The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Karl Folkers - One of the best experts on this subject based on the ideXlab platform.
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pharmacological assessment of Spantide ii analogues
European Journal of Pharmacology, 1994Co-Authors: Zunyi Wang, Dongmei Feng, Karl Folkers, Yali Wang, Steven R Tung, Kin Wong, Gary R Strichartz, R HakansonAbstract:We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on Spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the Spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than Spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of Spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5–7.5 at the NK1 receptor and of 5.9–7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than Spantide II in causing histamine release from rat peritoneal mast cells.
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comparison of Spantide ii and cp 96 345 for blockade of tachykinin evoked contractions of smooth muscle
Biochemical and Biophysical Research Communications, 1991Co-Authors: R Hakanson, Zunyi Wang, Karl FolkersAbstract:Abstract CP-96,345, a quinuclidine, is a potent inhibitor of substance P for the NK1 receptor of bovine brain, but has reduced potency for the corresponding receptor of the rat and mouse, and none for NK2 or NK3 receptors. A related quinuclidine showed similar but lower potency than CP-96,345 for NK1. CP-96,345 was more potent than the Spantide I of 1984, D-Arg1,Pro2,Lys3,Pro4,Gln5,Gln6,D-Trp7,Phe8,D-Trp9,Leu10,Leu11,NH2. Our continued designs for antagonists of substance P led to Spantide II in 1990 which is: D-NicLys1,Pro2,3-Pal3,Pro4,D-Cl2Phe5,Asn6,D-Trp7,Phe8,D-Trp9,Leu10,Nle11-NH2. The pA2 values of Spantide II and CP-96,345 for guinea pig taenia coli were 7.6 and 6.8, respectively. The pIC50 values for blockade of tachykinin-mediated neurotransmission in the rabbit iris sphincter were 6.1 and 5.4, respectively. Spantide II was nearly 10 times more potent than CP-96,345 in these two assays.
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Tachykinns mediate changes in spinal reflexes after activation of unmyelinated muscle afferents in the rat
Acta Physiologica Scandinavica, 1991Co-Authors: Z. Wiesenfeld-hallin, Dongmei Feng, X J Xu, Rolf Håkanson, Karl FolkersAbstract:: The effect of intrathecally applied tachykinin antagonist D-NicLys1, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.9, Nle11-substance P, Spantide II, on the long-term increase of spinal cord excitability after activation of unmyelinated muscle afferents was studied in decerebrate, spinalized, unanaesthetized rats. A conditioning stimulus train (1 Hz, 20 s) that activated unmyelinated fibres in the gastrocnemius muscle nerve facilitated the flexor reflex for about 1 h, which was strongly blocked by pretreatment with Spantide II (3 micrograms). The present results indicate that the facilitation of the flexor reflex by conditioning stimulation of a muscle nerve is mediated by tachykinins and possibly other neuropeptides which may be released from the central terminals of these unmyelinated afferents.
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activity of Spantide i and ii at various tachykinin receptors and nk 2 tachykinin receptor subtypes
European Journal of Pharmacology, 1991Co-Authors: Carlo Alberto Maggi, Dongmei Feng, Riccardo Patacchini, Karl FolkersAbstract:Abstract We compared the ability of Spantide I and II to antagonize tachykinins in monoreceptor bioassays. Both peptides antagonized the response to substance P methylester in the guinea-pig ileum (NK-1 receptor-mediated) with greater affinity than the responses mediated by NK-2 or NK-3 receptors in other bioassays. Spantide II was about 10 times more potent than Spantide I as an NK-1 antagonist and also possessed some selectivity for the NK-2 receptor subtype present in the hamster trachea. Spantide II is a suitable tool to assess the role of NK-1 receptors in the central and peripheral nervous system.
