Efficacy of Olanzapine in Addition to Standard Triplet Antiemetic Therapy for Cisplatin-Based Chemotherapy: A Secondary Analysis of the J-FORCE Randomized Clinical Trial.

Importance: It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of randomized clinical trials using olanzapine may provide insight into the effectiveness of olanzapine for chemotherapy-induced nausea and vomiting (CINV), including cisplatin. Objective: To examine the add-on effect of olanzapine according to risk factors for CINV. Design, Setting, and Participants: This preplanned secondary analysis evaluated results of the J-FORCE trial, a large double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Japan from February 9, 2017, to July 18, 2018. Participants were enrolled from 26 participating hospitals across Japan and included patients aged 20 to 75 years who had a malignant tumor and were cisplatin-naive. The efficacy analysis population of the J-FORCE trial was analyzed according to allocation adjustment factors (sex [male or female], age [≥55 years or <55 years], and cisplatin dose [≥70 mg/m2 or <70 mg/m2]) and patient-related risk factors (history of motion sickness, drinking habit [defined as alcoholic drinks consumption in excess of occasional drinking], and history of morning sickness during pregnancy). Statistical analysis was performed from February 18 to April 18, 2020. Interventions: Patients were randomized 1:1 to receive 5 mg of olanzapine or placebo combined with standard triplet antiemetic therapy. Main Outcomes and Measures: The primary end point was complete response (CR, defined as no vomiting and no use of rescue medication) in the delayed phase (24-120 hours after cisplatin-based chemotherapy administration). Secondary end points were CR, complete control, and total control in the acute, delayed, and overall phases for 6 CINV risk factors as well as time to treatment failure. The CR point estimates and 95% CIs of the differences between groups were calculated, and a Mantel-Haenszel test was performed. Results: Of the 705 patients (mean [SD] age, 63.0 [9.2] years; 471 males [66.8%]) included in the efficacy analysis population; 581 patients (82.4%) were 55 years or older, and 526 (74.6%) were treated with a cisplatin dose of 70 mg/m2 or more. Risk difference (RD) for a CR in the delayed phase was significantly greater in the olanzapine group than the placebo group in males (RD, 12.6% [95% CI, 5.0%-20.1%]; P = .001); in females (RD, 14.5% [95% CI, 2.2%-26.3%]; P = .02); in those 55 years or older (RD, 11.1% [95% CI, 3.9%-18.2%]; P = .003) or younger than 55 years (RD, 23.6% [95% CI, 7.3%-38.3%]; P = .005); for a cisplatin dose of 70 mg/m2 or more (RD, 13.5% [95% CI, 5.9%-21.0%]; P < .001); for those without a history of motion sickness (RD, 13.9% [95% CI, 6.9%-20.6%]; P < .001); for those with a drinking habit (RD, 14.9% [95% CI, 6.1%-23.4%]; P = .001) or without a drinking habit (RD, 12.0% [95% CI, 2.5%-21.3%]; P = .01); and for those with a history of morning sickness during pregnancy (RD, 27.2% [9.7%-42.6%]; P = .002). In other subgroups, a delayed CR was higher in the olanzapine group than the placebo group, although not significantly higher. Conclusions and Relevance: Results of this study suggest a benefit of using 5 mg of olanzapine plus triplet antiemetic therapy to counter CINV regardless of the presence or absence of risk factors. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000024676.

Risk factors associated with nausea and vomiting in children with cancer receiving chemotherapy.

INTRODUCTION: Despite treatment with antiemetic medications, nausea remains uncontrolled for many children receiving chemotherapy. One reason is that risk factors for nausea in children remain poorly explored. The purpose of this study was to identify risk factors for chemotherapy-induced nausea (CIN) in children. METHODS: Prospective, observational study including 101 children (median age 6.4 years, range 0.8-17.9) with cancer receiving moderately or highly emetogenic chemotherapy. Primary endpoints were complete control of acute and delayed CIN, defined as no nausea in the acute phase 0-24 h after chemotherapy and in the delayed phase starting after the acute phase and ending 5 days later. Multivariable analyses included age, sex, cancer type, susceptibility to motion sickness, chemotherapy duration, numbers of antiemetics, co-administration with opioids or tricyclic antidepressants, and previously uncontrolled nausea or vomiting. RESULTS: Acute CIN was associated with susceptibility to motion sickness (odds ratio [OR] 5.73, 95% confidence interval [CI] 1.36-33.7) and older age (OR 4.19, 95% CI 1.30-14.7), comparing age group 8-18 years with 0-3 years. Delayed CIN was associated with uncontrolled acute nausea or vomiting (OR 10.3, 95% CI 2.65-50.9), highly emetogenic chemotherapy (OR 8.26, 95% CI 1.17-76.8), and having a hematologic cancer type (OR 7.81, 95% CI 1.05-79.2). CONCLUSIONS: Susceptibility to motion sickness and age can influence the risk of acute CIN. More research is needed on how best to integrate risk information in preventive antiemetic strategies. Sufficient acute nausea and vomiting control are crucial to prevent delayed CIN.

Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions.

Enhanced cholinergic activity contributes to the production of complex autonomic manifestations of motion sickness (MS). However, whether anti-cholinergics exert their anti-MS effects through central or peripheral actions remained unclarified. In the present study, we investigated the effects of mecamylamine (MEC) and scopolamine (SCOP) on rotation-induced gastrointestinal symptoms (conditioned gaping and defecation), locomotion disturbances (hypoactivity and impaired balance performance), hypothermia as well as Fos expression in vestibulo-autonomic regions in rats. We also observed the effects of hexamethonium (HEX) and methyl scopolamine (MSCP) on those MS behavioral responses. The efficacy of all these drugs on rotation-induced emesis and other MS symptoms in cats was also examined. We found that intragastric administration of MEC and SCOP inhibited rotation-induced gaping and defecation in rats, but only MEC showed a dose-dependent manner. MEC aggravated rotation-induced balance disorder and failed to attenuate rotation-induced hypothermia as the SCOP did. MEC was more effective for inhibiting Fos expression in the caudal vestibular nucleus and nucleus of solitary tract than SCOP. Intraperitoneal injection of HEX and MSCP also significantly alleviated rotation-induced gastrointestinal symptoms, and showed benefit to balance performance in rats. In cats, MEC, SCOP and HEX had prophylactic effects against rotation-induced emesis and salivation, and deceased non-retching/vomiting symptoms, but MSCP only attenuated emesis. It suggested that MEC and SCOP might alleviate gastrointestinal symptoms of MS via inhibiting peripheral autonomic nervous system and central vestibulo-autonomic pathways. The nicotinic acetylcholine receptor inhibitors like MEC might be new candidates against gastrointestinal symptoms induced by MS or other vestibular disorders.

Effects of naloxone on motion sickness in cats alone and with broad spectrum antiemetics.

Doses of naloxone far below those which elicit emesis increase the sensitivity to motion sickness. In order to evaluate the possible interaction with broad spectrum antiemetics, low doses of naloxone were tested alone and in combination with 8-hydroxy-2-(di-n-propylamine)tetralin (DPAT), fentanyl and the NK1 antagonist CP-99994. A modified autonomic symptom rating scale was unaffected by any drug and thus considered of little value. Fentanyl and NK1 antagonists decreased the duration of the retch/vomit sequence. Naloxone alone and in combination with each of the drugs increased the duration of retching/vomiting. Naloxone also increased the number of vomiting sequences. The results are interpreted in terms of possible site(s) of action of the antiemetic drugs.

Integration of vestibular and gastrointestinal inputs by cerebellar fastigial nucleus neurons: multisensory influences on motion sickness.

Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO4) alters the responses to vestibular stimulation of a large fraction of neurons in brainstem regions that mediate nausea and vomiting, thereby affecting motion sickness susceptibility. Other studies suggested that the processing of vestibular inputs by cerebellar neurons plays a critical role in generating motion sickness and that neurons in the cerebellar fastigial nucleus receive visceral inputs. These findings raised the hypothesis that stimulation of gastrointestinal receptors by a nauseogenic compound affects the processing of labyrinthine signals by fastigial nucleus neurons. We tested this hypothesis in decerebrate cats by determining the effects of intragastric injection of CuSO4 on the responses of rostral fastigial nucleus to whole-body rotations that activate labyrinthine receptors. Responses to vestibular stimulation of fastigial nucleus neurons were more complex in decerebrate cats than reported previously in conscious felines. In particular, spatiotemporal convergence responses, which reflect the convergence of vestibular inputs with different spatial and temporal properties, were more common in decerebrate than in conscious felines. The firing rate of a small percentage of fastigial nucleus neurons (15%) was altered over 50% by the administration of CuSO4; the firing rate of the majority of these cells decreased. The responses to vestibular stimulation of a majority of these cells were attenuated after the compound was provided. Although these data support our hypothesis, the low fraction of fastigial nucleus neurons whose firing rate and responses to vestibular stimulation were affected by the administration of CuSO4 casts doubt on the notion that nauseogenic visceral inputs modulate motion sickness susceptibility principally through neural pathways that include the cerebellar fastigial nucleus. Instead, it appears that convergence of gastrointestinal and vestibular inputs occurs mainly in the brainstem.

