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[This corrects the article DOI: 10.1371/journal.pone.0261473.].
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Reactive sulfur species including sulfides, polysulfides and cysteine hydropersulfide play extensive roles in health and disease, which involve modification of protein functions through the interaction with metals bound to the proteins, cleavage of cysteine disulfide (S-S) bonds and S-persulfidation of cysteine residues. Sulfides over a wide micromolar concentration range enhance the activity of Cav3.2 T-type Ca2+ channels by eliminating Zn2+ bound to the channels, thereby promoting somatic and visceral pain. Cav3.2 is under inhibition by Zn2+ in physiological conditions, so that sulfides function to reboot Cav3.2 from Zn2+ inhibition and increase the excitability of nociceptors. On the other hand, polysulfides generated from sulfides activate TRPA1 channels via cysteine S-persulfidation, thereby facilitating somatic, but not visceral, pain. Thus, Cav3.2 function enhancement by sulfides and TRPA1 activation by polysulfides, synergistically accelerate somatic pain signals. The increased activity of the sulfide/Cav3.2 system, in particular, appears to have a great impact on pathological pain, and may thus serve as a therapeutic target for treatment of neuropathic and inflammatory pain including visceral pain.
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Canais de Cálcio Tipo T , Sulfetos , Canal de Cátion TRPA1 , Sulfetos/farmacologia , Canal de Cátion TRPA1/metabolismo , Humanos , Canais de Cálcio Tipo T/metabolismo , Canais de Cálcio Tipo T/fisiologia , Animais , Zinco/metabolismo , Dor/metabolismo , Dor/tratamento farmacológico , Nociceptores/metabolismo , Nociceptores/efeitos dos fármacosRESUMO
Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni's test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and ß-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Animais , Camundongos , Humanos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Estudos Retrospectivos , AntiviraisRESUMO
Community pharmacists may play a key role in promoting deprescribing of potential inappropriate medications (PIMs) that are highly prevalent among community-dwelling elderly with dementia. To characterize PIMs categories that need a special attention for dementia patients, in the present study, we analyzed the anonymized pharmacy claims data of patients aged 65 years and older (n = 333869) who visited nationwide 905 community-based pharmacies of Sugi Pharmacy Co., Ltd. during December 1-31, 2019. A dementia group was defined as patients who received typical dementia medications marketed in Japan, i.e., donepezil, galantamine, memantine or rivastigmine, and a non-dementia group was defined as patients who received no such medications. After propensity score matching on the basis of patients' age, gender and home healthcare insurance usage, the data of 11486 patients in each group were subjected to logistic regression analyses, to identify PIMs categories particularly important for dementia patients. Univariate analysis indicated that the proportions of dementia patients who received 1 and 2≤ of PIMs were significantly (p < 0.001) greater than those of non-dementia patients (odds ratios were 1.35 and 1.47, respectively). Multivariate analyses identified 5 categories of PIMs that were significantly more frequently prescribed in dementia patients, i.e., 'H2 blockers,' 'drugs for overactive bladder,' 'anti-diabetes drugs' and 'sulpiride' listed as PIMs categories for non-specific cases (adjusted odds ratios (aORs): 1.29, 1.91, 1.17, and 1.38, respectively), in addition to 'antipsychotics' listed only for dementia patients (aOR: 4.29). These results provide useful information to establish strategies for pharmacist-led deprescribing of PIMs in dementia patients.
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Demência , Farmácias , Farmácia , Idoso , Humanos , Lista de Medicamentos Potencialmente Inapropriados , Prescrição Inadequada , Demência/tratamento farmacológicoRESUMO
Cav3.2 channels belong to the T-type calcium channel (T-channel) family, i.e., low voltage-activated calcium channels, and are abundantly expressed in the nociceptors, playing a principal role in the development of pathological pain. The channel activity of Cav3.2 is suppressed by zinc under physiological conditions. We thus tested whether dietary zinc deficiency would cause Cav3.2-dependent nociceptive hypersensitivity in mice. In the mice fed with zinc deficient diet for 2 weeks, plasma zinc levels declined by more than half, and mechanical allodynia developed. The dietary zinc deficiency-induced allodynia was restored by T-channel inhibitors or by Cav3.2 gene silencing. These data demonstrate that zinc deficiency induces Cav3.2-dependent nociceptive hypersensitivity in mice, thereby suggesting that pain experienced by patients with diseases accompanied by zinc deficiency (e.g., chronic kidney disease) might involve the increased Cav3.2 activity.