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Spantide ii a novel tachykinin antagonist and galanin inhibit plasma extravasation induced by antidromic c fiber stimulation in rat hindpaw
Neuroscience, 1991Co-Authors: X J Xu, Karl Folkers, Z Wiesenfeldhallin, Ha R Kanson, Ho T KfeltAbstract:Abstract The effect of intradermal injection of Spantide II, a novel tachykinin antagonist and the neuropeptide galanin on neurogenic plasma extravasation induced by antidromic stimulation of C-fibers in the sciatic nerve was examined in the hindpaws of rats. Activation of C-fibers by antidromic sciatic nerve stimulation (2 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans Blue in the skin area of the hindpaw innervated by the sciatic nerve. Intradermal injection of 3 nmol Spantide II significantly inhibited this response. The plasma extravasation was nearly totally abolished when the concentration of Spantide II was increased to 9 nmol. Intradermal injection of 1.5 and 15 nmol galanin also inhibited plasma extravasation. Intradermal injection of 9 nmol Spantide II effectively blocked the plasma extravasation in the hindpaw induced by 8 nmol intravenous substance P. Plasma extravasation induced by intravenous substance P was also inhibited by the higher, but not by the lower, dose of galanin injected intradermally. The present results indicate that Spantide II, a potent non-toxic tachykinin antagonist, effectively blocks the neurogenic plasma extravasation induced by antidromic C-fiber stimulation, thus supporting the view that tachykinins play an important role in this neurogenic inflammatory process. It is further shown that galanin, a naturally occurring neuropeptide present in primary afferents, also inhibits C-fiber activation-evoked plasma extravasation, indicating an interaction between galanin and tachykinins in the peripheral terminals of primary afferents, possibly through both pre- and postsynaptic mechanisms.
Mandip Singh - One of the best experts on this subject based on the ideXlab platform.
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stability and degradation profiles of Spantide ii in aqueous solutions
European Journal of Pharmaceutical Sciences, 2006Co-Authors: Loice Kikwai, Narayanasamy Kanikkannan, Jayachandra R Babu, Mandip SinghAbstract:Abstract Spantide II is an 11 amino acid peptide that has been shown to be a potential anti-inflammatory agent. The stability and degradation profiles of Spantide II in aqueous solutions were evaluated with the long-term objective of developing topical formulations of this compound for various skin disorders. The stability profile of Spantide II at various temperature and pH conditions was monitored by high performance liquid chromatography (HPLC) and the resulting degradation products were identified by liquid chromatography-mass spectroscopy (LC-MS). Forced degradation of Spantide II was performed at extreme acidic (pH 10.0) conditions and by addition of hydrogen peroxide (oxidizing agent). The degradation pattern of Spantide II followed pseudo first-order kinetics. The shelf life (T90%) of Spantide II in aqueous ethanol (50%) was determined to be 230 days at 25 °C. Spantide II was susceptible to degradation at pH 5 and showed maximum stability at pH 3–5. The stability under various pH conditions indicates that Spantide II was most stable at pH 3.0 with a half-life of 95 days at 60 °C. Spantide II degradation was attributed to hydrolysis of peptide bonds [Pro2-(pyridyl)Ala3, (nicotinoyl)Lys1-Pro2, Pro4-PheCl25, Trp7-Phe8, Phe8-Trp9, Nle11-NH2), racemization of the peptide fragments that resulted from hydrolysis, cleavage and formation of (nicotinoyl)Lys1-Pro2 diketopiperazine. In the presence of an oxidizing agent, Pro2,4 residues degraded by ring opening to form glutamyl-semialdehyde and by bond cleavage at Pro4 to form 2-pyrrolidone, while Phe5,8 degraded to form 2-hydroxyphenylalanine. Spantide II was found to be stable in aqueous medium with T90% of 230 days. The major degradation pathways of Spantide II were identified as hydrolysis, racemization, cleavage and formation of diketopiperazine.
