Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the serotonin (5HT)1B/D-like agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-sensitive structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. In this study we determined the effect of intravenous administration of the novel anti-migraine compound zolmitriptan (311C90) upon evoked neuronal activity in trigeminal neurons. Nine adult cats were anaesthetised with alpha-chloralose (60 mg/kg, i.p.; 20 mg/kg, i.v., 2-hourly) with all surgery being conducted under halothane (1-3%). The superior sagittal sinus was isolated for electrical stimulation. Recordings were made from caudal trigeminal neurons at the C2 level of the cervical spinal cord with tungsten-in-glass microelectrodes. Signals were amplified and analysed by a custom-written program that enabled software filtering and extraction of both evoked potential and single cell data. Data were collected before and after administration of zolmitriptan. Electrical stimulation of the superior sagittal sinus resulted in activation of neuronal elements within the trigeminal nucleus that could be monitored as single unit activity or as evoked potentials, the latter reflecting both primary afferent and trigeminal cell body activity. The evoked potential recorded from the trigeminal nucleus was 207 +/- 14 microV and was reduced by zolmitriptan (100 micrograms/kg, i.v.) to a mean of 98 +/- 17 microV. Similarly, the probability of firing for trigeminal neurons was reduced from a control level of 0.63 +/- 0.1 to 0.13 +/- 0.05 after a dose of 100 micrograms/kg intravenously. These effects were dose-dependent and were significantly different from the effect of vehicle (P < 0.05). These data demonstrate that systemically administered zolmitriptan can inhibit evoked trigeminovascular activity within the trigeminal nucleus. This inhibition of trigeminal activity may play a role in the anti-migraine actions of this compound and offers the prospect of a third pathophysiologically consistent target site for anti-migraine drug effects.
Pain 1996 Oct
PMID:Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine? 895 29

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.
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PMID:Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. 935 Mar 94

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.
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PMID:Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group. 937 90

The trigeminovascular system consists of bipolar neurons innervating pain-producing intracranial structures, such as the superior sagittal sinus (SSS), and projecting to the medullary and upper cervical dorsal horn second order neurons. Zolmitriptan is a newly developed 5HT1B/1D receptor agonist with both peripheral and central sites of action in the trigeminovascular system due to greater lipophilicity relative to the more hydrophilic antimigraine compound sumatriptan. Given that we have seen electrophysiological and autoradiographic binding data to suggest that the compound may inhibit activity at second-order neurons this study was designed to examine whether such an effect could be demonstrated in a population of trigeminal neurons using Fos immunohistochemistry. Cats were anesthetised with alpha-chloralose (60 mg/kg intraperitoneal then 20 mg/kg intravenous maintenance) with all surgery being conducted using halothane (1-3%). The animals were prepared for physiological monitoring, including blood pressure, heart rate, rectal temperature, and end-expiratory CO2. They were intubated, ventilated, and paralyzed with gallamine triethiodide (6 mg/kg i.v.). A midline craniotomy was performed to expose the sinus for electrical stimulation using hook electrodes. Twenty-four hours after completion of the surgical procedures the animal was ready for treatment. Vehicle, sumatriptan (85 micrograms/kg), or zolmitriptan (30 micrograms/kg) was administered and the SSS was stimulated (250 microseconds, 100 V at 0.3 Hz) for 1 h. Following an additional 1 h the animal was perfused and immunohistochemistry was used to detect the protein product of the immediate early gene c-Fos. We compared the dorsal horns of the medulla (trigeminal nucleus caudalis) and the C1 and C2 cervical spinal cords in control animals with those receiving zolmitriptan or sumatriptan. We noted a significant reduction in Fos expression after treatment with zolmitriptan but no effect with sumatriptan. Given that zolmitriptan accesses central neurons and that the method of stimulation we have employed would bypass peripheral trigeminal mechanisms it is likely that the reduction in second-order trigeminal neuronal activity was due to a direct inhibitory effect of the compound on those cells. These neurons form a possible site for the treatment of acute attacks of migraine.
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PMID:Comparison of more and less lipophilic serotonin (5HT1B/1D) agonists in a model of trigeminovascular nociception in cat. 951 27

