NRD.E1, an innovative non-opioid therapy for painful diabetic peripheral neuropathy-A randomized proof of concept study.

BACKGROUND: Painful diabetic peripheral neuropathy (PDPN) affects up to 26% of patients with diabetes mellitus, with major impacts on their general health and well-being. Most available drugs fail to deliver acceptable pain reduction in the majority of patients and are often poorly tolerated. NRD.E1 is a novel product that has shown anti-nociceptive preclinical effects and good tolerability in healthy volunteer studies. METHODS: This phase 2a, randomized, dose-finding, Proof of Concept study enrolled patients with PDPN of ≥3 months duration. After at least one treatment-free week (WO week), 88 patients entered a 1-week single-blind (SB)-placebo run-in period, followed by 3 weeks' double-blind (DB) treatment, during which they received NRD.E1 at 10, 40 or 150 mg/day or placebo. RESULTS: The primary endpoint (change from SB-placebo run-in week to week 3 in weekly mean of daily average numerical rating scale [NRS] pain intensity) showed clinically relevant placebo-corrected treatment effect pain reductions at 40 mg and 150 mg/day of 0.82 (95% CI: 0.07, 1.58, p = 0.034) and 0.66 (95% CI: -0.03, 1.35; p = 0.061) NRS points, respectively, though did not meet the pre-specified value of p = 0.016 required due to multiplicity. An additional post hoc endpoint looking at the change from WO baseline to week 3 in weekly mean of daily average NRS showed the placebo-corrected treatment effect was 1.46 (95% CI: 0.26, 2.66), and 1.20 (95% CI: 0.10, 2.29) NRS points, respectively. Secondary and post hoc analyses of NRS pain data (including 30 & 50% responder rate and NNT), sleep interference, Short-form McGill pain questionnaire (especially pain intensity assessed on Visual Analogue Scale), Patient's and Clinician's Global Impression of Change showed effects consistent with the primary findings. NRD.E1 was well tolerated, with only headache reported in more than two patients and more frequently on NRD.E1 than placebo. CONCLUSIONS: The data suggest that NRD.E1 potentially represents a novel non-opioid therapeutic option for patients with PDPN, with at least similar efficacy and better tolerability than available therapies, justifying its further evaluation in larger-scale confirmatory studies. SIGNIFICANCE: NRD.E1 is a novel non-opioid therapeutic which is being developed for the treatment of PDPN. In this randomized, controlled, dose-finding, Proof of Concept study, NRD.E1 induced a clinically relevant pain reduction and it was well tolerated. Available data suggest that NRD.E1 has at least similar efficacy and better tolerability than the currently available therapies, potentially offering a promising new therapeutic option to patients with PDPN and possibly other neuropathic pain indications.

First-in-Human Single-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1, an Innovative Nonopioid Therapy for Painful Diabetic Peripheral Neuropathy.

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.

Leukocytes and coronary heart disease.

Inflammation has been demonstrated to be an important risk factor for the development of cardiovascular events. Patients with elevated white blood cell counts have been shown to be in a higher risk of developing acute myocardial infarction and acute coronary and vascular events. We review the clinical data of high white blood cell counts and the prognosis, and demonstrate several possible mechanisms. It is possible that measuring white blood cell count and subpopulations could be used for a better way of risk stratification of patients admitted with acute vascular events.

Kidney allografts and remaining contralateral donor kidneys before and after transplantation: assessment by quantitative (99m)Tc-DMSA SPECT.

UNLABELLED: We used (99m)Tc-dimercaptosuccinic acid (DMSA) quantitative SPECT (QDMSA) to assess the function of kidneys before harvesting and after transplantation as well as the function of remaining donor kidneys. METHODS: Nineteen kidney donors underwent a baseline QDMSA study before nephrectomy. The allografts of these kidneys were studied in recipients at 1 wk, 1-2 mo, and 6-15 mo after transplantation. The kidneys remaining in 16 donors were studied at 1-2 mo and 6-15 mo after harvesting. The parameters obtained in each SPECT study included functional volume, concentration of (99m)Tc-DMSA per cubic centimeter of renal tissue, and total kidney uptake. Clinical evaluation and determination of serum creatinine levels took place at the same time as SPECT. RESULTS: On the basis of the clinical evaluation, 14 grafts had normal function and 5 were impaired. The mean +/- SD of kidney uptake values expressed as percentage of baseline values were 131% +/- 30% in normal grafts versus 57% +/- 5% in impaired grafts at 1 wk (P < 0.01), 173% +/- 57% versus 65% +/- 10% at 1-2 mo (P < 0.001), and 190% +/- 50% versus 69% +/- 14% at 6-15 mo after transplantation (P < 0.01). Uptake values in the donors' remaining kidneys were 159% +/- 27% of baseline values at 1-2 mo and 164% +/- 30% at 6-15 mo after nephrectomy. Allografts and remaining kidneys showed a similar increase in total kidney uptake as a result of an increase in both functional volume and concentration. CONCLUSION: QDMSA may be a noninvasive assessment tool in kidney transplantation from living donors.

Coronary stent bacterial infection with multiple organ septic emboli.

We describe an 80-year-old patient who developed Staphylococcus aureus septicemia several days after the implantation of a double stent in the proximal and mid-left anterior descending artery. The infection was complicated by multiple abscesses in the lungs and liver, as well as by bilateral bacterial endophthalmitis requiring right vitrectomy. Long-term antibiotic treatment was successful. Rarity notwithstanding, heightened awareness of this potential complication of a common cardiac procedure is important since diagnosis and immediate therapy are mandatory.

Human erythropoietin gene therapy for patients with chronic renal failure.

Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with erythropoietin. The objective of this study was to develop a therapeutic platform for serum-secreted proteins like erythropoietin. We developed a tissue protein factory based on dermal cores (Biopump) harvested and implanted autologously. In this study, an adenovector was designed to express the human erythropoietin under the control of the cytomegalovirus (CMV) promoter. This vector transduced the harvested dermal cores ex vivo. The transduced cores were implanted, and erythropoietin and reticulocyte counts were measured. Dermal cores were harvested from 13 patients with chronic renal failure, and implantation was performed in 10. There were no significant drug-related side effects to this procedure. Erythropoietin serum levels increased significantly to therapeutic levels from day 1 after implantation reaching a peak during the first week of follow-up. The expression period was transient for up to 14 days. The rise of erythropoietin was followed by a transient significant increase in reticulocyte counts. The decrease of erythropoietin expression coincided with a significant dermal infiltrate of CD8 cytotoxic T cells. Antierythropoietin antibodies were not detected until day 90 following implantation. Implantation of dermal cores ex vivo transduced with human genes could eventually be used in the clinical setting to express therapeutic serum proteins. However, nonimmunogenic delivery system should be tested as gene vehicles.