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Biomedical subjects

J Herrstedt

Publications and source records attributed to J Herrstedt.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dose-finding study of oral metopimazine.

A few studies indicate a dose-response effect of the antiemetic metopimazine. The aim of this study was therefore to investigate the tolerability of increasing doses of metopimazine given orally every 4 h for eleven doses. The dose levels 20 mg, 30 mg, 40 mg, 50 mg and 60 mg were studied in 36 patients completing 46 cycles of chemotherapy. Serum concentrations of metopimazine and the acid metabolite AMPZ were measured by HPLC in 13 patients (15 cycles). The dose-limiting toxicity was moderate to severe dizziness caused by orthostatic hypotension as seen in 0, 0, 17%, 42% and 50% of patients at the respective dose levels. Other side effects were few and mild, and only a single possible extrapyramidal adverse event was observed in a patient at the 60-mg dose. High serum concentrations were not predictive for toxicity, as found on comparison of patients with and without symptoms, but in individual patients symptoms were seen at the time of Cmax. We found that metopimazine was safe with a dosage of 30 mg x 6. This dose is four times higher than that previously recommended for antiemetic use.

Administration, Oral↗
PubMed1997

Clinical and methodological issues in antiemetic therapy: a worldwide survey of experts' opinions. Multinational Association of Supportive Care in Cancer.

During the 1995 Multinational Association of Supportive Care in Cancer (MASCC) Congress, a consensus conference was planned by the Subcommittee for Antiemetics. To define the topics to be discussed, a questionnaire containing both clinical and methodological issues was sent to 118 experts in 31 countries. The questionnaire contained 33 items on clinical and 19 items on methodological issues, and each response was rated on a 4-level categorical scale. The clinical issues were evaluated for interest, that is clinical importance, and feasibility, that is availability of sufficient data to make them suitable topics for the consensus conference. About 60% of questionnaires were returned, with a small number of missing responses. The responses to the items of clinical interest showed that about two-thirds of the issues identified by the Subcommittee were found by the experts to be of at least high interest, but often the availability of data was found to be insufficient for their discussion. Prevention of acute emesis induced by cisplatin and by moderately emetogenic chemotherapy and the optimal intravenous dose and schedule of the 5-HT3 receptor antagonists were the items with the highest interest and feasibility. The issues in the methodological section were also mostly found to be of at least high interest. The distinction between acute and delayed emesis, the evaluation of the persistence of antiemetic efficacy in subsequent cycles of chemotherapy and the statistical analysis of delayed emesis were the methodological issues in which the highest interest was recorded. Data collected will be used to define the main topics to be discussed during the planned consensus conference.

Antiemetics↗
PubMed1997

Randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as antiemetic prophylaxis during platinum-based chemotherapy in patients with cancer.

PURPOSE: To investigate the antiemetic effect and tolerability of the 5-hydroxytryptamine3(5-HT3) antagonist ondansetron plus the dopamine D2 antagonist metopimazine versus ondansetron alone in patients receiving platinum-based chemotherapy. PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients who were scheduled to receive two consecutive courses of platinum-based chemotherapy were randomized between ondansetron 8 mg intravenously (IV) followed by 8 mg orally twice a day plus metopimazine 35 mg/m2 as a 24-hour continuous infusion followed by 30 mg orally four times a day for 4 days, or ondansetron plus placebo. The study used a double-blind, crossover, placebo-controlled design. RESULTS: Ninety-four patients completed the crossover. Complete response (CR; no emetic episodes) was obtained on day 1 in 77.7% of the patients who received the combination versus 50.0% of those who received ondansetron alone (P = .00002), and in 51.7% versus 31.0% on days 2 to 6 (P = .0009). The overall CR (days 1 to 6) was 48.9% versus 25.3% (P = .0002). Additionally, significantly less nausea was observed with the combination on day 1 (P = .0002), days 2 to 6 (P = .0001), and days 1 to 6 (P = .00004). Patient preference was 63.6% for the combination and 13.6% for ondansetron alone; 22.7% expressed no treatment preference (P < .0001; therapeutic gain 50.0%; 95% confidence interval [CI], 31.6% to 68.4%). Adverse reactions were mild and without significant differences between the two treatments. CONCLUSION: Metopimazine plus ondansetron was significantly superior to ondansetron alone, concerning all efficacy parameters assessed, in patients who received platinum-based chemotherapy.

Adult↗
PubMed1996

New perspectives in antiemetic treatment.

