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Pharmaceutical Research Feb 2022To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol,...
PURPOSE
To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake.
METHODS
Stable isotope-labeled [C]sucrose and [C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (K) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance.
RESULTS
The three-compartment model was able to describe the experimental data well, yielding estimates for K of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 μl.min.g, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) μl.min.g, which were not statistically different. K values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points.
CONCLUSIONS
Using the three-compartment model allows determination of K for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.
Topics: Animals; Brain; Chromatography, Liquid; Drug Elimination Routes; Injections, Intravenous; Male; Mannitol; Mice, Inbred C57BL; Models, Biological; Permeability; Sucrose; Tandem Mass Spectrometry; Tissue Distribution; Wakefulness; Mice
PubMed: 35146590
DOI: 10.1007/s11095-022-03175-4 -
The Cochrane Database of Systematic... Jul 2014Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain tumour difficult. To ease surgical tumour removal, measures are taken to reduce brain swelling, often referred to as brain relaxation. Brain relaxation can be achieved with intravenous fluids such as mannitol or hypertonic saline. This review was conducted to find out which of the two fluids may have a greater impact on brain relaxation.
OBJECTIVES
The objective of this review was to compare the effects of mannitol versus those of hypertonic saline on intraoperative brain relaxation in patients undergoing craniotomy.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), MEDLINE via Ovid SP (1966 to October 2013) and EMBASE via Ovid SP (1980 to October 2013). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that compared the use of hypertonic saline versus mannitol for brain relaxation. We also included studies in which any other method used for intraoperative brain relaxation was compared with mannitol or hypertonic saline. Primary outcomes were longest follow-up mortality, Glasgow Outcome Scale score at three months and any adverse events related to mannitol or hypertonic saline. Secondary outcomes were intraoperative brain relaxation, intensive care unit (ICU) stay, hospital stay and quality of life.
DATA COLLECTION AND ANALYSIS
We used standardized methods for conducting a systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a fixed-effect model when no evidence was found of significant heterogeneity between studies, and a random-effects model when heterogeneity was likely.
MAIN RESULTS
We included six RCTs with 527 participants. Only one RCT was judged to be at low risk of bias. The remaining five RCTs were at unclear or high risk of bias. No trial mentioned the primary outcomes of longest follow-up mortality, Glasgow Outcome Scale score at three months or any adverse events related to mannitol or hypertonic saline. Three trials mentioned the secondary outcomes of intraoperative brain relaxation, hospital stay and ICU stay; quality of life was not reported in any of the trials. Brain relaxation was inadequate in 42 of 197 participants in the hypertonic saline group and in 68 of 190 participants in the mannitol group. The risk ratio for brain bulge or tense brain in the hypertonic saline group was 0.60 (95% confidence interval (CI) 0.44 to 0.83, low-quality evidence). One trial reported ICU and hospital stay. The mean (standard deviation (SD)) duration of ICU stay in the mannitol and hypertonic saline groups was 1.28 (0.5) and 1.25 (0.5) days (P value 0.64), respectively; the mean (SD) duration of hospital stay in the mannitol and hypertonic saline groups was 5.7 (0.7) and 5.7 (0.8) days (P value 1.00), respectively
AUTHORS' CONCLUSIONS
From the limited data available on the use of mannitol and hypertonic saline for brain relaxation during craniotomy, it is suggested that hypertonic saline significantly reduces the risk of tense brain during craniotomy. A single trial suggests that ICU stay and hospital stay are comparable with the use of mannitol or hypertonic saline. However, focus on other related important issues such as long-term mortality, long-term outcome, adverse events and quality of life is needed.
Topics: Adolescent; Adult; Brain Neoplasms; Child; Child, Preschool; Craniotomy; Encephalitis; Female; Glasgow Outcome Scale; Humans; Hypertonic Solutions; Infant; Male; Mannitol; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic; Young Adult
PubMed: 25019296
DOI: 10.1002/14651858.CD010026.pub2 -
The Cochrane Database of Systematic... Aug 2013Mannitol is sometimes effective in reversing acute brain swelling, but its effectiveness in the ongoing management of severe head injury remains unclear. There is... (Review)
Review
BACKGROUND
Mannitol is sometimes effective in reversing acute brain swelling, but its effectiveness in the ongoing management of severe head injury remains unclear. There is evidence that, in prolonged dosage, mannitol may pass from the blood into the brain, where it might cause increased intracranial pressure.
