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P Ward - One of the best experts on this subject based on the ideXlab platform.
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gr205171 a novel antagonist with high affinity for the tachykinin nk1 receptor and potent broad spectrum anti Emetic Activity
Regulatory Peptides, 1996Co-Authors: C J Gardner, D R Armour, D T Beattie, J D Gale, A B Hawcock, G J Kilpatrick, D J Twissell, P WardAbstract:Abstract It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-Emetic Activity in a range of species. To optimise this Activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitutions at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-Emetic Activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-Emetic Activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-Emetic agent.
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the broad spectrum anti Emetic Activity of the novel non peptide tachykinin nk1 receptor antagonist gr203040
British Journal of Pharmacology, 1995Co-Authors: C J Gardner, C C Jordan, T J Dale, C. Bountra, J D Gale, G J Kilpatrick, D J Twissell, P WardAbstract:1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-Emetic in ferrets, we have examined the anti-Emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various Emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-Emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-Emetic agent, and the broad spectrum of anti-Emetic Activity, together with Activity observed in three species, suggests that this compound is worthy of clinical investigation.
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Anti-Emetic Activity of Neurokinin NK1 receptor antagonists is mediated centrally in the ferret [abstract]
British Journal of Pharmacology, 1994Co-Authors: C J Gardner, C C Jordan, D J Twissel, K.t. Bunce, T J Dale, C. Bountra, P WardAbstract:IthasbeenshownpreviouslyintheferetthataneurokininNKIreceptorantagonist(NK1 antagonist)administeredperipherallyexertsan anti-Emeticactionagainstawiderangeofemetogens(Bountraetal.,1993). Inthepresentstudy,theeffectsofcentraladministrationof NK1 antagonists (a peptide, GR82334, and non-peptides, racemic CP-99,994 and its less active enantiomer, CP-100,263) on eme'sis inducedbycisplatinwereinvestigatedintheconsciousferet. Inaddition,substanceP(SP)wasadministeredcentrallyinnon-cisplatin treatedferets. A guide-cannula was implanted in the hindbrain of adult, male ferrets (body weights 1.2-1.8kg) under general anaesthesia ( Higgins et al.,1989),andaminimumof48hwasallowedbeforeexperimentaluse. Emesiswasinducedbyintraperitonealcisplatin(200mgm-2 bodysurfacearea). TheNK1 antagonistsorsalinecontrolwereadministered(dosevolume,2p1)afterthefirstEmeticresponseintothe hind-brain,intheregionofthenucleustractussolitarius,viaaneedlepassedthroughtheimplantedguide-cannula. Thenumberof retcheswasrecordedovera4hperiodaftercentraladministration,andtheresultsareshown inTable 1. Two non-cisplatin-treatedferets receivedSPcentrally(1Oggin2p1)on7occasionsat30minintervals. Racemic CP-99,994 produced a dose-related inhibition of cisplatin- (mean±S.E.M.) (%) inducedemesis,andthe10tgdoseofCP-100,263showedsimilaranti- Emetic Activity to the 1jg dose of the racemate. Peripheral administration of GR82334 (5.4mg kg-1 i.v., n=4) showed no anti- Emetic Activity in cisplatin-treated ferets, whereas central administrationofthepeptideproducedinhibition. Repeatedcentral administration of SP consistently induced an immediate, short-lived Table1 Treatment Dose Salinecontrol 2,u1 (±)CP-99,994 1jg 1O0,g CP-100,263 1Ojg GR82334 1Ig I0[tg 5 28±15.3t 77 tsignificantdifferencefromcontrol,p
John A Rudd - One of the best experts on this subject based on the ideXlab platform.
