Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial

(Headache 2011;51:73‐84) Objective.— To evaluate the long‐term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.— Telcagepant is a calcitonin gene‐related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine. Methods.— Migraine patients were randomized 2:1 to double‐blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2‐24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with ≥1 triptan‐related adverse events in the 14‐day period post dose. Results.— Of 1068 patients randomized, 641 (90%) patients treated ≥1 attack with telcagepant and 313 (88%) treated ≥1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan‐related adverse events (difference: ?6.2%; 95% CI ?10.4, ?2.6; P < .001) and drug‐related adverse events (difference: ?15.6%; 95% CI ?22.2, ?9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence >5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%). Conclusions.— Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan‐related and drug‐related adverse events favored telcagepant over rizatriptan.     

运动平板试验Duke评分对胸痛患者预后价值的研究

目的评价平板运动试验Duke评分(DTS)对胸痛患者预后判定的临床价值。方法选择169例运动试验阳性和可疑阳性同时行冠状动脉造影的患者为研究对象,按Duke评分分为DTS低危组(Duke≥5分,n=35)、中危组(DTS-10～+4分,n=77)和DTS高危组(DTS≤-11分,n=57),比较3组患者冠状动脉病变和临床特点,进行2年的随访,比较3组发生主要不良心血管事件(MACE),并根据是否发生MACE分为2组,分析DTS预测MACE的价值。结果胸痛患者有随访资料的169例,失访9例,失访率5.33%,160例完成随访。MACE主要发生在随访1个月,在DTS高危组和中危组中发生MACE明显高于DTS低危组(P<0.05),在DTS低危组随访1个月内无MACE发生;MACE组中的运动参数,静息心率、DTS、ST段偏移值和运动最大心率时ST改变涉及导联数目明显高于无MACE组(P<0.05)。而MACE组中运动持续时间和运动最大心率明显低于无MACE组(P<0.05);DTS与冠状动脉病变的严重程度相关,冠状动脉造影结果显示MACE组冠状动脉造影Gensini积分显著高于无MACE组;Logistic多因素回归分析显示,DTS与心血管事件发生风险有关(OR=1.397,95%CI:1.262～1.546)(Waldχ2=41.5781,P<0.0001)。结论运动试验DTS与冠状动脉病变狭窄程度高度相关;DTS中高危组发生MACE明显高于低危组,应用该评分可以有效的对临床中胸痛患者进行危险分层及预后的判定,对于DTS高危组的患者应迅速进行评估并考虑早期行再灌注治疗。     

Comparison of carvedilol and atenolol efficacy in patients with stable effort angina

AIM: To compare effectiveness of carvedilol--beta-adrenoblocker with vasodilating action--with atenolol which is beta-adrenoblocker having no vasodilating activity in coronary heart disease (CHD) patients with stable effort angina. MATERIAL AND METHODS: The trial entered 28 CHD patients with a history of myocardial infarction (MI). All the patients had no contraindications to beta-adrenoblockers, had positive exercise tolerance test. After the control period of 7-10 days the patients received either carvedilol (14 patients) or atenolol (14 patients) in a mean daily dose 20.5 mg (6.25 to 50 mg) and 25.9 mg (12.5 to 100 mg), respectively, twice a day. The course of the treatment took 4 weeks. The effect was evaluated at treadmill exercise test. RESULTS: Both drugs diminished heart rate, carvedilol was less effective in this respect. Both drugs significantly prolonged time of exercise to the anginal attack and ST depression by 1.0 mm. Side effects arose in 6 and 4 patients, respectively. CONCLUSION: Carvedilol and atenolol are equally effective in the treatment of stable effort angina.     

Excellent tolerability but relatively low initial clinical efficacy of telcagepant in migraine

In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. Telcagepant, thus, has excellent tolerability in migraine. Only a quarter (26%) (334/1307) of patients were, however, pain free after 2 hours, while 56% (729/1297) of patients had pain relief at 2 hours. Telcagepant 300 mg in one randomized clinical trial was equipotent to zolmitriptan 5 mg. Based on results from a meta-analysis, rizatriptan 10 mg (41%) and almotriptan (35%) seem superior to telcagepant (26%) for pain free at 2 hours whereas rizatriptan 10 mg (25%) showed no difference from telcagepant 300 mg (19 %) for sustained pain free (2-24 hours). The introduction of calcitonin gene-related peptide receptor antagonism in the acute treatment of migraine is a major step forward but so far mostly because of its specific mode of action and excellent tolerability.     

