FARMACI PER IL DOLORE CRONICO E LA CEFALEA: NOVITA’ IN CANTIERE

FARMACI IN CANTIERE
BASI PER I NUOVI FARMACI CONTRO IL DOLORE CRONICO E L’EMICRANIA

Contributi dai membri della Fondazione

Nicolodi M., Volpe AR. , Torcia S., Spillantini MG. Fibromialgia: Aspetti Clinici , Meccanismi Neurobiochimici/Ormonali – Un circuito di interconnessioni. Proceedings XXIV Congresso SISC, Caserta 2010

Nicolodi M., Spillantini M. G.,Sicuteri F. & Del Bianco E. NGF and SP in the saliva of migraine sufferers using FANs daily Cephalalgia Vol. 23 (7) pp. 641, 2003
Nicolodi M. Interaction of EAAs and gabaergic system. Int. J. Clin. Pharmacol. Res., XVIII (2): 79-85, 1998
Nicolodi M. Nostril capsaicin application as a model of trigeminal primary sensory neurons activation. Cephalalgia 14:134-138, 1994
Nicolodi M, Volpe AR, Porcelli G, Sicuteri R, , Curradi C, Sicuteri F. Coupling between nitric oxide level and inheritable hyperalgesia characterizes migraine diathesis. In: F Clifford Rose (ed) Advances in Headache Research: 4, London: Smith-Gordon p 115-120, 1994
Nicolodi M. Neurogenic inflammation speculated through the changes of salivary substance P and calcitonin gene-related Peptide. The semantic ford of idiopathic headaches. Catania 10-12 ottobre 1991, p 37

Nicolodi M., Del Bianco E. Sensory neuropeptides (substance P, calcitonin gene-related peptide) and vasoactive intestinal polypeptide in human saliva: their pattern in migraine and cluster headache. Cephalalgia 10: 39-50,1990

Caleri D, Nicolodi M, Andreini R, Curradi C, Sicuteri F. Effects of glucagon on plasma cyclic AMP in headache. Cephalalgia 7(6): 151-153, 1987

Contributi dall’estero

HCN2 CHANNELS E AMP CICLICO
DOLORI CRONICI NEUROPATICI

Science. 2011 Sep 9;333(6048):1462-6.
HCN2 ion channels play a central role in inflammatory and neuropathic pain.
Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA.
Source
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Abstract
The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.

CGRP E ANTAGONISTI CGRP
SPECIFICI CONTRO LA CEFALEA, SVILUPPATI COME ANTIEMICRANICI

The Lancet, Volume 372, Issue 9656, Pages 2115 – 2123, 20 December 2008
doi:10.1016/S0140-6736(08)616g26-8 Cite or Link Using DOI
This article can be found in the following collections: Neurology (Headache & migraine)
Published Online: 25 November 2008
Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial
Dr Tony W Ho MD a , Prof Michel D Ferrari MD b, Prof David W Dodick MD c, Vince Galet PhD a, James Kost PhD a, Xiaoyin Fan PhD a, Heather Leibensperger BS a, Samar Froman BS a, Christopher Assaid PhD a, Christopher Lines PhD a, Hille Koppen MD b, Paul K Winner DO d

The antagonists-CGRP receptors, are a new class of drugs which is expected in a short time the availability for the acute treatment of migraine. The GCRP can probably play an important role in the pathophysiology of migraine and cluster headache. Occurs in the trigeminal ganglia and has a dilation of cerebral and dural vessels. During attacks of migraine and headache in clusters, were measured high concentrations of GCRP in jugular venous blood and saliva. GCRP-receptor antagonists have been developped for the treatment of migraine chiefly; they do not act as vasoconstrictive compounds. Thus, they may represent a treatment option for patients with comorbid vascular diseases.
Mechanism of action
The manuscript by Goadsby and co-workers presents results that indicate that CGRP has a role in mediating nociceptive information in the cerebrovascular circulation. Indeed, the manuscript provides evidence that two CGRP receptor antagonists (BIBN4096BS and CGRP8–37) inhibit neurons in the trigeminocervical complex following peripheral activation by stimulation of the superior sagittal sinus and activation by locally applied glutamate.

CGRP-receptor antagonists have demonstrated efficacy in migraine attacks: In a study1 randomized double-blind, placebo-controlled iv was effective application Olcegepant CGRP-antagonists. The CGRP antagonist telcagepant applied orally, in a randomized double-blind controlled doses of 300-600 mg HAD similar efficacy as rizatriptan 10 mg and more effective than placebo2. In a study3 controlled trial, 300 mg of telcagepant was just as effective as 5 mg of zolmitriptan and more effective than telcagepant 150 mg or placebo. In this study near 700 patients were treated with telcagepant.
Problems:
In another study on prophylaxis, in a small number of patients, were found elevated liver values every day taking this substance, which has delayed admission for telcagepant and that could have an overall effect on the substance.
Thus it is expected, after the approval of telcagepant and / or other CGRP antagonist a new treatment option for migraine, which probably will be used in patients with vascular disease. By a different mechanism of action, the GCRP-receptor antagonists may possibly be an alternative in patients unresponsive to triptans. Therefore, there are other provisions and possibilities in this respect (see Triptans).

