Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery

Dolasetron (dolasetron mesilate) is a pseudopelletierine-derived 5-HT3 antagonist which has recently become available for clinical use. It is rapidly converted in vivo to its active major metabolite, hydrodolasetron, which appears to be largely responsible for its pharmacological activity. In clinical trials, single intravenous or oral doses of dolasetron were effective in preventing acute chemotherapy-induced nausea and vomiting (CINV). Intravenous doses of 1.8 mg/kg achieved complete suppression of vomiting in approximately 50% of patients receiving highly emetogenic cisplatin-containing chemotherapy and in approximately 60 to 80% of patients receiving moderately emetogenic chemotherapy. In the latter setting, oral doses of 200 mg achieved similar response rates. In comparative studies, intravenous dolasetron 1.8 mg/kg was as effective as intravenous granisetron 3 mg or ondansetron 32 mg after highly emetogenic chemotherapy, and oral dolasetron 200 mg was equivalent to multiple oral doses of ondansetron (3 or 4 doses of 8 mg) after moderately emetogenic chemotherapy. Dolasetron 1.8 mg/kg was superior to metoclopramide in preventing emesis induced by high dose cisplatin or by moderately emetogenic chemotherapy in high risk subgroups. Dolasetron has also shown efficacy in preventing radiotherapy-induced nausea and vomiting (RINV) in preliminary studies. Single intravenous or oral dolasetron doses ranging from 12.5 to 100 mg and 25 to 200 mg, respectively, were significantly more effective than placebo in preventing postoperative nausea and vomiting (PONV) in female surgical patients. A 50 mg intravenous dose was as effective in preventing PONV as ondansetron 4 mg in a mixed-gender group. Intravenously administered dolasetron was also effective in treating established PONV, although complete suppression of vomiting was achieved in < 40% of patients. Dolasetron has a tolerability profile characteristic of this class of compounds, with headache, dizziness and diarrhoea being the most commonly occurring adverse events in clinical trials. Diarrhoea is not thought to be related to dolasetron administration, being experienced mostly by patients receiving chemotherapy. Dolasetron and other 5-HT3 receptor antagonists have been associated with minor changes in ECG intervals, but these generally do not appear to be clinically important. Thus, available evidence suggests that dolasetron will provide an alternative to other 5-HT3 receptor antagonists for the management of CINV and PONV. Further studies are required to determine whether it offers any advantages over other agents in these settings and to determine the optimum dosage for preventing RINV.     

Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study

PURPOSE: The antiemetic effectiveness and safety of single-dose oral granisetron were compared with intravenous (I.V.) ondansetron in chemotherapy-naive patients who received moderately emetogenic chemotherapy. PATIENTS AND METHODS: In this double-blind, parallel-group study, patients naive to emetogenic chemotherapy (N = 1,085) who were scheduled to receive cyclophosphamide- (500 to 1,200 mg/m2) or carboplatin (> or = 300 mg/m2) based chemotherapy, were randomized to receive either oral granisetron (n = 542) or I.V. ondansetron (n = 543). Efficacy assessments included the proportion of patients in each treatment group with total control over the 24 and 48 hours following chemotherapy initiation, as well as incidence and severity of nausea and emesis and use of antiemetic rescue medication. Prophylactic corticosteroids were allowed. Safety assessment was based on patients' reports of adverse experiences. RESULTS: Approximately 80% of patients received prophylactic corticosteroids. Single-dose oral granisetron (2 mg) and I.V. ondansetron (32 mg) resulted in equivalent levels of total emetic control during the first 48 hours after chemotherapy. The proportion of nausea- and emesis-free patients at 24 and 48 hours were also approximately equivalent. The most commonly reported adverse experiences were headache, asthenia, and constipation. More patients who received ondonsetron than granisetron reported dizziness (9.6% v 5.4%, respectively; P = .011) and abnormal vision (4.2% v 0.6%, respectively; P < .001). CONCLUSION: A single oral dose of granisetron (2 mg) resulted in equivalent levels of antiemetic protection as I.V. ondansetron (32 mg). Both agents were well tolerated, although more dizziness and abnormal vision were reported with ondansetron. Because the two antiemetic regimens exhibited equivalent efficacies, additional factors such as convenience and cost of therapy should be considered.     

