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Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on APCMin/+ mice and on cancer progression when combined with oxaliplatin, both in vivo on APCMin/+ mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in APCMin/+ mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.

International audience; Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K+ channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K+ channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K+ channel expression in oxaliplatin-treated mice.

Several low-impact laparoscopic strategies have been developed to improve the safety of pneumoperitoneum. We conducted a systematic review to establish the current evidence base for the use of the AIRSEAL® insufflation device for low-pressure pneumoperitoneum in laparoscopic surgery. We searched the literature using several electronic databases, for studies with comparative design published in the English language from January 2010 to April 2020. The population of interest included patients with any type of health condition who underwent laparoscopic surgery using the AIRSEAL® insufflation system or a standard CO2 insufflator. Ten studies (four randomized clinical trials/six non-randomized clinical trials), that enrolled 1394 participants in total who underwent urology, gynaecology or abdominal surgeries, were included. Total complication rates were similar between groups. Only three studies evaluated the impact of the insufflation system on post-operative pain, and showed inconsistent benefit of AIRSEAL® (significant decrease in pain in two studies, no difference in one). The same was observed in the two sole studies in which pain killers consumption was measured (significant decrease in morphine consumption 24 h after surgery in one study, no difference in the other). Operative duration was significantly shorter with AIRSEAL® in three studies. For both post-operative room and total length of stay, there was no difference between groups. No studies reported economic outcomes. Current literature supports the feasibility of the AIRSEAL® system during laparoscopic surgery but more studies are required to establish the added clinical benefit and to explore the preferences of physicians and patients.

Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for neurologists and pain physicians. Although many drugs have been assessed in scientific studies, few have demonstrated a clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raised the question on the benefit-risk ratio when used in patients experiencing peripheral neuropathies.The authors conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat neuropathic pain. This first review was focused on antidepressant and antiepileptic medications. The aim was to provide an overview of the treatment-emergent adverse events (≥10%) and the serious adverse effects described in clinical trials.Among antiepileptics and antidepressants, duloxetine appeared to have the most detailed safety for the treatment of peripheral neuropathic pain. Over all studies, the most commonly reported adverse effects were dizziness, drowsiness, nausea, and constipation. Only 20.0% of the included studies (N = 90) presented a good description of adverse effects that included a statistical comparison

International audience; Purpose Bortezomib is a neurotoxic drug used in multiple myeloma and responsible for chemotherapy-induced peripheral neuropathy (CIPN). In a previous cross-sectional study, CIPN prevalence was about 26.9% in 67 patients. A second data analysis was performed to explore the relation between CIPN and auditory difficulties. Methods Based on 66 multiple myeloma patients from a single center, auditory difficulties were assessed with a self-questionnaire and compared to sensory CIPN (QLQ-CIPN20 questionnaire), patients' characteristics and anticancer treatments. Results The prevalence of auditory difficulties was about 42.4% (95% CI [30.6-55.2]) of the 66 patients analyzed and was higher in patients with CIPN than without (82.4% vs. 28.6%, p < 0.001). Auditory difficulties were not related to the characteristics of patients and treatments. The severity of auditory difficulties were correlated to CIPN severity (spearman's coefficient: 0.49, p = 0.009). Odds-ratio of auditory difficulties (multivariable analysis adjusted for sensory CIPN, recreation or professional noise exposure, gender, age, and treatments) was significantly associated with CIPN (18.7, 95% CI [3.0-117.1], p = 0.002). Conclusion This relation between CIPN and auditory difficulties raises concerns about hearing safety in multiple myeloma patients treated by bortezomib. Trial registration number: NCT03344328.