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease

Objective.— To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. Background.— Calcitonin gene‐related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. Methods.— Randomized, double‐blind, two‐period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280‐mg tablet/300‐mg capsule), Period 2: acetaminophen (1000‐mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2‐hour pain freedom during the first attack of Period 1. Results.— One hundred and sixty‐five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2‐hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. Conclusion.— The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.     

Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81–92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT_1B/1D receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients.     

Trapidil is as effective as isosorbidedinitrate for treating stable angina pectoris—

OBJECTIVE: Nitrates have long been used in the treatment of stable angina pectoris. We set out to show that trapidil, a triazolo-pyrimidine with a mode of action different from that of nitrates, is not inferior to isosorbide-dinitrate (ISDN) in the treatment of this clinical syndrome. PATIENTS AND METHODS: We studied the efficacy of 200 mg trapidil (t.i.d.) vs. ISDN (20 mg b.i.d.) in patients with chronic stable angina treated for 12 weeks. The therapeutic effect was measured in terms of responder rate as change in total exercise time (TET) by at least 60 seconds using the bicycle ergometer test. RESULTS: A total of 648 patients were included in the study. Responder rates in the Per- Protocol (PP) population (n = 529) were 50.4% (n = 133) in the trapidil group and 52.5% (n = 139) in the ISDN group (p = 0.233). As the lower non-inferiority limit (-15%) was clearly excluded from the 95% CI (pp: -10.6%, +6.4%; ITT -9.7%, 5.7%), non-inferiority of trapidil compared to ISDN can be concluded. Trapidil 200 mg t.i.d. combined with short-acting NTG prn as rescue medication over 12 weeks in subjects with chronic stable angina pectoris proved to have similar effects on TET and on other clinical endpoints as ISDN 20 mg b.i.d. The secondary efficacy analyses did not reveal any clinically relevant differences between treatment groups, and were not in conflict with the non-inferiority claim. Patients in the ISDN group had significantly more headache (34.1%; n = 110) compared to those taking trapidil (19.3%, n = 62; p <0.0001). CONCLUSIONS: Overall results of this study show that both drugs are equally effective and safe for the short-term treatment of patients with chronic stable angina pectoris and that trapidil can be considered as therapeutically equivalent to ISDN.     

Comparison of the effectiveness of slow-release propranolol (Inderal LA) 80, 160 and 320 mg orally daily in the treatment of angina pectoris

Doses of 80, 160 and 320 mg of Inderal LA (slow-release propranolol) were compared in 12 patients with stable angina pectoris. There was an unpredictable and variable individual response to treatment and hence no differences were detected between the effects of the three doses on mean treadmill exercise duration, time to angina, frequency of angina or glyceryl/trinitrate consumption. There was a marked deterioration in two patients whilst on 320 mg Inderal LA. In these patients, the time to angina fell by 2 minutes 50 seconds and 4 minutes 20 seconds on 320 mg daily and 160 mg daily respectively. Given the inter-patient variability in response to Inderal LA, the dose for each patient should be individually titrated according to response. Two patients reported here suggest that some subjects may benefit from lower doses, although further work is required to clarify this point. Possible explanations for this finding are discussed.     

Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study

(Headache 2011;51:954‐960) Objective.— The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. Background.— Triptans are effective acute anti‐migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene‐related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene‐related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. Methods.— In this randomized, double‐blind, placebo‐controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300 mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12‐lead ambulatory electrocardiographic (Holter) monitoring was performed. Results.— Twenty‐eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment‐related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. Conclusions.— Two doses of 300‐mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.     

Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism?

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the perception of exercise-induced fatigue. Sumatriptan is a selective 5-HT(1B/D) receptor agonist which does not cross the blood-brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 28.4+/-10.8 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively; 95% confidence interval (CI) of difference 12.1 s, 59.1 s; P = 0.008]. There was no significant effect on peak oxygen consumption (placebo, 50.6+/-6.3 ml.min(-1).kg(-1); sumatriptan, 51.7+/-7.6 ml.min(-1).kg(-1)). Sumatriptan administration resulted in decreases in both heart rate (sumatriptan, 188+/-14 beats/min, placebo, 196+/-12 beats/min; 95% CI of difference 12.6, 2.6; P = 0.008) and respiratory exchange ratio (sumatriptan, 1.23+/-0.06; placebo, 1.26+/-0.07; 95% CI of difference 0.05, 0.01; P = 0.01) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation.     

