Oral zolmitriptan is effective in the acute treatment of cluster headache.

OBJECTIVE: To evaluate the efficacy and tolerability of oral zolmitriptan 5 mg and 10 mg and placebo in cluster headache. METHODS: A multicenter, double-blind, randomized, three-period, crossover, outpatient study. Adult patients received placebo and zolmitriptan 5 mg and 10 mg orally for the acute treatment of episodic or chronic cluster headache. Headache intensity was rated by a five-point scale: none, mild, moderate, severe, or very severe. Patients only treated moderate to very severe headaches. The primary efficacy measure was headache response (two-point or greater reduction from baseline in the cluster headache rating scale) at 30 minutes. Secondary efficacy measures included proportion of patients with initial headache relief within 15 and 30 minutes, mild or no pain at 30 minutes, meaningful headache relief, and use of escape medication. RESULTS: A total of 124 patients took at least one dose of study medication, with 73% having episodic and 27% chronic cluster headache. For the primary endpoint, there was a treatment-by-cluster-headache-type interaction (p = 0.0453). Therefore, results are presented separately for chronic and episodic cluster headache. In patients with episodic cluster headache, the difference between zolmitriptan 10 mg and placebo at 30 minutes reached significance (47% versus 29%; p = 0.02). Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% patients treated with zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo (both p

Ratio of inhaled corticosteroid to bronchodilator treatment and asthma hospitalisation.

BACKGROUND: Previous research based on aggregated data has led to conflicting interpretations of the relationship between the corticosteroid:bronchodilator (C:B) ratio and outcome measures. OBJECTIVES: To assess whether the C:B ratio is associated with hospital contact for asthma at individual patient level. METHODS: The study was a retrospective multivariate analysis, using data from the U.K. General Practice Research Database from 1993 to 1996. The subjects were 3465 asthma-diagnosed patients receiving bronchodilator and corticosteroid medication. The main outcome measures were asthma-related hospital contacts. RESULTS: There was an inverse association between the C:B ratio and hospital contact after controlling for age. The odds ratio for the C:B ratio was 0.87 (95 % CI 0.73-0.98) and 1.04 (95% CI 1.01-1.07) for five-year agebands among patients aged five years and over. There was no systematic relationship between the C:B ratio and hospital contacts for patients aged under five years. CONCLUSION: The results of this study show that higher C:B ratios are associated with lower levels of hospital contacts at patient level, although there are exceptions possibly linked to disease severity. For patients under five years, the ratio may not be a good outcome measure, perhaps owing to the difficulty in diagnosing asthma or poor compliance.

A long-term study to maximise migraine relief with zolmitriptan.

Part 1 of this international study was a randomised, double-blind, placebo-controlled study of 2.5 mg and 5 mg zolmitriptan (Zomig) in the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. Part 2 was a non-comparative evaluation of long-term, unrestricted zolmitriptan use for treatment of initial, persistent and recurrent migraine headaches. In Part 1, following the treatment of moderate or severe persistent headache, two-hour headache response rates with 5 mg zolmitriptan (51.6%, n = 322), 2.5 mg zolmitriptan (49.7%, n = 324) and placebo (51.6%, n = 343) were not significantly different. However, the pain-free response rate following the treatment of persistent migraine headache of any intensity was significantly higher with 5 mg zolmitriptan than with placebo (36.0% vs. 25.5%; p < 0.001). This was predominantly due to effects in the subgroup of patients with mild headache. Thus, migraine relief in patients whose initial headache shows a partial response to 2.5 mg zolmitriptan may be maximised by a second 5 mg dose. In Part 2 (involving 2499 evaluable patients), 65.8% of attacks were treated with a single dose of zolmitriptan (2.5 mg or 5 mg). Of those migraine attacks initially treated with 2.5 mg zolmitriptan, 70.3% required no further dose, similarly 62.7% of migraine attacks treated initially with 5 mg zolmitriptan only required a single dose. Over the whole attack (i.e. initial and any persistent headache), headache response rates to one or two zolmitriptan doses were greater than 88.8%. 'Level of pain' was the primary factor influencing the choice of dose. Zolmitriptan provided consistent migraine headache relief in the majority of patients and was well tolerated.