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Canais de Cálcio Tipo T , Hipersensibilidade , Desnutrição , Animais , Camundongos , Nociceptividade , Zinco , Hiperalgesia/etiologia , DorRESUMO
Cav3.2, a T-type calcium channel (T-channel) family member, is expressed in the nociceptors and spinal cord, and its activity is largely suppressed by zinc under physiological conditions. In rats, intrathecal and intraplantar administration of a zinc chelator, TPEN, caused T-channel-dependent mechanical hyperalgesia, and the intraplantar, but not intrathecal, TPEN induced Cav3.2 upregulation in the dorsal root ganglion. In mice, intraplantar TPEN also caused mechanical allodynia, which was abolished by T-channel inhibitors or Cav3.2 gene deletion. Together, spinal and peripheral zinc deficiency appears to enhance Cav3.2 activity in the spinal postsynaptic neurons and nociceptors, respectively, thereby promoting pain.
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Canais de Cálcio Tipo T , Hiperalgesia , Ratos , Camundongos , Animais , Hiperalgesia/induzido quimicamente , Roedores , Quelantes , Zinco , Canais de Cálcio Tipo T/genética , Gânglios EspinaisRESUMO
Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including H2S, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Cav3.2 T-type Ca2+ channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn2+ linked via coordinate bonding to His191 of Cav3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Cav3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and 1H NMR techniques, we demonstrated that THGP directly reacted with sulfides including Na2S and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl2. In Cav3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca2+ channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar Na2S. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca2+ channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Cav3.2 activity, leading to suppression of Cav3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.
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Canais de Cálcio Tipo T , Cistite , Sulfeto de Hidrogênio , Pancreatite , Dor Visceral , Camundongos , Humanos , Animais , Células HEK293 , Canais de Cálcio Tipo T/fisiologia , Sulfetos/farmacologia , Cistite/induzido quimicamente , Sulfeto de Hidrogênio/metabolismoRESUMO
Irregular regeneration or inappropriate remodeling of the axons of the primary afferent neurons after peripheral nerve trauma could be associated with the development of neuropathic pain. We analyzed the molecular mechanisms for the neuritogenesis and neurite outgrowth caused by prostaglandin E2 (PGE2) in mouse dorsal root ganglion (DRG) neurons, and evaluated their opioid modulation. PGE2 in combination with IBMX, a phosphodiesterase inhibitor, caused neuritogenesis/neurite outgrowth in DRG cells, an effect abolished by a prostanoid EP4, but not EP2, receptor antagonist, and inhibitors of adenylyl cyclase or protein kinase A (PKA). Blockers of T-type Ca2+ channels (T-channels), that are responsible for window currents involving the sustained low-level Ca2+ entry at voltages near the resting membrane potentials and can be functionally upregulated by PKA, inhibited the neuritogenesis/neurite outgrowth caused by PGE2/IBMX or dibutylyl cyclic AMP, a PKA activator, in DRG neurons, an inhibitory effect mimicked by ZnCl2 and ascorbic acid that block Cav3.2, but not Cav3.1 or Cav3.3, T-channels. Morphine and DAMGO, µ-opioid receptor (MOR) agonists, suppressed the neuritogenesis and/or neurite outgrowth induced by PGE2/IBMX in DRG neurons and also DRG neuron-like ND7/23 cells, an effect reversed by naloxone or ß-funaltrexamine, a selective MOR antagonist. Our data suggest that the EP4 receptor/PKA/Cav3.2 pathway is involved in the PGE2-induced neuritogenesis/neurite outgrowth in DRG neurons, which can be suppressed by MOR stimulation. We propose that MOR agonists including morphine in the early phase after peripheral nerve trauma might delay the axonal regeneration of the primary afferent neurons but prevent the development of neuropathic pain.