Gli antagonisti CGRP-ricettori, sono una nuova classe di sostanze di cui si prevede in breve tempo la disponibilità per il trattamento acuto dell’emicrania. Il GCRP probabilmente può giocare un importante ruolo nella patofisiologia dell’emicrania. Si libera nei gangli trigeminali e ha la capacità di dilatare i vasi cerebrali e durali. Durante gli attacchi di emicrania e cefalea a grappolo, sono state misurate elevate livelli di GCRP nel sangue venoso iugulare e nella saliva. Gli antagonisti del GCRP-recettore sono stati sviluppati per la terapia dell’emicrania; essi non agiscono in modo vasocostrittivo e potrebbero pertanto rappresentare un’opzione di trattamento per pazienti con malattie vascolari comorbide.

CGRP-receptor antagonists have demonstrated efficacy in migraine attacks: In a study randomized double-blind, placebo-controlled iv was effective administration CGRP-antagonists Olcegepant. The CGRP antagonist telcagepant administered orally, in a randomized double-blind controlled doses of 300-600 mg had similar efficacy as rizatriptan 10 mg and is more effective than placebo2. In a study3 controlled trial, 300 mg of telcagepant was as effective as 5 mg of zolmitriptan and more effective than telcagepant 150 mg or placebo. In this study nerar 700 patients were treated with telcagepant.

Gli antagonisti CGRP-ricettori hanno dimostrato efficacia negli attacchi di emicrania: in uno studio1 randomizzato in doppio cieco e controllato con placebo, risultava efficace un’applicazione i.v. di CGRP-antagonisti Olcegepant. Il CGRP-antagonista Telcagepant applicato oralmente, in uno studio controllato randomizzato in doppio cieco con dosaggi di 300-600 mg si dimostrava che questi avevano un’efficacia simile al Rizatriptan 10 mg e maggiore del placebo. In uno studio3 controllato randomizzato, 300 mg di Telcagepant risultava altrettanto efficace quanto 5 mg di Zolmitriptan e più efficace di Telcagepant 150 mg o placebo. In questo studio sono stati trattati quasi 700 pazienti con Telcagepant.

In un altro studio sulla profilassi, in un piccolo numero di pazienti, sono stati trovati dei valori epatici elevati assumendo giornalmente tale sostanza, cosa che ha fatto ritardare l‘ammissione per il Telcagepant e che potrebbe avere un effetto deterrente sull’uso sulla sostanza.

Così é previsto, dopo l’approvazione di Telcagepant e/o di un altro CGRP antagonista , vi sia una nuova opzione di trattamento per l’emicrania, la quale probabilmente verrà usata anche in pazienti con malattie vascolari. Da un differente maccanismo di azione, gli GCRP-ricettori-antagonisti probabilmente potrebbe derivare un’alternativa in pazienti che non rispondono ai triptani. È quindi vi sono altre possibilità riguardo l’impiego di tali farmaci nei confronti di altri già in commercio (vedi Triptani).

Riferimenti selezionati:
1. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;350:1104-10.
2. Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70:1304-12.
3. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 2008;372:2115-23.

