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WO2017068388A2 - Utilisation du peptide synthétique pntx-19 pour le traitement de la douleur - Google Patents

Utilisation du peptide synthétique pntx-19 pour le traitement de la douleur Download PDF

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WO2017068388A2
WO2017068388A2 PCT/IB2015/057220 IB2015057220W WO2017068388A2 WO 2017068388 A2 WO2017068388 A2 WO 2017068388A2 IB 2015057220 W IB2015057220 W IB 2015057220W WO 2017068388 A2 WO2017068388 A2 WO 2017068388A2
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peptide
pntx
pge2
pain
opioid
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PCT/IB2015/057220
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WO2017068388A3 (fr
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Igor Dimitri Gama Duarte
Maria Elena DE LIMA PEREZ GARCIA
Ana Cristina NOGUEIRA FREITAS
Daniela DA FONSECA PACHECO
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Universidade Federal De Minas Gerais - Ufmg
Fundação De Amparo À Pesquisa Do Estado De Minas Gerais- Fapemig
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Publication of WO2017068388A3 publication Critical patent/WO2017068388A3/fr

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  • the present invention relates to the use of synthetic peptide PnTx-19 in the preparation of analgesic drugs for the treatment of patients with neuropathic pain, nociceptive pain (prostaglandin E2 sensitization of nociceptors) and inflammatory.
  • Synthetic peptide PnTx-19 is a very interesting pharmacological tool for use as an analgesic drug as it triggers cannabinoid and opioid antinociceptive response and probably does not trigger tolerance or dependence.
  • IASP International Association for the Study of Pain
  • Nociception refers to the activity of the afferent system induced by noxious stimuli, both exogenous (mechanical, chemical, physical and biological) and endogenous (inflammation, increased peristalsis, tissue ischemia) and peripheral perception occurs through activation of specific structures located at the nerve endings free of primary afferent fibers called nociceptors. Following, the stimuli are conducted through sensory nerve pathways to the central nervous system and at the thalamic and cortical level occurs the integration of painful sensation (FLIRST, S. Transmittersinvolved in antinociception in thespinalcord. Brain Res. Bull, 48: 129-1141, 1999).
  • the emotional reactivity to pain corresponds to the affective interpretation of this condition, having an individual character and being influenced by psychological states, previous experiences and cultural, social and environmental factors. These factors are able to modulate or distort painful sensation, which would be approximately equal in all individuals with intact nerve pathways (KLAUMANNetó / .Pathophysiology of pain. ArchivesofVeterinary Science, 13 (1): 1 -12, 2008). Therefore, the terms nociception and antinociception, equivalent to the terms pain and analgesia respectively, are more suitable for studies involving experimental animals.
  • Opioid receptor agonists are the major class of drugs used for acute control of moderate to severe pain. They exert their effects by binding mainly to ⁇ , ⁇ and ⁇ receptors located in the periphery, spinal cord and supraspinatus structures (SINGH, VK, et al. Molecular biologyofopioidreceptors: recentadvances. Neuroimmunomodulation, 4: 285-297, 1997). Morphine, a naturally occurring agonist of major historical importance, purified from the Papaversomniferum plant, is still widely used, however, synthetic and semi-synthetic opioids contribute to pharmacokinetic and pharmacodynamic versatility (FUCHSe ⁇ al. Clinical Pharmacology.
  • analgesic efficacy of different substances may vary according to the characteristic, duration, stimulus intensity, dosage and species and it has been observed that they are not equally effective for all types of pain.
  • neuropathic pain a type of pain that results from central or peripheral nervous system injury or dysfunction, the response to opioids is poor or short-lived (RIBEIRO et al.
  • the use of opioids in the treatment of chronic non-cancer pain is poor or short-lived.
  • ⁇ and ⁇ receptors are responsible for most of the analgesic effect of opioids and for some of the major undesirable effects (respiratory depression, euphoria, sedation and dependence) (RANGetó /. Analgesic drugs.
  • RANG HP
  • DALE RITTER
  • Addiction one of the major problems associated with opioid use, can be defined as a condition that develops as a result of the adaptation produced by readjusting homeostatic mechanisms in response to repeated drug use. In this state of adaptation, the individual needs continuous administration of the drug to maintain its normal functions (FUCHSetó /. Clinical Pharmacology. Rio de Janeiro: Guanabara Koogan, 2006. 1074p).
