The impact of pharmacogenetics for migraine.

Migraine is a paroxysmal neurological disorder affecting up to 12% of males and 24% of females in the general population. As migraine has been demonstrated to have a strong, but complex, genetic component, pharmacogenetics bears great promise in providing new targets for drug development and optimization of individual specific therapy. Better, preferably prophylactic, treatment of migraine patients is desired because the drugs now used are not effective in all patients, allow recurrence of the headache in a high percentage of patients and sometimes have severe adverse side-effects. With the recent identification of the brain-specific P/Q-type Ca(2+)channel gene CACNA1A as a pivotal player in the pathogenesis of migraine, the first step has been taken to identify primary biochemical pathways leading to migraine. The work on migraine can also have implications for the increasing number of additional neurological episodic disorders having the common denominator of channelopathy.

Prolonged duration of standing up is an early dopa-sensitive abnormality in Parkinson's disease.

We studied the influence of dopaminergic medication on the duration of standing up, static posture and gait in five patients with Parkinson's disease (Hoehn and Yahr stage 1.5 to 3) and four healthy controls, using an optoelectronic camera system. Duration of standing up was prolonged in patients, while static posture and gait were largely unaffected. The prolonged duration of standing up was corrected by dopaminergic medication. These results suggest that an increased duration of standing up is a relatively early and dopa-sensitive abnormality in Parkinson's disease.

Bovine isolated middle cerebral artery contractions to antimigraine drugs.

Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all contract cranial blood vessels and this effect seems to be primarily responsible for their efficacy in migraine. We have compared the contractile effects of a number of ergot and triptan derivatives on the bovine isolated middle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine (8.0+/-0.1) approximately dihydroergotamine (8.0+/-0.1) > avitriptan (7.4+/-0.3) >5-HT (7.0+/-0.1) > naratriptan (6.8+/-0.1) > methylergometrine (major metabolite of methysergide; 6.5+/-0.2) > rizatriptan (6.3+/-0.3) approximately zolmitriptan (6.2+/-0.1) approximately sumatriptan (6.0+/-0.2) approximately methysergide (5.9+/-0.3). The rank order of efficacy (Emax expressed as % of contraction to 100 mM K+) was 5-HT (127+/-11) > sumatriptan (56+/-5) > ergotamine (48+/-5) approximately dihydroergotamine (44+/-8) approximately methyl-ergometrine (44+/-7) > avitriptan (37+/-7) approximately rizatriptan (33+/-5) approximately methysergide (29+/-10) approximately zolmitriptan (28+/-3) approximately naratriptan (23+/-2). The concentration-response curve to 5-HT appeared to be biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan-induced contractions, but clearly antagonised the second more efficacious phase of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the concentration-response curves to 5-HT (in the presence of 10 microM ketanserin) and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all acutely acting antimigraine drugs contract the bovine isolated middle cerebral artery. Whereas sumatriptan contracts the artery via the 5-HT1B/1D receptor, the 5-HT-induced contraction is mediated partly by the 5-HT2A receptor and partly by another, possibly novel receptor differing from the 5-HT1B/1D receptor. This receptor may be a target for the development of future antimigraine drugs.

Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials.

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.

A new sublingual formulation of apomorphine in the treatment of patients with Parkinson's disease.

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.

Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials.

BACKGROUND: The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice. METHOD: We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials. RESULTS: 53 clinical trials (12 unpublished) involving 24089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post dose); and 67% (63-70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12.5 mg almotriptan showed similar efficacy at 2 h but better other results; 2.5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2.5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy. INTERPRETATION: At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success.

Repeatability of the intensity dependence of cortical auditory evoked potentials in the assessment of cortical information processing.

Data on repeatability and optimal settings are needed when studying the influence of drugs on the intensity dependence of auditory evoked cortical potentials (IDAP). IDAP was recorded at intervals of 1, 2, and 24 h at two centers in 22 healthy volunteers. Settings were modified to compare fixed versus randomly varied stimulus repetition rate, as well as 30 Hz and 100 Hz low pass filters. Repeatability was assessed for different intervals and different settings. Group means did not differ between centers, the 2-h or 24-h retest, or when using different settings. We observed an order effect for the 1 h retest. Fixed repetition rate and the 30 Hz filter improved repeatability with still high intraindividual variability. IDAP group means can be compared between centers for retest intervals of 2 h and 24 h and different settings. Variability is too large to compare individuals.

Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks.

AIMS: To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement. METHODS: Twenty-seven migraine patients (age: 18-65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (Cmax), time to Cmax (tmax), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration-time profile, obtained from 10 blood samples in each patient, during each of the two administrations. RESULTS: Alniditan was rapidly absorbed into the systemic circulation (tmax=11 min). All investigated pharmacokinetic parameters (Cmax, tmax, AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n = 13) and the 4 mg group (n = 14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (Ct=5) in responders (21+/-16 ng ml(-1); n=10) was significantly higher than the Ct=5 in nonresponders (3+/-3 ng ml(-1); P=0.01; n=4). However, the Cmax and AUC(0,2 h) in responders (33+/-18 ng ml(-1) and 12+/-6 ng ml(-1) h) were also significantly higher than the Cmax and AUC(0,2 h) in nonresponders (13+/-9 ng ml(-1); P=0.048 and 5+/-3 ng ml(-1) h; P=0.03). CONCLUSIONS: Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.

