig skin undergoes significant structural changes during the in vitro diffusion cell studies. Although the skin permeability values determined experimentally using the traditional steady-state method normally correspond to a highly hydrated skin sample, the two-parameter Fickian diffusion model enables an estimation of the skin permeability of the skin membrane at its less-hydrated state (a condition more representative of in vivo and clinical situations). Using the two-parameter Fickian diffusion model and a recently developed skin porous-pathway theory, the effects of skin hydration on the skin porous pathway within the excised pig skin were characterized. Specifically, we found that hydration leads to induction of new pores/reduction of the tortuosity of existing pores within the excised pig skin during the 48 h diffusion cell studies conducted, while the skin average pore radii remain relatively constant ($26 Å ) for up to 48 h. ß

Background: A new indirect bronchial provocation test measuring airway responsiveness by using inhaled mannitol was recently introduced. Objective: The aim of this study was to examine the diagnostic properties of airway responsiveness to inhaled mannitol in the assessment of asthma in an unselected sample of young adults. Methods: Two hundred thirty-eight young adults randomly drawn from the nationwide civil registration list were challenged with inhaled, dry-powder mannitol. A respiratory specialist, blind to the test results, classified all 238 subjects with respect to the presence of asthma. The classification was based on respiratory symptoms, spirometric results, atopy, and fraction of exhaled nitric oxide values and response to inhaled b 2 -agonists. On this basis, sensitivity, specificity, and predictive values were assessed to different cutoff values of the test. A receiver operating characteristic curve was constructed, and the accuracy of the test, defined as the area under the curve, was computed. Results: Fifty-one (21.4%) subjects had current asthma. Of 33 subjects with airway hyperresponsiveness to mannitol, 30 had current asthma. The specificity and sensitivity were 98.4% (95% CI, 96.2% to 99.4%) and 58.8% (95% CI, 50.7% to 62.6%), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 90.9% (95% CI, 78.4% to 96.8%) and 89.8 (95% CI, 87.7% to 90.7%), respectively. The area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.95). Conclusions: In an unselected sample of young adults, bronchial provocation with inhaled dry-powder mannitol had a high diagnostic specificity for the diagnosis of asthma. (J Allergy Clin Immunol 2009;124:928-32.)

Ischemia/reperfusion (I/R) injury is an important cause of acute renal failure because of oxidative, inflammatory, and apoptotic mechanisms. The aim of the present study was to examine any possible protective effects of levosimendan in an in vivo pig model of renal I/R injury. In 40 anesthetized pigs (eight groups of five pigs each), I/R was induced by clamping-reopening the left renal artery. During ischemia, in three groups of pigs, levosimendan and the multiorgan preservation solution Custodiol, alone or in combination with levosimendan, were infused in the renal artery. In two other groups of animals, levosimendan in combination with Custodiol was administered after the intrarenal nitric-oxide (NO) synthase blocker N -nitro-L-arginine methyl ester (L-NAME) or the mitochondrial ATP-sensitive K ϩ channel (K ATP channel) inhibitor 5-hydroxydecanoate (5-HD). In the other animals, saline, L-NAME, or 5-HD were administered alone. Throughout the experiments, urinary N-acetyl-␤-glucosaminidase (NAG) release was measured, and renal function was assessed. Moreover, renal biopsy samples were taken for the detection of apoptosis and tissue peroxidation. In pigs treated with levosimendan or the combination of levosimendan and Custodiol, NAG, peroxidation, and apoptotic markers were lower than in animals treated with Custodiol alone. In addition, renal function was better preserved, and cell survival and antioxidant systems were more activated. All beneficial effects were prevented by L-NAME and 5-HD. In conclusion, levosimendan alone or in combination with Custodiol exerted better protection against renal I/R injuries than Custodiol alone through antioxidant, antiapoptotic, and prosurvival actions depending on mitochondrial K ATP channels and NO-related mechanisms.

Background: The effectiveness of aerosol therapy is significantly reduced by the mucus layer covering the airways of the tracheobronchial tree. According to the present concept, drug particles are delivered to the lung together with the functional carrier particle that facilitates both the drug transport into the lungs and the penetration of deposited particles through the mucus. The approach of manufacturing multicomponent powders with mucoactive compounds and anti-asthmatic medicines (DSCG) bound together in a single particle is additionally considered. Methods: Powders were produced with the spray-drying technique from aqueous precursor solutions containing pure low molecular weight dextran, pure mannitol and dextran/mannitol-N-acetyl cysteine (NAC) mixtures (4:1 and 1:1). NAC has been selected for this purpose as a compound, which is known to be mucolytic. Dextran and mannitol are potentially applicable in the field of inhalation drug delivery. They have been used as stabilizers of functional carrier particles. Powders were characterized for their yield and physicochemical properties including: morphology (SEM), moisture content and thermal properties (DSC). Aerosol performance was determined with NGI impactor after standardized aerosolization of the produced powders in a commercial DPI. Results: Particle size distributions of dextran-NAC powders were characterized by high fine particle fraction (45-62%), which assures good particle deposition in the lower airways. The thermodynamic properties of the powders based on the temperature of the glass transition T g (50-63 • C) suggest the required stability during storage at moderate humidity. Conclusions: Preliminary examination of the required properties of these particles confirms their potential as functional carriers for pulmonary drug delivery.

