Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrollment randomized withdrawal design. DPN subjects with a pain score ≥ 4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4 weeks. Subjects achieving ≥ 30% pain relief (26/37) were then randomized and treated with either flexible-dose nabilone 1-4 mg/day (n=13) or placebo (n=13) in a further 5-week double-blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P=0.02), with an average nabilone dose at end point of 2.9 ± 1.1mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P<0.05). Nabilone run-in-phase responders reported greater global end-point improvement with nabilone than with placebo (100% vs 31%; P<0.05). Medication-related confusion led to discontinuation in 2/37 subjects during single-blind nabilone treatment. Potential unmasking occurred in 62% of both groups. Flexible-dose nabilone 1-4 mg/day was effective in relieving DPN symptoms, improving disturbed sleep, quality of life, and overall patient status. Nabilone was well tolerated and successful as adjuvant in patients with DPN.
An affinity resin for the F 1 sector of the Escherichia coli ATP synthase was prepared by coupling the b subunit to a solid support through a unique cysteine residue in the N-terminal leader. b 24 -156 , a form of b lacking the N-terminal transmembrane domain, was able to compete with the affinity resin for binding of F 1 . Truncated forms of b 24 -156 , in which one or four residues from the C terminus were removed, competed poorly for F 1 binding, suggesting that these residues play an important role in b-F 1 interactions. Sedimentation velocity analytical ultracentrifugation revealed that removal of these C-terminal residues from b 24 -156 resulted in a disruption of its association with the purified ␦ subunit of the enzyme. To determine whether these residues interact directly with ␦, cysteine residues were introduced at various C-terminal positions of b and modified with the heterobifunctional cross-linker benzophenone-4-maleimide. Cross-links between b and ␦ were obtained when the reagent was incorporated at positions 155 and 158 (two residues beyond the normal C terminus) in both the reconstituted b 24 -156 -F 1 complex and the membranebound F 1 F 0 complex. CNBr digestion followed by peptide sequencing showed the site of cross-linking within the 177-residue ␦ subunit to be C-terminal to residue 148, possibly at Met-158. These results indicate that the b and ␦ subunits interact via their C-terminal regions and that this interaction is instrumental in the binding of the F 1 sector to the b subunit of F 0 .In the process of oxidative phosphorylation or photophosphorylation, the electron transport chain generates a transmembrane proton gradient. The ATP synthase, or F 1 F 0 -ATPase, allows protons to flow down this electrochemical gradient and uses the energy obtained to synthesize ATP (for reviews, see Refs. 1-4). Under appropriate conditions ATP synthase can hydrolyze ATP to pump protons. The enzyme is composed of two sectors; the F 0 sector is membrane-integral and is responsible for proton translocation, and the F 1 sector is attached to the membrane via F 0 and houses the catalytic sites for ATP synthesis. F 1 is easily detached from the membrane and can be purified as a soluble protein with ATPase activity.ATP synthases contain at least eight types of subunits. In the relatively simple enzyme from Escherichia coli, the F 1 sector has the stoichiometry ␣ 3  3 ␥ 1 ␦ 1 ⑀ 1 , whereas F 0 is composed of three subunits of stoichiometry a 1 b 2 c 9 -12 . The a and c subunits, but not b, contain residues essential for the translocation of protons across the membrane (3). The 156-residue b subunit is believed to span the membrane once at its hydrophobic N terminus, whereas the remainder of the protein is very hydrophilic. b is thought to exist as a dimer in the complex (5-7), and proteolysis studies have shown that the hydrophilic region of b is required for the association of F 1 with the membrane (7-9). Removal of two residues from the C terminus of b disrupts normal assembly of the complex (10), as does mut...
Neuropathic pain (NeP) is prevalent in patients with peripheral neuropathy (PN), regardless of etiology. We sought to compare the efficacy of the cannabinoid nabilone as either monotherapy or adjuvant therapy with a first-line medication for NeP, gabapentin, in a patient population with PN-NeP. Patients diagnosed with PN-NeP were permitted to initiate monotherapy (nabilone or gabapentin) or add one of these two medications (adjuvant therapy) to their existing NeP treatment regimen in a non-randomized open-label nature. Baseline data collected included a primary outcome (visual analog scores [VAS] of pain) and secondary outcomes (quality of life [EuroQol 5 Domains and Short-Form 36] assessments and assessments of sleep [Medical Outcomes Sleep Study Scale {MOSSS}], anxiety and depression [Hospital Anxiety and Depression Scale], and pain [Brief Pain Inventory]). Reassessment and modulation of dosing and/or medications occurred at 3- and 6-month intervals. Medication adverse effects and drug efficacy, as well as questionnaires, were assessed at 6 months. Matched analysis of variance testing was performed to compare 3- and 6-month scores with baseline, as well as to compare therapies at equal time points. Significant improvements in pain VAS were seen in all treatment groups at 6 months. Numerous sleep parameters within MOSSS, Brief Pain Inventory, and Short-Form 36 improved in patients receiving nabilone or gabapentin either as monotherapy or adjuvant treatment. Hospital Anxiety and Depression Scale-A scores were significantly improved in all treatment groups. Sleep adequacy and the sleep problems index within the MOSSS improved in nabilone monotherapy patients in particular. The benefits of monotherapy or adjuvant therapy with nabilone appear comparable to gabapentin for management of NeP. We advocate for head-to-head randomized, double-blind studies for current therapies for NeP in order to determine potential advantages beneficial in this patient population.
Background and Purpose: Improving door-to-needle times (DNTs) for thrombolysis of acute ischemic stroke patients improves outcomes, but participation in DNT improvement initiatives has been mostly limited to larger, academic medical centers with an existing interest in stroke quality improvement. It is not known whether quality improvement initiatives can improve DNT at a population level, including smaller community hospitals. This study aims to determine the effect of a provincial improvement collaborative intervention on improvement of DNT and patient outcomes. Methods: A pre post cohort study was conducted over 10 years in the Canadian province of Alberta with 17 designated stroke centers. All ischemic stroke patients who received thrombolysis in the Canadian province of Alberta were included in the study. The quality improvement intervention was an improvement collaborative that involved creation of interdisciplinary teams from each stroke center, participation in 3 workshops and closing celebration, site visits, webinars, and data audit and feedback. Results: Two thousand four hundred eighty-eight ischemic stroke patients received thrombolysis in the pre- and postintervention periods (630 in the post period). The mean age was 71 years (SD, 14.6 years), and 46% were women. DNTs were reduced from a median of 70.0 minutes (interquartile range, 51–93) to 39.0 minutes (interquartile range, 27–58) for patients treated per guideline ( P <0.0001). The percentage of patients discharged home from acute care increased from 45.6% to 59.5% ( P <0.0001); the median 90-day home time increased from 43.3 days (interquartile range, 27.3–55.8) to 53.6 days (interquartile range, 36.8–64.6) ( P =0.0015); and the in-hospital mortality decreased from 14.5% to 10.5% ( P =0.0990). Conclusions: The improvement collaborative was likely the key contributing factor in reducing DNTs and improving outcomes for ischemic stroke patients across Alberta.
Despite the limitations of performing a real-world, uncontrolled study, patients with NeP benefit from enrollment in a small interdisciplinary clinic. Education and a complete diagnostic evaluation are hypothesized to lead to improvements in anxiety and, subsequently, pain severity. Questions remain regarding the long-term maintenance of these improvements and the optimal structure of specialized pain clinics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.