A novel method of 2-channel dual-pulse gastric electrical stimulation improves solid gastric emptying in dogs.

BACKGROUND: Gastric electrical stimulation (GES) is known to improve vomiting with short pulses, normalize dysrhythmia with long pulses, and accelerate gastric emptying with 2 channels. The aim of this study was to assess the effects of a new method GES, namely, 2-channel GES with dual pulses on gastric emptying of solids as well as gastric dysrhythmia and emetic responses. METHODS: Seven beagle dogs implanted with 4 pairs of electrodes were studied. A novel method of GES was proposed: 2-channel dual-pulse GES in which each stimulus was composed of a short pulse followed with a long pulse, and stimulation was delivered at 2 different locations. The study was performed to test the effects of this new method of GES on vasopressin-induced delayed gastric emptying of solids, gastric dysrhythmia, and emetic responses. RESULTS: (1) Vasopressin-induced gastric dysrhythmia and emetic responses, as well as delayed gastric emptying of solids (P < .01). (2) Two-channel, but not 1-channel, dual-pulse GES was able to accelerate vasopressin-induced delayed gastric emptying of solids. (3) Both 1- and 2-channel dual-pulse GES was capable of improving dysrhythmia and emetic responses (P < .01). CONCLUSIONS: The novel method of 2-channel dual-pulse GES is capable of accelerating gastric emptying of solids and improving dysrhythmia and emetic responses induced by vasopressin. This new method of GES may have a potential for gastroparesis.

Effects of gastric electrical stimulation with short pulses and long pulses on gastric dysrhythmia and signs induced by vasopressin in dogs.

AIMS: This study was to investigate the effect of gastric electrical stimulation (GES) with short pulses, long pulses, short-pulse trains or long-pulse trains on gastric dysrhythmia and motion-sickness signs induced by vasopressin. METHODS: Seven male beagle dogs implanted with four pairs of electrodes on gastric serosa were studied. The study was performed in six sessions in a randomized order. In session 1 or 2, either saline or vasopressin was infused without GES. In session 3, 4, 5 and 6, GES with short pulses, long pulses, trains of short pulses or trains of long pulses was performed before and during vasopressin infusion. Gastric slow waves and motion-sickness signs were recorded in each session. RESULTS: (1) Vasopressin induced gastric dysrhythmia and motion sickness-like signs (ANOVA, P < 0.001). (2) GES with short pulses or trains of short pulses was capable of preventing vasopressin-induced emetic response (P < 0.001), but did not normalize gastric dysrhythmia. (3) GES with long pulses or trains of long pulses was able to normalize gastric dysrhythmia induced by vasopressin (P < 0.001), but showed no effects on vasopressin-induced motion-sickness signs. CONCLUSION: GES with short pulses or trains of short pulses prevents vasopressin-induced emetic response with no improvement in gastric dysrhythmia. GES with long pulses or trains of long pulses normalizes gastric dysrhythmia induced by vasopressin with no effects on signs.

Two-channel gastric electrical stimulation accelerates delayed gastric emptying induced by vasopressin.