Generating a normalized geometric liver model using warping

This review discusses the development and use of 5-hydroxytryptamine3 (5-HT3) antagonists, especially granisetron, for the treatment of chemotherapy-induced emesis. Following recent evidence suggesting that high-dose chemotherapy is more effective in increasing tumor response rate and median survival time, more effective antiemetic control is essential. Granisetron, a new 5-HT3, is approximately 400 times more potent than metoclopramide and, unlike metoclopramide, does not produce extrapyramidal side effects. Granisetron has been shown to be effective as a single prophylactic dose, over 5 days and in patients receiving repeated cycles of chemotherapy. Patients with nausea and vomiting within the first 24 h after chemotherapy are more likely to experience delayed symptoms; however, episodes of breakthrough nausea and vomiting can be controlled by intervention with one, and in some cases more, doses of granisetron. The development of granisetron represents an important advance in the control of chemotherapy induced emesis.     

Modern aspects of antiemetic therapy

We summarized the current knowledge about chemotherapy and radiotherapy-induced nausea and vomiting. Nausea and vomiting are among the most frequent side effects in the treatment of malignancies, and they are very unpleasant for the patient. We reviewed basic aetiological and physiological mechanisms (except that of delayed emesis, which is not enough explored), particularly the role of serotonin in acute chemotherapy and radiotherapy-induced nausea and vomiting. An oncologist cannot make many changes in the treatment of malignancies and patient-related prognostic factors, but he (she) can make changes in the treatment of nausea and vomiting in order to improve the quality of life of patients with malignancies. We also listed some of the most widely used antiemetic drugs with their most important pharmacological properties. Important progress in the control of nausea and vomiting was obtained by the use of selective antagonists of 5-HT3-receptors such as ondansetron, granisetron, tropisetron and dolasetron. Usually ondasetron and granisetron were used. Their clinical activity is similar but better results were obtained with the combination of 5-HT3-antagonists and corticosteroids (complete response was approximately 90%) than by their individual use (complete response was approximately 50%). The problem of delayed emesis has not yet been solved, and best results were obtained with the combination of metoclopramide and corticosteroids. For the control of nausea and vomiting caused by radiotherapy, orally given ondansetron is effective.     

Comparative studies of various antiemetic regimens

Since 1981, when high-dose intravenous metoclopramide was demonstrated to be efficacious, slow but constant improvement in the prevention of chemotherapy-induced emesis has been achieved. Today, a combination of a serotonin receptor 3 (5-HT3) antagonist plus dexamethasone can be considered the most efficacious treatment for the prevention of emesis induced by cisplatin and by moderately emetogenic chemotherapy. Which 5-HT3receptor antagonist should be used? Preclinical differences among 5-HT3receptor antagonists have been reported with regard to selectivity of receptor binding, potency, dose response, and duration of action. Twelve comparative studies among 5-HT3receptor antagonists have been carried out. Unfortunately, all these trials have some important shortcomings (patient population not large enough to show small but clinically important differences; not blinded studies; no association with steroids to maximize treatment efficacy) and, therefore, no definitive conclusions can be drawn. Very recently three large, well-conducted double-blind comparative studies have been published. All three showed that 5-HT3receptor antagonists have almost identical antiemetic efficacy and tolerability. Therefore, the choice among the 5-HT3receptor antagonists should be based only on the acquisition cost of the prescribed dose in each country for each compound.     

Control of emesis by intravenous granisetron in breast cancer patients treated with 5-FU, epirubicin and cyclophosphamide