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action of bacopa monnieri to antagonize cisplatin induced emesis in suncus murinus house musk shrew
Journal of Pharmacological Sciences, 2017Co-Authors: Ihsan Ullah, Fazal Subhan, Zengbing Lu, Sze Wa Chan, John A RuddAbstract:Abstract Bacopa monnieri ( BM , family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol ( BM -MetFr) and BM n -butanol fractions ( BM -ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM -MetFr (10–40 mg/kg, s.c.) and BM -ButFr (5–20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ∼59.4% ( p p 3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ∼71% ( p N -(2-mercaptopropionyl)-glycine (30–300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non-significantly by 44% ( p > 0.05). In conclusion, the n -butanol fractions of BM have anti-Emetic Activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-Emetic drugs for the treatment of chemotherapy-induced emesis in man.
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profile of antiEmetic Activity of netupitant alone or in combination with palonosetron and dexamethasone in ferrets and suncus murinus house musk shrew
Frontiers in Pharmacology, 2016Co-Authors: John A Rudd, Man P Ngan, Zengbing Lu, Guy A Higgins, Claudio Giuliano, Emanuela Lovati, Claudio PietraAbstract:Background and Aims: Chemotherapy-induced acute and delayed emesis involves the activation of multiple pathways, with 5-hydroxytryptamine (5-HT; serotonin) playing a major role in the initial response. Substance P tachykinin NK1 receptor antagonists can reduce emesis induced by disparate Emetic challenges and therefore have a clinical utility as broad inhibitory anti-Emetic drugs. In the present studies, we investigate the broad inhibitory anti-Emetic profile of a relatively new NK1 receptor antagonist, netupitant, alone or in combination with the long acting 5-HT3 receptor antagonist, palonosetron, for a potential to reduce emesis in ferrets and shrews. Materials and Methods: Ferrets were pretreated with netupitant and/or palonosetron, or their combination, and then administered apomorphine (0.125 mg/kg, s.c.), morphine (0.5 mg/kg, s.c.), ipecacuanha (1.2 mg/kg, p.o.), copper sulphate (100 mg/kg, intragastric), or cisplatin (5-10 mg/kg, i.p.); in other studies netupitant was administered to Suncus murinus before motion (4 cm horizontal displacement, 2 Hz for 10 min). Results: Netupitant (3 mg/kg, p.o.) abolished apomorphine-, morphine-, ipecacuanha- and copper sulphate-induced emesis. Lower doses of netupitant (0.03-0.3 mg/kg, p.o.) dose-dependently reduced cisplatin (10 mg/kg, i.p.)-induced emesis in an acute (8 h) model, and motion-induced emesis in Suncus murinus. In a ferret cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis model, netupitant administered once at 3 mg/kg, p.o., abolished the first 24 h response and reduced the 24-72 h response by 94.6 %; the reduction was markedly superior to the effect of a three times per day administration of ondansetron (1 mg/kg, i.p.). A single administration of netupitant (1 mg/kg, p.o.) plus palonosetron (0.1 mg/kg, p.o.) combined with dexamethasone (1 mg/kg, i.p., once per day), also significantly antagonized cisplatin-induced acute and delayed emesis and was comparable with a once-daily regimen of ondansetron (1 mg/kg, p.o.) plus aprepitant (1 mg/kg, p.o.) in combination with dexamethasone (1 mg/kg, i.p.). Conclusion: Netupitant has potent and long lasting anti-Emetic Activity against a number of Emetic challenges indicating broad inhibitory properties. The convenience of protection afforded by the single dosing of netupitant together with palonosetron was demonstrated and also is known to provide an advantage over other therapeutic strategies to control emesis in man.
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Olvanil: a non-pungent TRPV1 activator has anti-Emetic properties in the ferret.
Neuropharmacology, 2009Co-Authors: Man-piu Ngan, Paul L R Andrews, Chi-kong Yeung, Nathalie Percie Du Sert, John A RuddAbstract:Abstract Anti-Emetic drugs such as the tachykinin NK 1 receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-Emetic Activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-Emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05–5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants. In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-Emetic Activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-Emetic properties via central and/or peripheral mechanisms after peripheral administration.
