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Tanabe, Mitsuo, Keiko Takasu y Hideki Ono. "Spinal HCN channels contribute to neuropathic pain". Neuroscience Research 58 (enero de 2007): S126. http://dx.doi.org/10.1016/j.neures.2007.06.1305.
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Jiang, Yu-Qiu, Qian Sun, Hui-Yin Tu y You Wan. "Characteristics of HCN Channels and Their Participation in Neuropathic Pain". Neurochemical Research 33, n.º 10 (7 de mayo de 2008): 1979–89. http://dx.doi.org/10.1007/s11064-008-9717-6.
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Yang, Lujia, Xiaoyan Liu, Kai Yao, Yan sun, Fan Jiang, Haitao Yan, Peng Mao et al. "HCN channel antagonist ZD7288 ameliorates neuropathic pain and associated depression". Brain Research 1717 (agosto de 2019): 204–13. http://dx.doi.org/10.1016/j.brainres.2019.03.036.
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He, Jin-Ting, Xiao-Yan Li, Xin Zhao y Xiaoliang Liu. "Hyperpolarization-activated and cyclic nucleotide-gated channel proteins as emerging new targets in neuropathic pain". Reviews in the Neurosciences 30, n.º 6 (26 de julio de 2019): 639–49. http://dx.doi.org/10.1515/revneuro-2018-0094.
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Abstract Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are activated during hyperpolarization, and there is an inward flow of current, which is termed as hyperpolarization-activated current, Ih. Initially, these channels were identified on the pacemaker cells of the heart. Nowadays, these are identified on different regions of the nervous system, including peripheral nerves, dorsal root ganglia, dorsal horns, and different parts of the brain. There are four different types of HCN channels (HCN1–HCN4); however, HCN1 and HCN2 are more prominent. A large number of studies have shown that peripheral nerve injury increases the amplitude of Ih current in the neurons of the spinal cord and the brain. Moreover, there is an increase in the expression of HCN1 and HCN2 protein channels in peripheral axons and the spinal cord and brain regions in experimental models of nerve injury. Studies have also documented the pain-attenuating actions of selective HCN inhibitors, such as ivabradine and ZD7288. Moreover, certain drugs with additional HCN-blocking activities have also shown pain-attenuating actions in different pain models. There have been few studies documenting the relationship of HCN channels with other mediators of pain. Nevertheless, it may be proposed that the HCN channel activity is modulated by endogenous opioids and cyclo-oxygenase-2, whereas the activation of these channels may modulate the actions of substance P and the expression of spinal N-methyl-D-aspartate receptor subunit 2B to modulate pain. The present review describes the role and mechanisms of HCN ion channels in the development of neuropathic pain.
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Du, Lu, Shao-Jun Wang, Jian Cui, Wen-Juan He y Huai-Zhen Ruan. "The role of HCN channels within the periaqueductal gray in neuropathic pain". Brain Research 1500 (marzo de 2013): 36–44. http://dx.doi.org/10.1016/j.brainres.2013.01.035.
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Du, Lu, Shao-Jun Wang, Jian Cui, Wen-Juan He y Huai-Zhen Ruan. "Inhibition of HCN channels within the periaqueductal gray attenuates neuropathic pain in rats." Behavioral Neuroscience 127, n.º 2 (abril de 2013): 325–29. http://dx.doi.org/10.1037/a0031893.
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Ding, Weihua, Zerong You, Shiqian Shen, Jinsheng Yang, Grewo Lim, Jason T. Doheny, Shengmei Zhu, Yi Zhang, Lucy Chen y Jianren Mao. "Increased HCN Channel Activity in the Gasserian Ganglion Contributes to Trigeminal Neuropathic Pain". Journal of Pain 19, n.º 6 (junio de 2018): 626–34. http://dx.doi.org/10.1016/j.jpain.2018.01.003.
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Tsantoulas, Christoforos, Elizabeth R. Mooney y Peter A. McNaughton. "HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain". Biochemical Journal 473, n.º 18 (12 de septiembre de 2016): 2717–36. http://dx.doi.org/10.1042/bcj20160287.
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Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.
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Yang, Liuyue, Weihua Ding, Zerong You, Jinsheng Yang, Shiqian Shen, Jason T. Doheny, Lucy Chen, Ruhui Li y Jianren Mao. "Alleviation of trigeminal neuropathic pain by electroacupuncture: the role of hyperpolarization-activated cyclic nucleotide-gated channel protein expression in the Gasserian ganglion". Acupuncture in Medicine 37, n.º 3 (12 de abril de 2019): 192–98. http://dx.doi.org/10.1177/0964528419841614.
