Pii: s0014-2999(01)00915-3

Action of glucocorticoids to antagonise cisplatin-induced acute and Tasia S.W. Sam, Shun W. Chan, John A. Rudd), John H.K. Yeung Department of Pharmacology, Faculty of Medicine, The Chinese UniÕersity of Hong Kong, Shatin, N.T., Hong Kong SAR, China Received 4 January 2001; received in revised form 5 March 2001; accepted 13 March 2001 Abstract
Cisplatin 5 mgrkg, i.p. induced an acute Žday .
3 emetic response in the ferret that was used to investigate the potential anti-emetic activity of several glucocorticoids. Betamethasone Ž0.3–3 mgrkg, i.p. reduced the emesis occurring during theinitial 0–24-h period by 71.1–99.5% Ž P - 0.05. The action of methylprednisolone Ž1.0–10.0 mgrkg, i.p. and hydrocortisone Ž1.0–30.0mgrkg, i.p. could not be assessed because the controls exhibited weak emetic responses and dexamethasone produced a non-significant64.0% reduction at 0.3 mgrkg Ž P ) 0.05. However, all glucocorticoids dose-dependently reduced retching q vomiting during thesubsequent 24–56-h period. The rank order of anti-emetic potency was betamethasone ŽID - 0.3 mgr kg . Dexamethasone was ineffective to antago- nise the retching q 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 q vomiting response occurring during the 56–72-h period. In conclusion, the rank orderof anti-emetic potency suggests that inflammation, or mediators of inflammation, contribute to the retching q vomiting response inducedby cisplatin. q 2001 Published by Elsevier Science B.V.
Keywords: Emesis; Cisplatin; Glucocorticoid 1. Introduction
detailing the action of dexamethasone to reduce motion-in- Cisplatin-based chemotherapy is commonly associated with severe nausea and vomiting. The acute phase com- clear dose-ranging studies to establish the optimal anti- prises emetic episodes occurring during the first 24 h emetic doses of glucocorticoids or the most effective dos- following the start of chemotherapy and is particularly ing schedule to use. The mechanism of anti-emetic action of the glucocorticoids to reduce emesis is also unknown.
The delayed phase is less sensitive to 5-HT In our previous studies, we have shown that dexametha- antagonists or conventional anti-emetics and comprises sone is ineffective to antagonise apomorphine-, morphine- episodes occurring after the initial 24-h period; the most or copper sulphate-induced emesis in the ferret ŽRudd et intense period of delayed emesis occurs during the 48–72-h 1996a . Dexamethasone also failed to antagonise the period and is not satisfactorily controlled by single agent emesis induced by cisplatin 10 mgrkg ŽRudd and Naylor, 1997 but was remarkably effective to antagonise emesis Glucocorticoids are useful agents to combine with other induced by a lower dose of cisplatin 5 mgrkg ŽRudd and anti-emetics to control both the acute and delayed phases 1996 . The lower dose of cisplatin in the ferret may partly mimic the acute and delayed emesis seen in reduce post-operative nausea and vomiting ŽBaxendale et man and provides a model to dissect the anti-emetic al., 1993; Fujii et al., 1999; Splinter and Roberts, mechanism of action of the glucocorticoids ŽRudd and and have been used to prevent hyperemesis gravidarum 1996 . We have demonstrated using the model that ) Corresponding author. Tel.: q852-2609-6789; fax: q852-2603-5139.
ondansetron could be increased in combination with dexa- E-mail address: jar@cuhk.edu.hk ŽJ.A.
methasone and that a more frequent administration of 0014-2999r01r$ - see front matter q 2001 Published by Elsevier Science B.V.
PII: S 0 0 1 4 - 2 9 9 9 Ž 0 1 . 0 0 9 1 5 - 3 T.S.W. Sam et al.r European Journal of Pharmacology 417 ( dexamethasone was associated with an improved anti- oral expulsion of solid or liquid material from the gastro- have shown that dexamethasone may be a useful agent to combine with the new NK receptor antagonists ŽTattersall retching andror vomiting bouts were considered separate 2000 ; such an interaction is also demonstrated in when the animal changed its location in the observation cage, or when the interval between retches andror vomits In the present studies, we have used several glucocorti- coids in dose-ranging studies to establish the rank order ofant-emetic potency to antagonise cisplatin-induced acute and delayed emesis in the ferret. The studies were alsodesigned to define the glucocorticoid-sensitive phase of In each animal, the latency to retch or vomit andror and the total number of retches, vomits and episodes wascalculated in each 1 h period for the duration of theexperiment. The significance of difference between treat- 2. Methods
ANOVA followed by a Fisher’s Protected Least Castrated male or normal female ferrets Ž0.8–1.8 Student’s t-test, as appropriate. Differences were consid- were obtained from a reputable breeder in New Zealand ered significant when P - 0.05. ID and were housed communally at 22 " 18C under artificial mined on the mean data by non-linear regression analysis lighting, with lights on between 0700 and 2100 h. They were fed a dry pellet diet ŽLaboratory Feline Diet 5003,PMI Nutrition, St. Louis, Cisplatin was purchased as a sterile saline solution at an 2.2. Induction and measurement of emesis active concentration of 1 mgrml ŽDavid Bull Laboratories,Victoria, Australia . Dexamethasone 21-phosphase dis- Animals were transferred to individual observation cages and allowed at least 48 h to adapt to the new environment.