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anti Emetic Activity of ghrelin in ferrets exposed to the cytotoxic anti cancer agent cisplatin
Neuroscience Letters, 2006Co-Authors: John A Rudd, Man P Ngan, Andrew G King, Jason Witherington, Paul L R Andrews, Gareth J SangerAbstract:Abstract Emesis may be modulated via multiple mechanisms. The actions of ghrelin suggest an ability to couple an induction of hunger with preparation of the stomach for ingestion of food. Such a process might reduce any tendency to vomit, so an anti-Emetic Activity of ghrelin was investigated in the ferret cisplatin-induced emesis model. In controls, intra-peritoneal cisplatin (10 mg/kg) induced 41.4 ± 8.4 episodes of emesis comprising 310.4 ± 55.3 retches and 28.8 ± 6.9 vomits during the 6 h observation; the latency to onset of the first Emetic episode was 108.9 ± 4.8 min. Intra-peritoneal ghrelin (1 mg/kg, split as a 30 min pre- and 30 min-post dose) did not induce a change in behaviour or modify cisplatin-induced emesis ( p > 0.05). Intracerebroventricular (i.c.v.) administration (third ventricle) was achieved via a pre-implanted cannula. At the first Emetic episode following cisplatin, ghrelin or vehicle (20 μl saline) was administered i.c.v. During the 30 min following the initial episode of emesis, control animals exhibited 18.0 ± 2.6 Emetic episodes comprising 160.3 ± 24.1 retches and 13.8 ± 2.7 vomits. Ghrelin 10 μg i.c.v. reduced the number of retches by 61.5% ( p p p p p > 0.05). An ability of ghrelin to reduce emesis is consistent with a role in modulating gastro-intestinal functions and identifies a novel approach to the treatment of emesis.
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Anti-Emetic Activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin.
Neuroscience letters, 2005Co-Authors: John A Rudd, Man P Ngan, Andrew G King, Jason Witherington, Paul L R Andrews, Gareth J SangerAbstract:Emesis may be modulated via multiple mechanisms. The actions of ghrelin suggest an ability to couple an induction of hunger with preparation of the stomach for ingestion of food. Such a process might reduce any tendency to vomit, so an anti-Emetic Activity of ghrelin was investigated in the ferret cisplatin-induced emesis model. In controls, intra-peritoneal cisplatin (10 mg/kg) induced 41.4+/-8.4 episodes of emesis comprising 310.4+/-55.3 retches and 28.8+/-6.9 vomits during the 6h observation; the latency to onset of the first Emetic episode was 108.9+/-4.8 min. Intra-peritoneal ghrelin (1mg/kg, split as a 30 min pre- and 30 min-post dose) did not induce a change in behaviour or modify cisplatin-induced emesis (p>0.05). Intracerebroventricular (i.c.v.) administration (third ventricle) was achieved via a pre-implanted cannula. At the first Emetic episode following cisplatin, ghrelin or vehicle (20 microl saline) was administered i.c.v. During the 30 min following the initial episode of emesis, control animals exhibited 18.0+/-2.6 Emetic episodes comprising 160.3+/-24.1 retches and 13.8+/-2.7 vomits. Ghrelin 10 microg i.c.v. reduced the number of retches by 61.5% (p
C J Gardner - One of the best experts on this subject based on the ideXlab platform.
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gr205171 a novel antagonist with high affinity for the tachykinin nk1 receptor and potent broad spectrum anti Emetic Activity
Regulatory Peptides, 1996Co-Authors: C J Gardner, D R Armour, D T Beattie, J D Gale, A B Hawcock, G J Kilpatrick, D J Twissell, P WardAbstract:Abstract It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-Emetic Activity in a range of species. To optimise this Activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitutions at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-Emetic Activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-Emetic Activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-Emetic agent.