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Introduction: The aim of this study was to examine the effect of electroacupuncture (EA) on trigeminal neuropathic pain in rats and explore the potential mechanism underlying the putative therapeutic effect of EA. Methods: Trigeminal neuropathic pain behavior was induced in rats by unilateral chronic constriction injury of the distal infraorbital nerve (dIoN-CCI). EA was administered at ST2 ( Sibai) and Jiachengjiang. A total of 60 Sprague Dawley rats were divided into the following four groups ( n = 15 per group) to examine the behavioral outcomes after surgery and/or EA treatment: sham (no ligation); dIoN-CCI (received isoflurane only, without EA treatment); dIoN-CCI+EA-7d (received EA treatment for 7 days); and dIoN-CCI+EA-14d (received EA treatment for 14 days). Both evoked and spontaneous nociceptive behaviors were measured. Of these, 12 rats ( n = 4 from sham, dIoN-CCI, and dIoN-CCI+EA-14d groups, respectively) were used to analyze protein expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the Gasserian ganglion (GG) by immunohistochemistry. Results: dIoN-CCI rats exhibited mechanical allodynia and increased face-grooming activity that lasted at least 35 days. EA treatment reduced mechanical allodynia and face-grooming in dIoN-CCI rats. Overall, 14 days of EA treatment produced a prolonged anti-nociceptive effect as compared to 7-day EA treatment. The counts of HCN1 and HCN2 immunopositive puncta were increased in the ipsilateral GG in dIoN-CCI rats and were reduced by 14 days of EA treatment. Discussion: EA treatment relieved trigeminal neuropathic pain in dIoN-CCI rats, and this effect was dependent on the duration of EA treatment. The downregulation of HCN expression may contribute to the anti-nociceptive effect of EA in this rat model of trigeminal neuropathic pain.
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Santoro, Bina y Mala M. Shah. "Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders". Annual Review of Pharmacology and Toxicology 60, n.º 1 (6 de enero de 2020): 109–31. http://dx.doi.org/10.1146/annurev-pharmtox-010919-023356.
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The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits ( HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.
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Ma, Yanqiao, Ji Chen, Deqian Yu, Bangcong Wei, Huan Jin, Junwei Zeng y Xiaohong Liu. "cAMP-PKA signaling is involved in regulation of spinal HCN channels function in diabetic neuropathic pain". Neuroscience Letters 750 (abril de 2021): 135763. http://dx.doi.org/10.1016/j.neulet.2021.135763.
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Thakur, M., N. Baruch y A. Dickenson. "518 STUDY OF THE HCN CHANNEL BLOCKER ZD7288 IN PRECLINICAL MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN". European Journal of Pain Supplements 4, S1 (abril de 2010): 146. http://dx.doi.org/10.1016/s1754-3207(10)70523-x.
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Weerasinghe, Dinushi, Parvathi Menon y Steve Vucic. "Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds". Journal of Neurophysiology 118, n.º 6 (1 de diciembre de 2017): 3044–50. http://dx.doi.org/10.1152/jn.00576.2017.
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Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying ( Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90–100 ms was significantly increased in lower threshold sensory axons times ( F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold ( I/ V) gradient was significantly increased in lower threshold axons ( F = 3.191, P < 0.05). The minimum I/ V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets. NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents ( Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.
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Dolphin, Annette C., Paul A. Insel, Terrence F. Blaschke y Urs A. Meyer. "Introduction to the Theme “Ion Channels and Neuropharmacology: From the Past to the Future”". Annual Review of Pharmacology and Toxicology 60, n.º 1 (6 de enero de 2020): 1–6. http://dx.doi.org/10.1146/annurev-pharmtox-082719-110050.
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“Ion Channels and Neuropharmacology: From the Past to the Future” is the main theme of articles in Volume 60 of the Annual Review of Pharmacology and Toxicology. Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca2+ and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca2+ channels, and AMPA receptors, as well as the aquaporin channels. Molecular identification of exactly where drugs bind in the structure not only elucidates their mechanism of action but also aids future structure-based drug discovery efforts to focus on relevant pharmacophores. The ion channels discussed here are targets for multiple nervous system diseases, including epilepsy and neuropathic pain. This theme complements several previous themes, including “New Therapeutic Targets,” “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development,” and “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology.”
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García-Cerván, Laura y Alejandro Campos-Zafra. "Tratamiento alternativo en el dolor crónico en pacientes adultos". Enfermería Cuidándote 4, n.º 1 (30 de abril de 2021): 10–20. http://dx.doi.org/10.51326/ec.4.1.5024827.
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Objetivos: Buscar evidencias sobre los beneficios de los tratamientos alternativos para el dolor neuropático. Metodología: Se ha llevado a cabo una búsqueda en bases de datos online (pubmed, cochrane, trip, epistemonikos) teniendo en cuenta artículos publicados en los últimos 5 años. Los estudios incluidos agrupan adultos mayores de 18 años que presenten dolor crónico neuropático. Resultados: De 166 artículos obtenidos inicialmente; 9 de ellos han sido incluidos. Se probó la existencia de una variabilidad en la efectividad de los tratamientos estudiados, llegando en algunos casos a igualar al tratamiento habitual. Conclusión: Las terapias estudiadas han demostrado ser efectivas en mayor o menor medida, aunque se necesita un mayor estudio de estos tratamientos a largo plazo y en situaciones determinadas.
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Hu, Kun, Zerong You, Weihua Ding y Jianren Mao. "201 HCN Channels Blockade Attenuates Chemotherapy-Induced Pain". Neurosurgery 64, CN_suppl_1 (24 de agosto de 2017): 254. http://dx.doi.org/10.1093/neuros/nyx417.201.
