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PubMed1987

Emesis induced by cisplatin in the ferret as a model for the detection of anti-emetic drugs.

The intravenous injection of cisplatin in the ferret caused a consistent emetic (vomiting/retching) response. Emesis induced by cisplatin was abolished by the 5-hydroxytryptamine (5-HT) M-receptor antagonists ICS205-930, zacopride, dazopride and metoclopramide. The neuroleptic agents haloperidol, fluphenazine, domperidone, sulpiride and tiapride also antagonized emesis induced by cisplatin but only a proportion of the animals were completely protected and diazepam and prednisolone only reduced the intensity of the response. It is concluded that compounds used in the clinic to antagonise emesis induced by chemotherapy are effective in the ferret model. Antagonism of emesis induced by cisplatin in the ferret was most potently achieved by the use of the 5-HT M-receptor antagonists ICS205-930 and zacopride. However, an antagonism of dopamine receptors would appear relevant to the anti-emetic effects of the neuroleptic agents and may contribute to the anti-emetic effects of metoclopramide. Diazepam and prednisolone exert their modest antagonism by unknown mechanisms. The use of the 5-HT M-receptor antagonists is revealed as a novel approach to the treatment of emesis induced by cisplatin.

Animals↗
PubMed1993

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.

Animals↗
PubMed1990

Correlation of anti-emetic efficacy and plasma levels of ondansetron.

Intravenous ondansetron was administered at doses from 0.01 to 0.48 mg/kg every 4 h for three doses to patients receiving cisplatin 60-120 mg/m2 for the first time. Plasma samples were collected from 28 patients at baseline and at suitable times post-dose for pharmacokinetic analysis, and were assayed for ondansetron by high-pressure liquid chromatography. Plasma trough level was defined as the level before the third dose and 4 h area-under-the-curve (AUC4) was calculated with the linear trapezoidal method. Despite wide inter-patient variation, a correlation was seen between both trough level (r = 0.737, P less than 0.0001) and AUC4 (r = 0.903, P less than 0.001) related to dose. Trough level was also predictive of AUC4 (r = 0.824, P less than 0.0001). Frequency of complete protection (no emetic episodes) was equivalent throughout the AUC4 range, suggesting anti-emetic activity even at low AUC4. However, a trend toward better protection against failure (5 or more episodes) was seen when higher values of AUC4 were achieved, suggesting more consistent anti-emetic activity at moderate to high AUC4.

Adult↗
PubMed1994

The roles of patient and observer assessments in anti-emetic trials.

The endpoints assessed by both patients and nurses were compared in three anti-emetic studies. In a parallel subjects study, there was no significant difference between the patients' and nurses' assessment of the number of vomiting episodes, but the duration of vomiting, the severity and duration of nausea, and the side-effects of the anti-emetic were given higher scores by the nurses. In two cross-over studies, the patients recorded more vomiting episodes than the nurses, while the nurses recorded more anxiety and sedation than the patients. This resulted in the patients detecting a difference between the side-effects of the anti-emetics being compared that was not apparent from the nurses' forms. Many of the differences reflect differences in the timing and frequency of data collection. Nurses collected data regularly during the assessment period whereas patients reported their experiences only at the completion of 24 h. Both assessments provide useful perspectives on the study outcomes.

Cross-Over Studies↗
PubMedDate not supplied

Modification of reserpine-induced emetic response in pigeons by alpha 2-adrenoceptors.

In the present study, an attempt has been made to elucidate the role of alpha 2-adrenoceptors in reserpine-induced emesis in pigeons. Reserpine was found to induce dose-dependent emesis and a 500 micrograms kg-1 dose was found to be the 100% emetic dose. alpha 2-adrenoceptor agonists clonidine and alpha-methylnoradrenaline inhibited the reserpine induced emesis. Out of the two selective alpha 2-adrenoceptor antagonists idazoxan and yohimbine, only the latter induced a dose-dependent emesis. However, both the drugs potentiated reserpine-induced emesis and antagonised its inhibition by clonidine. Prior depletion of monoamines by reserpine also blocked the emetic response of reserpine. These observations indicate that release of monoamines is responsible for its emetic response in pigeons which is modulated by presynaptic alpha 2-adrenoceptors in a predictable manner.

Animals↗
PubMed2005

Effects of dexamethasone in preventing postoperative emetic symptoms after total knee replacement surgery: a prospective, randomized, double-blind, vehicle-controlled trial in adult Japanese patients.

