Inflammatory pain

Various pain states (e.g. headache, toothache and migraine), primarily pathophysiological inflammatory pain, e.g. rheumatic pain and pain caused by bone metastases... 

Tendinitis is an inflammatory painful tendon disorder which can be caused by quinolones. Typical cases are characterized by acute onset, palpation and sharp pain mostly of one or both Achilles tendons, but other tendons may also be affected. Magnetic resonance imaging (MRI) is used to support the diagnosis. Estimates for the incidence of quinolone-induced tendinitis range from approximately 1 100 to 1 10,000. The etiology remains unknown, concomitant... 

Compound (20) eventually emerged as an optimized lead (EC50 = 4nM) with satisfactory pharmacokinetic and solubility properties as well as potent activity in animal models of visceral and chronic inflammatory pain [85]. 

Bristol-Myers Squibb has recently disclosed two different series of carbamate-based FAAH inhibitors. The first of these is a series of 4,5-diaryl-imidazoles in which 30 compounds are specifically claimed, an example being compound (57). This compound is reported to have an IC50 value of < 10 nM. In addition, (57) was also active in vivo in rodent models of chemo-induced, thermal and neuropathic pain [72]. The second series of compounds is based on oxime carbamoyl FAAH inhibitors such as (58). Compound (58) is reported to have an IC50 value of < 10 nM and activity in rodent models of inflammatory pain, thermal pain and inflammatory oedema [73]. 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons 933 Peripheral sensitization lowers nociceptor activation threshold 933... 

In this chapter we highlight the mechanisms and neurochemical basis for nociceptive pain as well as the pain that occurs clinically after tissue injury (inflammatory pain) or nerve damage (neuropathic pain). 

Clinical pain is characterized by the presence of spontaneous pain or hypersensitivity to pain-provoking stimuli. Hypersensitivity includes pain produced by low-intensity stimuli that normally only elicit an innocuous sensation (allodynia), or an exaggerated response to a noxious stimulus (hyperalgesia). There are two distinct forms of clinical pain, the pain that occurs after tissue injury or inflammatory diseases (inflammatory pain) and the pain associated with a lesion or disease of the nervous system (neuropathic pain). Although the mechanisms responsible for the initiation and maintenance of these pains differ, they are both characterized by heightened... 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons. The alterations in primary sensory neurons fall into two broad categories (a) a reduction in threshold and an increase in the response of the peripheral terminals of nociceptors (peripheral sensitization), and (b) an alteration in transmitter content modifying synaptic input to the spinal cord. In the dorsal horn, peripheral inflammation results in an increase in membrane excitability and synaptic efficacy, which is the phenomenon of central sensitization [12]. 

Harvey, R. J. et al. GlyR alpha3 an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science 304 884-887, 2004. 

Samad T.A. et al. Interleukin-1-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410 471M75, 2001. 

Of course, it is not always necessary to rely on biomarkers for rapid evaluation of dose-response relationships in ED. Thus, efficacy of new drugs is readily demonstrated in terms of the clinical endpoint for diseases, such as migraine, inflammatory pain, asthma, psoriasis, glaucoma and many others. 

A third basic option available in the case of some therapeutic categories is to develop an over-the-counter version of a product subject to patent expiration. The strategy has been employed for example for anti-inflammatory pain relievers such as Motrin and Naprosyn, anti-ulcer therapies such as the H2 blockers Tagamet and Zantac, proton pump inhibitors such as Prilosec, and in several other therapeutic categories. However, a shift to OTC status requires approval by the FDA that the drug is safe for self-medication (Juhl 2000 McCarran 1991 Schweitzer 1997). A company will normally need to submit new clinical trial evidence to that effect. If approved by the FDA, the company receives a three-year exclusivity period for its OTC product in recognition for the new clinical trial work. 

Evidence from experimental pain research has revealed that mGluRs play a pivotal role in nociceptive processing, inflammatory pain and hyperalgesia. mGluRs have been implicated in dorsal horn neuronal nociceptive responses and pain associated with short-term inflammation (Neugebauer 2002) as well as its emotional component involving hmbic structures such as the amygdala (Han et al. 2004). 

Recently, a third generation of B2-receptor antagonists was developed examples are FR 173657, FR 172357, and NPC 18884. These antagonists block both human and animal B2 receptors and are orally active. They have been reported to inhibit bradykinin-induced bronchoconstriction in guinea pigs, carrageenin-induced inflammatory responses in rats, and capsaicin-induced nociception in mice. These antagonists have promise for the treatment of inflammatory pain in humans. 

Icatibant Selective antagonist of kinin B2 receptors Blocks effects of kinins on pain, hyperalgesia, and inflammation Potential use for inflammatory pain and inflammation... 

---