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Analgésicos Opioides , Neuralgia , Animais , Camundongos , 1-Metil-3-Isobutilxantina/farmacologia , Analgésicos Opioides/farmacologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Gânglios Espinais/metabolismo , Morfina/farmacologia , Neuralgia/metabolismo , Crescimento Neuronal , Neurônios/metabolismo , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP2 , RatosRESUMO
T-type Ca2+ channels (T-channels), particularly Cav3.2 and Cav3.1 isoforms, are promising targets for treating various diseases including intractable pain. Given the potent inhibitory activity of pimozide, an antipsychotic, against T-channels, we conducted structure-activity relationship studies of pimozide derivatives, and identified several compounds including 3a, 3s, and 4 that had potency comparable to that of pimozide in inhibiting T-channels, but little binding affinity to dopamine D2 receptors. The introduction of a phenylbutyl group on the benzoimidazole nuclei of pimozide was considered a key structural modification to reduce the binding affinity to D2 receptors. Those pimozide derivatives potently suppressed T-channel-dependent somatic and visceral pain in mice, without causing any motor dysfunctions attributable to D2 receptor blockade, including catalepsy. The present study thus provides an avenue to develop novel selective T-channel inhibitors available for pain management via the structural modification of existing medicines.
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Canais de Cálcio Tipo T , Dor Visceral , Camundongos , Animais , Pimozida/farmacologia , Pimozida/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Dor Visceral/tratamento farmacológico , Dopamina , Bloqueadores dos Canais de Cálcio/química , Receptores Dopaminérgicos/metabolismoRESUMO
Oxaliplatin often induces peripheral neuropathy, a dose-limiting adverse reaction, and in rare cases leads to sinusoidal obstruction syndrome. We thus conducted a retrospective cohort study to examine the relationship between oxaliplatin-induced peripheral neuropathy (OIPN) and hepatic impairment, and then perform a fundamental study to analyze the underlying mechanisms. Analysis of medical records in cancer patients treated with oxaliplatin indicated that laboratory test parameters of hepatic impairment including AST, ALT and APRI (AST to platelet ratio index) moderately increased during oxaliplatin treatment, which was positively correlated with the severity of OIPN (grades 1-4), and associated with later incidence of survivors with OIPN grades ≥2. In mice, hepatic injury induced by CCl4 or ethanol accelerated OIPN in mice, an effect prevented by inactivation of high mobility group box 1 (HMGB1), known to participate in OIPN, by the neutralizing antibody or thrombomodulin alfa capable of promoting its thrombin-dependent degradation. Oxaliplatin also aggravated the hepatic injury in mice. CCl4 released HMGB1 from cultured hepatic parenchymal cells, and oxaliplatin at clinically achievable concentrations released HMGB1 from hepatic parenchymal and non-parenchymal cells. Our clinical and preclinical data suggest that the development of mild hepatic impairment during oxaliplatin treatment is associated with later aggravation of OIPN.
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Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Humanos , Masculino , Camundongos Endogâmicos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/genética , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
We examined the role of ATP and high mobility group box 1 (HMGB1) in paclitaxel-induced peripheral neuropathy (PIPN). PIPN in mice was prevented by HMGB1 neutralization, macrophage depletion, and P2X7 or P2X4 blockade. Paclitaxel and ATP synergistically released HMGB1 from macrophage-like RAW264.7 cells, but not neuron-like NG108-15 cells. The paclitaxel-induced HMGB1 release from RAW264.7 cells was accelerated by co-culture with NG108-15 cells in a manner dependent on P2X7 or P2X4. Paclitaxel released ATP from NG108-15 cells, but not RAW264.7 cells. Thus, PIPN is considered to involve acceleration of HMGB1 release from macrophages through P2X7 and P2X4 activation by neuron-derived ATP.