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Abstract INTRODUCTION Painful peripheral neuropathy is a common dose-limiting side effect caused by chemotherapy agents, such as oxaliplatin. Mechanisms underlying this devastating condition are largely unknown. METHODS We established a rat model of chemotherapy induced pain by administering oxaliplatin at 2 mg/Kg for 5 consecutive days. Mechanical hyperalgesia, a typical nociceptive pain behavior, developed after treatment with oxaliplatin. We investigated the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the dorsal root ganglia (DRG) at both gene transcripts level (real-time PCR) and protein level (immunofluorescence). In addition, we examined the functional significance of HCN upregulation after oxaliplatin treatment by using a pan HCN channels blocker-ZD 7288. RESULTS >DRG HCN 1 and HCN 2 were higher in oxaliplatin- treated rats than saline-treated controls, both for gene transcripts and proteins. ZD7288, when administered intrathecally, was able to alleviate, albeit not abrogate, oxaliplatin induced-pain. Interestingly, pre-treatment with ZD7288 prior to oxaliplatin administration did not prevent the development of mechanical hyperalgesia. CONCLUSION Taken together, HCN1 and HCN2 channels are upregulated by oxaliplatin treatment, and that HCN blockade alleviates oxaliplatin-induced pain. Therefore, targeting HCN channels may provide a therapeutic avenue to treat chemotherapy induced-pain.
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Sobeh, Mansour, Mona F. Mahmoud, Samar Rezq, Mohamed A. O. Abdelfattah, Islam Mostafa, Amira E. Alsemeh, Assem M. El-Shazly, Aziz Yasri y Michael Wink. "Haematoxylon campechianum Extract Ameliorates Neuropathic Pain via Inhibition of NF-κB/TNF-α/NOX/iNOS Signalling Pathway in a Rat Model of Chronic Constriction Injury". Biomolecules 10, n.º 3 (2 de marzo de 2020): 386. http://dx.doi.org/10.3390/biom10030386.
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In this study, the phytochemical composition and the possible prophylactic effects of an aqueous ethanol extract of Haematoxylon campechianum flowers (HCF) on peripheral neuropathic pain in a chronic constriction injury (CCI) rat model are investigated. Rats with induced CCI were subjected to neuropathic pain behaviour tests and evaluated by chemical, thermal, and mechanical sensation tests and functional recovery of the brain stem and sciatic nerve at 7- and 14-day intervals. The effect of the extract on acute pain and inflammation is also investigated. The extract exerted both peripheral and central analgesic and anti-inflammatory properties in addition to antipyretic effects that are clear from targeting COX, LOX and PGE. It was found that CCI produced significant thermal and mechanical hyperalgesia, cold allodynia and deleterious structural changes in both sciatic nerve and brain stem. Treatments with HCF extract significantly improved cold and thermal withdrawal latency, mechanical sensibility and ameliorated deleterious changes of sciatic nerve and brain stem at different dose levels. The extract also ameliorated oxidative stress and inflammatory markers in brain stem and sciatic nerve. It suppressed the apoptotic marker, p53, and restored myelin sheath integrity. The effects of HCF extract were more potent than pregabalin. Fifteen secondary metabolites, mainly gallotannins and flavonoids, were characterized in the extract based on their retention times and MS/MS data. The identified phenolic constituents from the extract could be promising candidates to treat neuropathic pain due to their diverse biological activities, including antioxidant, anti-inflammatory and neuroprotective properties.
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Supuran, Claudiu T. "Emerging role of carbonic anhydrase inhibitors". Clinical Science 135, n.º 10 (mayo de 2021): 1233–49. http://dx.doi.org/10.1042/cs20210040.
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Abstract Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) was clinically exploited for decades, as most modern diuretics were obtained considering as lead molecule acetazolamide, the prototypical CA inhibitor (CAI). The discovery and characterization of multiple human CA (hCA) isoforms, 15 of which being known today, led to new applications of their inhibitors. They include widely clinically used antiglaucoma, antiepileptic and antiobesity agents, antitumor drugs in clinical development, as well as drugs for the management of acute mountain sickness and idiopathic intracranial hypertension (IIH). Emerging roles of several CA isoforms in areas not generally connected to these enzymes were recently documented, such as in neuropathic pain, cerebral ischemia, rheumatoid arthritis, oxidative stress and Alzheimer’s disease. Proof-of-concept studies thus emerged by using isoform-selective inhibitors, which may lead to new clinical applications in such areas. Relevant preclinical models are available for these pathologies due to the availability of isoform-selective CAIs for all human isoforms, belonging to novel classes of compounds, such as coumarins, sulfocoumarins, dithiocarbamates, benzoxaboroles, apart the classical sulfonamide inhibitors. The inhibition of CAs from pathogenic bacteria, fungi, protozoans or nematodes started recently to be considered for obtaining anti-infectives with a new mechanism of action.
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Littman, Susan Joy, Erik S. Knudsen, Agnieszka Witkiewicz, Terry Hyslop, Nancy Lewis, Madhavan V. Pillai, Christina Brus y Edith P. Mitchell. "A phase II study of PD-0332991 in patients with advanced hepatocellular cancer." Journal of Clinical Oncology 31, n.º 4_suppl (1 de febrero de 2013): 321. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.321.
