A controlled trial of ondansetron in the pruritus of cholestasis.

BACKGROUND: In patients with pruritus of cholestasis, response to conventional drug treatment may be unsatisfactory. Activation of 5-hydroxytryptamine receptors on dermal sensory nerve-endings plays a role in the perception of pruritus. The 5-hydroxytryptamine(3) receptor antagonist, ondansetron, has been used in the treatment of pruritus of cholestasis, but there are few controlled data. AIM: To determine whether ondansetron is effective in treating the pruritus of cholestasis. METHODS: A total of 19 patients with resistant pruritus were randomized, double blind, to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for 5 days. Patients' perception of pruritus was recorded hourly using a visual analogue scale, and scratching activity measured by means of a piezo-electric crystal attached to the fingernail. RESULTS: Mean pruritus score using visual analogue scale and scratching activity were reduced on the first treatment day compared with baseline in both the ondansetron and placebo groups (P < 0.05), but there were no significant differences in mean pruritus perception or scratching activity between the two groups. CONCLUSION: Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.

Drug development in anaesthesia: the remifentanil.

Drug development in anaesthesia poses specific challenges. Describing the development of remifentanil highlights some of these. A new drug in anaesthesia must achieve its clinical goals in all patients and significant levels of toxicity are unacceptable. Rather than asking, "What new drugs does the anaesthetist need?" it may be more relevant to pose the question, "How can we design drugs to do things better?". Recent trends in anaesthesia have led to the development of short acting agents--one of these agents, remifentanil, has been designed to provide a mu-opioid receptor agonist with a rapid and predictable offset of action. The insertion of an alkyl ester group into this 4-anilidopiperidine molecule has resulted in a compound which, whilst retaining the desired mu-opioid receptor pharmacology, is susceptible to metabolism by non-specific esterases in the blood and tissues. The rapid onset and offset of action means that the anaesthetist can deliver high doses of opioid resulting in stable anaesthesia and the lack of accumulation ensures that even after prolonged infusion remifentanil does not compromise recovery. This ability to control the anaesthetic process has relevance in both short and long procedures and the unique characteristics of remifentanil may also in the future prove to have utility in the intensive care setting.

Nausea and vomiting after gynaecological surgery: a meta-analysis of factors affecting their incidence.

A total of 1442 patients who had major gynaecological surgery were recruited into three multicentre studies using a standard general anaesthetic technique in order to assess the efficacy of various doses of orally administered ondansetron in the prevention of postoperative nausea and vomiting. A total of 1257 patients were included in this analysis: 420 received oral formulations of placebo and 212, 296 and 329 received ondansetron 1, 8 and 16 mg, respectively. The following factors were measured in these studies and were considered to have a possible influence on the proportion of patients experiencing postoperative nausea and vomiting: age of patient; volatile anaesthetic; intraoperative dose of fentanyl; postoperative dose of morphine; country; anaesthesia duration; neuromuscular blocker; neuromuscular block antagonist; premedicant; recovery time; type of surgery; antiemetic treatment; body weight. Using a process of elimination based on logistic regression techniques, the factors found to be the most important influences on the frequencies of nausea and vomiting were antiemetic treatment, type of surgery, neuromuscular blocker, country, volatile anaesthetic and age. A statistically significant interaction between type of surgery and age was observed. Adjusted probabilities of nausea and vomiting were obtained from the model, including all the above factors, together with the type of surgery by age interaction. Ondansetron 8 mg showed the smallest adjusted probability of nausea (0.54) and vomiting (0.34) and placebo the greatest (nausea 0.75, vomiting 0.61). A similar pattern of adjusted probabilities over neuromuscular blocking agents was seen for nausea and vomiting, with the greatest occurring in patients receiving pancuronium (nausea 0.74, vomiting 0.57) and the least in patients receiving alcuronium (nausea 0.59, vomiting 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical development of ondansetron for use in the prevention and treatment of postoperative nausea and vomiting.