cortisone 21-hemisuccinate sodium salt Ž presented with 100 g of commercially available cat food were prepared in distilled water and administered in a volume of 0.5 mlrkg. 6a-Methylprednisolone 21-hemi- h, the ferrets were removed from their observation cages Sigma-Aldrich was prepared in distilled water and injected intraperitoneally with dexamethasone Ž0.1–1.0 and administered in a volume of 1 mlrkg. Cisplatin was mgrkg, i.p., betamethasone Ž0.3–3.0 mgrkg, i.p., meth- administered in a volume of 5 mlrkg. Doses are expressed ylprednisolone Ž1.0–10.0 mgrkg, i.p. or hydrocortisone Ž1.0–30.0 mgrkg, i.p. or their respective vehicles, 30 spost the administration of cisplatin 5 mgrkg, i.p. Žt s .
Glucocorticoid or vehicle treatment was continued at regu- 3. Results
lar 8-h intervals for the duration of the experiment. Aftertreatment, the animals were returned to individual observa- 3.1. General profile of emesis induced by cisplatin tion cages for the assessment of retching andror vomitingduring the subsequent 72-h observation period. During this Our investigations used castrated male and normal fe- time period food ŽLaboratory Feline Diet 5003, PMI Nutri- male animals but each experiment had a balanced design, were appropriate. The experiments were not designed to separate experiment, animals were injected with cisplatin 5 directly compare castrated male and normal female re- mgrkg, i.p. and were allowed to develop an acute emetic sponses to cisplatin. However, pooling of the control data response. At 24 h post-cisplatin injection, the animals were from the experiments utilising distilled water as the vehicle administered dexamethasone 1 mgrkg, i.p. or vehicle.
female did not reveal statistically signifi- Drug or vehicle treatment was then continued at regular cant differences in the total numbers of episodes Žmale 8-h intervals for the remainder of the experiment.
69.1 " 12.5, female 82.5 " 9.2., retches Žmale 345.5 " Animal behaviour was recorded remotely using a closed 70.5, female 443.6 " 65.8. or vomits Žmale 34.2 " 7.3, circuit video recording system and analysed at the end of female 40.3 " 3.7. or the latency to onset of emesis Žmale the experiment. Emesis was characterised by rhythmic abdominal contractions that were either associated with the T.S.W. Sam et al.r European Journal of Pharmacology 417 ( 3.2. Antagonism of cisplatin-induced emesis by corticos-teroids The profile of cisplatin-induced acute and delayed eme- sis and the effect of dexamethasone Ž0.1–1 mgrkg, i.p.
are shown in Fig. 1. In the vehicle-treated animals, cis-platin induced emesis within 4.4 " 1.2 h and there were84.3 " 32.7 retches q vomits on day 1, 182.7 " 66.8retches q vomits on day 2 and 142.7 " 50.1 retches qvomits on day 3. The profile of emesis occurring on days 2and 3 was representative of the emesis that occurred in theother experiments where the control animals received dis-tilled water as vehicle and cisplatin. However, some of thecontrol animals in experiments involving the use of meth-ylprednisolone and hydrocortisone failed to develop astrong retching and vomiting response during the initial24-h period and the effect of drug treatment could not beassessed ŽFig. .
Dexamethasone produced a trend to reduce emesis oc- curring during the initial 0–24-h period but the reductions tive vehicles, on the profile of retchingqvomiting in the ferret inducedby a single injection of cisplatin, 5 mgrkg. All drugs were administeredintraperitoneally. Cisplatin was injected at t s 0 h followed 30 s later bycorticosteroid or vehicle administration. Glucocorticoid or vehicle admin-istration was repeated every 8 h for the duration of the experiment.
Results represent the mean"S.E.M. of the total numbers of retchesqvomits occurring in 0–24-, 24–56- and 56–72-h time intervals Ž ns Significant differences in retchingqvomiting in cisplatin vehicle-treatedanimals and the respective cisplatin glucocorticoid-treated animals are were not statistically significant Ž P ) 0.05; Figs. 1 and .