BACKGROUND: Postoperative emetic symptoms (nausea, retching, and vomiting) are common following total joint replacement, with an incidence as high as 83% when no prophylactic antiemetic is provided. However, most antiemetics currently used in Japan, such as antihistamines (eg, hydroxyzine), butyrophenones (eg, droperidol), and dopamine receptor antagonists (eg, metoclopramide), have been associated with adverse effects (AEs), such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal symptoms. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of 3 doses of intravenous dexamethasone monotherapy versus vehicle in preventing emetic symptoms after total knee replacement performed under combined general and epidural anesthesia. METHODS: This prospective, randomized, double-blind, vehicle-controlled trial was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba, Japan. Adult Japanese patients scheduled to undergo total knee replacement were eligible. Patients were randomly assigned to 1 of 4 treatment groups: dexamethasone 4, 8, or 16 mg, or vehicle (control). Patients received combination anesthesia with sevoflurane and nitrous oxide in pure oxygen (general) and lidocaine (epidural). Study drugs were administered intravenously after the completion of surgery. An investigator blinded to treatment assignment monitored patients for emetic symptoms for 24 hours after the patient awoke. Patients rated their satisfaction with the study drug using a linear, 11-point scale (0 = complete satisfaction to 10 = complete dissatisfaction). Tolerability was assessed by the study investigator using spontaneous reporting and patient interview. RESULTS: A total of 80 patients were enrolled (58 women, 22 men; mean [SD] age, 59 [10] years; mean [SD] height, 154 [7] cm; mean [SD] body weight, 55 [7] kg; 20 patients per treatment group). The demographic, clinical, and surgical data were comparable between the 4 treatment groups. The rates of emesis-free patients were 35% (7 patients), 70% (14), and 75% (15) with dexamethasone 4, 8, and 16 mg, respectively, compared with 30% (6) with vehicle (P = NS, 0.013, and 0.005, respectively). Median (range) patient satisfaction scores were significantly higher in the groups receiving dexamethasone 8 and 16 mg (both, 0.0 [0-9]) compared with controls (6.0 [0-10]) (P = 0.013 and 0.008, respectively). This effect was not found with the 4-mg dose. No clinically serious AEs attributed to the study drug were observed in any of the 4 treatment groups. CONCLUSIONS: In this study of a small, select group of adult Japanese patients undergoing total knee replacement, the rates of emesis-free patients were higher with dexamethasone 8 and 16 mg compared with vehicle 24 hours after anesthesia induction. This effect was not found with the 4-mg dose. All treatments were well tolerated.

Adult↗
PubMed2003

Action of prostanoids on the emetic reflex of Suncus murinus (the house musk shrew).

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Effect of a selective GABA(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects.

The management of excessive adverse effects of opioids is a major clinical problem. The present study was undertaken to investigate the effect of a selective gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Either morphine or fentanyl produced a dose-dependent antinociceptive effect in both ferrets using Randall-Selitto test and mice using tail-flick test. Under these conditions, pretreatment of baclofen produced an additive antinociception induced by morphine or fentanyl. Furthermore, the augmentation of antinociception induced by systemic administration of baclofen with morphine or fentanyl was completely abolished by either i.c.v. or i.t. pretreatment with the selective GABA(B) receptor antagonist CGP 35348 in mice. We next investigated the emetic response induced by mu-opioid receptor agonist in ferrets. Morphine at lower doses than that used for antinociceptive assay produced both retching and vomiting, whereas fentanyl failed to produce the retching and vomiting in ferrets. Here we reported for the first time that baclofen significantly suppressed the retching and vomiting induced by morphine, indicating the involvement of GABA(B) receptor in emetic control pathway. Furthermore, baclofen also inhibited place preference elicited morphine or fentanyl in rats. Taken together, these results suggest that co-administration of baclofen with mu-opioid receptor agonist produced a potentiation of antinociceptive effect, whereas an untoward effect was completely blocked.

Analgesics, Opioid↗
PubMed1999

The site of the anti-emetic action of tachykinin NK1 receptor antagonists may exist in the medullary area adjacent to the semicompact part of the nucleus ambiguus.