The role of calcium-mediated signaling has been extensively studied in plant responses to abiotic stress signals. Calcineurin Blike proteins (CBLs) and CBL-interacting protein kinases (CIPKs) constitute a complex signaling network acting in diverse plant stress responses. Osmotic stress imposed by soil salinity and drought is a major abiotic stress that impedes plant growth and development and involves calcium-signaling processes. In this study, we report the functional analysis of CIPK21, an Arabidopsis (Arabidopsis thaliana) CBL-interacting protein kinase, ubiquitously expressed in plant tissues and up-regulated under multiple abiotic stress conditions. The growth of a loss-of-function mutant of CIPK21, cipk21, was hypersensitive to high salt and osmotic stress conditions. The calcium sensors CBL2 and CBL3 were found to physically interact with CIPK21 and target this kinase to the tonoplast. Moreover, preferential localization of CIPK21 to the tonoplast was detected under salt stress condition when coexpressed with CBL2 or CBL3. These findings suggest that CIPK21 mediates responses to salt stress condition in Arabidopsis, at least in part, by regulating ion and water homeostasis across the vacuolar membranes. Drought and salinity cause osmotic stress in plants and severely affect crop productivity throughout the world. Plants respond to osmotic stress by changing a number of cellular processes (

Background: 1E10 monoclonal antibody is a murine anti-idiotypic antibody that mimics N-glycolyl-GM3 gangliosides. This antibody has been tested as an anti-idiotypic cancer vaccine, adjuvated in Al(OH) 3 , in several clinical trials for melanoma, breast, and lung cancer. During early clinical development this mAb was obtained in vivo from mice ascites fluid. Currently, the production process of 1E10 is being transferred from the in vivo to a bioreactor-based method.

Background: Poly-L-lactic acid gained U.S. Food and Drug Administration approval for use in human immunodeficiency virus-related facial lipoatrophy in August of 2004. Since that time, it has become available for use in the United States for human immunodeficiency virus facial lipoatrophy patients and for off-label uses in other areas for soft-tissue contouring. This article is intended to enumerate reconstitution, injection techniques, management, and avoidance of complications. Methods: The authors have pooled their experiences to arrive at a consensus opinion for recommendations on treatment protocols for injectable poly-L-lactic acid use. Results: This article prescribes techniques to achieve safer, consistent results while minimizing risks of complications with injectable poly-L-lactic acid. Although the product has been used widely in Europe since 1999, physicians in the United States have only recently begun to explore the uses of Sculptra as a volumizing agent in the face and the body. U.S. physicians have benefited from the European experience with this product, including early problems secondary to overaggressive use, low-volume reconstitution, higher volume injection of product at one session, and inadequate time between injection sessions. Conclusions: The authors therefore have opted for a more conservative approach in their treatment recommendations. Higher volume dilution (8 to 12 cc), fewer vials used at each session, injections placed in the subcutaneous plane without any product being placed in the dermis, adequate time between injection sessions (at least 6 weeks), and postinjection patient massage should decrease the risks and avoid the potential complications associated with poly-L-lactic acid soft-tissue augmentation.

The objective of the present study was to investigate the iontophoretic transport behavior across multiple membranes of different barrier properties. Spectra/ Por 1 (SP) and Ionac membranes were the synthetic membranes and sclera was the biomembrane in this model study. The barrier properties of SP membranes were determined individually in passive and iontophoresis transport experiments with tetraethylammonium ion (TEA), chloride ion (Cl), and mannitol as the model permeants. Passive and iontophoretic transport experiments were then conducted with an assembly of SP membranes. The contribution of electroosmosis to iontophoresis was assessed using the mannitol data. Model analysis was performed to study the contribution of diffusion and electromigration to electrotransport across the multiple membrane system. The effects of membrane barrier thickness upon ion-exchange membrane-enhanced iontophoresis were examined with Ionac, SP, and sclera. The present study shows that iontophoretic transport of TEA across the membrane system was related to the thicknesses and permeability coefficients of the membranes and the electromobilities of the permeant across the individual membranes in the assembly. Model analysis suggests significant contribution of diffusion within the membranes across the membrane system, and this mechanism is relatively independent of the current density applied across the system in iontophoresis dominant transport. ß Ã Mean AE SD, n ! 3. a Number of membranes in parentheses. b Calculated using Eq. (3).