Granisetron, a potent and selective 5-hydroxytryptamine receptor (5-HT3) antagonist was reported to be an effective antiemetic agent both in animal studies and in patients given highly emetogenic chemotherapy. A sample of 43 patients with breast cancer was accrued from September to November 1992 in a phase II study to assess the efficacy of granisetron in patients receiving FEC (5-FU, epirubicin, cyclophosphamide). Each patient received 3 mg intravenous granisetron as a single dose just prior to chemotherapy. Oral metoclopromide was prescribed to each patient as a rescue anti-emetic. The emetic episodes and degree of nausea were evaluated on a daily basis. Good control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) was in the range 77%-98% and 77%-93% respectively. There was a complete response (no emetic episodes throughout the 6-day period) in 16 patients (37.2%). Onset of emesis tends to occur on day 1 and tend to subside after day 3; 85% of patients had onset of emesis in the first 2 days after chemotherapy. Control of emesis and nausea tends to improve after day 3, which could be the result of the reduced emetogenicity of the combination FEC with time. Altogether, 77% had good control of acute emesis; control of delayed emesis was better with 84% achieving a major response on day 2 after chemotherapy, which improved to more than 90% after day 4. Granisetron was generally tolerated with headache being the most common side-effect followed by constipation and flushing. This study suggests that granisetron is an effective and well-tolerated anti-emetic agent, which deserves randomised trials to elucidate its efficacy further.     

Effects of granisetron with doxorubicin or epirubicin on ECG intervals

Commercially available serotonin-type 3 (5-HT3) receptor antagonists (ondansetron, granisetron, and tropisetron) have shown no clinically significant adverse effects on the cardiovascular system. In the dose-ranging evaluation of dolasetron, computer-generated ECGs revealed clinically asymptomatic prolongations of ECG intervals. We performed a clinical trial in which the possible changes in ECG intervals following a single 3-mg i.v. injection of granisetron and an injection of either doxorubicin or epirubicin were registered using computerized ECG analysis in cancer patients. A total of 30 patients who were designated to receive 3 mg granisetron i.v. for the prophylaxis of emesis induced by doxorubicin or epirubicin were entered into the study. Computer-generated ECG tracings were obtained before treatment, following the injection of 3mg granisetron, and immediately after doxorubicin or epirubicin injection. The mean PR interval duration increased from 160 to 166 ms after granisetron infusion (P=0.02). Doxorubicin and epirubicin did not potentiate this change. There was no statistically significant change in cardiac rhythm, QRS duration, or QTc intervals. The observed minor changes in the PR time following i.v. injection of granisetron do not seem to be of clinical relevance.     

Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels

Recently, the availability of 5-hydroxytryptamine-3 antagonists has provided better protection from chemotherapy-induced emesis. These drugs, in combination with dexamethasone, are more expensive but more cost-effective than the alternative antiemetic regimens in the prevention of acute emesis induced by high single dose and low and repeated doses of cisplatin and, probably, of acute emesis induced by moderately emetogenic chemotherapy. In the prevention of emesis induced by oral cyclophosphamide-methotrexate-fluorouracil and in the prevention of delayed emesis induced by cisplatin and moderately emetogenic chemotherapy, the most cost-effective choices are represented, respectively, by a combination of intravenous dexamethasone on day 1 and 8 plus 14-day oral metoclopramide (a combination of oral dexamethasone plus metoclopramide and oral dexamethasone alone). In all cases, the 5-hydroxytryptamine-3 antagonists should be used only in patients in whom the most cost-effective antiemetic regimens either fail or are not tolerated.     

Patients' self-reported functional status after granisetron or ondansetron therapy to prevent chemotherapy-induced nausea and vomiting at six cancer centers

Patient functional status after administration of either granisetron or ondansetron to prevent acute chemotherapy-induced nausea and vomiting (CINV) was studied. Pharmacists and nurses from six cancer centers distributed Functional Living Index-Emesis (FLIE) questionnaires to 115 outpatients receiving either granisetron or ondansetron for prevention of CINV. The emetogenic potential of each patient's chemotherapy regimen was high, moderately high, or moderate. Immediately before and 72 hours after chemotherapy, each patient rated his or her reaction to each of 18 items on the questionnaire on a 7-point scale. Possible scores ranged from 18 to 126, with higher scores indicating higher levels of functioning. The occurrence of nausea in the granisetron group was 40.0% compared with 43.2% in the ondansetron group; the occurrence of vomiting was 18.8% in the granisetron group and 11.1% in the ondansetron group. Patients who received highly emetogenic chemotherapy had significantly lower scores on the FLIE after chemotherapy than before. Patients with both nausea and vomiting reported a much higher negative impact on functional status after chemotherapy than those with nausea only. The mean prechemotherapy and postchemotherapy FLIE scores were 124.2 and 110.4 for granisetron and 124.9 and 111.9 for ondansetron. Granisetron and ondansetron did not differ significantly in their effect on functional status reported by patients before and 72 hours after receiving cancer chemotherapy.     