NK1 receptor antagonists have been shown to act centrally and to produce a broad-spectrum anti-emetic action. To determine precisely the site of this action, we microinjected GR205171, an NK1 receptor antagonist, into the left medulla oblongata in decerebrate paralyzed dogs. The right medulla was transected 2.5 mm rostral to the obex to eliminate the emetic function of that half. Fictive retching induced by vagal stimulation was still observed after each of 32 injections (0.5-5 microgram in 1-30 microliter) in the area ventrolateral to the solitary complex in six dogs. Retching was also observed for 30 min or more after all but 2 of 30 injections (0.5-1 microgram in 0.5-1 microliter) in the area dorsal to the retrofacial nucleus in 17 dogs. In contrast, retching disappeared within 5-30 min after each of 20 injections (0.5-1 microgram in 1 microliter) in the area adjacent to the semicompact part of the nucleus ambiguus (scAMB) in 15 dogs. The threshold dose for abolition of the retching response was examined in seven dogs and was about 0.1 ng in 1 microliter. The maximum velocity of salivation occurred before the onset of retching and significantly decreased after its abolition. These results suggest that the site of the anti-emetic action of NK1 receptor antagonists may lie in a limited area adjacent to the scAMB, and that neurons in the site induce prodromal signs and retching in a sequential manner.

Animals↗
PubMed1997

In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists.

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 < or = 0.85 mg/kg), and acute retching induced by cisplatin (ID50 < or = 0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-m ethoxyphenyl)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-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)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.

Administration, Oral↗
PubMed2002

The COX inhibitors indomethacin and meloxicam exhibit anti-emetic activity against cisplatin-induced emesis in piglets.

We analysed the effects of four cyclooxygenases (COX) inhibitors on cisplatin-induced emesis in piglets. Ninety-five animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. One hour prior to cisplatin, controls (n=29) were dosed with a saline solution while experimental animals received an i.v. or i.p. injection of one of the COX inhibitors. Additional injections of COX inhibitor were given at 15 and 39 h after cisplatin administration (or every 6h in one group receiving diclofenac). The latencies to the first emetic episode (EE) compared to controls (2.1+/-0.4 h) increased in groups receiving naproxen (4.66+/-0.94 h, n=9, 30 mg kg(-1)) and indomethacin (6.19+/-1.13 h, n=7, 10 mg kg(-1)) i.v. Indomethacin significantly decreased the incidence of both the acute (by 40%) and delayed (by 66%) phases of emesis. The total number of EE during the 60 h compared to controls (28.3+/-1.9 EE) was significantly reduced in piglets receiving indomethacin (14.9+/-3.2 EE, n=7) and meloxicam (17.6+/-3.6 EE, n=11, 0.3 mg kg(-1)). Four piglets receiving meloxicam (0.3 mg kg(-1), i.v.) did not vomit during the delayed phase. The anti-emetic activity of two COX inhibitors suggests that prostaglandins contribute to the activation of the emetic reflex in response to cisplatin.

Animals↗
PubMed1999

Anti-emetic principles of Pogostemon cablin (Blanco) Benth.

Bioassay-guided fractionation of anti-emetic extracts and constituents of 8 traditional Chinese herbal drugs was performed. Twenty extracts described in Table 1 showed anti-emetic activity on copper sulfate induced-emesis in young chicks. From the n-hexane extract of Pogostemon cablin, patchouli alcohol (1), pogostol (2), stigmast-4-en-3-one (3), retusin (4), and pachypodol (5) were tested and exhibited anti-emetic effects.

Animals↗
PubMed1997

An overview of randomised studies comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting.

Ten years after it was demonstrated in the ferret that cisplatin-induced emesis could be blocked by the selective 5-HT3 receptor antagonist MDL 72222, 5-HT3 receptor antagonists have become routine anti-emetic agents for chemotherapy-induced emesis. However, although in association with highly emetogenic, mainly cisplatin-containing regimens, the use of these agents is well justified, the net benefit of 5-HT3 receptor antagonists in association with moderately emetogenic regimens has not been that well clarified. Here, we present an overview of 30 randomised studies comparing 5-HT3 antagonists with the conventional anti-emetics in the prophylaxis of acute vomiting induced by cytotoxic chemotherapy. A meta-analysis showed that 5-HT3 antagonists reduce the risk of acute vomiting in comparison to conventional anti-emetics both with cisplatin treatments (15 trials; odds ratio 0.60; 95% confidence interval 0.51-0.70) and with moderately emetogenic treatments (11 trials; odds ratio 0.47; 95% confidence interval 0.39-0.58). The risk of acute vomiting seems to be further reduced when 5-HT3 antagonists are combined with dexamethasone.

Acute Disease↗
PubMed1996

Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret.

In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Effects of altering the time of administration and the time frame of quality of life assessments in clinical trials: an example using the EORTC QLQ-C30 in a large anti-emetic trial.

