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BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

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BACKGROUND: Painful diabetic peripheral neuropathy is one of the frequent presenting complaints in diabetes and endocrine clinics. Our main objective was to compare effectiveness of three commonly prescribed drugs: amitriptyline, pregabalin and duloxetine for treatment of painful diabetic peripheral neuropathy. METHODS: This was a comparative, prospective, observational study conducted among 99 diabetic patients with painful diabetic peripheral neuropathy having numeric rating pain scale ≥ 4. Thirty-three patients in each group were consecutively prescribed amitriptyline, pregabalin and duloxetine in lower dose (10mg/75mg/20mg) for first two weeks to gradually up titrate to higher dose (25mg/150mg/30mg) as per pain response for total duration of eight weeks. RESULTS: At the end of eight weeks, 84.9% in amitriptyline, 78.7% in pregabalin and 60.6% in duloxetine group had adequate pain reduction in form of mild or no pain. Among total patients, 42.5% patients had severe pain at baseline that decreased to 5% by the end of our study. Out of three drugs, 45.5% patients in amitriptyline group had complete resolution of pain as compared to 24.2% in pregabalin and 18.2% in duloxetine group (p value 0.05). Drowsiness (42.4%), dizziness (21.2%) and dry mouth (21.2%) were the commonest side effects among total participants in our study. CONCLUSIONS: Amitriptyline, pregabalin and duloxetine were all associated with adequate pain reduction among patients of painful diabetic peripheral neuropathy in our study, however, amitriptyline had more favorable findings with tolerable side effects.

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Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line oral options in clinical practice. Other strategies may be used as part of individualized comprehensive pain management plans. This article provides an overview of the most recent US guidelines for managing painful DPN, with a focus on the two most recently approved treatment options (SCS and capsaicin 8% topical system), as well as evidence for using FDA-approved and guideline-supported drugs and devices. Also discussed are unmet needs for this patient population, and evidence for potential future treatments for painful DPN, including drugs with novel mechanisms of action, electrical stimulation devices, and nutraceuticals.

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Painful diabetic peripheral neuropathy(PDPN)is a chronic complication of diabetes mellitus.The proportion of patients with PDPN is relatively high in China.At present,the latest guidelines recommend a batch of first-line analgesic drugs for PDPN treatment.Many large-scale randomized trials have confirmed the effectiveness of combination therapy.However,the pathological and physiological mechanisms of PDPN are not fully understood.The clinical treatment effect is still not ideal.This article reviews the research progress on the mechanism of PDPN occurrence.

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Background: Painful Diabetic Peripheral Neuropathy (PDPN) is a common complication of diabetes, it severely affects the quality of life of patients. Acupuncture has been shown to be effective in the treatment of PDPN. To evaluate the efficacy and safety of acupuncture for pain relief in patients diagnosed with diabetic peripheral neuropathy, we conducted a systematic review and meta-analysis. Method: We thoroughly searched specific databases, which included PUBMED, EMBASE, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Database, the Chinese National Knowledge Infrastructure, China Science and Technology Journal Database and the Wanfang Data. All randomized controlled trials of acupuncture therapy for PDPN with pain change scales were included. Included studies were assessed for methodological quality according to the risk of bias from the Cochrane handbook. Meta-analyses were carried out to analyze the outcomes, subgroup analyses, sensitivity analyses, and funnel plot analyses were undertaken. Results: This systematic review evaluated a total of 25 trials of acupuncture therapy in combination with conventional treatment, involving a total of 1,561 patients with PDPN. According to the results, among 16 trials using VAS scores with a total of 1,552 patients, 2 acupoint injection trials (MD -2.38, 95% CI: -2.76 to -2.01, p < 0.00001), 12 acupuncture trials (MD -1. 31, 95% CI: -1.60 to -1.02, p < 0.00001) and 2 moxibustion trials showed that acupuncture therapy combined with conventional treatment improved pain better than conventional treatment (MD -2.50, 95% CI: -2.76 to -2.24, p < 0.00001). In the subgroup analysis of the acupuncture group, the results of the 5 trials in which the location of acupuncture was only in the limbs (MD -1.27, 95% CI: -1.54 to -1.01, p < 0.00001) and the 7 trials both in limbs and torso (MD -1.38, 95% CI: -1.81 to -0.95, p < 0.00001) also demonstrated that acupuncture was effective in pain improvement. Conclusion: This meta-analysis analyzed the possible efficacy of acupuncture in combination with conventional treatment for pain in diabetic peripheral neuropathy, particularly when acupoints are located in the limbs. However, there are limitations to this meta-analysis and future clinical studies are needed to confirm these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023449447, identifier (CRD42023449447).

