An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee

@article{Huggins2012AnER,
  title={An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee},
  author={John P. Huggins and Trevor S. Smart and Stephen R. Langman and Louise Taylor and Tim Young},
  journal={PAIN{\textregistered}},
  year={2012},
  volume={153},
  pages={1837-1846}
}
A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Phase I Study of Analgesic/Antihyperalgesic Properties of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Healthy Female Subjects
TLDR
AS8477 was well tolerated in this study and showed significant effects on down-scoring the VAS pain score and a significant difference in LEP for ASP8477 100 mg over placebo but did in subjects who demonstrated positive capsaicin skin effects.
Prostatic Diseases and Male Voiding Dysfunction Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis / Chronic Pelvic Pain Syndrome : An Adaptive Double-blind , Randomized Controlled Trial
OBJECTIVE To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome
Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase
TLDR
The design and synthesis of a novel series of heterocyclic‐N‐carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs).
The MOBILE Study—A Phase IIa Enriched Enrollment Randomized Withdrawal Trial to Assess the Analgesic Efficacy and Safety of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Patients with Peripheral Neuropathic Pain
TLDR
ASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo.
Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase.
TLDR
An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial, and the underlying mechanism of this toxic cerebral syndrome remains unknown.
NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain
TLDR
NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception, in this exploratory study.
Brain permeant and impermeant inhibitors of fatty‐acid amide hydrolase suppress the development and maintenance of paclitaxel‐induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro
TLDR
It is suggested that FAAH inhibitors reduce pac litaxel‐induced allodynia without the occurrence of CB1‐dependence in vivo and may, in fact, enhance the anti‐tumor actions of paclitaxel in vitro.
Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double-Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers
TLDR
V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs, and maximum increases in plasma EC's occur with V1588 66 doses of 300–500 mg/day.
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Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects.
TLDR
FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg, and there was no evidence of effects of PF-04457845 on cognitive function.
Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen.
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Single daily doses of valdecoxib 5 mg and 10 mg were well tolerated and demonstrated improved GI tolerability compared to naproxen, in treating symptomatic OA of the hip.
Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial.
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In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo and no major adverse effects were observed.
Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial
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Dronabinol has a modest but clinically relevantanalgesic effect on central pain in patients with multiple sclerosis and on the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo.
Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee.
TLDR
AZD3582 375 mg and 750 mg twice a day were superior to placebo and as effective as rofecoxib 25 mg/day in treating the signs and symptoms of OA of the knee.
The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice
TLDR
Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content, which reinforce the proposed role of FAAH as a target for analgesic drug development.
Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain
TLDR
Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.
Comparative Efficacy and Safety of Celecoxib and Naproxen in the Treatment of Osteoarthritis of the Hip
TLDR
Celecoxib at a dose of 200 mg/day is as effective as a standard therapeutic dose of the conventional NSAID, naproxen, in reducing the pain associated with OA of the hip.
Reversible Inhibitors of Fatty Acid Amide Hydrolase That Promote Analgesia: Evidence for an Unprecedented Combination of Potency and Selectivity
TLDR
A class of α-keto-heterocycles are identified that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation.
Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders
TLDR
This review highlights advances in the development of FAAH inhibitors of different mechanistic classes and their in vivo efficacy, selectivity and drug-like pharmacokinetic properties.
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