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AIMS: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Cav ). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants. METHODS: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method. RESULTS: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses. CONCLUSIONS: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.
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Anticonvulsivantes , Etossuximida , Humanos , Zonisamida , Anticonvulsivantes/efeitos adversos , Levetiracetam , Ligantes , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Cálcio/metabolismoRESUMO
Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies.
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Hipertensão , Síndrome da Leucoencefalopatia Posterior , Acidente Vascular Cerebral , Ratos , Animais , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/etiologia , Síndrome da Leucoencefalopatia Posterior/patologia , Imageamento por Ressonância Magnética/efeitos adversos , Hipertensão/complicações , Convulsões , Acidente Vascular Cerebral/complicações , Modelos Teóricos , Ratos Endogâmicos SHRRESUMO
BACKGROUND: The worldwide development of immune system targeting/anticancer drugs has revolutionized immuno-oncology, but their implication in thrombotic microangiopathy syndromes (TMA) is increasingly suspected. Using real-world data, the aim of this study was to identify drugs associated with TMA reporting and to describe the evolution of TMA reporting over time with a focus on these drugs. METHODS: A global disproportionality study was performed using the individual case safety reports (ICSRs) extracted from the World Health Organization (WHO) pharmacovigilance database (VigiBase) from its inception (1968) to April 30, 2022. RESULTS: Of the 31,251,040 ICSRs, 6946 cases of suspected drug-induced TMA were included from 55 countries. The outcome was fatal in 18.2% of cases. A total of 72 immune system targeting/anticancer drugs were associated with significant overreporting, including 17 drugs with a potential new safety concern for TMA. Although the rate of TMA reporting per million of ICSRs has remained fairly stable, an absolute increase in reported cases of suspected drug-induced TMA has been observed over the last decade. The pattern of drugs reported in TMA has evolved with a substantial increase in the proportion of cases involving immune system-targeting drugs/anticancer drugs from 47.3% (205/433) in the period 1992-2001 to 80.7% (3819/4730) in the period 2012-2021. CONCLUSION: Several recently marketed immune system targeting/anticancer drugs have been identified as potential new drugs associated with TMA, which will require confirmatory studies. The number of drugs associated with TMA reporting markedly increased within the past 10 years, primarily due to innovative anticancer drugs.
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BACKGROUND: Although a few case reports have shown that immune checkpoint inhibitors (ICIs) are potential inducers of capillary leak syndrome (CLS), an incidental finding cannot be ruled out. The aim of this study was to describe the clinical characteristics of ICI-induced CLS through a systematic review and to assess a potential safety signal. METHODS: Medline/PubMed, Embase, and Reactions Weekly were screened, and a global disproportionality study was performed using the World Health Organization pharmacovigilance database through January 15, 2023. A signal of disproportionate reporting was defined as a Bayesian information component (IC) with a 95% credibility interval (CrI) lower boundary that exceeds 0. RESULTS: A total of 47 cases of ICI-associated CLS were included, 14 from the systematic review (of 61 screened articles) and 33 from VigiBase (of 34,058,481 reports of adverse drug reactions). The median time to CLS onset from the start of ICI was 12 weeks (interquartile range 8-49, n = 24). A total of 57% (8/14) of patients experienced an immune-related adverse event (irAE) before CLS. A fatal outcome was reported in 23% (7/31) of patients. A significant overreporting of CLS was found with ICIs compared with all other drugs (IC 2.4, 95% CrI from 1.8 to 2.8). CONCLUSION: This study showed a significant signal of disproportionality reporting for ICI-induced CLS, characterized by a long time to onset, and compared with the idiopathic form of the disease with a less abrupt onset and a less consistent hemoconcentration pattern.
