ABSTRACT
This study examined the effect of age on placebo response rates in rizatriptan trials in adults. Data from eight rizatriptan adult trials involving patients treating moderate/severe migraine attacks with rizatriptan 5 mg (N = 1819), rizatriptan 10 mg (N = 2046) or placebo (N = 1322) were pooled for post hoc analysis. Logistic regression was used to model 2-h pain relief (reduction to mild or none) and 2-h pain freedom rates by treatment groups. Older patients had lower placebo response rates than younger patients; the estimated odds ratio (older vs. younger) for a 10-year age increase was 0.83 for pain relief [95% confidence interval (CI) 0.75, 0.93] and 0.81 for pain freedom (95% CI 0.68, 0.97). The response proportion vs. age trend was flat for rizatriptan 5 mg and slightly increased for rizatriptan 10 mg. The treatment-by-age interaction was significant for pain relief (P < 0.001) and pain freedom (P = 0.001), suggesting an increasing trend of treatment advantage of rizatriptan over placebo as age increased. Age appeared to be an important predictor of placebo response rate in rizatriptan trials, with older patients being less likely to respond to placebo and more likely to respond to rizatriptan.
Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Triazoles/therapeutic use , Tryptamines/therapeutic use , Adolescent , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Placebo Effect , Randomized Controlled Trials as Topic , Young AdultABSTRACT
BACKGROUND: Rizatriptan (MK-462) is a new 5-hydroxytryptamine1D (serotonin1D; 5-HT1D) receptor agonist for the acute treatment of migraine that has improved pharmacokinetic properties compared with sumatriptan succinate. OBJECTIVE: To assess the efficacy and tolerability of 10-, 20-, and 40-mg doses of oral rizatriptan vs a 100-mg dose of oral sumatriptan succinate and placebo for the acute treatment of migraine. DESIGN: Randomized, double-blind, parallel-group, placebo-controlled, outpatient trial. SETTING: Ten US and 4 Dutch investigator centers. PATIENTS: Patients who had migraine with or without aura (N = 449). MAIN OUTCOME MEASURE: The proportion of patients whose conditions improved from severe or moderate headache immediately before dosing to mild or no headache at 2 hours after drug administration (ie, headache relief). RESULTS: The proportion of patients with headache relief was 18% for placebo; 46% for sumatriptan; and 52% for 10-mg, 56% for 20-mg, and 67% for 40-mg rizatriptan. All differences with placebo were statistically significant (P < .001), and 40-mg rizatriptan was superior to sumatriptan (P = .01). The proportion of patients who became free of pain at 2 hours was 3% for the placebo-treated group; 22% for the sumatriptan-treated group; and 26%, 35%, and 47% for the group of patients who took the 10-, 20-, and 40-mg doses of rizatriptan, respectively (all differences with placebo, P < .005; 40-mg rizatripan vs sumatriptan, P = .001). The recurrence of headache within 24 hours was found to be equal across all treatment groups-approximately 40%. Adverse events (most commonly short-lasting mild or moderate dizziness and drowsiness) occurred more frequently after a 40-mg dose of rizatriptan was given than after the other treatments. CONCLUSIONS: The antimigraine effect of 10- and 20-mg rizatriptan was superior to placebo, and comparable with that of 100-mg sumatriptan succinate; the efficacy of 40-mg rizatriptan was superior to that of both placebo and 100-mg sumatriptan succinate, although it was associated with a high frequency of adverse events.
Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Sumatriptan/therapeutic use , Triazoles/therapeutic use , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Sumatriptan/adverse effects , Triazoles/adverse effects , TryptaminesABSTRACT
OBJECTIVE: To compare the efficacy of oral rizatriptan 10 mg with oral doses of sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures. METHODS: Retrospective analysis of data from five randomized, placebo-controlled, double-masked clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (n = 772), 50 mg (n = 1116), 25 mg (n = 1183), naratriptan 2.5 mg (n = 413), and zolmitriptan 2.5 mg (n = 580) for the acute treatment of a moderate or severe migraine attack. OUTCOME MEASURES: Percentage of patients pain-free at 2 hours, symptom-free at 2 hours (no pain, nausea, photophobia, phonophobia, vomiting, or functional disability), 24-hour sustained pain-free (no headache at 2 hours, no recurrence, and no additional antimigraine medications for 24 hours). RESULTS: More patients taking rizatriptan 10 mg were pain-free at 2 hours than were patients taking sumatriptan 100 mg (40% vs 33%, p = 0.019), sumatriptan 50 mg (40% vs 35%, p = 0.009), sumatriptan 25 mg (38% vs 27%, p < 0.001), naratriptan 2.5 mg (45% vs 21%, p < 0.001), and zolmitriptan 2.5 mg (43% vs 36%, p = 0.041). More patients taking rizatriptan 10 mg were symptom-free at 2 hours than were patients taking sumatriptan 100 mg (31% vs 22%, p = 0.002), sumatriptan 50 mg (33% vs 28%, p = 0.003), sumatriptan 25 mg (33% vs 24%, p < 0.001), naratriptan 2.5 mg (30% vs 11%, p < 0.001), and zolmitriptan 2.5 mg (31% vs 24%, p = 0.042). More patients taking rizatriptan 10 mg had a 24-hour sustained pain-free response than did patients taking sumatriptan 100 mg (27% vs 23%, p = 0.112), sumatriptan 50 mg (30% vs 26%, p = 0.015), sumatriptan 25 mg (27% vs 20%, p = 0.005), naratriptan 2.5 mg (29% vs 17%, p = 0.004), and zolmitriptan 2.5 mg (32% vs 24%, p = 0.013). CONCLUSION: Oral rizatriptan 10 mg was more effective than oral sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures of pain-free response at 2 hours, symptom-free response at 2 hours, and 24-hour sustained pain-free response.
Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/administration & dosage , Sumatriptan/administration & dosage , Triazoles/administration & dosage , Administration, Oral , Humans , Indoles/administration & dosage , Oxazolidinones/administration & dosage , Patient Satisfaction , Piperidines/administration & dosage , Randomized Controlled Trials as Topic , Retrospective Studies , TryptaminesABSTRACT
OBJECTIVE: To determine the within-patient consistency of response for rizatriptan, a 5-HT(1B/1D) receptor agonist for the acute treatment of migraine. METHODS: Post hoc analysis was performed on data from a randomized, double-blind, placebo-controlled clinical trial. Four hundred seventy-three patients with migraine diagnosed according to the criteria of the International Headache Society were randomly assigned to one of five sequence groups in which each patient was scheduled to treat four separate moderate or severe migraine attacks. Patients in four groups received 10 mg of rizatriptan for three of four attacks and placebo for the remaining attack; patients in the fifth group received 10 mg of rizatriptan for all four attacks. Headache severity, functional disability, and associated migraine symptoms were measured immediately before dosing and at regular intervals up to 4 hours after the dose. The analysis was based on efficacy at 2 hours after dosing, the last time point before escape medications were allowed. The percentages of patients who responded in a specified number of attacks after treatment with rizatriptan were calculated. The analysis was descriptive, and no formal statistical testing was performed. RESULTS: Of the evaluable patients who treated three migraine attacks with 10 mg of rizatriptan (with an additional interspersed placebo-treated attack in most patients), 216 of 252 (86%) had pain relief (reduction of pain to mild or none), 122 of 252 (48%) were pain free, 211 of 250 (84%) had no nausea, 163 of 251 (65%) had no photophobia, 182 of 252 (72%) had no phonophobia, 136 of 249 (55%) had no functional disability, and 233 of 252 (92%) had no need for escape medications at 2 hours after dosing in at least two of three attacks. CONCLUSION: The response to 10 mg of oral rizatriptan within individual patients was consistent over three attacks on a range of measures.
Subject(s)
Migraine Disorders/drug therapy , Triazoles/therapeutic use , Adolescent , Adult , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Triazoles/administration & dosage , TryptaminesABSTRACT
In primates fibres from nasal retinae project contralaterally and those from temporal retinae ipsilaterally. At the border between these two regions an area of overlap where ipsi- and contralaterally projecting ganglion cells intermingle has been demonstrated in monkeys and cats. However, behavioural studies have failed to provide confirmatory evidence in humans. In this experiment simple reaction times to lateralized light flashes at four points of eccentricity (1/2, 1, 2 and 4 degrees) were recorded in an acallosal female. Responses made by the directly stimulated hemisphere were subtracted from those made by the indirectly stimulated hemisphere to arrive at estimates of interhemispheric transmission time. If present, a region of overlap should result in information being available to both hemispheres and consequently alleviate the need for any interhemispheric crossing. However, a large transmission time was found, even with stimuli presented close to fixation, thereby providing no evidence for the existence of such a region in humans.
