Sex and psychiatric comorbidity correlates of the premonitory urge for tic scale in youth with persistent tic disorders.

The premonitory urge for tics scale (PUTS) is a common self-report measure of premonitory sensations preceding tics. The present study aimed to examine the internal consistency and concurrent validity of the PUTS by sex and psychiatric comorbidity status; and explored interactions between sex and psychiatric comorbidity in predicting premonitory urge and tic symptom severity. Seventy-four youth and young adults with persistent tic disorders completed the PUTS, while their parents completed the parent tic questionnaire (PTQ) and a demographic measure. Independent samples t-tests revealed no significant sex differences in PUTS items or total score. The PUTS total score also did not significantly differ between participants with and without attention-deficit hyperactivity disorder (ADHD) and/or obsessive-compulsive disorder (OCD) comorbidity. Internal consistency did not significantly differ between females (α = 0.85) and males (α = 0.75), and those with comorbid ADHD and/or OCD (α = 0.83) relative to those without (α = 0.69). With respect to concurrent validity, the PUTS total was significantly correlated with PTQ tic frequency, intensity, number, and severity for males but not for females. Among those with ADHD and/or OCD, the PUTS total score was correlated significantly and strongly with tic number and moderately with tic intensity. Interactions between sex and psychiatric comorbidity performed using 2 × 2 analysis of variance did not significantly predict the PUTS total or PTQ subscale scores. Findings suggest sex and comorbidity status may influence premonitory urge expression. Results have implications for understanding and measurement of the premonitory urge.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Integrin-binding peptides containing RGD produce coronary arteriolar dilation via cyclooxygenase activation.

Integrin binding by Arg-Gly-Asp (RGD)-containing peptides has been shown to alter vascular tone in a variety of blood vessels and has been implicated as a mechanism of vasoregulation during tissue injury. However, the effect of these peptides in the coronary circulation has not been examined. Thus the purpose of our study was to test the hypothesis that integrins act as receptors linked to the regulation of coronary vasomotor function. In particular, the ability of RGD-containing peptides to influence vascular tone by interacting with the alpha(v)beta(3)- and alpha(5)beta(1)-integrins was studied in isolated pig coronary arterioles. All vessels developed basal tone and dilated in a concentration-dependent manner to soluble peptides cyclic GPenGRGDSPCA (cyclic RGD), an alpha(v)beta(3)-cyclic-binding peptide (XJ735), DMP7677, an alpha(5)beta(1)-binding peptide, and to protease-generated (neutrophil elastase) fragments of denatured collagen type I (a major RGD-containing extracellular matrix protein). The vasodilations to cyclic RGD, XJ735, and collagen fragments were almost completely blocked by endothelial removal or by the cyclooxygenase inhibitor indomethacin. In contrast, after endothelial removal and incubation with indomethacin, coronary arterioles showed concentration-dependent constriction to the alpha(5)beta(1)-integrin ligand DMP7677 but not to cyclic RGD or XJ735. Collectively, our results indicate that activation of endothelial alpha(v)beta(3)- and alpha(5)beta(1)-integrins mediates coronary arteriolar dilation via the endothelial production of cyclooxygenase-derived prostaglandins. These data support a role for integrins in the regulation of coronary vascular tone that may be particularly important during myocardial injury.

Topiramate titration and tolerability.

OBJECTIVE: To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blindtrial. METHODS: After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100-200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively. RESULTS: Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (ie., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with 250% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the mean percent seizure reduction was 51% and 54%, respectively. CONCLUSIONS: Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.

Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache.

