Analgesic and preventive effects of donepezil in animal models of chemotherapy-induced peripheral neuropathy: Involvement of spinal muscarinic acetylcholine M2 receptors.

BACKGROUND: Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN. METHODS: using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities. The involvement of muscarinic M2 acetylcholine receptors (m2AChRs) in analgesic effects was investigated at the spinal level. The absence of interference of donepezil with the cytotoxic effect of chemotherapy has been controlled in cancer cell lines. RESULTS: the analgesic efficacy of donepezil was demonstrated for all CIPN models, mainly on tactile hypersensitivity (maximal efficacy at 60 min, p < 0.05 vs. vehicle group). This effect was suppressed by an intrathecal injection of methoctramine (m2AChR antagonist). Regarding preventive effects, donepezil limited tactile hypersensitivity induced by paclitaxel, but not for other CIPN models. Donepezil did not modify the viability of cancer cells or the efficacy of anticancer drugs. CONCLUSIONS: donepezil had a broad analgesic effect on animal models of CIPN and this effect involved spinal m2AChRs. This work validates the repositioning of donepezil in the management of CIPN.

Ketamine-Magnesium for Refractory Chronic Cluster Headache: A Case Series.

OBJECTIVES: To evaluate the safety and efficacy of ketamine-magnesium combination to reduce attacks in a series of patients with refractory chronic cluster headache (rCCH). BACKGROUND: Refractory chronic cluster headache (CCH) is a rare but highly debilitating condition that needs new treatment options. A previous publication reported that a single infusion of ketamine-magnesium combination was effective in 2 patients with rCCH. METHODS: The treatment was proposed to consecutive patients with rCCH seen in 2 French hospitals between November 2015 and February 2020 and who were resistant to at least 3 preventive treatments. They received a single ketamine infusion (0.5 mg/kg over 2 hours) combined with magnesium sulfate (3000 mg). The main outcome was a comparison of the number of daily attacks 2 weeks prior to the ketamine-magnesium infusion and 1 week after (on days 7 and 8). The second outcome was the percentage of responders (patients with ≥50% reduction in the frequency of daily attacks). Safety was assessed by the recording of adverse events during infusion. Descriptive statistics are presented as mean ± standard deviation. RESULTS: Seventeen patients (14 men), with an age of 35.2 ± 8.1 years, were included. They presented with CCH for 6.6 ± 4.3 years. The number of daily attacks decreased from 4.3 ± 2.4 before treatment to 1.3 ± 1.0 after treatment (difference: -3.1 (95% CI: -4.5 to -1.6), P < .001). Seventy six percent (13/17) were responders. Transient and mild sedation was reported by 7/17 patients (41.2%). CONCLUSIONS: The ketamine-magnesium combination seems an effective and well-tolerated therapy for rCCH. Placebo-controlled studies should be conducted to further confirm these findings.

Multiple sclerosis as differential diagnosis of radionecrosis for post-irradiation brain lesions: A case report.

INTRODUCTION: Demyelination can occur after brain radiotherapy in tissue adjacent to irradiated tumours. To date, no correlation has been found between conventional-dose radiotherapy and the development of multiple sclerosis, but radiotherapy could be a triggering factor among women with known multiple sclerosis. To the best of our knowledge, this is the first well-documented case of this association with a dosimetric analysis. CASE PRESENTATION: The case we report here describes the development of multiple sclerosis in a 36-year-old woman without significant past medical history 3 months after the last session of fractionated stereotactic radiotherapy for a pituitary macroadenoma. Our dosimetric analysis suggests that all the multiple sclerosis lesions occurred in the brain regions irradiated with a mean biologically effective dose (BED2) of 33.9 Gy (27.3-49.6 Gy). CONCLUSION: Consequently special caution towards radiotherapy is required among patients with demyelinating illnesses or for 35-45-year-old women who are at risk. In addition, multiple sclerosis lesions can look like metastases. We should therefore keep differential diagnoses in mind in order not to make mistakes that would delay treatment.

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review.

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a "stocking and glove" distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.