The utilization of cryopreserved red blood cell (RBC) units had been limited by a maximum postdeglycerolization storage of 24 hours at 1 to 6°C until the recent development of a closed system for the glycerolization and deglycerolization process. STUDY DESIGN AND METHODS: Sixty leukoreduced additive solution (AS), AS-1 (n = 30) and AS-3 (n = 30) RBC units from 500-mL whole blood (WB) collections were stored for 6 days, glycerolized, frozen at −70 ± 5°C for at least 14 days, thawed, deglycerolized, and stored for 15 days at 1 to 6°C. Glycerolization and deglycerolization were performed with the ACP 215. In-vitro variables were tested before glycerolization, on Day 0, and Day 15 after deglycerolization storage. Forty donors were assessed for double-label 24-hour percent recovery, and T 1/2 survival time was measured for 20 donors. RESULTS: Postdeglycerolization mean ± standard deviation in-vitro RBC mass recoveries were 93 ± 5 percent for AS-1 and 95 ± 4 percent for AS-3. Mean hemoglobin ± standard deviation after deglycerolization was 50.5 ± 5.5g for AS-1 and 50.1 ± 3.5g for AS-3. Mean hemolysis (Day 15) was 0.36 ± 0.11 percent for AS-1 and 0.38 ± 0.13 percent for AS-3. Double-label 24-hour in-vivo recoveries were 82.5 ± 7.8 percent for AS-1 and 81.4 ± 7.1 percent for AS-3. The 51 Cr T 1/2 value was 41.8 ± 3.97 for AS-1 and 40.6 ± 7.11 for AS-3. Other in-vitro variables were as expected. CONCLUSION: Leukoreduced AS-1 and AS-3 RBCs after frozen storage at −70 ± 5°C can be stored for up to 14 days when processing is performed with the ACP 215 system with resuspension of deglycerolized RBCs in AS-3.

Three procedures for pre-operative preparation of the colon were compared during a controlled multicentre study in 215 patients. Though mechanical irrigation with a 10 p. cent mannitol solution is definitely superior as far as the degree of intestinal emptying obtained, no significant difference was noted in the frequency or severity os postoperative infections after conventional preparations by digestive tract irrigation with or without intestinal antibiotics. This method is limited by its tolerance (67 p. cent), its advantages are its rapidity and cost, elective indications being ascending colon lesions with little or no stenosis in young subjects. In other circumstances it has to be compared with the conventional methods of preparation, which should still be employed before operation in subjects who are elderly and/or have moderate to severe stenosis. The addition of antibiotics (neomycin, metronidazole by mouth) reduces the incidence of postoperative sepsis to a marked but non-s...

Background: The combination of bicarbonate and mannitol (BIC/MAN) is commonly used to prevent renal failure (RF) in patients with rhabdomyolysis despite the absence of sufficient evidence validating its use. The purpose of this study was to determine whether BIC/ MAN is effective in preventing RF in patients with rhabdomyolysis caused by trauma.

The budding yeast Pichia pastoris is an attractive system for exploring certain questions in cell biology, but experimental use of this organism has been limited by a lack of convenient expression vectors. Here we describe a set of compact vectors that should allow for the expression of a wide range of endogenous or foreign genes in P. pastoris. A gene of interest is inserted into a modified pUC19 polylinker; targeted integration into the genome then results in stable and uniform expression of this gene. The utility of these vectors was illustrated by expressing the bacterial -glucuronidase (GUS) gene. Constitutive GUS expression was obtained with the strong GAP promoter or the moderate YPT1 promoter. The regulatable AOX1 promoter yielded very strong GUS expression in methanol-grown cells, negligible expression in glucose-grown cells, and intermediate expression in mannitol-grown cells.

The metabolism of glucose by nongrowing cells of Lactococcus lactis strain FI7851, constructed from the wild-type L. lactis strain MG1363 by disruption of the lactate dehydrogenase (ldh) gene [Gasson, M.J., Benson, K., Swindel, S. & Griffin, H. (1996) Lait76, 33–40] was studied in a noninvasive manner by 13C-NMR. The kinetics of the build-up and consumption of the pools of intracellular intermediates mannitol 1-phosphate, fructose 1,6-bisphosphate, 3-phosphoglycerate, and phosphoenolpyruvate as well as the utilization of [1-13C]glucose and formation of products (lactate, acetate, mannitol, ethanol, acetoin, 2,3-butanediol) were monitored in vivo with a time resolution of 30 s. The metabolism of glucose by the parental wild-type strain was also examined for comparison. A clear shift from typical homolactic fermentation (parental strain) to a mixed acid fermentation (lactate dehdydrogenase deficient; LDHd strain) was observed. Furthermore, high levels of mannitol were transiently produced and metabolized once glucose was depleted. Mannitol 1-phosphate accumulated intracellularly up to 76 mm concentration. Mannitol was formed from fructose 6-phosphate by the combined action of mannitol-1-phosphate dehydrogenase and phosphatase. The results show that the formation of mannitol 1-phosphate by the LDHd strain during glucose catabolism is a consequence of impairment in NADH oxidation caused by a highly reduced LDH activity, the transient production of mannitol 1-phosphate serving as a regeneration pathway for NAD+ regeneration. Oxygen availability caused a drastic change in the pattern of intermediates and end-products, reinforcing the key-role of the fulfilment of the redox balance. The flux control coefficients for the step catalysed by mannitol-1-phosphate dehydrogenase were calculated and the implications in the design of metabolic engineering strategies are discussed.

