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Nutrients Jul 2017In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal... (Review)
Review
In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.
Topics: Administration, Cutaneous; Administration, Oral; Biological Transport; Humans; Magnesium; Magnesium Deficiency
PubMed: 28788060
DOI: 10.3390/nu9080813 -
JAMA Psychiatry Sep 2019Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.
OBJECTIVE
To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
DESIGN, SETTING, AND PARTICIPANTS
In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
INTERVENTIONS
Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.
MAIN OUTCOMES AND MEASURES
Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.
RESULTS
Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.
CONCLUSIONS AND RELEVANCE
For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02493868.
Topics: Administration, Intranasal; Administration, Oral; Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Remission Induction; Secondary Prevention
PubMed: 31166571
DOI: 10.1001/jamapsychiatry.2019.1189 -
American Family Physician Oct 2017Chronic rhinosinusitis is an inflammatory disease of the paranasal sinuses that occurs in 1% to 5% of the U.S. (Review)
Review
UNLABELLED
Chronic rhinosinusitis is an inflammatory disease of the paranasal sinuses that occurs in 1% to 5% of the U.S.
POPULATION
It may significantly decrease quality of life. Chronic rhinosinusitis is defined by the presence of at least two out of four cardinal symptoms (i.e., facial pain/pressure, hyposmia/anosmia, nasal drainage, and nasal obstruction) for at least 12 consecutive weeks, in addition to objective evidence. Objective evidence of chronic rhinosinusitis may be obtained on physical examination (anterior rhinoscopy, endoscopy) or radiography, preferably from sinus computed tomography. Treatment is directed at enhancing mucociliary clearance, improving sinus drainage/outflow, eradicating local infection and inflammation, and improving access for topical medications. First-line treatment is nasal saline irrigation and intranasal corticosteroid sprays. There may be a role for antibiotics in patients with evidence of an active, superimposed acute sinus infection. If medical management fails, endoscopic sinus surgery may be effective. Patients not responding to first-line medical therapy should be referred to an otolaryngologist, and selected patients with a history suggestive of other comorbidities (e.g., vasculitides, granulomatous diseases, cystic fibrosis, immunodeficiency) may also benefit from referral to an allergist or pulmonologist.
Topics: Administration, Intranasal; Administration, Oral; Administration, Topical; Anti-Bacterial Agents; Chronic Disease; Female; Humans; Male; Nasal Sprays; Quality of Life; Rhinitis; Sinusitis; Sodium Chloride; Therapeutic Irrigation; United States
PubMed: 29094889
DOI: No ID Found -
The American Journal of Geriatric... Feb 2020Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment.
METHODS
This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset.
RESULTS
For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks.
CONCLUSIONS
Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).
Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Nasal Sprays; Treatment Outcome
PubMed: 31734084
DOI: 10.1016/j.jagp.2019.10.008 -
The Cochrane Database of Systematic... Jun 2018Allergic rhinitis is a common condition affecting both adults and children. Patients experience symptoms of nasal obstruction, rhinorrhoea, sneezing and nasal itching,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Allergic rhinitis is a common condition affecting both adults and children. Patients experience symptoms of nasal obstruction, rhinorrhoea, sneezing and nasal itching, which may affect their quality of life.Nasal irrigation with saline (salty water), also known as nasal douching, washing or lavage, is a procedure that rinses the nasal cavity with isotonic or hypertonic saline solutions. It can be performed with low positive pressure from a spray, pump or squirt bottle, with a nebuliser or with gravity-based pressure in which the person instils saline into one nostril and allows it to drain out of the other. Saline solutions are available over the counter and can be used alone or as an adjunct to other therapies.
OBJECTIVES
To evaluate the effects of nasal saline irrigation in people with allergic rhinitis.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the ENT Trials Register; CENTRAL; Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 November 2017.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing nasal saline irrigation, delivered by any means and with any volume, tonicity and alkalinity, with (a) no nasal saline irrigation or (b) other pharmacological treatments in adults and children with allergic rhinitis. We included studies comparing nasal saline versus no saline, where all participants also received pharmacological treatment (intranasal corticosteroids or oral antihistamines).
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. Primary outcomes were patient-reported disease severity and a common adverse effect - epistaxis. Secondary outcomes were disease-specific health-related quality of life (HRQL), individual symptom scores, general HRQL, the adverse effects of local irritation or discomfort, ear symptoms (pain or pressure) and nasal endoscopy scores. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.