Granisetron

Granisetron is the second agent in the 5-HT3 receptor antagonist class to be approved for the prophylaxis of acute emesis caused by cancer chemotherapy. It is equally effective to ondansetron as a first-line agent in the prevention of acute chemotherapy-induced emesis and has a similar low toxicity profile. Granisetron will be marketed in early 1994, according to SmithKline Beecham. Additional studies will be needed to determine the role of granisetron in the current management of chemotherapy-induced emesis.     

Computer simulation of changes in nursing productivity from early tracheal extubation of coronary artery bypass graft patients

A total of 530 patients were treated in this multicenter, double-blind, double-dummy, parallel group study to compare the anti-emetic efficacy and safety of a once daily ondansetron oral regimen with a once daily i.v. dosing regimen over a 24 h period, administered to patients prior to receiving cisplatin (50 mg/m2 or greater) chemotherapy. Patients were randomized to receive a single dose of ondansetron plus dexamethasone given either orally (ondansetron 24 mg and dexamethasone 12 mg, n=262) or i.v. (ondansetron 8 mg and dexamethasone 20 mg, n=268). Complete control of emesis (i.e. no emetic episodes, no rescue and no premature withdrawal) was achieved for 85% of patients (224 of 262) in the oral group and 83% (223 of 268) in the i.v. group. No nausea was reported in 70% of patients in the oral group and 68% in the i.v. group. There were no statistically significant differences between the two groups for any of the assessments of efficacy, which included time to first emetic episode, number of emetic episodes and the worst grade of nausea occurring over the 24 h study period. Once daily ondansetron oral and i.v., in combination with dexamethasone, was well tolerated in this study. In conclusion, once daily oral ondansetron 24 mg plus dexamethasone is equally effective in the control of emesis and nausea induced by highly emetogenic chemotherapy as once daily ondansetron 8 mg i.v. plus dexamethasone.     

Early neuropsychological impairment in HIV-seropositive intravenous drug users: evidence from the Italian Multicentre Neuropsychological HIV Study

The purpose of this study was to document the emetogenic potential of intrathecal chemotherapy (IC) in children and to evaluate the efficacy of ondansetron in reducing nausea and vomiting with this chemotherapy treatment. Patients less than 18 years of age with acute lymphoblastic leukemia were eligible to participate in a survey project measuring the emetogenic potential of various chemotherapy treatments. Patients surveyed for 1 or more IC treatments were included in this report. The IC consisted of methotrexate, hydrocortisone and cytarabine, dosed according to patient age. A nausea/vomiting survey instrument was completed by each patient and/or parent following IC treatment. The instrument rated nausea, vomiting and daily activity interference (DAI) on a 4-point scale of 0 = none, 1 = mild, 2 = moderate and 3 = severe, and collected data on the number of vomiting and/or retching episodes in addition to the child's appetite following the chemotherapy treatment. When ondansetron was employed, it was administered in an i.v. infusion at a dose of 0.15 mg/kg before and after chemotherapy or as an oral dose of 4 mg or 8 mg before chemotherapy. Courses of IC without antiemetics were analyzed to determine the emetogenic potential of IC. For patients receiving IC both with and without ondansetron, courses were compared with each patient used as their own control to determine the influence of ondansetron upon survey responses. Statistical analysis consisted of nonparametric Friedman 2-way ANOVA for ordinal variables and a paired t-test for continuous variables. The binomial test was employed to analyze for differences between ondansetron and no antiemetic in the number of patients with complete control of both nausea and vomiting or vomiting alone. A total of 63 children with a mean age of 7.6 +/- 4.2 years were each studied on one or more occasions. Thirty-seven children were surveyed for 87 IC treatments without antiemetics (group I), and 17 children from this group were surveyed for 48 IC courses with i.v. ondansetron (group IA). An additional 18 children were subsequently surveyed for 39 IC courses with i.v. ondansetron (group II). Fifteen patients (7 of whom were members of group I) were surveyed following 33 IC courses with oral ondansetron (group III). The survey scores for group I patients were: nausea severity 1.3 +/- 1.1, vomiting severity 1.2 +/- 1.1, DAI 1.2 +/- 1.0 and mean number of emetic episodes 4.7 +/- 8.4. The mean appetite score was 1.5 +/- 1.1. For patients in group IA, nausea severity (0.8 +/- 0.9), vomiting severity (0.5 +/- 0.8), DAI (0.7 +/- 0.8), and the number of emetic episodes (1.4 +/- 2.8) were all significantly lower than with prior IC treatments without ondansetron. For complete protection, children receiving i.v. ondansetron had greater complete protection rates from both nausea and vomiting or vomiting alone than did patients receiving no antiemetic. Survey responses were also lower for patients receiving oral ondansetron, but insufficient control data did not allow for statistical analysis. IC results in mild to moderate nausea and vomiting in children. The emetogenic potential of IC is significantly reduced by i.v. ondansetron.     