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the broad spectrum anti Emetic Activity of the novel non peptide tachykinin nk1 receptor antagonist gr203040
British Journal of Pharmacology, 1995Co-Authors: C J Gardner, C C Jordan, T J Dale, C. Bountra, J D Gale, G J Kilpatrick, D J Twissell, P WardAbstract:1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-Emetic in ferrets, we have examined the anti-Emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various Emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-Emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-Emetic agent, and the broad spectrum of anti-Emetic Activity, together with Activity observed in three species, suggests that this compound is worthy of clinical investigation.
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Anti-Emetic Activity of Neurokinin NK1 receptor antagonists is mediated centrally in the ferret [abstract]
British Journal of Pharmacology, 1994Co-Authors: C J Gardner, C C Jordan, D J Twissel, K.t. Bunce, T J Dale, C. Bountra, P WardAbstract:IthasbeenshownpreviouslyintheferetthataneurokininNKIreceptorantagonist(NK1 antagonist)administeredperipherallyexertsan anti-Emeticactionagainstawiderangeofemetogens(Bountraetal.,1993). Inthepresentstudy,theeffectsofcentraladministrationof NK1 antagonists (a peptide, GR82334, and non-peptides, racemic CP-99,994 and its less active enantiomer, CP-100,263) on eme'sis inducedbycisplatinwereinvestigatedintheconsciousferet. Inaddition,substanceP(SP)wasadministeredcentrallyinnon-cisplatin treatedferets. A guide-cannula was implanted in the hindbrain of adult, male ferrets (body weights 1.2-1.8kg) under general anaesthesia ( Higgins et al.,1989),andaminimumof48hwasallowedbeforeexperimentaluse. Emesiswasinducedbyintraperitonealcisplatin(200mgm-2 bodysurfacearea). TheNK1 antagonistsorsalinecontrolwereadministered(dosevolume,2p1)afterthefirstEmeticresponseintothe hind-brain,intheregionofthenucleustractussolitarius,viaaneedlepassedthroughtheimplantedguide-cannula. Thenumberof retcheswasrecordedovera4hperiodaftercentraladministration,andtheresultsareshown inTable 1. Two non-cisplatin-treatedferets receivedSPcentrally(1Oggin2p1)on7occasionsat30minintervals. Racemic CP-99,994 produced a dose-related inhibition of cisplatin- (mean±S.E.M.) (%) inducedemesis,andthe10tgdoseofCP-100,263showedsimilaranti- Emetic Activity to the 1jg dose of the racemate. Peripheral administration of GR82334 (5.4mg kg-1 i.v., n=4) showed no anti- Emetic Activity in cisplatin-treated ferets, whereas central administrationofthepeptideproducedinhibition. Repeatedcentral administration of SP consistently induced an immediate, short-lived Table1 Treatment Dose Salinecontrol 2,u1 (±)CP-99,994 1jg 1O0,g CP-100,263 1Ojg GR82334 1Ig I0[tg 5 28±15.3t 77 tsignificantdifferencefromcontrol,p
Dongliang Hu - One of the best experts on this subject based on the ideXlab platform.
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Biological characteristics of staphylococcal enterotoxin Q and its potential risk for food poisoning.
Journal of Applied Microbiology, 2017Co-Authors: Dongliang Hu, S. Isayama, R. Okada, Masashi Okamura, X.‐c. ZhangAbstract:AIMS: To elucidate the biological characteristics and stability of a newly identified staphylococcal enterotoxin Q (SEQ) against heating and digestive enzymes and to evaluate the risk of seq-harbouring Staphylococcus aureus in food poisoning. METHODS AND RESULTS: Purified SEQ was treated with heating, pepsin and trypsin which are related to food cooking, stomach and intestine conditions, respectively. Superantigenic Activity of SEQ was assessed by determining the ability of IL-2 induction in mouse spleen cells. The Emetic Activity of SEQ was assessed using house musk shrew, a small Emetic animal model. The results revealed that SEQ exhibits a remarkable resistance to heat treatment and pepsin digestion and has significant superantigenic and Emetic activities. Furthermore, a sandwich ELISA for detection of SEQ production was developed, and the results showed that seq-harboring S. aureus isolates produce a large amount of SEQ. CONCLUSIONS: The newly identified SEQ had remarkable stability to heat treatment and digestive enzyme degradation and exhibited significant superantigenic and Emetic activities. In addition, seq-harbouring S. aureus isolated from food poisoning outbreaks produced a large amount of SEQ, suggesting that seq-harbouring S. aureus could potentially be a hazard for food safety. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found, for the first time, that SEQ, a nonclassical SE, had remarkable stability to heat treatment and enzyme degradation and exhibited significant Emetic Activity, indicating that SEQ is a high-risk toxin in food poisoning.