  • the increase in dopamine in the mesolimbic system triggered by opioid use, with consequent increase in dopaminergic transmission is considered primordial for the development of addiction. (HEIT, HA The truthaboutpain management: thedifferencebetween a painpatientand in addictedpatient. , 2001).
  • opioid use is often associated with the development of tolerance, in which repeated use of a constant dose of the drug results in decreased therapeutic effect.
  • the molecular mechanisms responsible for tolerance remain controversial and may involve the reduction of receptor numbers and modification of the signal transduction pathway.
  • changes in receptor numbers or binding affinity may be caused by receptor inactivation through cell surface receptor phosphorylation, internalization, and degradation (GOLANe ⁇ al. Principles of Pharmacology. Rio de Janeiro: Guanabara Koogan, 2009 952p).
  • opiorphine an encephalinase inhibitor (enzyme that cleaves the endogenous opioid enkephalin), allows encephalin to remain bioavailable longer producing analgesia without induction of tolerance (ROUGEOT etó / .SystemicalIyactivehumanopiorphinis a potentyet non-addictiveanalgesicwithoutdrugtoleranceeffects.
  • Cannabinoids are also compounds that have, among a variety of pharmacological effects, the antinociceptive effect. These effects are related to the biological activities of A 9- tetrahydrocannabinol (THC), an active ingredient in the Cannabis sativa plant. They exert their effects by binding to CB1 and CB2 receptors (DEWEY, WL Cannabinoid pharmacology. Pharmacol. Rev., 38: 151-155, 1986). CB1 receptors are expressed mainly in central and peripheral neurons and CB2 receptors in immune cells (HOWLETTetó / .International Union ofPharmacology XXVII. Classificationofcannabinoidreceptors. Pharmacol. Rev., 54: 161-202, 2002), although later studies have shown the presence of these receptors in many brain regions
  • Pharmacol., 50: 83-90, 1995 established the existence of a modulatory endocannabinoid analgesic system.
  • neuropathic pain the use of cannabinoids for pain relief is well characterized.
  • cannabinoidSativex NURMIKKOete / .Sativex successfully treats neuropathic pain characterized by allodynia: A randomized, double-blind, placebo-controlled clinical trial. Pain, 133: 210-220, 2007), which primarily activates cannabinoid-type receptors. CB1, shows success in its treatment.
  • the antinociceptive effect of the synthetic peptide PnTx-19 was tested and the results suggest that this peptide induces the release of endogenous opioids, as there was no total reversal of the analgesic effect when opioid antagonists were administered, which may indicate that peptide produces antinociception without tolerance. It has also been shown that the antinociceptive mechanism of PnTx-19 is also related to the cannabinoid pathway. It is possible that the synthetic peptide PnTx-19 is a promising substance in the treatment of neuropathies, since the data of the present invention showed that the peptide activates CB1-type peripheral receptors.
  • PnTx-19 was developed from the probable three-dimensional structure of the native PnTx2-6 toxin from the Phoneutr ⁇ anegriventer spider.
  • PnTx-19 is made up of a short polypeptide chain of only 19 amino acids which allows its easy commercialization, enabling the development of pharmaceutical compositions.
  • the development of this PnTx-19 peptide is described in patent application BR102012020800-8, but its use is claimed for the treatment of erectile dysfunction and / or the enhancement of erectile function as well as the PI 0800596- toxin TX2-6. 6 There are no reports in the state of the art of the antinociceptive effect induced by PnTx-19.
  • PI 0605484-6 relates to the use of Pha1 B toxin, PnTx3-6, in pharmaceutical compositions, including for treatment of painful processes.
  • US2012015886 relates to pharmaceutical formulations containing the spider toxin derived peptide GsMTx4 for pain relief.
  • no prior peptide similar to that of the present invention has been found for the treatment of pain.
  • US2004024005 relates to a composition for reducing, preventing or retarding the development of Tolerance and / or physical dependence on certain drugs intended for opioid receptors.
  • pharmaceutical compositions including: a drug that targets a GPCR (G protein-coupledreceptors), a GPCR agonist and a pharmaceutically acceptable carrier.
  • GPCR G protein-coupledreceptors
  • USRE36547E relates to a method for selectively increasing the analgesic potency of clinically used bimodal morphine and opioid agonists while simultaneously attenuating the development of physical dependence, tolerance and other undesirable side effects through co-administration of a opioid is an opioid receptor antagonist that selectively inactivates excitatory opioid receptor-mediated side effects.