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In vitro and in vivo evaluation of topical formulations of Spantide II
AAPS PharmSciTech, 2005Co-Authors: Loice Kikwai, Renata Prado, Alexandra Kolot, Cheryl A. Armstrong, John C. Ansel, R. Jayachandra Babu, Mandip SinghAbstract:The purpose of this study was to develop and evaluate topical formulations of Spantide II, a neurokinin-1 receptor (NK-1R) antagonist, for the treatment of inflammatory skin disorders. Spantide II lotion and gel was formulated with and without n-methyl-2-pyrrolidone (NMP) as a penetration enhancer. The release of Spantide II from gels was evaluated using microporous polyethylene and polypropylene membranes in a Franz Diffusion cell setup. In vitro percutaneous absorption of Spantide II from lotion and gel formulations was evaluated using the above setup by replacing the membranes with hairless rat skin. The in vivo anti-inflammatory activity of Spantide II formulations was evaluated in an allergic contact dermatitis (ACD) mouse model. Among different gels studied, PF127 gel showed highest (70-fold) release of Spantide II compared with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) gels. Lotion and gel formulations with or without NMP showed no detectable levels of Spantide II in the receiver compartment of the Franz diffusion cell until 24 hours. However, Spantide II showed significant retention in epidermis and dermis from lotion and gel formulations at 24 hours. The dermal levels increased ≈3.5- and 2-fold when the lotion and gel formulations contained NMP as compared with the formulation with no NMP (P
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Stability and degradation profiles of Spantide II in aqueous solutions.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2005Co-Authors: Loice Kikwai, R. Jayachandra Babu, Narayanasamy Kanikkannan, Mandip SinghAbstract:Spantide II is an 11 amino acid peptide that has been shown to be a potential anti-inflammatory agent. The stability and degradation profiles of Spantide II in aqueous solutions were evaluated with the long-term objective of developing topical formulations of this compound for various skin disorders. The stability profile of Spantide II at various temperature and pH conditions was monitored by high performance liquid chromatography (HPLC) and the resulting degradation products were identified by liquid chromatography-mass spectroscopy (LC-MS). Forced degradation of Spantide II was performed at extreme acidic (pH 10.0) conditions and by addition of hydrogen peroxide (oxidizing agent). The degradation pattern of Spantide II followed pseudo first-order kinetics. The shelf life (T90%) of Spantide II in aqueous ethanol (50%) was determined to be 230 days at 25 degrees C. Spantide II was susceptible to degradation at pH 5 and showed maximum stability at pH 3-5. The stability under various pH conditions indicates that Spantide II was most stable at pH 3.0 with a half-life of 95 days at 60 degrees C. Spantide II degradation was attributed to hydrolysis of peptide bonds [Pro2-(pyridyl)Ala3, (nicotinoyl)Lys1-Pro2, Pro4-PheCl2(5), Trp7-Phe8, Phe8-Trp9, Nle11-NH2), racemization of the peptide fragments that resulted from hydrolysis, cleavage and formation of (nicotinoyl)Lys1-Pro2 diketopiperazine. In the presence of an oxidizing agent, Pro(2,4) residues degraded by ring opening to form glutamyl-semialdehyde and by bond cleavage at Pro4 to form 2-pyrrolidone, while Phe(5,8) degraded to form 2-hydroxyphenylalanine. Spantide II was found to be stable in aqueous medium with T90% of 230 days. The major degradation pathways of Spantide II were identified as hydrolysis, racemization, cleavage and formation of diketopiperazine.
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in vitro and in vivo evaluation of topical formulations of Spantide ii
Aaps Pharmscitech, 2005Co-Authors: Loice Kikwai, Renata Prado, Alexandra Kolot, Cheryl A. Armstrong, John C. Ansel, Jayachandra R Babu, Mandip SinghAbstract:The purpose of this study was to develop and evaluate topical formulations of Spantide II, a neurokinin-1 receptor (NK-1R) antagonist, for the treatment of inflammatory skin disorders. Spantide II lotion and gel was formulated with and without n-methyl-2-pyrrolidone (NMP) as a penetration enhancer. The release of Spantide II from gels was evaluated using microporous polyethylene and polypropylene membranes in a Franz Diffusion cell setup. In vitro percutaneous absorption of Spantide II from lotion and gel formulations was evaluated using the above setup by replacing the membranes with hairless rat skin. The in vivo anti-inflammatory activity of Spantide II formulations was evaluated in an allergic contact dermatitis (ACD) mouse model. Among different gels studied, PF127 gel showed highest (70-fold) release of Spantide II compared with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) gels. Lotion and gel formulations with or without NMP showed no detectable levels of Spantide II in the receiver compartment of the Franz diffusion cell until 24 hours. However, Spantide II showed significant retention in epidermis and dermis from lotion and gel formulations at 24 hours. The dermal levels increased ≈3.5- and 2-fold when the lotion and gel formulations contained NMP as compared with the formulation with no NMP (P<.05). The in vivo studies indicated that Spantide II formulations with NMP were effective in significantly reducing ACD response, similar to dexamethasone (0.5 mM). In conclusion, Spantide II was stable as a topical formulation and delivered to target skin tissue (epidermis and dermis) for the treatment of ACD. In addition this study supports the role of cutaneous neurosensory system in modulating inflammatory responses in the skin.
