Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety.

In this double-blind study, 301 patients with subjective and objective signs of sore throat were randomly assigned to flurbiprofen 8.75 mg (n = 129), flurbiprofen 12.5 mg (n = 43) or placebo (demulcent lozenge without active drug [n = 129]). Efficacy was assessed by changes in subjective rating scales primarily after a single dose and also over a 4-day period. Flurbiprofen 8.75 mg was superior to placebo in a number of efficacy parameters, notably throat soreness. Throat soreness was significantly reduced after 15 minutes (p < 0.05), with effects sustained for at least 2 hours (p < 0.05). Multiple dosing with flurbiprofen 8.75 mg lozenges continued to provide effective symptomatic relief over the 4-day treatment period. The small sample size was considered contributory to the variable results obtained with flurbiprofen 12.5 mg lozenges, but overall these were not inconsistent with previous trials. Both treatments were tolerated well. Flurbiprofen 8.75 mg lozenges provide an effective and well tolerated treatment for sore throat.

Repeated-dose pharmacodynamics of clopidogrel in healthy subjects.

The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.

Pharmaceutical registration and how to get a drug on the market.

In this article we describe how to get a drug onto the market and outline the product development stages. Drug development programmes and regulatory control processes are complex, so only a basic outline will be given.

Novel delivery systems: electrotransport.

Electrotransport involves the transport of ionized drugs across the skin under the influence of an electric current. This method of delivery has been used for many years to deliver drugs locally to the skin or the mouth, but now it is being studied as a means of delivering drugs for their systemic effects. Opioid analgesics may be administered via this route.

No effect of cisapride on paracetamol absorption after oral simultaneous administration.

We have measured the effect of oral cisapride on paracetamol absorption in 12 healthy volunteers in a double-blind placebo-controlled study. Volunteers received paracetamol plus placebo, paracetamol plus cisapride 10 mg and paracetamol plus cisapride 20 mg. Mean plasma paracetamol AUC at 60 min were 1070, 1051 and 1031 micrograms.min.ml-1 and maximum paracetamol concentrations were 31.5, 29.3 and 27.4 micrograms.ml-1 respectively (no significant differences). There was no difference also in time to maximum paracetamol concentration [median (range) 30 (15-120), 30 (15-90) and 30 (15-60) min, respectively]. .

Continuous ambulatory ECG monitoring in the perioperative period: relationship of preoperative status and outcome.

We have used continuous ambulatory electrocardiography in the perioperative period to monitor 108 patients with known cardiovascular disease undergoing non-cardiac surgery. There was a high incidence of ischaemic ST segment changes and ventricular arrhythmias. For the group as a whole, anaesthesia and surgery were followed by increased ventricular ectopic activity, but did not worsen myocardial ischaemia. However, the mean duration of ischaemic ST segment changes was increased significantly in those patients with treated hypertension. Of the risk factors considered, preoperative ischaemia and peroperative systolic arterial pressure were significant correlates with postoperative myocardial ischaemia.

Temazepam absorption in patients before surgery.

We have compared the rates of absorption and efficacies of temazepam 30 mg in elixir and capsule formulations in 100 patients before surgery. Both formulations provided anxiolysis and sedation, but there was wide variation in plasma concentrations of temazepam between individuals and between formulations. The presence or absence of anxiety did not influence the absorption of the preparations. It is suggested that plasma concentrations in excess of 200 ng ml-1 are required for sedation and anxiolysis, and that this may be achieved more reliably using the elixir formulation.

Effect of different rates of infusion of propofol for induction of anaesthesia in elderly patients.

The effect of changing the rate of infusion of propofol for induction of anaesthesia was studied in 60 elderly patients. Propofol was administered at 300, 600 or 1200 ml h-1 until loss of consciousness (as judged by loss of verbal contact with the patient) had been achieved. The duration of induction was significantly longer (P less than 0.001) with the slower infusion rates (104, 68 and 51 s), but the total dose used was significantly less (P less than 0.001) in these patients (1.2, 1.6 and 2.5 mg kg-1, respectively). The decrease in systolic and diastolic arterial pressure was significantly less in the 300-ml h-1 group at the end of induction and immediately after induction (P less than 0.01). The incidence of apnoea was also significantly less in the slower infusion group.

