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Educational Status↗
Biomedical subjects
J A Rudd
Publications and source records attributed to J A Rudd.
Genital grooming and emesis induced by vanilloids in Suncus murinus, the house musk shrew.
The potential of resiniferatoxin and capsaicin to modulate emesis and genital grooming was investigated in Suncus murinus. Resinifertoxin (3-30 nmol, i.c.v.), E-capsaicin (10-100 nmol, i.c.v.) and Z-capsaicin (100 nmol, i.c.v.) induced emesis (P<0.05) and subsequently antagonised the emetic response induced by intragastric copper sulphate (480.6 micromol/kg; P<0.05). However, resiniferatoxin failed to affect nicotine-induced (30.7 mol/kg, s.c.) emesis (P>0.05). Only resiniferatoxin induced genital grooming that was antagonised (P<0.05) by capsazepine (300-600 nmol, i.c.v.) and ruthenium red (3 nmol, i.c.v.). E-capsaicin-induced emesis was antagonised by capsazepine (300-600 nmol, i.c.v.; P<0.05) and ruthenium red (3 nmol, i.c.v.; P<0.05) but resiniferatoxin-induced emesis was resistant to capsazepine (30-600 nmol, i.c.v.; P>0.05). The emetic action of resiniferatoxin but not E-capsaicin was subject to tachyphylaxis. In cross-tachyphylaxis experiments, E-capsaicin reduced the genital grooming induced by resiniferatoxin (P<0.05). The data are discussed in relation to the classification of vanilloid receptors and mechanisms involved in emesis and genital grooming.
Animals↗
Action of glucocorticoids to antagonise cisplatin-induced acute and delayed emesis in the ferret.
Cisplatin 5 mg/kg, i.p. induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of several glucocorticoids. Betamethasone (0.3-3 mg/kg, i.p.) reduced the emesis occurring during the initial 0-24-h period by 71.1-99.5% (P<0.05). The action of methylprednisolone (1.0-10.0 mg/kg, i.p.) and hydrocortisone (1.0-30.0 mg/kg, i.p.) could not be assessed because the controls exhibited weak emetic responses and dexamethasone produced a non-significant 64.0% reduction at 0.3 mg/kg (P>0.05). However, all glucocorticoids dose-dependently reduced retching+vomiting during the subsequent 24-56-h period. The rank order of anti-emetic potency was betamethasone (ID(80)<0.3 mg/kg)>/=dexamethasone (ID(80)=0.32 mg/kg)>methylprednisolone (ID(80)=0.66 mg/kg)&z.Gt;hydrocortisone (ID(80)>30 mg/kg). Dexamethasone was ineffective to antagonise the retching+vomiting response during the 24-56-h period when the administration was delayed until 24 h post-cisplatin injection. None of the glucocorticoids reduced the retching+vomiting response occurring during the 56-72-h period. In conclusion, the rank order of anti-emetic potency suggests that inflammation, or mediators of inflammation, contribute to the retching+vomiting response induced by cisplatin.
Acute Disease↗
Cisplatin-induced emesis in the cat: effect of granisetron and dexamethasone.
The emetic action of cisplatin was investigated in the cat using a closed circuit video recording system. In initial investigations, cisplatin 3 and 5 mg/kg, i.v. induced emesis over a 2-day period following a latency of 17.6+/-9.6 and 15.6+/-7.8 h, respectively. The anti-emetic efficacy of granisetron and dexamethasone was investigated in the cisplatin 5 mg/kg, i.v.-induced emesis model. In these experiments, cisplatin induced 47.0+/-14.0 and 20.0+/-9.0 retches+vomits on days 1 and 2, respectively, following a latency of 2.4+/-0.4 h. Granisetron (1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response induced by cisplatin on days 1 and 2 by 100.0% (P<0.05) and 75.0% (P<0.05), respectively; dexamethasone (0.01-1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response by 68.8-100.0% (P<0.05) and 33.3-100.0% (P<0.05) on days 1 and 2, respectively. The emetic action of cisplatin 7.5 mg/kg, i.v. was also investigated. This dose of cisplatin-induced emesis following a latency of 1.2+/-0.2 h and comprised 119.0+/-20.8 retches+vomits over a 24-h period. Granisetron and dexamethasone antagonized the emesis occurring in the first 3-h period (P<0.05) but were less effective to antagonize the subsequent emetic response (P0.05). The pharmacological sensitivity of low dose cisplatin-induced emesis in the cat is variable but unique and not representative of the clinical situation.