The growing number of oral antineoplastic agents delivered by French community pharmacies has modified the job and roles of community pharmacists. Coordination between hospitals (oncology centers) and community pharmacies has become essential for a quality work in this field. The goal of this work was to obtain information about the feeling of the community pharmacies teams in a French county (Aveyron) regarding the communication tools offered by various hospitals with an oncology service (when receiving a beginning prescription for an oral antineoplastic drug), and to evaluate the impact of these tools on their practice.A declarative survey was submitted to the 109 community pharmacies of this county to evaluate their relationship with their nearest oncology centers (including communication tools) and collect their opinion on the quality of the coordination and their pharmaceutical exercise.The response rate was of 54% (59 community pharmacies). Communication between the oncology centers and the pharmacies was limited (only 50% of the pharmacies received information complementary to the prescription), the available tools were not used very frequently (44% of pharmacies didn't use shared medical records) and there was a strong feeling of rupture between the pharmacies and the oncology centers, impacting the quality of their work (46% of respondents indicated being little or incapable of correctly validating the indication of the anticancer drug).This study illustrates the under-use of the available hospital-community pharmacy communication tools and the fact that the pharmacies feel difficulties to correctly deliver oral antineoplastic medications due to a lack of information.

Background Community pharmacists are among the frontline health professionals who manage patients with an opioid-related disorder (ORD). Pharmacists frequently have a negative attitude toward these patients, which could have a negative impact on their management. However, education on ORD may improve the attitude of future healthcare professionals. This cross-sectional study aimed to assess French pharmacy students’ perceptions of ORD. Methods This online survey was performed by emails sent to French pharmacy schools (between January 14, 2019 and May 31, 2019). The primary outcome was the perception (visual analogic scale) of ORD as a disease, the roles of community pharmacies (delivery of opioid agonist therapy—OAT and harm reduction kits), and the efficacy of OAT. The secondary outcomes assessed professional experience, university experience of and education on ORD, and the individual characteristics of students. Results Among the 1,994 students included, 76.3% perceived ORD as a disease and felt that it was normal for pharmacists to deliver OAT (78.9%) and harm reduction kits (74.6%). However, only 46.9% perceived OAT as being effective. Multivariable analyses showed that females had a more positive perception in recognizing ORD as a disease. The progression through university years increased the positive perception of ORD as a disease and the delivery of OAT and harm reduction kits by pharmacists. Education on substance-related disorders had no impact on any scores. Students who had already delivered OAT had a negative perception of their efficacy. The students who had already performed pharmacy jobs or traineeships had a negative perception of harm reduction kit delivery. Conclusion Education on substance-related disorders had no impact on students’ perceptions. It seemed that the maturity acquired through university years had a stronger impact on the students’ perceptions of ORD. Efforts must be made to improve our teaching methods and reinforce the confidence of students in the roles of community pharmacists.

International audience; Among postmenopausal women with estrogen receptor-positive breast cancer, more than 80% receive hormone therapy including aromatase inhibitors (AIs). Half of them develop chronic arthralgia - characterized by symmetric articular pain, carpal tunnel syndrome, morning stiffness, myalgia and a decrease in grip strength - which is associated with treatment discontinuation. Only a few animal studies have linked AI treatment to nociception, and none to arthralgia. Thus, we developed a new chronic AI-induced nociceptive disorder model mimicking clinical symptoms induced by AIs, using subcutaneous letrozole pellets in ovariectomized (OVX) rats. Following plasma letrozole dosage at the end of the experiment (day 73), only rats with at least 90 ng/ml of letrozole were considered significantly exposed to letrozole (OVX + high LTZ group), whereas treated animals with less than 90 ng/ml were pooled in the OVX + low LTZ group. Chronic nociceptive disorder set in rapidly and was maintained for more than 70 days in the OVX + high LTZ group. Furthermore, OVX + high LTZ rats saw no alteration in locomotion, myalgia or experimental anxiety during this period. Bone parameters of the femora were significantly altered in all OVX rats compared to Sham+vehicle pellet. A mechanistic analysis focused on TRPA1, receptor suspected to mediate AI-evoked pain, and showed no modification in its expression in the DRG. This new long-lasting chronic rat model, efficiently reproduces the symptoms of AI-induced nociceptive disorder affecting patients' daily activities and quality-of-life. It should help to study the pathophysiology of this disorder and to promote the development of new therapeutic strategies.