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preformulation stability of Spantide ii a promising topical anti inflammatory agent for the treatment of psoriasis and contact dermatitis
Journal of Pharmacy and Pharmacology, 2004Co-Authors: Loice Kikwai, R J Babu, Narayanasamy Kanikkannan, Mandip SinghAbstract:: Substance P is readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.
R Hakanson - One of the best experts on this subject based on the ideXlab platform.
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pharmacological assessment of Spantide ii analogues
European Journal of Pharmacology, 1994Co-Authors: Zunyi Wang, Dongmei Feng, Karl Folkers, Yali Wang, Steven R Tung, Kin Wong, Gary R Strichartz, R HakansonAbstract:We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on Spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the Spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than Spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of Spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5–7.5 at the NK1 receptor and of 5.9–7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than Spantide II in causing histamine release from rat peritoneal mast cells.
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Spantide III, a superior tachykinin antagonist with high potency and negligible neurotoxicity
Amino Acids, 1993Co-Authors: K Folkers, R Hakanson, D M Feng, J. C. Xu, A. Janecka, Z. -y. WangAbstract:Five new antagonists of Substance P were designed and synthesized toward increasing potency and safety. One of them was more effective than Spantide II, which was the basis for the design. It was named Spantide III and has the structure: D-NicLys,Pro,Pal,Pro,D-Cl_2Phe,Asn,D-Trp,Phe,D-Pal,Leu, NleNH_2.
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comparison of Spantide ii and cp 96 345 for blockade of tachykinin evoked contractions of smooth muscle
Biochemical and Biophysical Research Communications, 1991Co-Authors: R Hakanson, Zunyi Wang, Karl FolkersAbstract:Abstract CP-96,345, a quinuclidine, is a potent inhibitor of substance P for the NK1 receptor of bovine brain, but has reduced potency for the corresponding receptor of the rat and mouse, and none for NK2 or NK3 receptors. A related quinuclidine showed similar but lower potency than CP-96,345 for NK1. CP-96,345 was more potent than the Spantide I of 1984, D-Arg1,Pro2,Lys3,Pro4,Gln5,Gln6,D-Trp7,Phe8,D-Trp9,Leu10,Leu11,NH2. Our continued designs for antagonists of substance P led to Spantide II in 1990 which is: D-NicLys1,Pro2,3-Pal3,Pro4,D-Cl2Phe5,Asn6,D-Trp7,Phe8,D-Trp9,Leu10,Nle11-NH2. The pA2 values of Spantide II and CP-96,345 for guinea pig taenia coli were 7.6 and 6.8, respectively. The pIC50 values for blockade of tachykinin-mediated neurotransmission in the rabbit iris sphincter were 6.1 and 5.4, respectively. Spantide II was nearly 10 times more potent than CP-96,345 in these two assays.