Animals↗
Non-prostanoid prostacyclin mimetics as neuronal stimulants in the rat: comparison of vagus nerve and NANC innervation of the colon.
The spontaneous activity of the rat isolated colon is suppressed by prostacyclin analogues such as cicaprost (IC(50)=4.0 nM). Activation of prostanoid IP(1)-receptors located on NANC inhibitory neurones is involved. However, several non-prostanoids, which show medium to high IP(1) agonist potency on platelet and vascular preparations, exhibit very weak inhibitory activity on the colon. The aim of the study was to investigate this discrepancy. Firstly, we have demonstrated the very high depolarizing potency of cicaprost on the rat isolated vagus nerve (EC(50)=0.23 nM). Iloprost, taprostene and carbacyclin were 7.9, 66, and 81 fold less potent than cicaprost, indicating the presence of IP(1) as opposed to IP(2)-receptors. Three non-prostanoid prostacyclin mimetics, BMY 45778, BMY 42393 and ONO-1301, although much less potent than cicaprost (195, 990 and 1660 fold respectively), behaved as full agonists on the vagus nerve. On re-investigating the rat colon, we found that BMY 45778 (0.1 - 3 microM), BMY 42393 (3 microM) and ONO-1301 (3 microM) behaved as specific IP(1) partial agonists, but their actions required 30 - 60 min to reach steady-state and only slowly reversed on washing. This profile contrasted sharply with the rapid and readily reversible contractions elicited by a related non-prostanoid ONO-AP-324, which is an EP(3)-receptor agonist. The full versus partial agonism of the non-prostanoid prostacyclin mimetics may be explained by the markedly different IP(1) agonist sensitivities of the two rat neuronal preparations. However, the slow kinetics of the non-prostanoids on the NANC system of the colon remain unexplained, and must be taken into account when characterizing neuronal IP-receptors.
Acetates↗
Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew).
The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 microg/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg/kg, s.c.), naloxone (1 mg/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2'-hydroxy-7,7-benzomorphan; 1 mg/kg) but not by naloxone methylbromide (1 mg/kg, s.c.), naloxone methyliodide (1 mg/kg, s.c.), naltrindole (1 mg/kg, s.c.), DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)-ethyl]acetamide; 3 mg/kg, i.p.) or naloxonazine (35 mg/kg, i.p.). This indicates an involvement of mu2-opioid receptors within the brain to mediate the anti-emetic effect of fentanyl. In other studies, naloxone 10-60 mg/kg, s.c. induced dose-related emesis but naltrexone was only emetic at 60 mg/kg, s.c. and naloxone methylbromide failed to induce emesis at doses up to 60 mg/kg, s.c. The emesis induced by a high dose of naloxone 60 mg/kg, s.c. was antagonized by CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; 3-30 mg/kg, i.p.), 8-OH-DPAT, ((+/-)-8-hydroxy-dipropylaminotetralin; 0.003-0.3 mg/kg, s.c.), buspirone (3 mg/kg, s.c.) and fluphenazine (1-3 mg/kg, i.p.) but not by naltrexone (1-30 mg/kg, s.c.), metoclopramide (0.3-3 mg/kg, i.p.), sulpiride (0.3-3 mg/kg, i.p.), domperidone (0.1-3 mg/kg, i.p.), ondansetron (0.3-3 mg/kg, i.p.), granisetron (0.3-3 mg/kg, i.p.), scopolamine (0.3-3 mg/kg, i.p.) or promethazine (0.3-3 mg/kg, i.p.). The data is discussed in relation to opioid receptor mechanisms moderating emesis and the identification of potential sites of drug action available to inhibit the emetic reflex.
Animals↗
Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew).
The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.
Animals↗
5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin.