Migraine pharmacotherapy with oral triptans: a rational approach to clinical management.

The recent clinical development of a number of migraine specific 5-HT1B/1D agonist triptans with enhanced lipophilicity (TELs), relative to the first drug of this class sumatriptan, and with a range of different metabolic, pharmacokinetic and receptor affinity profiles, provides the potential for critically different clinical profiles. Eletriptan, naratriptan, rizatriptan and zolmitriptan display both increased stability to first pass metabolic inactivation by monoamine oxidase (MAO-A) and enhanced lipophilicity (4- to > 120-fold more than sumatriptan), leading to increased oral bioavailability (2- to 5-fold more than the 14% reported for oral sumatriptan). Central penetration and increased receptor affinity and selectivity for the neuronal (5-HT1D) receptor also combine to allow for lower total oral dosing (i.e., unit doses of 15 mg or less compared with 50-300 mg doses of sumatriptan) and reduced peripheral exposure to the coronary vasoconstrictor (5-HT1B) receptor. The notable exception being eletriptan, where an active P-glycoprotein blood-brain barrier efflux system effectively negates these benefits and requires an 80 mg oral dose. Differences in the metabolic balance between hepatic P450 (especially CYP 1A2) and MAO-A inactivation lead to potential drug interactions for all TELs with the oral contraceptive pill (OCP), fluvoxamine and the quinilone antibiotics (with increased triptan levels). An important but complex MAO-A interaction between a metabolite of propranolol and rizatriptan mandates dosage reduction (to 5 mg) for rizatriptan in the presence of propranolol treatment. There is also an absolute contraindication for the concurrent administration of the MAO-A inhibitor moclobemide and rizatriptan. All the new-marketed TELs have potential clinical benefits and were well-tolerated relative to sumatriptan. Both rizatriptan (10 mg) and zolmitriptan (2.5 mg and 5 mg) demonstrate at least equivalent efficacy to sumatriptan 25, 50 and 100 mg, respectively, making them suitable first line agents for moderate or severe migraine headaches. Rizatriptan has the fastest onset of effect of the TELs. Naratriptan would appear to have lower recurrent headache rate than sumatriptan, rizatriptan or zolmitriptan. Therefore, for headaches of long duration and with a tendency to recur naratriptan may be the most appropriate treatment. Thus, knowledge of the metabolic, pharmacokinetic and clinical profiles of the TELs facilitates the selection of a triptan which allows optimisation of the clinical benefits for individual patients, minimising the risk of drug interactions and a minimally effective dose to reduce potential adverse events (AEs).

Rational migraine management: optimising treatment with the triptans.

In the last two years, a number of 5-HT1B/1D agonist triptans with enhanced lipophilicity (TELs) relative to the first drug of this class, sumatriptan, have been approved for marketing in most countries of the world (naratriptan, rizatriptan and zolmitriptan). In addition, at least three others are in advanced stage of clinical development (almotriptan, eletriptan, and frovatriptan). This paper sets out to review the recent data with the aim of identifying: 1) What are the critical differences between the TELs and sumatriptan? 2) How do the currently licensed TELs compare? 3) Is it possible to provide a rational approach to migraine therapy based on objective differences in the clinical profile of these new drugs? Recent randomised controlled and comparator data were reviewed, including the independent FDA assessment of rizatriptan. Critical differences for the new TELs (naratriptan, rizatriptan and zolmitriptan) which may lead to more rational migraine management: Both rizatriptan (10 mg) and zolmitriptan (2.5 mg and 5.0 mg) have demonstrated superior efficacy to sumatriptan 100 mg, and 25 and 50 mg respectively. Therefore, for first line use either rizatriptan or zolmitriptan would be appropriate for moderate and severe headache. Rizatriptan has a more rapid onset of action than sumatriptan 100 mg. Both rizatriptan and zolmitriptan have a more rapid onset of action than naratriptan. Therefore, for a rapid onset of action either rizatriptan or zolmitriptan would be appropriate. Naratriptan would appear to have a lower recurrent headache rate than sumatriptan, rizatriptan or zolmitriptan. However, 24-hour efficacy rates for zolmitriptan 2.5 mg were significantly greater than for sumatriptan 25 mg and 50 mg and were not significantly different from naratriptan. Therefore, for headaches of long duration and with a tendency to recur (e.g. menstrual headaches) either naratriptan or zolmitriptan would be appropriate. Naratriptan has lower reported adverse event rates comparable with placebo. This would support the use of naratriptan 2.5 mg in patients who have demonstrated poor tolerance to the "triptan type" adverse events.