Freeze drying is a complex, time consuming and thus expensive process, hence creating a need for understanding the material behaviour in the process environment and for process optimization. Near-infrared (NIR) spectroscopy offers the opportunity to monitor physicochemical changes of the formulation during freeze-drying. The aim of this work was to examine whether NIR spectroscopy allows in-line monitoring of all components during the entire freeze-drying process of a multi-component pharmaceutical formulation (a solution of fenofibrate and mannitol in a mixture of tertiary-butyl alcohol, and water). To extract useful information of all components in the formulation from the large multivariate data-sets obtained during in-line spectroscopic monitoring, several spectral pre-processing techniques and spectral data analysis techniques such as the mean of selected wavenumbers (Mws), the correlation coefficient (Cor-rCoef) and principal component analysis (PCA) have been evaluated and compared. To find out whether these chemometric techniques are also able to differentiate between changes in the process settings influencing the freeze-drying process of the formulation, freeze-drying processes were performed at four different conditions. Results demonstrated that in-line measurements using NIR spectroscopy were possible in an icy environment and that a further process understanding could be obtained. Data-analysis revealed the crystallization behaviour of each of the four components. In addition, using the three preprocessing techniques allowed observe the sublimation of the solvents. Mws and CorrCoef have proven to be adequate methods for monitoring the main physicochemical changes of product during the processes; this affirmation was confirmed by observing the outputs of PCA for entire processes.

Background/Aims: The aim of this exploratory trial was to establish if the probiotic Bifidobacterium natren life start (NLS) strain strain may affect the clinical course and pathophysiological features of patients with untreated celiac disease (CD). Positive findings would be helpful in directing future studies.

Several inborn errors of metabolism with abnormal polyol concentrations in body fluids are known to date. Most of these defects can be diagnosed by the assessment of urinary concentrations of polyols. We present two methods using tandem mass spectrometry for screening for inborn errors affecting polyol metabolism. Urine samples supplemented with internal standards ([ 13 C 4 ]erythritol, [ 13 C 2 ]arabitol and [ 2 H 3 ]sorbitol) were desalted by a mixed-bed ion-exchange resin. Separation was achieved by two different columns. Sugar isomers could not be separated using a Prevail Carbohydrate ES 54 column (method 1), whereas with the other column (Aminex HPX-87C) separation of the isomers was achieved (method 2). Multiple reaction monitoring polyol detection was achieved by tandem mass spectrometry with an electron ion-spray source operating in the negative mode. Age-related reference ranges of polyols (erythritol, treitol, arabitol, ribitol, xylitol, galactitol, mannitol, sorbitol, sedoheptitol and perseitol) in urine were established. The applicability of the method was demonstrated by the abnormal polyol concentrations observed in patients with transaldolase deficiency, ribose-5-phosphate isomerase deficiency and classical galactosaemia. This paper describes two methods for the analysis of urinary polyols by liquid chromatography-tandem mass spectrometry. Method 1 is a fast screening method with the quantification of total isomers and method 2 is a more selective method with the separate quantification of the polyols. Both methods can be used for diagnosing inborn errors of metabolism affecting polyol metabolism. Polyols, or polyhydric alcohols, can be formed by the reduction of sugars and are classified on the basis of the numbers of carbon atoms: erythritol and threitol are C 4-polyols (tetritols);

Purpose. To study the effect of processing conditions on the physical state of mannitol during various stages of the lyophilization cycle of a protein formulation. Materials and Methods. Mannitol and trehalose were used as the bulking agent and lyoprotectant, respectively. The physical state of mannitol during various stages of freeze-drying cycle, in the absence and presence of a model protein, was characterized using low temperature X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC). Results. Mannitol did not crystallize even when the solution for lyophilization was cooled to j45-C at a slow cooling rate of 1-C/min. Annealing facilitated mannitol crystallization, and in the absence of the protein, a mixture of d-mannitol and mannitol hemihydrate was obtained at both low (j18-C) and high (j8-C) annealing temperatures. However, in the presence of protein, the high annealing temperature promoted d-mannitol crystallization and inhibited formation of mannitol hemihydrate, while the low annealing temperature facilitated the formation of mannitol hemihydrate. Interestingly, the hemihydrate in the frozen solution was retained in the final lyophile, even when the primary and secondary drying temperatures were as high as j5 and 65-C, respectively. Conclusions. The presence of protein as well as the processing conditions (annealing temperature and time, primary and secondary drying temperatures) influenced the physical form of mannitol in the final lyophile. The protein promoted formation of d-mannitol while inhibiting the formation of mannitol hemihydrate. Since the physical form of mannitol was greatly influenced by the presence of protein, it will be prudent to conduct the preliminary lyophilization cycle development studies in the presence of the protein. If mannitol hemihydrate is formed during annealing, its dehydration may require high secondary drying temperature.

