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The European Respiratory Journal May 2022Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis.
METHODS
We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV) of ≥100 mL from baseline.
RESULTS
Cumulatively the three trials included 984 patients. Changes in FEV, QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV in the azithromycin and aztreonam trials (r= -0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV is not a responsive measure in bronchiectasis.
CONCLUSIONS
Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders.
Topics: Anti-Bacterial Agents; Azithromycin; Aztreonam; Bronchiectasis; Humans; Mannitol; Quality of Life
PubMed: 34675045
DOI: 10.1183/13993003.00777-2021 -
Journal of Veterinary Internal Medicine Jan 2021Hyperosmolar agents frequently are used to decrease intracranial pressure but their effects on electrolyte and acid-base variables have not been prospectively...
BACKGROUND
Hyperosmolar agents frequently are used to decrease intracranial pressure but their effects on electrolyte and acid-base variables have not been prospectively investigated.
OBJECTIVES
Compare duration and magnitude of changes in electrolyte and acid-base variables after hyperosmolar treatment.
ANIMALS
Twenty-eight client-owned dogs with intracranial hypertension caused by various pathologies.
METHODS
Prospective, randomized, nonblinded, experimental cohort study. Fifteen dogs received a single dose (4 mL/kg) of 7.2% hypertonic saline (HTS), 13 dogs received 20% mannitol (MAN) 1 g/kg IV. Electrolyte and acid-base variables were measured before (T ), and 5 (T ), 60 (T ), and 120 (T ) minutes after administration. Variables were compared between treatments and among time points within treatment groups.
RESULTS
Mean plasma sodium and chloride concentrations were higher after HTS than MAN at T (158 vs 141 mEq/L; 126 vs 109 mEq/L) and significant differences were maintained at all time points. After HTS, plasma sodium and chloride concentrations remained increased from T at all time points. After MAN, plasma sodium and chloride concentrations decreased at T , but these changes were not maintained at T and T . Plasma potassium concentration was lower at T after HTS compared with T (3.6 vs 3.9 mEq/L) and compared to MAN (3.6 vs 4.1 mEq/L). At T and T , plasma ionized calcium concentration was lower after HTS than MAN (1.2 vs 1.3 mmol/L). No significant differences were found in acid-base variables between treatments.
CONCLUSIONS AND CLINICAL IMPORTANCE
At the administered dose, dogs receiving HTS showed sustained increases in plasma sodium and chloride concentrations, whereas dogs receiving MAN showed transient decreases. Future studies should assess the effects of multiple doses of hyperosmolar agents on electrolyte and acid-base variables.
Topics: Animals; Cohort Studies; Dog Diseases; Dogs; Electrolytes; Intracranial Hypertension; Mannitol; Prospective Studies
PubMed: 33236379
DOI: 10.1111/jvim.15973 -
Neurogastroenterology and Motility Jul 2016Gastrointestinal (GI) and non-GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose...
BACKGROUND
Gastrointestinal (GI) and non-GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose and mannitol ingestion. Inadvertent dietary consumption of (12) Carbon ((12) C, regular) mannitol in food or from other sources may interfere with the test's interpretation. (13) Carbon ((13) C) constitutes 1% of carbon in nature and (13) C mannitol is a stable isotope. Our aim was to determine the performance of (13) C mannitol for measurement of intestinal permeability.
METHODS
Ten healthy volunteers underwent intestinal permeability assay using coadministered (12) C mannitol, (13) C mannitol and lactulose, followed by timed urine collections. Urinary sugar concentrations were measured using tandem high performance liquid chromatography-mass spectrometry.
KEY RESULTS
We found that (13) C mannitol can be distinguishable from (12) C mannitol on tandem mass spectrometry. In addition, (13) C mannitol had ~20-fold lower baseline contamination compared to (12) C mannitol. We describe here the (13) C mannitol assay method for the measurement of intestinal permeability.
CONCLUSIONS & INFERENCES
In conclusion, (13) C mannitol is superior to (12) C mannitol for measurement of intestinal permeability. It avoids issues with baseline contamination and erratic excretions during the testing period.
Topics: Biomarkers; Carbon Isotopes; Humans; Intestinal Absorption; Intestinal Mucosa; Male; Mannitol; Middle Aged; Permeability; Tandem Mass Spectrometry
PubMed: 26914765
DOI: 10.1111/nmo.12802 -
Journal of Bacteriology Aug 1972The addition of mannitol to cultures of Salmonella typhimurium mutants missing mannitol-1-phosphate dehydrogenase causes stasis or lysis. Mannitol-1-phosphate...
The addition of mannitol to cultures of Salmonella typhimurium mutants missing mannitol-1-phosphate dehydrogenase causes stasis or lysis. Mannitol-1-phosphate accumulates intracellularly to concentrations of 20 mm. The incorporation of acetate into lipid is inhibited before cell wall, protein, or nucleic acid synthesis.
Topics: Acetates; Alcohol Oxidoreductases; Bacterial Proteins; Bacteriolysis; Carbon Isotopes; Cell Wall; Chromatography, Paper; Genetics, Microbial; Lipids; Mannitol; Microbial Sensitivity Tests; Mutation; Nucleic Acids; Phenylalanine; Pimelic Acids; Salmonella typhimurium; Stereoisomerism; Time Factors; Tritium; Uracil
PubMed: 4559727
DOI: 10.1128/jb.111.2.351-355.1972 -
BMC Women's Health Dec 2022Brain edema is a rare and serious complication of assisted reproductive technology (ART). The increased intracranial pressure and injured brain parenchyma are...