NGF e ANTAGONISTI NGF
DOLORI CRONICI
Targeting nerve growth factor in pain: what is the therapeutic potential?
Watson JJ, Allen SJ, Dawbarn D.
Source
University of Bristol, Bristol, UK.
Abstract
Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
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Volume 79, Issue 2 , Pages 265-274, 1 February 1999
Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve
• Long-Sun Ro
,
• Sien-Tsong Chen
,
• Lok-Ming Tang
,
• Jean M. Jacobs
Received 10 September 1997; received in revised form 12 August 1998; accepted 25 August 1998.
• Abstract
• Full Text
• PDF
• Images
• References
Abstract
The systemic administration of anti-nerve growth factor (NGF) antibodies can prevent local sensory hypersensitivity and block nociceptive fibers from sprouting into denervated adult rat skin. However, in the case of chronic constriction injury (CCI) in a rat, there is evidence that NGF reverses some effects of axotomy and alleviates thermal hyperalgesia. It is with this in mind that we investigated the influence of local anti-NGF and NGF on neuropathic pain and collateral sprouting caused by CCI. In our study, we looked at the effects to the ligated nerves after 30 consecutive days of local injections of anti-NGF and NGF. A high-dose of anti-NGF (1800 ng) was found to eradicate heat and cold hyperalgesia during postoperative days 16–28 and from days 8 to 34 after CCI, respectively. Our results show that a low-dose anti-NGF (18 ng) only mildly alleviates heat hyperalgesia but not cold hyperalgesia. There is evidence that a rebound phenomenon occurs for a short period of time after the anti-NGF injections cease. Results show that anti-NGF injections, whether in a high or low dose, significantly reduces the severity of autotomy or prevents the spread of collateral sprouting from the saphenous nerve into the sciatic innervation territory. In contrast, when a NGF (0.75 ng/g body weight) was applied to the ligated nerve immediately after the ligation, heat and cold hyperalgesia were eradicated during postoperative days 4–68 and from days 4 to 28, respectively. The results show that the effect of anti-NGF is delayed at the onset, is short in duration, and is dependent on the dosage. However, anti-NGF but not NGF blocked collateral sprouting and decreased the severity of autotomy, suggesting that anti-NGF may be a better potential alternative analgesic for the treatment of neuropathic pain in humans. The different initiation times to abolish thermal hyperalgesia by anti-NGF (delayed onset) and NGF (early onset) suggests that alterations in neurotrophic factors contribute to the development of behavioral hyperalgesia via a complex mechanism in CCI rats.

Il fattore di crescita dei nervi (NGF) gioca un ruolo cruciale nella generazione del dolore ed iperalgesia in molti stati dolorosi acuti e cronici. Antagonizzare l’NGF è uno dei nuovi approcci nello sviluppo di farmaci contro il dolore. Molti anticorpi specifici per NGF sono in studi di fase di sperimentazione, inclusi il tanezumab (Pfizer), SAR164877/REGN475 (Sanofi-Aventis/Regeneron) e JNJ-42160443/AMG403 (Johnson & Johnson/Amgen). Se approvato (forse nel 2012), tanezumab della Pfizer sarà verosimilmente il primo biologico per il trattamento del dolore cronico, e potrebbe diventare il primo farmaco della categoria ad essere approvato

The nerve growth factor (NGF) plays a crucial role in the generation of pain and hyperalgesia in several acute and chronic pain states. Antagonize the NGF is one of the new approaches in the development of drugs for pain. Many NGF-specific antibodies are in Phase II / III, including tanezumab (Pfizer), SAR164877/REGN475 (Sanofi-Aventis/Regeneron) and JNJ-42160443/AMG403 (Johnson & Johnson / Amgen). If approved (perhaps in 2012), tanezumab Pfizer will be the first biologic for the treatment of chronic pain

Targeting nerve growth factor in pain: what is the therapeutic potential?
Watson JJ, Allen SJ, Dawbarn D.
Source
University of Bristol, Bristol, UK.
Abstract
Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
Anticorpi anti NGF(Nerve Growth Factor) di sintesi contro il dolore son stati messi a punto e dimostrati quali proteine capaci di bloccare in modo selettivo l’azione della proteina NGF, il fattore di crescita
nervoso scoperto dal Premio Nobel Rita Levi Montalcini, interrompendo la serie
di reazioni cellulari che portano al dolore. ”I test sugli animali dell’Mnac13,
questo il nome dell’anticorpo monoclonale, hanno dato risultati veramente incoraggianti sia sul
dolore infiammatorio che su quello neuropatico senza manifestare effetti
collaterali nell’animale da laboratorio
Se i test clinici saranno altrettanto positivi entro qualche anno
potremmo avere gia’ i primi farmaci”. L’azione degli anticorpi monoclonali, cioe’
sintetizzati in laboratorio, e’ simile a quella degli anticorpi naturalmente presenti
nell’organismo, cioe’ il ‘sequestro’ di molecole, che per i secondi sono agenti
infettanti esterni. ”Nel nostro caso le molecole da sequestrare seguendo l’obiettivo dell’anticorpo e’
l’ NGF. Il nostro anticorpo lega il recettore, e gli impedisce di legarsi al fattore di crescita”. I test effettuati hanno dimostrato che l’anticorpo e’ in grado di indurre un innalzamento della soglia di
sensibilita’ al dolore in un modello di sofferenza legata alle infiammazioni, simile
al dolore postoperatorio, e un durevole effetto analgesico anche sul dolore
neuropatico, caratteristico di numerose neuropatie cliniche come la neuropatia posterpetica e altre che son protagoniste del dolore cronico