Background: To determine whether renal perfusion with cold crystalloid solution enriched with histidine-tryptophanketoglutarate (Custodiol; Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) provides better protection against renal ischemic injury than cold lactated Ringer's solution in patients undergoing thoracoabdominal aortic aneurysm open repair. Methods: We analyzed a prospectively compiled database containing all 111 consecutive patients who underwent thoracoabdominal aortic aneurysm open repair at our center from 2008 to 2011. A cohort of 104 consecutive patients was identified of which 50 (48%) had renal perfusion with Custodiol and 54 (52%) with lactated Ringer's solution. Propensity score matching based on baseline clinical variables, which were expected to influence renal outcomes, was performed to correct for any bias that may have been associated with the use of Custodiol. Acute kidney injury (AKI) as defined by Kidney Disease Improving Global Outcomes guidelines and perioperative estimated glomerular filtration rate were compared in the two groups. Independent predictors of AKI were also identified by multivariate analysis. Results: After propensity score matching, we were able to match 42 Custodiol cases one-to-one with those receiving perfusion with lactated Ringer's solution. Overall 30-day mortality was 5.9%; temporary hemodialysis or continuous veno-venous hemofiltration was needed in 4.8% of the patients without any case of dialysis at discharge. Freedom from AKI was significantly increased in the Custodiol group (38.1% vs 9.5%; P [ .002) despite longer total renal ischemic time (51.5 6 16.4 minutes vs 43.6 6 16.0 minutes; P [ .05). By analysis of variance for repeated measures, a significant upward trend of perioperative estimated glomerular filtration rate was observed in the Custodiol group (group 3 time interaction [ F 3,66 ; P < .001), and by multivariate analysis, Custodiol perfusion was the only independent predictor of non-AKI (P [ .04). Conclusions: The use of Custodiol was safe and provided improved perioperative renal function compared with lactated Ringer's solution. Randomized trials are needed to confirm these data and to assess their clinical consequences. (J Vasc Surg 2014;59:623-33.) From the Vascular Surgery a and Anesthesia and Intensive Care, b Università Vita-Salute, San Raffaele Scientific Institute.

The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions. ß A 4 mL 5% (w/v) d-mannitol (further abbreviated as ''mannitol'') solution was used as model for

subdural hematomas who received preoperative high-dose mannitol (HDM) versus conventional-dose mannitol treatment. METHODS: One hundred seventy-eight adult patients with non-missile, traumatic, acute, subdural hematomas were prospectively and randomly assigned to receive emergency, preoperative, intravenous HDM treatment (91 patients), compared with a control group treated with a lower preoperative mannitol dose (87 patients). RESULTS: Preoperative improvement of abnormal pupillary widening was significantly more frequent in the study group than in the control group of patients (P < 0.0001). Preoperative HDM treatment was also associated with significantly better clinical outcomes at 6-month follow-up evaluations (P < 0.01). Postoperative physiological findings revealed statistically significant between-group differences, with higher intracranial pressure and lower cerebral extraction of oxygen (relative cerebral hyperperfusion) in the control group, compared with the HDM group. Postoperative global brain ischemia (abnormally low arteriojugular lactate difference values) was rare and was detected in 2.2 and 3.4% of the patients in the study and control groups, respectively. CONCLUSION: Emergency preoperative HDM administration was associated with improved clinical outcomes for patients with acute subdural hematomas. Preoperative improvement of abnormal pupillary widening and better postoperative control of intracranial hypertension and associated relative cerebral hyperperfusion seemed to be relevant factors associated with improved outcomes. (Neurosurgery 49:864-871, 2001)

1,6-Diamino-1,6-dideoxy-2,3,4,5-tetra-O-methyl-D-mannitol (and its L-iditol analogue) suitable for their utilization as monomers in the preparation of linear polyamides are described. Regio-and stereoregular polyamides of the AABB-type have been prepared by the active ester polycondensation method from these C 2 symmetric monomers and suberic and dodecanedioic acids. The resulting polyamides were obtained in fair yields (70-60%) and were characterized by elemental analyses and infrared and 1 H and 13 C NMR spectroscopies. Their M w and M w /M n were determined by GPC relative to polystyrene standards. All of them were gummy non-crystalline solids.

The hPepT1-mediated transport properties of a series of 11 synthesized -and γ-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two -dipeptides act as substrates and are transported across the cell monolayers. These two are lessefficient substrates than R-peptides. Larger derivatives than -dipeptides do not act as hPepT1 substrates, but instead, they appear to be substrates for P-glycoprotein efflux. ionization; HOBt, 1-hydroxy-1H-benzotriazole hydrate; TFA, trifluoroacetic acid. Three-letter amino-acid abbreviations are used for homologated amino acid derivatives: hXaa ( n , homoamino acid) 1 and γhhXaa (γ m,n , doubly homologated amino acid), where n indicates the position of the proteinogenic side chain.

Mannitol is a fructose-derived, 6-carbon sugar alcohol that is widely found in bacteria, yeasts, fungi, and plants. Because of its desirable properties, mannitol has many applications in pharmaceutical products, in the food industry, and in medicine. The current mannitol chemical manufacturing process yields crystalline mannitol in yields below 20 mol% from 50% glucose/50% fructose syrups. Thus, microbial and enzymatic mannitol manufacturing methods have been actively investigated, in particular in the last 10 years. This review summarizes the most recent advances in biological mannitol production, including the development of bacterial-, yeast-, and enzyme-based transformations.

The objective of this study was to subject mannitol, either as a sole carbon source or in combination with glucose, and aqueous extracts of the kelp Saccharina spp., containing mannitol and laminarin, to acetone-butanol fermentation by Clostridium acetobutylicum (ATCC 824). Both mannitol and glucose were readily fermented. Mixed substrate fermentations with glucose and mannitol resulted in diauxic growth of C. acetobutylicum with glucose depletion preceding mannitol utilization. Fermentation of kelp extract exhibited triauxic growth, with an order of utilization of free glucose, mannitol, and bound glucose, presumably laminarin. The lag in laminarin utilization reflected the need for enzymatic hydrolysis of this polysaccharide into fermentable sugars. The butanol and total solvent yields were 0.12 g/g and 0.16 g/g, respectively, indicating that significant improvements are still needed to make industrial-scale acetone-butanol fermentations of seaweed economically feasible.