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the Emetic Activity of staphylococcal enterotoxins sek sel sem sen and seo in a small Emetic animal model the house musk shrew
Microbiology and Immunology, 2017Co-Authors: Shouhei Hirose, Dongliang Hu, Katsuhiko Omoe, Ikunori Naito, Yusuke Satoo, Krisana Asano, Akio NakaneAbstract:: Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are the most recognizable causative agents of Emetic food poisoning in humans. New types of SEs and SE-like (SEl) toxins have been reported. Several epidemiological investigations have shown that the SEs and SEl genes, particularly, SEK, SEL, SEM, SEN and SEO genes, are frequently detected in strains isolated from patients with food poisoning. The purpose of the present study was to evaluate the Emetic Activity of recently identified SEs using a small Emetic animal model, the house musk shrew. The Emetic Activity of these SEs in house musk shrews was evaluated by intraperitoneal administration and Emetic responses, including the number of shrews that vomited, Emetic frequency and latency of vomiting were documented. It was found that SEs induce Emetic responses in these animals. This is the first time to demonstrate that SEK, SEL, SEM, SEN and SEO possess Emetic Activity in the house musk shrew.
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Identification and Characterization of a Novel Staphylococcal Emetic Toxin
Applied and Environmental Microbiology, 2015Co-Authors: Yusuke Sato'o, Dongliang Hu, Katsuhiko Omoe, Shouhei Hirose, Ikunori Naito, Krisana Asano, Junzo Hisatsune, Kouji Narita, Motoyuki SugaiAbstract:Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus have superantigenic and Emetic activities, which cause toxic shock syndrome and staphylococcal food poisoning, respectively. Our previous study demonstrated that the sequence of SET has a low level of similarity to the sequences of other SEs and exhibits atypical bioactivities. Hence, we further explored whether there is an additional SET-related gene in S. aureus strains. One SET-like gene was found in the genome of S. aureus isolates that originated from a case of food poisoning, a human nasal swab, and a case of bovine mastitis. The deduced amino acid sequence of the SET-like gene showed 32% identity with the amino acid sequence of SET. The SET-like gene product was designated SElY. In the food poisoning and nasal swab isolates, mRNA encoding SElY was highly expressed in the early log phase of cultivation, whereas a high level of expression of this mRNA was found in the bovine mastitis isolate at the early stationary phase. To estimate whether SElY has both superantigenic and Emetic activities, recombinant SElY was prepared. Cell proliferation and cytokine production were examined to assess the superantigenic Activity of SElY. SElY exhibited superantigenic Activity in human peripheral blood mononuclear cells but not in mouse splenocytes. In addition, SElY exhibited Emetic Activity in house musk shrews after intraperitoneal and oral administration. However, the stability of SElY against heating and pepsin and trypsin digestion was different from that of SET and SEA. From these results, we identified SElY to be a novel staphylococcal Emetic toxin.