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321 Background: Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide and the 3rd most frequent cause of cancer-related mortality. Surgical resection & liver transplantation are the main curative options. Most patients present with advanced stage and poor liver function and are ineligible. Cytotoxic drugs give poor response rates and little benefit. The MKI sorafenib has been shown to significantly increase PFS and OS in advanced HCC in 2 rPhase 3 trials. PD-0332991 is an orally available, pyridopyrimidine-derived, selective inhibitor of CDK4/6, that results in the inhibition of RB protein phosphorylation & cell cycle arrest. In preclinical studies, PD-0332991 has cytostatic activity, dependent on RB protein Methods: This is an open-label non-randomized single-institution study for subjects with inoperable, recurrent/refractory advanced HCC. Subjects must have failed or be intolerant of standard first-line therapy, sorafinib. Subjects receive 125 mg PD-0332991 po/d 1-21 of 28-day cycle until disease or clinical progression, unacceptable toxicity, withdrawal of consent or death. Tumor response by CT or MRI using mRECIST v1.1 is q8 w. Subjects are assessed for toxicity per NCI CTCAE, v4.0. Results: 10 pts (8m,2f) have been enrolled. Median age is 61.7 (r32-74) yr. PD-0332991 is well tolerated. The most common toxicities were neutropenia and thrombocytopenia with 3 G3 neutropenia requiring therapy delay. Non-serious AEs were ascites, pain, nausea, vomiting, diarrhea, lightheadedness, anorexia, neuropathy. LFT abnormalities were consistent with underlying ESLD. 3 pts expired due to liver failure before disease progression was observed by RECIST, at 70, 85 and 136 d. 3 subjects developed PD at 3, 5 and 8 m. 2 have received additional therapy. 4 subjects are on therapy, with best PFS being 8 m. Conclusions: PD-0332991 is well tolerated in subjects with HCC and cirrhosis. Primary toxicity is neutropenia and thrombocytopenia consistent with known safety profile of PD-0332991. No unexpected toxicities have been observed. Preliminary responses are encouraging. TTP compares favorably to other drug regimens. Clinical trial information: NCT01356628.
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Martin, M. E., L. A. Ferguson, D. A. Williams y D. A. Laber. "A phase I/II study of docetaxel in combination with doxorubicin HCI liposome injection in advanced androgen-independent prostate cancer". Journal of Clinical Oncology 24, n.º 18_suppl (20 de junio de 2006): 14588. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14588.
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14588 Background: There is no cure for men with AIPC. Recently two landmark studies demonstrated an improvement in survival for men with AIPC treated with docetaxel based chemotherapy. Doxorubicin is a very active agent against AIPC. Doxil is liposome-encapsulated doxorubicin with less toxicity. Methods: Objectives are to evaluate the efficacy and safety of DoxTax. A phase I dose escalation study was performed. Three cohorts according to the following dose escalation schedule were formed. In the absence of DLT, level 3 was the recommended dose for the phase II study. Response was assessed by size of measurable and non-measurable lesions (RECIST JNCI.2000), and PSA levels (JCO.1999). Toxicity was graded by the NCI CTCAE. Results: Eleven subjects with AIPC were enrolled and evaluated for toxicity and response. Total number of cycles administered: 59, median of 5.5 cycles/patient. Patient characteristics: Median age 67 years (53–81); prior hormonal manipulations 2 (1–2); prior chemotherapy 1 (0–2); ECOG performance status 1 (1–2); and median PSA 78 ng/ml (8.73–783). Objective response: Out of 11 subjects, four men (36%) achieved a reduction in PSA of > 50%, while one (9%) achieved a >80% PSA reduction, for an overall PSA response of 45%. Seven patients had measurable lesions. Using RECIST criteria, five of seven subjects maintained (SD). Palliative response: Nine subjects (82%) improved their ECOG performance status. Additionally, 8 men (73%) had decreased level of pain. Toxicity: No dose limiting toxicity occurred. One patient had grade 3 generalized weakness related to disease progression. Grade 1–2 adverse events were not related to the dose and included: 64% fatigue, 45% anemia, 18% neutropenia, alopecia, anorexia, vomiting, 9% each for nausea, thrombocytopenia, weakness, hand/foot, and neuropathy. Conclusions: DoxTax is a well-tolerated, easy to administer and effective therapy for patients with metastatic AIPC. Accrual to the phase II trial is ongoing. [Table: see text] [Table: see text]
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Guduru, Harshendra, Santosh Kumar R. Jeevanagi, Shantiling Nigudgi y Smita V. Bhandare. "A prospective study on the prescription pattern of anti-cancer drugs and adverse drug reaction in a tertiary care hospital". International Journal of Basic & Clinical Pharmacology 8, n.º 2 (24 de enero de 2019): 200. http://dx.doi.org/10.18203/2319-2003.ijbcp20190134.