Various formulations of Loratadine Chewable tablets containing different pharmaceutical compositions with simple manufacturing procedures were developed by using different excipients. The excipients used here are Lactose, Mannitol, Ethyl cellulose, Microcrystalline cellulose, Maize Starch, Citric Acid, Aspartame, Colloidal silicon dioxide, Magnesium Stearate, D & C Yellow No 10 and Raspberry flavour. Oral chewable tablets are the most preferred among the conventional dosage forms due to its aesthetic appeal and ease of administering to children, which has entered the market. Loratadine is formulated into chewable tablets by wet granulation method using suitable excipients as mentioned earlier, which are evaluated by using simple analytical equipments. The chewable tablet was better presented using artificial sweetener Aspartame and Raspberry flavour as flavouring agent. The chewable tablets are prepared to ensure that they are easily crushed by chewing. The tablets were evaluated for weight variation, hardness, friability; drug content and mouth feel along with in-vitro dissolution. As per monograph, the chewable tablets are not required to comply with disintegration test. Wet granulation process using Mannitol, Lactose, Micro crystalline cellulose (Avicel-CE 15), Ethyl cellulose and Sweeteners and Flavours were found to be simple and robust method to prepare chewable tablets.

Purpose. To develop a procedure based on manometric temperature measurement (MTM) and an “expert system” for good practices in freeze drying that will allow development of an optimized freeze-drying process during a single laboratory freeze-drying experiment. Methods. Freeze drying was performed with a FTS Dura-Stop/Dura-Top freeze dryer with the manometric temperature measurement software installed. Five percent solutions of glycine, sucrose, or mannitol with 2 ml to 4 ml fill in 5 ml vials were used, with all vials loaded on one shelf. Details of freezing, optimization of chamber pressure, target product temperature, and some aspects of secondary drying are determined by the expert system algorithms. MTM measurements were used to select the optimum shelf temperature, to determine drying end points, and to evaluate residual moisture content in real-time. MTM measurements were made at 1 hour or half-hour intervals during primary drying and secondary drying, with a data collection frequency of 4 points per second. The improved MTM equations were fit to pressure-time data generated by the MTM procedure using Microcal Origin software to obtain product temperature and dry layer resistance. Using heat and mass transfer theory, the MTM results were used to evaluate mass and heat transfer rates and to estimate the shelf temperature required to maintain the target product temperature. Results. MTM product dry layer resistance is accurate until about two-thirds of total primary drying time is over, and the MTM product temperature is normally accurate almost to the end of primary drying provided that effective thermal shielding is used in the freeze-drying process. The primary drying times can be accurately estimated from mass transfer rates calculated very early in the run, and we find the target product temperature can be achieved and maintained with only a few adjustments of shelf temperature. The freeze-dryer overload conditions can be estimated by calculation of heat/mass flow at the target product temperature. It was found that the MTM results serve as an excellent indicator of the end point of primary drying. Further, we find that the rate of water desorption during secondary drying may be accurately measured by a variation of the basic MTM procedure. Thus, both the end point of secondary drying and real-time residual moisture may be obtained during secondary drying. Conclusions. Manometric temperature measurement and the expert system for good practices in freeze drying does allow development of an optimized freeze-drying process during a single laboratory freeze-drying experiment.

An extensive matrix of different growth conditions including media, incubation time, inoculum volume, surface area and media volume were investigated in order to maximize the yield of bacterial cellulose produced by Gluconacetobacter xylinus, which will be used as reinforcement material to produce fully biodegradable composites. Crystallinity was shown to be controllable depending on the media and conditions employed. Samples with significant difference in crystallinity in a range from 50% to 95% were produced. Through experimental design, the yield of cellulose was maximized; primarily this involved reactor surface area design, optimized media and the use of mannitol being the highest celluloseproducing carbon source. Increasing the volume of the media did achieve a higher cellulose yield, however this increase was not found to be cost or time effective.

Montanide® ISA 720 is an experimental adjuvant, formulated as water-in-oil emulsions, that induces high antibody titers in several animal species. It has been used in human vaccine trials with malaria and HIV vaccines. The heightened response is likely due, in part, to the formation of a depot at the injection site. However, post-formulation modifications were seen with seven proteins tested during storage of ISA 720 formulations at 37 °C for 1 week and two proteins stored longer at 4 °C. Potency studies in mice, in which the stored vaccines were diluted into placebo emulsions for appropriate dosing, indicated that this instability could lead to loss of immunogenicity in the post-injection depot, limiting the allowable storage time of preformed vaccines. We describe point-of-injection formulation for ISA 720 vaccines that meets the requirement for in vitro stability. For preformed vaccines, addition of glycine or glycylglycine prevented antigen modification on storage at 37 °C, providing a potential way of stabilizing antigen/ISA 720 formulations for in vitro storage and the post-injection depot.

A co-processed excipient was prepared from commercially available crystalline mannitol and αchitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol-chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol-chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and lowstrength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.