  • PI9610248 provides opioid-like peptide compounds associated with conventional peripherally acting analgesics that selectively bind to the ⁇ -opioid receptor.
  • US2007060638 describes combination therapies of a cannabinoid receptor agonist and a cannabinoid antagonist in an amount effective to potentiate but not antagonize the therapeutic effect of the agonist receptor.
  • cannabinoid / opioid therapy may be capable of producing long-term antinociceptive effects at doses devoid of significant side effects, avoiding tolerant neuronal biochemical changes (WELCH, SP, Interactionofthecannabinoid andopioid systems in themodulationofnociception.
  • WELCH, SP Interactionofthecannabinoid andopioid systems in themodulationofnociception.
  • Other documents such as US 200931 1227, US2009029984 and WO2008045556 propose compositions comprising the synergistic combination of opioid and cannabinoid receptor agonists for use in the treatment of pain.
  • US 2008188508 comprises the combination of opioid receptor agonist and cannabinoid receptor antagonist.
  • the synthetic peptide PnTx-19 is a very interesting pharmacological tool for use as an analgesic drug as it triggers cannabinoid and opioid antinociceptive response.
  • Specific activation of CB1 receptors and their local action make the promising peptide for the treatment of neuropathic pain, but can also be used for other pain models, such as nociceptive (prostaglandin E2 sensitization of nociceptors) and inflammatory.
  • nociceptive prostaglandin E2 sensitization of nociceptors
  • inflammatory such as nociceptive (prostaglandin E2 sensitization of nociceptors) and inflammatory.
  • nociceptive prostaglandin E2 sensitization of nociceptors
  • FIG. 1 Intracerebroventricular administration of synthetic peptide Pntx-19: Only two doses (0.4 nmol and 0.2 nmol) were able to increase the nociceptive threshold of animals for up to 15 min.
  • the control group received saline solution (0.9% w / v NaCl).
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measurement expressed in seconds (s) for the N of 4 animals. * P ⁇ 0.05 compared to the Saline group.
  • FIG. 1 Intrathecal administration of synthetic peptide Pntx-19: None of the doses administered were able to alter the nociceptive threshold of the animals.
  • the control group received saline solution (0.9% w / v NaCl). Each symbol represents the mean ⁇ SEM of the nociceptive threshold measurement expressed in seconds (s) for the N of 2 animals. * P ⁇ 0.05 compared to the Saline group.
  • FIG. 3 Intraplantar administration of synthetic peptide Pntx-19: The two doses administered (4nmol and 2nmol) were able to alter the nociceptive threshold of the animals. The 8nmol dose was able to prolong the antinociceptive effect of 5min. to 10min. Control group received 2 ⁇ g of PGE2. Each symbol represents the mean ⁇ SEM of the nociceptive threshold measurement. expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to the control group.
  • Figure 4 - 4nmol non-local effect exclusion test of synthetic peptide Pntx-19 The peptide showed only local antinociceptive effect when administered via intraplantar at 4nmol dose.
  • Control group received 2 ⁇ g of PGE2.
  • Vein physiological saline (0.9% w / v NaCl); PD: right paw; PE: left paw.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to the Saline + PGE2 group.
  • FIG. 5 Effect on nociceptive threshold caused by synthetic peptide Pntx-19 against opioid receptor antagonists: naloxone (nonspecific opioid receptor antagonist) was able to partially reverse the antinociceptive effect of the peptide in a dose-dependent manner.
  • Control group received 2 ⁇ g of PGE2.
  • Veid saline (0.9% w / v NaCl) applied 30 min before the third hour of PGE2.
  • Veic2 saline applied 5 min before the third hour of PGE2.
  • Naloxone was applied 30 min before the third hour of PGE2.
  • PnTx-19 was applied 5 min before the third hour of PGE2.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams for the N of 4 animals.
  • Figure 6 Effect on nociceptive threshold caused by synthetic peptide Pntx-19 against ⁇ -opioid receptor antagonism: clocinamox ( ⁇ -opioid receptor specific antagonist) was able to partially reverse the antinociceptive effect of the peptide.
  • Control group received 2 ⁇ g of PGE2.
  • Veid saline (0.9% w / v NaCl) applied 35 min before the third hour of PGE2.
  • Veic2 saline applied 5 min before the third hour of PGE2.
  • Clocinamox was applied 35 min before the third hour of PGE2.
  • PnTx-19 was applied 5 min before the third hour of PGE2.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to Veiei + Veic2 + PGE2 group. . # P ⁇ 0.05 relative to the PGE2 + Veic1 + PnTx-19 (4 nmol) group.
  • Veid saline (0.9% w / v NaCl) applied 35min before the third hour of PGE2.
  • Veic2 saline applied 5 min before the third hour of PGE2.
  • Naltrindole was applied 35 min before the third hour of PGE2.
  • PnTx-19 was applied 5 min before the third hour of PGE2.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams for the N of 4 animals. * P ⁇ 0.05 compared to Veiei + Veic2 + PGE2 group. # P ⁇ 0.05 relative to the PGE2 + Veic1 + PnTx-19 (4 nmol) group.
  • FIG. 8 Effect on nociceptive threshold caused by synthetic peptide Pntx-19 against ⁇ -opioid receptor antagonism: NOR BNI ( ⁇ -opioid receptor specific antagonist) was not able to reverse the antinociceptive effect of the peptide.
  • Control group received 2 ⁇ g of PGE2.
  • Veid saline (0.9% w / v NaCl) applied 35 min before the third hour of PGE2.
  • Veic2 saline (0.9% w / v NaCl) applied 5 min before the third hour of PGE2.
  • NOR BNI was applied 35 min before the third hour of PGE2.
  • PnTx-19 was applied 5 min before the third hour of PGE2.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to Veid + Veic2 + PGE2 group.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to Veid + Veic2 + PGE2 group. # P ⁇ 0.05 relative to the PGE2 + Veic1 + PnTx-19 (4 nmol) group.
  • FIG. 10 Effect on nociceptive threshold caused by synthetic peptide Pntx-19 against cannabinoid receptor antagonismCB2: AM630 (CB2 cannabinoid receptor specific antagonist) was not able to reverse the antinociceptive effect of the peptide.
  • Control group received 2 ⁇ g of PGE2.
  • Veid saline (0.9% w / v NaCl) applied 15 min before the third hour of PGE2.
  • Veic2 saline applied 5min before the third hour of PGE2.
  • AM630 was applied 15 min before the third hour of PGE2.
  • PnTx-19 was applied 5 min before the third hour of PGE2.
  • Each symbol represents the mean ⁇ SEM of the nociceptive threshold measure expressed in grams (g) for the N of 4 animals. * P ⁇ 0.05 compared to Veiei + Veic2 + PGE2 group.
  • the present invention relates to the use of PnTx-19 peptide (SEQ ID NO: 1 Q) derived Phoneutr ⁇ anegr ⁇ venter spider toxin, in the preparation of analgesic medicaments.
  • drugs comprising PnTx-19 peptide may be presented in the following forms: solid, such as tablets, pills, capsules and suppository; as solutions, suspensions, syrups, as well as aerosols, pastes, creams, ointments and lotions for local application or with transdermal devices, and in injectable liquid form.
  • Medicaments comprising PnTx-19 peptide may be used individually or in combination with other analgesics and may be administered by the oral, rectal, intramuscular, subcutaneous, intravenous routes.
  • the applied algesometric assays were the "TailFIick” thermal stimulation test and the “Randall and Selitto” test (RANDALL, L.O; SELITTO, J.J. A method for measurementofanalgesicactivityoninflamedtissues.
  • the tail test Flick is the modified D'amour & Smith test (D7WIOUR FE; SMITH DLA, A method for determining loss of pain sensation. J PharmacolExpTher. Baltimore, v. 72, p.74-79, May 1941), which consists in the determination latency time for the animal to remove its tail after a nociceptive thermal stimulus. This test was used for the study of central antinociception by administering the synthetic peptide PnTx-19 by intracerebroventricular and intrathecal pathways.
  • the peptide has 19 amino acid residues (Ac - GERRQYFWIAWYKLANSKK - NH2), is acetylated at the N-terminus and amidated at the C-terminus, and is derived from the Phoneutr ⁇ anegriventer spider toxin PnTx2-6.
  • the peptide was initially synthesized at the Federal University of Minas Gerais, Belo Horizonte and later larger quantities were ordered from a company (China Peptides). The peptide used in this work was the one obtained by the company, but the quality control was attested by mass spectrometry at the Animal Poison and Toxins Laboratory of the Institute of Biological Sciences of the Federal University of Minas Gerais - UFMG.
  • mice Male rats of the species ftaftL / sno / veg / / sdalinhagemWistar, weighing between 170 and 230 g; and male Mus musculus mice, Swiss strain, weighing between 25 and 30g. Both were provided by the Bioterismo Center - CEBIO of the Instituto de Biological Sciences of the Federal University of Minas Gerais, Belo Horizonte. All animals were kept in 17 x 34 x 40 cm polypropylene cages, with standard feeding and ad libitum drinking water, and a 12 h light and 12 h dark cycle.
  • mice For administration of the peptide via intracerebroventricular (ICV) mice were used only. The mice were trichotomized in the region that received the ICV injection and were then placed in a container. The animals were manually immobilized on the head region and then received the peptide administration. The 2mm depth was controlled with a lock placed on the needle of a 5.0 ⁇ Hamilton® microsyringe. The volume administered inside the ventricles was 2.0 ⁇ , with the peptide carried in physiological saline solution (0.9% w / v NaCl) and injected in the amounts of 0.4 nmol, 0.2 nmol and 0, 1 nmol per mouse. The choice of mice for this route of administration avoids previous surgical intervention to enable access to the cerebral ventricles, which would be necessary if rats were used as an experimental model.
  • ICV intracerebroventricular
  • rats were used, they have larger intervertebral spaces and easier access than mice, reducing the chance of any discomfort for the animal after the procedure.
  • rats Prior to drug administration, rats were trichotomized in the dorsolumbar region, facilitating palpation of intervertebral spaces.
  • injection was performed using a 13 x 0.3 mm needle attached to the hypodermic syringe (BD®, Brazil) directly into the subarachnoid space between the fifth and sixth lumbar vertebrae.
  • the administered volume was 20 ⁇ , the peptide delivered in physiological saline and injected in the amounts of 8.0 nmol, 10.0 nmol, 10.8 nmol, 12.0 nmol and 16.0 nmol.
  • PGE2 Prostaglandin E2
  • ENU Life Sciences, USA
  • PGE2 was kept at -5 ° C in a stock solution with concentration dei ⁇ / ⁇ in ethanol. Prior to the experiment, PGE2 was diluted in physiological saline and kept on ice until injections of 2 g / paw in 100 ⁇ volume.
  • Pntx-19 peptide was delivered in physiological saline (0.9% w / v NaCl) and administered in the amounts of 2 nmol, 4 nmol and 8 nmol from the third hour. Once the peak of action of the peptide and its best dose were established, it was administered via intraplantar so that the peak of its action coincided with
  • AM251 (1- (2,4-dichlorophenyl) -5- (iodophenyl) -4-methyl- / v- (1-piperidyl) pyrazol-3-carboxamide) (Tocrisolve, USA) (80 ⁇ g and 160 ⁇ g) and AM630 ( [6-Iodo-2-methyl-1 - [2- (4-morpholinyl) ethyl] -1H-indol-3-yl] (4ethoxyphenyl) methanone) (Tocrisolve, USA) (100 ⁇ g) was administered 15 minutes before third hour of PGE2.
  • the tail of the animal was positioned close to a nickel-chrome helical resistor, so that a point on the dorsal surface of the tail, previously marked and distant 1.0 cm from the tail end, came into contact with the wire of the tail. electrical resistance.
  • a current is passed through the resistor to heat it.
  • a timer coupled to the system is triggered.
  • heat becomes sufficient to produce nociception the animal exhibits reflex movement of tail removal.
  • the device is switched off manually, interrupting its heating and timer operation. This procedure aims to determine the time elapsed from the beginning of the stimulation until the appearance of the tail pull reflex response (response latency, measured in seconds).
  • the device is automatically switched off to avoid tissue damage. It is important to note that the animal is acclimatized to the device on the day before the test, this is to subject the animal to same situation that will be experienced on the day of the experiment.
  • the animal is carefully kept horizontally on the bench by one of the experimenter's hands, while the test foot is presented, by its plantar surface, to the compressing part of the apparatus. It consists of two surfaces, one flat on which the animal's foot rests, and the other tapered with an area of 1.75 mm 2 at the end.
  • the tapered end is responsible for applying pressure to the plantar surface of the rat, and the intensity of this pressure increases at a constant rate of 32 g / s by the pedal being operated by the experimenter.
  • the experimenter disengages the pedal.
  • naloxone a nonspecific opioid receptor antagonist
  • Figure 5 Naloxone was only partially able to reverse the antinociceptive effect of the peptide at all doses tested.
  • the antinociceptive action of the peptide is due to the participation of endogenous opioids, but this is not the only mechanism involved, since the antagonism was only partial.
