Paul L.R. Andrews

Neuropharmacology of emesis induced by anti-cancer therapy.

Abstract Cancer patients receiving certain cytotoxic therapies can experience severe nausea and vomiting, lasting for up to five days. Conventional antiemetic treatments may be poorly effective or evoke side-effects normally unacceptable in other areas o f medicine. The recent discovery that 5-HT 3 receptor antagonists can prevent or greatly reduce severe emesis has, therefore, prompted Gareth Sanger and his co-workers to re-evaluate the neuropharmacology of vomiting. They suggest a sequence of events, evoked by anti-cancer therapies, which could form the basis for further experimental investigation .

Differential Effects of Paroxetine on Fatigue and Depression: A Randomized, Double-Blind Trial From the University of Rochester Cancer Center Community Clinical Oncology Program

PURPOSE Fatigue and depression typically occur together in cancer patients, suggesting a common etiology, perhaps based on serotonin. This randomized clinical trial tested whether paroxetine, a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin, would reduce fatigue in cancer patients and whether any reduction was related to depression. PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue. Of 704 patients who reported fatigue at their second chemotherapy cycle, 549 patients were randomly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks. The assessments of fatigue and depression were performed at cycles 3 and 4 of chemotherapy. RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data. No difference was detected in fatigue between patient groups. At the end of the study, there was a difference between groups in the mean level of depression (Center for Epidemiologic Studies Depression scores, 12.0 v 14.8, respectively; P <.01). CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy. A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels.

The anti-emetic effects of CP-99,994 in the ferret and the dog : role of the NK1 receptor

1 The selective NK1 receptor antagonist, CP‐99,994, produced dose‐related (0.1‐1.0 mg kg−1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2 Parallel studies with the enantiomer, CP‐100,263 (1 mgkg−1, s.c), which is > 1 000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine‐induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately l/10th the potency of CP‐99,994. 3 The 5‐HT3 receptor antagonist, tropisetron (lmgkg−1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4 CP‐99,994 (lmgkg−1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP‐99,994 (1 mg kg−1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2‐methyl‐5‐HT challenge (von Bezold‐Jarisch reflex). 5 Using in vitro autoradiography, [3H]‐substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP‐99,994 in a concentration‐related manner. 6 In dogs, CP‐99,994 (40 μg kg−1 bolus and 300 μg kg−1 h−1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7 Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP‐99,994 are responsible for its broad spectrum anti‐emetic effects. They also suggest that CP‐99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction

Vagal afferents are extensively distributed in the digestive tract from the oesophagus to the colon. They are involved in the reflex control of normal gastrointestinal (GI) tract function (e.g. secretion and motility) as well as reflexes more characteristic of diseases such as functional dyspepsia and gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal sphincter relaxation and gastric accommodation). They are also implicated in signalling non-painful sensations (e.g. nausea and early satiety) associated with disease. A variety of receptors has been identified on vagal afferents, which can either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin, leptin, k-opioid and GABAB receptors) activity, offering a range of potential therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack an emetic reflex, and the implications of this for models of upper GI disorders have been explored in the light of expanding knowledge of the neuropharmacology of the emetic reflex implicating glutamate, prostanoids, cannabinoids and substance P. Additional pathophysiological roles for vagal afferents (e.g. in thermoregulation, arousal and fatigue) are being investigated, raising the intriguing possibility of the vagus as a target in non-GI disorders.

A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome.

Purpose To determine the prevalence of cancer-related fatigue syndrome (CRFS) in a population of disease-free breast cancer survivors and to investigate the relationship between CRFS and clinical variables. Patients and methods Women (200) were recruited. All participants were between 3 months and 2 years after completion of primary therapy for breast cancer and were disease free. Subjects completed a diagnostic interview for CRFS and structured psychiatric interview. Participants also completed quality of life, mood and fatigue questionnaires, and provided a blood sample for haematological and biochemical analysis and a 24-h urine specimen for cortisol estimation. Subjects wore a wrist actigraph for 7 days to measure activity and sleep. Results Sixty women (30% of participants) were found to fulfil the criteria for CRFS. There were statistically significant differences between fatigued and non-fatigued women with respect to fatigue severity (p < 0.01), mood (p < 0.01) and quality of life scores (p < 0.05). There were significant differences in blood variables including raised total white cell count and lower sodium (all p < 0.02). There was no difference in the 24 h urinary free cortisol levels. Actigraphic data demonstrated significant differences in sleep quality and disturbance, but not in overall levels of daytime activity or circadian rhythm. Conclusion CRFS affects 30% of women after breast cancer treatment and has significant effects on quality of life and mood. There is some evidence that CRFS is related to sleep disturbance or to a persistent inflammatory or immune response.

Resinferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret

Resinferatoxin (100 micrograms/kg, s.c.), the ultrapotent analogue of capsaicin, when given acutely blocked radiation-(200 rads) and copper sulphate (40 mg% 30 ml, p.o.)-induced emesis in ferrets and substantially decreased loperamide (0.5 mg/kg, s.c.)-induced vomiting, without significantly affecting the von Bezold-Jarisch reflex or gag reflex. It also produced a decrease in core temperature as has been reported for capsaicin. The observation that resinferatoxin reduced or blocked emesis induced by both centrally (loperamide) and peripherally (CuSO4, radiation) acting stimuli suggests a novel anti-emetic action that may provide an insight into clinically useful innovative anti-emetics. The mechanism by which resinferatoxin has its anti-emetic effect is at present unknown, although the combination of results from the present study suggest a central site of action involving modulation of release of neurotransmitter, possibly in the nucleus tractus solitarius.

Anti-emetic activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin

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<0.05) and at a dose of 30 microg i.c.v. ghrelin reduced the number of episodes, individual retches and vomits by 74.4 (p<0.05), 80.4 (p<0.01), and 72.5% (p<0.05), respectively. At subsequent time periods there were no differences between ghrelin- or saline-treated animals (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.

Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study.

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity–key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.

The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew

In Suncus murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1–1000 μg kg−1, s.c. The latency was inversely related to dose and ranged from 41.2±4.4 min. (1 μg kg−1, s.c.) to 2.7±0.6 min. (1000 μg kg−1, s.c.). The emetic response to RTX (10 or 100 μg kg−1, s.c.) was blocked or markedly reduced by pre‐treatment with RTX (100 μg kg−1, s.c.), 8‐OH‐DPAT (100 μg kg−1, s.c.), morphine (2 mg kg−1, s.c.), neonatal capsaicin (100 mg kg−1, s.c.) and the NK1 receptor antagonist CP‐99,994 (10–20 mg kg−1, s.c.) but not by the 5‐HT3 receptor antagonist tropisetron (200 μg kg−1, s.c.). RTX (100 μg kg−1, s.c.) induced c‐fos‐like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed. RTX (10 and 100 μg kg−1, s.c.) had broad‐spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg−1, i.p.), intragastric copper sulphate (40 mg kg−1, p.o.), nicotine (10 mg kg−1, s.c.) and RTX (100 μg kg−1, s.c.) itself. It is proposed that the site of the anti‐emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed. The general utility of Suncus for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

The Role of Tachykinins and the Tachykinin NK1 Receptor in Nausea and Emesis

Nausea and vomiting are both components of the body’s defensive system to protect against the effects of accidentally ingested toxins. Whilst these responses have survival value in the wild, they can also be induced by diseases and disease treatments with one of the most unpleasant examples being the treatment of cancer using cytotoxic drugs and radiation. Understanding the mechanisms by which this occurs has been a major impetus to the identification of novel anti-emetic agents. The recent licensing of an NK1 receptor antagonist for the treatment of chemotherapy-induced emesis provides the first example of a drug acting to block the effects of substance P. Whilst the blockade of emesis by selective NK1 receptor antagonists provides the most powerful evidence implicating substance P in emesis there is a considerable body of supporting evidence including: presence of substance P (usually by immunohistochemistry) in relevant sites (e.g. vagal afferents, nucleus tractus solitarius, gastrointestinal mucosa); presence of NK1, receptors in relevant sites (e.g. nucleus tractus solitarius); induction of emesis by administration of NK1 receptor agonists. Pre-clinical studies in a variety of species revealed the broad-spectrum anti-emetic effects of NK1 receptor antagonists against stimuli including the anti-cancer agent cisplatin (acute and delayed phases), radiation, opioids, copper sulphate, apomorphine, motion and electrical stimulation of abdominal vagal afferents. Species differences in response to NK1 receptor antagonists and species-specific iso-forms of the receptor are discussed and the potential implications for transfer of data from these animal models to humans reviewed. The spectrum of antiemetic effects against stimuli acting via both peripheral and centrally acting emetic stimuli, a requirement for brain penetration and blockade of emesis by microinjection of antagonists into the brain stem all support a central site of action with the nucleus tractus solitarius and the vicinity of the Botzinger complex being the favoured locations although definitive studies are awaited. Evidence for a contribution from a peripheral site in the delayed phase of cytotoxic druginduced emesis is reviewed. The unique pre-clinical profile and especially the observation that NK1, receptor antagonists could block both the acute and delayed phase of cisplatin-induced emesis prompted clinical trials of a number of agents [CJ11974 (ezlopitant), GR205171 (vofopitant), MK869/L754030 (aprepi-tant)] in patients undergoing chemotherapy. These studies and others in motion and post-operative nausea and vomiting are reviewed in detail. In general the trials in chemotherapy show NK1 receptor antagonists have demonstrable efficacy against acute (first 24 h after therapy) emesis when given alone and enhance the efficacy of 5-hydroxytryptamine3 receptor antagonists and dexamethasone when given in combination. Of particular clinical significance is the efficacy of NK1 receptor antagonists given in combination with dexamethasone to reduce emesis in the delayed phase (days 2–5) as this phase of emesis is poorly con trolled using current treatments. Efficacy against nausea has been reported but to date the effects appear less clear than against emesis and further studies are required. The availability of NK1 receptor antagonists in the clinic will provide a useful tool to further investigate the involvement of NK1 receptors in emesis and to explore the roles of central and peripheral substance P in health and disease.