平板运动试验与冠状动脉造影对冠心病危险分层的意义

目的评估平板运动试验在心肌缺血诊断、危险分层方面的价值和意义。方法对均进行平板运动试验及冠状动脉造影两项检查的52例患者进行观察和分析,对平板试验阳性者28例、平板试验阴性者24例与各自的冠状动脉造影对比,评判平板运动试验对胸痛、胸闷等不同症状患者心肌缺血程度初步估测,进行危险评估。结果活动平板运动试验检测心肌缺血的灵敏度为96%,特异性88%,预测阳性值为89%,ST段的下移形态、程度及导联数是评估的重要指标。对冠状动脉造影中血管狭窄85%以上、平板运动试验阳性的18例中的8例(强阳性)行PTCA术,其余10例用药物治疗,疗效满意。结论活动平板运动试验对缺血性心脏病的诊断价值是可以肯定的,对冠心病进行危险分层及选择治疗、评估预后有重要意义。     

Randomized controlled study of telcagepant plus Ibuprofen or acetaminophen in migraine

(Headache 2011;51:533‐543) Objective.— To evaluate the efficacy and tolerability of telcagepant when co‐administered with ibuprofen or acetaminophen for the acute treatment of migraine. Background.— Telcagepant is an oral calcitonin gene‐related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. Methods.— Randomized, double‐blind, placebo‐controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N = 170), or placebo (N = 171). The primary efficacy endpoint was 2‐hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. Results.— The percentages of patients with 2‐hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. Conclusions.— The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).     

心脏变时性功能不全对冠心病的诊断价值研究

摘要： 目的 探讨心脏变时性功能不全（chronotropic incompetence，CI）对冠心病的诊断价值。方法 对349例经平板运动试验(treadmill exercise testing， TET)和冠状动脉造影（coronary angiography，CAG）检查的患者的结果进行分析，比较TET中CI与传统标准对诊断冠心病的敏感性、特异性和准确性。结果 与传统标准相比，CI诊断冠心病的敏感性、特异性和准确性无明显差别（Ｐ＞0.05），在传统标准阳性的基础上，CI诊断冠心病的特异性（88.5％）和准确性（81.9％）有显著提高（Ｐ＜0.05）。结论 运动试验中CI是诊断冠心病的一个可靠指标，与传统标准相结合可提高TET对冠心病的诊断价值。     

Plasma verapamil levels and exercise performance

Our study in 10 patients with stable, exercise-related angina under a double-blind, placebo-controlled protocol correlated plasma verapamil levels after single oral doses of 120 and 240 mg and exercise performance. Plasma verapamil levels peaked at 2 hr in seven patients and 4 hr in three patients and declined thereafter, with a mean plasma t1/2 of 3.22 and 4.54 hr after the 120- and 240-mg dose. Despite the relatively short t1/2s, total exercise duration and time to onset of angina and S-T segment depression were longer than placebo values for 4 hr after the 120-mg dose and for 8 hr after the 240-mg dose. Percentage increase in treadmill time and log of plasma verapamil levels correlated. All patients with plasma levels above 100 ng/ml had at least a 50% increase in exercise duration. Thus measurement of plasma verapamil levels are useful in patients who fail to respond to a dose of verapamil. If the level is below 100 ng/ml, increasing the dose of verapamil may improve response.     

平板运动试验在诊断女性冠状动脉疾病中的临床意义

目的：评价平板运动试验(treadmill exercise testing，TET)在诊断女性冠状动脉疾病(coronary artery disease，CAD)中的应用价值。方法：回顾性分析1995年3月-2002年11月在本院作冠状动脉造影(coronary arteriography,CAG)并同时行TET检查的104例女性患的临床资料。TET检查采用日本国立心血管疾病中心(NCVC)制定的方案，评价指标包括ST段压低程度、运动后3min收缩期血压(SBP)与运动高峰时SBP比值[SBP比(3’)]和是否发生心绞痛(angina pectoris，AP)。结果：单用ST段压低作为诊断指标，其灵敏度为98．2％，特异度为4．2％；ST段压低结合SBP比(3’)时，其灵敏度为83．9％，特异度为89．6％；ST段压低结合AP作为诊断指标，其灵敏度为89．3％．特异度为95．8％。结论：ST段压低与SBP比(3')及AP的综合评估可提高TET对女性CAD的临床诊断的准确性。     

Inhibition of PKC beta by ruboxistaurin does not enhance the acute blood pressure response to nitroglycerin

Ruboxistaurin is a selective protein kinase C beta inhibitor undergoing clinical investigation for treatment of diabetic microvascular complications. This study assessed a possible blood pressure (BP) interaction between ruboxistaurin and the exogenous nitric oxide donor, glyceryl trinitrate (GTN). Subjects (N=22) with chronic stable angina received placebo or ruboxistaurin 96 mg/day orally to steady state in a crossover design. Graded GTN (0, 5, 10, 20, 40, 80, and 120 microg/min) or 5% dextrose solution was then infused intravenously and BP was measured following each dose. Ruboxistaurin did not alter the slope of change in standing systolic BP (DeltasSBP/1n[GTN dose]) curve (P=0.272 analysis of covariance) or affect the DeltasSBP at the estimated GTN dose producing a 10-mm Hg reduction in sSBP from baseline on placebo (mean difference -0.9 mm Hg; 95% confidence of interval, -3.3-1.5). In conclusion, ruboxistaurin does not potentiate the acute BP-lowering effects of GTN.     

