A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design

Nathan, Paul C.; Tomlinson, George; Dupuis, L. Lee; Greenberg, Mark; Ota, Sylvia; Bartels, Ute; Feldman, Brian M.

doi:10.1007/s00520-005-0875-7

Cited by 32 publications

(24 citation statements)

References 21 publications

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“…2c) yielded several product ions whose formation could be deduced from MS 3 , MS 4 and MS 5 experiments (Scheme 1b). Two classes of product ions were observed, i.e.…”

Section: Resultsmentioning

confidence: 98%

“…the product ions characteristic of the phenothiazine moiety (m/z 411, 401, 372, 350, 318, 304, 290, 272, 239 and 225) and the product ions characteristic of the piperidine moiety (m/z 152, 126 and 124). The piperidine ions B and C1 (at m/z 126 and 152, respectively) could be generated through a [1,4] proton transfer from A ion. Thus, the proposed mechanism for B formation, displayed in Scheme 1b (pathway 1, arrows b), involved the proton transfer from phenothiazine Cα, whereas the mechanism for C1 formation implicated the proton from phenothiazine Cβ (pathway 2, arrows c).…”

Section: Resultsmentioning

confidence: 99%

“…For MS 2 experiments, each precursor ion was selected with an isolation width of 0.7 m/z unit and was excited by a voltage of 1 V. For MS 3 , MS 4 and MS 5 , the isolation width was 4 m/z unit and the amplitude voltage 0.85 V. The low mass cut-off value (LCMO) was set at 28% of the precursor ion m/z value.…”

Section: Esi-ms N Experimentsmentioning

confidence: 99%

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Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange

et al. 2010

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Metopimazine (MPZ) is a phenothiazine derivative used to prevent emesis during chemotherapy where few structural analysis of the aforementioned compound have been described in the literature. Thus, this work reports, for the first time, the detailed study of fragmentation pathways of MPZ and its metabolite (AMPZ) using electrospray ionization (EI) with multistage mass spectrometry (ESI-MS n ) in positive-ion mode. The structures of 21 product ions were identified and their accurate masses were determined using high resolution mass spectrometry (HRMS) experiments. Characteristic product ions of these two phenothiazine derivatives are more particularly displayed along with differences between their relative abundances and their structures checked by H/D exchange experiments.

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“…2c) yielded several product ions whose formation could be deduced from MS 3 , MS 4 and MS 5 experiments (Scheme 1b). Two classes of product ions were observed, i.e.…”

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange

et al. 2010

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“…Two studies have been published since the last update [21,25]. In the first small pilot study, ondansetron versus ondansetron plus metopimazine was studied in ten patients receiving highly emetogenic chemotherapy [25].…”

Section: Nk1 Receptor Antagonistsmentioning

confidence: 99%

“…In the first small pilot study, ondansetron versus ondansetron plus metopimazine was studied in ten patients receiving highly emetogenic chemotherapy [25]. The combination antiemetic therapy of ondansetron and metopimazine was more effective especially in the delayed phase than the monotherapy without additional toxicity.…”

Section: Nk1 Receptor Antagonistsmentioning

confidence: 99%

Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009

Jordan¹,

Roila

Molassiotis

et al. 2010

Support Care Cancer

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Only a few studies have been carried out in children on the prevention of chemotherapy-induced nausea and vomiting (CINV). 5-HT 3 receptor antagonists have been shown to be more efficacious and less toxic than metoclopramide, phenothiazines and cannabinoids. Most dose studies are available for the 5-HT 3 receptor antagonists ondansetron and granisetron. The new 5-HT 3 receptor antagonist palonosetron was evaluated in one comparative study so far showing promising activity. Combinations of a 5-HT 3 receptor antagonist and dexamethasone showed increased efficacy with respect to a 5-HT 3 receptor antagonist alone. All paediatric patients receiving chemotherapy of high or moderate emetogenic potential should receive a combination of a 5-HT 3 receptor antagonist and dexamethasone to prevent acute emesis. No studies have specifically evaluated antiemetic drugs in the prevention of chemotherapy-induced delayed and anticipatory emesis in children. The role of the NK1 receptor antagonists in children has to be further investigated, although one small study is published so far, showing promising activity in the prevention of CINV with aprepitant. The new proposed guideline from the Multinational Association of Supportive Care in Cancer and the European Society of Clinical Oncology summarises the updated data from the literature and takes into consideration the existing guidelines.

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Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

Stunnenberg

Raaphorst

Groenewoud

et al. 2018

JAMA

131

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IMPORTANCE In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. OBJECTIVE To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. DESIGN, SETTING, AND PARTICIPANTS A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. INTERVENTIONS Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. MAIN OUTCOMES AND MEASURES Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. RESULTS Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). CONCLUSIONS AND RELEVANCE In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.

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A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design

Abstract: Based on this pilot study, we believe that the high likelihood that metopimazine is an effective adjunct to ondansetron monotherapy suggests that this combination therapy is worthy of further study in children receiving emetogenic chemotherapy.

Cited by 32 publications

References 21 publications

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange

Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

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A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design

Abstract: Based on this pilot study, we believe that the high likelihood that metopimazine is an effective adjunct to ondansetron monotherapy suggests that this combination therapy is worthy of further study in children receiving emetogenic chemotherapy.

Cited by 32 publications

References 21 publications

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSn, HR‐MS and H/D exchange

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSn, HR‐MS and H/D exchange

Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

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Product

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Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSⁿ, HR‐MS and H/D exchange