Long-term efficacy and tolerability of rizatriptan wafers in migraine. (41/414)

CONTEXT: Rizatriptan is a selective 5-HT1B/1D receptor agonist for the acute treatment of migraine. It is available in a unique wafer formulation that dissolves rapidly in the mouth and can be taken without liquids, thereby offering patients a very convenient way to take treatment. OBJECTIVE: To investigate the long-term efficacy of rizatriptan 10-mg and 5-mg wafers in migraineurs. SETTING: 19 headache clinics in 5 countries. PATIENTS: 458 patients diagnosed with migraine according to International Headache Society criteria. DESIGN: 6-month, open-label, extension, which followed a double-blind, placebo-controlled study. INTERVENTIONS: Patients were randomly assigned to 1 of 3 treatments for moderate or severe migraines: rizatriptan 10-mg wafer, rizatriptan 5-mg wafer, or "standard care" (usual migraine treatment -- eg, nonsteroidal anti-inflammatory drugs [NSAIDs], analgesics, other triptans). Patients randomized to rizatriptan were blinded to the dose. MAIN OUTCOME MEASURES: Headache severity (none, mild, moderate, severe) and adverse events were recorded on a diary card. RESULTS: 181 patients treated 3393 attacks with rizatriptan 10-mg wafer, 191 treated 3254 attacks with rizatriptan 5-mg wafer, and 86 treated 1582 attacks with standard care. The median number of treated attacks per patient was 16 for rizatriptan 10-mg wafer, 13 for rizatriptan 5-mg wafer, and 14 for standard care. The median patient on rizatriptan 10-mg wafer reported pain relief at 2 hours (reduction of headache from moderate or severe at baseline to mild or none) in 82% of attacks, vs 73% of attacks for standard care (odds ratio [95% confidence interval] = 1.63 [1.14, 2.34], P <.01) and 72% of attacks for rizatriptan 5-mg wafer (OR [95% CI] = 1.60 [1.23, 2.08], P <.001). The median patient on rizatriptan 10-mg wafer was pain free at 2 hours in 46% of attacks, vs 30% of attacks for standard care (OR [95% CI] = 1.50 [1.06, 2.12], P <.05) and 25% of attacks for rizatriptan 5-mg wafer (OR [95% CI] = 1.93 [1.50, 2.49], P <.001). All treatments were generally well tolerated. Compared with standard care, rizatriptan 5-mg wafer was associated with fewer specific adverse events of asthenia/fatigue, back pain, nausea, pharyngeal discomfort, upper respiratory infection, and vomiting (P values <.05), and, compared with rizatriptan 10-mg wafer, fewer overall drug-related adverse events (P <.05). CONCLUSIONS: Rizatriptan 10-mg wafer was more effective than standard care and rizatriptan 5-mg wafer for treating intermittent moderate or severe migraine attacks occurring over periods of up to 6 months. Rizatriptan wafers were well tolerated.  (+info)

The involvement of two p450 enzymes, CYP83B1 and CYP83A1, in auxin homeostasis and glucosinolate biosynthesis. (42/414)

The first committed step in the biosynthesis of indole glucosinolates is the conversion of indole-3-acetaldoxime into an indole-3-S-alkyl-thiohydroximate. The initial step in this conversion is catalyzed by CYP83B1 in Arabidopsis (S. Bak, F.E. Tax, K.A. Feldmann, D.A. Galbraith, R. Feyereisen [2001] Plant Cell 13: 101-111). The knockout mutant of the CYP83B1 gene (rnt1-1) shows a strong auxin excess phenotype and are allelic to sur-2. CYP83A1 is the closest relative to CYP83B1 and shares 63% amino acid sequence identity. Although expression of CYP83A1 under control of its endogenous promoter in the rnt1-1 background does not prevent the auxin excess and indole glucosinolate deficit phenotype caused by the lack of the CYP83B1 gene, ectopic overexpression of CYP83A1 using a 35S promoter rescues the rnt1-1 phenotype. CYP83A1 and CYP83B1 heterologously expressed in yeast (Saccharomyces cerevisiae) cells show marked differences in their substrate specificity. Both enzymes convert indole-3-acetaldoxime to a thiohydroximate adduct in the presence of NADPH and a nucleophilic thiol donor. However, indole-3-acetaldoxime has a 50-fold higher affinity toward CYP83B1 than toward CYP83A1. Both enzymes also metabolize the phenylalanine- and tyrosine-derived aldoximes. Enzyme kinetic comparisons of CYP83A1 and CYP83B1 show that indole-3-acetaldoxime is the physiological substrate for CYP83B1 but not for CYP83A1. Instead, CYP83A1 catalyzes the initial conversion of aldoximes to thiohydroximates in the synthesis of glucosinolates not derived from tryptophan. The two closely related CYP83 subfamily members therefore are not redundant. The presence of putative auxin responsive cis-acting elements in the CYP83B1 promoter but not in the CYP83A1 promoter supports the suggestion that CYP83B1 has evolved to selectively metabolize a tryptophan-derived aldoxime intermediate shared with the pathway of auxin biosynthesis in Arabidopsis.  (+info)