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Trifosfato de Adenosina/fisiologia , Proteína HMGB1/metabolismo , Macrófagos/metabolismo , Neurônios/metabolismo , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Células RAW 264.7 , Receptor Cross-Talk/imunologia , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/metabolismoRESUMO
Background: Accurate prognosis in terminal cancer patients is useful to improve their quality of life and also to decide the cessation of fluid administration. Nonetheless, few prognostic indicators are available for prediction of such a short-term life expectancy. Objectives: The present study aimed at evaluating the efficacy of C-reactive protein (CRP)/albumin (CRP/Alb) ratio, prognostic nutritional index (PNI), fibrosis-4 (FIB-4) index, and albumin-bilirubin (ALBI) score in identifying terminal cancer patients who have a life expectancy less than two weeks. Design: Retrospective study. Setting/Subjects: Of 483 patients who died between April 2019 and March 2020 at a single center in Japan, 102 who met the inclusion criteria were enrolled in this study. Measurements: CRP/Alb, PNI, FIB-4, and ALBI were calculated from the laboratory data collected 1-13, 14-27, 28-83, and 168-365 days before death and subjected to statistical analyses. Results: CRP/Alb, PNI, FIB-4, and ALBI values were significantly associated with the time before death during terminal 365 days. CRP/Alb ≥4.4, PNI <30, FIB-4 ≥ 9.4, and ALBI ≥ -1.26 were significantly associated with the transition from the first half to the second half of terminal four weeks. Of those prognostic indicators, three and four combinations provided significantly reliable estimation of a life expectancy less than two weeks. Conclusions: CRP/Alb, PNI, FIB-4, ALBI, and their combinations are considered to help identify cancer patients who have a life expectancy less than two weeks, which is useful to make appropriate end-stage treatment decisions, for example, cessation of artificial hydration therapy.
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Neoplasias , Avaliação Nutricional , Albuminas/análise , Bilirrubina , Proteína C-Reativa/análise , Fibrose , Humanos , Expectativa de Vida , Prognóstico , Qualidade de Vida , Estudos RetrospectivosRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients' information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients' age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN.
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Antineoplásicos/efeitos adversos , Sobreviventes de Câncer , Tratamento Farmacológico/métodos , Paclitaxel/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cloridrato de Duloxetina/farmacologia , Feminino , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/tratamento farmacológico , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, antagonists of the receptor for advanced glycation end-products (RAGE) and C-X-C motif chemokine receptor 4 (CXCR4), known as HMGB1-targeted membrane receptors, or macrophage depletion with liposomal clodronate, as reported in a CIPN model caused by paclitaxel. In macrophage-like RAW264.7 cells, bortezomib as well as MG132, a well-known proteasome inhibitor, caused HMGB1 release, an effect inhibited by caspase inhibitors but not inhibitors of NF-κB and p38 MAP kinase, known to mediate paclitaxel-induced HMGB1 release from macrophages. Bortezomib increased cleaved products of caspase-8 and caused nuclear fragmentation or condensation in macrophages. Repeated treatment with the caspase inhibitor prevented CIPN caused by bortezomib in mice. Our findings suggest that bortezomib causes caspase-dependent release of HMGB1 from macrophages, leading to the development of CIPN via activation of RAGE and CXCR4.
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Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Proteína HMGB1/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Apoptose , Modelos Animais de Doenças , Masculino , CamundongosRESUMO
To identify risk factors for the prognosis of prostate cancer (PC), we retrospectively analyzed the impact of lifestyle-related disorders as well as PC characteristics at initial diagnosis on the progression to castration-resistant PC (CRPC) in PC patients undergoing hormone therapy. Of 648 PC patients, 230 who underwent hormone therapy and met inclusion criteria were enrolled in this study. CRPC developed in 48 patients (20.9%). Univariate analysis using Cox proportional hazard model indicated that newly developed diabetes mellitus (DM) following hormone therapy (postDM), but not preexisting DM, as well as PC characteristics at initial diagnosis including prostate-specific antigen (PSA) ≥ 18 were significantly associated with the progression to CRPC. A similar tendency was also observed in the relationship between newly developed hypertension following hormone therapy and CRPC progression. On the other hand, neither dyslipidemia nor hyperuricemia, regardless the onset timing, exhibited any association with CRPC progression. In multivariate analysis, postDM and PSA ≥ 18 were extracted as independent risk factors for CRPC progression (adjusted hazard ratios, 3.38 and 2.34; p values, 0.016 and 0.019, respectively). Kaplan-Meier analysis and log-rank test clearly indicated earlier progression to CRPC in PC patients who developed postDM or had relatively advanced initial PC characteristics including PSA ≥ 18. Together, the development of lifestyle-related disorders, particularly DM, following hormone therapy, as well as advanced PC characteristics at initial diagnosis is considered to predict earlier progression to CRPC and poor prognosis in PC patients undergoing hormone therapy.