The natural history of headache: predictors of onset and recovery.

The objective of this study was to determine predictors of onset of new headache episodes and recovery from headache over one year. A population-based cohort study was conducted, comprising a baseline postal survey to a random sample of adults aged>or=18 years, with follow-up survey after 1 year. Risk factor data at baseline were compared with headache status at follow-up in two groups: (i) those free of recent headache at baseline and (ii) those with a recent headache at baseline. In respondents free of recent headache at baseline, previous headache [risk ratio (RR) 4.15], the presence of other pain at baseline (RR 1.43), severe sleep problems (RR 1.67) and drinking caffeine (RR 1.99) increased the risk of a new headache episode during the follow-up year. In respondents with recent headache at baseline, less severe headaches at baseline predicted recovery during the follow-up year, as did the absence of anxiety [recovery ratio (ReR) 2.84] and of sleep problems (ReR 2.77). Risks for increased headache-related disability reflected those for onset of a new episode and these risks increased in strength for large increases in disability. Sleep problems and caffeine consumption increase the risk of developing headache and thus provide targets for prevention. Low levels of anxiety, sleep problems and the absence of other pain improve the likelihood of recovering and remaining free from headache.

Tolerability profile of zolmitriptan (Zomig; 311C90), a novel dual central and peripherally acting 5HT1B/1D agonist. International clinical experience based on > 3000 subjects treated with zolmitriptan.

Zolmitriptan (Zomig, formerly 311C90) at doses of 0.5-50 mg was administered to 316 unique volunteers in clinical pharmacology studies and 2,750 unique patients in eight clinical studies of acute migraine treatment. Overall, subjects received almost 50,000 doses; 97% of exposures were at doses > or = 2.5 mg. In the clinical pharmacology studies, the overall incidence of subject exposures experiencing at least one adverse event was 52% with zolmitriptan 2.5 mg (28% with placebo). In placebo-controlled studies, the overall incidence of patients with at least one adverse event was dose-dependent for zolmitriptan over the 1-15 mg dose range, e.g. 42% and 46% with 1 and 2.5 mg, respectively and 58% with 5 mg (29% with placebo). Only four serious adverse events attributable to zolmitriptan were reported. In a long-term study, during which 2,058 outpatients treated a total of 31,579 migraine attacks with either one or two zolmitriptan 5 mg doses over a period of up to 1 year, the number of attacks associated with at least one adverse event was similar after one (26%) and two (24%) doses. The majority (59%) of the adverse events reported in this study (59%) occurred within 2 h of dosing, were predominantly mild (59%) or moderate (35%) in intensity, of < or = 4 h duration (58%), required no further action (94%). In placebo-controlled studies, the percentage of patients who reported severe adverse events was similar with zolmitriptan 2.5 mg (4%) and placebo (5%). The most frequently reported adverse events with zolmitriptan in the placebo-controlled clinical studies were asthenia, heaviness (other than chest or neck), dry mouth, nausea, dizziness, somnolence, paresthesia and warm sensations. The type and severity of the adverse events was not influenced by gender (although the frequency of reported adverse events was higher in females, as was the case in the placebo group), age, presence of aura prior to the attack, association of migraine with menstruation, concurrent medication, or by the addition of a second zolmitriptan dose. Zolmitriptan showed a similar tolerability profile in the long-term study, in which a low withdrawal rate due to adverse events of 8% was observed. Zolmitriptan was not associated with an increased frequency of central nervous system-related adverse events in a comparative study of sumatriptan, despite pre-clinical and neurophysiological evidence of a dual peripheral and central action of zolmitriptan. Moreover, zolmitriptan doses of 5-20 mg produced no statistically significant effects on objective assessments of psychometric function. Zolmitriptan had no clinically significant effects on blood pressure (even in patients with controlled mild to moderate hypertension or impaired renal function), ECGs (e.g. there was no evidence of ischemic events) or clinical chemistry, hematological or urinalysis measurements. In summary, zolmitriptan is well tolerated, particularly at the recommended dose of 2.5 mg. Zolmitriptan has a well-defined dose-response with 2.5 mg proving highly effective and optimizing the benefit/risk ratio of treatment. Thus, zolmitriptan is well suited as an acute oral treatment for migraine in the outpatient setting.