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Background: Cancers is a group of disease involving abnormal cell multiplication with the ability to spread to other parts of the body. Common side effects seen with chemotherapy are fatigue, hair loss, easy bruising and bleeding, infection, anemia, nausea and vomiting, appetite changes, constipation etc. The need of this study is to evaluate the prescribing pattern and the adverse drug reaction associated with chemotherapeutic drugs. The study is aimed to analyze the prescribing pattern of anticancer drugs in medical oncology department of a tertiary care hospital, Karnataka.Methods: An observational study was conducted on 30 patients of either sex admitted for chemotherapy for a period of 6 months in at HCG Cancer Institute, Gulbarga and Basaveshwar Teaching and General Hospital (BTGH), Gulbarga. The data collected is analysed statistically using descriptive statistics and presented as counts and percentages. Results are depicted in the form of tables.Results: A total of 30 prescriptions were collected with 10 (33.3%) male and 20 (66.6%) female. the maximum number of cases were noted in the age group of 46years to 55 years (10) and least in age group of 15-25 years having a single patient. In our study we found that more number of patients are breast cancer (12 patients) followed by cervical cancer and ovarian cancer (3 patients) and least are Ewing’s sarcoma and Non-Hodgkin’s lymphoma (1 patient). Most commonly prescribed anti-cancer drug is carboplatin and paclitaxel i.e. for 12 patients out of 30 patients, followed by cyclophosphamide for 10 patients and less commonly prescribed drug being dactinomycin and pemitrexate. Adverse drug reactions seen in maximum patients is hair loss among 20 pts followed by peripheral neuropathy (17) and taste change (16) and the less commonly noted side effects being chest pain and ototoxicity.Conclusions: The study concluded that the drugs which were used in the treatment of various neoplastic conditions are in adherence and in accordance with the standard treatment guidelines and most of them were prescribed with generic name which leads to reduce in cost of treatment.
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Unizony, S., S. Mohan, J. Han y J. H. Stone. "POS0808 CHARACTERISTICS OF GIANT CELL ARTERITIS FLARES AFTER SUCCESSFUL TREATMENT WITH TOCILIZUMAB: RESULTS FROM THE LONG-TERM EXTENSION OF A RANDOMIZED CONTROLLED PHASE 3 TRIAL". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de mayo de 2021): 656.2–657. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2602.
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Background:GiACTA investigated tocilizumab (TCZ) for the treatment of giant cell arteritis (GCA).Objectives:To investigate disease flare characteristics after successful treatment with TCZ in GiACTA.Methods:We report a post hoc analysis from part 2 of GiACTA. Part 1 was a 52-week, double-blind, randomized controlled period and part 2 was a 2-year open-label follow-up. In part 1, patients received TCZ 162 mg subcutaneously every week or every other week with a 26-week prednisone taper or placebo plus a 26- or 52-week prednisone taper. Patients who were in remission at week 52 were to enter part 2 on no TCZ treatment. Part 2 treatment was at the investigator’s discretion. We report characteristics of first disease flare in patients assigned to TCZ in part 1 who were in sustained remission at week 52 and experienced flare in part 2. Flare was defined as reappearance of cranial symptoms (headaches, jaw claudication, visual manifestations, scalp tenderness) or polymyalgia rheumatica (PMR) symptoms or elevation of erythrocyte sedimentation rate (ESR) ≥30 mm/h attributable to GCA that required treatment.Results:Of 149 patients assigned to TCZ in part 1, 81 (54%) were in sustained remission on entering part 2. Of these 81 patients, 37 (46%) experienced at least one flare in part 2, including 17 with new-onset GCA and 20 with relapsing GCA at baseline. Median time to flare was 26.6 weeks. In patients with new-onset GCA, flares included cranial (53%) more often than PMR symptoms (18%). Cranial and PMR symptoms were balanced (both 60%) at the time of flare in patients with relapsing GCA. Visual manifestations occurred in two patients (5%) (Table 1). ESR and CRP were elevated in 65% and 36% of patients, respectively, at the time of flare. Three (8%) flares occurred with elevated ESR without clinical symptoms.Table 1.Clinical manifestations during flare in part 2Part 1 TreatmentaTCZ QW+PredTCZ Q2W+PredAll TCZNew-onset diseasePatients, n281442Patients with ≥1 flare, n (%)b9 (32.1)8 (57.1)17 (40.5)Patients with ESR ≥30 mm/h during flare, n (%)b6 (66.7)6 (75.0)12 (70.6)Patients with CRP ≥10 mg/L during flare, n (%)b4 (44.4)2 (25.0)6 (35.3)Patients with GCA signs or symptoms during flare, n (%)c7 (77.8)7 (87.5)14 (82.4)PMR symptoms1 (11.1)2 (25.0)3 (17.6)Cranial symptomsd4 (44.4)5 (62.5)9 (52.9) Amaurosis fugax000 Blurred vision1 (11.1)01 (5.9) Diplopia000 Blindness000 Ischemic optic neuropathy000Fever1 (11.1)01 (5.9)Othere3 (33.3)2 (25.0)5 (29.4)Relapsing diseasePatients, n281139Patients with ≥1 flare, n (%)b14 (50.0)6 (54.5)20 (51.3)Patients with ESR ≥30 mm/h during flare, n (%)b8 (57.1)4 (66.7)12 (60.0)Patients with CRP ≥10 mg/L during flare, n (%)b5 (35.7)3 (50.0)8 (40.0)Patients with GCA signs or symptoms during flare, n (%)c14 (100)6 (100)20 (100)PMR symptoms8 (57.1)4 (66.7)12 (60.0)Cranial symptomsd8 (57.1)4 (66.7)12 (60.0)Amaurosis fugax1 (7.1)01 (5.0)Blurred vision000Diplopia000Blindness000Ischemic optic neuropathy1 (7.1)01 (5.0)Fever000Othere6 (4.3)1 (16.7)7 (35.0)aPatients from part 1 TCZ+Pred groups who were in sustained remission at week 52 entered part 2 on no treatment.bPercentage based on N in disease-onset group.cPercentage based on number of flare patients in disease-onset group. Individual signs or symptoms are shown as number of patients with each symptom; patients could have ≥1 sign or symptom at the time of flare.dNew-onset localized headache, scalp tenderness, temporal artery tenderness or decreased pulsation, ischemia-related vision loss, or jaw pain claudication.eIncludes fatigue, malaise, subjective weakness, and night sweats.Conclusion:Overall, 46% of GCA patients successfully treated with TCZ for 1 year experienced disease flare within the next 2 years. Flares in patients with new-onset disease occurred more often with cranial than PMR symptoms. Visual manifestations were rare, and no blindness occurred. ESR and CRP were normal in a sizable percentage of patients experiencing flare.Disclosure of Interests:Sebastian Unizony Consultant of: Sanofi and Kiniksa Pharmaceuticals, Grant/research support from: Genentech, Inc., Shalini Mohan Shareholder of: Genentech, Inc., Employee of: Genentech, Inc., Jian Han Shareholder of: Genentech, Inc., Employee of: Genentech, Inc., John H. Stone Consultant of: Roche/Genentech and Sanofi
