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- Chemotherapy induced peripheral neuropathic pain
- Amitriptyline in the Prevention of Chemotherapy-induced Neuropathic Symptoms
A blood sample for the measurement of amitriptyline and nortriptyline concentrations was taken at week 8.
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The protocol was approved by the Ethics Committee of the Helsinki University Central Hospital and written informed consent was obtained from all participants. Randomization and dosing of study medication. A computer-generated randomization schedule was used to allocate the patients to either the amitriptyline or the placebo group.
The randomization was stratified according to the chemotherapy group and the diagnosis.
The hospital pharmacy performed the randomization and provided identical capsules of either placebo or amitriptyline 25 mg. The treatment was started with one 25 mg drug capsule or placebo per day. In the case of intolerable adverse effects, dose escalation was terminated and the dose was reduced by 25 mg, if necessary. The treatment was continued until the end of the neurotoxic chemotherapy. Both patients and clinicians were blinded during the whole treatment period. Follow-up visits. The baseline visit was before commencement of chemotherapy, or if that was not possible, with the shortest possible delay after the first dose of chemotherapy.
The follow-up visits were performed every two months. The patients were asked about their neuropathic symptoms and side-effects of the study medication on the visits. Additionally, a neurological examination was performed. The patients graded neuropathic symptoms by visual analogue scale VAS in a diary twice a week during the whole study period to report the intensity of their neuropathic symptoms. During the visits they assessed sensory and motor symptoms, and side-effects of the study medication on a four-point verbal scale none, mild, moderate, severe.
The primary end point was the appearance or progression of neuropathic symptoms based on the diary data. Statistical analyses. Analyses were performed on the intent-to-treat ITT population, defined as all randomized patients who returned their diaries at the follow-up visits. The last-observation-carried-forward LOCF approach was used for missing data. Statistical comparison between groups was made by using either t -test or Chisquare test.
The area under the curve AUC for neuropathy score was calculated with the trapezoidal method. Permutation test was used to test differences between groups for side effects and bootstrap-based multiplicity adjustment was applied to correct levels of significance for multiple testing. Quality of life data were analyzed using generalizing estimating equations GEE models with the exchangeable correlation structure. Correlation coefficients were calculated by the Spearman method. The planned study size was patients.
According to the original protocol, interim analyses were carried out when patients had been randomized. Because of the negative results in the interim analyses, recruitment was cancelled after patients had been randomized. After randomization of patients, 5 patients were excluded from the study because of diseases confusing the assessment of neuropathic symptoms.
An additional 4 patients were excluded because of multiple lines of chemotherapy. Fifteen patients did not return the diaries 4 on amitriptyline and 11 on placebo. Thus, data of 99 patients 54 on amitriptyline and 45 on placebo were available in the final analyses. Pre-treatment characteristics were well balanced between the groups Table I.
The median follow-up time was 21 weeks for the amitriptyline group and 19 weeks for the placebo group. Eight patients 3 on amitriptyline and 5 on placebo withdrew their consent after 1 to 47 weeks median, 7 weeks : two patients on amitriptyline because of side-effects dry mouth , one patient on amitriptyline because she suspected she was receiving placebo and one patient on placebo because of fear of interactions of the study drug. Four patients did not report the reason for their consent withdrawal. Amitriptyline dose and side-effects. In general, amitriptyline mg per day was well tolerated.
Forty out of 54 patients were on the target dose. The daily dose was reduced to 25 mg in one patient and to 50 mg in 13 patients.school97ufa.ru/cache/2020-03-03/4373-znakomstvo-sving-par.php
Chemotherapy induced peripheral neuropathic pain
Dry mouth, visual disturbances and constipation caused dose reduction in one patient each. In the placebo group the dose was reduced to 50 mg in 4 patients out of 45 because of palpitation, dizziness, dry mouth and tiredness in one patient each. The severity of the side-effects in the amitriptyline and placebo groups is presented at the stable dose in Figure 1. There was no significant association between the severity of the side-effects and the drug concentration. Appearance of neuropathic symptoms.
Results of the neuropathy score are presented in Figure 2. The intensity of neuropathy was in general mild. There was no significant difference between the amitriptyline and placebo groups. Keywords: Pain, chemotherapy, neuropathy, paclitaxel. This work is published and licensed by Dove Medical Press Limited.
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There is a yin and yang between ceramide and S1P.
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Ceramide kills cancer cells, and S1P allows them to survive. Salvemini and colleagues used both genetic and pharmacologic techniques to test their idea. First, the researchers used liquid chromatography-mass spectrometry to look at sphingolipid metabolism in the rat dorsal horn spinal cord and compared tissue from bortezomib-treated animals to those receiving saline.
Amitriptyline in the Prevention of Chemotherapy-induced Neuropathic Symptoms
Rats treated with the chemotherapeutic agent showed both mechanical allodynia and mechanical hyperalgesia. This led to dysregulation of sphingolipid metabolism, which previous studies have linked to the development of pain. As expected, this ameliorated pain behaviors in the rats. Other S1PR1-targeting drugs, including the functional S1PR1 antagonists ponesimod and fingolimod, which cause irreversible downregulation of S1PR1, prevented rats from developing neuropathic pain for 20 days after bortezomib treatment.
The investigators then looked to genetically modified mice with reduced levels of, or removal of, S1PR1 protein from spinal cord astrocytes; these cells have been implicated in neuroinflammation, and contain much higher amounts of S1PR1 than microglia and neurons. The researchers found that they could prevent or delay neuropathic pain in these animals after bortezomib treatment, compared to littermate controls. When the researchers blocked S1PR1 with antagonist drugs like NIBR14 in mice, they saw fewer activated astrocytes, as well as decreased production of inflammatory cytokines, in the spinal cord.
And electrophysiological experiments revealed increased glutaminergic signaling after bortezomib treatment, which was decreased after treatment with fingolimod. While Salvemini was happy to elucidate the pathways that contribute to CIPN, she wanted to find a way to reverse it.