Subject(s)
Agenesis of Corpus Callosum , Retina/physiology , Visual Cortex/physiology , Visual Perception/physiology , Adult , Brain Mapping , Fixation, Ocular , Humans , Reaction Time/physiology , Species Specificity , Visual Pathways/anatomy & histology , Visual Pathways/physiologyABSTRACT
In two experiments, simple reaction time to left-field or right-field stimulation was measured as a function of light intensity. The response made on each trial in Experiment 1 was a finger movement, and in Experiment 2 a spoken word. In Experiment 1, the advantage of "uncrossed" over "crossed" reaction times remained invariant across intensities. In Experiment 2, however, the advantage of right over left visual-field stimuli in eliciting a vocal reaction varied inversely with intensity. It is suggested that the use of vocal reactions may permit an estimation of a visual commissural transmission time.
Subject(s)
Dominance, Cerebral/physiology , Reaction Time/physiology , Visual Perception/physiology , Adolescent , Adult , Corpus Callosum/physiology , Female , Functional Laterality/physiology , Humans , Male , Motor Skills/physiology , Synaptic Transmission , Visual Fields , Visual Pathways/physiologyABSTRACT
Visual evoked potentials (VEPs) to lateralized light flashes were recorded from the parietal midline, and from homologous occipital and central sites, in a GO/ NOGO reaction time task. The N160 component of the VEP was found to be larger over the hemisphere contralateral to the visual field of stimulus exposure at all pairs of lateral electrodes. At the occipital sites only, N160 latency was also shorter from the contralateral hemisphere, by an average of approximately 14 msec. This was not so centrally, where a non-significant value of approximately 4 msec was obtained. These data are considered to be consistent with Milner and Lines' hypothesis that callosal transmission occurs at different rates in different functional regions of the corpus callosum.
Subject(s)
Cerebral Cortex/physiology , Evoked Potentials, Visual , Functional Laterality/physiology , Corpus Callosum/physiology , Female , Humans , Male , Neural Pathways/physiology , Occipital Lobe/physiology , Photic Stimulation , Reaction Time/physiology , Visual FieldsABSTRACT
Event-related potentials (ERPs) were recorded in two experiments involving selective visual processing. In Experiment 1, subjects attended to light flashes emanating from one visual field, in order to detect occasional slightly deviant "targets", while ignoring equiprobable stimuli from the opposite field. ERPs elicited by stimuli in an attended field were characterised by larger posteriorly distributed P120 and N170 components, and a larger anteriorly distributed N145 component. In addition, these ERPs were, in comparison to those elicited by unattended stimuli, more negative-going in the latency region of approx. 200-400 msec. This late effect had a marked fronto-central distribution. In Experiment 2 subjects attended to either horizontal or vertical bars, displayed equiprobably in the same spatial location. No enhancement of early components was observed as a function of attention but, as in Experiment 1, a late, sustained, fronto-centrally distributed negative shift was observed in ERPs elicited by "attended" compared to "unattended" stimuli. It was concluded that the enhancement of P120 (P1) observed in Experiment 1 reflects the engagement of attentional mechanisms specific to the selection of stimuli on the basis of spatial cues. The later sustained negative shift seen in both experiments was considered to reflect a feature of within-channel processing common to both spatial and non-spatial selective tasks.
Subject(s)
Attention , Evoked Potentials, Visual , Space Perception , Visual Perception , Adult , Humans , Orientation , Reaction TimeABSTRACT
A young acallosal man was intensively tested in a standard simple reaction time (RT) paradigm using briefly-presented lateralized spots for light. In Experiment 1, findings on previous acallosal patients of a large disadvantage for crossed (e.g. right hemifield-left hand) as against uncrossed (e.g. left hemifield-left hand) RTs were replicated. This crossed-uncrossed difference (CUD), as in previous work, turned out to be smaller in a bimanual response task than in the conventional unimanual task. Experiment 2 was a factorial study of unimanual RTs in which (a) stimulus intensity and (b) spatial S-R compatibility, were varied. As in a previously tested patient, decreased intensity resulted in a greatly increased CUD. S-R compatibility on the other hand had no effect on CUD. The results are interpreted as favouring a role for visual commissural neurones in the acallosal CUD, and as evidence against a spatial compatibility hypothesis.