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Antineoplásicos Imunológicos , Síndrome de Vazamento Capilar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Inibidores de Checkpoint Imunológico , Farmacovigilância , Teorema de Bayes , Antineoplásicos Imunológicos/efeitos adversos , Estudos RetrospectivosRESUMO
Peripheral facial palsy (PFP) is a rare adverse reaction identified from clinical trials of coronavirus disease 2019 (COVID-19) vaccines (messenger ribonucleic acid [mRNA] and viral vector). Few data are available on their onset patterns and risk of recurrence after re-injection of a COVID-19 vaccine; the objective of this study was to describe PFP cases attributed to COVID-19 vaccines. All cases of facial paralysis reported to the Regional Pharmacovigilance Center of Centre-Val de Loire area between January and October 2021, in which the role of a COVID-19 vaccine was suspected, were selected. Based on initial data and following additional information requested, each case was reviewed and analyzed to include only confirmed cases of PFP for which the role of the vaccine could be retained. From the 38 cases reported, 23 were included (15 excluded because of diagnosis not retained). They occurred in 12 men and 11 women (median age of 51 years). The first clinical manifestations occurred with a median time of 9 days after COVID-19 vaccine injection, and the paralysis was homolateral to the vaccinated arm in 70%. The etiological workup, always negative, included brain imaging (48%), infectious serologies (74%) and Covid-19 PCR (52%). Corticosteroid therapy was prescribed for 20 (87%) patients, combined with aciclovir in 12 (52%). At 4-month follow-up, clinical manifestations had regressed completely or partially in 20 (87%) of the 23 patients (median time of 30 days). From them 12 (60%) received another dose of COVID-19 vaccine and none had a recurrence and the PFP regressed despite the second dose in 2 of the 3 patients not fully recovered at 4 months. The potential mechanism of PFP after COVID-19 vaccine, which don't have a specific profile, is probably the interferon-γ. Moreover, the risk of recurrence after a new injection appears to be very low, which makes it possible to continue the vaccination.
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COVID-19 , Paralisia Facial , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Vacinas contra COVID-19/efeitos adversos , Paralisia Facial/induzido quimicamente , Paralisia Facial/epidemiologia , COVID-19/prevenção & controle , Farmacovigilância , SARS-CoV-2RESUMO
Pharmacovigilance and pharmacoepidemiology studies regarding the sex difference in adverse drug reactions are numerous, and it is now a challenge to take them into account in order to increase drug safety. Here, we present an overview of this topic through data on epidemiology, mechanisms, and methods used for assessing sex differences in drug safety. Because the literature is extensive, we choose to expose a few examples of studies for cardiovascular drugs, anti-infectious, psychotropics, antidiabetics, anticancer drugs and some specific drugs to illustrate our purpose. Many studies show a higher risk in women for most of drugs involving in sex differences. However, physiological, methodological and subjective points have to be taken into account to interpret these results. Clinical trials must also enroll more women to better evaluate sex differences both in efficacy and pharmacovigilance. Nevertheless, when there is a pharmacological rationale underlying the observed association between sex and drug safety profile, it is now unavoidable to think about its consideration for a personalized prescription.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Caracteres Sexuais , Humanos , Masculino , Feminino , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Farmacovigilância , Farmacoepidemiologia/métodos , Prescrições , Sistemas de Notificação de Reações Adversas a MedicamentosRESUMO
OBJECTIVE: IgA vasculitis (IgAV) can occur after vaccination. We aimed to assess a potential safety signal on the association between coronavirus disease 2019 (COVID-19) vaccines and IgAV. METHODS: Cases of IgAV involving COVID-19 vaccines were retrieved in VigiBase. Disproportionate reporting was assessed using the Bayesian information component (IC) with all other drugs and vaccines as control groups. RESULTS: Three hundred thirty patients with de novo IgAV from 24 countries were included, mostly from the United States (193/330, 58%). Fifty percent (163/328) were female and median age was 32 years (IQR 15-59), of which 33% (84/254) were young (1-17 yrs). Median time to onset of IgAV was 7 days (IQR 2-16; n = 256) and 85% (280/330) of patients were vaccinated with mRNA vaccines. Seriousness was reported in 188/324 (58%) cases. Sixty-five percent (95/147) recovered and 1% (2/147) died. A positive rechallenge was reported for 3 of 4 patients (75%). A total of 996 cases of IgAV were identified with other vaccines. There was a small significant increase in IgAV reporting with COVID-19 vaccines compared with all other drugs (IC 0.22, 95% credible interval [CrI] 0.04 to 0.35). No disproportionality signal was found between COVID-19 vaccines and other vaccines (IC -1.42, 95% CrI -1.60 to -1.28). There was no significant difference between mRNA vaccines and viral vector COVID-19 vaccines. Men and children had a significant overreporting of IgAV compared with women and adults, respectively. CONCLUSION: This study provides reassuring results regarding the safety of COVID-19 vaccines in the occurrence of IgAV compared to other vaccines.