The aim of this study was to investigate the effects of two-channel gastric electrical stimulation (GES) on delayed gastric emptying, gastric dysrhythmias, and motion sickness-like symptoms induced by vasopressin. Seven dogs implanted with four pairs of gastric electrodes and a duodenal cannula were studied in four randomized sessions (saline, vasopressin, single-channel GES, and two-channel GES). The experiment in each session was conducted sequentially as follows: 30-min baseline, ingestion of a liquid meal, 30-min iv infusion of vasopressin or saline, and two 30-min postprandial recordings. In the GES sessions, GES was applied via the first pair of electrodes for single-channel GES or the first and third pairs of electrodes for two-channel GES. Gastric emptying was collected every 15 min via the cannula for a period of 90 min. Results were as follows. (1) Vasopressin induced gastric dysrhythmias, motion sickness-like symptoms, and delayed gastric emptying (P < 0.01, ANOVA). (2) GES normalized gastric dysrhythmias (P < 0.01) but showed no effects on vasopressin-induced emetic response. (3) Two-channel GES improved delayed gastric emptying induced by vasopressin. In comparison with the vasopressin session, two-channel GES, but not single-channel GES, significantly increased gastric emptying at 30 min (43.9+/-12.6 vs. 27.5+/-7.7%; P < 0.03), 60 min (75.3+/-15.1 vs. 54.0+/-17.8%; P < 0.05), and 90 min (91.6+/-9.8 vs. 80.3+/-9.0%; P < 0.05). GES with long pulses is able to normalize gastric dysrhythmias. Two-channel GES improves delayed gastric emptying induced by vasopressin.

Effects of intestinal electrical stimulation on intestinal dysrhythmia and symptoms in dogs.

The aim of this study was to investigate the effect of intestinal electrical stimulation on small intestinal dysrhythmia and motion sickness-like symptoms induced by vasopressin. Female dogs chronically implanted with two pairs of electrodes on jejunum serosa were used in a four-session study. Saline and vasopressin were infused in sessions 1 and 2, respectively. Sessions 3 and 4 were the same as session 2, except a long- or short-pulse intestinal electrical stimulation was applied on the proximal pair of electrodes. Intestinal slow waves and motion sickness-like symptoms were recorded in each session. Results were as follows. (1) Vasopressin induced intestinal dysrhythmia, uncoupling of slow waves, and vomiting and motion sickness-like symptoms (P < 0.05, ANOVA). (2) Intestinal electrical stimulation with long pulses, but not short pulses, was capable of preventing vasopressin-induced intestinal dysrhythmia. (3) Intestinal electrical stimulation with short pulses, but not long pulses, prevented vomiting and the motion sickness-like symptoms. It is concluded that vasopressin induces intestinal dysrhythmia. Long-pulse intestinal stimulation normalizes vasopressin-induced intestinal slow-wave abnormalities with no improvement in symptoms. Short-pulse stimulation prevents emetic symptoms induced by vasopressin but has no effect on slow waves. These data suggest different mechanisms involved with different methods of intestinal stimulation.

The effect of serotonin and serotonin receptor antagonists on motion sickness in Suncus murinus.

In the present study, we investigated the effect of 5-hydroxytryptamine (5-HT) and 5-HT receptor agonists and antagonists on motion sickness in Suncus murinus, and the possibility that the emetic stimulus of 5-HT can alter the sensitivity of the animals to the different emetic stimulus of motion sickness. 5-HT (1.0, 2.0, 4.0 and 8.0 mg/kg ip) induced emesis and that was antagonised by methysergide (1.0 mg/kg ip), the 5-HT(4) receptor antagonist sulphamate[1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate (GR125487D; 1.0 mg/kg ip) and granisetron (0.5 mg/kg ip). Pretreatment with 5-HT caused a dose-related attenuation of the emetic response induced by a subsequent motion stimulus, which was not significantly modified by methysergide, granisetron or GR125487D pretreatment. (+)-1-(2,5-Dimethoxy-4-iodophenyl)-2-amino-propane (DOI; 0.5 and 1.0 mg/kg ip), 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg/kg ip) but not methysergide, GR125487D or granisetron, attenuated motion-induced emesis, and that was not affected by pretreatment with ketanserin (2.0 mg/kg, ip) or N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrocholoride (WAY-100635; 1.0 mg/kg ip), respectively. Indeed, ketanserin alone (0.1, 0.3, 1.0 and 2.0 mg/kg ip) attenuated motion sickness. These data indicate that 5-HT(1/2), 5-HT(3) and 5-HT(4) receptors are involved in the induction of 5-HT-induced emesis. However, agonist action at the 5-HT(1A/7) and 5-HT(2) receptors, and antagonist action at the 5-HT(2A) receptors can attenuate motion sickness in S. murinus.

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.

Cholinergic influence on vestibular stimulation-induced locus coeruleus inhibition in rats.

