Mark J Field

• Doctor of Philosophy
• CEO at Eptiva Therapeutics

The present disclosure is directed to a platform for linking therapeutic compounds to pain phenotypes/conditions and thereby identifying potential novel analgesic therapies. The platform can generate patient selection criteria and/or identify a subset of patients that would be suitable for a clinical trial related to the selected therapeutic compou...

Disclosed are methods for the treatment of peripheral neuropathic pain disorders associated with keratin dysregulation via localized, topical administration of calcitriol and/or calcitriol analogues. Such keratin-related peripheral neuropathic pain disorders include pachyonychia congenita, Olmsted syndrome, and other disorders involving palmoplanta...

Chronic pain is a huge burden to patients and society as a whole with a lack of safe and effective analgesic treatments Innovation in the pain area is extremely low with few new medicines reaching patients due to exceptionally high attrition rates in R&D. New transformative approaches for pain drug development are required to improve the probabilit...

Overviewing the impact of pain and its huge global burden. Why pain is an area with some of the LOWEST R&D success rates. Learning what factors are hindering analgesic development. Highlighting how developing precision analgesics can radically improve probability of success.

To determine the feasibility of complex home-based phenotyping, 1,876 research participants from the customer base of 23andMe completed an online version of a Pain Sensitivity Questionnaire (PSQ) as well as a cold pressor test (CPT) which is used in clinical assessments of pain. Overall our online version of the PSQ performed similarly to the origi...

Our pain detecting sensory system is an essential part of our body, keeping us safe, away from harm and aiding the healing process when we are injured. However, in various circumstances this system can malfunction and we are left suffering chronic pain. THE PAIN PARADOX “THE SENSORY SYSTEM THAT PROTECTS US FROM HARM CAN MALFUNCTION AND CAUSE US CHR...

To determine the feasibility of complex home-based phenotyping, 1,876 research participants from the customer base of 23andMe participated in an online version of a Pain Sensitivity Questionnaire (PSQ) as well as a cold pressor test (CPT) which is used in clinical assessments of pain. Overall our online version of the PSQ performed similarly to the...

“Patient-Inspired R&D: The Missing Part of Patient Engagement”

Analgesic trials frequently fail to demonstrate efficacy of drugs known to be efficacious. Poor pain reporting accuracy is a possible source for this low essay-sensitivity. We report the effects of Accurate-Pain-Reporting-Training (APRT) on the placebo response in a trial of Pregabalin for painful-diabetic-neuropathy. The study was a two-stage rand...

Asentral Inc IRB approved protocol. (PDF)

Per protocol dataset. (XLSX)

Approaching pain as a disease – not just a symptom; Mapping the landscape of pain; Using a target-to-disease approach to identify novel compounds for development

A two-week, in-patient Phase 2a trial in patients with peripheral neuropathy.

Peripheral nerve injury is associated with a spinal microglial response that has been correlated with the development of behaviours reflective of neuropathic pain. To examine whether this phenomenon is generalizable to neuropathic pain of non-traumatic aetiology, this study investigated the association between spinal microgliosis and behavioural me...

This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grünenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from...

Chronic neuropathic pain is a common condition which is challenging to treat. Many people with neuropathic pain are managed in the community, so primary care records may allow more appropriate subjects to be recruited for clinical studies. We investigated whether primary care records can be used to identify patients with diseases associated with ne...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h prega...

The instant invention relates to a combination, particularly a synergistic combination, of an alpha-2-delta ligand and a dual serotonin-noradrenaline re-uptake inhibitor (DSNRI) or one or both of a selective serotonin re-uptake inhibitor (SSRI) and a selective noradrenaline re-uptake inhibitor (SNRI), and pharmaceutically acceptable salths thereof,...

A range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.

Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. The pharmacokin...

A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with...

EFFECT OF OXYCODONE AND IBUPROFEN ON UV-INDUCED HEAT THRESHOLDS AND MECHANICAL PAIN IN HUMAN VOLUNTEERS

UV burn model can be used both preclinically and clinically with similar results from standard analgesics

Microgliosis is implicated in the pathophysiology of several neurological disorders, including neuropathic pain. Consequently, perturbation of microgliosis is a mechanistic and drug development target in neuropathic pain, which highlights the requirement for specific, sensitive and reproducible methods of microgliosis measurement. In this study, we...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Pregabalin, a 3-substituted analogue of gamma-amino butyric acid has recently been approved for treatment of neuropathic pain. We have investigated the anatomical binding profile of [(3)H] pregabalin following chronic constriction injury (CCI) and compared this with alpha 2 delta 1 subunit expression using in situ hybridisation. We report here that...

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics suc...

A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabap...

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prep...

Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Spra...

Gabapentin [l-(aminomethyl)cyclohexaneacetic acid; Neurontin] is a cyclic y-aminobutyric acid (GABA) analogue with ability to penetrate into the CNS. However, it does not interact with GABA receptors (1). It was originally synthesized to treat spasticity, but is currently in clinical use as an add-on therapy in patients with partial and generalized...

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against st...

This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhib...

The present study examines the effect of pregabalin (previously S-Isobutylgaba and CI-1008) in two distinct rat models of anxiety. Pregabalin binds with high affinity and selectivity to the α2δ subunit of voltage dependent calcium channels (VDCC). Its corresponding R-enantiomer (R-isobutylgaba) is approximately 10 fold weaker. Pregabalin dose-depen...

Ovariohysterectomy in the rat led to the induction of abdominal postures and referred mechanical allodynia in the hind paws. The latter was differentiated into static and dynamic subtypes. The abdominal postures were present up to 4-5 h, whilst the two types of allodynia lasted for at least 2 days. A single administration of morphine 30 min before...