MAIN RESULTS
We included 14 studies (747 participants). The studies included children (seven studies, 499 participants) and adults (seven studies, 248 participants). No studies reported outcomes beyond three months follow-up. Saline volumes ranged from 'very low' to 'high' volume. Where stated, studies used either hypertonic or isotonic saline solution.Nasal saline versus no saline treatmentAll seven studies (112 adults; 332 children) evaluating this comparison used different scoring systems for patient-reported disease severity, so we pooled the data using the standardised mean difference (SMD). Saline irrigation may improve patient-reported disease severity compared with no saline at up to four weeks (SMD -1.32, 95% confidence interval (CI) -1.84 to -0.81; 407 participants; 6 studies; low quality) and between four weeks and three months (SMD -1.44, 95% CI -2.39 to -0.48; 167 participants; 5 studies; low quality). Although the evidence was low quality the SMD values at both time points are considered large effect sizes. Subgroup analysis showed the improvement in both adults and children. Subgroup analyses for volume and tonicity were inconclusive due to heterogeneity.Two studies reported methods for recording adverse effects and five studies mentioned them. Two studies (240 children) reported no adverse effects (epistaxis or local discomfort) in either group and three only reported no adverse effects in the saline group.One study (48 children) reported disease-specific HRQL using a modified RCQ-36 scale. It was uncertain whether there was a difference between the groups at any of the specified time points (very low quality). No other secondary outcomes were reported.Nasal saline versus no saline with adjuvant use of intranasal steroids or oral antihistamines Three studies (40 adults; 79 children) compared saline with intranasal steroids versus intranasal steroids alone; one study (14 adults) compared saline with oral antihistamines versus oral antihistamines alone. It is uncertain if there is a difference in patient-reported disease severity at up to four weeks (SMD -0.60, 95% CI -1.34 to 0.15; 32 participants; 2 studies; very low quality) or from four weeks to three months (SMD -0.32, 95% CI -0.85 to 0.21; 58 participants; 2 studies; very low quality). Although none of the studies reported methods for recording adverse effects, three mentioned them: one study (40 adults; adjuvant intranasal steroids) reported no adverse effects (epistaxis or local discomfort) in either group; the other two only reported no adverse effects in the saline group.It is uncertain if saline irrigation in addition to pharmacological treatment improved disease-specific HRQL at four weeks to three months, compared with pharmacological treatment alone (SMD -1.26, 95% CI -2.47 to -0.05; 54 participants; 2 studies; very low quality). No other secondary outcomes were reported.Nasal saline versus intranasal steroidsIt is uncertain if there was a difference in patient-reported disease severity between nasal saline and intranasal steroids at up to four weeks (MD 1.06, 95% CI -1.65 to 3.77; 14 participants; 1 study), or between four weeks and three months (SMD 1.26, 95% CI -0.92 to 3.43; 97 participants; 3 studies), or indisease-specific HRQL between four weeks and three months (SMD 0.01, 95% CI -0.73 to 0.75; 83 participants; 2 studies). Only one study reported methods for recording adverse effects although three studies mentioned them. One (21 participants) reported two withdrawals due to adverse effects but did not describe these or state which group. Three studies reported no adverse effects (epistaxis or local discomfort) with saline, although one study reported that 27% of participants experienced local discomfort with steroid use. No other secondary outcomes were reported.
AUTHORS' CONCLUSIONS
Saline irrigation may reduce patient-reported disease severity compared with no saline irrigation at up to three months in both adults and children with allergic rhinitis, with no reported adverse effects. No data were available for any outcomes beyond three months. The overall quality of evidence was low or very low. The included studies were generally small and used a range of different outcome measures to report disease severity scores, with unclear validation. This review did not include direct comparisons of saline types (e.g. different volume, tonicity).Since saline irrigation could provide a cheap, safe and acceptable alternative to intranasal steroids and antihistamines further high-quality, adequately powered research in this area is warranted.
Topics: Administration, Intranasal; Adrenal Cortex Hormones; Adult; Child; Histamine Antagonists; Humans; Nasal Sprays; Randomized Controlled Trials as Topic; Rhinitis, Allergic; Sodium Chloride; Therapeutic Irrigation
PubMed: 29932206
DOI: 10.1002/14651858.CD012597.pub2 -
Clinical Pharmacology and Therapeutics Feb 2021This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with... (Observational Study)
Observational Study Randomized Controlled Trial
This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Prospective Studies; Risk Assessment; Treatment Outcome; Young Adult
PubMed: 32860422
DOI: 10.1002/cpt.2024 -
The Journal of Clinical Psychiatry May 2020To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).
OBJECTIVE
To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation.
METHODS
This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate.
RESULTS
Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence.
CONCLUSIONS
These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03039192.
Topics: Administration, Intranasal; Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Suicidal Ideation; Young Adult
PubMed: 32412700
DOI: 10.4088/JCP.19m13191 -
Journal of Affective Disorders Feb 2021Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have... (Randomized Controlled Trial)
Randomized Controlled Trial
Meaningful Change in Depression Symptoms Assessed with the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) Among Patients with Treatment Resistant Depression in Two, Randomized, Double-blind, Active-controlled Trials of Esketamine Nasal Spray Combined...
BACKGROUND
Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for esketamine nasal spray (SPRAVATO).
METHODS
Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores.
RESULTS
Baseline scores were similar for the PHQ-9 and MADRS between the esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the esketamine/AD group compared to 65.0% in the placebo/AD group.
CONCLUSIONS
Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Humans; Ketamine; Nasal Sprays; Patient Health Questionnaire; Treatment Outcome
PubMed: 33261932
DOI: 10.1016/j.jad.2020.11.066