MD Biosciences, in collaboration with PainReform Ltd and Lahav Research Institute, tested two new anesthetic formulations in the recent publication “Prolonged Analgesic Effect of PRF-108 and PRF-110 on Post-operative Pain in Pigs”, on which MD Biosciences’ CSO Sigal Meilin was the principal author. This article demonstrated how the pig POP model could be used to assess the efficacy of new anesthetic test compounds or new formulations. Results indicate that the tested drug formulations showed great promise over current, commercially available anesthetics.
As we wind down to years end, we at MD Biosciences would like to thank everyone, especially our collaborators, for making this year a success. We have undergone significant growth that we expect to continue throughout the upcoming year.
The pig peripheral neuritis trauma (PNT) model is an important transitional model that bridges the gap between animal research and the clinic. While we discussed how the the pig PNT model shares many morphological and molecular pathology similarities with skin biopsies from human pain conditions in our poster pdf, our chief scientist was the last, principle author in a preceding publication entitled “Peripheral Neuritis Trauma In Pigs: A Neuropathic Pain Model” in the Journal of Pain. In this paper, authors examine this model in terms of how it relates to the human pain response.
Last week, MD Biosciences presented a poster at the Society for Neurosciences 2015 Conference in Chicago. As strong advocates for the use of pig in translational neuropathic pain research, we introduced a new pig proximal peripheral neuritis trauma (PNT) model that shares many similarities in morphological and molecular pathologies with skin biopsies from human pain conditions. This is particularly true in comparisons with patients suffering from persistent area pain conditions such as postherpetic neuralgia (PHN) and complex regional pain syndrome (CRPS) as well as other chronic pain conditions.
The 9th Annual Congress of the European Pain Federation EFIC® was anything but painful as it concluded last week in Vienna with three days of riveting talks. The speakers consisted of expert pain practitioners, scientists, and policy makers who came together with the goal of “translating evidence into practice”.
If you work in drug discovery and development, you are well aware of the failure rate at clinical trials. Industry estimates are that clinical candidates have a 85-90% chance of failure during clinical trials, the most costly stage of evaluation. A report in Nature Biotechnology32,40–51 breaks this success/failure rate down between phases as well as the likelihood of approval from the start of clinical trials. For candidates that are suspended during clinical stages, 83% of these reported efficacy or safety as the reason for suspension.
This is costly and time consuming for drug developers. So is there a way to increase the predictability from preclinical phases to clinical phases? We have been evaluating this question for a number of years in our Research Group at MD Biosciences. Animal models used in preclinical development phases are pivotal for understanding mechanisms that contribute to human disease conditions and effective therapies. Rodent models are commonly employed due to their reproducibility and simplicity, however the predictability to the clinic is often times lacking.
Historically, rodent models have been used for the discovery of various biological mechanisms within disease states as well as preclinical development of therapeutics. Unfortunately there are many ways that the biology of rodents fails to accurately predict the clinical conditions of humans - this is particularly the case in pain therapeutics. This can be evidenced by the estimates that as many as 80% of all drug candidates across therapeutic areas fail in the most expensive stages of development - clinical trials. While the failures can be attributed to various reasons such as insufficient efficacy, unacceptable safety profiles or PK properties. With the high cost of developing new therapeutics, there is certainly the need to validate biological and pharmacological findings in models using larger species, which can also address some of the known differences between rodents and human. The pig is one species which may provide more translatable data to the human condition, particularly in therapeutic areas such as cardiovascular, skin or wound healing conditions, metabolic and pain.
The management of post-operative pain is a challenge for both physicians and patients. In addition to a comfortable recovery, the prevention of chronic pain and improvement of conventional outcomes are important in post-operative pain management.
Management of acute pain related to surgical intervention, termed postoperative pain, continues to be a major problem facing physicians and patients today. The most common method for addressing post-operative pain is through pharmacotherapy. [1,2] Table 1 lists a selection of the most common analgesics used to treat acute surgical pain, their methods of delivery, and the mechanism by which they are thought to act.  Significant progress in the pain management field has been made in recent years mostly in the areas of new delivery methods and multimodal analgesia. Novel drug delivery systems for postoperative pain medications include, for example, patient-controlled analgesia, means of sustained or extended release, transdermal delivery using iontophoresis, and transmucosal and intranasal delivery systems. While a few of these methods may not yet be approved in all geographies, the majority now serve as new tools available to physicians to treat their surgical patients. [1,2] Multimodal analgesia is based on the idea that simultaneous administration of more than one pain therapy strategy offers opportunities for results that are either additive or synergistic. Although clinical data on these types of strategies are still somewhat inconsistent, some clinical trial data do demonstrate improved outcomes and reduced incidence of persistent post-operative pain. 
In the context of neuropathic pain (NP), toll-like receptor member 4 (TLR4) is known to be expressed exclusively on spinal microglia and significantly up-regulated upon peripheral nerve injury. TLR4-knockout mice display reduced effects of chronic chonstriction injury (CCI) induced nerve damage. Similary, TLR4 loss-of-function mutant mice as well as TLR4 antisense oligonucleotide-treated rats both display attenuated neuropathic pain symptoms after nerve damage. Further, intrathecal administration of a TLR4 antagonist after CCI treatment results in relief of neuropathic pain symptoms. Many exogenous and endogenous ligands are known to stimulate TLR4-mediated signaling. However, both in vitro and in vivo studies involving spinal nerve ligation (SNL) treated animals implicate Fibronectin in neuropathic pain-related TLR4 signaling. Fibronectin is an extracellular matrix protein that is commonly produced in response to tissue injury. When administered intrathecally to intact rats, Fibronectin induces microglial up-regulation of the purigenic receptor, P2X4, and symptoms of neuropathic pain. This stimulation of P2X4 expression can be suppressed by interuption of Fibronectin binding the TLR4 receptor after SNL injury in rats.
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