Characterization of the receptors involved in the 5-HT-induced excitation of canine antral longitudinal muscle. (43/414)

1. We aimed to characterize the 5-HT receptors involved in the 5-HT-induced effect on electrically induced contractions of dog antrum longitudinal muscle in vitro. 2. In the presence of L-NOARG (0.1 mM), electrical field stimulation (EFS) induced atropine- and tetrodotoxin-sensitive contractions. Tetrodotoxin or atropine left any agonist tested ineffective. These EFS-induced contractions were on average enhanced by 5-HT (0.3 microM), however, pronounced variation in the response to 5-HT was observed. There were non-significant trends of the selective 5-HT3 receptor antagonist granisetron (1 microM), and methysergide (1 microM; preventing interactions of 5-HT with 5-HT1, 5-HT2, 5-ht5, 5-HT6 and 5-HT7 receptors) to increase the response to 5-HT. The selective 5-HT4 receptor antagonist GR 113808 (0.1 microM) displayed a non-significant trend to inhibit the 5-HT-induced increase. 3. Combination experiments with methysergide (1 microM), granisetron (1 microM) and GR 113808 (0.1 microM) revealed that the 5-HT (0.3 microM)-induced response consisted of (1) an excitatory component blocked by GR 113808, (2) excitatory and inhibitory components both blocked by methysergide. 4. The selective 5-HT4 receptor agonist prucalopride (0.3 microM) increased EFS-induced contractions, an effect prevented by GR 113808 (0.1 microM). 5. The increase of EFS-induced contractions by the preferential 5-HT2 receptor agonist alpha-Me-5-HT (0.3 microM) was antagonized by 5-HT2B receptor antagonists. 6. The 5-HT1/5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT; 0.3 microM) inhibited EFS-induced contractions. This was prevented by methysergide (1 microM), the 5-HT7 receptor antagonist mesulergine (0.3 microM) and the selective 5-HT7 receptor antagonist SB-269970 (0.3 microM). 7. In the presence of GR 113808 (0.1 microM), alpha-Me-5-HT (1 microM) increased EFS-induced contractions. The 5-HT (0.3 microM)-induced inhibition of the stimulation by alpha-Me-5-HT was prevented by SB-269970 (0.3 microM). 8. In conclusion, dog antral longitudinal muscle is endowed with (1) excitatory neuronal 5-HT4 receptors and 5-HT2B receptors and (2) inhibitory smooth muscle 5-HT7 receptors.  (+info)

Effects of microinjection of melatonin and its receptor antagonists into anterior hypothalamic area on blood pressure and heart rate in rats. (44/414)

AIM: To examine the effects of microinjection of melatonin and its receptor antagonists into the anterior hypothalamic area (AHA) on blood pressure (BP) and heart rate (HR) in normotensive and stress-induced hypertensive rats. METHODS: Melatonin and its receptor antagonists were microinjected into the AHA, then BP, mean arterial pressure (MAP), and HR were synchronously recorded. RESULTS: Microinjection of melatonin produced a fall in MAP. Prazosin, an antagonist of melatonin ML2 receptor, could not antagonize the depressive response induced by melatonin. While luzindole, a competitive antagonist of melatonin ML1 receptor, was able to almost completely prevented the depressive response induced by injection of melatonin. CONCLUSION: Melatonin acts as a hypotensive factor and the effects are mainly due to activation of ML1 receptors in rat brain, and the AHA may be one of the important central areas where melatonin can exert modulatory effects on BP and HR.  (+info)

Cost savings in migraine associated with less chest pain on new triptan therapy. (45/414)

OBJECTIVES: This article constructs an economic model to estimate cost of chest-pain-related care in migraine patients receiving almotriptan 12.5 mg compared with those receiving sumatriptan 50 mg. STUDY DESIGN: This population-based, retrospective cohort study used data from the MEDSTAT Marketscan database (Ann Arbor, Michigan) to quantify incidence and costs of chest-pain-related diagnoses and procedures. After a 6-month exclusion period, the study used a pre-post design, with baseline and treatment periods defined, respectively, as 5 months before and after receiving sumatriptan therapy. An economic model was constructed to estimate annual cost savings per 1,000 patients receiving almotriptan instead of sumatriptan as a function of differing rates of chest pain. Annual direct medical cost avoided was calculated for a hypothetical health plan covering 1 million lives. RESULTS: Among a cohort of 1,390 patients, the incidence of chest-pain-related diagnoses increased significantly (43.6%) with sumatriptan, from 110 during the baseline period to 158 during the treatment period (P= .003). Aggregate costs for chest-pain-related diagnoses and procedures increased 33.1%, from $22,713 to $30,234. Payments for inpatient hospital services rose 10-fold; costs for primary care visits and outpatient hospital visits rose 53.1% and 14.4%, respectively. Payments for angiography increased from $0 to $462, and costs for chest radiographs and electrocardiograms increased 58.7% and 31.2%, respectively. Sumatriptan treatment was associated with a 3-fold increase in payments for services for painful respiration and other chest pain. The model predicted $11,215 in direct medical cost savings annually per 1000 patients treated with almotriptan instead of sumatriptan. Annual direct medical costs avoided for the health plan totaled $195,913. CONCLUSION: Using almotriptan instead of sumatriptan will likely reduce the cost of chest-pain-related care for patients with migraine headaches.  (+info)