Several low-impact laparoscopic strategies have been developed to improve the safety of pneumoperitoneum. We conducted a systematic review to establish the current evidence base for the use of the AIRSEAL

Chemotherapy-induced peripheral neuropathy (CIPN) is challenging for oncologists. Many publications mention the high incidence of CIPN and the lack of effective preventive/management strategies and robust diagnostic tools. This cross-sectional study was aimed at assessing the practice of French oncologists for CIPN prevention, diagnosis and management. This web-based survey was sent to French oncologists by the regional cancer networks. Incidence and impact of CIPN were assessed using visual analogue scales (VAS) and diagnostic strategies were recorded. Also recorded were the drugs used to prevent or manage CIPN and their perceived efficacy and safety (VAS). Among the 210 oncologists included, the perceived incidence of CIPN was about 36.2 ± 22.1% of patients. About 99.5% of oncologists declared that they assess CIPN during medical follow-up. The use of drugs to prevent CIPN was reported by 9.6% of oncologists (group B vitamins (35.0%) and calcium and magnesium infusion (25.0%)). In the case of CIPN, the therapeutic adjustment of neurotoxic anticancer drugs is performed by 99.0% of oncologists (chemotherapy change (49.8%), dose reduction (30.9%) or interruption (19.3%)). The pharmacological management of CIPN was declared by 72.9% of oncologists. The main drugs used are pregabalin (75.8%), amitriptyline (32.7%) and gabapentin (25.5%). Duloxetine (ASCO recommendation) is used by only 11.8% of oncologists. Oncologists were clearly aware of CIPN risks, but its incidence tended to be underestimated and the ASCO recommendations for the management of CIPN were not followed. The prevention, diagnosis and management of CIPN remain problematic in clinical practice in France. ClinicalTrials.gov : NCT03854864

(1) Background: Oxaliplatin is among the most neurotoxic anticancer drugs. Little data are available on the long-term prevalence and consequences of chemotherapy-induced peripheral neuropathy (CIPN), even though the third largest population of cancer survivors is made up of survivors of colorectal cancer. (2) Methods: A multicenter, cross-sectional study was conducted in 16 French centers to assess the prevalence of CIPN, as well as its consequences (neuropathic pain, anxiety, depression, and quality of life) in cancer survivors during the 5 years after the end of adjuvant oxaliplatin chemotherapy. (3) Results: Out of 406 patients, the prevalence of CIPN was 31.3% (95% confidence interval: 26.8&ndash, 36.0). Little improvement in CIPN was found over the 5 years, and 36.5% of patients with CIPN also had neuropathic pain. CIPN was associated with anxiety, depression, and deterioration of quality of life. None of the patients with CIPN were treated with duloxetine (recommendation from American Society of Clinical Oncology), and only 3.2%, 1.6%, and 1.6% were treated with pregabalin, gabapentin, and amitriptyline, respectively. (4) Conclusions: Five years after the end of chemotherapy, a quarter of patients suffered from CIPN. The present study showed marked psychological distress and uncovered a failure in management in these patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is common with specific semiological characteristics. When CIPN appears, there are many difficulties in guaranteeing sustained treatment, especially with optimal protocol. Moreover, CIPN have bad repercussions on quality of life after cancer disease. In this article, we have achieved a current state of CIPN and try to report details about semiological characteristics and topography. We have also produced some epidemiological data. Nonetheless, we have not voluntarily introduced treatment because it will be the topic of further work.

Peripheral neuropathic pain is a disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies.We conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat peripheral neuropathic pain. This second review was focused on opioids, cannabinoids, and other medications. The aim was to provide an overview of the treatment-emergent adverse events (TEAEs) (≥10%) and the serious adverse effects described in clinical trials.Opioids and cannabinoids had significantly more TEAEs than placebos. Locally administered analgesics, such as capsaicin, lidocaine, botulinum toxin A seemed to have the most acceptable safety with only local adverse effects. The results for NMDA antagonists were inconclusive since no safety report was available. Less than half of the studies included presented a good description of TEAEs that included a statistical comparison versus a placebo group. Major methodological improvements must be made to ameliorate the assessment of medication safety in future clinical trials.