Oral combination antiemetics in patients with small cell lung cancer receiving cisplatin or cyclophosphamide plus doxorubicin

BACKGROUND: Intravenous antiemetic combinations containing a 5-HT3 receptor antagonist (like metoclopramide, ondansetron, or granisetron) with dexamethasone have become the standard therapy for the treatment of acute chemotherapy-induced vomiting. Intravenous antiemetics, however, can be more costly and take more time to prepare and deliver, and therefore are not preferred for home, outpatient, or office use. The objective of this study was to determine the antiemetic activity and safety of the oral combination antiemetic regimen of metoclopramide, dexamethasone, and diphenhydramine in patients with small cell lung cancer receiving standard outpatient chemotherapy programs. METHODS: Fifty-two patients receiving initial cisplatin (60 mg/m2) or cyclophosphamide (600-1500 mg/m2) plus doxorubicin (30-45 mg/m2) received an oral regimen of metoclopramide (3 mg/kg x 2 then 2 mg/kg x 2 or 4 doses), dexamethasone (20 mg) and diphenhydramine (50 mg x 2 or 3 doses) (oral MDD), beginning 30 minutes before chemotherapy. RESULTS: Vomiting was prevented in 15 of 21 (76%) patients (95% confidence interval [CI], 53%-92%) receiving cisplatin and 21 of 31 (71%) individuals (95% CI, 52%-86%) given cyclophosphamide plus doxorubicin. Adverse effects were mild and transient and included sedation, loose stools, akathisia, and hiccoughs. CONCLUSIONS: The oral MDD antiemetic regimen prevented acute emesis in 73% of the patients entered and was well tolerated in this population of patients with small cell lung cancer.     

Immunoglobulin production by human peripheral B cells against Staphylococcus aureus

Patterns of antiemetic therapy and its outcomes in patients undergoing high-dose antineoplastic therapy were studied. The study, conducted at a cancer center, included both a retrospective evaluation of patients undergoing highly emetogenic high-dose chemotherapy with peripheral blood stem-cell rescue between November 1994 and December 1995 and a concurrent evaluation of patients treated between January and May 1996. During the study period the recommended antiemetic regimen for highly emetogenic chemotherapy was a single dose of granisetron 1 mg i.v. daily 30 minutes before treatment on days of chemotherapy. Severity of nausea and vomiting during both the acute phase (from day 1 of chemotherapy to 24 hours after its completion) and delayed phase (from 24 hours to five days after the end of chemotherapy) was graded according to the Common Toxicity Criteria Grading Scale. A total of 59 patients were evaluable; 41 were reviewed retrospectively, and 18 were reviewed concurrently. On day 1 of the acute phase, 53 patients (90%) had no vomiting and 51 patients (86%) had no nausea. The frequency and severity of nausea and vomiting increased on successive acute-phase days, and it was necessary to add other antiemetics. Nausea and vomiting continued to be significant problems throughout the delayed phase; 32 (54%) of the patients had a maximum of grade 3 nausea, and 29 patients (49%) had a maximum of grade 2 vomiting. Substantial numbers of patients who received selective serotonin type 3 receptor antagonists before high-dose antineoplastic agents had significant nausea and vomiting that required the addition of other antiemetics.     