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intranigral substance p stimulation of striatal dopamine release is inhibited by Spantide ii a new tachykinin antagonist without apparent neurotoxicity
Brain Research, 1990Co-Authors: M S Reid, R Hakanson, Dongmei Feng, Karl Folkers, T Hokfelt, Mario Herreramarschitz, M Goldstein, Urban UngerstedtAbstract:Abstract The effects of intranigral injections of Spantide II, a novel tachykinik antagonist, on extracellular dopamine, and dihydroxyphenylacetic acid (DOPAC) levels in the rat striatum were studied using in vivo microdialysis. The ability of Spantide II to inhibit intranigral substance P or neurokinin A stimulation of striatal dopamine levels was also studied. A unilateral injection (all substances were injected in a volume of 0.2 μl) of Spantide II (0.7 nmol) intot he substantia nigra, pars reticulata (SNR) of halothane anaesthetized rats produced a short-lasting decrease in dopamine levels in the spsilateral striatum. Striatal DOPAC levels showed no change after Spantide II. A unilateral injection of substance P (0.07 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was prevented when substance P was co-administered with Spantide II (0.7 nmol). A unilateral injection of neurokinin A (0.09 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was not modified when neurokinin A was co-administered with Spantide II (0.7 nmol). Immunohistochemical analysis using antisera to tyrosine hydroxylase and neuropeptide K, as well as Cresyl violet staining, revealed that intranigral injections of Spantide II (0.7 nmol) did not produce significant damage in the substantia nigra. The results indicate that Spantide II is not ‘neurotoxic’ when injected intranigrally, and that it is a selective antagonist of substance P in the substantia nigra. Furthermore, the reduction of striatal dopamine levels after intranigral Spantide II injections suggests that nigrostriatal dopamine projection is tonically stimulated by striatonigral substance P.
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Intranigral substance P stimulation of striatal dopamine release is inhibited by Spantide II: a new tachykinin antagonist without apparent neurotoxicity.
Brain research, 1990Co-Authors: M S Reid, R Hakanson, T Hokfelt, M Goldstein, M Herrera-marschitz, D M Feng, K Folkers, Urban UngerstedtAbstract:The effects of intranigral injections of Spantide II, a novel tachykinin antagonist, on extracellular dopamine, and dihydroxyphenylacetic acid (DOPAC) levels in the rat striatum were studied using in vivo microdialysis. The ability of Spantide II to inhibit intranigral substance P or neurokinin A stimulation of striatal dopamine levels was also studied. A unilateral injection (all substances were injected in a volume of 0.2 microliter) of Spantide II (0.7 nmol) into the substantia nigra, pars reticulata (SNR) of halothane anaesthetized rats produced a short-lasting decrease in dopamine levels in the ipsilateral striatum. Striatal DOPAC levels showed no change after Spantide II. A unilateral injection of substance P (0.07 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was prevented when substance P was co-administered with Spantide II (0.7 nmol). A unilateral injection of neurokinin A (0.09 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was not modified when neurokinin A was co-administered with Spantide II (0.7 nmol). Immunohistochemical analysis using antisera to tyrosine hydroxylase and neuropeptide K, as well as Cresyl violet staining, revealed that intranigral injections of Spantide II (0.7 nmol) did not produce significant damage in the substantia nigra. The results indicate that Spantide II is not 'neurotoxic' when injected intranigrally, and that it is a selective antagonist of substance P in the substantia nigra. Furthermore, the reduction of striatal dopamine levels after intranigral Spantide II injections suggests that the nigrostriatal dopamine projection is tonically stimulated by striatonigral substance P.
Dongmei Feng - One of the best experts on this subject based on the ideXlab platform.
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pharmacological assessment of Spantide ii analogues
European Journal of Pharmacology, 1994Co-Authors: Zunyi Wang, Dongmei Feng, Karl Folkers, Yali Wang, Steven R Tung, Kin Wong, Gary R Strichartz, R HakansonAbstract:We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on Spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the Spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than Spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of Spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5–7.5 at the NK1 receptor and of 5.9–7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than Spantide II in causing histamine release from rat peritoneal mast cells.
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Tachykinns mediate changes in spinal reflexes after activation of unmyelinated muscle afferents in the rat
Acta Physiologica Scandinavica, 1991Co-Authors: Z. Wiesenfeld-hallin, Dongmei Feng, X J Xu, Rolf Håkanson, Karl FolkersAbstract:: The effect of intrathecally applied tachykinin antagonist D-NicLys1, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.9, Nle11-substance P, Spantide II, on the long-term increase of spinal cord excitability after activation of unmyelinated muscle afferents was studied in decerebrate, spinalized, unanaesthetized rats. A conditioning stimulus train (1 Hz, 20 s) that activated unmyelinated fibres in the gastrocnemius muscle nerve facilitated the flexor reflex for about 1 h, which was strongly blocked by pretreatment with Spantide II (3 micrograms). The present results indicate that the facilitation of the flexor reflex by conditioning stimulation of a muscle nerve is mediated by tachykinins and possibly other neuropeptides which may be released from the central terminals of these unmyelinated afferents.