PurposeThe aim of the present study was to describe the profiles of a sample of young cannabis users not seeking care, for use in general practice in France.MethodsIn this cross-sectional study, baseline data were used from a previous clinical randomized trial, in which a brief intervention was tested. The participants were 262 cannabis users aged 15 to 25 years who smoked at least one joint per month. Assessment was undertaken both by the GP and via an anonymous self-reporting questionnaire. All statistical analyses were performed using Stata software and R. We used multiple correspondence analysis to determine the profiles of users.ResultsAmong the 262 patients, 46.2% were daily users (more than 30 joints per month), 25.6% were regular users (from 10 to 29 joints per month), and 28.2% were recent users (fewer than 10 joints per month). The higher the frequency of use, the greater the incidence of unaccompanied use, daily use and week use (p from 0.05).ConclusionsThe results provide support for the practice of asking young patients systematically about their cannabis use, allowing GPs to identify users who require medical care. GPs should consider the differences between participants according to their profile in order to determine the appropriate type of care.Trial registrationClinicaltrials.gov NCT01433692.

IntroductionS100B serum analysis in clinical routine could reduce the number of cranial CT (CCT) scans performed on children with mild traumatic brain injury (mTBI). Sampling should take place within 3 hours of trauma and cut-off levels should be based on paediatric reference ranges. The aim of this study is to evaluate the utility of measuring serum S100B in the management of paediatric mTBI by demonstrating a decrease in the number of CCT scans prescribed in an S100B biomonitoring group compared with a ‘conventional management’ control group, with the assumption of a 30% relative decrease of the number of CCT scans between the two groups.Methods and analysisThe protocol is a randomised, multicentre, unblinded, prospective, interventional study (nine centres) using a stepped wedge cluster design, comparing two groups (S100B biomonitoring and control). Children in the control group will have CCT scans or be hospitalised according to the current recommendations of the French Society of Paediatrics (SFP). In the S100B biomonitoring group, blood sampling to determine serum S100B protein levels will take place within 3 hours after mTBI and subsequent management will depend on the assay. If S100B is in the normal range according to age, the children will be discharged from the emergency department after 6 hours’ observation. If the result is abnormal, CCT scans or hospitalisation will be prescribed in accordance with current SFP recommendations. The primary outcome measure will be the proportion of CCT scans performed (absence/presence of CCT scan for each patient) in the 48 hours following mTBI.Ethics and disseminationThe protocol presented (Version 5, 03 November 2017) has been approved by the ethics committee Comité de Protection des Personnes sud-est 6 (first approval 08 June 2016, IRB: 00008526). Participation in the study is voluntary and anonymous. The study findings will be disseminated in international peer-reviewed journals and presented at relevant conferences.Trial registration numberNCT02819778.

IntroductionMost patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%–50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects.Methods and analysisRILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety.Ethics and dessiminationThe study was approved by a French ethics committee (ref:39/18_1, ‘Comité de Protection des Personnes’ Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov.Trial registration numberN°2017-002320-25;NCT03722680

International audience; Neurotoxicity remains the most common adverse effect of oxaliplatin, limiting its clinical use. In the present study, we developed a mouse model of chronic oxaliplatin-induced neuropathy, which mimics both sensory and motor deficits observed in patients, in a clinically relevant time course. Repeated oxaliplatin administration in mice induced both cephalic and extracephalic long lasting mechanical and cold hypersensitivity after the first injection as well as delayed sensorimotor deficits and a depression-like phenotype. Using this model, we report that riluzole prevents both sensory and motor deficits induced by oxaliplatin as well as the depression-like phenotype induced by cumulative chemotherapeutic drug doses. All the beneficial effects are due to riluzole action on the TREK-1 potassium channel, which plays a central role in its therapeutic action. Riluzole has no negative effect on oxaliplatin antiproliferative capacity in human colorectal cancer cells and on its anticancer effect in a mouse model of colorectal cancer. Moreover, riluzole decreases human colorectal cancer cell line viability in vitro and inhibits polyp development in vivo. The present data in mice may support the need to clinically test riluzole in oxaliplatin-treated cancer patients and state for the important role of the TREK-1 channel in pain perception.