Are triptans with enhanced lipophilicity used for the acute treatment of migraine associated with an increased consulting rate for depressive illness?

1997, sumatriptan-treated migraineurs had significantly higher depression PCRs (22.3%) compared with non-triptan users (19.3%), a difference of 6.4% (95% confidence interval (CI) 4.6-8.4%, P < 0.001). In the year (April 1997 to March 1998) following the launch of the TELs, depression PCRs were significantly higher among patients using these compounds compared with sumatriptan-treated patients (5.1%, CI 1.8-12.0%, P < 0.05). However, after taking account of prior depression (odds ratio (OR) 6.45, 95% CI 3.63-11.43), TELs were not significantly associated with depression (OR 0.27, 95% CI 0.03-2.13). Furthermore, rates of newly diagnosed depression after treatment were similar in the two triptan groups (sumatriptan 4.2%; TELs 3.9%). Although, the TELs are being prescribed to patients with higher pre-existing rates of depression, they are not associated with subsequently increased consulting for depressive illness compared with patients taking sumatriptan. This study highlights the potential to use GPRD to test targeted hypotheses exploring pharmacovigilance issues for patients using new medicines.

Head lice diagnosed in general practice in the West Midlands between 1993 and 2000: a survey using the General Practice Research Database.

The potential of the General Practice Research Database (GPRD) for communicable disease surveillance was explored using head lice as an example. All diagnoses of head lice and prescriptions for parasiticidal agents from 1993 to 2000 in the West Midlands were analysed. Diagnoses reached a peak of 28.2 per 1,000 patient years at risk and total prescriptions reached a peak of 27.1 per 1,000 patient years at risk in 1997. Malathion and permethrin were prescribed most often. The proportion of further parasiticidal prescriptions issued within 30 days of the initial prescription increased to a peak of 11.5% of prescriptions in 1997. The ratio of the same:different further prescriptions changed during the study period, reaching a high of 5:1 in 2000. These trends are mirrored by the Royal College of General Practitioners (RCGP) Weekly Returns Service and Prescribing Analysis and Cost (PACT) data. Use of GPRD provides additional insights into patient data, particularly on prescribing, that would not be available from other sources.

Upper gastroduodenal ulceration in arthritis patients treated with celecoxib.