This international open-label study evaluated the tolerability and efficacy of zolmitriptan (Zomig, 311C90), a selective 5-HT1B/1D receptor agonist, in the long-term treatment of multiple migraine attacks. Patients who had previously participated in placebo-controlled zolmitriptan studies were recruited. A total of 2058 patients treated 31,579 migraine attacks (average 15 per patient), for up to 1 year. Twenty-six percent of attacks treated with a single zolmitriptan 5-mg dose were associated with at least one adverse event (24% treated with two doses). The most frequent adverse events included asthenia (14% of patients), nausea (12%), somnolence (10%), dizziness (11%), and paresthesia (11%). The rank order of the most common adverse events was not influenced by sex, age, or number of zolmitriptan doses taken and was similar between attacks 1 and 45. The majority of adverse events (59%) occurred within 2 hours of dosing, were of either mild (59%) or moderate (35%) intensity, of 4 hours' duration or less (67%), and required no further action (94%). Following an initial 5-mg dose of zolmitriptan, the 2-hour headache response rate (reduction in headache pain from moderate or severe before treatment to mild or no pain at 2 hours posttreatment) was 81% in patients treating moderate and severe attacks (19,639 of 24,161). Patients were pain-free at 2 hours in 55% of all attacks (16,510 of 29,808). The efficacy of zolmitriptan was not influenced by age, sex, weight, use of prophylactic antimigraine medication, or association of attacks with menstruation. Analysis of the overall population and a subgroup who treated 30 or more migraine attacks showed that zolmitriptan was consistently effective across attacks. Overall, 67% of patients who treated five or more attacks reported zolmitriptan to be effective in 80% to 100% of attacks. Zolmitriptan produced meaningful migraine relief and improvement in normal activity impairment in 73% and 78% of moderate and severe attacks, respectively. Patients treated recurrence of moderate or severe headache with a second zolmitriptan dose in 32% of attacks which responded to the first dose within 2 hours. Where required, a second zolmitriptan 5-mg dose for treatment of recurrence produced a headache response rate of 90% at 2 hours postdose. Thus, zolmitriptan 5 mg (plus an optional second 5-mg dose for treatment of recurrence) is well tolerated and effective in the acute treatment of multiple migraine attacks over periods up to 1 year.
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PMID:The long-term tolerability and efficacy of oral zolmitriptan (Zomig, 311C90) in the acute treatment of migraine. An international study. The International 311C90 Long-term Study Group. 956 7

Zolmitriptan is a new serotonergic agonist with excellent oral bioavailability exhibiting a potent symptomatic antimigraine effect. Zolmitriptan is a selective agonist of 5-HT1B/D receptors. 5-HT1B receptors are concentrated in the wall of the cranial extracerebral arteries. 5-HT1D receptors are located on the trigeminal terminals which receive pain from the leptomeningeal vessels. Migraine pain has its origin on cranial vessels. In fact, during a migraine attack the trigeminovascular system, which is composed by the cranial vessels and its trigeminal terminals, is activated. The activation of this system induces both dilatation and aseptic inflammation of cranial vessels. Zolmitriptan blocks both vascular phenomena. Its agonist action upon the 5-HT1D receptor ends the aseptic inflammation by inhibiting the release of vasoactive peptides. The dilatation of meningeal vessels disappears due to the stimulation of zolmitriptan of 5-HT1B receptors. As this drug crosses the blood brain barrier, zolmitriptan has both peripheral and central actions over the espinal trigeminal nucleus, which is rich in 5-HT1B/D receptors. Thus, the mechanism of action of zolmitriptan is double. On the one hand, zolmitriptan acts peripherally inhibiting dilatation and inflammation of cranial vessels. On the other, zolmitriptan exhibits a central nociceptive action in the brainstem nuclei. This dual action of zolmitriptan on migraine pain is completed with its beneficial effects on nausea and vomiting, due to its binding to the nucleus of the tractus solitarius, the center for control of vomiting.
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PMID:[Mechanism of action of zolmitriptan]. 985 90

Zolmitriptan is a selective 5-HT1B/1D receptor agonist for acute oral migraine therapy. This randomized, placebo-controlled, parallel-group study investigated the efficacy and tolerability of oral zolmitriptan (5, 10, 15 and 20 mg) in the treatment of single acute migraine attacks. Of 1181 patients randomized, 840 were evaluable for the primary efficacy analysis. Headache response rates (a reduction in headache intensity from severe or moderate at baseline to mild or no pain at 2 hours post-treatment) were similar across the zolmitriptan dose groups (66%, 71%, 69% and 77% for 5 mg, 10 mg, 15 mg and 20 mg, respectively) and were significantly higher than that for placebo (19%; all groups P < 0.001). A headache response was reported at 1 hour by 40-50% of zolmitriptan recipients (16% placebo). At 2 hours post dose, 39-47% of zolmitriptan-treated patients were pain-free, compared with 1% of placebo recipients. Headache recurrence occurred in 21-29% (upper 95% CI 37.1) of zolmitriptan-treated patients and in 65% (95% CI 38.3, 85.8) of placebo recipients. Zolmitriptan was well tolerated at each dose. The most commonly reported adverse events were asthenia, dizziness, paraesthesia and feelings of heaviness. Most adverse events were of mild or moderate intensity and were transient. The frequency of adverse events was dose-related. Although, zolmitriptan 5 mg exhibited the most favourable efficacy and tolerability profile, the dose response data suggest that lower doses would also offer significant efficacy. Copyright 1998 Lippincott Williams & Wilkins
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PMID:Zolmitriptan, a 5-HT1B/1D receptor agonist for the acute oral treatment of migraine: a multicentre, dose-range finding study. 1021 Aug 88


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