International audience; Background: The use of psychotropic medications and illegal drugs is a worldwide public health issue, leading to addiction, psychiatric and somatic disorders, and death. Pharmacy students are more exposed to psychotropic medications than other students (non-medical), which could lead to an overuse. The main objective of this study was to assess the prevalence of psychotropic drug use (medications and illegal drugs) by French pharmacy students, by carrying out a nationwide cross-sectional study. The relation of these medications and illegal drug use with several comorbidities and academic achievement was also assessed. Methods: This online survey was performed by emails sent to all French pharmacy faculties over a period of 66 days (March 16, 2016 to May 20, 2016). The survey assessed the prevalence of uses of psychotropic medications and illegal drugs during the last 3 months. These uses were compared to student characteristics (personal and university) and comorbidities (anxiety, depression, stress, and fatigue). Results: Of the 2,609 questionnaires received, 2,575 were completed and useable for the analysis. Among French pharmacy students and during the 3 last months, 9.4% have used psychotropic medications, 21.5% illegal drugs and 3.3% both psychotropic medications and illegal drugs. Psychotropic medications were used in the cases of a medical prescription (49.0%), a self-medication (42.4%) or a non-medical intent (26.3%). Stress scores of the last 7 days were higher for psychotropic medication users compared to non-users and illegal drug users. Proportions of anxiety and depression at the time of answer were higher for psychotropic medication users than for non-users and illegal drug users. Fatigue scores of the last 7 days were lower for illegal drug users compared to non-users and self-medicated students. Annual average marks of the last year, attendance and perception of study difficulty were lower for illegal drug users than for non-users. Conclusion: French pharmacy students were less exposed to psychotropic medications and illegal drugs than the general French population. However, in comparison to other students in other countries, the use of psychotropic medications seemed to be lower, but with a proportionally higher use of anxiety/sedative medications and a lower use of opioid medications.

Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS1H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment.SIGNIFICANCE STATEMENTOur study describes a decrease in cholinergic neurotransmission in the posterior insular cortex in neuropathic pain condition and the involvement of M2 receptors. Targeting these cortical muscarinic M2 receptors using central cholinomimetics could be an effective therapy for neuropathic pain treatment.

Chemotherapy-induced peripheral neuropathies (CIPN) are a dose-limiting adverse effect of certain anticancer drugs (platinum salts, vinca alkaloids, taxanes, bortezomib, thalidomide, epothilones, eribulin). CIPN are mainly responsible for sensory disturbances and are associated with a decrease in quality of life. After the end of chemotherapy, CIPN can last for several months and even years. Unfortunately, recent meta-analyses of clinical trials have demonstrated that there is no univocal gold standard for the prevention and treatment of CIPN.Using animal models of CIPN, several new strategies to prevent or treat CIPN are under development. These new strategies involve several pathways, including ion channels, neuroprotectants, glutamatergic neurotransmission, oxidative stress, cannabinoid system, inflammation, and mitochondrial functions.To date, based on meta-analyses of clinical trials, no drug can be proposed as a gold standard to prevent or treat CIPN. Consequently, there is a strong discrepancy between the optimistic results of animal studies and the poor outcomes of clinical trials. Pain assessment in preclinical and clinical studies is probably not the best outcome measurement tool and all these studies should include composite outcomes including the full complexity of CIPN symptoms, such as positive symptoms (pain, paresthesia, and dysesthesia) and negative ones (numbness).