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Ma, Xiaqing, Wenjie Du, Wenying Wang, Limin Luo, Min Huang, Haiyan Wang, Raozhou Lin et al. "Persistent Rheb-induced mTORC1 activation in spinal cord neurons induces hypersensitivity in neuropathic pain". Cell Death & Disease 11, n.º 9 (septiembre de 2020). http://dx.doi.org/10.1038/s41419-020-02966-0.
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Abstract The small GTPase Ras homolog enriched in the brain (Rheb) can activate mammalian target of rapamycin (mTOR) and regulate the growth and cell cycle progression. We investigated the role of Rheb-mediated mTORC1 signaling in neuropathic pain. A chronic constriction injury (CCI) model was dopted. CCI induced obvious spinal Rheb expression and phosphorylation of mTOR, S6, and 4-E-BP1. Blocking mTORC1 signal with rapamycin alleviated the neuropathic pain and restored morphine efficacy in CCI model. Immunofluoresence showed a neuronal co-localization of CCI-induced Rheb and pS6. Rheb knockin mouse showed a similar behavioral phenotype as CCI. In spinal slice recording, CCI increased the firing frequency of neurons expressing HCN channels; inhibition of mTORC1 with rapamycin could reverse the increased spinal neuronal activity in neuropathic pain. Spinal Rheb is induced in neuropathic pain, which in turn active the mTORC1 signaling in CCI. Spinal Rheb-mTOR signal plays an important role in regulation of spinal sensitization in neuropathic pain, and targeting mTOR may give a new strategy for pain management.
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Yan, Yi, Mengye Zhu, Xuezhong Cao, Gang Xu, Wei Shen, Fan Li, Jinjin Zhang et al. "Thalamocortical Circuit Controls Neuropathic Pain via Up-regulation of HCN2 in the Ventral Posterolateral Thalamus". Neuroscience Bulletin, 20 de diciembre de 2022. http://dx.doi.org/10.1007/s12264-022-00989-5.
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AbstractThe thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL–S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.
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Tanaka, Satoshi, Takashi Ishida, Kumiko Ishida, Satoshi Fuseya, Mariko Ito, Akiyuki Sakamoto y Mikito Kawamata. "A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers". Scientific Reports 12, n.º 1 (14 de octubre de 2022). http://dx.doi.org/10.1038/s41598-022-22309-7.
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AbstractHyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.
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Cook, Daniel C. y Peter A. Goldstein. "Non-canonical molecular targets for novel analgesics: Intracellular calcium and HCN channels". Current Neuropharmacology 19 (19 de enero de 2021). http://dx.doi.org/10.2174/1570159x19666210119153047.
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Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered.
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Caudle, Robert M. y John K. Neubert. "Effects of Oxaliplatin on Facial Sensitivity to Cool Temperatures and TRPM8 Expressing Trigeminal Ganglion Neurons in Mice". Frontiers in Pain Research 3 (11 de mayo de 2022). http://dx.doi.org/10.3389/fpain.2022.868547.
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The chemotherapeutic agent oxaliplatin is commonly used to treat colorectal cancer. Although effective as a chemotherapeutic, it frequently produces painful peripheral neuropathies. These neuropathies can be divided into an acute sensitivity to cool temperatures in the mouth and face, and chronic neuropathic pain in the limbs and possible numbness. The chronic neuropathy also includes sensitivity to cool temperatures. Neurons that detect cool temperatures are reported to utilize Transient Receptor Potential Cation Channel, Subfamily M, Member 8 (TRPM8). Therefore, we investigated the effects of oxaliplatin on facial nociception to cool temperatures (18°C) in mice and on TRPM8 expressing trigeminal ganglion (TRG) neurons. Paclitaxel, a chemotherapeutic that is used to treat breast cancer, was included for comparison because it produces neuropathies, but acute cool temperature sensitivity in the oral cavity or face is not typically reported. Behavioral testing of facial sensitivity to 18°C indicated no hypersensitivity either acutely or chronically following either chemotherapeutic agent. However, whole cell voltage clamp experiments in TRPM8 expressing TRG neurons indicated that both oxaliplatin and paclitaxel increased Hyperpolarization-Activated Cyclic Nucleotide-Gated channel (HCN), voltage gated sodium channel (Nav), and menthol evoked TRPM8 currents. Voltage gated potassium channel (Kv) currents were not altered. Histological examination of TRPM8 fibers in the skin of the whisker pads demonstrated that the TRPM8 expressing axons and possible Merkel cell-neurite complexes were damaged by oxaliplatin. These findings indicate that oxaliplatin induces a rapid degeneration of TRG neuron axons that express TRPM8, which prevents evoked activation of the sensitized neurons and likely leads to reduced sensitivity to touch and cool temperatures. The changes in HCN, Nav, and TRPM8 currents suggest that spontaneous firing of action potentials may be increased in the deafferented neurons within the ganglion, possibly producing spontaneously induced cooling or nociceptive sensations.
