Toxic and drug-induced peripheral neuropathies: updates on causes, mechanisms and management.

PURPOSE OF REVIEW: This review discusses publications highlighting current research on toxic, chemotherapy-induced peripheral neuropathies (CIPNs), and drug-induced peripheral neuropathies (DIPNs). RECENT FINDINGS: The emphasis in clinical studies is on the early detection and grading of peripheral neuropathies, whereas recent studies in animal models have given insights into molecular mechanisms, with the discovery of novel neuronal, axonal, and Schwann cell targets. Some substances trigger inflammatory changes in the peripheral nerves. Pharmacogenetic techniques are underway to identify genes that may help to predict individuals at higher risk of developing DIPNs. Several papers have been published on chemoprotectants; however, to date, this approach has not been shown effective in clinical trials. SUMMARY: Both length and nonlength-dependent neuropathies are encountered, including small-fiber involvement. The introduction of new diagnostic techniques, such as excitability studies, skin laser Doppler flowmetry, and pharmacogenetics, holds promise for early detection and to elucidate underlying mechanisms. New approaches to improve functions and quality of life in CIPN patients are discussed. Apart from developing less neurotoxic anticancer therapies, there is still hope to identify chemoprotective agents (erythropoietin and substances involved in the endocannabinoid system are promising) able to prevent or correct painful CIPNs

Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases.

A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow-up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non-vertebral fractures. The pretreatment predictors of the post-treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: A randomized double-blind controlled trial

Background: Dyspnea represents a very frequent and distressing symptom in patients with advanced cancer. This study was undertaken to assess the efficacy of morphine on dyspnea and its safety for ventilatory function in elderly advanced cancer patients. Patients and methods: Nine elderly patients with dyspnea due to lung involvement were randomized to receive either morphine subcutaneously (5 mg in seven opioid-naïve patients and 3.75 mg in two patients on top of their regular oral dose of 7.5 mg q4h) or placebo on day 1. On day 2, they were crossed over to receive the alternate treatment. Dyspnea was assessed every fifteen minutes using a visual analogue scale (VAS: 0-100 mm) and the ordinal scale developed by Borg (0-10 points). Pain, somnolence and anxiety were assessed using VAS. Respiratory effort, respiratory rate and oxygen saturation were also measured repeatly. Results: Mean changes in dyspnea 45 minutes after injection were −25 ± 10 mm and −1.2 ± 1.2 points for morphine, versus 0.6 ± 7.7 mm (P < 0.01) and −0.1 ± 0.3 points (P = 0.03) for placebo on VAS and Borg scale, respectively. No relevant changes were observed in somnolence, pain, anxiety, respiratory effort and rate, and oxygen saturation. Conclusions: Morphine appears effective for cancer dyspnea, and it does not compromise respiratory function at the dose level use

Late onset tacrolimus-induced life-threatening polyneuropathy in a kidney transplant recipient patient

A 59-year-old kidney recipient was diagnosed with a late onset of severe chronic inflammatory demyelinating polyradiculoneuropathy and almost fully recovered after stopping tacrolimus and one course of intravenous immunoglobulin treatment. Unique features of this patient are the unusually long time lapse between initiation of tacrolimus and the adverse effect (10 years), a strong causality link and several arguments pointing toward an inflammatory etiology. When facing new neurological signs and symptoms in graft recipients, it is important to bear in mind the possibility of a drug-induced adverse event. Discontinuation of the suspect drug and immunomodulation are useful treatment options