Chemotherapy-induced peripheral neuropathy (CIPN) is common with specific semiological characteristics. When CIPN appears, there are many difficulties in guaranteeing sustained treatment, especially with optimal protocol. Moreover, CIPN have bad repercussions on quality of life after cancer disease. In this article, we have achieved a current state of CIPN and try to report details about semiological characteristics and topography. We have also produced some epidemiological data. Nonetheless, we have not voluntarily introduced treatment because it will be the topic of further work.

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.

Breastfeeding is the optimal method for feeding a newborn. However, some mothers may have difficulties lactating. Domperidone is widely used as a galactagogue but to the best of our knowledge has not been approved by any health authority. The objective of this review was to assess the benefit-risk ratio of domperidone for stimulating lactation. The benefit-risk ratio of domperidone as a galactagogue was assessed following a literature search of the PubMed database up to July 2013. Four studies were selected to assess domperidone efficacy and demonstrated an increased milk production. The limited data (60 mother-baby pairs) and the moderate methodological quality of 1 study remain insufficient to conclude on domperidone efficacy. Regarding the safety of domperidone, 7 studies were selected that exposed 113 infants to domperidone through breastfeeding. No adverse effects were observed in 85 infants, and no information was provided for the remaining 28. The limited data available remain in favor of a safe domperidone profile in infants and mothers. However, in large studies focused on gastrointestinal disorders, domperidone is responsible for drug-induced long QT syndrome and sudden cardiac death. The use of domperidone as a galactagogue is worrisome as drug-induced long QT syndrome occurred mostly in women. In these circumstances, an improvement of breastfeeding practices seems to be more effective and safer than the use of an off-label domperidone treatment.

Thermal sensitivity is an essential characteristic of some painful states, including oxaliplatin-induced neuropathy. The thermal place preference test (TPPT) was designed to finely assess thermal sensitivity in rodents. The TPPT monitors the time spent by unrestrained rodents on a test plate at fixed temperatures (5-50°C) compared with an adjacent reference plate at a neutral temperature (25°C). Here, we report the results of a study designed (i) to validate the optimal methodological parameters for measuring thermal sensitivity in rats, (ii) to assess the thermal sensitivity of healthy rats and animal models of pain and (iii) to explore the pharmacological effects of analgesic drugs. The most reproducible conditions occurred when the TPPT was performed in the morning and in the dark for 3 min with the reference plate set to 25°C. The temperature preferences of healthy rats were more than 17°C and less than 40°C. When compared with control animals, oxaliplatin-treated rats showed thermal hypersensitivity at 12, 20 and 35°C, and carrageenan-treated rats showed thermal hypersensitivity at 15 and 45°C. Duloxetine (2.5 mg/kg, intraperitoneal) reversed oxaliplatin-induced cold hypersensitivity (20°C) and morphine (1 mg/kg, intravenous) reversed carrageenan-induced heat hypersensitivity (45°C). We conclude that the TPPT enables a fine-grained assessment of thermal sensitivity that is relevant to the pathophysiological exploration of animal pain models and to the pharmacological assessment of analgesic drugs.

Le terme epigenetique definit les modifications transmissibles et reversibles de l’expression des genes ne s’accompagnant pas de changements des sequences nucleotidiques.