OBJECTIVE: To determine the effectiveness and tolerability of intravenous valproate for the acute treatment of migraine headache with or without aura (International Headache Society diagnostic criteria 1.1 and 1.2) compared with intramuscular metoclopramide 10 mg followed 10 minutes later by intramuscular dihydroergotamine 1 mg. BACKGROUND: Divalproex sodium is approved for prophylaxis of migraine headache. We studied the possible effectiveness of intravenous sodium valproate for the treatment of acute migraine headache. Valproate offers a treatment option for patients with migraine who recently have used a triptan or dihydroergotamine, theoretically avoiding the risk of drug interactions or cardiovascular complications. DESIGN/METHODS: In an open-label randomization, patients with an established diagnosis of migraine with or without aura were administered either intravenous valproate or intramuscular dihydroergotamine with metoclopramide to treat moderate-to-severe migraine headache of 24 to 96 hours' duration. Forty patients alternately received either 500 mg intravenous valproate or 10 mg metoclopramide intramuscularly followed by 1 mg dihydro- ergotamine. Patients rated severity of headache and the presence or absence of nausea, photophobia, or phonophobia at baseline, and at 1, 2, 4, and 24 hours. RESULTS: With intravenous valproate, 50% of patients reported headache improvement from moderate or severe to none or mild at 1 hour following treatment, 60% reported such improvement at 2 hours, 60% at 4 hours, and 60% at 24 hours. Corresponding improvement rates for dihydroergotamine were 45% at 1 hour, 50% at 2 hours, 60% at 4 hours, and 90% at 24 hours. Intravenous valproate and intramuscular dihydroergotamine provided similar relief from associated migrainous symptoms (nausea, photophobia, and phonophobia) during the first 4 hours following treatment. While none of the patients who received intravenous valproate experienced drug-related side effects during treatment, 15% of patients who took dihydroergotamine experienced one or more episodes of nausea and diarrhea during the first 4 hours of treatment. CONCLUSIONS: Intravenous valproate is similar in effectiveness to dihydroergotamine/metoclopramide as abortive therapy for prolonged moderate-to-severe acute migraine headache. Although the results were not statistically significant (P =.3635), intravenous valproate appears to offer a safe, effective, and well-tolerated treatment for patients with acute migraine. Relative to dihydroergotamine/metoclopramide, however, headache relief was not as likely to be sustained at 24 hours as with intravenous valproate.

Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischemic stroke.

BACKGROUND AND PURPOSE: Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor and is neuroprotective in experimental focal cerebral ischemia models at a plasma concentration of 10 ng/mL. In human volunteers, dose-limiting effects of aptiganel are blood pressure increases and central nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non-weight-adjusted doses of aptiganel in patients with acute ischemic stroke. METHODS: This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Ascending single intravenous bolus doses of aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization schedule. In 15 subsequent patients, selected bolus doses were followed by constant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; then 4.5 mg plus 0.75 mg/h, n=15) in a 4:1 randomization schedule. Prospectively collected pharmacokinetic data guided selection of infusion rates. Neurological and functional status were recorded at entry and after 1 week, although the study was not designed to test efficacy. RESULTS: Forty-six patients were randomized from 4 centers (3 in the United States and 1 in the United Kingdom): 36 received aptiganel HCl, and 10 were given placebo. Hypertension and CNS events were commonly reported after a bolus dose of 7.5 mg and after a 6-mg bolus followed by an infusion of 1 mg/h. The lower regimen of 4.5-mg bolus followed by infusion of 0.75 mg/h achieved plasma aptiganel concentrations of >10 ng/mL and was well tolerated by patients but still raised systolic blood pressure by approximately 30 mm Hg over baseline. CONCLUSIONS: A 4.5-mg intravenous bolus of aptiganel HCl followed by infusion of 0.75 mg/h for 12 hours is a tolerable dose that can produce plasma drug concentrations shown to be neuroprotective in animal models. However, increases in systolic blood pressure and an excess of CNS effects were both observed at this dose.

Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.

CONTEXT: Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies. OBJECTIVE: To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy. DESIGN: Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997. SETTING: Outpatient clinics at 20 sites. PATIENTS: The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale. INTERVENTION: Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo. MAIN OUTCOME MEASURES: The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality of Life Questionnaire scores, and the Profile of Mood States results. RESULTS: Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06). CONCLUSION: Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.