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Vacinas contra COVID-19 , COVID-19 , Vasculite por IgA , Adulto , Criança , Feminino , Humanos , Masculino , Teorema de Bayes , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Imunoglobulina A , Farmacovigilância , Vacinação/efeitos adversos , VacinasRESUMO
BACKGROUND AND PURPOSE: Although several case series have described nitrous-oxide-associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous-oxide-induced neurological disorders. METHODS: All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts-de-France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included. RESULTS: A total of 20 cases from five hospitals were included. The male-to-female ratio was 6:1 and the median age was 19 years (range 16-34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5-960; n = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7-54; n = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p = 0.042). CONCLUSIONS: A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.
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Doenças do Sistema Nervoso , Doenças do Sistema Nervoso Periférico , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Adulto , Ataxia , Feminino , Humanos , Masculino , Óxido Nitroso/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/complicações , Vitamina B 12/efeitos adversos , Adulto JovemRESUMO
INTRODUCTION: Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure in connection with a potentially dual mechanism, vascular and cardiac. OBJECTIVES & METHODS: All cases of peripheral edema or heart failure involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were included to describe their onset patterns (e.g., time to onset). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries and on the electrophysiological properties of rat ventricular cardiomyocytes. RESULTS: A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57-85, range 32-95). The median time to onset were 23 days (IQR 10-54) and 17 days (IQR 3-30) for non-cardiogenic edema and acute heart failure, respectively. Cardiogenic and non-cardiogenic peripheral edema occurred frequently after a dose escalation (27/45, 60%), and the course was rapidly favorable after discontinuation of gabapentinoid (median 7 days, IQR 5-13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Acute application of gabapentinoids had no significant effect on Cav1.2 currents of ventricular cardiomyocytes. CONCLUSION: Gabapentinoids can cause concentration-dependent peripheral edema of early onset. The primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Cav1.2 blockade under the experimental conditions tested.
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Edema , Gabapentina , Insuficiência Cardíaca , Idoso , Idoso de 80 Anos ou mais , Experimentação Animal , Animais , Edema/induzido quimicamente , Feminino , Gabapentina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Pregabalina/efeitos adversos , RatosRESUMO
In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-h urine uric acid was increased to 2195 mmol/24 h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinization by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.
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Crotonatos/efeitos adversos , Hidroxibutiratos/efeitos adversos , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Nitrilas/efeitos adversos , Toluidinas/efeitos adversos , Urolitíase/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Urolitíase/induzido quimicamenteRESUMO
Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.
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Insuficiência Cardíaca , Linfedema , Preparações Farmacêuticas , Edema/induzido quimicamente , Humanos , VasodilataçãoRESUMO
BACKGROUND: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure. METHODS: Tacrolimus whole blood trough levels (C0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C0 < 20 ng/mL) or toxic concentrations (C0 ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients. RESULTS: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. CONCLUSIONS: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.