Background Like other health professionals, community pharmacists are exposed to stress factors (being efficient, avoiding mistakes and bearing emotional load), but they are also under the pressure of entrepreneurial responsibilities. The main objective was to assess the level of work-related stress in French community pharmacies. The other objectives of the study were to assess the associated comorbidities and causes of work-related stress. Methods This observational cross-sectional study was sent to all French community pharmacies by email. The survey was anonymous and designed to collect the following items: socio-demographic factors, professional status, characteristics of community pharmacy, work-related stress (visual analogic scale—VAS), fatigue (VAS), sleep disturbances (questions), anxiety and depression symptoms (hospital anxiety and depression scale), medical consultation for work-related stress, medication use for work related stress, psychoactive drug-use and causes of work-related stress. Participants were included in the survey if they were pharmacists (owner or assistant) or pharmacy technicians working in a community pharmacy at the time of the survey. Exclusion criteria were defined as follows: pharmacy students or other professionals involved in a community pharmacy (e.g. dietician, beautician) and lack of professional status information. There was no age limitation. Results After three months of data collection, 1,339 participants answered the survey and 1,272 participants were included in conformity with the inclusion and exclusion criteria, and to avoid missing data on the primary endpoint. Work-related stress was detected in 32.8% (417/1,272) of individuals (scores ≥70/100). Men were significantly more affected than women and there was no difference between professional statuses and no relation with the age of the participants. Work-related stress was significantly associated with anxiety, depression, fatigue, sleep disturbances, medical consultations, medication use, alcohol consumption above the WHO recommendations for men and psychoactive drug use. Three causes of stress were clearly identified and related to stress levels, workload, working atmosphere and deterioration of work quality. However, causes of work-related stress were significantly different among professionals, for example: entrepreneurial burden for pharmacists-in-charge and workload for employees (assistant pharmacists and pharmacy technicians). Discussion Work-related stress has a very strong impact in French community pharmacies. This stress was associated with several comorbidities and induces health resource consumption. Several causes of work-related stress have been identified such as workload, working atmosphere and deterioration of work quality; however, these causes could be detected and managed to improve stress levels. We recommend developing individual and organizational stress management in French community pharmacies.

The creation of a pneumoperitoneum for laparoscopic surgery is performed by the insufflation of carbon dioxide (CO2). The insufflated CO2 is generally at room temperature (20–25 °C) and dry (0–5 % relative humidity). However, these physical characteristics could lead to alterations of the peritoneal cavity, leading to operative and postoperative complications. Warming and humidifying the insufflated gas has been proposed to reduce the iatrogenic effects of laparoscopic surgery, such as pain, hypothermia and peritoneal alterations. Two medical devices are currently available for laparoscopic surgery with warm and humidified CO2. Clinical studies were identified by searching PubMed with keywords relating to humidified and warmed CO2 for laparoscopic procedures. Analysis of the literature focused on postoperative pain, analgesic consumption, duration of hospital stay and convalescence, surgical techniques and hypothermia. Bibliographic analyses reported 114 publications from 1977 to 2015, with only 17 publications of clinical interest. The main disciplines focused on were gynaecological and digestive surgery ). Analysis of the studies selected reported only a small beneficial effect of warmed and humidified laparoscopy compared to standard laparoscopy on immediate postoperative pain and per procedure hypothermia. No difference was observed for later postoperative shoulder pain, morphine equivalent daily doses, postoperative body core temperature, recovery room and hospital length of stay, lens fogging and procedure duration. Only few beneficial effects on immediate postoperative pain and core temperature have been identified in this meta-analysis. Although more studies are probably needed to close the debate on the real impact of warmed and humidified CO2 for laparoscopic procedures.

Clinical assessment of new antineuropathic strategies for chemotherapy-induced peripheral neuropathy: pain should not be the principal endpoint

Pain from anticancer drugs-induced neuropathies is difficult to treat and can significantly alter the patient's quality of life. These neuropathies are considered relatively resistant to conventional analgesic drugs (opioids). Opioids are also P-glycoprotein substrates and it has been demonstrated that the P-glycoprotein is linked to the integrity of blood-brain barrier protecting the nervous system. Previous works presented an increase of P-glycoprotein in vincristine- and cisplatin-induced neuropathy which could potentially decrease opioid efficiency. To test this hypothesis, the efflux inhibition of P-glycoprotein and the antinociceptive effect of morphine were assessed in normal and cisplatin-induced neuropathic rats after the administration of the P-glycoprotein inhibitor (R101933). R101933 (20 mg/kg) inhibited significantly the efflux transporter under the condition of the study and had no analgesic effect. Nociceptive thresholds were measured by the paw pressure test. R101933 (20 mg/kg) enhanced antinociceptive activity of morphine (0.5 mg/kg) to a maximum of +58% and +35%, respectively compared with control animals and animals treated by morphine alone (0.5 mg/kg). R101933 increased morphine (2 mg/kg) antinociceptive activity to a maximum of +105% compared with control animals and to a maximum of +41% compared with morphine alone (2 mg/kg). This study demonstrated that cisplatin-induced neuropathy may present a particular pathophysiology with a multidrug resistance, of the central nervous system, to analgesics. This resistance can be blocked by a P-glycoprotein inhibitor which may enhance analgesia of low doses of morphine.