Current analgesic therapy is dominated by NSAIDs and opiates, however these agents have limited efficacy in the treatment of neuropathic pain. The novel anticonvulsant agent gabapentin (Neurontin) has been shown to be an effective treatment for neuropathic pain in the clinic. Recent studies have demonstrated that gabapentin selectively interacts wi...

CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin respons...

In the present study, chronic constrictive injury (CCI model) of the sciatic nerve or tight ligation of L5 and L6 spinal nerves (Chung model) produced both dynamic and static components of mechanical allodynia in rats. The two responses were detected, respectively, by lightly stroking the hind paw with cotton wool or application of pressure using v...

A series of conformationally restricted Gabapentin analogues has been synthesised. The pyrrolidine analogue (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (3a) had an IC50 of 120 nM, similar to that of Gabapentin (IC50 = 140 nM), at the Gabapentin binding site on the alpha2delta subunit of a calcium channel. Compound (3a) also reversed...

A single injection of streptozocin (50 mg/kg, i.p.) led to the development of static and dynamic allodynia in the rat. The two responses were detected, respectively, by application of pressure using von Frey hairs or lightly stroking the hind paw with a cotton bud. Static allodynia was present in the majority of the animals within 10 days following...

Enadoline is a highly selective and potent kappa-opioid receptor agonist. This report describes and compares the activities of enadoline and morphine in a rat model of postoperative pain. A 1 cm incision through the muscle and skin of the plantar surface of the right hind paw induced thermal hyperalgesia as well as static and dynamic allodynia last...

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with...

PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph) is a selective tachykinin NK1 receptor antagonist. Its effect on development and maintenance of thermal and mechanical hypersensitivity was examined in a rat model of surgical pain. When administered 30 min before surgery, PD 154075 dose-dependently (3-100 mg/kg, s.c.) prevented t...

We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and l...

We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low...

The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post‐withdrawal. This ethanol‐induced inc...

Gabapentin and S-(+)-3-isobutylgaba are anticonvulsant agents that selectively interact with the alpha2delta subunit of voltage-dependent calcium channels. This report describes the activities of these two compounds in a rat model of postoperative pain. An incision of the plantaris muscle of a hind paw induced thermal hyperalgesia and tactile allod...

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2 delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates...

Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to eva...

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies,...

This study uses immediate early transcription factor gene expression to map neuronal activation after a single exposure to the elevated X-maze. Exposure to this novel environment leads to widespread upregulation in the gene expression of c-fos, NGFI-A and NGFI-B (the nerve growth factor induced genes), but not c-jun nor jun B as shown by in situ hy...

This report describes the activity of the antiepileptic agent gabapentin (Neurontin) in animal models predictive of anxiolysis and analgesia. Gabapentin displayed anxiolytic-like action in the rat conflict test, the mouse light/dark box and the rat elevated X-maze with respective minimum effective doses (MEDs) of 3, 10 and 30 mg/kg. Furthermore, ga...

The ability of a mixed CCKA/B receptor antagonist PD 142898 (benzenebutanic acid, beta-[[3-(1 H-indol-3-yl)-2-methyl-2-[[[(2-methyl- cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1 S-[1 alpha [S*(R*)]-2 beta]]) to modulate the antinociceptive, positive reinforcing and gastrointestinal actions of morphine was investigated in the rat. PD 142898...

1. The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2. PD 140548 dose-dependently (0.001-1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0...

Several novel cholecystokinin (CCK) receptor ligands with differing degrees of receptor selectivity were characterised in both in vitro and in vivo models. In radioligand binding assays, the dipeptoid PD 135666 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino],-[R-(...

The ability of a selective cholecystokininB (CCKB) receptor antagonist, CI-988, to block benzodiazepine withdrawal effects was examined in mice. The discontinuation of twice daily administration of diazepam (1 mg kg-1, i.p.) induced withdrawal anxiogenesis and a proconvulsant effect. In contrast, no such effects were seen following withdrawal from...

The behavioural effects of a selective cholecystokinin B (CCK B ) receptor antagonist CI‐988 were investigated in rodents. In three rodent tests of anxiety (rat elevated X‐maze, rat social interaction test and mouse light/dark box) CI‐988 over the dose range 0.001–10.0 mg kg ⁻¹ , (i.p.) produced an anxiolytic‐like action. The magnitude of this effe...

A scopolamine-like delay-dependent impairment in spatial delayed response performance in rhesus monkeys was induced by irrelevant interpolated activity or by using extended retention intervals. Physostigmine readily reversed the effects of scopolamine but had no effect on performance in young monkeys performing an irrelevant distractor task or in m...

The effect of neuropeptide cholecystokinin (CCK) receptor agonists and antagonists was examined in the rat elevated X-maze model of anxiety. The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200....

Cognitive facilitation by physostigmine and tetrahydroaminoacridine (THA) was compared in two primate models. Disruption of spatial delayed response performance by scopolamine (0.03 mg/kg) was fully reversed by coadministration of 5 doses of physostigmine in the range 0.03-0.08 mg/kg, but by only one dose (4.0 mg/kg) of THA; partial reversal of som...

The ability of four central cholinomimetics to reverse a scopolamine-induced spatial memory impairment or to improve visual recognition memory in primates was examined. Physostigmine (0.04-0.08 mg/kg IM) fully reversed the effects of scopolamine (0.03 mg/kg). Coadministration of pilocarpine (3.0-5.0 mg/kg) caused partial reversal of the scopolamine...