Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug's pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action. Perioperative Medicine: Efficacy, Safety and Outcom

The ultraviolet B inflammation model: postinflammatory hyperpigmentation and validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy subjects

Background Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitization. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre. In addition, re-evaluation of the UVB inflammation model using a reduced exposure paradigm (2MED) was performed in healthy subjects. Methods In the first study, all 142 subjects previously exposed to 3MED UVB were invited for a clinical evaluation of PIH. In the second study, 18 healthy subjects were exposed to 2MED UVB, and heat pain detection threshold (PDT) and PIH were evaluated. Results In total, 78 of the 142 subjects responded. The prevalence of PIH among responders was 53.8%. In the second study, we found a significant and stable difference in PDT between UVB-exposed and control skin 3 hr after irradiation; 13 hr post-irradiation, the least squares mean estimate of the difference in PDT ranged from -2.6 degrees C to -4.5 degrees C (p < 0.0001). Finally, the prevalence of PIH was lower in the 2MED group compared to the 3MED group. Conclusions The 3MED model is associated with a relatively high prevalence of long-lasting PIH. In contrast, 2MED exposure produces stable hyperalgesia and has a lower risk of PIH and is therefore recommended for modelling inflammatory pain. Significance Postinflammatory hyperpigmentation is an unwanted long-term side effect associated with the UVB inflammation model using the 3x minimal erythema dose (3MED) paradigm. In contrast, using a 2MED paradigm results in hyperalgesia that is stable for 36 hr and has a lower risk of inducing postinflammatory hyperpigmentation.Drug Delivery Technolog

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models

AIMInhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans.METHODSA randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo.RESULTSTwenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64–1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints.CONCLUSIONSThe study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator

Aims A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers.Methods In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.Results LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. C-max, AUC(0-24) and AUC(0-inf) increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.Conclusions These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

De permeabiliteit van rubberachtige stoffen voor gassen

Applied Science