Though antiemetic therapy has improved markedly in the past 15 years, patients still regard nausea and vomiting as two of the most distressing adverse events during chemotherapy. A major progress was the development of the serotonin3 (5-HT3) receptor antagonists. A possible antiemetic effect, achieved by interference with the "serotonergic system", is not restricted to antagonism at 5-HT3 receptors, however, but also includes agonism at 5-HT1A and 5-HT2 receptors, and serotonin synthesis inhibitors. The number of receptors thought to be involved in the emetic reflex has been augmented by neurokinin1 receptors with substance P as the preferred ligand. Animal studies have demonstrated a broad antiemetic profile of substance P antagonists. The somatostatin analogue octreotide has an antiemetic effect in patients with gastrointestinal obstruction, but has not been investigated against chemotherapy-induced emesis. The next few years will disclose, whether the efficacy and safety profiles of one or more of these drugs will make it clinically useful in the treatment of chemotherapy-induced nausea and vomiting.

Antiemetics↗
PubMed1996

Bioavailability of the antiemetic metopimazine given as a microenema.

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

Administration, Oral↗
PubMed1995

Development of antiemetic therapy in cancer patients.

Patients still consider nausea and vomiting to be severe adverse consequences of cancer chemotherapy. The physiology of chemotherapy-induced nausea is generally unknown, but the finding that high doses of metoclopramide induce the antiemetic effect by antagonizing 5-HT3 receptors, has evoked increased interest in serotonin as a possible neurotransmitter. This has led to development of more selective 5-HT3 antagonists, such as ondansetron, granisetron and tropisetron, with improvement of antiemetic therapy, especially in patients receiving cisplatin-based chemotherapy. The efficacy of serotonin antagonists is further optimized by the addition of steroids and the dopamine D2 antagonist metopimazine. Many questions in antiemetic treatment are still unanswered and future trials should focus on patients receiving multiple-day chemotherapy or multiple cycles of chemotherapy and on patients resistant to initial antiemetic therapy.

Antiemetics↗
PubMed1994

[Treatment of drug-induced nausea and vomiting].

Patients consider nausea (N) and vomiting (V) as severe adverse events to chemotherapy (CT). The introduction of the 5-HT3 antagonists have added a new dimension to the treatment of acute N and V. A review of the pathophysiology of N and V induced by CT and of the prescription of antiemetics used in Denmark is given. Dopamine D2 antagonists such as metoclopramide and metopimazine have a moderate antiemetic effect, when given in conventional low doses. A combination of one of these drugs and a steroid is recommended as first choice in patients receiving moderately emetogenic CT. In severe emetogenic CT, especially cisplatin-based, the 5-HT3 antagonists have resulted in a significant improvement and ondansetron, granisetron or tropisetron are in these patients recommended as first choice, either given alone or in combination with steroids. The duration of such a treatment should be restricted to the first 24 hrs after CT, as none of these expensive drugs seem to improve treatment of delayed emesis. The best known treatment of delayed emesis is the combination of a dopamine D2 antagonist and a steroid. Many pathophysiological and clinical questions are unanswered. Future trials using correct methodology should focus on patients receiving multiple-day CT, patients receiving multiple cycles of CT and on patients resistant to first-line antiemetic treatment.

Antiemetics↗
PubMed1994

Sex hormone levels in postmenopausal women with advanced metastatic breast cancer treated with CGS 169 49A.

30 postmenopausal patients with metastatic breast cancer were treated with three different doses of fadrozole hydrochloride (CGS 169 49A), a non-steroidal competitive aromatase inhibitor. The effect of 0.5, 1 and 2 mg given twice daily upon the levels of oestrogens, their androgen precursors and upon the concentration of sex hormone binding globulin (SHBG) was investigated after 1 and 3 months and then every 3 months until progression of disease. A significant reduction in the serum concentration of oestrone (P < 0.0001) was obtained at all doses. Also, the serum concentration of oestrone sulphate was significantly reduced (P < 0.0001). However, after 1 month, the concentration was significantly different from pretreatment levels (P < 0.01) only at the 4 mg daily dose. A decline was also observed in the concentration of SHBG (P < 0.05), with a concomitant elevation of the percentage non-SHBG-bound oestradiol. The androgens, testosterone and dehydroepiandrosterone sulphate, were unaltered during treatment, while androstendione was significantly elevated at the 2 mg daily dose (P < 0.001).

Aged↗
PubMed1993

Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy.

BACKGROUND AND METHODS: The serotonin (5-hydroxytryptamine3) antagonists have improved the treatment of acute chemotherapy-induced nausea and vomiting, but their ability to prevent delayed nausea and vomiting seems less pronounced. The results of a preliminary open trial suggested that the addition of a selective dopamine D2 antagonist could improve the antiemetic efficacy of the serotonin antagonists. In a randomized, double-blind, crossover trial, we compared oral treatment with ondansetron (8 mg twice a day) and the dopamine D2 antagonist metopimazine (30 mg four times a day) with treatment with ondansetron alone for three days in 30 patients who had vomited during the previous cycle of chemotherapy. All the patients received moderately emetogenic chemotherapy. RESULTS: Combination treatment with ondansetron and metopimazine significantly reduced the incidence of acute (P = 0.006) and delayed (P = 0.02) nausea and acute (P = 0.02) and delayed (P = 0.006) vomiting, as compared with treatment with ondansetron alone. Patients had significantly fewer days of nausea (P = 0.03) and vomiting (P = 0.003) if they received combination therapy. Sixty-seven percent of the patients preferred ondansetron and metopimazine, and 33 percent favored ondansetron alone (P = 0.10). Adverse reactions were mild with both regimens. With the exception of constipation, which was reported more frequently with combination therapy (P = 0.03), there were no significant differences in adverse reactions. CONCLUSIONS: Ondansetron plus metopimazine is a highly effective and safe antiemetic regimen that is markedly superior to treatment with ondansetron alone in patients receiving moderately emetogenic chemotherapy.