The maximum reduction observed was 64.0% at 0.3 mgrkgŽ P ) 0.05. Betamethasone caused a dose-related antago-nism of the retching q vomiting during the initial 24-hperiod and a 71.1% reduction was seen at 0.3 mgrkgŽ P - 0.05.; increasing the dose to 3 mgrkg antagonisedemesis by 99.5% Ž P - 0.05; Fig. .
apparent increase in the latency to onset of cisplatin-in-duced retching q vomiting. The increases in latency seen with dexamethasone at 0.3 mgrkg and betamethasone at 3 methasone 1.0 mgrkg on the profile of retchingqvomiting in the ferret mgrkg were significant Ž P - 0.05; Fig.
induced by a single injection of cisplatin, 5 mgrkg. All drugs were cance of the increase in the latency induced by methyl- administered intraperitoneally. Cisplatin was injected at t s 0 h followed prednisolone and hydrocortisone could not be statistically 30 s later by dexamethasone or vehicle administration. Dexamethasone or analysed since some of the treatment groups in the respec- vehicle administration was repeated every 8 h for the duration of theexperiment. Results represent the mean"S.E.M. of the total numbers of tive experiments had less than three animals responding retchesqvomits occurring in 1-h time intervals Ž ns .
T.S.W. Sam et al.r European Journal of Pharmacology 417 ( Fig. 3. The effect of dexamethasone, betamethasone, methylprednisolone or hydrocortisone or their respective vehicles, on the latency to onset ofretching q vomiting in the ferret induced by a single injection of cisplatin, 5 mgrkg. All drugs were administered intraperitoneally. Cisplatin was injectedat t s 0 h followed 30 s later by corticosteroid or vehicle administration. Glucocorticoid or vehicle administration was repeated every 8 h for the durationof the experiment. Open circles represent the individual latencies. Filled circles represent the mean latencies of the respective treatment groups. Thenumbers of animals retching andror vomiting out of the number of animals tested ŽRVr .
T is indicated as a ‘fraction’ for each treatment group.
Examining the effect of dexamethasone on the profile groups receiving cisplatin and distilled water, there were of cisplatin-induced emesis occurring during the remaining 70.8 " 47.1, 353.3 " 144.1 and 88.5 " 16.7 retches q 2-day period revealed that emesis could be practically vomits during the 0–24-, 24–56- and 56–72-h periods, abolished Ž P - 0.05. in a dose-related manner up to 56 h following cisplatin administration Žmaximum reduction in emesis and the numbers of retches q vomits occurring in the 24–56 h period was 96.7% at 1 mgrkg; see Figs. 1 the 0–24-h period of the dexamethasone group Žlatency s 2 . The protective effect during the 24–56-h period 7.2 " 1.7 h, retches q vomits s 70.8 " 47.1. was not sta- was shared by betamethasone Žmaximum reduction was99.0% at 3 mgrkg; P - 0.05. and methylprednisoloneŽmaximum reduction was 98.9% at 10 mgrkg; P - 0.05.
Hydrocortisone produced a non-significant trend to antago-nise retching q vomiting Žmaximum reduction was 66.6%at 30 mgrkg; P ) 0.05. Žsee Fig. 2; profiles not Analysis of the data revealed the following rank order ofanti-emetic potency to reduce the 24–56 h retching qvomiting response: betamethasone ŽID - 0.3 mgr kg . None of the glucocorticoids antagonised signifi- cantly the retching q vomiting response occurring duringthe 56–72-h period Ž P ) 0.05; Fig. .
3.3. The action of dexamethasone (1 mg r kg, i.p.) adminis- tered as an interÕention treatment on an established de- 1.0 mgrkg on the profile of retchingqvomiting in the ferret induced by a layed retching and Õomiting response induced by cisplatin single injection of cisplatin, 5 mgrkg. All drugs were administeredintraperitoneally. Cisplatin was injected at t s 0 h followed 24 h later bydexamethasone or vehicle administration. Dexamethasone or vehicle ad- Ferrets were randomised to receive 8-h administrations ministration was repeated every 8 h for the remainder of the experiment.
of dexamethasone Ž1 mgrkg, i.p. or distilled water Ž0.5 Results represent the mean"S.E.M. of the total numbers of retchesq mlrkg, i.p. starting 24 h post-cisplatin injection. In the vomits occurring in 1-h time intervals Ž ns .
T.S.W. Sam et al.r European Journal of Pharmacology 417 ( tistically different Ž P ) 0.05. from the control animals emetic responsiveness of the ferret to cisplatin has been Žlatency s 8.8 " 2.5 h, retches q vomits s 136.5 " 57.6.