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Chen, Yong, Dan Li, Ningcen Li, PeiYong Loh, Yi Guo, Xiyou Hu, Jingyu Zhang et al. "Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain". Frontiers in Neurology 14 (23 de enero de 2023). http://dx.doi.org/10.3389/fneur.2023.1093849.
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Neurogenic pain rises because of nervous system damage or dysfunction and is the most difficult to treat among other pathological pains. Acupuncture has been reported as a great treatment option for neurogenic pain owing to its unlimited advantages. However, previous studies on the analgesic effects of acupuncture for NP were scattered and did not form a whole. In this study, we first comprehensively review the relevant basic articles on acupuncture for NP published in the last 5 years and summarize the analgesic mechanisms of acupuncture in terms of nerve signaling, neuro-immune crosstalk, and metabolic and oxidative stress regulation. Acupuncture inhibits the upstream excitatory system and suppresses neuronal transmission efficiency by downregulating glutamate, NMDA receptors, P2XR, SP, CGRP, and other neurotransmitters and receptors in the spinal cord, as well as plasma channels such as TRPV1, HCN. It can also activate the downstream pain inhibitory pathway by upregulating opioid peptide (β-endorphin), MOR receptors, GABA and GABA receptors, bi-directional regulating 5-hydroxytryptamine (5-HT) and its receptors (upregulate 5-HT 1A and downregulate 5-HT7R) and stimulating hypothalamic appetite-modifying neurons. Moreover, neuroinflammation in pain can be inhibited by acupuncture through inhibiting JAK2/STAT3, PI3K/mTOR pathways, down regulating chemokine receptor CX3CR1 on microglia and up regulating adenosine receptor A1Rs on astrocytes, inhibiting the activation of glia and reducing TNF-α and other inflammatory substances. Acupuncture also inhibits neuronal glucose metabolism by downregulating mPFC's GLUT-3 and promotes metabolic alterations of the brain, thus exerting an analgesic effect. In conclusion, the regulation of nerve signal transduction and neuroimmune crosstalk at the peripheral and central levels mediates the analgesic effects of acupuncture for neuropathic pain in an integrated manner. These findings provide a reliable basis for better clinical application of acupuncture in the management of neuropathic pain.
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Alles, Sascha R. A. y Peter A. Smith. "Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets". Frontiers in Pain Research 2 (13 de diciembre de 2021). http://dx.doi.org/10.3389/fpain.2021.750583.
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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.
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Lauria, Giuseppe. "Neuropathic pain and diabetes: focus on mechanisms and potential therapeutic strategies". Hot Topics in Neurology and Psychiatry, 2011. http://dx.doi.org/10.4147/htn-111000.
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Pasutharnchat, Nath, Chamaiporn Taychargumpoo, Yongkasem Vorasettakarnkij y Jakkrit Amornvit. "Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort". BMC Neurology 21, n.º 1 (22 de mayo de 2021). http://dx.doi.org/10.1186/s12883-021-02243-3.
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Abstract Background Ala97Ser transthyretin amyloidosis-associated polyneuropathy (ATTRA97S-PN) is a rare form of inherited polyneuropathy, usually manifesting with late-onset (> 50) progressive polyneuropathy. This mutation is mostly prevalent in Taiwanese and Han-Chinese individuals. The aim of this study was to describe the clinical and comprehensive neurophysiological profiles of ATTRA97S-PN in Thai patients. Methods The clinical profiles and serial neurophysiologic studies (nerve conduction study (NCS), quantitative sensory test (QST), and comprehensive autonomic function test (AFT)) of symptomatic ATTRA97S-PN patients who had been followed-up at King Chulalongkorn Memorial Hospital during 2010–2020 were retrospectively reviewed. Results Nine symptomatic patients (55.6 % were male) from four unrelated families were included. All were Thais of mixed Thai Chinese descent. The mean age of onset was 48.3 (32–60) years. The mean age at diagnosis was 54.8 (33–66) years. Three patients developed early-onset (< 40y) polyneuropathy. The mean Neuropathy Impairment Score was 41.33 (10–92) at diagnosis. Sensory (9/9) and autonomic (9/9) neuropathies were more frequent than motor neuropathy (5/9), which appeared in the late stage of disease. Hypoesthesia in the feet, and gastrointestinal autonomic symptoms were frequently reported as the initial symptoms. The course of neuropathy progressed over years to decades. The worsening of neuropathy tended to progress faster once motor nerves were affected in both clinical and neurophysiological aspects. Concurrent cardiac amyloidosis was found in 6/9 patients. NCS showed length-dependent sensorimotor axonal polyneuropathy in 5/9 patients, and median neuropathy at the wrist (mostly bilateral) in 7/9 patients. QST showed abnormalities in the vibratory detection threshold, the cold detection threshold and the heat pain sensation in 8/9, 8/9 and 7/7 tested patients, respectively. AFT results were abnormal in all. The mean composite autonomic severity score was 5 (3–9). Conclusions This clinical study is the first of ATTRA97S-PN in Thai patients. The mixed polyneuropathy-cardiopathy phenotype was the most common manifestation. In this cohort, the age of onset was lower, and the course of neuropathy was relatively longer, than that in previous studies. Some patients may develop early-onset polyneuropathy. This mutation has not yet been documented in any population other than Han Chinese-related populations, probably suggesting a founder effect. Further studies are warranted.
