Constipation triggered the malignant syndrome in Parkinson's disease.

A 69-year-old, chronically constipated patient with Parkinson's disease developed fecal impaction and the malignant syndrome simultaneously, even while the patient was taking anti-parkinsonian drugs as prescribed. Administration of intravenous levodopa and oral Dai-kenchu-tou, an herbal medicine with serotonergic 5-HT3 receptor agonistic property successfully ameliorated his clinical symptoms. Constipation may trigger worsening of Parkinson's disease and occurrence of the malignant syndrome by affecting levodopa absorption. Further, improved bowel motility may prevent worsening of Parkinson's disease and occurrence of the malignant syndrome.

Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects.

Palonosetron (Aloxi, Onicit) is a selective 5-HT(3) receptor antagonist recently approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. This study was performed to determine the pharmacokinetics and assess the safety and tolerability of intravenous (IV) palonosetron in healthy U.S. and Japanese subjects. Subjects were administered a single IV dose of palonosetron, ranging from 0.3 to 90 microg/kg in either of two randomized, double-blind, placebo-controlled, ascending-dose studies (n = 80 and n = 32, respectively). Serial blood samples were obtained in both studies to evaluate the pharmacokinetics of palonosetron and its N-oxide metabolite, M9. Intravenous palonosetron was well tolerated across a wide range of doses in both studies. The incidence and severity of adverse events (AEs) were similar between subjects receiving palonosetron and those receiving placebo, with no dose-dependent incidences. The most frequently reported AEs were headache, transient elevation of liver enzymes, and constipation. Systemic exposure (AUC and C(max)) for palonosetron generally increased with increasing dose. Mean total body clearance, elimination half-life, and apparent volume of distribution ranged from 1.11 to 3.90 mL/min/kg, 33.7 to 54.1 hours, and 3.85 to 12.6 L/kg, respectively, in U.S. subjects and from 2.58 to 3.50 mL/min/kg, 30.8 to 36.8 hours, and 6.96 to 9.85 L/kg, respectively, in Japanese subjects. The pharmacokinetics of palonosetron appeared to be independent of dose, with no dose adjustment required in Japanese subjects. The plasma concentration profile of palonosetron, as represented by a half-life of approximately 40 hours, may provide a clinical advantage over other 5-HT(3) antagonists.

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response.

GOALS OF WORK: Prevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response. PATIENTS AND METHODS: 1,044 patients receiving cisplatin (> or = 70 mg/m2) were randomly assigned to control regimen [ondansetron (O) 32 mg i.v. and dexamethasone (D) 20 mg p.o. on day 1; D 8 mg twice daily on days 2-4] or aprepitant (A) regimen (A 125 mg p.o. plus O 32 mg and D 12 mg on day 1; A 80 mg and D 8 mg once daily on days 2-3; and D 8 mg on day 4). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1-5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression. MAIN RESULTS: Women comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men. CONCLUSION: The addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

5-hydroxytryptamine type-3 receptor antagonists for chemotherapy-induced and radiotherapy-induced nausea and emesis: can we safely reduce the dose of administered agents?

BACKGROUND: Nausea and emesis as a consequence of chemotherapy or radiotherapy can have an adverse effect on patients' quality of life during cancer treatment and may last for > 5 days after administration. Guidelines suggest that, used at appropriate doses, the 5-hydroxytryptamine type-3 (5-HT3) receptor antagonists--which are considered the antiemetic "gold standard" when they are administered in combination with corticosteroids--demonstrate equivalent efficacy and safety. However, due to financial considerations, these agents often are used at lower doses than recommended. METHODS: A literature review of relevant publications pertaining to the control of chemotherapy-induced nausea and emesis and dosing issues of the 5-HT3 receptor antagonists was undertaken to provide a comprehensive review of dosing issues relevant to the 5-HT3 receptor antagonists. RESULTS: The issue of "down dosing" was particularly pertinent because of the nature of the 5-HT3 receptor antagonist dose-response curve: A steep dose-response profile within a narrow dose range suggests that antiemetic control will be lost suddenly after dose deescalation. However, the array of predisposing and confounding patient factors indicates that it is unlikely that a loss of antiemetic control will be apparent across a population; rather, individuals will experience loss of control as the dose is reduced below threshold. Of the 4 5-HT3 receptor antagonists currently licensed in the United States (granisetron, ondansetron, dolasetron, and palonosetron), ondansetron is used sometimes at lower than optimal doses, and there is evidence to suggest that even the approved oral dose of dolasetron may be suboptimal. CONCLUSIONS: Suboptimal dosing not only will be detrimental to patients' quality of life but, ultimately, will prove counterproductive in terms of hospital resources, and it will add to the already significant socioeconomic burden associated with cancer therapy. Therefore, the dose of antiemetic agent administered should be sufficiently high to ensure good emesis control across the whole patient population.

5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial.

BACKGROUND: Despite widespread use of short-acting antagonists for the 5-hydroxytryptamine (5-HT) receptor, about 50% of patients given moderately emetogenic chemotherapy have delayed nausea. We aimed to assess whether a 5-HT-receptor antagonist was more effective than was prochlorperazine for control of delayed nausea and delayed vomiting caused by doxorubicin. METHODS: 691 patients who previously had not had chemotherapy and who were scheduled to receive doxorubicin were given a short-acting 5-HT-receptor antagonist and dexamethasone before doxorubicin (day 1), and were randomly assigned to one of three regimens for days 2 and 3: 10 mg prochlorperazine taken orally every 8 h; any first-generation 5-HT-receptor antagonist (except palonosetron) taken as standard dose intravenously or orally; or 10 mg prochlorperazine taken as needed. Nausea and vomiting were assessed by use of a home record. The primary endpoint was mean severity of delayed nausea. The secondary endpoint was quality of life. Analyses were done by intention to treat. FINDINGS: 519 (77%) of the 671 evaluable patients had delayed nausea, with a mean severity of 3.33 (95% CI 3.22-3.44). 161 (71%) of 226 patients assigned prochlorperazine every 8 h reported delayed nausea (mean severity 3.37 [3.16-3.58]), as did 179 (79%) of 226 patients assigned 5-HT-receptor antagonists (3.29 [3.09-3.48]) and 179 (82%) of 219 patients assigned prochlorperazine as needed (3.33 [3.15-3.50]); groups did not differ in mean severity (p=0.853, one-way ANOVA). Patients allocated prochlorperazine every 8 h had less delayed nausea than did those allocated 5-HT-receptor antagonists (p=0.05, t test) and those allocated prochlorperazine as needed (p=0.009, t test). INTERPRETATION: Short-acting 5-HT-receptor antagonists are no better than is prochlorperazine in control of delayed nausea caused by doxorubicin. Although fewer patients taking prochlorperazine report delayed nausea, the proportion was unacceptably high.