An international clinical trial programme has been established to assess the efficacy and safety of ondansetron in the prevention and treatment of postoperative nausea and vomiting. The programme included nine pilot studies and six key placebo-controlled studies. These studies have evaluated both oral and intravenous formulations of ondansetron in the prevention of postoperative nausea and vomiting, and intravenously administered ondansetron in the treatment of established symptoms. Most patients included in the trials were adult women, less than 50 years of age, receiving anaesthesia for gynaecological surgery. The primary efficacy analysis for emesis was based on the assessment of complete response (i.e. absence of emetic episodes or nausea in the first 24 h postoperatively). These trials clearly demonstrated the anti-emetic efficacy of ondansetron in the prevention and treatment of postoperative nausea and vomiting.

Efficacy of orally administered ondansetron in the prevention of postoperative nausea and vomiting: a dose ranging study.

In a placebo-controlled, double-blind study, we have compared the efficacy of ondansetron 16 mg, 8 mg and 1 mg administered 8-hourly for prevention of postoperative nausea and vomiting. We studied 995 patients undergoing major gynaecological surgery; 982 were included in the analysis. Study medication was administered 1 h before induction of anaesthesia and second and third doses were given 8 and 16 h after the first. The treatment groups were similar for patient characteristics, surgical procedures, anaesthetics administered and opioids given. The frequency of nausea was 75%, 70%, 56% and 55% after placebo and ondansetron 1 mg, 8 mg and 16 mg, respectively; the corresponding frequencies of vomiting were 60%, 55%, 37% and 37%. Ondansetron 8 mg was as effective as 16 mg and both resulted in significant reductions in nausea and vomiting compared with placebo and ondansetron 1 mg (P less than 0.001).

Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist.

Ondansetron (GR38032F) is a selective antagonist of 5-hydroxytryptamine (5-HT) type 3 receptors. This randomized, double-blind, cross-over study was undertaken to evaluate and compare the effect of ondansetron with placebo on gastrointestinal transit in 10 healthy male volunteers. There were no significant differences between the effects of placebo and ondansetron on gastric emptying or mouth-to-caecum transit time. However, significant differences in mean whole-gut transit time were observed, that is 54.8 h with ondansetron and 32.1 h with placebo. Therefore, 5-HT3 receptors may be involved in the regulation of colonic transit and ondansetron may prove useful as an anti-diarrhoeal agent.

In vitro interactions between endogenous polyamines and superoxide anion.

Endogenous polyamines with anti-inflammatory activity scavenge superoxide and possibly other oxy-radicals produced by xanthine oxidase or from stimulated polymorphonuclear leucocytes. Polyamines incubated with stimulated cells are in part metabolised. Putrescine is converted to metabolites tentatively identified as gamma-aminobutyraldehyde, delta'-pyrolline and gamma-aminobutyric acid. The metabolism of spermidine, spermine and cadaverine was not as extensively studied but metabolites were formed that gave positive reaction to Schiffs reagent on tlc plates. The possible relevance of the results to the anti-inflammatory action of polyamines is discussed.

The influence of the O and K antigens of Klebsiella aerogenes on surface hydrophobicity and susceptibility to phagocytosis and antimicrobial agents.

The surface hydrophobicity of Klebsiella aerogenes is influenced by the presence of capsular (K) and lipopolysaccharide (O) antigens. Loss of both K and O antigens (K-O-), but not the K antigen alone (K-O+), increased surface hydrophobicity and susceptibility to phagocytosis. Unheated serum (i.e., containing complement) increased the surface hydrophobicity and phagocytosis of the K-O+ and K-O- strains, but not of the K+O+ encapsulated parent strain. Despite the altered susceptibility to phagocytosis caused by the presence or absence of the K and O antigens, their loss did not influence sensitivity to a range of hydrophilic, hydrophobic or cationic antimicrobial agents.