Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Migraine is a chronic neurological disorder, characterized by attacks of severe, usually unilateral and throbbing headache accompanied by nausea, vomiting, and photophobia and photophobia. Sometimes transient neurological (aura) symptoms may precede or accompany the headaches. Acute drug therapy comprises nonspecific drugs, including simple analgesics and non-steroidal anti-inflammatory drugs, often in combination with antiemetics, and specific antimigraine drugs, such as ergotamine, dihydroergotamine and sumatriptan. Sumatriptan is a potent and selective serotonin1D receptor agonist, which can be administered orally and via the subcutaneous or intranasal route. The drug is well tolerated and is consistently highly effective in most patients. Significant limitations, however, include the occurrence of chest symptoms, suggestive of cardiac ischaemia; recurrence of the headache within 24 h after initial successful treatment; and in a minority of patients, abuse of sumatriptan with daily 'sumatriptan-dependent headaches'. Administration during the aura phase does not affect the aura itself, but is not recommended because the subsequent headache will not be prevented in that case. Preliminary data of new serotonin1D receptor agonists, such as 311C90 and MK-462 are promising in terms of increased efficacy after oral administration, but side-effect profile and incidence of headache recurrence are similar to those observed after the use of sumatriptan. Intranasal administration of dihydroergotamine may also be effective, but data are very limited.
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PMID:Acute treatment of migraine attacks. 755 Nov 26

Migraine headache involves the activation of trigeminal afferents that are predominantly found in the first or ophthalmic division of the nerve. The headache is often pounding and the connections of the trigeminal nerve, the trigeminovascular system, have therefore been implicated in the pathophysiology of migraine and studied extensively. Considerable attention has been given to the peripheral ramifications of the system as a possible locus of action for anti-migraine drugs while little attention has been focused upon possible central sites of action. It has been shown that certain peptides can act as markers for the trigeminal system, in particular calcitonin gene-related peptide (CGRP), and that CGRP is elevated in migraine. We have employed an animal model for activation of the trigeminovascular system to evaluate a new antimigraine compound, 311C90, that may have central and as well as peripheral trigeminal actions. Cats were anesthetized by halothane induction and alpha-chloralose maintenance (60 mg/kg, intraperitoneal), intubated, paralyzed and ventilated. Biparietal craniotomies were carried out to measure cerebral blood flow using laser Doppler flowmetry (CBFLDF). The external jugular vein was cannulated and blood drawn, centrifuged and frozen until processing. Stimulation of the trigeminal ganglion resulted in a mean maximum increase in CBFLDF of 39 +/- 5% at 20/s. The 5HT1 agonist 311C90 was administered intravenously in two doses (30 and 100 micrograms/kg) to cover the range of doses likely to be effective clinically. At each dose the CBFLDF effect of trigeminal ganglion stimulation was inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
Headache
PMID:Joint 1994 Wolff Award Presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. 792 23

Migraine is an episodic headache disorder that occurs with or without aura and is often accompanied by other symptoms. Treatment must address these associated symptoms as well as the headache, and it can involve either acute or preventive therapy alone or a combination of both. Acute therapy treats the individual attack; preventive therapy aims to reduce the frequency and severity of attacks. Drug choice requires careful consideration and depends on the character of the migraine attack. Acute drug therapy using sumatriptan, MK-462, 311C90, dihydroergotamine, nonsteroidal anti-inflammatory drugs, butorphanol, metoclopramide, and domperidone is discussed. Prophylactic drug therapy using valproate and fluoxetine is also discussed.
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PMID:Treatment of the migraine attack. 808 20

311C90 is a novel, centrally and peripherally, acting 5-hydroxytryptamine1D receptor agonist. We investigated the efficacy and safety of 1, 5, and 25 mg of oral 311C90 in the acute treatment of migraine in a randomized, double-blind, placebo-controlled, parallel-group clinical trial involving 84 patients. The proportion of patients in whom the headache improved within 2 hours from moderate or severe to mild or no pain (primary efficacy measure) was 15% for placebo-treated patients and 27% (1 mg), 62% (5 mg), and 81% (25 mg) for patients treated with 311C90. Treatment differences compared with placebo were 12% (95% CI - 12, 37; p = 0.460) for 1 mg 311C90, 47% (CI 21, 73; p < 0.005) for 5 mg 311C90, and 66% (CI 43,89; p < 0.001) for 25 mg 311C90. Photophobia and nausea also showed improvement after 311C90. Adverse events were generally mild and transient in all treatment groups. There were no clinically significant changes in ECG recordings, blood pressure, or laboratory tests. Oral 311C90 (5 and 25 mg) is highly effective and well tolerated in the acute treatment of migraine. The response rates and treatment differences compared with placebo in this study suggest possible superiority over existing antimigraine therapies. This needs to be confirmed in formal comparative trials.
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PMID:311C90, a new central and peripherally acting 5-HT1D receptor agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range finding study. 861 25