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activity of Spantide i and ii at various tachykinin receptors and nk 2 tachykinin receptor subtypes
European Journal of Pharmacology, 1991Co-Authors: Carlo Alberto Maggi, Dongmei Feng, Riccardo Patacchini, Karl FolkersAbstract:Abstract We compared the ability of Spantide I and II to antagonize tachykinins in monoreceptor bioassays. Both peptides antagonized the response to substance P methylester in the guinea-pig ileum (NK-1 receptor-mediated) with greater affinity than the responses mediated by NK-2 or NK-3 receptors in other bioassays. Spantide II was about 10 times more potent than Spantide I as an NK-1 antagonist and also possessed some selectivity for the NK-2 receptor subtype present in the hamster trachea. Spantide II is a suitable tool to assess the role of NK-1 receptors in the central and peripheral nervous system.
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intranigral substance p stimulation of striatal dopamine release is inhibited by Spantide ii a new tachykinin antagonist without apparent neurotoxicity
Brain Research, 1990Co-Authors: M S Reid, R Hakanson, Dongmei Feng, Karl Folkers, T Hokfelt, Mario Herreramarschitz, M Goldstein, Urban UngerstedtAbstract:Abstract The effects of intranigral injections of Spantide II, a novel tachykinik antagonist, on extracellular dopamine, and dihydroxyphenylacetic acid (DOPAC) levels in the rat striatum were studied using in vivo microdialysis. The ability of Spantide II to inhibit intranigral substance P or neurokinin A stimulation of striatal dopamine levels was also studied. A unilateral injection (all substances were injected in a volume of 0.2 μl) of Spantide II (0.7 nmol) intot he substantia nigra, pars reticulata (SNR) of halothane anaesthetized rats produced a short-lasting decrease in dopamine levels in the spsilateral striatum. Striatal DOPAC levels showed no change after Spantide II. A unilateral injection of substance P (0.07 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was prevented when substance P was co-administered with Spantide II (0.7 nmol). A unilateral injection of neurokinin A (0.09 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was not modified when neurokinin A was co-administered with Spantide II (0.7 nmol). Immunohistochemical analysis using antisera to tyrosine hydroxylase and neuropeptide K, as well as Cresyl violet staining, revealed that intranigral injections of Spantide II (0.7 nmol) did not produce significant damage in the substantia nigra. The results indicate that Spantide II is not ‘neurotoxic’ when injected intranigrally, and that it is a selective antagonist of substance P in the substantia nigra. Furthermore, the reduction of striatal dopamine levels after intranigral Spantide II injections suggests that nigrostriatal dopamine projection is tonically stimulated by striatonigral substance P.
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Spantide ii a novel tachykinin antagonist having high potency and low histamine releasing effect
Regulatory Peptides, 1990Co-Authors: R Hakanson, S Leander, Naoki Asano, Dongmei Feng, Karl FolkersAbstract:Two undecapeptide substance P (SP) analogues, Spantide I and Spantide II, were tested for their capacity to block the contractile effect of SP on the guinea pig isolated taenia coli and the contractile effect of electrical stimulation of the rabbit isolated (and atropinized) iris sphincter, and for their capacity to mobilize histamine from rat isolated peritoneal mast cells. Spantide I and Spantide II have one feature in common, namely d-tryptophan in positions 7 and 9. Spantide I: d-Arg, Pro2, Lys3, Pro4, Gln5, Gln6, D-Trp7, Phe8, d-Trp9, Leu10, Leu11-NH2. Spantide II: d-NicLys1, Pro2, 3-Pal3, Pro4, d-Cl2Phe5, Asn6, D-Trp7, Phe8, D-Trp9, Leu10, Nle11-NH2. Both Spantide I and II were found to be competitive antagonists to SP on the taenia coli and to be capable of blocking the electrically induced non-cholinergic contraction of the iris sphincter. Spantide II had higher pA2 value (taenia coli) than Spantide I, 7.7 versus 7.0, and higher pIC50 value (blockade of tachykinin-mediated neurotransmission in iris sphincter), 6.0 versus 5.1. Both Spantide I and II mobilized histamine from rat peritoneal mast cells but Spantide II was less effective. Spantide I and II were tested for antagonistic specificity. Both blocked contractions of the taenia induced by SP and neurokinin A. In the concentration used, Spantide II in addition blocked the response to neurokinin B. The contractions induced by carbachol, 5-hydroxytryptamine, histamine and prostaglandins (F2α and E1) were not affected; the contractile response to bombesin was inhibited by Spantide I but not by Spantide II.
Loice Kikwai - One of the best experts on this subject based on the ideXlab platform.
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stability and degradation profiles of Spantide ii in aqueous solutions
European Journal of Pharmaceutical Sciences, 2006Co-Authors: Loice Kikwai, Narayanasamy Kanikkannan, Jayachandra R Babu, Mandip SinghAbstract:Abstract Spantide II is an 11 amino acid peptide that has been shown to be a potential anti-inflammatory agent. The stability and degradation profiles of Spantide II in aqueous solutions were evaluated with the long-term objective of developing topical formulations of this compound for various skin disorders. The stability profile of Spantide II at various temperature and pH conditions was monitored by high performance liquid chromatography (HPLC) and the resulting degradation products were identified by liquid chromatography-mass spectroscopy (LC-MS). Forced degradation of Spantide II was performed at extreme acidic (pH 10.0) conditions and by addition of hydrogen peroxide (oxidizing agent). The degradation pattern of Spantide II followed pseudo first-order kinetics. The shelf life (T90%) of Spantide II in aqueous ethanol (50%) was determined to be 230 days at 25 °C. Spantide II was susceptible to degradation at pH 5 and showed maximum stability at pH 3–5. The stability under various pH conditions indicates that Spantide II was most stable at pH 3.0 with a half-life of 95 days at 60 °C. Spantide II degradation was attributed to hydrolysis of peptide bonds [Pro2-(pyridyl)Ala3, (nicotinoyl)Lys1-Pro2, Pro4-PheCl25, Trp7-Phe8, Phe8-Trp9, Nle11-NH2), racemization of the peptide fragments that resulted from hydrolysis, cleavage and formation of (nicotinoyl)Lys1-Pro2 diketopiperazine. In the presence of an oxidizing agent, Pro2,4 residues degraded by ring opening to form glutamyl-semialdehyde and by bond cleavage at Pro4 to form 2-pyrrolidone, while Phe5,8 degraded to form 2-hydroxyphenylalanine. Spantide II was found to be stable in aqueous medium with T90% of 230 days. The major degradation pathways of Spantide II were identified as hydrolysis, racemization, cleavage and formation of diketopiperazine.
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In vitro and in vivo evaluation of topical formulations of Spantide II
AAPS PharmSciTech, 2005Co-Authors: Loice Kikwai, Renata Prado, Alexandra Kolot, Cheryl A. Armstrong, John C. Ansel, R. Jayachandra Babu, Mandip SinghAbstract:The purpose of this study was to develop and evaluate topical formulations of Spantide II, a neurokinin-1 receptor (NK-1R) antagonist, for the treatment of inflammatory skin disorders. Spantide II lotion and gel was formulated with and without n-methyl-2-pyrrolidone (NMP) as a penetration enhancer. The release of Spantide II from gels was evaluated using microporous polyethylene and polypropylene membranes in a Franz Diffusion cell setup. In vitro percutaneous absorption of Spantide II from lotion and gel formulations was evaluated using the above setup by replacing the membranes with hairless rat skin. The in vivo anti-inflammatory activity of Spantide II formulations was evaluated in an allergic contact dermatitis (ACD) mouse model. Among different gels studied, PF127 gel showed highest (70-fold) release of Spantide II compared with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) gels. Lotion and gel formulations with or without NMP showed no detectable levels of Spantide II in the receiver compartment of the Franz diffusion cell until 24 hours. However, Spantide II showed significant retention in epidermis and dermis from lotion and gel formulations at 24 hours. The dermal levels increased ≈3.5- and 2-fold when the lotion and gel formulations contained NMP as compared with the formulation with no NMP (P
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Stability and degradation profiles of Spantide II in aqueous solutions.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2005Co-Authors: Loice Kikwai, R. Jayachandra Babu, Narayanasamy Kanikkannan, Mandip SinghAbstract:Spantide II is an 11 amino acid peptide that has been shown to be a potential anti-inflammatory agent. The stability and degradation profiles of Spantide II in aqueous solutions were evaluated with the long-term objective of developing topical formulations of this compound for various skin disorders. The stability profile of Spantide II at various temperature and pH conditions was monitored by high performance liquid chromatography (HPLC) and the resulting degradation products were identified by liquid chromatography-mass spectroscopy (LC-MS). Forced degradation of Spantide II was performed at extreme acidic (pH 10.0) conditions and by addition of hydrogen peroxide (oxidizing agent). The degradation pattern of Spantide II followed pseudo first-order kinetics. The shelf life (T90%) of Spantide II in aqueous ethanol (50%) was determined to be 230 days at 25 degrees C. Spantide II was susceptible to degradation at pH 5 and showed maximum stability at pH 3-5. The stability under various pH conditions indicates that Spantide II was most stable at pH 3.0 with a half-life of 95 days at 60 degrees C. Spantide II degradation was attributed to hydrolysis of peptide bonds [Pro2-(pyridyl)Ala3, (nicotinoyl)Lys1-Pro2, Pro4-PheCl2(5), Trp7-Phe8, Phe8-Trp9, Nle11-NH2), racemization of the peptide fragments that resulted from hydrolysis, cleavage and formation of (nicotinoyl)Lys1-Pro2 diketopiperazine. In the presence of an oxidizing agent, Pro(2,4) residues degraded by ring opening to form glutamyl-semialdehyde and by bond cleavage at Pro4 to form 2-pyrrolidone, while Phe(5,8) degraded to form 2-hydroxyphenylalanine. Spantide II was found to be stable in aqueous medium with T90% of 230 days. The major degradation pathways of Spantide II were identified as hydrolysis, racemization, cleavage and formation of diketopiperazine.
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in vitro and in vivo evaluation of topical formulations of Spantide ii
Aaps Pharmscitech, 2005Co-Authors: Loice Kikwai, Renata Prado, Alexandra Kolot, Cheryl A. Armstrong, John C. Ansel, Jayachandra R Babu, Mandip SinghAbstract:The purpose of this study was to develop and evaluate topical formulations of Spantide II, a neurokinin-1 receptor (NK-1R) antagonist, for the treatment of inflammatory skin disorders. Spantide II lotion and gel was formulated with and without n-methyl-2-pyrrolidone (NMP) as a penetration enhancer. The release of Spantide II from gels was evaluated using microporous polyethylene and polypropylene membranes in a Franz Diffusion cell setup. In vitro percutaneous absorption of Spantide II from lotion and gel formulations was evaluated using the above setup by replacing the membranes with hairless rat skin. The in vivo anti-inflammatory activity of Spantide II formulations was evaluated in an allergic contact dermatitis (ACD) mouse model. Among different gels studied, PF127 gel showed highest (70-fold) release of Spantide II compared with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) gels. Lotion and gel formulations with or without NMP showed no detectable levels of Spantide II in the receiver compartment of the Franz diffusion cell until 24 hours. However, Spantide II showed significant retention in epidermis and dermis from lotion and gel formulations at 24 hours. The dermal levels increased ≈3.5- and 2-fold when the lotion and gel formulations contained NMP as compared with the formulation with no NMP (P<.05). The in vivo studies indicated that Spantide II formulations with NMP were effective in significantly reducing ACD response, similar to dexamethasone (0.5 mM). In conclusion, Spantide II was stable as a topical formulation and delivered to target skin tissue (epidermis and dermis) for the treatment of ACD. In addition this study supports the role of cutaneous neurosensory system in modulating inflammatory responses in the skin.
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preformulation stability of Spantide ii a promising topical anti inflammatory agent for the treatment of psoriasis and contact dermatitis
Journal of Pharmacy and Pharmacology, 2004Co-Authors: Loice Kikwai, R J Babu, Narayanasamy Kanikkannan, Mandip SinghAbstract:: Substance P is readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.