  • specific antagonists were administered for each type of opioid receptor.
  • peripheral nervous system REIS et. al. Opioid receptor and NO / cGMP pathway as a mechanism of peripheral antinociceptive action of the cannabinoid receptor agonist anandamide. Life Sci, Oxford, v. 85, pp 351-356, Aug 2009; PACHECO et al.The ⁇ -opioid receptor agonist morphine, but not agonists at delta or kappa opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors. London, v. 154, pp. 143-119, May 2008).
  • the peptide activates these two pathways, but does not directly bind to the opioid or cannabinoid receptor sites, since antagonism in both pathways was only partial, and a complementary response between opioids and endogenous cannabinoids is required for the peptide to have its maximum analgesic action triggered. This mechanism should be further studied to verify a possible interaction of the peptide with different sites on these receptors.
  • Results were presented as mean ⁇ SEM of hyperalgesia intensity and analysis of variance (ANOVA), followed by Bonferroni test. Thus it was possible to verify the significance of the differences between the means (multiple comparisons), being considered significant when P values were less than 0.05.
  • ANOVA analysis of variance
  • the Prisma program was used for the construction of graphs and application of statistical analysis. Assuming the reliability of the study at 90% and considering an absolute error of 10.4 g, it was possible to perform the N samplei calculation that was defined in four animals for each experimental group.

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Abstract

La présente invention concerne l'utilisation du peptide synthétique PnTx-19 dans la préparation de médicaments analgésiques pour le traitement de patients souffrant de douleur neuropathique, de douleur nociceptive (sensibilisation de nocicepteurs par prostaglandine E2) et de douleur inflammatoire. Le peptide synthétique PnTx-19 est un outil pharmacologique très intéressant pour une utilisation comme médicament analgésique étant donné qu'il déclenche une réponse antinociceptive via cannabinoïde et opioïde et ne provoque probablement pas de tolérance ni de dépendance.
PCT/IB2015/057220 2015-09-18 2015-09-18 Utilisation du peptide synthétique pntx-19 pour le traitement de la douleur WO2017068388A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020006617A1 (fr) * 2018-07-05 2020-01-09 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Peptides synthétiques, promédicaments, compositions pharmaceutiques et utilisations
WO2021042193A1 (fr) * 2019-09-03 2021-03-11 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Procédé et utilisation de pnpp-19 pour prévenir et traiter des maladies oculaires
WO2024168415A1 (fr) * 2023-02-17 2024-08-22 Biozeus Biopharmaceutical S.A. Formulation peptidique topique pour le traitement d'un dysfonctionnement sexuel

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* Cited by examiner, † Cited by third party
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DE602006014186D1 (de) * 2005-10-18 2010-06-17 Seoul Nat Univ Ind Foundation Verfahren zur herstellung eines rekombinanten peptids aus spinnengift, und das peptid enthaltende analgetische zusammensetzung
BRPI0605484A8 (pt) * 2006-11-21 2017-03-07 Fund Amparo Pesquisa Estado Minas Gerais Fapemig Toxina ph(alfa)1b, cdna do gene da toxina ph(alfa)1b, composições farmacêuticas contendo a toxina ph(alfa)1b, processo para sua obtenção, processo para obtenção do cdna, e produto
BRPI0800596A2 (pt) * 2008-01-31 2009-09-22 Univ Minas Gerais método para a potencialização da função erétil através do uso das composições farmacêuticas de toxina tx2-6 da aranha phoneutria nigriventer
BR102012020800A2 (pt) * 2012-08-20 2014-12-16 Univ Minas Gerais Peptídeo sintético pntx (19), composições farmacêuticas e uso

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020006617A1 (fr) * 2018-07-05 2020-01-09 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Peptides synthétiques, promédicaments, compositions pharmaceutiques et utilisations
US10905738B2 (en) 2018-07-05 2021-02-02 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Synthetic peptides, prodrugs, pharmaceutical compositions and uses
WO2021042193A1 (fr) * 2019-09-03 2021-03-11 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Procédé et utilisation de pnpp-19 pour prévenir et traiter des maladies oculaires
CN114302734A (zh) * 2019-09-03 2022-04-08 生物医药产品开发公司 PnPP-19用于预防和治疗眼病的方法和用途
WO2024168415A1 (fr) * 2023-02-17 2024-08-22 Biozeus Biopharmaceutical S.A. Formulation peptidique topique pour le traitement d'un dysfonctionnement sexuel

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