In our previous study, caloric stimulation (CS) of the vestibular apparatus inhibited noradrenergic neuronal activity in the locus coeruleus (LC) in urethane-anaesthetized rats. Therefore, the inhibition of LC noradrenergic neurons is involved in vestibulo-autonomic responses. Since motion sickness can be cured by scopolamine, cholinergic neuron system may also be involved in vestibulo-autonomic responses. The present study examined the effects of intracerebroventricular injection of ethylcholine mustard aziridinium ion (AF64A), a presynaptic cholinergic neurotoxin, on CS-induced LC inhibition. In AF64A-treated rats, the CS-induced LC inhibition was less pronounced than in normal rats. In a subsequent series of experiments, the intravenous injection of scopolamine blocked the CS-induced LC inhibition. These findings suggest that central cholinergic neurons are associated with noradrenergic neuronal inhibition during the vestibulo-autonomic reflex.

Safety of air medical transportation after tissue plasminogen activator administration in acute ischemic stroke.

BACKGROUND AND PURPOSE: We sought to determine the safety of air medical transport (AMT) of patients with acute ischemic stroke (AIS) immediately after or during administration of tissue plasminogen activator (tPA). Patients with AIS treated with tPA in nonuniversity hospitals frequently need transfer to tertiary care centers that can provide specialized care. AMT is a widely available mode of transport that is crucial in providing expedient and quality health care to critically ill patients while assuring high level of care during transportation. The safety of AMT of patients with AIS after or during administration of tPA has not been examined. METHODS: We performed retrospective chart review of 24 patients with AIS who were treated with intravenous tPA and transferred by helicopter to the Hospital of the University of Pennsylvania or the University of Cincinnati Hospital. The charts were reviewed for neurological complications, systemic complications, and adherence to the National Institutes of Neurological Disorders and Stroke (NINDS) protocol for AIS management. RESULTS: No major neurological or systemic complications occurred. Four patients had hypertension warranting treatment, 3 patients experienced motion sickness, 1 patient developed a transient confusional state, and 1 patient experienced minor systemic bleeding. Four NINDS protocol violations occurred, all related to blood pressure management. CONCLUSIONS: In this small series, AMT of AIS patients after thrombolysis was not associated with any major neurological or systemic complications. Flight crew education on the NINDS AIS protocol is essential in limiting the number of protocol violations. AMT of patients with AIS provides fast and safe access to tertiary centers that can provide state of the art stroke therapy.

Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.

The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethamine.HCL, may potentiate doxorubicin in the treatment of metastatic breast cancer: Results of a pilot study.

N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl (DPPE) is a diphenylmethane analog of tamoxifen that antagonizes the intracellular binding of histamine to growth-regulatory sites, a proportion of which represents P450 enzymes, in microsomes and nuclei. We previously reported increased response rates and decreased myelotoxicity in patients with prostate and other cancers who received an intensive dose/schedule of DPPE plus single-agent chemotherapy. We now report the results of a study of DPPE combined with a standard dose/schedule of doxorubicin in twenty-three patients with metastatic breast cancer, sixteen of whom had received prior non-anthracycline chemotherapy. DPPE (6 mg/kg) was infused intravenously (i.v.) over 80 minutes. Doxorubicin (60 mg/m2) was administered i.v. over the last 20 minutes of the DPPE infusion. Treatment was repeated every 3 weeks (maximum, 7 cycles). Patients achieving complete response (CR) were followed off treatment until relapse. All patients were evaluable for toxicities and efficacy. Sixteen patients (69%; 95% C.I. = 47-87%) responded (7 CR and 9 PR). Eleven responders, including 6 with CR, had prior chemotherapy. Five responders (2CR, 3PR) had a poor (ECOG 3/4) performance status pre-treatment. Median CR duration was 11 (range 5-18) months. Hematological toxicity was low; GI toxicity (nausea/vomiting/dyspepsia) appeared somewhat higher than historical experience, but responded well to anti-emetics, ranitidine, and/or dexamethasone in most patients; a mean absolute drop in left ventricular ejection fraction of 8% occurred in 17 patients who received = or > 300 mg/m2 doxorubicin. The observed response rate in DPPE/doxorubicin-treated patients appeared to be higher than historically reported for doxorubicin alone in this setting, suggesting a chemopotentiating effect of DPPE. A multi-centre trial of this regimen in an additional 32 patients with early metastatic breast cancer has been conducted by the Clinical Trials Group, National Cancer Institute of Canada, and a phase 3 study is planned.

Male/female differences in drug-induced emesis and motion sickness in Suncus murinus.