Use of oral and intravenous ondansetron in patients treated with cisplatin

Ondansetron, a selective 5-HT3 antagonist, has been shown to be effective in preventing chemotherapy-induced nausea and vomiting. From July and August 1991, 25 patients were accrued in a phase II study to assess the efficacy of ondansetron in patients receiving cisplatin-containing chemotherapy. Patients received intravenous cisplatin 100 mg/m2, given either as a 24-hour infusion on day 1 or in divided doses as eight-hour infusions daily on days 1 to 3. Each patient received 24 mg of ondansetron per day for six days. Intravenous dexamethasone 24 mg was given daily on the days of cisplatin infusion. The emetic episodes and degree of nausea were evaluated daily. "Good" control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) ranged from 64-100% and 88-100% respectively. Failure in emesis control occurred most frequently on days 3 and 4. Ondansetron was generally well tolerated with only minimal side-effects. One patient developed unexplained encephalopathy which resolved completely. Our results suggest that ondansetron is an effective anti-emetic agent with minimal toxicities. Randomised studies comparing ondansetron against "standard" anti-emetics should be conducted.     

Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo

PURPOSE: To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis. PATIENTS AND METHODS: Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy. RESULTS: Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066). CONCLUSION: Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.     

The effect of continuous light on refractive error and the ocular components of the rat

The anti-emetic efficiency of orally administered ondansetron and granisetron has been tested in macaques exposed to a mixed y and neutron radiation (6 Gy) with a high neutron/gamma-ray ratio. Our experiments reveal that a single delivery of ondansetron (1 or 2 mg kg(-1)) or of granisetron (0.25 mg kg(-1)) 45-90 min before irradiation or 35-45 min after irradiation was not totally effective. Conversely, the delivery of two doses with the same delay prior to and after exposure led to a complete prevention of vomiting and retching. These observations can be explained by the dual mechanism of radiation-induced emesis: an early peripheral mechanism and a later central mechanism. Two deliveries of 5-HT3 receptor antagonists seem to disrupt serotonergic transmission at the brain stem structures and to affect the peripheral release of serotonin from the gut, thus completely preventing radiation-induced vomiting. This study confirms that the 5-HT3-dependent mechanisms that mediate emesis are similar for both neutron and gamma radiation.     

A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11

The purpose of the study was to assess the toxicity and efficacy of an oral, combination antiemetic regimen including granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA, USA) in the setting of highly emetogenic conditioning chemotherapy for stem cell transplantation. Antiemetic prophylaxis consisted of oral granisetron 2 mg once daily, oral prochlorperazine 10 mg q 6 h and oral dexamethasone 4 mg q 6 h, beginning 1 h prior to chemotherapy on each of the 4 days of chemotherapy and continuing until 24 h after the completion of high-dose chemotherapy (HDC). Patients received either CVP (cyclophosphamide 6 g/m2, VP-16 1800 mg/m2 and carboplatin 1200 mg/m2) or CTP (thiotepa 500 mg/m2 in place of VP-16) in four daily doses given over 4 h from days -4 to -1. Previously mobilized and cryopreserved peripheral blood stem cells (PBSC) were reinfused on day +1. Evaluation of nausea, emetic episodes (EE), adverse events, and rescue medications were recorded on a daily patient diary. Thirty-six patients were entered. Fifty-three percent (95% CI = 37-75%) of patients achieved complete response for emesis (CR = 0 EE/24 h) and 75% (95% CI = 58-90%) had combined complete and major response (CR+MR = 0-3 EE/24 h) during all 5 of the treatment days. During the 5 study days, the average number of patient-days with no emesis was 3.7 (74%) and with 1-3 EE was 4.3 (86%). On days -4, -3, -2, -1 and 0, the combined CR+MR rate for emesis was 97, 92, 86, 78 and 75%, respectively. Nausea was absent or mild on all 5 study days in 57% (95% CI = 37-75%). Eight patients had severe late-onset emesis occurring on days +1 to +3 after reinfusion of stem cells. No clinically significant toxicities attributable to the antiemetic regimen were observed. An all oral antiemetic regimen of granisetron, prochlorperazine and dexamethasone appears to be safe and highly effective in patients receiving multiple, daily, high-dose chemotherapy regimens. This regimen offers the advantage of cost-savings, a low side-effect profile and ease of administration in the predominately outpatient setting of HDC with peripheral blood stem cell transplant (PBSCT).     