OBJECTIVES
To assess the effects of different mannitol therapy regimens, of mannitol compared to other intracranial pressure (ICP) lowering agents, and to quantify the effectiveness of mannitol administration given at other stages following acute traumatic brain injury.
SEARCH METHODS
We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), ISI Web of Science (SCI-EXPANDED & CPCI-S) and PubMed. We checked reference lists of trials and review articles, and contacted authors of trials. The search was updated on the 20th April 2009.
SELECTION CRITERIA
Randomised controlled trials of mannitol, in patients with acute traumatic brain injury of any severity. The comparison group could be placebo-controlled, no drug, different dose, or different drug. We excluded cross-over trials, and trials where the intervention was started more than eight weeks after injury.
DATA COLLECTION AND ANALYSIS
We independently rated quality of allocation concealment and extracted the data. Relative risks (RR) and 95% confidence intervals (CI) were calculated for each trial on an intention to treat basis.
MAIN RESULTS
We identified four eligible randomised controlled trials. One trial compared ICP-directed therapy to 'standard care' (RR for death = 0.83; 95% CI 0.47 to 1.46). One trial compared mannitol to pentobarbital (RR for death = 0.85; 95% CI 0.52 to 1.38). One trial compared mannitol to hypertonic saline (RR for death = 1.25; 95% CI 0.47 to 3.33). One trial tested the effectiveness of pre-hospital administration of mannitol against placebo (RR for death = 1.75; 95% CI 0.48 to 6.38).
AUTHORS' CONCLUSIONS
Mannitol therapy for raised ICP may have a beneficial effect on mortality when compared to pentobarbital treatment, but may have a detrimental effect on mortality when compared to hypertonic saline. ICP-directed treatment shows a small beneficial effect compared to treatment directed by neurological signs and physiological indicators. There are insufficient data on the effectiveness of pre-hospital administration of mannitol.
Topics: Acute Disease; Brain Injuries; Diuretics, Osmotic; Humans; Intracranial Hypertension; Intracranial Pressure; Mannitol; Pentobarbital; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic
PubMed: 23918314
DOI: 10.1002/14651858.CD001049.pub5 -
Therapeutic Advances in Respiratory... Apr 2010Therapies shown to be effective in cystic fibrosis are often provided to patients with bronchiectasis, without definitive evidence of benefit. In recent years, there has... (Review)
Review
Therapies shown to be effective in cystic fibrosis are often provided to patients with bronchiectasis, without definitive evidence of benefit. In recent years, there has been increased interest in validating and developing new therapies for patients with noncystic fibrosis bronchiectasis. While inhaled tobramycin improves microbiologic parameters, improvements in outcomes have been more difficult to demonstrate, in part due to the occurrence of bronchospasm in a significant minority of treated patients. Outcome data from studies of inhaled aztreonam and ciprofloxacin have not yet been reported, although the microbiologic data appear to be promising. Preliminary data regarding inhaled hyperosmolar agents such as hypertonic saline and mannitol are also promising, but these therapies cannot yet be recommended for routine therapy of patients with bronchiectasis. Macrolide antibiotics have anti-inflammatory properties in patients with chronic suppurative lung disease, through a variety of mechanisms. They have been proven to be beneficial in diffuse panbronchiolitis and are commonly being used in patients with bronchiectasis. Many small studies support their use in this population, although several had methodologic flaws. Thus, although chronic low-dose macrolide therapy is often used in these patients, more conclusive evidence is awaited.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bronchial Spasm; Bronchiectasis; Humans; Macrolides; Mannitol; Saline Solution, Hypertonic
PubMed: 20388725
DOI: 10.1177/1753465810366858 -
Critical Care (London, England) Feb 2012Hyperosmolar therapy is the principal medical management strategy for elevated intracranial pressure. Mannitol has been the primary hyperosmolar agent for nearly a... (Review)
Review
Hyperosmolar therapy is the principal medical management strategy for elevated intracranial pressure. Mannitol has been the primary hyperosmolar agent for nearly a century and remains the de facto gold standard for medical management of intracranial hypertension. Over the past 25 years, however, hypertonic saline (HTS) has become a progressively more common alternative to mannitol, and several recent studies have suggested its relative superiority. These findings have prompted calls for large-scale comparator trials of mannitol and HTS, but such trials would only be necessary if the designation of mannitol as the gold standard is appropriate and if current evidence suggests its therapeutic equipoise with HTS. Mounting evidence supporting HTS suggests that neither of these conditions is necessarily true and, instead, mandates reassessment of the actual gold-standard agent for hyperosmolar therapy. In the present article I make the case that current evidence supports HTS, not mannitol, as the better choice for gold-standard therapy for medical management of intracranial hypertension. This is accomplished first by examining the evidence on which the apparent designation of mannitol as the presumed gold-standard is based, then by reviewing the recent comparative efficacy data for HTS versus mannitol, and finally by discussing additional clinical considerations for appropriate designation of a gold-standard agent for hyperosmolar therapy. This assessment has important implications both for patient care and for clinical trial design.