Almotriptan: a review of pharmacology, clinical efficacy, and tolerability. (46/414)

OBJECTIVE: This article summarizes preclinical and clinical data for almotriptan. METHODS: Almotriptan has been evaluated in more than 3,500 acute migraine patients in phase 2 and 3 double-blind, randomized trials and in 1,500 patients in long-term open-label trials. RESULTS: Controlled clinical trials show that almotriptan 12.5 mg is significantly more effective than placebo. These results are observed across different endpoints examined, including pain relief at 2 hours, pain-free outcome at 2 hours, recurrence rate, use of escape medication, and sustained pain-free outcome. The onset of pain relief is observed as early as 30 minutes after administration. Results from a multiple-attack study show that almotriptan maintains a consistency of response across 3 attacks, and results from long-term studies confirm that patients continue to respond to almotriptan for up to 1 year. Results from 2 comparative studies show that almotriptan 12.5 mg has comparable efficacy to sumatriptan 50 or 100 mg, but almotriptan has a superior tolerability profile. Early use of almotriptan results in a higher proportion of patients achieving pain relief or complete freedom from pain. CONCLUSIONS: Because almotriptan has a tolerability profile comparable to that of placebo, it may be more acceptable for early administration. The incidence of treatment-related adverse events with almotriptan is comparable to that of placebo and significantly lower than recorded with sumatriptan. In addition, almotriptan has a low incidence of chest symptoms, an adverse event associated with triptan use. Because of its comparable efficacy and superior tolerability profile, almotriptan offers a potential improvement over existing triptans for the treatment of acute migraine.  (+info)

Health outcomes evaluations: estimating the impact of almotriptan in managed care settings. (47/414)

OBJECTIVE: Almotriptan, a new treatment for acute migraine attacks, may improve health outcomes while reducing expenditures on drug costs and the costs associated with unwanted adverse events. This article describes the clinical, humanistic, and economic data available for almotriptan and compares these data with published data for sumatriptan, which is considered the gold standard comparator for triptans. PATIENTS AND METHODS: Clinical trial data and published materials describing the pharmacoeconomics of sumatriptan were reviewed. RESULTS: Formulary and prescribing decision makers consider clinical, humanistic, and economic dimensions when evaluating migraine treatments. Within those dimensions, critical elements to consider include efficacy, tolerability, health-related quality of life, patient satisfaction, productivity, medication cost, and healthcare resource use. In direct comparisons, almotriptan has demonstrated efficacy, short-term health-related quality of life, and productivity results similar to sumatriptan 50 mg. Almotriptan also has an improved tolerability profile compared with sumatriptan, including a lower incidence of drug-related adverse events, a lower incidence of chest pain, and better patient satisfaction in terms of adverse events. CONCLUSIONS: Almotriptan and sumatriptan exhibit comparable efficacy for the treatment of acute migraine. The acquisition cost of almotriptan is lower than sumatriptan, and given its excellent tolerability profile, almotriptan may be preferred by patients for the treatment of migraine attacks.  (+info)

Almotriptan versus sumatriptan in migraine treatment: direct medical costs of managing adverse chest symptoms. (48/414)

OBJECTIVE: Triptans, a popular class of drugs for treatment of migraine headaches, can cause adverse events including chest symptoms. This study estimated the direct medical costs of managing chest symptoms in patients treated for acute migraine with almotriptan or sumatriptan using an economic model. METHODS: The economic model of this study combined data from a randomized clinical trial that compared almotriptan with sumatriptan and data from a practice pattern survey of physicians. The pertinent clinical evaluation period was the time immediately after administration of the first medication dose. The model was developed from the perspective of a managed care payer. RESULTS: The average direct medical cost of managing chest symptoms that appeared after the first dose of an oral triptan was $0.22 for patients treated with almotriptan and $1.64 for patients treated with sumatriptan, a difference of $1.42 per patient. CONCLUSION: Relative to sumatriptan, treatment with almotriptan is likely to reduce patient care costs associated with chest symptom adverse events.  (+info)