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OBJECTIVE: Spinal cord stimulation at 10 kHz has provided effective pain relief and improved function in painful diabetic peripheral neuropathy. This study aims to confirm the clinical outcomes for 10-kHz spinal cord stimulation treatment of painful diabetic peripheral neuropathy and explore its impact on objective quantitative measures of nerve pathology and function. METHODS: This single-academic center, prospective, open-label, observational study examined the pain relief success of 10-kHz spinal cord stimulation in patients >18 years of age with diabetic peripheral neuropathy. Patients underwent skin biopsies to measure intra-epidermal nerve fiber densities and corneal confocal microscopy measurements before implantation and at the 3-, 6-, and 12-month follow-up visits. Numerical rating scale for pain, visual analog scale, neuropathy pain scale, Short Form-36, and Neuropen (pin prick and monofilament) assessments were also conducted. RESULTS: Eight patients met the criteria and were enrolled in the study. A successful trial was achieved in 7 subjects, and 6 completed the study. Significant pain relief (P < .001) was achieved at all follow-up visits. Neurological assessments showed reduced numbers of "absent" responses and increased "normal" responses from baseline to 12 months. Both proximal and distal intra-epidermal nerve fiber densities were higher at 12 months than at baseline (P < .01). Confocal microscopy measurements showed a steady increase in nerve density from baseline (188.8% increase at 12 months; P = .029). CONCLUSIONS: We observed pain relief and improvements in sensory function after stimulation that were accompanied by increases in lower-limb intra-epidermal nerve fiber density and corneal nerve density. Further evaluation with a blinded and controlled study is needed to confirm the preliminary findings in this study.

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Introduction: Current treatments for painful diabetic peripheral neuropathy (DPN) are insufficiently effective for many individuals and do not treat nonpain signs and symptoms. The enzyme histone deacetylase type 6 (HDAC6) may play a role in the pathophysiology of painful DPN, and inhibition of HDAC6 has been proposed as a potential treatment. Objectives: To assess the efficacy and safety of the novel HDAC6 inhibitor ricolinostat for the treatment of painful diabetic peripheral neuropathy. Methods: We conducted a 12-week randomized, double-blind, placebo-controlled phase 2 study of the efficacy of ricolinostat, a novel selective HDAC6 inhibitor, in 282 individuals with painful DPN. The primary outcome was the change in the patient-reported pain using a daily diary, and a key secondary outcome was severity of nonpain neuropathic signs using the Utah Early Neuropathy Scale (UENS) score. Results: At the 12-week assessment, changes in average daily pain and UENS scores were not different between the ricolinostat and placebo groups. Conclusion: These results do not support the use of the HDAC6 inhibitor ricolinostat as a treatment for neuropathic pain in DPN for periods up to 12 weeks.

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Prescription-strength (8%) capsaicin topical system is a US FDA-approved treatment for painful diabetic peripheral neuropathy of the feet. A 30 min application of the capsaicin 8% topical system can provide sustained (up to 3 months) local pain relief by desensitizing and reducing TRPV1-expressing cutaneous fibers. Capsaicin is not absorbed systemically; despite associated application-site discomfort, capsaicin 8% topical system is well tolerated, with no known drug interactions or contraindications, and could offer clinical advantages over oral options. Capsaicin 8% topical system are not for patient self-administration and require incorporation into office procedures, with the added benefit of treatment compliance. This article reviews existing literature and provides comprehensive, practical information regarding the integration of capsaicin 8% topical systems into office procedures.

Capsaicin 8% topical system is used to treat diabetic nerve pain of the feet. This in-office 30 min application can provide lasting relief of pain (for up to 3 months) by targeting the nerves damaged by diabetes. Since capsaicin acts at the site of diabetic nerve pain without being absorbed into the bloodstream, it is unlikely to interfere with other treatments and has few undesirable effects. Discomfort at the application site is the most commonly reported adverse event. Capsaicin 8% topical system must be applied by a healthcare professional and up to four topical systems can be used per treatment. Incorporating the use of capsaicin 8% topical systems into office procedures can help provide relief for patients living with diabetic nerve pain of the feet and may improve treatment compliance.