Efficacy with currently marketed antimigraine compounds is less than optimal. 311C90 is a novel and selective 5-HT1D receptor agonist in development for the acute treatment of migraine. It shows evidence of both central and peripheral activity within the trigemino-vascular system and it is rapidly absorbed following oral administration. In clinical studies in migraine patients, a headache response at 2 hours has been observed in 65-81% of patients at doses above 1 mg. Favourable response rates are reported as early as 1 hour post-dose and efficacy rates continue to improve up to 4 hours. Headache recurrence is reported by 25-35% of patients and 311C90 is also effective in relieving the non-headache symptoms of migraine.
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PMID:The clinical effectiveness of 311C90 in the acute treatment of migraine. 879 Oct 25

The purpose of this pilot study was to determine whether 20 mg oral 311C90 can prevent the development of migraine headache when taken during the aura phase of a migraine attack. The study also aimed to provide an initial safety profile for 311C90 when taken during the aura. Forty patients (31 females, 9 males) were entered into this outpatient, double-blind, placebo-controlled, 2-period crossover trial. They all almost invariably experienced a migraine headache after the aura phase. Patients treated two migraine attacks during the aura phase in a random order, one with 311C90 20 mg and the other with placebo. Efficacy assessments were recorded on standard diary cards completed by each patient. A primary response was defined as the complete absence of headache pain in the 24 hour period following administration of the first dose of study medication. Safety assessments included ECGs, laboratory tests and the recording of adverse experiences. Twenty patients completed the study by treating 2 attacks, 16 of these were fully adherent to the study protocol. Three of the 16 patients responded to 311C90 whereas all patients developed a migraine headache after taking placebo. Two patients who did not respond to 311C90 described the developing headache as being "non-migraine'. Adverse experiences reported were similar to those experienced by patients in previous studies when 311C90 was taken during a migraine headache. There were no reports of 311C90-related adverse effects on the aura. These preliminary results suggest that oral 311C90 may be of value in preventing a migraine headache and is safe when taken during the aura phase. This intriguing possibility therefore warrants further investigation possibly utilising formulations that would deliver meaningful plasma levels of drug more rapidly.
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PMID:Can oral 311C90, a novel 5-HT1D agonist, prevent migraine headache when taken during an aura? 879 Oct 30

The oral absorption of a 10-mg oral dose of the novel 5-hydroxytryptamine (5HT1D) agonist, 311C90, was compared during a moderate or severe migraine headache and in a migraine-free period in an open, two-period study. The safety and efficacy of 311C90 in acute migraine were also assessed. Twenty patients attended the clinics during a moderate or severe migraine attack and 18 patients returned for a second dose in a migraine-free period. 311C90 was less rapidly absorbed during a migraine attack compared to the migraine-free period, consistent with gastric stasis during a migraine attach. The median area under the curve (AUC) was 15.7 ng/mlh lower during a migraine (median AUC: 18.4 ng/ml.h, range: 0-60.8 ng/ml.h) compared to the migraine-free period (median AUC: 33.4 ng/ml.h, range 9.4-79.5 ng/ml.h) (95% confidence interval: 6.9, 25.3) and the time to reach maximum plasma concentration was delayed (n = 18). Eleven out of 20 patients experienced a significant improvement in migraine headache intensity at 2 h post-dose. Plasma 311C90 concentrations were generally higher in those patients who responded to treatment with 311C90 in the plasma, but there was one patient with no quantifiable 311C90 in the plasma whose headache improved. Minor adverse experiences were reported in 11 out of 20 patients during a migraine attack and in 11 out of 18 patients outside an attack. They occurred shortly following drug administration and were of short duration, but their occurrence did not appear to be related to plasma 311C90 concentration. There were no clinically significant changes in blood pressure or 12-lead ECG during the assessment period.
Cephalalgia 1996 Jun
PMID:311C90 (Zolmitriptan), a novel centrally and peripheral acting oral 5-hydroxytryptamine-1D agonist: a comparison of its absorption during a migraine attack and in a migraine-free period. 879 40

