Monique van Velzen

ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes

Although erythropoietin ameliorates experimental type 2 diabetes with neuropathy, serious side effects limit its potential clinical use. ARA 290, a nonhematopoietic peptide designed from the structure of erythropoietin, interacts selectively with the innate repair receptor that mediates tissue protection. ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. To evaluate the potential activity of ARA 290 in type 2 diabetes and painful neuropathy, subjects were enrolled in this phase 2 study. ARA 290 (4 mg) or placebo were self-administered subcutaneously daily for 28 d and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Subjects receiving ARA 290 exhibited an improvement in hemoglobin A1c (Hb A1c) and lipid profiles throughout the 56 d observation period. Neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly in the ARA 290 group. Mean corneal nerve fiber density (CNFD) was reduced significantly compared with normal controls and subjects with a mean CNFD >1 standard deviation from normal showed a significant increase in CNFD compared with no change in the placebo group. These observations suggest that ARA 290 may benefit both metabolic control and neuropathy in subjects with type 2 diabetes and deserves continued clinical evaluation.

ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.

Clinical impact of HLA class I expression in rectal cancer.

PurposeTo determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas.Experimental designTumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10).ResultsTumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with ≤50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival.ConclusionsDown-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient’s prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed.

Opioid-induced respiratory depression: reversal by non-opioid drugs.

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.

ARA 290 for treatment of small fiber neuropathy in sarcoidosis

Introduction: Painful peripheral neuropathy is a common, difficult-to-treat complication associated with a variety of diseases, including diabetes mellitus and sarcoidosis. It is caused by damage of small and autonomic nerve fibers, resulting in potentially debilitating symptoms of neuropathic pain and autonomic dysfunction. The limited efficacy of current treatment options dictates a rationalized design of novel compounds. Areas covered: The authors present the recent data from two Phase II clinical trials on ARA290, an erythropoietin derivative with tissue protective and healing properties that does not stimulate erythropoiesis. ARA 290 treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients, evidenced by a decrease in pain scores on validated questionnaires. Moreover, ARA 290 treatment resulted in significant increases in corneal nerve fibers, improved sensory pain thresholds, improved quality of life and physical functioning. Expert opinion: Current treatment modalities of neuropathy are based on a trial-and-error approach, have limited efficacy and come with significant side effects. Given the excellent safety profile while reducing neuropathy symptoms, the prospects of ARA 290 treatment in sarcoid neuropathy seem promising. The long-lasting beneficial effects of ARA 290 on both pain-related and non-pain-related symptoms in sarcoidosis patients prompt additional studies on potential disease-modifying properties of ARA 290.

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

Purpose Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]). Methods Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days. Results The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43+ fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157). Conclusions Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.

ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response

BackgroundNeuropathic pain is a difficult to treat disorder arising from central or peripheral nervous system lesions. The etiology of neuropathic pain consists of several overlapping pathways converging into an exaggerated pain state with symptoms such as allodynia and hyperalgesia. One of these pathways involves activation of spinal cord microglia and astrocytes, which drive and maintain the inflammatory response following the lesion. These cells are a potential target for drugs for neuropathic pain relief. In this current study, we investigated the dose-effect relationship of the tissue protective peptide ARA 290, derived from the tertiary structure of erythropoietin, on allodynia and concurrent spinal cord microglia and astrocytes.ResultsFollowing a spared nerve injury in rats, vehicle or ARA290 (administered in either one of 4 doses: 3, 10, 30 and 60 μg/kg) was administered on days 1, 3, 6, 8 and 10. ARA290 exerted a dose–response effect by significantly reducing mechanical allodynia up to 20 weeks when compared to vehicle. The reduction of cold allodynia was significant up to 20 weeks for the doses 3, 10, 30 and 60 μg/kg when compared to vehicle. The effect 10 and 30 μg/kg ARA290 and vehicle on the microglia response (iba-1-immunoreactivity, iba-1-IR) and astrocyte reaction (GFAP-immunoreactivity, GFAP-IR) was investigated in animals surviving 2 (group 1) or 20 (group 2) weeks following lesion or sham surgery. In group 1, significant microglia reactivity was observed in the L5 segment of the spinal cord of animals treated with vehicle when compared to sham operated, while animals treated with 10 or 30 μg/kg did not show a increase. In group 2, a more widespread and increased microglia reactivity was observed for animals treated with 0 and 10 μg/kg when compared to sham operated animals, indicated by involvement of more spinal cord segments and higher iba-1-IR. Animals treated with 30 μg/kg did not show increased microglia reactivity. No difference in astrocyte reaction was observed.ConclusionsThe erythropoietin-analogue ARA290 dose-dependently reduced allodynia coupled to suppression of the spinal microglia response, suggestive of a mechanistic link between ARA290-induced suppression of central inflammation and relief of neuropathic pain symptoms.

A Randomized Controlled Trial on the Effect of Tapentadol and Morphine on Conditioned Pain Modulation in Healthy Volunteers.

Background Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. Methods and Results On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate release tablet) or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus) but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9%) at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2%) at 120-150 min after drug intake (p = 0.001). No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6%) at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9%) at 120-150 min after drug intake (p = 0.60). Conclusions Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol’s main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic stimulation on descending controls. Trial Registration Netherlands Trial Register NTR2716

Pain Experience and Perception in the Obese Subject Systematic Review (Revised Version)

Pain is an integral part of life and has an important protective function. Pain perception has been shown to differ between subjects and changes with gender, race, and culture. In addition, it has been suggested that obesity influences pain perception and that obesity can be a risk factor for increased pain thresholds. The aim of this systematic review was to examine pain thresholds in obese subjects compared to non-obese subjects. The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and EMBASE were searched using combinations of terms for obese, pain measurement, visual analog scale, quantitative sensory testing, and pain perception. Studies without comparison as well as cross-sectional studies, case series, and case reports were excluded. The search was conducted without restrictions on language or date of publication. From a total of 1818 identified studies, seven studies fulfilled the inclusion criteria, whereby only one study tested the pain threshold difference between obese and non-obese and also before and after body weight loss surgery. Two studies showed a lower pain threshold and four studies a higher pain threshold in obese subjects compared to non-obese subjects. Two studies showed no difference in pain threshold before and after substantial body weight loss due to surgery. Weight loss after surgery was not identified as a factor for higher pain thresholds in obese subjects. In view of the heterogeneity of the studies, the variability of the subjects and differences in methodological quality, a meta-analysis could not be performed. From the available literature, there is a tendency towards higher pain thresholds in obese subjects. Neither substantial weight loss, nor gender, were factors explaining difference in threshold. Future randomized, controlled trials should explore demographic variables that could influence pain perception or pain thresholds in obese individuals, and multimodal pain testing is necessary for better understanding of the apparent differences in pain thresholds in obese individuals.

Ketamine for pain

The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.