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Several clinical studies have shown an association between vitamin D deficiency and painful diabetic peripheral neuropathy (DPN). However, it is still unclear whether vitamin D status and inflammatory markers correlate in patients with painful DPN. In this context, we aimed to investigate the associations between serum vitamin D levels and inflammatory status in Kurdish type 2 diabetes patients (T2DM) with painful DPN and without painful DPN. A clinical case-control study was conducted on 86 Kurdish patients with T2DM. The patients were divided into two groups: the case group consisted of 45 patients with painful DPN and the control group consisted of 41 age- and sex-matched diabetics without DPN. In T2DM patients with and without painful DPN, the prevalence of severe vitamin D deficiency was observed in 46.67% and 21.95% of the patients, respectively (p = 0.0283). The mean serum 25(OH)-vitamin D level in patients with painful DPN (mean = 12.00, SD = 5.78) was significantly lower than in patients without DPN (mean = 16.36, SD = 7.86; p = 0.0041). Regression analysis revealed that vitamin D deficiency (p = 0.0120) and higher glycated hemoglobin (HbA1c) (p = 0.00003) were identified as predictive risk factors for painful DPN. However, there was no significant association between inflammatory status and vitamin D levels. The duration of sun exposure was the only controlling factor for vitamin D in painful DPN patients. In the Kurdish population, lower vitamin D and high HbA1c levels were predictive factors for painful DPN.

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Spinal cord stimulation (SCS) is a last resort treatment for pain relief in painful diabetic peripheral neuropathy (PDPN) patients. However, the effectivity of SCS in PDPN is limited. New SCS paradigms such as high frequency (HF) and differential target multiplexed (DTM) might improve responder rates and efficacy of SCS-induced analgesia in PDPN patients, and are suggested to modulate the inflammatory balance and glial response in the spinal dorsal horn. The aim of this study was to research the effects of Con-, HF- and DTM-SCS on pain behavior and the spinal inflammatory balance in an animal model of PDPN. Streptozotocin-induced PDPN animals were stimulated for 48 hours with either Con-SCS (50Hz), HF-SCS (1200Hz) or DTM-SCS (combination of Con- and HF-SCS). Mechanical hypersensitivity was assessed using Von Frey (VF) test and the motivational aspects of pain were assessed using the mechanical conflict avoidance system (MCAS). The inflammatory balance and glial response were analyzed in the dorsal spinal cord based on RNA expression of pro- and anti-inflammatory cytokines (Tnf-α, Il-1ß, Il-4, Il-10), a microglia marker (Itgam), an astrocyte marker (Gfap), a T-cell marker (Cd3d), microglia proliferation markers (Irf8, Adgre1) and P2X4, p13-MAPK, BDNF signaling markers (P2x4, Mapk14, Bdnf). The results show that Con-, HF-, and DTM-SCS significantly decreased hypersensitivity after 48 hours of stimulation compared to Sham-SCS in PDPN animals, but at the same time did not affect escape latency in the MCAS. At the molecular level, Con-SCS resulted in a significant increase in spinal pro-inflammatory cytokine Tnf-α after 48 hours compared to DTM-SCS and Sham-SCS. In summary, Con-SCS showed a shift of the inflammatory balance towards a pro-inflammatory state whilst HF- and DTM-SCS shifted the balance towards an anti-inflammatory state. These findings suggest that the underlying mechanism of Con-SCS induced pain relief in PDPN differs from that induced by HF- and DTM-SCS.