BACKGROUND
Brain edema is a rare and serious complication of assisted reproductive technology (ART). The increased intracranial pressure and injured brain parenchyma are life-threatening and may even result in death. The pathogenesis may involve increased vascular permeability mediated by vascular endothelial growth factor and other vasoactive substances, including interleukin 6, interleukin 1β, angiotensin II, insulin-like growth factor 1, transforming growth factor β, and the renin-angiotensin system.
CASE PRESENTATION
We presented a unique case report of a 29-year-old woman developed sudden irritability, blurred consciousness, and vomiting 8 h after oocyte retrieval. Blood examinations showed hyponatremia and cranial computed tomography showed swelling of the brain parenchyma. After therapeutic use of hypertonic saline and mannitol infusion, the patient's consciousness recovered and her neurological state improved.
CONCLUSIONS
Brain edema is a rare and serious complication of ART. Quick infusion of hypertonic salt solution and mannitol is a key treatment. A good prognosis can be achieved after prompt treatment.
Topics: Female; Humans; Brain Edema; Vascular Endothelial Growth Factor A; Saline Solution, Hypertonic; Mannitol
PubMed: 36510239
DOI: 10.1186/s12905-022-02098-x -
Biology Open Jan 2020The ability of polyols to disrupt holometabolous insect development has not been studied and identifying compounds in food that affect insect development can further our...
The ability of polyols to disrupt holometabolous insect development has not been studied and identifying compounds in food that affect insect development can further our understanding of the pathways that connect growth rate, developmental timing and body size in insects. High-sugar diets prolong development and generate smaller adult body sizes in We tested for concentration-dependent effects on development when larvae are fed mannitol, a polyalcohol sweetener. We also tested for amelioration of developmental effects if introduction to mannitol media is delayed past the third instar, as expected if there is a developmental sensitive-period for mannitol effects. Both male and female larvae had prolonged development and smaller adult body sizes when fed increasing concentrations of mannitol. Mannitol-induced increases in mortality were concentration dependent in 0 M to 0.8 M treatments with mortality effects beginning as early as 48 h post-hatching. Larval survival, pupariation and eclosion times were unaffected in 0.4 M mannitol treatments when larvae were first introduced to mannitol 72 h post-hatching (the beginning of the third instar); 72 h delay of 0.8 M mannitol introduction reduced the adverse mannitol effects. The developmental effects of a larval mannitol diet closely resemble those of high-sugar larval diets.This article has an associated First Person interview with the first author of the paper.
Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Size; Disease Susceptibility; Drosophila melanogaster; Female; Larva; Longevity; Male; Mannitol
PubMed: 31822472
DOI: 10.1242/bio.047084 -
International Journal of Pharmaceutics Mar 2016Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of...
Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and β-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and β-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1 MPa at a main compression pressure of 260 MPa. Moreover the friability of tablets compressed at 184 MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing.
Topics: Acetaminophen; Desiccation; Drug Compounding; Mannitol; Povidone; Tablets; Tensile Strength
PubMed: 26851355
DOI: 10.1016/j.ijpharm.2016.02.001 -
Cells May 2022Hyperosmolality can occur during industrial fed-batch cultivation processes of Chinese hamster ovary (CHO) cells as highly concentrated feed and base solutions are added...
Hyperosmolality can occur during industrial fed-batch cultivation processes of Chinese hamster ovary (CHO) cells as highly concentrated feed and base solutions are added to replenish nutrients and regulate pH values. Some effects of hyperosmolality, such as increased cell size and growth inhibition, have been elucidated by previous research, but the impact of hyperosmolality and the specific effects of the added osmotic-active reagents have rarely been disentangled. In this study, CHO cells were exposed to four osmotic conditions between 300 mOsm/kg (physiologic condition) and 530 mOsm/kg (extreme hyperosmolality) caused by the addition of either high-glucose-supplemented industrial feed or mannitol as an osmotic control. We present novel single-cell cultivation data revealing heterogeneity in mass gain and cell division in response to these treatments. Exposure to extreme mannitol-induced hyperosmolality and to high-glucose-oversupplemented feed causes cell cycle termination, mtDNA damage, and mitochondrial membrane depolarization, which hints at the onset of premature stress-induced senescence. Thus, this study shows that both mannitol-induced hyperosmolality (530 mOsm/kg) and glucose overfeeding induce severe negative effects on cell growth and mitochondrial activity; therefore, they need to be considered during process development for commercial production.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Glucose; Mannitol; Single-Cell Analysis
PubMed: 35681457
DOI: 10.3390/cells11111763 -
Nature Protocols Jan 2022The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of... (Review)
Review
The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable. We demonstrated that this variability could be highly reduced or eliminated when the procedure of osmotic BBB opening is performed under the guidance of interventional MRI. Studies have reported the utility and applicability of this technique in several species. Here we describe a protocol to open the BBB by IA injection of hyperosmotic mannitol under the guidance of MRI in mice. The procedures (from preoperative preparation to postoperative care) can be completed within ~1.5 h, and the skill level required is on par with the induction of middle cerebral artery occlusion in small animals. This MRI-guided BBB opening technique in mice can be utilized to study the biology of the BBB and improve the delivery of various therapeutic agents to the brain.
Topics: Animals; Blood-Brain Barrier; Capillary Permeability; Injections, Intra-Arterial; Magnetic Resonance Imaging; Male; Mannitol; Mice; Mice, SCID; Osmotic Pressure
PubMed: 34903870
DOI: 10.1038/s41596-021-00634-x -
The AAPS Journal Mar 2014This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for...
This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10(-6) and MA 10(-3) M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.
Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Cells, Cultured; Cilia; Drug Therapy, Combination; Humans; Lung Diseases; Mannitol; Microscopy, Electron, Scanning; Mucus; Muscle, Smooth
PubMed: 24431080
DOI: 10.1208/s12248-014-9560-4