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Antagonistas de Receptores de Andrógenos/uso terapêutico , Diabetes Mellitus/epidemiologia , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.
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Gânglios Espinais/metabolismo , Macrófagos/metabolismo , Neuroimunomodulação , Neurônios/metabolismo , Limiar da Dor , Dor/metabolismo , Transdução de Sinais , Animais , Comunicação Celular , Citocinas/metabolismo , Gânglios Espinais/imunologia , Gânglios Espinais/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Neurônios/imunologia , Neuropeptídeos/metabolismo , Dor/imunologia , Dor/fisiopatologia , FenótipoRESUMO
We performed clinical retrospective study in female cancer patients and fundamental experiments in mice, in order to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, 131 of 189 female outpatients with cancer undergoing paclitaxel-based chemotherapy met inclusion criteria. Breast cancer survivors (n = 40) showed significantly higher overall PIPN (grades 1-4) incidence than non-breast cancer survivors (n = 91). Multivariate sub-analyses of breast cancer survivors showed that 57 years of age or older and endocrine therapy before paclitaxel treatment were significantly associated with severe PIPN (grades 2-4). The age limit was also significantly correlated with overall development of severe PIPN. In the preclinical study, female mice subjected to ovariectomy received repeated administration of paclitaxel, and mechanical nociceptive threshold was assessed by von Frey test. Ovariectomy aggravated PIPN in the mice, an effect prevented by repeated treatment with 17ß-estradiol. Repeated administration of thrombomodulin alfa (TMα), known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in the ovariectomized mice. Collectively, breast cancer survivors, particularly with postmenopausal estrogen decline and/or undergoing endocrine therapy, are considered a PIPN-prone subpopulation, and may require non-hormonal pharmacological intervention for PIPN in which TMα may serve as a major candidate.
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Antineoplásicos Fitogênicos/efeitos adversos , Estrogênios/deficiência , Estrogênios/fisiologia , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias da Mama , Sobreviventes de Câncer , Feminino , Humanos , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Ovariectomia/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Pós-Menopausa , Ratos , Estudos Retrospectivos , Fatores de Risco , Trombomodulina/administração & dosagemRESUMO
T-Type Ca2+ channels (T-channels), particularly Cav3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking T-channels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.
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Analgésicos/uso terapêutico , Bepridil/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Colite/tratamento farmacológico , Cistite/tratamento farmacológico , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Pimozida/uso terapêutico , Dor Visceral/tratamento farmacológico , Animais , Canais de Cálcio Tipo T , Colite/induzido quimicamente , Ciclofosfamida , Cistite/induzido quimicamente , Feminino , Masculino , Camundongos , Ácido Trinitrobenzenossulfônico , Dor Visceral/induzido quimicamenteRESUMO
OBJECTIVE: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis. RESULTS: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01). CONCLUSION: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.
Assuntos
Síndrome do QT Longo , Torsades de Pointes , Bepridil/efeitos adversos , Eletrocardiografia , Humanos , Japão , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Estudos Retrospectivos , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/diagnósticoRESUMO
High-mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end-product specific receptor (receptor for advanced glycation end-products; RAGE) or Toll-like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, markedly increase thrombin-dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1-dependent pathological pain. Low MW compounds that directly inactivate HMGB1 or antagonize HMGB1-targeted receptors would be useful to reduce various forms of intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.