We have used the rat to examine the involvement of the 5-HT3 receptor in the mechanism(s) of conditioned taste aversion induced by 5-hydroxytryptamine (5-HT) and selected emetic drugs. 5-HT, ipecacuanha and cisplatin all induced conditioned taste aversion at doses known to induce emesis in other species but the responses were resistant to treatment with the 5-HT3 receptor antagonists ondansetron and granisetron. Further, m-chlorophenylbiguanide, a selective and potent 5-HT3 receptor agonist, failed to induce a conditioned taste aversion. The data provide strong evidence that the 5-HT3 receptor is not involved in conditioned taste aversion mechanisms in the rat. Results are discussed in terms of the usefulness of the rat conditioned taste aversion paradigm to anti-emetic research.
Animals↗
Serotonin-independent model of cisplatin-induced emesis in the ferret.
para-Chlorophenylalanine (PCPA, 100-200 mg/kg) was used as a pharmacological tool to characterize the 5-hydroxytryptamine (5-HT) involvement in the emesis occurring 24 hr after the administration of cisplatin (10 mg/kg) in the ferret. PCPA was effective to antagonize the initial 8 hr period of retching and vomiting, but potentiated the emesis that occurred during the remaining 8- to 24-hr observation period. Tissue samples removed from the brainstem at 24 hr post injection of cisplatin alone revealed an elevation of 5-HT, dopamine and homovanillic acid that was antagonized by the injection of PCPA. Cisplatin also induced increases in the urinary levels of 5-hydroxyindoleacetic acid that was similarly antagonized by PCPA. Results are discussed in terms of the relevance of 5-HT to the model of cisplatin (10 mg/kg)-induced emesis in the ferret compared to the problem of acute and delayed emesis in man. The residual or delayed phase of cisplatin-induced emesis may involve a 5-HT-independent mechanism.
5-Hydroxytryptophan↗
The actions of ondansetron and dexamethasone to antagonise cisplatin-induced emesis in the ferret.
The ability of ondansetron and dexamethasone to antagonise cisplatin 10 mg/kg i.p. induced emesis was investigated in the ferret during a 24 h period. Ondansetron 0.5-5 mg/kg, as a single injection, effectively antagonised the response for approximately 4 h and revealed a subsequent response that was sensitive to further ondansetron treatment. The three times per day administration of dexamethasone 1 mg/kg i.p. alone or combined with ondansetron 1 mg/kg i.p. significantly reduced the vomiting response by 49 and 79%, respectively. The results are discussed in terms of their relevance to acute and delayed emesis in man.
Animals↗
The interaction of dexamethasone with ondansetron on drug-induced emesis in the ferret.
The potential of dexamethasone (0.5-20 mg/kg i.p.) to antagonize the emesis induced by cisplatin (10 mg/kg i.v.), apomorphine (0.25 mg/kg s.c.), morphine (0.5 mg/kg s.c.) and copper sulphate (100 mg/kg intragastric) was investigated alone and in combination with ondansetron in the ferret. There was a trend for dexamethasone 0.1-5 mg/kg to reduce cisplatin-induced emesis and for 0.05-2.5 mg/kg to delay the onset of apomorphine-induced emesis but doses of dexamethasone up to 20 mg/kg were without effect to modify morphine- or copper sulphate-induced emesis. The combination of dexamethasone 2.5 mg/kg with ondansetron 0.1 mg/kg did not have additive effects to reduce cisplatin-induced emesis but did reduce significantly the total numbers of episodes recorded. Ondansetron 1 mg/kg was without effect to modify apomorphine-, morphine- or copper sulphate-induced emesis but the combination pretreatment of ondansetron 1 mg/kg with dexamethasone 2.5 and 5 mg/kg reduced significantly apomorphine-induced retching. Data are discussed in terms of the antiemetic effectiveness of dexamethasone to antagonize chemotherapy-induced emesis in man.
Animals↗
An interaction of ondansetron and dexamethasone antagonizing cisplatin-induced acute and delayed emesis in the ferret.