运动心肺功能在冠心病PTCA术后康复评定中的应用

对１５例心肌梗塞和心绞痛病人经皮冠状动脉成形术（ＰＴＣＡ）术后测定运动心肺功能。采用麦加菲心肺运动仪测定气体代谢指标，如摄氧量（ＶＯ２）、二氧化碳排出量（ＶＣＯ２）、肺通气量（ＶＥ）、呼吸交换率（ＲＥＲ）、无氧阈值（ＡＴ）、氧脉搏（ＶＯ２／ＨＲ）等。根据病变程度和体能分为平板组（ＴＥＴ）和功率自行车组（ＥＥＴ）。１５例病人当运动强度增加时摄氧量（ＶＯ２）缓慢上升，达到较低的峰值ＶＯ２，尤其ＥＥＴ且     

Acute and chronic effects of once-daily isosorbide-5-mononitrate on the exercise capacity of patients with angina pectoris treated with a beta-blocking drug.

Forty-four patients with stable effort angina pectoris were included in a double-blind, randomised, placebo-controlled, parallel group study to compare the effect of two slow-release forms of isosorbide-5-mononitrate ('Ismo-Retard' 40 mg and 'Imdur' 60 mg) on exercise capacity when given as an adjunctive treatment to beta adrenoreceptor blocking therapy. In a symptom-limited exercise test performed three hours after the first dose, Ismo-retard increased the total duration of exercise by 92 seconds (confidence interval (CI) 5.1-116.9) p less than 0.006, and the time of onset to anginal pain by 117 seconds (CI 27.8, 156.1) p less than 0.004. A similar improvement in total duration of exercise (by 87 seconds) was noted three hours following 15 consecutive once-daily doses (CI 16.8-128) p less than 0.02, and in the time of onset to anginal pain by 101 seconds (CI 19.8-139.6) p less than 0.01. For Imdur the corresponding results were 53 seconds (CI 12.7-56.3), 84 seconds (CI 15.4-103.7), p less than .02, 54 seconds (CI 1.4-78.4) and 85 seconds (CI 6.9-120.5) respectively. These results would suggest that both active treatments were effective anti-anginal agents.     

Antimigraine efficacy of telcagepant based on patient's historical triptan response

(Headache 2011;51:64‐72) Objective.— To evaluate whether the same or different patients respond to triptans and telcagepant. Background.— Telcagepant is an oral calcitonin gene‐related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans. It is currently unknown whether migraine patients who cannot be adequately helped with triptans might benefit from treatment with telcagepant. Methods.— Post‐hoc analysis of data from a randomized, controlled trial of telcagepant (150 mg, 300 mg) zolmitriptan 5 mg, or placebo for a moderate/severe migraine. Responder rates were analyzed according to patients' self‐reported historical triptan response (HTR): (1) good HTR (N = 660): response in 75‐100% of attacks; (2) intermediate HTR (N = 248): response in 25‐74% of attacks; (3) poor HTR/no use (N = 407): response in <25% of attacks, or patient did not take triptans. A limitation of the analysis is that the last subgroup comprised mainly (91%) patients who reported that they did not take triptans, but it was not known whether these patients were triptan‐naïve or had previously used triptans and stopped taking them. Results.— For zolmitriptan, 2‐hour pain relief rates were higher in the good HTR subgroup (116/162, 72%) than in the intermediate (29/62, 47%) and poor/no use (44/111, 40%) HTR subgroups. The 2‐hour pain relief rates were similar across HTR subgroups for telcagepant 150 mg (48‐58%), 300 mg (52‐58%), and placebo (26‐31%). In the poor/no use HTR subgroup, more patients receiving telcagepant 300 mg (56/98, 57.1%) had 2‐hour pain relief than those receiving zolmitriptan (44/111, 39.6%; odds ratio = 2.11 [95% CI: 1.20,3.71], P = .009); the percentage for telcagepant 150 mg (57/119, 47.9%) was not significantly different from zolmitriptan (odds ratio = 1.41 [95% CI: 0.82, 2.40], P = .211). Conclusions.— This suggests that different patients may respond to triptans or telcagepant 300 mg. Caution should be exercised in interpreting the results because of the post‐hoc nature of the analysis (clinical trial registry: NCT00442936).     

Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.