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Purpose: An online survey was conducted in the USA to obtain information about the knowledge and experiences of patients with painful diabetic peripheral neuropathy (pDPN). Patients and Methods: 506 adults with diabetes and pDPN affecting the feet for ≥6 months, for which pain medication had been prescribed for ≥6 months, completed an online survey questionnaire in March 2021. Results: 79% of respondents had type 2 diabetes, 60% were male, 82% were Caucasian and 87% had comorbidities. Pain was significant to severe in 49% of respondents, and 66% had disability due to nerve pain. Anticonvulsants, over-the-counter pills and supplements were the most commonly used medications. Topical creams/patches were prescribed in 23% of respondents. 70% had tried multiple medications for their pain. 61% of respondents had to see ≥2 doctors before receiving a correct diagnosis of pDPN. 85% of respondents felt that the doctor understood their pain and its impact on their life. 70% had no difficulty finding the information they wanted. 34% felt insufficiently informed about their condition. A medical professional was the primary, and most trusted, source of information. Frustration, worry, anxiety and uncertainty were the most commonly reported emotions. Respondents were generally eager to find new medications for pain relief and desperate for a cure. Lifestyle changes because of nerve pain were most commonly associated with physical disabilities and sleep disturbance. Better treatments and freedom from pain were the overriding perspectives when considering the future. Conclusion: Patients with pDPN are generally well informed about their pain and trust their doctor but remain unsatisfied with their current treatment and struggle to find a lasting solution for their pain. Early identification and diagnosis of pain in diabetics, and education about treatments, is important to minimize the impact of pain on quality of life and emotional well-being.

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Painful diabetic peripheral neuropathy (PDPN) is present in nearly a quarter of people with diabetes. It is estimated to affect over 100 million people worldwide. PDPN is associated with impaired daily functioning, depression, sleep disturbance, financial instability, and a decreased quality of life. Despite its high prevalence and significant health burden, it remains an underdiagnosed and undertreated condition. PDPN is a complex pain phenomenon with the experience of pain associated with and exacerbated by poor sleep and low mood. A holistic approach to patient-centred care alongside the pharmacological therapy is required to maximise benefit. A key treatment challenge is managing patient expectation, as a good outcome from treatment is defined as a reduction in pain of 30-50%, with a complete pain-free outcome being rare. The future for the treatment of PDPN holds promise, despite a 20-year void in the licensing of new analgesic agents for neuropathic pain. There are over 50 new molecular entities reaching clinical development and several demonstrating benefit in early-stage clinical trials. We review the current approaches to its diagnosis, the tools, and questionnaires available to clinicians, international guidance on PDPN management, and existing pharmacological and non-pharmacological treatment options. We synthesise evidence and the guidance from the American Association of Clinical Endocrinology, American Academy of Neurology, American Diabetes Association, Diabetes Canada, German Diabetes Association, and the International Diabetes Federation into a practical guide to the treatment of PDPN and highlight the need for future research into mechanistic-based treatments in order to prioritise the development of personalised medicine.

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AIMS: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship. METHODS: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire. RESULTS: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain. CONCLUSIONS: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

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AIMS: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements. METHODS: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination. RESULTS: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%. CONCLUSION: This study suggests that CAN predominantly co-exists with concomitant DPN.

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Functional magnetic resonance imaging (fMRI) has been shown successfully to assess and stratify patients with painful diabetic peripheral neuropathy (pDPN). This supports the idea of using neuroimaging as a mechanism-based technique to individualise therapy for patients with painful DPN. The aim of this study was to use deep learning to predict treatment response in patients with pDPN using resting state functional imaging (rs-fMRI). We divided 43 painful pDPN patients into responders and non-responders to lidocaine treatment (responders n = 29 and non-responders n = 14). We used rs-fMRI to extract functional connectivity features, using group independent component analysis (gICA), and performed automated treatment response deep learning classification with three-dimensional convolutional neural networks (3D-CNN). Using gICA we achieved an area under the receiver operating characteristic curve (AUC) of 96.60% and F1-Score of 95% in a ten-fold cross validation (CV) experiment using our described 3D-CNN algorithm. To our knowledge, this is the first study utilising deep learning methods to classify treatment response in pDPN.

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Objectives@#Knowing the limited epidemiological studies on painful diabetic peripheral neuropathy (pDPN) in the Philippines, the present review aimed to map the prevalence of pDPN and identify the associated healthcare gaps. @*Materials and Methods@#A systematic search of MEDLINE, Embase and BIOSIS was conducted using predefine inclusion criteria, and relevant studies published in English between 2004 and 2021 were identified. An unstructured literature search was also conducted on public and government websites with no date restriction. Data combined from all sources were synthesized and presented as a simple mean.@*Results@#Three studies were considered for final analyses of the 26 articles retrieved from structured and unstructured searches. The sample sizes for the three studies were 103, 172, and 100, respectively. The simple mean prevalence of pDPN was estimated at 26.5%. Awareness of pDPN based on a published study was 89%. According to published studies, screening and diagnosis of pDPN were 65% and 76.7%, respectively. One-third of the patients with pDPN (75%) were treated. No literature is available for adherence and control.@*Conclusion@#Limited data exist on the different management stages of patients with pDPN in the Philippines. The study analysis will help address the knowledge gaps, improve patient care and pain management, and aid decisionmaking.

