An overview of offset analgesia and the comparison with conditioned pain modulation : a systematic literature review

Background: Offset analgesia (OA) is an increasingly described phenomenon to measure endogenous pain inhibition, in which a greater decrease in pain intensity is experienced than would be predicted by the decrease in painful stimulation. The temporal filtering in this OA phenomenon differs from the spatial filtering in the commonly described conditioned pain modulation (CPM). Yet, the knowledge on the efficacy of OA in chronic pain patients is scarce, compared to CPM efficacy. Objective: This systematic review has been conducted to provide an overview of the current knowledge regarding OA, and to compare it to CPM. Study Design: A systematic review of research studies that investigated the application or mechanisms of OA. Setting: The present study took place at Ghent University and the University of Antwerp. Methods: This systematic review follows the PRISMA guidelines. The electronic databases Pubmed and Web of Science were searched in January 2015. Full text clinical reports addressing OA were included. The checklists for randomized controlled trials, case-control studies, and cohort-studies provided by the Dutch Institute for Healthcare Improvement and the Dutch Cochrane Centre were used to assess methodological quality. The articles received a level of evidence A1, A2, B, C, or D, based on study design and risk of bias. These levels were used to determine the strength of conclusion (level 1 to 4). Results: Seventeen articles met the inclusion criteria. Sixteen studies used quantitative sensory testing to provoke OA; however, differences in protocols are present. OA can function as a non-opioid mediated assessment tool for endogenous pain inhibition, and activates brain regions such as periaqueductal gray (PAG), dorsolateral prefontral cortex, insula, medulla, pons and cerebellum, indicating strong brain derived pain modulation. The primary somatosensory cortex is, conversely, less activated during OA. OA is decreased in neuropathic patients. Nonetheless, evidence for the influence of individual factors on OA is limited. OA and CPM seem to rely on different mechanisms. Limitations: Search strategy was taken wide, wherefore a large variety of research perspectives were included. Conclusions: This systematic review displays OA as a temporal filtering mechanisms that is more brain-derived compared to the spatial assessment method CPM. There is strong evidence for reduced OA in neuropathic patients, however, evidence regarding OA in (sub) acute and central sensitization patients, and the influence of personal factors on OA is currently scarce and needs further investigation

Inventory of personal factors influencing conditioned pain modulation in healthy people: a systematic literature review

Background: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. Methods: This systematic review follows the PRISMA guidelines. Pubmed and Web of Science were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. Results: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. Conclusion: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required

Comparison of effectiveness of cefovecin, doxycycline, and amoxicillin for the treatment of experimentally induced early Lyme borreliosis in dogs

Background While Koch’s postulates have been fulfilled for Lyme disease; causing transient fever, anorexia and arthritis in young dogs; treatment of sero-positive dogs, especially asymptomatic animals, remains a topic of debate. To complicate this matter the currently recommended antibiotic treatments of Lyme Disease in dogs caused by Borrelia burgdorferi require daily oral administrations for 31 days or longer, which makes non-compliance a concern. Additionally, there is no approved veterinary antimicrobial for the treatment of Lyme Disease in dogs in the USA and few recommended treatments have been robustly tested. In vitro testing of cefovecin, a novel extended-spectrum cephalosporin, demonstrated inhibition of spirochete growth. A small pilot study in dogs indicated that two cefovecin injections two weeks apart would be as efficacious against B. burgdorferi sensu stricto as the recommended treatments using doxycycline or amoxicillin daily for 31 days. This hypothesis was tested in 17–18 week old Beagle dogs, experimentally infected with B. burgdorferisensu stricto, using wild caught ticks, 75 days prior to antimicrobial administration. Results Clinical observations for lameness were performed daily but were inconclusive as this characteristic sign of Lyme Disease rarely develops in the standard laboratory models of experimentally induced infection. However, each antibiotic tested was efficacious against B. burgdorferi as measured by a rapid elimination of spirochetes from the skin and reduced levels of circulating antibodies to B. burgdorferi. In addition, significantly less cefovecin treated animals had Lyme Disease associated histopathological changes compared to untreated dogs. Conclusions Convenia was efficacious against B. burgdorferi sensu stricto infection in dogs as determined by serological testing, PCR and histopathology results. Convenia provides an additional and effective treatment option for Lyme Disease in dogs

Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity

Summary: Background This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Methods Sequential patient cohorts (3+3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m2) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n=30) or volasertib/carboplatin (n=31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. Results The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m2 and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Conclusions Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Discovery of sarolaner:A novel, Orally administered, broad-spectrum, Isoxazoline ectoparasiticide for dogs

AbstractThe novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11–12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25–5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs