Suspected acorn toxicity in nine horses.

REASONS FOR PERFORMING STUDY: Acorn toxicity has been anecdotally reported to cause fatal colitis and colic in horses but reports in the scientific literature are sparse. OBJECTIVES: This study reports the diagnosis, treatment, prognosis and outcome of 9 cases with suspected acorn toxicity admitted to 2 referral hospitals. STUDY DESIGN: Retrospective case series. METHODS: Case records from 2004 to 2013 were reviewed. Horses were included in the study if they met 3 of 4 criteria: exposure to acorns; clinical and laboratory data suggesting alimentary or renal dysfunction; acorn husks in the faeces or gastrointestinal tract; and necropsy and histopathological findings consistent with acorn toxicity. Data collected included case history, clinical presentation, clinicopathological data, ultrasonographic findings, case progression, and necropsy and histopathological findings. RESULTS: Nine horses met the inclusion criteria. Five cases presenting with haemorrhagic diarrhoea deteriorated rapidly and were subjected to euthanasia or died. Four cases showed signs of colic with gas distension, displacement of the large colon and diarrhoea. Three of these (33%) survived with medical management, the fourth was subjected to euthanasia. Post mortem examination of 6 cases demonstrated submucosal oedema of the large intestine and caecum (n = 6), acute tubular nephrosis (n = 6), diffuse necrohaemorrhagic and ulcerative typhlocolitis and enteritis (n = 4), and small intestinal oedema (n = 3). CONCLUSIONS: Acorn ingestion may be associated with typhylocolitis leading to diarrhoea, colic and acute renal tubular nephrosis. Recovery is possible in mildly affected cases; more severe cases show hypovolaemia, intractable pain, renal dysfunction and cardiovascular failure, and often succumb to the disease process. Disease is only seen in a small proportion of the population exposed to acorns and there seems to be an increased occurrence in certain years. Further investigation into factors predisposing to disease is required, but limiting exposure to acorns in the autumn seems prudent.

Comparison of flunixin meglumine and meloxicam for post operative management of horses with strangulating small intestinal lesions.

REASONS FOR PERFORMING STUDY: Ex vivo evidence suggests that cyclo-oxygenase (COX) 2-preferential inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, have a less detrimental effect on intestinal healing than flunixin meglumine (FM). Whether this translates to a beneficial effect in horses with naturally occurring strangulating small intestinal (SSI) lesions is unknown. OBJECTIVES: To compare the clinical outcome of horses with naturally occurring SSI lesions treated with meloxicam or FM. STUDY DESIGN: Randomised prospective study. METHODS: Cases presenting to the Royal Veterinary College Equine Referral Hospital and Bell Equine Veterinary Clinic during 2010 and 2011 in which an SSI lesion was identified at exploratory laparotomy were eligible for inclusion. Horses received either 1.1 mg/kg bwt FM or 0.6 mg/kg bwt meloxicam i.v. q. 12 h. Clinical outcomes and clinical and laboratory parameters associated with endotoxaemia were compared between groups. RESULTS: Sixty cases were enrolled, 32 horses received FM and 28 received meloxicam. There was no difference in signalment, physical examination or surgical factors between groups. The overall survival to discharge was 81%; there was no difference in survival (P = 0.14) or incidence of post operative ileus (P = 0.25) between groups. There was no significant difference between the plasma lipopolysaccharide (LPS) concentrations at 0 h (P = 0.18) or 48 h (P = 0.60); however, there was a significant difference between neutrophil count at 48 h (P<0.05) and at 96 h (P<0.01) with significantly greater cell numbers in horses receiving meloxicam compared with FM. Blinded pain score evaluation showed that more horses receiving meloxicam showed gross signs of pain than those treated with FM (P = 0.04). CONCLUSIONS: Nonsteroidal anti-inflammatory drug choice did not affect major clinical outcomes in horses with SSI lesions but had some effects on signs of pain. This study provides no evidence to recommend one NSAID treatment above another based on survival or the incidence of ileus; however, evaluation of a larger number of cases is required.

Blood lactate concentrations in ponies and miniature horses with gastrointestinal disease.

REASONS FOR PERFORMING STUDY: Clinical impression suggested that pony and miniature breeds (collectively referred to as ponies) presenting to a referral hospital for investigation of gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses. OBJECTIVES: The study tested the hypothesis that ponies with gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses with similar disease severity. STUDY DESIGN: Retrospective case-control study. METHODS: Medical records from September 2006 to July 2011 were reviewed for ponies with a primary presenting complaint of gastrointestinal disease. Two larger breed horses with gastrointestinal disease were selected as controls for each case. Data collected included case details, historical and clinicopathological findings, diagnosis and outcome. RESULTS: Information was collected on 50 ponies and 100 horses. Ponies had higher mean ± s.d. respiratory rates (27 ± 13 vs. 21 ± 13 beats/min; P = 0.01) and rectal temperatures (37.9 ± 0.6 vs. 37.4 ± 0.6°C; P = 0.006) and a longer median duration of clinical signs prior to presentation (10 h [1-72 h] vs. 6 h [1-120]; P<0.001). Median blood lactate concentrations on admission were higher in ponies than in horses (2.8 mmol/l [0.7-18.0] vs. 1.6 mmol/l [0.4-8.1]; P = 0.001). All other parameters relating to colic severity were not significantly different between groups, although more horses underwent exploratory laparotomy (19/50 ponies and 55/100 horses; P = 0.05). Median blood lactate concentrations in ponies with large intestinal disease, nonstrangulating lesions, undergoing medical treatment and surviving ponies were significantly higher than in horses in the same category. In contrast to horses, no differences in blood lactate concentrations exist between ponies with medical vs. surgical treatment, strangulating and nonstrangulating lesions and surviving and nonsurviving ponies. CONCLUSION AND POTENTIAL RELEVANCE: Ponies might present with higher blood lactate concentrations than horses and might falsely be suspected of having a surgical lesion or a poorer prognosis if veterinarians are not aware of breed differences.

Evaluation of cardiac phenotype in horses with type 1 polysaccharide storage myopathy.

BACKGROUND: Type 1 polysaccharide storage myopathy (PSSM1), an equine glycogen storage disorder caused by a gain of function mutation (R309H) in the gene encoding glycogen synthase (GYS1), is associated with the accumulation of amylase-resistant alpha-crystalline polysaccharide inclusions within skeletal muscle. Several glycogenoses in humans have a cardiac phenotype, and reports exist of horses with PSSM and polysaccharide inclusions in cardiac muscle. HYPOTHESIS/OBJECTIVES: To investigate the hypothesis that horses with PSSM1 display a cardiac phenotype. Our objectives were to compare plasma cardiac troponin I (cTnI) concentration and the incidence of cardiac arrhythmias in PSSM1 homozygotes, heterozygotes, and control horses. METHODS: One hundred and twenty-five Belgian and Percheron horses under the same management were genotyped for the R309H GYS1 mutation. From these, 8 age-, breed-, and sex-matched cohorts of each genotype were identified. Plasma cTnI concentration and incidence of cardiac arrhythmias (determined by 24-hour Holter ECG) were compared between the groups. RESULTS: Although some PSSM1-affected horses had mildly increased plasma cTnI concentrations, there was no significant difference in cTnI concentrations between groups. There were no significant differences in the incidence of ectopic beats, cardiac conduction intervals or mean heart rate between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: We found no evidence of clinically relevant cardiac myocyte injury or arrhythmias in horses with PSSM1. Additional study is required to determine whether myocardial function may be compromised in this disorder.

Histopathology and computed tomography of age-associated degeneration of the equine temporohyoid joint.

REASONS FOR PERFORMING STUDY: The aetiology of temporohyoid osteoarthropathy (THO) is unknown; both primary infectious and degenerative causes have been suggested. HYPOTHESIS: There is a significant association between increasing age and severity of temporohyoid joint degeneration. To examine the histopathology of the temporohyoid articulation in aged horses and to compare the appearance of the joint with computed tomography (CT) and peripheral quantitative CT (pQCT). METHODS: pQCT scans of the temporohyoid articulations were obtained bilaterally from 31 horses (range age 1-44 years) post mortem and images were graded by 2 blinded observers on 2 occasions for the presence of osteophytes, irregularity of the joint surface and mineralisation. Eight heads had been examined previously by CT, with the images similarly graded for the shape and density of the proximal stylohyoid bones, bone proliferation surrounding the joint, mineralisation of the tympanohyoid cartilage and the relationship of the petrous temporal bone to the stylohyoid bone. Sixteen temporohyoid joints were then evaluated histologically. RESULTS: There was significant association between the mean pQCT degeneration score and age (rho = 0.75; P<0.0001), between the pQCT and CT score (rho = 0.63; P = 0.01) and between the degenerative changes identified within each temporohyoid joint within each horse (rho = 0.81; P<0.0001). Age-associated changes included the development of a club shape by the proximal stylohyoid bone, rounding of the synostosis with the petrous temporal bone and extension of osteophytes from the petrous temporal bone to envelope the stylohyoid head and bridge the joint. In no horse was there any evidence of osteomyelitis within the petrous temporal bone, stylohyoid bone or tympanohyoid cartilage. CONCLUSIONS: This study provides evidence that age is associated with increasing severity of degenerative changes in the equine temporohyoid joint and that similar changes are commonly found bilaterally. POTENTIAL RELEVANCE: The changes identified appear similar, albeit milder to the changes reported in horses with THO, suggesting that degenerative, rather than infectious causes may underlie the aetiology of THO. Future work should be directed at examining the histopathology of clinical THO cases.

The effect of fluoxetine on electrical field stimulation-induced responses in the isolated rat small intestine.

The effects of fluoxetine, a serotonin reuptake inhibitor, were studied in the isolated rat small intestine. Electrical field stimulation (EFS) triggered relaxant and/or contractile responses that were sensitive to tetrodotoxin and fluoxetine at 1.0-10.0 µM. In 0.1 mM hexamethonium-treated tissues, fluoxetine (1.0 µM) induced a relaxant response at 10.0 Hz, while it decreased the attenuation of the contractile responses to EFS. In PCPA pretreated rat jejunum and ileum, 1.0 µM of fluoxetine induced a greater relaxation response to EFS and significantly attenuated the contractile responses to EFS (10.0 Hz) in the duodenum. In a separate experiment, the application of reboxetine (1.0-10.0 µM), a noradrenergic reuptake inhibitor, reduced the contraction and increased the relaxation responses to EFS at 10.0 Hz in most regions. In the presence of hexamethonium (0.1 mM) the application of 10.0 µM reboxetine reduced contractile responses to ESF while enhancing the relaxant responses to EFS at 10.0 Hz. The data suggest that the effects of fluoxetine appear to be related to the selected region of the intestine and may contribute to a better understanding of the serotonergic and cholinergic transmitter mechanisms involved in ileal activity and the gastrointestinal discomfort associated with the clinical use of fluoxetine.

Decreasing paediatric prescribing errors in a district general hospital.

BACKGROUND: In paediatric inpatients, medication errors occur as frequently as 1 in 4.2 drug orders, with up to 80% of these being prescribing errors. CONTEXT: The children's unit of a district general hospital in West Yorkshire, UK. KEY MEASURES FOR IMPROVEMENT: Prescribing errors and preventable adverse drug events STRATEGIES FOR CHANGE: (1) The introduction of a junior doctor prescribing tutorial. (2) The introduction of a bedside prescribing guideline. EFFECTS OF CHANGE: The introduction of the junior doctor prescribing tutorial decreased the prescribing errors by 46%. The introduction of a bedside prescribing guideline did not decrease prescribing errors but may have been helpful to those doctors unable to attend a prescribing tutorial. LESSONS LEARNT: By investing time and providing appropriate written resources, we have been able to reduce our paediatric prescribing errors on the children's ward by almost half.

Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

Modulation of 5-HT4 receptor function in the rat isolated ileum by fluoxetine: the involvement of endogenous 5-hydroxytryptamine.

The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 microM. Fluoxetine (10 microM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 microM) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg-1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.

Opioid receptor involvement in the adaptation to motion sickness in Suncus murinus.

The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of 1 Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, i.p.) or morphine (0.1 mg/kg, i.p.) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, i.p.) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, i.p.) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.

Pharmacological characterization of the 5-HT receptor-mediated contraction in the mouse isolated ileum.

The pharmacological characterization of a 5-HT receptor-mediated contractile response in the mouse isolated ileum is described. In the presence of methysergide (1 microM), 5-hydroxytryptamine (5-HT, 0.3 - 100 microM) produced phasic concentration-dependent contractions of segments of the mouse isolated ileum with a pEC(50) value of 5.47+/-0.09. The 5-HT(3) receptor selective agonists m-chlorophenylbiguanide (0.3 - 100 microM, pEC(50) 5.81+/-0.04), 1-phenylbiguanide (3 - 100 microM, pEC(50) 5.05+/-0.06) and 2-methyl-5-HT (3 - 100 microM, pEC(50) 5.00+/-0.07) acted as full agonists to induce contractile responses. 5-methoxytryptamine (0.1 - 100 microM), RS 67506 (0.1 - 100 microM) and alpha-methyl-5-HT (0.1 - 100 microM) failed to mimic the 5-HT responses. The contractile response to 5-HT was not antagonized by either 5-HT(2) receptor antagonists ritanserin (0.1 microM) or ketanserin (1 microM) nor the 5-HT(4) receptor antagonist SB 204070 (0.1 microM). The 5-HT(3) receptor selective antagonists granisetron (0.3 - 1 nM), tropisetron (1 - 10 nM), ondansetron (10 nM - 1 microM) and MDL 72222 (10 nM - 1 microM) caused rightward displacement of the concentration-response curves to 5-HT. The lower concentrations of the antagonists caused approximate parallel rightward shifts of the concentration-response curves to 5-HT with apparent pK(B) values for granisetron (9.70+/-0. 39), tropisetron (9.18+/-0.20), ondansetron (8.84+/-0.24) and MDL 72222 (8.65+/-0.35). But higher concentrations of antagonists resulted in a progressive reduction in the maximum responses. The contractile response to 5-HT was abolished by tetrodotoxin (0.3 microM); atropine (0.1 and 1 microM) decreased the maximum response of the 5-HT concentration-response curve by approximately 65%. It is concluded that a neuronally located 5-HT(3) receptor mediates a contractile response to 5-HT in the mouse ileum. The 5-HT(3) receptor in the mouse ileum has a different pharmacological profile to that reported for the guinea-pig ileum.

Characterisation of 5-HT2 receptor subtypes in the Suncus murinus intestine.

The involvement of 5-HT2 receptor subtypes in mediating a contraction response in the isolated intestine of Suncus murinus was investigated using DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane, a 5-HT2 receptor agonist) which produced a bell-shaped concentration response curve that was significantly (p < 0.05) reduced by methysergide (a 5-HT1/2 receptor antagonist, 1 microM) but not ketanserin (a 5-HT2A receptor antagonist, 1 microM), yohimbine (a 5-HT2B receptor antagonist, 1 microM) or a combination of ondansetron (a 5-HT3 receptor antagonist, 1 microM) plus SB204070 (8-amino-7-chloro(N-butyl-4-piperidyl) methylbenzo-1,4-dioxan-5-carboxylate hydrochloride, a 5-HT4 receptor antagonist, 1 nM). The contraction response to the lower concentrations of DOI (10 nM-0.3 microM) was reduced in the presence of SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole, a 5-HT2B/2C receptor antagonist, 1 microM), whilst conversely, the reducing response to the higher concentrations of DOI (1-30 microM) was prevented. A repeated challenge with 3 microM DOI produced a smaller response (desensitisation) and also reduced the response to 5-HT (5-hydroxytryptamine, 0.3 microM) that was inhibited by SB206553 (1 microM). Data indicate that 5-HT2C receptors are likely candidates to mediate the contractile response to DOI and demonstrate desensitisation to repeated challenges.