311C90 (Zomig; zolmitriptan) is a novel, selective serotonin (5HT)1B/1D receptor agonist with both central and peripheral activity, now in late-stage clinical development for acute oral treatment of migraine. Several studies have demonstrated the tolerability and efficacy of 311C90 in the treatment of a single migraine headache. The objectives of this open-label study were to assess the tolerability and efficacy of repeated doses of 5 mg of 311C90 for acute treatment of multiple attacks for up to 1 year. Patients were allowed to treat as many migraine headaches (mild, moderate, or severe) as desired with an initial dose. A second 5-mg dose could be used to treat recurrence should it develop. Safety assessments included ECG, the frequency, intensity, and duration of adverse experiences, and routine hematology, urinalysis, and clinical chemistry parameters. Efficacy assessments included headache severity at 2 hours (i.e., severe, moderate, mild, or none), the proportion of patients pain-free at 2 hours, the use of a second tablet to treat headache recurrence if it developed, and the consistency of these findings over time. The efficacy profile and the nature/incidence of adverse events reported appear to be consistent with previous 311C90 studies. The dosing regimen was well tolerated during multiple exposures. Notably, headache response rates were consistently good after both initial and repeated exposure (> 80% across 1 to 30 attacks). For 67% of patients who treated at least five attacks, 311C90 was effective 80 to 100% of the time.
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PMID:311C90: long-term efficacy and tolerability profile for the acute treatment of migraine. International 311C90 Long-Term Study Group. 907 Dec 67

The trigeminovascular system consists of bipolar neurons which innervate pain-sensitive intracranial structures and projecting to neurons in the superficial laminae of the caudal trigeminal nucleus and of the dorsal horns of C1 and C2. The serotonin (5HT1B/D) agonist zolmitriptan (311C90) has been shown to be effective in the treatment of acute attacks of migraine and experimental data suggest that it may have both peripheral and central sites of action. This study sought to further investigate possible central effects of zolmitriptan (311C90) by examining its distribution in the central nervous system. Specific binding of [3H]-zolmitriptan was determined both ex vivo and in vitro in the cat brain. For the ex vivo studies, cats were anaesthetized with halothane and alpha-chloralose (60 mg/kg intraperitoneal). A femoral vein catheter was inserted for injection of the [3H]-zolmitriptan and then 1 h after injection the brain removed. For the in vitro studies fresh frozen brain slices were incubated with labelled and masking concentrations of zolmitriptan. The distribution of [3H]-zolmitriptan was determined using quantitative autoradiographic methods. The in vitro work demonstrated specific binding of [3H]-zolmitriptan in the superficial laminae of the trigeminal nucleus caudalis and dorsal horns of the C1 and C2 cervical spinal cord. The density of binding was 53 +/- 9 fmol/mg for the trigeminal nucleus caudalis, 47 +/- 7 fmol/mg for C1 and 50 +/- 6 fmol/mg for C2. The ex vivo work demonstrated binding in anatomically identical areas which was less dense than that seen with the in vitro method. These data confirm the existence of a population of receptors that specifically bind zolmitriptan following systemic administration. These receptors may, in part, be responsible for its clinical efficacy and reinforce the importance of central trigeminal neurons as a possible site of action of anti-migraine drugs.
Cephalalgia 1997 May
PMID:Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. 935 Mar 94

In 1996, our knowledge of acute antimigraine therapy expanded in three major areas. First, large surveys have confirmed the remarkable efficacy profile of sumatriptan in clinical practice. No satisfying clinical, pharmacokinetic or genetic explanations were found for its major shortcomings: nonresponders, headache recurrence and noncardiac chest symptoms. Second, the novel 5-HT1B/D agonists zolmitriptan (311C90), rizatriptan (MK-462), eletriptan (UK-116,044), avitriptan (BMS-180048) and alniditan (R091274) were all proved superior to placebo for attack treatment, but their advantages over sumatriptan are yet to be analysed in more detail. A higher lipophilicity explains (except for alniditan) their greater oral bioavailability and better central nervous system penetration. A central action now proved experimentally in animals and in humans for 5-HT1B/D agonists such as zolmitriptan may be advantageous for the antimigraine efficacy, but it could also increase sedation. Third, an endothelin (Ro470203, bosentan) and a neurokinin 1 (RPR100893) receptor antagonist were found to be ineffective in migraine. Both compounds are potent inhibitors of neurogenic plasma extravasation in rat dura mater, which might suggest that this pharmacological property does not necessarily predict efficacy in aborting migraine attacks.
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PMID:Acute migraine therapy: the newer drugs. 922 32


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