Modified oral ondansetron regimen for cyclophosphamide-induced emesis in lupus nephritis

OBJECTIVE: To evaluate the antiemetic efficacy of a modified regimen of oral ondansetron and dexamethasone in patients with lupus nephritis undergoing treatment with cyclophosphamide whose conventional antiemetic regimen had failed. DESIGN: A before-after prospective observational pilot project. SETTING: A federal research hospital. PATIENTS: Fourteen outpatients with lupus nephritis receiving intravenous cyclophosphamide 0.75-1.0 g/m2 had previously experienced chemotherapy-induced emetic events (vomiting or retching) while receiving a standard combination intravenous antiemetic regimen. The regimen consisted of four doses of thiethylperazine 10 mg and diphenhydramine 25 mg every 6 hours, and two doses of lorazepam 0.5 mg every 6 hours starting at 1 hour prior to cyclophosphamide. A subset of 8 patients previously completed a blinded study in which they received the intravenous formulation of ondansetron (4 doses of 4-16 mg q4h) administered orally beginning 30 minutes prior to the cyclophosphamide infusion. MAIN OUTCOME MEASURES: The number of emetic events and cost of drug administration were assessed for the modified ondansetron intervention and compared with those of the standard antiemetic regimen. The incidence of emetic events and visual analog nausea scores for the subset of eight patients were also evaluated. INTERVENTIONS: To account for the delayed onset of emesis associated with cyclophosphamide, patients received both ondansetron 8 mg orally every 4 hours (3 doses) and dexamethasone 10 mg orally (1 dose) beginning 4 hours after the cyclophosphamide infusion. This is different from the manufacturer's recommended dose schedule, in which ondansetron is administered prior to chemotherapy. RESULTS: No emetic events were observed following the administration of oral ondansetron/dexamethasone. The 95% confidence interval for the true rate of emesis was 0% to 19.3%. There was a significant difference in efficacy between ondansetron/dexamethasone and the triple antiemetic regimen (p < 0.0002). None of the patients experienced adverse effects while receiving the ondansetron/dexamethasone regimen. Cost comparisons (including admixture and nursing administration times) for standard combination therapy and oral ondansetron/dexamethasone were $109.09 and $70.24, respectively. No difference in emetic events or nausea ratings was observed between oral ondansetron/dexamethasone tablets and oral administration of ondansetron using the intravenous formula. CONCLUSIONS: This study suggests that a modified oral ondansetron/dexamethasone regimen is safe and efficacious, and costs less than alternative regimens to prevent cyclophosphamide-induced emesis in patients with lupus nephritis.     

Paraneoplastic pemphigus associated with Hodgkin''s disease

Highly emetogenic drugs such as cisplatin induce an increase in the urinary 5-hydroxyindoleacetic acid (5-HIAA) level, the main metabolite of serotonin (5-HT), within the first 24 h following a single infusion, thus providing a possible cause for acute emesis and an explanation for the action of 5-HT3 antagonists. No further excretion peaks have been observed, suggesting that additional or serotonin-independent mechanisms cause delayed emesis. Our aim was to study the mechanisms behind emesis seen during a highly emetogenic chemotherapy regimen given as a continuous infusion over several days. Seven women treated with a 4-day high-dose chemotherapy (HDCT) regimen for breast cancer entered the study. Pooled urine samples were collected prior to and during chemotherapy for determining 5-HIAA excretion. An excretion peak in the urinary 5-HIAA level was observed within the first 24 h with no further peaks thereafter. Thus, the mechanisms behind the emesis experienced during this highly emetogenic multiple-day chemotherapy regimen from days 2-3 onwards would appear to be at least partially serotonin independent and would not be expected to be completely relieved by 5-HT3 antagonists alone.