Previous studies conducted by our group suggested that the ability to demonstrate an impact of emesis control on quality of life might depend upon when an quality of life instrument was administered in relation to chemotherapy and on the time frame of the questionnaire. This study was conducted to address this issue. Six hundred and fifty patients receiving moderately emetogenic chemotherapy in a randomized trial comparing a variety of anti-emetic regimens were allocated to four different modes of administration (days 4 and 8; 3 and 7 day time frames) of the QLQ-C30. Patients who completed the questionnaire at the time of maximal impact of chemotherapy (day 3) were more likely to report deterioration in quality of life. Patients who completed questionnaires at day 8 were more likely to report deterioration in quality of life if their questionnaire had a 7 day time frame rather than a 3 day time frame. Patients receiving more effective anti-emetic therapy had better quality of life. It was concluded that better anti-emetic control improves quality of life after moderately emetogenic chemotherapy. In studying quality of life in situations where the impact of treatment waxes and wanes, careful attention needs to be paid to scheduling the administration of questionnaires and to their time frame.

Adult↗
PubMed1983

Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy.

Nabilone, a synthetic cannabinoid, and Prochlorperazine were compared in a double-blind crossover study of 34 patients with lung cancer undergoing a 3-day schedule of chemotherapy with Cyclophosphamide, Adriamycin and Etoposide. Symptom scores were significantly better for patients on nabilone for nausea, retching and vomiting (P less than 0.05). Fewer subjects vomited with nabilone (P = 0.05) and the number of vomiting episodes was lower (P less than 0.05); no patients on nabilone required additional parenteral anti-emetic. More patients preferred nabilone for anti-emetic control (P less than 0.005). Adverse effects common with nabilone were drowsiness (57%), postural dizziness (35%) and lightheadedness (18%). Euphoria was seen in 14% and a "high" in 7%. Erect systolic blood pressure was lower in nabilone patients on Day 1 (P = 0.05) but postural hypotension was a major problem in only 7%. Nabilone is an effective oral anti-emetic drug for moderately toxic chemotherapy, but the range and unpredictability of its side-effects warrant caution in its use.

Adult↗
PubMed1988

The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694.

In ferrets, the selective 5-hydroxytryptamine (5-HT) 5-HT3 receptor antagonist BRL 43694 given as a single injection (0.05-0.5 mg kg-1 i.v.) before cisplatin, or by divided dose (2 x 0.005-2 x 0.5 mg kg-1 i.v.) before and after cisplatin dramatically reduced or abolished the severe cisplatin-induced vomiting. BRL 43694 also substantially reduced the vomiting induced by cyclophosphamide:doxorubicin, and prevented the trimelamol-induced emesis. The severe emesis caused by whole body exposure to X-irradiation was prevented by intravenous or oral BRL 43694. A single i.v. dose of BRL 43694 given during an emetic episode or within the peak emetic period, abolished the vomiting induced by the cytotoxic drugs and by X-irradiation, usually within 30 s. Where the induction of emesis was prevented or subsequently abolished by BRL 43694, the associated behaviour (subjectively assessed as nausea) was also absent or greatly attenuated. BRL 43694 (0.1 mg kg-1 i.v.) did not affect the emesis evoked in dogs by the dopamine agonist apomorphine. The potent anti-emetic activity of BRL 43694 is discussed in terms of potential clinical use, and of the fundamental role that 5-HT3 receptors may play in the mechanisms of nausea and vomiting.

Animals↗
PubMed1988

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist.

Twenty patients receiving a variety of emetogenic cytotoxics (including cisplatin in 5) were given a single i.v. infusion of 40 micrograms kg-1 of BRL43694 (as the hydrochloride salt) in successive groups of 3-4 patients between 0-6 hours after chemotherapy. Eleven patients were completely protected from vomiting; 9 had mild to moderate nausea and vomiting, but none severe enough to require alternative anti-emetic 'rescue'. In 4 of the patients in whom BRL43694 was delayed until 4-6 h after chemotherapy, vomiting had already begun; in each case immediate termination of vomiting occurred when BRL43694 was infused. No adverse effects attributable to the anti-emetic were observed. Mean pharmacokinetic parameters in 14 patients in whom plasma assay data are available were: Maximum observed concentration = 30.7 ng ml-1; terminal phase half-life = 8.96 h; total body clearance = 0.376 (1 h-1) kg-1; apparent volume of distribution = 2.85 l kg-1. This study shows BRL43694 to be an effective and well tolerated anti-emetic. Further studies aimed at defining an optimal dose and schedule for use against the most emetogenic cytotoxics are in progress.

Adolescent↗