Subject(s)
Agenesis of Corpus Callosum , Dominance, Cerebral/physiology , Reaction Time/physiology , Visual Perception/physiology , Adult , Corpus Callosum/physiopathology , Functional Laterality/physiology , Humans , Male , Psychomotor Performance/physiology , Tomography, X-Ray Computed , Visual FieldsABSTRACT
Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo.
Subject(s)
Cyclooxygenase Inhibitors/adverse effects , Digestive System/drug effects , Enzyme Inhibitors/adverse effects , Lactones/adverse effects , Prostaglandin-Endoperoxide Synthases/drug effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Humans , Intestinal Perforation/chemically induced , Isoenzymes/drug effects , Membrane Proteins , Osteoarthritis/drug therapy , Peptic Ulcer/chemically induced , SulfonesABSTRACT
Rats were tested for their ability to locate a hidden platform in the Morris swimming pool in which extrapool cues are required to guide locomotion. At the end of each trial, the rats were either removed immediately or allowed to remain on the platform for 60 s. Bilateral lesions of the superior colliculus (SC), as in a previous experiment (Milner & Lines, 1983), were found to produce a severe deficit. Permitting the rats to stay on the platform did not significantly affect performance in either rats with SC lesions or sham-operated controls. The results indicated that the reduced orienting behavior on the platform observed in the rats with lesions in the previous experiment was not the cause of their navigational impairment. It is concluded that the impairment following SC lesions comes about during the swimming itself and therefore that it may be attributed to a disturbance of, or a failure to utilize, ambient vision.
Subject(s)
Orientation/physiology , Psychomotor Performance/physiology , Space Perception/physiology , Superior Colliculi/physiology , Animals , Brain Mapping , Male , Rats , Swimming , Transfer, PsychologyABSTRACT
The muscarinic antagonist scopolamine and the benzodiazepine lorazepam both produce transient impairments in memory and attention in normal volunteers. These impairments can be reversed by appropriate agents such as the cholinesterase inhibitor physostigmine in the case of scopolamine or the benzodiazepine antagonist Ro 15-1788 in the case of lorazepam. In this paper we investigated the pharmacological specificity of these reversals by examining the interactions of scopolamine and Ro 15-1788 and of lorazepam and physostigmine. There was no evidence that the effects of scopolamine and lorazepam on cognitive function could be attenuated by Ro 15-1788 and physostigmine, respectively. The results are discussed in terms of pharmacological models of Alzheimer's disease.
Subject(s)
Anti-Anxiety Agents/pharmacology , Dementia/chemically induced , Flumazenil/pharmacology , Physostigmine/pharmacology , Scopolamine/pharmacology , Acoustic Stimulation , Adult , Anti-Anxiety Agents/antagonists & inhibitors , Attention/drug effects , Cognition Disorders/chemically induced , Cognition Disorders/psychology , Dementia/psychology , Disease Models, Animal , Female , Humans , Male , Memory Disorders/chemically induced , Memory Disorders/psychology , Photic Stimulation , Psychomotor Performance/drug effects , Pupil/drug effects , Reaction Time/drug effects , Scopolamine/antagonists & inhibitorsABSTRACT
OBJECTIVE: To determine the efficacy of oral rizatriptan 10 mg and 5 mg for treating menstrually associated migraine attacks. METHODS: Data from two large clinical trials with identical designs were included in a retrospective analysis. The studies were randomized, double-masked, placebo-controlled, incomplete block, two-period, crossover designs. Women with migraines were randomly assigned to one of five treatment sequences for the treatment of two migraine attacks. Only data from the first attack in women with migraines who were treated with rizatriptan or placebo were included in the analysis. A menstrually associated attack was defined as one that occurred within 3 days before or after the onset of the last menstrual period. RESULTS: In the subgroup of 335 women with menstrually associated migraine, rizatriptan was effective compared with placebo. At 2 hours after dosing, 68% of 139 women taking rizatriptan 10 mg and 70% of 115 women taking rizatriptan 5 mg with a menstrually associated migraine had pain relief compared with 44% of 81 patients taking placebo (P <.05). In all women, rizatriptan was as effective in treating menstrual as well as nonmenstrual migraine: 68% of 139 patients taking rizatriptan 10 mg with a menstrually associated migraine had pain relief at 2 hours after dosing compared with 69% of 393 patients with nonmenstrually associated attacks (test of menstrual association = nonsignificant; the analysis had 80% power to detect a difference of six percentage points between groups). Similar results were found for rizatriptan 5 mg (menstrual = 70%, nonmenstrual = 66%; not statistically significant). CONCLUSION: Rizatriptan is effective in the treatment of menstrually associated migraine attacks.