Effect of i.v. omeprazole on the pH and volume of gastric contents before surgery.

Gastric pH and volume were measured in 87 patients who had received i.v. omeprazole (a new gastric antisecretory agent) 40 mg or placebo 1 or 3 h before surgery. Omeprazole increased the pH of gastric contents in the majority of patients. Administration 1 h before surgery produced greater gastric pH and smaller volume than administration 3 h before surgery. There was a reduction in the number of patients with a pH of less than 2.5 and a volume of 25 ml or more in the treated groups compared with the combined placebo groups. Omeprazole may have a role in prophylaxis against acid aspiration syndrome.

A disposable device for patient-controlled analgesia with fentanyl.

A disposable nonelectronic patient-controlled analgesia device was used to deliver fentanyl after upper abdominal surgery. Pain relief was satisfactory and plasma fentanyl concentrations were similar to those obtained by other workers who used electronic patient-controlled analgesia devices.

A model to test the potency of inhalation anaesthetics.

The water flea Daphnia magna was studied as a potential model of the potency of inhalation anaesthetics in humans. Anaesthesia was defined as lack of movement to a noxious stimulus (strong light). Effective concentrations which produced anaesthesia of 50% of the individuals (EC50) for halothane, isoflurane and enflurane were 1.006, 1.156 and 1.415, respectively. Anaesthesia was reversible rapidly. It is suggested that Daphnia should replace vertebrates in early studies of inhalation anaesthetic potency.

Transdermal fentanyl for the relief of pain after upper abdominal surgery.

Transdermal fentanyl (n = 22) was compared with placebo (n = 18) in a double-blind study of pain after upper abdominal surgery. All patients also received i.v. morphine on demand for supplementary analgesia. The transdermal systems were applied 2 h before induction of anaesthesia and remained in situ for 24 h. After operation, pain scores were significantly lower and peak expiratory flow rates significantly higher in the transdermal fentanyl group, who demanded significantly less morphine than the control group. Mean plasma fentanyl concentrations at 12 and 24 h were within the therapeutic range (1.5 and 2.0 ng ml-1, respectively).

Gastric emptying after head injury.

Gastric emptying was measured in patients after head injury and compared with that of healthy volunteers using the rate of paracetamol absorption as an indicator of gastric emptying rate. There was a trend towards slower gastric emptying in the head injured patients, but the differences were not statistically significant.

Hypoxaemia during outpatient dental anaesthesia.

Eighty children, ASA grade 1, who had outpatient general anaesthesia for tooth extraction were studied. An inhalational induction was performed, with patients receiving halothane, nitrous oxide and either 33% or 50% oxygen. Oxygen saturation was measured throughout the procedure using the Ohmeda Biox 3700 pulse oximeter. No significant difference in the incidence of hypoxaemia was found between the two groups. There was no association between the grade of surgeon or anaesthetist and the incidence of hypoxaemia.

Comparison of the effect of cisapride and metoclopramide on morphine-induced delay in gastric emptying.

1. The effects of metoclopramide or cisapride on morphine-induced delay in gastric emptying in patients before surgery were compared. 2. Forty patients were allocated randomly to receive one of four premedications i.m.: placebo only, morphine 10 mg alone, morphine 10 mg with metoclopramide 10 mg and morphine 10 mg with cisapride 10 mg. Gastric emptying after each premedication was assessed indirectly from the rate of absorption of oral paracetamol. 3. Cisapride 10 mg reversed the delay in gastric emptying due to morphine. Its effects were significantly greater than those of metoclopramide 10 mg.

Changes in pupil diameter after oral administration of codeine.

Pupillary constriction occurs following administration of opioids and may be used as a marker of opioid activity. We have measured plasma concentrations and pupil diameters in 16 healthy volunteers after the oral administration of placebo or codeine. Pupil size decreased significantly after codeine compared with placebo. Pupil size was related to the plasma concentrations of codeine (P less than 0.05).