Hemodialysis for cefepime intoxication: A case report

Introduction: We report a case of cefepime intoxication with acute severe neurologic symptoms, which was treated by temporary hemodialysis. Patients (or Materials) and Methods: Cefepime 2 g BID for endovascular prosthesis infection was prescribed to a frail, chronically ill 88-year-old woman with a serum creatinine of 199 μmol/L and an estimated creatinine clearance of 13 mL/min (Cockroft formula). Two days later, she was transferred to a neurocritical care unit because of acute aphasia, myoclonic jerks, and delirium with a Glasgow coma scale score of 12/15. The following day, in the absence of other causes, cefepime intoxication was hypothesized, and cefepime was withdrawn after a total of 7 doses = 14 g. Over the next 24 hours, two 3-hour hemodialysis (HD) sessions were performed under cefepime concentration monitoring. Results: Cefepime plasma levels were measured by liquid chromatography/ mass spectrometry. There is no validated reference range, but a study (Chapuis T et al, Critical Care, 2010) found a 50% risk of neurotoxicity with residual levels &gt; 15 mg/L. In our patient, levels were 83.3 mg/L 10 hours after last dose, 24.1 mg/L immediately after the first HD session, 13.4 mg/L immediately before the second HD session, and 2.5 mg/L immediately after the second HD session. The patient made a full clinical recovery over the next 48 hours. The 70% to 80% fall in plasmatic levels observed during each HD session is in accordance with literature data (Schmaldienst S et al, Eur J Clin Pharmacol, 2000, and Manyor LM et al, Pharmacotherapy, 2008). According to kinetic simulation, cefepime dropped at a concentration &lt; 15 mg/L 15 hours earlier with HD than it would have without. Conclusion: Neuropsychiatric adverse effects of beta-lactam antibiotics can be easily overlooked by clinicians. One should be especially cautious with their use in very old and frail patients in whom plasma creatinine poorly estimates renal function and cognitive impairment is highly prevalent. Temporary hemodialysis effectively clears cefepime, but its role in hastening clinical recovery may be limited

Development and validation of a multiplex HPLC-MS/MS assay for the monitoring of JAK inhibitors in patient plasma.

Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose-response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H &lt;sub&gt;2&lt;/sub&gt; O was performed using a C &lt;sub&gt;18&lt;/sub&gt; column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5-200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1-400 ng/mL for tofacitinib; 0.5-400 ng/mL for ruxolitinib, and 10-800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges

Disposition of voriconazole during continuous veno-venous haemodiafiltration (CVVHDF) in a single patient

Objectives: To determine whether voriconazole dosage adjustment is required during continuous veno-venous haemodiafiltration (CVVHDF). Methods: Voriconazole pharmacokinetics were studied in a critically ill patient under CVVHDF. The analysis was carried out for 12 h following a 6 mg/kg dose. Voriconazole concentrations were measured by HPLC in blood inlet and outlet lines and in dialysate. Results: The total body clearance of voriconazole was 20.3 L/h, with a terminal half-life of 13.7 h and a distribution volume of 399 L. The estimated sieving coefficient was 0.53 and the filtration-dialysis clearance 1.2 L/h. Conclusions: CVVHDF does not significantly affect voriconazole disposition and requires no dosage adjustmen

Levetiracetam circulating concentrations and response in status epilepticus.

Intravenous levetiracetam (LEV) is broadly used in the treatment of status epilepticus (SE). A loading dose is usually infused, aiming to reach quickly the range of plasma concentrations considered as therapeutic (12-46 mg/l). The aim of the study was to evaluate the response to LEV in SE, correlated exposure assessed by plasma concentration monitoring, as well as calculated exposure parameters. We retrospectively analyzed a SE registry, including patients since 2015 with at least one available LEV plasma level measured less than 36 h after loading. A Bayesian maximum likelihood approach based on a population pharmacokinetic model was used to estimate LEV exposure parameters. We compared plasma levels and pharmacokinetics parameter estimates between responders and nonresponders. Therapeutic response was defined as SE cessation within 24 h following LEV introduction without a need for additional antiepileptic drug (AED). We included 29 patients (45 plasma levels). Variability was salient in LEV loading doses (ranging between 17 and 38 mg/kg) and monitoring practice. There was no difference in median plasma concentrations (19.5 versus 21.5 mg/l; p = 0.71), median estimated LEV exposure (25.8 versus 37.0 mg/l; p = 0.61), peak (30.4 versus 41.5 mg/l; p = 0.36), or residual levels after loading dose (14.4 versus 20.5 mg/l; p = 0.07) between responders and nonresponders. Levetiracetam exposure does not seem to differ significantly between responders and nonresponders; greater exposure was not associated with better outcome. Loading doses of 30 mg/kg seem, however, appropriate to quickly reach the target exposure level. The short LEV half-life makes standardized sampling measurement necessary to obtain directly interpretable LEV levels