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Yue, Rongcai, Haiping Liu, Yaxin Huang, Jing Wang, Dongmei Shi, Yanping Su, Yufei Luo, Ping Cai, Guilin Jin y Changxi Yu. "Sempervirine Inhibits Proliferation and Promotes Apoptosis by Regulating Wnt/β-Catenin Pathway in Human Hepatocellular Carcinoma". Frontiers in Pharmacology 12 (7 de diciembre de 2021). http://dx.doi.org/10.3389/fphar.2021.806091.
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Gelsemium elegans (G. elegans) Benth., recognized as a toxic plant, has been used as traditional Chinese medicine for the treatment of neuropathic pain and cancer for many years. In the present study, we aim to obtain the anti-tumor effects of alkaloids of G. elegans and their active components in hepatocellular carcinoma (HCC) and the potential mechanism was also further investigated. We demonstrated that sempervirine induced HCC cells apoptosis and the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and down-regulation of cyclin D1, cyclin B1 and CDK2. Furthermore, sempervirine inhibited HCC tumor growth and enhances the anti-tumor effect of sorafenib in vivo. In addition, inactivation of Wnt/β-catenin pathway was found to be involved in sempervirine-induced HCC proliferation. The present study demonstrated that alkaloids of G. elegans were a valuable source of active compounds with anti-tumor activity. Our findings justified that the active compound sempervirine inhibited proliferation and induced apoptosis in HCC by regulating Wnt/β-catenin pathway.
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Rodrigues, Diana, Inês Laranjeira, João Barbosa, Diana Amorim, Armando Almeida y Filipa Pinto-Ribeiro. "Nociceptive, emotional and electrophysiological characterization of the chronic constriction injury model of experimental traumatic neuropathic pain in female Wistar Han rats." Frontiers in Cellular Neuroscience 13 (2019). http://dx.doi.org/10.3389/conf.fncel.2019.01.00016.
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Hai, Tajrina, Yll Agimi y Katharine Stout. "Clusters of conditions among US service members diagnosed with mild TBI from 2017 through 2019". Frontiers in Neurology 13 (9 de noviembre de 2022). http://dx.doi.org/10.3389/fneur.2022.976892.
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BackgroundMany US Military Service Members (SMs) newly diagnosed with mild Traumatic Brain Injury (mTBI) may exhibit a range of symptoms and comorbidities, making for a complex patient profile that challenges clinicians and healthcare administrators. This study used clustering techniques to determine if conditions co-occurred as clusters among those newly injured with mTBI and up to one year post-injury.MethodsWe measured the co-occurrence of 41 conditions among SMs diagnosed with mTBI within the acute phase, one or three months post-mTBI diagnosis, and chronic phase, one year post-mTBI diagnosis. Conditions were identified from the literature, clinical subject matter experts, and mTBI care guidelines. The presence of conditions were based on medical encounters recorded within the military health care data system. Through a two-step approach, we identified clusters. Principal component analysis (PCA) determined the optimal number of clusters, and hierarchical cluster analyses (HCA) identified the composition of clusters. Further, we explored how the composition of these clusters changed over time.ResultsOf the 42,018 SMs with mTBI, 23,478 (55.9%) had at least one condition of interest one-month post-injury, 26,831 (63.9%) three months post-injury, and 29,860 (71.1%) one year post injury. Across these three periods, six clusters were identified. One cluster included vision, cognitive, ear, and sleep disorders that occurred one month, three months, and one year post-injury. Another subgroup included psychological conditions such as anxiety, depression, PTSD, and other emotional symptoms that co-occurred in the acute and chronic phases post-injury. Nausea and vomiting symptoms clustered with cervicogenic symptoms one month post-injury, but later shifted to other clusters. Vestibular disorders clustered with sleep disorders and headache disorders one-month post-injury and included numbness and neuropathic pain one year post-injury. Substance abuse symptoms, alcohol disorders, and suicidal attempt clustered one year post-injury in a fifth cluster. Speech disorders co-occurred with headache disorders one month and one year post-injury to form a sixth cluster.ConclusionPCA and HCA identified six distinct subgroups among newly diagnosed mTBI patients during the acute and chronic phases post-injury. These subgroups may help clinicians better understand the complex profile of SMs newly diagnosed with mTBI.