1. Cisplatin, 5 mg kg-1, i.p., administered as a single treatment, induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of ondansetron and dexamethasone and their interaction over a three day period. 2. Ondansetron, 1 mg kg-1, i.p., administered three times per day in two experiments, antagonized significantly the retching and vomiting that occurred on days 1 and 2 by 60-76 and 73-84%. On the third day of treatment there was a trend for a 38% reduction in one experiment and a 74% reduction in the other. 3. There was a trend for dexamethasone, 1 mg kg-1, i.p., administered as a single daily injection for three days, to reduce by 37% the retching and vomiting response that occurred on day 1, the reduction of 77% on day 2 achieved significance and dexamethasone non-significantly increased the retching and vomiting response by 46% on day 3. However, dexamethasone 1 mg kg-1 i.p. administered three times per day for three days significantly reduced the retching + vomiting response by 85, 97 and 86% on days 1, 2 and 3 respectively. 4. The combination of dexamethasone, 1 mg kg-1, i.p., as single daily injections with ondansetron, 1 mg kg-1, i.p., administered three times per day improved the control of the retching and vomiting response, significantly reducing the total numbers of retches and vomits by more than 70% over a three day period. The combination of dexamethasone (1.0 mg kg-1) and ondansetron (1.0 mg kg-1), both administered three times daily, abolished cisplatin-induced emesis over the three day period. 5. The three times per day administration of ondansetron, 1 mg kg-1, i.p., plus dexamethasone, 1 mg kg-1, i.p., administered only on day 1 prevented day 1 emesis but did not modify the retching and vomiting that occurred on days 2 and 3. 6. The present results indicate that ondansetron and dexamethasone significantly reduce cisplatin-induced emesis in the ferret during both the acute and delayed phase; drug/co-treatment can exert an additive action to abolish cisplatin-induced emesis. The ferret model may be useful to detect anti-emetic drug action for treatment of chemotherapy-induced acute and delayed emesis in man.
Animals↗
The action of the NK1 tachykinin receptor antagonist, CP 99,994, in antagonizing the acute and delayed emesis induced by cisplatin in the ferret.
1. The anti-emetic effects of the NK1 tachykinin receptor antagonist, CP 99,994 (10 mg kg-1) were investigated in the ferret using a cisplatin-induced acute (day 1) and delayed (day 2 and 3) retching and vomiting model. 2. With a single cisplatin (10 mg kg-1) emetogenic challenge, the i.p. administration of CP 99,994 given as a single injection immediately following the first emetic episode, promptly abolished the retching and vomiting for a 4 h period. CP 99,994 was as efficacious as ondansetron (1.0 mg kg-1). The general toxicity of cisplatin 10 mg kg-1 precluded its use in studies of delayed emesis. 3. With a single cisplatin (5 mg kg-1) emetogenic challenge, the single administration of either CP 99,994 (10 mg kg-1) or ondansetron (1.0 mg kg-1) immediately following the first emetic episode markedly reduced or abolished the retching and vomiting for 4 h. Such single treatments failed to modify significantly the intensity of delayed emesis appearing on the second and third day. 4. With a cisplatin (5 mg kg-1) emetogenic challenge, administration of CP 99,994 (10 mg kg-1) at 8 hourly intervals, the first injection being administered 30 s post cisplatin, was associated with 4 or more abolitions of emesis during both the acute and delayed phase. A 4 hourly administration of CP 99,994 for 20 h during delayed emesis completely abolished the retching and vomiting. 5. It is concluded that cisplatin 5 mg kg-1 provides an emetogenic challenge causing an acute and delayed phase of retching and vomiting and that CP 99,994 can abolish both phases. The results may be relevant to the understanding and treatment of chemotherapy-induced emesis in man.
Animals↗
Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models.
Animal models of chemotherapy/radiotherapy-induced emesis successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists for the control of acute emesis. Further studies in animals have provided valuable information relating to the pathophysiology of emesis and the mechanism of action of 5-HT3 receptor antagonists. These agents inhibit emesis by blocking the action of 5-HT at 5-HT3 receptors on the vagus nerve in the gastrointestinal tract and in the hindbrain vomiting system. 5-HT is hypothesized to be released from enterochromaffin cells following cytotoxic therapy or radiation. The mechanism by which 5-HT is released from enterochromaffin cells is unknown and, although various mechanisms have been proposed, none of these have provided convincing supportive evidence. In collaboration with scientists at Glaxo we have pioneered two models of cisplatin-induced acute and delayed emesis [Rudd et al., 1994]. In the first model, ferrets are given a low dose of cisplatin (5 mg/kg i.p.) and observed for 3 days. A pattern of emesis similar to that seen in the clinic has been observed with two distinct phases of emesis. Ondansetron, and particularly ondansetron plus high-dose dexamethasone, are effective in reducing the emetic response over days 1-3. The second model uses a higher dose of cisplatin (10 mg/kg i.p.) and an observation period of 24 h. Part of the emetic response over this time is resistant to 5-HT3 receptor antagonism. Studies into the mechanism of the emesis induced in both models may give an insight into cisplatin-induced emesis in man that is not controlled with 5-HT3 receptor antagonists.
Animals↗
Profiles of emetic action of cisplatin in the ferret: a potential model of acute and delayed emesis.
The emetic profile of action of cisplatin 5 and 10 mg/kg i.p. was investigated in the ferret over a 72 and 40 h period respectively. Cisplatin 10 mg/kg induced retching and vomiting which rapidly declined after the first 8 h. Cisplatin 5 mg/kg induced a less intense emetic response which declined after 16 h but reappeared at approximately 32 h to reveal a 'delayed' retching and vomiting response. The use of cisplatin 5 mg/kg may offer a regimen to model cytotoxic acute and delayed emesis.
Animals↗
Effects of 5-HT3 receptor antagonists on models of acute and delayed emesis induced by cisplatin in the ferret.
The emetic profile of action of cisplatin 5 and 10 mg/kg i.p. was investigated in the ferret over a 72 and 24 hr period respectively. The 5-HT3 receptor antagonists ondansetron and alosetron markedly antagonized or abolished the emesis during the "acute phase" and, whilst antagonizing the emesis during the delayed phase, also revealed a 5-HT3 receptor antagonist resistant component. These cisplatin paradigms may provide models relevant to the study of acute and delayed emesis induced by cisplatin in man.
Animals↗
Emesis and anti-emesis.
From a consideration of the above evidence, it is possible to hypothesize that the 5-HT3 receptors, which are located both in the gut and in the AP/NTS, may play an important and perhaps pivotal part in the mechanism(s) of action of chemotherapy and radiotherapy to induce emesis in animals and humans and represent the anti-emetic sites of action of ondansetron and related agents (see Fig. 1). The value of ondansetron and the 5-HT3 receptor antagonists has been to greatly improve the treatment of nausea and emesis in the cancer patient and to cause a renaissance in emesis research. The 5-HT3 receptor antagonists have helped to redefine the phases of chemotherapy induced emesis and establish the first clear neurotransmitter links in the emetic reflex. It has also encouraged the analysis of emetic mechanisms that will identify further points for pharmacological intervention that may ultimately provide "broad spectrum" anti-emetic agents. Such compounds would further improve the quality of life and treatment of the cancer patient, leading to increased success in the treatment of malignant tumours.
Animals↗
The effect of 5-HT receptor ligands on the uptake of [3H]5-hydroxytryptamine into rat cortical synaptosomes.
The effect of 5-HT receptor agonists and antagonists to inhibit [3H]5-HT uptake was investigated in rat cortical synaptosomes. The 5-HT (5-hydroxytryptamine) uptake inhibitors paroxetine and fluoxetine yielded pKi values of 8.41 +/- 0.12 and 7.43 +/- 0.06 respectively. The 5-HT3/5-HT4 receptor antagonist tropisetron and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) had similar inhibitory potencies to cocaine (pKi values of 6.58 +/- 0.04, 6.47 +/- 0.14 and 6.45 +/- 0.12 respectively). The dopamine and noradrenaline uptake inhibitors GBR12909 and desipramine had comparable values of 6.5 +/- 0.05 and 6.13 +/- 0.07. Other 5-HT receptor ligands had pKi values less than 6.0 (R(+)-zacopride, MDL72222, R(+)/S(-)-zacopride) or 5.0 (5-methoxytryptamine, m-chlorophenylbiguanide, S(-)-zacopride, SDZ205-557, ondansetron and renzapride). It is concluded, with the possible exception of tropisetron and 8-OH-DPAT, that it is unlikely that the effects of the 5-HT receptor ligands to inhibit 5-HT uptake contribute to their effects in vivo.
8-Hydroxy-2-(di-n-propylamino)tetralin↗