Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain.

BACKGROUND: Cebranopadol is a potent, first-in-class analgesic with a novel mechanistic approach combining nociceptin/orphanin FQ peptide (NOP) and opioid peptide receptor agonism. OBJECTIVE: We aim to evaluate, for the first time, the analgesic efficacy, safety, and tolerability of cebranopadol in patients suffering from moderate to severe acute pain following bunionectomy. STUDY DESIGN: We conducted a phase IIa, randomized, multi-center, double-blind, double-dummy, placebo- and active-controlled, parallel group clinical trial. METHODS: A total of 258 patients who underwent a primary bunionectomy were randomly assigned to receive a single oral administration of cebranopadol 200 µg, 400 µg, or 600 µg, morphine controlled-release (CR) 60 mg, or placebo. The primary efficacy end-point was the sum of pain intensity (SPI) 2 to 10 hours (SPI2-10) after the first investigational medicinal product (IMP) intake time-point. RESULTS: Cebranopadol doses of 400 µg and 600 µg were more effective in reducing postoperative acute pain compared to placebo, from 2 hours until approximately 22 hours after the first IMP intake time-point. No difference was observed between cebranopadol 200 µg and placebo. Per the subject global impression of the IMP assessment, patients who received cebranopadol 400 µg and 600 µg were more satisfied with the ability of the medication to treat their pain compared to those who received morphine CR 60 mg. On the primary end-point, the effect of morphine CR 60 mg was smaller than that of cebranopadol 400 µg and 600 µg. However, the analgesic effect of morphine CR 60 mg emerged later relative to IMP intake, as shown by the fact that similar SPI results as seen for cebranopadol 400 µg and 600 µg were obtained for later time windows. Cebranopadol treatment was safe, and single-dose administrations of 400 µg were better tolerated than morphine CR 60 mg. The relative frequency of patients with at least one treatment-emergent adverse event (TEAE) increased with increasing cebranopadol doses and was highest in the morphine CR 60 mg group. LIMITATION: Although a double-dummy design was used to ensure blinding, a limitation of this trial was that cebranopadol and morphine CR were administered at 2 different time-points post-surgery, given the anticipated difference in the time to reach the maximum plasma concentration between the 2 treatments. CONCLUSION: Administration of single cebranopadol doses of 400 µg and 600 µg induced more effective analgesia following bunionectomy surgery compared to the traditional opioid morphine on the primary end-point (SPI2-10), while both cebranopadol doses and morphine ensured adequate 24-hour pain relief. Moreover, cebranopadol was better tolerated and received a better overall rating by the patients. KEY WORDS: Opioids, morphine, µ-opioid receptor, nociceptin/orphanin FQ peptide receptor, analgesic, bunionectomy, surgery, post-operative pain, single hallux valgus repair.

Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Highly efficient virus-induced gene silencing (VIGS) in California poppy (Eschscholzia californica): an evaluation of VIGS as a strategy to obtain functional data from non-model plants.

BACKGROUND AND AIMS: Eschscholzia californica (California poppy) is an emerging model plant for 'evo-devo' studies from the basal eudicot clade of Papaveraceae. California poppy has a relatively small genome, a short life cycle and, most importantly, it is amenable for transformation. However, since this transformation protocol is time consuming, virus-induced gene silencing (VIGS) was evaluated as a fast method to obtain functional data for California poppy genes. METHODS: Commercially available California poppy plants were infiltrated with Agrobacterium tumefaciens carrying the tobacco rattle virus plasmids pTRV1 and pTRV2. pTRV2 contained part of the eschscholzia Phytoene Desaturase (EcPDS) gene whose loss of function results in photobleaching of the green parts of the plant and in a lack of floral coloration. The degree and duration of these symptoms was evaluated for vegetative rosettes and plants in flower. KEY RESULTS: It is shown that VIGS is able to effectively down-regulate the EcPDS gene in eschscholzia. Various degrees of silencing were observed starting <2 weeks after infiltration with Agrobacterium tumefaciens in 92 % of the plants. Tissue with silencing symptoms also showed complete or strong reduction of EcPDS transcripts. Strong silencing resulted in almost completely white petals, fruits, shoots and leaves. Plants with a strong degree of silencing will eventually die off; however, others are able to produce EcPDS gene product even after a strong initial silencing and will recover. Silencing was found to be not always systemic, but was often restricted to certain organs or parts of organs. CONCLUSIONS: VIGS is an effective, fast and transient method to down-regulate gene expression in eschscholzia. It serves well to detect prominent phenotypes which may become obvious even if some target gene transcript remains in the plant tissue. However, subtle phenotypes will be more difficult to detect, as extremely strong silencing effects occur in <10 % of all flowers from infected plants.