No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized, double-blind, placebo-controlled clinical trials.

CP-122,288 is a highly potent inhibitor of neurogenic plasma extravasation in animal models at doses without vasoconstrictor effect. We evaluated the acute antimigraine efficacy of intravenous and oral CP-122,288 in two double-blind studies. In a crossover design, patients randomly received 31.25 microg of CP-122,288 intravenously, placebo, or both. In the oral study, patients received placebo or one of four doses of CP-122,288 between 3.125 and 312.5 microg, using a novel "up and down" design for randomization. Both studies were stopped prematurely when target efficacy could not be achieved. Responder rates were 29% for CP-122,288 versus 30% for placebo (difference, -1%; 95% CI, -24-22%; intravenous study) and an overall rate of 25% for CP-122,288 versus 0% for placebo (difference, 25%; 95% CI; 10-40%; oral study). CP-122,288 was not clinically effective at doses and plasma concentrations in excess of those required to inhibit neurogenic plasma extravasation in animals. Neurogenic plasma extravasation is unlikely to play a crucial role in the pathophysiology of migraine headache.

Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial.

BACKGROUND: Triptans (5-HT(1B/1D) receptor agonists) are effective drugs for acute migraine, but the side-effect of coronary vasoconstriction restricts their use in patients who are at risk of coronary artery disease. We have studied the efficacy of LY334370, a selective serotonin 1F (5-HT(1F)) receptor agonist with preclinical efficacy and no vasoconstriction, for migraine relief. METHODS: We gave LY334370 (20, 60, or 200 mg) or placebo to 99 outpatients with moderate or severe migraine headaches in a double blind, parallel group study. We measured efficacy by sustained response, response at 2 h, pain free at 2 h, and sustained pain free. FINDINGS: The proportions of patients with defined endpoints for placebo and LY334370 20, 60, and 200 mg, respectively, were: sustained response, two of 26 (8%), three of 22 (14%), 11 of 30 (37%), and 11 of 21 (52%) (dose response p<0.001); response, five of 26 (19%), four of 22 (18%), 15 of 30 (50%), and 15 of 21 (71%) (p<0.001); pain free, one of 26 (4%), none of 22, eight of 30 (27%), and eight of 21 (38%) (p=0.001); sustained pain free, one of 26 (4%), none of 22, seven of 30 (23%), and seven of 21 (33%) (p=0.002); recurrence rates, one of five (20%), none of four, four of 15 (27%), and three of 15 (20%). More patients given LY334370 than placebo reported asthenia, somnolence, and dizziness. INTERPRETATION: Our findings show that LY334370 is effective in treatment of acute migraine through selective trigeminovascular neuronal inhibition.

The influence of ergotamine abuse on psychological and cognitive functioning.

Migraine patients abusing ergotamine often have chronic daily headaches associated with tiredness, sleep and memory disturbances, and reduced general well-being. We quantified psychological and cognitive functioning in 12 migraine patients with and 12 without ergotamine abuse (> or = 5 days/week for > or = 6 months) and 12 healthy controls. Psychological functioning assessed by Symptom Checklist-90 (SCL-90) and Profile Of Mood State (POMS), was impaired in ergotamine abusers compared to healthy controls. Cognitive functioning divided into four domains: attention (critical flicker frequency analysis and mental control subscale of the Wechsler Memory Scale (WMS), speed of information processing (reaction time tasks and lexical decision tasks), memory (four subscales of the WMS) and cognitive flexibility (trailmaking test and WMS digits backwards), was impaired in ergotamine abusers in speed of information processing and cognitive flexibility. These differences disappeared after correction for total SCL-90 scores. In conclusion, ergotamine abuse is associated with high psychological distress but not with structural impaired cognitive functioning.

Auditory evoked potentials in the assessment of central nervous system effects of antimigraine drugs.

Because the "intensity dependence" of cortical auditory evoked potentials (IDAP) is under serotonergic control, it can be used to assess central antimigraine effects of 5HT1B/1D agonists. We measured IDAP before and 2 h after naratriptan (5 mg, n = 19) and zolmitriptan (5 mg, n = 19) in healthy volunteers. IDAP was expressed as the amplitude-stimulus intensity function ("ASF slope"). Naratriptan tended to increase ASF slope (mean difference 0.23 +/- 0.62 microV/10 dB, p = 0.06) while zolmitriptan (0.08 +/- 0.95 microV/10 dB, p = 0.35) did not. We assessed the suitability of IDAP for measuring central antimigraine drug effects using repeatability data (see companion paper). We calculated the trade-off between the size of the expected drug effects (ASF slope difference) and the necessary sample size. Because of poor repeatability 36 to 80 subjects are required to detect ASF slope changes in the 0.25-0.5 microV/10 dB range. These data can be used to design trials using IDAP.