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Respiratory Care Nov 2018Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during...
BACKGROUND
Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis.
METHODS
A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 μm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 μm; day 2: 6.5 μm), and the pattern of coughing was observed.
RESULTS
Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-μm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-μm particles. Spirometry was unaffected.
CONCLUSIONS
In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy.
Topics: Administration, Inhalation; Aged; Bronchial Spasm; Cough; Drug Carriers; Female; Forced Expiratory Volume; Humans; Idiopathic Pulmonary Fibrosis; Interferons; Male; Mannitol; Middle Aged; Nebulizers and Vaporizers; Particle Size; Vital Capacity
PubMed: 30154129
DOI: 10.4187/respcare.06153 -
Pediatric Critical Care Medicine : a... Mar 2014
Topics: Brain Edema; Diabetic Ketoacidosis; Female; Humans; Male; Mannitol; Saline Solution, Hypertonic
PubMed: 24608507
DOI: 10.1097/PCC.0000000000000062 -
Current Opinion in Pharmacology Jun 2010Mucociliary clearance (MCC) in CF lung disease is limited by airway dehydration, leading to persistent bacterial infection and inflammation in the airways. Agents... (Review)
Review
Mucociliary clearance (MCC) in CF lung disease is limited by airway dehydration, leading to persistent bacterial infection and inflammation in the airways. Agents designed to rehydrate the airway mucosa lead to improved MCC. Hyperosmolar agents, such as hypertonic saline and mannitol, create a luminal osmotic gradient, drawing water into the dehydrated ASL. Ion transport modulators function to activate alternative chloride channels and/or to block sodium hyperabsorption that occurs through a dysregulated ENaC channel. Combinations of these therapies may result in a synergistic improvement in airway hydration, and thus, restore MCC. Active ongoing phase II and III trials of new pharmacotherapeutics are covered in this review.
Topics: Animals; Clinical Trials as Topic; Cystic Fibrosis; Diuretics, Osmotic; Drug Synergism; Humans; Ion Transport; Mannitol; Mucociliary Clearance; Respiratory Mucosa; Saline Solution, Hypertonic
PubMed: 20439165
DOI: 10.1016/j.coph.2010.04.003 -
Molecules (Basel, Switzerland) Feb 2024Porous materials are widely used as an effective strategy for the solubilization of insoluble drugs. In order to improve the solubility and bioavailability of low...
Porous materials are widely used as an effective strategy for the solubilization of insoluble drugs. In order to improve the solubility and bioavailability of low water-solubility drugs, it is necessary to prepare porous materials. Mannitol is one of the most popular excipients in food and drug formulations. In this study, porous mannitol was investigated as a drug carrier for low water solubility drugs. Its fabrication, drug loading, and drug release mechanisms were investigated. Porous mannitol was fabricated using the co-spray-antisolvent process and utilizing polyvinylpyrrolidone K30 (PVP K30) as the template agent. Porous mannitol particles were prepared by changing the proportion of the template agent, spraying the particles with mannitol, and eluting with ethanol in order to regulate their pore structure. In subsequent studies, porous mannitol morphology and characteristics were determined systematically. Furthermore, curcumin and ibuprofen, two poorly water-soluble drugs, were loaded into porous mannitol, and their release profiles were analyzed. The results of the study indicated that porous mannitol can be prepared using PVP K30 as a template and that the amount of template agent can be adjusted in order to control the structure of the porous mannitol. When the template agent was added in amounts of 1%, 3%, and 5%, the mannitol pore size increased by 167.80%, 95.16%, and 163.98%, respectively, compared to raw mannitol. Molecular docking revealed that mannitol and drugs are adsorbents and adhere to each other by force interaction. The cumulative dissolution of curcumin and ibuprofen-loaded porous mannitol reached 69% and 70%, respectively. The release mechanism of curcumin and ibuprofen from drug-loaded mannitol was suitable for the Korsmeyer-Peppas kinetic model. In summary, the co-spray-antisolvent method proved effective in fabricating porous materials rapidly, and porous mannitol had a remarkable effect on drug solubilization. The results obtained are conducive to the development of porous materials.