In the 24–56-h period, dexamethasone produced a 63.1% sone significantly antagonised the early emetic response by reduction in retching q vomiting but potentiated the retch- up to 99.5% and dexamethasone produced a non-signifi- ing q vomiting response by 47.5% in the 56–72-h period.
cant trend for a 25.7–64.0% reduction. In our previous However, the changes did not achieve statistical signifi- study, dexamethasone at 1 mgrkg, i.p., administered three times per day, reduced the initial phase of emesis byapproximately 85% ŽRudd and Naylor, tion in anti-emetic potency may relate to the different 4. Conclusions
strains of ferrets used in the studies.
Inflammation involves components of the immune re- The present studies have partially confirmed the sponse and many different mediators ŽLeirisalo-Repo, anti-emetic action of dexamethasone 1 mgrkg, i.p., ad- 1996 , some of which are known to activate ministered three times per day to reduce significantly the emetic reflex. The classical mediators that are emetic the retching and vomiting response induced by a single include histamine Že.g. dog, Bhargava and Dixit, administration of cisplatin ŽRudd and Naylor, 5-HT Že.g. Suncus murinus, Torii et antagonism of emesis observed in the present studies was 1991 , prostaglandins Že.g. dog, Eiler and Paddleford, particularly apparent during the 24–56-h period following 1979 , substance P Že.g. ferret, Gardner et al., cisplatin injection but less effective to control emesis possibly leukotrienes Že.g. monkey, Jett et al., occurring after the 56-h period. Importantly, the other well known that glucocorticoids decrease histamine pro- glucocorticoids were also highly active to reduce emesis duction andror release from mast cells ŽHirasawa et al., during the 24–56-h period and the reductions seen were 1990 and prevent the synthesis of prostaglandins, throm- boxane and leukotrienes Vane and Botting, 1996 . Less potency of the glucocorticoids to antagonise emesis during information is available about the emetic potential of other the 24–56-h period was betamethasone ŽID - 0.3 mgr inflammatory mediators such as nitric oxide, bradykinin, cytokines and oxygen derived free radicals, which are also involved in inflammation and regulated by glucocorticoids ŽBarnes and Adcock, 1993; Dray and Bevan, 1993; Mon- The rank order of anti-emetic activity of the glucocorti- coids is remarkably similar to their known rank order of anti-inflammatory potency, where dexamethasone and be- If inflammation is involved in the model, a critical tamethasone are approximately equipotent but more potent question arising is how can cisplatin activate the inflamma- than methylprednisolone and hydrocortisone, respectively tory response or elevate levels of inflammatory mediators? Perhaps the trigger for cisplatin to induce inflammation or have been expected to be more potent but the difference the production of inflammatory mediators could relate to may be due to the compounds relatively short plasma half its cytotoxic and neurotoxic action ŽScott et al., life andror its additional mineralocorticoid activity Žre- andror the ability to modulate cytokine levels ŽCoulon et al., 1993; Preziosi et al., 1992; Rabinowitz et al., suggests that inflammation, or inflammatory mediatorsr Recent studies suggest that interleukins, Že.g. interleukin- products, contribute to the emesis seen during 24–56-h period following cisplatin treatment. At present, we do not stimulating factor or even tumour necrosis factor-a may know the site of proposed inflammation or if cisplatin be key players in triggering the mechanism as they are induces local inflammation following intraperitoneal injec- elevated following cisplatin treatment ŽPogrebniak et al., 1991; Rabinowitz et al., 1993; Shi et al., Based on the anti-emetic activity of dexamethasone Žpresent studies; Fukunaka et al., 1998; Rudd and Naylor, indirectly activates the inflammatory mechanism by reduc- ing the levels of the natural ‘decoy receptor’ for inter- flammatory response andror involvement of inflammatory mediatorsrproducts may also contribute to the initial phase well known to prevent the production of the cytokines h of emesis induced by cisplatin Žwe do not know if a pretreatment of the glucocorticoids would result in a prevent the involvement of many of the mediators in- volved in inflammation and possibly emesis.
argument cannot be made from the experiments involving We would like to hypothesise that the involvement of methylprednisolone and hydrocortisone since some of the cytokines and other pro-inflammatory mediators may oc- animals in the control groups failed to develop a strong cur early in response to cisplatin treatment since dexa- emetic response during this period. Such variation in the methasone was more effective to antagonise delayed eme- T.S.W. Sam et al.r European Journal of Pharmacology 417 ( Cytokine production during intraperitoneal chemohyperthermia. On- started on the first day. The data are partially consistent Dollery, C., 1991. Hydrocortisone. In: Dollery, C. ŽEd., Therapeutic with the clinical experience where a poor control of acute Drugs. Churchill Livingstone, London, England, pp. H55–H63.
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Gralla, R.J., Rittenberg, C., Peralta, M., Lettow, L., Cronin, M., 1996.
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