Topics: Animals; Disease Management; Humans; Intracranial Hypertension; Mannitol; Reference Standards; Saline Solution, Hypertonic; Treatment Outcome
PubMed: 22353146
DOI: 10.1186/cc11182 -
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 -
Respiratory Research Nov 2021The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and... (Review)
Review
BACKGROUND
The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and mast cell airway inflammation, and a positive mannitol test is highly predictive of a response to anti-inflammatory treatment with inhaled corticosteroids. The response to mannitol is a physiological biomarker that may, therefore, be used to assess the response to other anti-inflammatory treatments and may be of particular interest in early phase studies that require surrogate markers to predict a clinical response. The main objectives of this review were to assess the practical aspects of using mannitol as an endpoint in clinical trials and provide the clinical researcher and respiratory physician with recommendations when designing early clinical trials.
METHODS
The aim of this review was to summarise previous uses of the mannitol test as an outcome measure in clinical intervention studies. The PubMed database was searched using a combination of MeSH and keywords. Eligible studies included intervention or repeatability studies using the standard mannitol test, at multiple timepoints, reporting the use of PD as a measure, and published in English.
RESULTS
Of the 193 papers identified, 12 studies met the inclusion criteria and data from these are discussed in detail. Data on the mode of action, correlation with airway inflammation, its diagnostic properties, and repeatability have been summarised, and suggestions for the reporting of test results provided. Worked examples of power calculations for dimensioning study populations are presented for different types of study designs. Finally, interpretation and reporting of the change in the response to the mannitol test are discussed.
CONCLUSIONS
The mechanistic and practical features of the mannitol test make it a useful marker of disease, not only in clinical diagnoses, but also as an outcome measure in intervention trials. Measuring airway hyperresponsiveness to mannitol provides a novel and reproducible test for assessing efficacy in intervention trials, and importantly, utilises a test that links directly to underlying drivers of disease.
Topics: Administration, Inhalation; Asthma; Bronchial Provocation Tests; Diuretics, Osmotic; Humans; Mannitol; Practice Guidelines as Topic
PubMed: 34743708
DOI: 10.1186/s12931-021-01876-9 -
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 -
American Journal of Veterinary Research Aug 2023The lactulose-to-mannitol ratio test is a test to assess the disorders associated with gut permeability. The test requires an oral administration of the mixture of...
OBJECTIVE
The lactulose-to-mannitol ratio test is a test to assess the disorders associated with gut permeability. The test requires an oral administration of the mixture of lactulose and mannitol and urine collection. The urinary ratio of lactulose to mannitol is an indicator of intestinal permeability. Due to the complexity of urine collection in animal studies, plasma exposure ratios of lactulose to mannitol compared to their urinary concentration ratios were evaluated following an oral administration of the sugar mixture in pigs.
ANIMALS
10 pigs were orally dosed with a solution of lactulose and mannitol mixture.
PROCEDURES
Plasma samples were collected at predose, 10 and 30 minutes and 2, 4, and 6 hours postdosing, and cumulated urinary samples were collected at 6 hours for liquid chromatography-mass spectrometry analysis. The ratios of pharmacokinetic parameters of lactulose to mannitol and the plasma sugar ratios at a single time point or the mean values of several time points were compared to their urinary sugar ratios.
RESULTS
The results revealed that the lactulose-to-mannitol ratios of AUC0-6h, AUCextrap, and Cmax were correlated to the urinary sugar ratios, and the plasma sugar ratios of a single time point at 2, 4, or 6 hours and the mean values of those time points were also appropriate to replace their urinary ratios in pigs.
CLINICAL RELEVANCE
Following an oral administration of lactulose and mannitol mixture, blood collection, and assay can be an option for assessing intestinal permeability, especially in animal studies.
Topics: Animals; Swine; Intestinal Mucosa; Lactulose; Administration, Oral; Mannitol; Permeability; Intestinal Absorption
PubMed: 37277116
DOI: 10.2460/ajvr.23.01.0002 -
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