A three-day pretreatment of olive somatic embryos (SE) with 0.75 M sucrose, combined with cryoprotection (0.5 M DMSO, 1 M sucrose, 0.5 M glycerol and 0.009 M proline) and controlled rate cooling, supported regrowth (as 34.6% fresh weight gain) and resumption of embryo development after cryopreservation. Pretreatment with mannitol or sorbitol did not support regrowth. Profiles of sugars, proline, antioxidant enzymes, Reactive oxygen species (ROS), secondary oxidation products and ethylene were constructed for the most successful (0.75 M) pretreatment series. Sucrose was the optimal pretreatment for supporting recovery, it also elevated glutathione reductase (GR) activity compared to controls, whereas superoxide dismutase (SOD), catalase and guaiacol peroxidase activities remained relatively unchanged. Superoxide dismutase activity was higher in SE pretreated with sucrose, compared with those pretreated with polyols; H 2 O 2 was enhanced in SE pretreated with sorbitol and sucrose compared to mannitol. The overall trend for ethylene and • OH production revealed their levels were highest in SE pretreated with polyols albeit, for individual treatments this was not always the case. Generally, pretreatments did not significantly change embryo secondary oxidation profiles of ThioBarbituric Acid Reactive Substances (TBARS) and Schiff's bases. In combination these studies suggest oxidative processes may influence regrowth of cryopreserved olive SE and that optimal pretreatments could, in part, increase tolerance by an overall enhancement of endogenous antioxidants (particularly GR), proline and sugars.

Inhalable dry-powder aggregates of drug-loaded thermally sensitive poly(caprolactone) (PCL) nanoparticles are produced using spray-freeze-drying (SFD) as the low melting point of PCL prohibits the use of high-temperature spray-drying. The effects of freeze-drying adjuvant formulation on the particle morphology, aerodynamic diameter, aqueous re-dispersibility, flowability, and production yield are examined using mannitol and poly(vinyl alcohol) (PVA) as the adjuvants. The primary role of the adjuvant is to prevent irreversible nanoparticle coalescences during freeze-drying, thereby the nanoparticle aggregates can readily re-disperse into primary nanoparticles in an aqueous environment hence retaining their therapeutic functions. The nanoparticle aggregates produced using either adjuvant exhibit large, porous, and spherical morphologies suitable for dry-powder-inhaler delivery. The nanoparticle aggregates exhibit good flowability and effective aerosolization off the inhaler. The adjuvant selection governs the resultant nanoparticle-adjuvant structures, where PCL nanoparticles are physically dispersed in porous mannitol matrix, whereas PVA are coated onto the nanoparticle surface. Importantly, nanoparticle aggregates produced by SFD exhibit significantly higher aqueous re-dispersibility than those produced by spray-drying, which signifies the suitability of SFD as the method to produce solid-dosage-form of thermally sensitive nanoparticles. Overall, using PVA as adjuvant leads to more stable morphology, superior aqueous re-dispersibility, and higher production yield compared to the mannitol formulation.

The aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer ® inhaler device. Solid-state and morphological characterization showed that CM product was in pure ␤-form having particles with smaller ER (CM: ER = 1.62 ± 0.04) whereas ACM and ECM mannitol particles were in pure ␣ form with higher ER (ACM: ER = 4.83 ± 0.18, ECM: ER = 5.89 ± 0.19). CCM product crystallised as mixtures of ␤-form and ␦-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (D b ), smaller tap density (D t ), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a "limit" as increasing carrier ER from 4.83 ± 0.18 (ACM) to 5.89 ± 0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r 2 = 0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.

The insect pathogens Beauveria bassiana, Metarhizium anisopliae and Paecilomyces farinosus can be effective biocontrol agents when relative humidity (RH) is close to 100%. At reduced water availability, germination of propagules, and therefore host infection, cannot occur. Cultures of B. bassiana, M. anisopliae and P. farinosus were grown under different conditions t o obtain conidia with a modified polyol and trehalose content. Conidia with higher intracellular concentrations of glycerol and erythritol germinated both more quickly and at lower water activity (aw) than those from other treatments. In contrast, conidia containing up t o 2357 mg trehalose g-' germinated significantly (P < 095) more slowly than those with an equivalent polyol content but less trehalose, regardless of water availability. Conidia from control treatments did not germinate below 0*951-0.935 a , (

SAGM is currently the standard additive solution used in Europe, while AS-3 is the third additive solution that has been licensed in the USA, and is also the one used in part of Canada. Although AS-3 is based on a saline-adenine-glucose solution, it also contains citrate and phosphate. Storage of red blood cell concentrates in CPD-SAGM is known to lead to the accumulation of a wide series of storage lesions, including membrane protein fragmentation and vesiculation, as we could previously determine through 2-dimensional gel electrophoresis. Through 2D-SDS-IEF-polyacrilamide gel electrophoresis we performed a time course analysis (day 0, 21 and 42 of storage) of red blood cell membranes from leukocyte-filtered concentrates either stored in CPD-SAGM or CP2D-AS-3. From the present study it emerges that the membrane protein profile of red blood cells stored in presence of AS-3 appears to be slightly different from (better than) previous reports on SAGM-stored counterparts. However, the ...