A ‘synthetic antibody’ against pain ‘was made
and studied, it has shown that the protein tuning blocks so
selective action of NGF (Nerve Growth Factor), the growth factor
nervous discovered by Nobel laureate Rita Levi Montalcini, interrupting the series
of cellular reactions that lead to pain. ” Animal testing Mnac13, the monoclonal antibody, have yielded excellent results on neuropathic pain without manifesting side effects. Next step will be clinical trials. If they are equally positive in a few years
we will have ‘the first drugs”. The action of monoclonal antibodies, ie ‘
synthesized in the laboratory, is ‘similar to that of naturally occurring antibodies
in the organism, ie, ‘the’ capture ‘of molecules, which are agents for the seconds
external infectious. ” In our case the target of the antibody is’
the NGF. Antibody binds receptor, and prevents it from binding to the growth factor.” Animal tests have demonstrated that the antibody is capable of inducing an increase in the threshold of
sensitivity ‘to pain in an animal model , and also a durable analgesic effect on pain neuropathic, characteristic of many clinical neuropathies such as postherpetic neuralgia

COX E NOS INIBIZIONE
DOLORI CRONICI
Capnellene, a natural marine compound derived from soft coral, attenuates chronic constriction injury-induced neuropathic pain in rats.
by Yen-Hsuan Jean, Wu-Fu Chen, Chun-Sung Sung, Chang-Yih Duh, Shi-Ying Huang, …show all authors
Biological Sciences › Miscellaneous Papers
• Overview
• References5
• Related research
British journal of pharmacology (2009)
Volume: 158, Issue: 3, Publisher: Blackwell Publishing Ltd, Pages: 713-725
• DOI: 10.1111/j.1476-5381.2009.00323.x
• PubMed: 19663884
Available from www.pubmedcentral.nih.gov
or
Abstract
BACKGROUND AND PURPOSE: Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopentapentalene-2,3a-diol (GB9) exhibited anti-inflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopentapentalen-2-yl ester (GB10). EXPERIMENTAL APPROACH: Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-gamma (IFN-gamma)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry. KEY RESULTS: In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-gamma. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury. CONCLUSION AND IMPLICATIONS: Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-gamma-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.

Da un corallo deriva il principio che reca sollievo contro il dolore cronico ovvero il dolore neuropatico che può destruire la qualità di vita. Un composto estratto dal corallo Capnella imbricata, il capnellene, ha dimostrato effetti contro il dolore molto specifici in modelli animali di dolore neuropatico, come spiegato sul British Journal of Pharmacology (vedi Abstract all’inizio del sottocapitolo).

Il dolore neuropatico è una forma di dolore cronico per cui si percepisce dolore, molto forte, anche in risposta a stimoli di per sé non dolorosi nell’individuo sano. In pratica, mentre di norma sentiamo dolore in seguito a stimoli dolorosi sul nostro corpo che sono trasferiti da nervi periferici al midollo spinale, quindi al cervello, in chi soffre di dolore cronico questa trasmissione risulta alterata, per cui ai centri neurali del dolore arriva informazione “Dolore Forte” anche per stimoli che di per sé non sono affatto dolorosi.

Per ora ci sono pochissimi veramente pochissimi farmaci contro il dolore cronico, e i semplici analgesici son specifici in senso generale per il dolore acuto, quello che si sente per esempio quando ci si ferisce, ma poi prestamente si guarisce. Il capnellene estratto da un corallo presente al largo della costa di Taiwan riesce a inibire le sensazioni dolorose improprie e potrebbe divenire una nuova possibilità farmacologica contro il dolore cronico.

PHE377, a TRPV1 antagonist under clinical development
TABLE 1 | Therapeutic targeting of TRPV1
From the following article:
Transient receptor potential channels as therapeutic targets
Magdalene M. Moran, Michael Allen McAlexander, Tamás Bíró & Arpad Szallasi
Nature Reviews Drug Discovery 10, 601-620 (August 2011)

Il dolore viene spesso considerato come un campanello di allarme per una particolare malattia, quindi molto spesso curato con dei farmaci appartenenti alla categoria dei analgesici. Il cosiddetto dolore neuropatico insorge quando vi è un danno irreversibile che colpisce il sistema di percezione del dolore. La presenza di questo tipo di dolore avviene in pazienti affetti da alcune malattie del sistema nervoso centrale, ad esempio distrofie muscolari, sclerosi multipla ma anche in soggetti sottoposti ad amputazioni ( il dolore post-herpetico o arto-fantasma). Le caratteristiche variano da paziente a paziente di solito con l’insorgenza di bruciore e scosse elettriche. Dato la tipicità del dolore e soprattutto la particolarità dell’insorgenza è molto difficile da curare: i semplici analgesici compresa la morfina non bastano, spesso si ricorre all’uso di terapie palliative e di antidepressivi. Alcuni ricercatori hanno studiato molecole di interesse per poter portare alla produzione di un farmaco specifico che possa ridurre il dolore neuropatico. La ditta PharmEst, ha avviato la sperimentazione clinica della molecola Phe377.