Adult↗
PubMed1993

Toremifene and tamoxifen in advanced breast cancer--a double-blind cross-over trial.

Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study. 66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40 mg/day or TOR 240 mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10-41%) and with TAM 42% (95% confidence limits 25-61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over-looking a response rate of 20% or more is less than 1%. In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.

Adult↗
PubMed1993

Interaction of the antiemetic metopimazine and anticancer agents with brain dopamine D2, 5-hydroxytryptamine3, histamine H1, muscarine cholinergic and alpha 1-adrenergic receptors.

The interactions of the antiemetic metopimazine (MPZ) and of the chemotherapeutic agents, cisplatin, carboplatin, doxorubicin, etoposide and vincristine were investigated at five neurotransmitter receptor binding sites. MPZ had nanomolar affinity for alpha 1, dopamine D2 and histamine H1 receptors, weak affinity for muscarinic cholinergic receptors, but no affinity for 5-hydroxytryptamine3 (5-HT3) receptors. Except for vincristine, which showed nanomolar affinity of muscarinic cholinergic receptors, none of the chemotherapeutic agents showed affinity for any of the receptors investigated at concentrations ranging between 10(-5) and 10(-7) M. Accordingly, chemotherapy-induced nausea and vomiting seems to be mediated by mechanisms other than the direct interaction of cytostatics with the neurotransmitter receptors investigated. Our finding that MPZ is without affinity for 5-HT3 receptors and therefore seems to mediate its antiemetic effect predominantly by dopamine D2 receptor blockade makes it an interesting drug for use in combinations with the new class of antiemetics, the 5-HT3 receptor antagonists. Data obtained in a recent clinical trial support this observation.

Animals↗
PubMed1992

Increased myelosuppression during cytostatic treatment and pleural effusion in patients with small cell lung cancer.

30 patients with small cell lung cancer (SCLC) and malignant pleural effusion were compared with 30 matched patients with SCLC but without pleural effusion. In the 30 with pleural effusion, white blood cell and platelet counts fell significantly after initial chemotherapy, necessitating dose reduction. Of the patients with pleural effusion, 16 developed severe (WHO grade IV) leukopenia, 7 had severe thrombocytopenia, and 2 patients died of infection. Accordingly, exhaustive aspiration of radiologically verified pleural effusion before starting chemotherapy in patients with SCLC is recommended.

Adult↗
PubMed1991

High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting.

In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low-dose metoclopramide (LDM) (70 mg) + L (2.5 mg x 2 po) + dehydrobenzperidol (5 mg x 2 im). Among the 29 patients who completed the cross-over, HDM significantly reduced the number of vomiting episodes (p = 0.002) and the degree of nausea (p = 0.004). Seventeen patients preferred the HDM and 4 the LDM regimen (p = 0.01). Sedation was seen in all but 1 patient, and was graded as severe in 6 patients receiving the HDM and in 2 patients receiving the LDM regimen. No extrapyramidal adverse reactions were seen. We conclude that high-dose metoclopramide + lorazepam is a safe antiemetic regimen and significantly superior to low-dose metoclopramide + lorazepam + dehydrobenzperidol. Owing to the severe sedation which occurs in some patients, the dose of lorazepam should be individually adjusted.

Adult↗
PubMed1990

The limited value of routine chest X-ray in the follow-up of stage II breast cancer.

In 280 patients with stage II breast cancer, chest X-ray was performed at 6 and 12 months and yearly thereafter to the 6th year or until recurrence, another cancer was detected, the patient refused further follow-up or died. Among 1289 scheduled chest X-rays, malignant changes were found in 20 patients, of which only 3 had pulmonary symptoms. In a further 14 patients malignant changes were suspected, but follow-up examinations could not prove malignancy. 26 patients presented within 12 months after the last scheduled X-ray with pulmonary symptoms and a work-up chest X-ray revealed malignant changes. Thus, in only 1.3% of the scheduled X-rays were unsuspected malignant changes diagnosed. Median survival of patients with malignant chest X-rays found at scheduled controls versus between scheduled controls did not differ significantly (P = 0.26). It is concluded that routine chest X-ray is not indicated in patients with stage II breast cancer.

Adult↗
PubMed1990

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose-dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.

Adult↗