OBJECTIVE: To evaluate the comparative incidence of endoscopic gastroduodenal ulcers in patients with rheumatoid arthritis or osteoarthritis treated with celecoxib. DESIGN: Quantitative systematic review of randomized controlled trials. SUBJECTS: Patients (n = 4632) with rheumatoid arthritis or osteoarthritis reported in five trials. MAIN OUTCOME MEASURES: Rate ratios, rate differences, and the number needed to harm were calculated for the incidence of endoscopically documented gastroduodenal ulcers. RESULTS: Pooled rate ratios (RRs) relative to placebo for endoscopic ulcers at 12 weeks were 1.96 (95% CI 0.85 to 4.55) for celecoxib 100 mg twice daily and 2.35 (95% CI 1.02 to 5.38) for celecoxib 200 mg twice daily. There was no significant difference in gastroduodenal ulcers at 12 weeks between celecoxib 200 mg twice daily and celecoxib 100 mg twice daily; the corresponding pooled RR was 1.21 (95% CI 0.62 to 2.38). In contrast, celecoxib 200 mg twice daily was associated with a significantly lower rate of gastroduodenal ulcers than was naproxen 500 mg twice daily at 12 weeks (RR 0.24; 95% CI 0.17 to 0.33). On average, for every seven patients treated with naproxen, one more had an endoscopic ulcer than if they were treated with celecoxib. Celecoxib 200 mg twice daily also had a significantly lower risk of endoscopic ulcers than did either modified-release diclofenac 75 mg twice daily at 24 weeks (RR 0.24; 95% CI 0.11 to 0.52) or ibuprofen 800 mg three times daily at 12 weeks (RR 0.30; 95% CI 0.20 to 0.46). CONCLUSIONS: Endoscopic studies have shown that celecoxib, at a wide range of doses, is associated with a lower incidence of gastroduodenal ulcers than are diclofenac, ibuprofen, or naproxen. The incidence rates of gastroduodenal ulcers associated with celecoxib were similar, although not equivalent, to placebo. Head-to-head comparisons suggest that, at the wide range of doses studied (100-800 mg/d), there are no dose-related increases in endoscopic gastroduodenal ulcers with celecoxib. The results of longer term comparative trials of celecoxib based on clinical outcomes are needed to determine celecoxib's ultimate risk-benefit profile.

The effects of a 5-HT2 receptor antagonist (ICI 169,369) on changes in waking EEG, pupillary responses and state of arousal in human volunteers.

1. ICI 169,369 (2-(2-dimethylamino ethylthio)-3-phenyl quinoline) is a potent selective competitive antagonist of the 5-HT2 receptor in animal models. Effects of ICI 169,369 as single oral doses (80 and 120 mg) separated by 1 week, on the power spectrum of waking EEG, dark adapted pupil responses and sedation score, were studied in a double-blind, placebo controlled, randomised cross over within subject comparison, in six healthy male volunteers. 2. Pupillary responses were measured using a portable infrared pupillometer following 15 min dark adaptation, assessing resting vertical pupil diameter (RPD), light constricted diameter (MPD) and recovered final diameter (FPD) at the end of a 3 s measurement cycle. 3. Both doses of ICI 169,369 produced a mean 36% (range 10-54%) decrease in log 10 power of the waking EEG alpha activity with eyes closed (P less than 0.02), and mean 38% (range 2-86%) increase in theta activity at 2 h compared with placebo. 4. Both 80 and 120 mg doses of ICI 169,369 reduced RPD by approximately 30% from a predose value of 6.25 mm (+/- 0.87; 95% CI) and from placebo values 6.41 mm (+/- 1.06) and 7.48 mm (+/- 1.49) at 3 and 5 h after dosing. MPD was reduced by 50% with the 120 mg dose at 5 h after dosing (placebo 5.2 mm; ICI 169,369 2.7 mm; P less than 0.05). FPD was significantly reduced (P less than 0.01) by both doses at 3 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Trends in antibiotic prescribing and associated indications in primary care from 1993 to 1997.

BACKGROUND: Recent concerns that evidence on the appropriate use of antibiotics is not having an impact on prescribing trends are based on UK prescribing data relating to 1980-1991. The aim of this paper is to determine trends in antibiotic prescribing from 1993 to 1997 and link antibiotic prescriptions to diagnostic categories. METHODS: A retrospective analysis of antibiotic prescriptions linked to diagnostic codes was carried out using the West Midlands General Practice Research Database. RESULTS: The prescribing rate for antibiotics fell from 963 prescriptions/1,000 patients in 1993 to 807 prescriptions/1,000 patients in 1997 (p < 0.001). The proportion of antibiotic prescribing for respiratory conditions fell from 65 per cent in 1993 to 59 per cent in 1997 (p < 0.001). The main decreases in antibiotic prescribing are accounted for by non-specific lower respiratory tract infections (-22 prescriptions/1,000 patients), non-specific upper respiratory tract infections (-21/1,000 patients) and throat infections (-20/1,000 patients). There was increased prescribing for non-respiratory miscellaneous conditions (+6 prescriptions/1,000 patients). CONCLUSIONS: Overall antibiotic prescribing declined by 16 per cent between 1993 and 1997, primarily for respiratory conditions. These results of the current study are in marked contrast to an earlier review, which found an increase of 46 per cent between 1980 and 1991 in England. The level of antibiotic prescribing for conditions which may not be bacterial in origin is still high and there is scope for further reductions in antibiotic prescribing. This study highlights the need for regular epidemiological data to inform the debate on antibiotic prescribing.