In order to elucidate possible male/female differences in emesis, the effects of various emetogenic drugs (cisplatin, copper sulfate, veratrine, nicotine, serotonin) and motion stimulus were compared between male and female Suncus murinus. Cisplatin (IP), nicotine (SC), veratrine (SC) and copper sulfate (PO) induced dose-dependent emesis in either sex, and there was no apparent difference in estimated ED50 values. However, male animals tended to be more susceptible to serotonin-induced emesis. The ID50 values for tropisetron, a 5-HT3 receptor antagonist, to block serotonin-induced emesis were also similar between male and female animals. However, tropisetron was less effective against cisplatin-induced emesis in females. Therefore, cisplatin may release more serotonin to induce emesis in females. Reciprocal shaking (horizontal oscillation 40 mm, frequency 0.5 to 2.0 Hz, duration 5 min) induced more frequent emesis in male animals, and the latency to the first vomit was shorter in males than in females. These results suggest that there is substantial sex-dependent difference in the emetic responses and male animals are in general more susceptible. These results are discussed in the light of similar studies in man.

The effects of naloxone on body rotation-induced analgesia and anorexia in male mice.

The effects of body rotation in a horizontal plane and the opiate antagonist, naloxone, on the nociceptive responses and the feeding behavior of male mice were examined. In the first experiment the mice were rotated (70 rpm, schedule of 15 sec on; 5 sec off) for 60 minutes or exposed to sham rotation for the same duration. Midway through the rotation or sham procedure the mice were either injected with naloxone (1 mg/kg) or isotonic saline. At the end of the 60-minute treatment period the animals were placed on a warm surface (47.5 degrees C) and their latency to show a foot-licking response was measured. The rotation procedure produced a significant (p less than 0.01) increase in response latency in the saline-injected mice and the naloxone injections blocked this analgesic effect. This finding provides evidence for opioid involvement in the rotation-induced analgesia. In Experiment 2 mice on a food restriction schedule were rotated (70 rpm, 15 sec on; 5 sec off) or sham exposed for 60 minutes. Midway through this treatment period the mice were either injected with naloxone (1 mg/kg) or isotonic saline. Following the treatment period the mice were given access to food for 2 hours. The rotation procedure produced a significant (p less than 0.01) reduction in feeding (anorexia) in the first 30 minutes of food access for the saline-injected mice. Injections of naloxone significantly (p less than 0.05) enhanced the rotation-induced anorexia. These experiments demonstrate that rotation-induced analgesia in mice is blocked by the opiate antagonist, naloxone, whereas rotation-induced anorexia is not.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a susceptibility to motion sickness on the side effects of cancer chemotherapy.

The adequate management of cancer chemotherapy side effects continues to be a challenging problem. There is considerable variability in the side effects experienced by different patients to the same chemotherapeutic drugs. Clinical observations and previous findings of neuropathways between the vestibular system and vomiting center prompted this case-control study of whether susceptibility to motion sickness is a determinant of the type and magnitude of the side effects resulting from cancer chemotherapy. Eighty-three of 486 (17%) consecutive patients who were receiving chemotherapeutic drugs as their only treatment for histologically confirmed cancer reported previous motion sickness. Seventy-seven of these study patients were matched to cancer patient controls without previous motion sickness by sex, age, type and dose of chemotherapeutic drug received, and antiemetic medication. Study patients reported significantly greater nausea and vomiting (P less than 0.05), significantly more side effects (P less than 0.05), and a pattern of more frequent, severe, and longer-lasting nausea and vomiting than controls. Susceptibility to motion sickness appears to be a determinant of the side effects of cancer chemotherapy that may prove useful as a clinical marker of those patients who may require more intensive side effect management.

A cholinomimetic model of motion sickness and space adaptation syndrome.

The space adaptation syndrome is one of the more vexing problems confronted by our nation's astronauts during their journeys. This syndrome may be a variant of motion sickness, although this possibility has been questioned. Physostigmine, a centrally active cholinesterase inhibitor which increases brain acetylcholine, was found to cause a motion sickness-like syndrome--in psychiatric patients and normals--including nausea, emesis, malaise, dysphoria, increases in serum ACTH, beta-endorphin, cortisol, and prolactin, Neostigmine, a non-centrally acting cholinesterase inhibitor, and saline placebo caused no such effects. The above effects closely parallel those of motion sickness. Thus, the effects of physostigmine may be a convenient model for screening for treatments for motion sickness or space adaptation syndrome, or for predicting who will develop these syndromes.