This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy-induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized.

La promotion de la recherche clinique et de l’innovation est une orientation majeure en politique de sante. Afin d’optimiser la prise en charge therapeutique des patients, le ministere de la Sante a mis en place des programmes hospitaliers de recherche clinique et de soutien aux techniques innovantes couteuses, pour promouvoir une recherche clinique de qualite et assurer une diffusion efficiente des innovations.

Resume Les preparations de melanges nutritifs parenteraux sont des preparations magistrales et font donc partie des missions obligatoires des pharmacies a usage interieur. Une enquete a ete realisee pour faire un etat des lieux sur les principes de preparation et de controle effectues sur les melanges nutritifs parenteraux fabriques par les pharmacies. Cette enquete prospective de pratique a ete realisee aupres de 30 centres hospitaliers universitaires (CHU) de juillet 2006 a juillet 2007. L’enquete a ete menee par courrier, par telecopie, par courriel et par telephone. Les questionnaires ont permis d’evaluer la fabrication et les controles microbiologiques et physicochimiques des melanges nutritifs parenteraux. Le taux de reponse est de 93 %. Les melanges nutritifs parenteraux sont fabriques par 71 % des pharmacies. Les hottes a flux laminaire sont utilisees par 65 % des pharmacies. La production annuelle moyenne est de 7106 melanges nutritifs parenteraux et 80 % des melanges nutritifs parenteraux sont destines a la pediatrie. Les controles les plus frequents sont le controle de la sterilite (90 %) et le dosage des electrolytes (70 %). Enfin, les pourcentages de refus des preparations sont faibles puisque la moitie des pharmacies ont un taux de refus entre 0 et 1 % par an. La preparation des melanges nutritifs, notamment en pediatrie, est une activite importante des pharmacies. Cependant, une disparite des controles effectues sur les melanges nutritifs parenteraux est mise en evidence entre les differentes pharmacies. L’harmonisation des pratiques de preparation et de controle, deja initiee a ce jour, permettrait d’obtenir une meilleure demarche de qualite au sein des hopitaux.

Background: Cancer patients can be exposed to drug interactions during treatment with toxic anticancer drugs. The peripheral nervous system is a target for neurotoxic anticancer drugs. P-glycoprotein is essential for the functional integrity of blood-tissue barriers, and P-glycoprotein inhibition due to possible drug interactions could lead to adverse neurotoxic reactions. Methods: In a rat model of vincristine-induced neuropathy, we assessed the consequences of potential drug interactions of vincristine with some P-glycoprotein-inhibiting drugs, chosen because of their potency to increase the incorporation of 99mTc-sestamibi in nervous tissue. Results: Quinidine (30 mg/kg) increased 99mTc-sestamibi incorporation in dorsal root ganglia (DRG) but was toxic for rats. Verapamil (30 mg/kg) increased the tracer incorporation in the spinal cord, DRG and sciatic nerve. Combination treatment with the verapamil-vincristine regimen had a tendency to lower weight gain and altered nociceptive thresholds of neuropathic animals. Conclusion: Behavioral pain tests did not reveal an increase in vincristine neurotoxicity following combination treatment with verapamil and vincristine. This regimen only led to a slight increase in general toxicity.