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Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocromo P-450 CYP3A/metabolismo , Feminino , Genótipo , Humanos , Imunossupressores/metabolismo , Imunossupressores/intoxicação , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Tacrolimo/metabolismo , Tacrolimo/intoxicação , Adulto JovemRESUMO
Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by a typical brain edema. Its pathogenesis is still debated through hypoperfusion and hyperperfusion theories, which have many limitations. As PRES occurs almost exclusively in clinical situations with arginine vasopressin (AVP) hypersecretion, such as eclampsia and sepsis, we hypothesize that AVP plays a central pathophysiologic role. In this review, we discuss the genesis of PRES and its symptoms through this novel approach. We theorize that AVP axis stimulation precipitates PRES development through an increase in AVP secretion or AVP receptor density. Activation of vasopressin V1a receptors leads to cerebral vasoconstriction, causing endothelial dysfunction and cerebral ischemia. This promotes cytotoxic edema through hydromineral transglial flux dysfunction and may increase endothelial permeability, leading to subsequent vasogenic brain edema. If our hypothesis is confirmed, it opens new perspectives for better patient monitoring and therapies targeting the AVP axis in PRES.
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Arginina Vasopressina/metabolismo , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Animais , Biomarcadores/metabolismo , Comorbidade , Suscetibilidade a Doenças , Humanos , Modelos Biológicos , Síndrome da Leucoencefalopatia Posterior/patologiaRESUMO
Background: Posterior reversible encephalopathy syndrome (PRES) is a rare clinical and radiological entity characterized by a typical brain edema. Although several case reports have described PRES in a context of poisoning, to our knowledge, a comprehensive assessment has not been performed. The aim of this systematic review was to raise awareness on poisoning-specific PRES features and to encourage consistent and detailed reporting of substance abuse-and drug overdose-associated PRES. Methods: Medline/PubMed, Web of Science, and PsycINFO were screened through May 31, 2019, to systematically identify case reports and case series describing PRES associated with poisoning (i.e., alcohol, drugs, illicit drugs, natural toxins, chemical substances) in accidental context, intentional overdose, and substance abuse. The methodological quality of eligible case reports/series was assessed. Patients and exposure characteristics were recorded; relevant toxicological, radiological, and clinical data were extracted. Results: Forty-one case reports and one case series reporting 42 unique cases were included. The median time to PRES onset from the start of exposure was 3 days (IQR 2-10). Acute high blood pressure, visual disturbance, and seizure were reported in 70, 55, and 50% of patients, respectively. The initial clinical presentation was alertness disorders in 64% of patients. Nine patients (21%) required mechanical ventilation. One-third of patients had at least one risk factor for PRES such as chronic hypertension (17%) or acute/chronic kidney failure (24%). The main imaging pattern (67%) was the combination of classical parieto-occipital edema with another anatomical region (e.g., frontal, basal ganglia, posterior fossa involvement). Vasogenic edema was found in 86% of patients. Intracranial hemorrhage occurred in 14% of patients. Both brain infarction and reversible cerebral vasoconstriction syndrome were diagnosed in 5% of patients. Three patients (12%, 3/25) had non-reversible lesions on follow-up magnetic resonance imaging. The median time required to hospital discharge was 14 days (IQR 7-18). Mortality and neurological recurrence rate were null. Conclusions: Comorbidities such as chronic hypertension and kidney failure were less frequent than in patients with other PRES etiologies. Imaging analysis did not highlight a specific pattern for poisoning-induced PRES. Although less described, PRES in the context of poisoning, which shares most of the clinical and radiological characteristics of other etiologies, is not to be ignored.
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In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.
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Monitoramento de Medicamentos/métodos , Doenças Neurodegenerativas/terapia , Tomografia por Emissão de Pósitrons/métodos , Animais , Humanos , Medicina de PrecisãoRESUMO
INTRODUCTION: Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN. MATERIALS AND METHODS: We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin. RESULTS: There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups. CONCLUSION: We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.
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Síndromes Neurotóxicas/genética , Oxaliplatina/efeitos adversos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Células HEK293 , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/etiologia , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina/administração & dosagem , Técnicas de Patch-Clamp , Polimorfismo Genético , Repetições de TrinucleotídeosRESUMO
Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.
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Transplante de Rim , Traumatismo por Reperfusão/metabolismo , Animais , Humanos , Metabolômica , Traumatismo por Reperfusão/prevenção & controleRESUMO
Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatory foci are crucial for an adequate care for patients. In brain diseases, in vivo positron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal's quantification.