Subject(s)
Menstruation Disturbances/drug therapy , Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Triazoles/therapeutic use , Administration, Oral , Adult , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Multicenter Studies as Topic , Odds Ratio , Randomized Controlled Trials as Topic , Retrospective Studies , Serotonin Receptor Agonists/administration & dosage , Treatment Outcome , Triazoles/administration & dosage , Tryptamines , United StatesABSTRACT
Rats with bilateral ablation of the superior colliculus (SC) were compared with sham-operated rats in two experiments. In the first, it was found that discrimination performance deteriorated as a function of S-R separation, to a similar extent in both groups. In this experiment, unlike earlier ones which found a deficit, the separation was introduced in a horizontal direction. In the second experiment, spatial orientation in the Morris Swimming Pool was found to be impaired in the SC rats both when the target platform was visible and when invisible. During their presence on the platform, these rats also engaged less often in upward orienting movements, although horizontal movements were of normal frequency. It is proposed (i) that there is an anisotropy in the SC's control of orienting head and eye movements in rats, and (ii) that the swimming pool deficit may be due to an impairment of ambient vision.
Subject(s)
Discrimination Learning/physiology , Distance Perception/physiology , Orientation/physiology , Superior Colliculi/physiology , Visual Perception/physiology , Animals , Cues , Male , Motor Activity/physiology , Muridae , Pattern Recognition, Visual/physiology , Retina/physiology , Space Perception/physiology , Visual Pathways/physiologyABSTRACT
Rizatriptan is a selective 5-hydroxytriptamine1B/1D receptor agonist that was launched in 1998 for the acute treatment of migraine in adults. Based on data from 6 large clinical trials in patients > or =18 years of age in whom migraine was diagnosed according to International Headache Society criteria, the marketed 10-mg and 5-mg oral doses of rizatriptan are effective in relieving headache pain and associated migraine symptoms. The 10-mg dose is more effective than the 5-mg dose. At 2 hours after dosing, up to 77% of patients taking rizatriptan 10 mg had pain relief compared with 37% of those taking placebo, up to 44% were completely pain free compared with 7% of those taking placebo, and up to 77% were free of nausea compared with 58% of those taking placebo (P < 0.05 for all 3 comparisons). Both doses of rizatriptan are generally well tolerated. In placebo-controlled studies involving treatment of a single migraine attack, the most common side effects (incidence > or =2%) occurred in <10% of patients, typically were transitory (2 to 3 hours), and were mild or moderate. Rizatriptan is an effective and well-tolerated acute treatment for migraine.
Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Triazoles/therapeutic use , Administration, Oral , Dose-Response Relationship, Drug , Humans , Migraine Disorders/metabolism , Randomized Controlled Trials as Topic , Safety , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/pharmacokinetics , Triazoles/administration & dosage , Triazoles/pharmacokinetics , TryptaminesABSTRACT
Rizatriptan and sumatriptan are selective 5-HT(1B/1D) receptor agonists for theacute treatment of migraine. For oral formulations, the time to maximum plasma concentration is reached earlier with rizatriptan than with sumatriptan (1 h versus 2-2.5 h) and rizatriptan has greater bioavailability than sumatriptan (45% versus 15%). These pharmacological advantages appear to translate into a faster onset of action and a better overall response for oral rizatriptan versus oral sumatriptan. The two drugs have been directly compared in randomized, double-blind, placebo-controlled clinical trials of patients with moderate or severe migraine attacks. Rizatriptan 10 mg was generally superior to sumatriptan on a measure of time-to-pain-relief within 2 h, where pain relief was defined as a reduction of pain to mild or none (odds ratio for rizatriptan versus sumatriptan 100 mg = 1.21; odds ratios for rizatriptan 10 mg versus sumatriptan 50 mg = 1.14 and 1.10 in two studies). Rizatriptan 10 mg was also superior to sumatriptan on the International Headache Society recommended endpoint of the percentage of patients pain free at 2 h (40% for rizatriptan 10 mg, 33% for sumatriptan 100 mg, and 35% for sumatriptan 50 mg). Further advantages for rizatriptan were seen on stringent outcome measures of the percentage of patients who were completely free of all symptoms at 2 h, patient satisfaction with medication at 2 h, and 24-h sustained pain-free response. 5-HT(1B/1D) receptor agonists are contraindicated in patients with coronary artery disease because of their potential to cause vasoconstriction. In clinical trials which excluded such patients, rizatriptan and sumatriptan were both well-tolerated. The most common side-effects on both drugs occurred in <10% of patients and consisted of dizziness, drowsiness, and asthenia/fatigue. The adverse events were usually mild or moderate in severity and short-lasting.
Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Sumatriptan/therapeutic use , Triazoles/therapeutic use , Administration, Oral , Humans , Patient Satisfaction , Recurrence , Serotonin Receptor Agonists/pharmacology , Sumatriptan/pharmacology , Triazoles/pharmacology , TryptaminesABSTRACT
The effects of two doses of scopolamine (0.6 and 1.2 mg p.o.) on retrieval from semantic memory in normal young volunteers were examined using tests of verbal fluency and categorization latency. A visual contrast sensitivity test, which has previously shown a scopolamine-induced impairment at these doses (Broks et al., 1988), was also administered. In agreement with the work of Dunne (1990) and others, no evidence for a scopolamine deficit in semantic retrieval was found; in fact scopolamine improved letter fluency. However, scopolamine did produce the expected decrease in visual contrast sensitivity. The doses of scopolamine used here have also been shown to impair learning and attention (Broks et al., 1988). It is possible that earlier studies which found a scopolamine deficit on semantic retrieval, did so because they used elderly subjects and/or large drug doses.
ABSTRACT
Two studies were undertaken to investigate the effects of acute (Study 1) or repeated (Study 2) administration of the angiotensin converting enzyme (ACE) inhibitor enalapril on the cognitive deficits produced by scopolamine administration in volunteers. Enalapril at doses between 2.5 and 10.0 mg p.o. produced virtually complete blockade of plasma ACE activity. However, it did not influence the effects of scopolamine on a variety of cognitive tasks, including tests of memory, attention and sedation.
ABSTRACT
The transient impairments of memory produced by the muscarinic antagonist scopolamine have been adopted as a pharmacological model of Alzheimer-type dementia in normal volunteers. In this study we examined the effects of chronic (72 h) transdermal administration of scopolamine on memory, attention, sedation and visual function. The transdermal patches provided constant plasma levels of scopolamine for the duration of the study. Indices of the peripheral effects of scopolamine (visual near-point and pupil size) showed impairments that were sustained for 3 days. However, measures of sedation and memory revealed impairments that were maximal the day after patch application and which were no longer present 3 days after application. This pattern of results is discussed in relation to pharmacological modelling of Alzheimer's disease.
ABSTRACT
BACKGROUND: In animals, insulin-like growth factor-1 (IGF-1) increases clearance of beta-amyloid, a pathologic hallmark of Alzheimer disease (AD), from the CNS. Serum IGF-1 level decreases with age, and shows a further decrease in AD. We examined whether the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, slows the rate of progression of symptoms in patients with AD. METHODS: A double-blind, multicenter study was conducted in which 563 patients with mild to moderate AD were randomized to receive MK-677 25 mg or placebo daily for 12 months. Efficacy measures were mean change from baseline at month 12 on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC-plus), the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating-sum of boxes (CDR-sob). RESULTS: A total of 416 patients completed treatment and assessments at 12 months. Administration of MK-677 25 mg resulted in a 60.1% increase in serum IGF-1 levels at 6 weeks and a 72.9% increase at 12 months. In mixed-effects models that included treatment, time (month), randomization strata (baseline MMSE score < or =20 vs >20), and interaction of treatment-by-time, there were no significant differences between the treatment groups on the CIBIC-plus or the mean change from baseline scores on the ADAS-Cog, ADCS-ADL, or CDR-sob scores over 12 months. CONCLUSION: Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.