Epidemiology of headache in an English district.

Headache prevalence, characteristics and impact in adults were measured using a cross-sectional general population survey in North Staffordshire, UK. A postal survey was mailed out to 4885 adults (aged > or = 18 years) with an adjusted response rate of 56% (n = 2662). Of respondents 93% reported headache ever and 70% in the last 3 months. Women and younger people reported higher headache prevalences. Of those reporting headache in the last 3 months, 23% experienced headache at least weekly and 16% experienced severe headache pain. Headaches affected work, home or social activities in 43% of sufferers and 20% reported at least moderate headache-related disability. Higher levels of disability were associated with higher levels of pain, 61% with severe disability reporting severe pain compared with 13% who had mild or moderate disability. In the total adult population sample headache affected more than two-thirds in the last 3 months and 14% of all adults reported headache-related disability of at least moderate level, which translates to a large burden in the general population.

Advice and care for headaches: who seeks it, who gives it?

Using data from a cross-sectional survey and a prospective record linkage study the aims of this study were to: (i) determine sources of advice and care for headaches in a population survey of adults, and (ii) investigate prospectively the influences of headaches on general practice consultation in a 12-month follow-up of the responders to the population survey. A population based cross-sectional survey was mailed to 4885 adults (aged > or = 18 years) with an adjusted response rate of 56% (n = 2662). The main outcome measures of interest were (i) self-report advice and care-seeking in the survey (ii) consultation with general practitioner for headache and for other conditions in 12-month period subsequent to the survey. Reporting a recent GP consultation for headache was associated with younger age (mean: 46 vs 48 years), female gender (68% vs 60%), and greater headache severity as measured by frequency, pain, and associated disability. The commonest sources of advice and care in the past were GPs (27%), opticians (21%), and pharmacists (8%). Consultations for headache were not common in the 12-months following the survey (n = 144); however, those reporting a recent headache were almost 4 times more likely to consult subsequently with a headache than those not (relative risk; 95% CI: 3.7; 1.9, 7.0). Recent reporting of headache was also associated with an increased risk of consulting for mental disorders (1.7; 1.2, 2.6), diseases of the digestive (1.6; 1.1, 2.3) and respiratory system (1.4; 1.1, 1.8), and a decreased risk of consulting for circulatory diseases (0.8; 0.7, 1.0). Only a minority of headache sufferers consult their GP, regardless of severity, with opticians and pharmacists being other important sources of information. Headache appears to have an additional impact upon GP workload through increased rates of consultations for nonheadache conditions amongst headache sufferers. The interesting findings regarding rates of consultation for digestive and circulatory conditions amongst headache sufferers may be linked to the use of headache medication.

Should the corticosteroid to bronchodilator ratio be promoted as a quality prescribing marker?

In recent years the ratio of inhaled corticosteroid:bronchodilator (C:B) prescribing has been promoted as a quality marker for asthma treatment and cross-sectional data indicate an association with hospital admissions. If prescribing advice has been followed then it can be hypothesised that the C:B ratio will have increased and hospitalisation decreased. The West Midlands General Practice Research Database was used to monitor changes in the C:B ratio and hospital referrals for asthma between 1993 and 1996. The C:B ratio increased from 0.5 to 0.6 (P<0.001) and hospital referrals decreased from 7% to 4% per annum (P<0.001). Overall, 38% of the variation in hospital referrals was explained by the C:B ratio. This is higher than previous studies, perhaps because the study was longitudinal and the ratio assessed accurately in terms of volume rather than prescription items. When measured in defined daily doses, the C:B ratio does appear to have validity as an indicator of good prescribing in primary care. The General Practice Research Database offers an opportunity for assessing the validity of prescribing indicators before they are considered for wider use by Primary Care Groups and Health Authorities.

The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man.