Characterization of the 5-hydroxytryptamine receptors mediating contraction in the intestine of Suncus murinus.

1. The effects of 5-HT and 5-HT agonists to induce contraction and the 5-HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus murinus. 2. The contraction curves to 5-HT (3 nM - 30 microM) were shifted to the right by methysergide (1 microM) and ritanserin (0.1 microM), without affecting the maximum response. 3. In the central and terminal segments (but not the proximal segments) ondansetron (1 microM) and atropine (1 microM) significantly attenuated the contractions to higher concentrations of 5-HT. The selective 5-HT4 receptor antagonist SB204070 (1 nM), failed to modify 5-HT induced contractions in any segment examined. 4. 5-carboxamidotryptamine, alpha-methyl-5-HT and 5-methoxytryptamine (0.003 - 3.0 microM) induced contractions but unlike 5-HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2-methyl-5-HT (0.03 - 1.0 microM) was ten times less potent than 5-HT to induce contraction but achieved the same maximum response. 5. The contractions induced by the lower concentrations of 2-methyl-5-HT (0.03 - 1.0 microM) in all segments were markedly reduced or abolished by methysergide (1.0 microM); the response to the higher concentrations of 2-methyl-5-HT (3 - 30.0 microM) were markedly reduced by atropine (1.0 microM) and ondansetron (1.0 microM). 6. In all segments examined, tetrodotoxin (1 microM) significantly reduced the 5-HT-induced contraction. 7. It is concluded that the 5-HT-induced contraction was mediated via 5-HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5-HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions.

Variables of movement amplitude and frequency in the development of motion sickness in Suncus murinus.

The aim of the present study was to investigate the effect of different frequency and amplitude of horizontal movements to induce motion sickness and to identify gender differences and adaptation to motion stimulus in adult Suncus murinus. Each animal was subjected to a horizontal motion stimulus of 3, 7, 13, or 40 mm amplitude at a frequency of 0.5, 1, 2, or 3 Hz. The number of vomiting episodes and the latency of onset were recorded over a 10-min period. For the study of adaptation, different groups of males were exposed to repeated motion sickness (using 0.5 or 1 Hz frequency and the amplitude of 40 mm) either every 2 days for a period of 30 days, or once every week for a period of 28 days. In all animals the number of emetic episodes obtained at 1 and 2 Hz were significantly higher by 40-80% than those at 0.5 and 3 Hz using either 13 or 40 mm amplitude of movements; this was followed by shorter latency of emesis. Age-matched females were shown to be more responsive to the emetic stimuli than males as the number of emetic episodes at 1, 2, and 3 Hz (amplitude of 40 mm) were significantly higher by 33%, 42%, and 75%, respectively, than in males; this also was followed by a shorter latency of emetic response. In the study of adaptation, when used once every 2 days, by the second challenge (at 0.5 Hz) the number of emetic episodes was reduced by 62%, and to subsequent challenges emesis was absent or greatly reduced. Also, a reduction in responsiveness was observed at 1 Hz, which attained a maximum effect by the third challenge. The present results indicated that Suncus murinus is sensitive to horizontal motion stimulus, the emetic episodes were significantly greater at 1 and 2 Hz than at either a lower or higher frequency, a repeated challenge once every 2 days but not weekly reduced the number of emetic episodes, and in all experiments, age-matched female animals were more responsive than males to motion stimulus and in some experiments this achieved significance.

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.

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.

Neuropharmacology of emesis and its relevance to anti-emetic therapy. Consensus and controversies.

Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysiological processes in patients undergoing chemo- and radiotherapy. This article gives an overview of the area, outlines current controversies and makes recommendations for future clinical studies.