Sugarcane can be very susceptible to damage by freezes. Freeze-deteriorated cane can cause problems in processing and sometimes leads to a factory shut-down. This study was undertaken during the 2000/2001 harvest season to assess the cold tolerance performance of six commercial sugarcane varieties and to establish new and more sensitive criteria to measure cold tolerance. Two varieties CP 70-321 and CP 79-318, with known cold tolerance, were planted in the study as controls. The other varieties included LHo 83-153, LCP 85-384, HoCP 85-845 and HoCP 91-555. Freezing temperatures occurred on 20 December 2000 when the min. field temperature was À4.4 C, and again on 21 The lowest field temperature recorded was À5.6 C on 4 January. Freezing conditions prevailed for 8-15 h during each freeze incident. Stalks of all varieties were frozen to the ground following the initial freeze, with freeze cracks evident only after the 4 January freeze. For this study, samples were taken on the date of the first freeze, 20 December, and subsequently again at 7, 14, 22 and 30 days after the first freeze. Criteria used to measure overall stalk cold-tolerance included changes in pH, Brix, dextran (ASI-II method), sucrose, glucose, and fructose concentrations. Mannitol, ethanol and the oligosaccharides, palatinose, leucrose, isomaltotriose and 1-kestose, were simultaneuously measured using IC-IPAD. Marked differences were observed in most criteria for all varieties, particularly 22 and 30 days after the first freeze. Mannitol was strongly correlated (r 2 =0.84) with dextran, confirming its use as an indicator for cane dextran deterioration. In comparison, ethanol was only weakly correlated (r 2 =0.55) with dextran and did not always predict cane dextran deterioration. Iso maltotriose was the most sensitive oligosaccharide indicator of freeze deterioration, although both leucrose and palatinose could be used to confirm whether severe dextran formation ( >1500 ppm/Brix) has occurred in cane. Isomaltotriose was strongly correlated (r 2 =0.89) with dextran and pH (r 2 =À0.83); pH was also a strong indicator of both dextran (r 2 =À0.85) and mannitol (r 2 =À0.92) formation. Four of the varieties, CP 79-318, LCP 85-384, HoCP 85-845 and HoCP 91-555, were shown to be susceptible to other sources of microbial and enzymic deterioration as well as dextran deterioration from Leuconostoc bacteria, especially 30 days after the first freeze. This was indicated by increased glucose/fructose ratios, ethanol formation, changes in 1-kestose concentration, and further sucrose losses. Published by Elsevier Science Ltd.

The objective of the present study was to prepare and evaluate the alginate beads of Cefixime. Cefixime alginate beads were prepared by orifice-ionotropic gelation method using polymers such as HPMC (K 100 M), Carbopol 940P, Sodium CMC, Guar gum, Sodium Alginate, Ethyl Cellulose, Methyl Cellulose and Xanthan gum. Totally 15 different formulations of Cefixime alginate beads were prepared by using the above polymers. The alginate beads were characterized for drug content, entrapment efficiency, mucoadhesive property by in vitro wash-off test and in-vitro drug release. The formulation F10 was selected as an ideal formulation based on the in vitro release profile which shows an extended drug release of 97.11% upto 8 hours in phosphate buffer of pH 7.0. Surface morphology (SEM analysis) and drug-polymer interaction studies (FT-IR analysis) were performed only for the ideal formulation (F10). The alginate beads were smooth and elegant in appearance showed no visible cracks as confirmed by SEM and FT-IR studies indicated the lack of drug-polymer interactions in the ideal formulation (F10). The in vitro release data of all alginate beads formulations were plotted in various kinetic equations to understand the mechanisms and kinetics of drug release. The ideal formulation (F10) followed Higuchi kinetics and value of "n" is calculated to be 0.86 indicated that the drug release shows non-fickian diffusion.

Urinary excretion of previously identi ed mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before and for 90 min after challenge. The urinary concentrations of leukotriene (LT)E 4 , the prostaglandin (PG)D 2 metabolite and the mast cell marker 9a,11b-PGF 2 were measured by enzyme immunoassay. N t -methylhistamine was measured by radioimmunoassay.

The successful development of compressed ODTs utilises low compression forces to create a porous structure whereby excipients are added to enhance wicking/swelling action or provide strength to the fragile tablet framework. In this work, a systematic investigation comparing materials from two different categories was employed to understand their functionality in binary mixture tablets of the most commonly used diluent mannitol. Cellulose based excipients such as HPC (SSL-SFP), L-HPC (NBD-022) and MCC (Avicel PH-102) were compared with non-cellulosic materials such as PEO (POLYOX WSR N-10) and Crospovidone (XL-10). Pure excipient properties were studied using Heckel Plot, compressibility profile, SEM and XRPD, whereas the prepared binary mixture compacts were studied for hardness, disintegration time and friability. Results from our investigation provide insight into differences encountered in product performance of ODT upon inclusion of additional materials. For example, non-cellulosic excipients Polyox and Crospovidone showed higher plasticity (Py values 588 and 450MPa) in pure form but not in binary mixtures of mannitol. Cellulosic excipients, nonetheless, offer faster disintegration (<30 sec) specifically L-HPC and MCC tablets. Disintegration time for tablets with fully substituted-HPC was prolonged (200-500 sec) upon increasing concentration between 1-10% due to gelation/matrix formation. It can be concluded that despite the reasonably good plasticity of both cellulosic and noncellulosic excipients in pure form, the mechanical strength in binary mixtures is negatively impacted by the fragmentation/ fracture effect of mannitol.