Topics: Porosity; Ibuprofen; Curcumin; Mannitol; Molecular Docking Simulation; Solubility; Povidone; Water; Drug Carriers
PubMed: 38338458
DOI: 10.3390/molecules29030715 -
Journal of Cystic Fibrosis : Official... Nov 2021Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults.
METHODS
This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV averaged over the 26-week treatment period.
RESULTS
Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively.
CONCLUSIONS
In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.
Topics: Adult; Cystic Fibrosis; Double-Blind Method; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; Mannitol
PubMed: 33715994
DOI: 10.1016/j.jcf.2021.02.011 -
British Medical Journal Oct 1974
Topics: Brain Edema; Burns, Electric; Electric Injuries; First Aid; Heart Arrest; Heart Massage; Humans; Lightning; Mannitol; Respiration, Artificial; Respiratory Paralysis
PubMed: 4424803
DOI: No ID Found -
Respirology (Carlton, Vic.) Aug 2017Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human... (Meta-Analysis)
Meta-Analysis Review
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9-4.3% in forced expiratory volume in 1 s (FEV ) and 3.7-5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01-1.79 n = 349, one study). Some participants exhibited a reduction in FEV (≥10-15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.
Topics: Acetylcysteine; Administration, Inhalation; Bronchiectasis; Chronic Disease; Deoxyribonuclease I; Expectorants; Forced Expiratory Volume; Humans; Lung Diseases; Mannitol; Mesna; Mucociliary Clearance; Quality of Life; Recombinant Proteins; Saline Solution, Hypertonic; Symptom Flare Up; Vital Capacity
PubMed: 28397992
DOI: 10.1111/resp.13047 -
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 -
PloS One 2019Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Usually this... (Clinical Trial)
Clinical Trial
Measurement of intestinal permeability using lactulose and mannitol with conventional five hours and shortened two hours urine collection by two different methods: HPAE-PAD and LC-MSMS.
Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Usually this test involves a time consuming procedure of about 5 hour's urine collection, which makes the test incompatible to some extent. As the results are expressed as the ratio of lactulose and mannitol recovered in urine within certain time, it may be possible to get similar result despite the reduced urine collection time of 2 hours. Moreover, different laboratories do the test by different methods, which make the results incomparable between laboratories. Here, we are also trying to find the correlation between results from most commonly used methods: HPAE-PAD and LC-MSMS. The lactulose: mannitol (LM) test was performed in a cohort of Bangladeshi infants considered at-risk for environmental enteropathy. 208 urine specimens from 104 (52 male and 52 female) infants were collected at 2 and 5 hours after LM solution administration and were tested for lactulose and mannitol by two different methods, one HPAE-PAD platform and another LC-MSMS platform. Median age of the children was 15.0 months (range 6.9 to 25.8 months) and their mean weight-for-age z-score was -0.92. A higher percentage of lactulose and mannitol recovery was found in 5 hours urine collection than in the corresponding 2 hours by both HPAE-PAD and LC-MSMS method, but when results were expressed as lactulose to mannitol ratio (LMR) there was no significant difference between 2 and 5 hours urine collection in both HPAE-PAD (P = 0.138) and LC-MSMS (P = 0.099) method. LMR based on 2 hours urine collection correlated well with LMR based on traditional 5 hours urine collection (Spearman's correlation coefficient 0.578 and 0.604 respectively for HPAE-PAD and LC-MSMS). In future, LM test to assess intestinal permeability in children can be simplified by shortening the urine collection time from 5 hours to 2 hours.
Topics: Child, Preschool; Female; Humans; Infant; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Lactulose; Male; Mannitol; Permeability; Time Factors; Urine Specimen Collection
PubMed: 31393913
DOI: 10.1371/journal.pone.0220397 -
International Journal of Molecular... May 2023Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine...
Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood-retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [H]putrescine and [C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [H]Putrescine transport was significantly reduced under Na-free, Cl-free, and K-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [H]putrescine uptake, and CTL1 knockdown significantly reduced [H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.
Topics: Rats; Animals; Blood-Retinal Barrier; Putrescine; Rats, Wistar; Retina; Biological Transport; Polyamines; Mannitol
PubMed: 37240348
DOI: 10.3390/ijms24109003