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BACKGROUND AND AIMS: Painful diabetic peripheral neuropathy (PDPN) is a common complication of type 2 diabetes. The unrelenting pain associated with PDPN adversely affects a patient's quality of life. Recognizing the crucial role that sleep plays in the metabolic control of diabetes, this study aims to estimate the prevalence of sleep impairment in painful diabetic peripheral neuropathy (PDPN) and identify the factors associated with it. METHODS: We conducted a cross-sectional study among 156 patients in a tertiary care hospital in south India. We recruited consenting adults with PDPN. Sleep quality was analyzed using the Pittsburg sleep quality index (PSQI), a self-rating scale. Hba1c served as a measure of glycemic control. Anxiety and depression were assessed using the hospital anxiety and depression (HAD) scale. Data were analyzed in SPSS 26.0. RESULTS: A total of 156 patients were included in the study with a mean age of 58.39 ± 9.12 years. In 151 (96.79%) patients demonstrated sleep impairment with a global PSQI score of 10.92 ± 2.87. Female sex, ischemic heart disease (IHD), high anxiety levels and use of insulin, pregabapentin, and duloxetine; were significantly associated with poor sleep quality (p < 0.05). The median Hba1c was high (9% [7.46-11.1]). However, there was no statistical correlation between the degree of sleep impairment and glycemic control. CONCLUSION: We found a high prevalence of sleep impairment in patients with PDPN. Female sex, IHD, high anxiety levels and use of neuropathic drugs were predictors of poor sleep quality.

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Painful diabetic peripheral neuropathy is characterized by burning, stabbing, or electric shock-type pain, which severely impacts day-to-day functioning and quality of life. Here, we report the results of 3 phase I studies with NRD135S.E1 (referred to as NRD.E1), a new, orally available chemical entity, presently developed for the treatment of painful diabetic peripheral neuropathy. The first study was a first-in-human, randomized, placebo-controlled, single-ascending-dose study, where NRD.E1 was administered to healthy male subjects in single dosages ranging from 300 to 1200 mg. The second study was a randomized, placebo-controlled multiple-dose study, where healthy male subjects received 300 mg of NRD.E1 once daily for 5 consecutive days. The third study was an open-label food interaction study in healthy men and women following a crossover design, where NRD.E1 was administered under fed and fasted conditions at 40 mg. The studies revealed dose-dependent absorption, increased exposure to NRD.E1 when administered with food, and no relevant accumulation after once-daily administration. All 3 phase I studies consistently showed rapid absorption of orally administered NRD.E1 followed by fast elimination, mainly via metabolization (glucuronidation), and small secondary increases in plasma concentrations. NRD.E1 was well tolerated, with no subject discontinuation due to treatment-emergent adverse events in any study.

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Mechanical allodynia (MA) is the main reason that patients with diabetic peripheral neuropathy (DPN) seek medical advice. It severely debilitates the quality of life. Investigating hyperglycemia-induced changes in neural transcription could provide fundamental insights into the complex pathogenesis of painful DPN (PDPN). Gene expression profiles of physiological dorsal root ganglia (DRG) have been studied. However, the transcriptomic changes in DRG neurons in PDPN remain largely unexplored. In this study, by single-cell RNA sequencing on dissociated rat DRG, we identified five physiological neuron types and a novel neuron type MAAC (Fxyd7 + /Atp1b1 +) in PDPN. The novel neuron type originated from peptidergic neuron cluster and was characterized by highly expressing genes related to neurofilament and cytoskeleton. Based on the inferred gene regulatory networks, we found that activated transcription factors Hobx7 and Larp1 in MAAC could enhance Atp1b1 expression. Moreover, we constructed the cellular communication network of MAAC and revealed its receptor-ligand pairs for transmitting signals with other cells. Our molecular investigation at single-cell resolution advances the understanding of the dynamic peripheral neuron changes and underlying molecular mechanisms during the development of PDPN.