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Inhibition of Emetic and superantigenic activities of staphylococcal enterotoxin A by synthetic peptides
Peptides, 2012Co-Authors: Edward K. Maina, Dongliang Hu, Krisana Asano, Akio NakaneAbstract:Abstract Staphylococcus aureus is a major human pathogen producing different types of toxins. Enterotoxin A (SEA) is the most common type among clinical and food-related strains. The aim of the present study was to estimate functional regions of SEA that are responsible for Emetic and superantigenic activities using synthetic peptides. A series of 13 synthetic peptides corresponding to specific regions of SEA were synthesized, and the effect of these peptides on superantigenic Activity of SEA including interferon γ (IFN-γ) production in mouse spleen cells, SEA-induced lethal shock in mice, spleen cell proliferation in house musk shrew, and Emetic Activity in shrews were assessed. Pre-treatment of spleen cells with synthetic peptides corresponding to the regions 21–40, 35–50, 81–100, or 161–180 of SEA significantly inhibited SEA-induced IFN-γ production and cell proliferation. These peptides also inhibited SEA-induced lethal shock. Interestingly, peptides corresponding to regions 21–40, 35–50 and 81–100 significantly inhibited SEA-induced emesis in house musk shrews, but region 161–180 did not. These findings indicated that regions 21–50 and 81–100 of SEA are important for both superantigenic and Emetic activities of SEA molecule while region 161–180 is involved in superantigenic Activity but not Emetic Activity of SEA. These regions could be important targets for therapeutic intervention against SEA exposure.
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Identification and Characterization of Two Novel Staphylococcal Enterotoxins, Types S and T
Infection and Immunity, 2008Co-Authors: Katsuhiko Omoe, Dongliang Hu, Akio Nakane, Takehiko Uchiyama, Ken'ichi Imanishi, Hidehito Kato, Yoshihiro Iwakabe, Naoyuki Saito, Kunihiro ShinagawaAbstract:In addition to two known staphylococcal enterotoxin-like genes (selj and selr), two novel genes coding for two superantigens, staphylococcal enterotoxins S and T (SES and SET), were identified in plasmid pF5, which is harbored by food poisoning-related Staphylococcus aureus strain Fukuoka 5. This strain was implicated in a food poisoning incident in Fukuoka City, Japan, in 1997. Recombinant SES (rSES) specifically stimulated human T cells in a T-cell receptor Vβ9- and Vβ16-specific manner in the presence of major histocompatibility complex (MHC) class II+ antigen-presenting cells (APC). rSET also stimulated T cells in the presence of MHC class II+ APC, although its Vβ skewing was not found in reactive T cells. Subsequently, we examined the Emetic Activity of SES and SET. We also studied SElR to determine Emetic Activity in primates. This toxin was identified in previous studies but was not examined in terms of possession of Emetic Activity for primates. rSES induced Emetic reactions in two of four monkeys at a dose of 100 μg/kg within 5 h of intragastric administration. In one monkey, rSET induced a delayed reaction (24 h postadministration) at a dose of 100 μg/kg, and in the other one, the reaction occurred 5 days postadministration. rSElR induced a reaction in two of six animals within 5 h at 100 μg/kg. On this basis, we speculate that the causative toxins of vomiting in the Fukuoka case are SES and SER. Additionally, SES, SER, and SET also induced emesis in house musk shrews as in the monkeys.
Malcolm Maccoss - One of the best experts on this subject based on the ideXlab platform.
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in vitro and in vivo predictors of the anti Emetic Activity of tachykinin nk1 receptor antagonists
European Journal of Pharmacology, 1997Co-Authors: N M J Rupniak, David F Tattersall, Angela R Williams, W Rycroft, Emma J Carlson, Margaret A Cascieri, S Sadowski, Jeffrey J Hale, Sander G Mills, Malcolm MaccossAbstract:The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (d-Ala-[l-Pro9,Me-Leu8]substance P-(7–11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (±)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2,4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50≤0.85 mg/kg), and acute retching induced by cisplatin (ID50≤0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50>10 mg/kg). High doses (3–10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl]-4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-propyl]-N-methyl-N-phenylmethyl-l-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-Emetic in this dose range. SR140333 ((S)-1-{2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl}-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3–10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 receptor were highly correlated (r=0.93, P=0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-Emetic Activity in ferrets (r=0.75, P<0.01). These findings confirm that the anti-Emetic Activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.