Dimensions of the impact of cancer pain in a four country sample: new information from multidimensional scaling.

We investigated the question of how cultural and linguistic backgrounds affect relationships among ratings (reported by patients with metastatic cancer) of pain's interference with such functions as activity, mood, and sleep. Multidimensional scaling (MDS) was used to analyze ratings of pain interference from a sample consisting of four culturally and linguistically different groups from the US (n = 1106), France (n = 324), the Philippines (n = 267), and China (n = 146). Patients all completed the Brief Pain Inventory, a self-report measure of pain and its interference with function. For each of these samples, MDS solutions consistently revealed two interpretable dimensions. In all samples, one dimension represented affect and the other dimension represented activity. The dimensions were consistently interpretable across all four samples and across three levels of pain severity ('mild', 'moderate', and 'severe'). The dimensions were most prominent when pain was moderate, rather than mild (when little interference was produced) or severe (when all domains were highly interfered with). These dimensions may have utility in the study of the epidemiology of pain and of the effectiveness of pain treatment. They may also be useful in clinical assessment to describe different patterns of pain interference.

Effects of oral morphine on cold pressor tolerance time and neuropsychological performance.

We investigated the analgesic effects of escalating doses (0.214, 0.286, 0.357, and 0.429 mg/kg) of oral morphine on tolerance to painful cold pressor in a double-blind, active placebo-controlled (diphenhydramine) study in 45 normal volunteers. The highest dose of morphine administered is equivalent to the starting dose recommended by the Agency for Health Care Policy and Research for the management of cancer pain and acute postoperative pain. We assessed analgesia in terms of cold pressor tolerance time and self-reported ratings of pain intensity and unpleasantness. Subjects receiving the highest dose of oral morphine showed significantly higher tolerance time than subjects receiving diphenhydramine. Neither morphine or diphenhydramine significantly reduced ratings of pain intensity and unpleasantness. Neuropsychological testing revealed that the two highest doses of morphine impaired the episodic retrieval of a word list, but the same doses did not affect motor, perceptual, or attentional tasks.

Disruption of human eyeblink conditioning after central cholinergic blockade with scopolamine.

Human (Homo sapiens) volunteers (N = 72) received saline, a low dose of oral scopolamine (0.6 mg), a high dose of oral scopolamine (1.2 mg), or a peripheral analogue (glycopyrrolate). They then underwent classical conditioning of the eyeblink response to a tone conditioned stimulus (CS) and a corneal airpuff unconditioned stimulus (UCS) in a delay conditioning paradigm. There was a dose-related decline in acquisition of the conditioned response. These drug-induced conditioning deficits were similar to those previously reported in rabbit eyeblink conditioning and could not be attributed to such nonassociative factors as changes in auditory thresholds to the tone CS, magnitude of reflexive blinks to the airpuff UCS, or to changes in spontaneous blink rates.

Efficacy of porcine parvovirus vaccines.

Three inactivated porcine parvovirus vaccines were tested for efficacy in 66 susceptible gilts. The gilts were challenged with virulent virus on the 40th day of gestation. All the vaccines provided excellent protection against fetal mortality despite insignificant serological responses to one of them. Good protection was obtained with two of the vaccines even when the dose was substantially reduced. Unvaccinated controls had very few viable fetuses.

Isolation of chlorine-containing antibiotic from the freshwater cyanobacterium Scytonema hofmanni.

Scytonema hofmanni, a filamentous freshwater cyanobacterium (blue-green alga), produces secondary metabolites which inhibit the growth of other cyanobacteria and green algae. A rapid, qualitative assay for this inhibition has been developed with Synechococcus as the test organism. This assay procedure has led to the isolation and characterization of an antibiotic (named cyanobacterin) from Scytonema. The antibiotic has a molecular weight of 430 and an empirical formula of C23H23O6Cl and contains a gamma-lactone and a chlorinated aromatic nucleus. It inhibits the growth of various algae but has limited effect on nonphotosynthetic bacteria or protozoans and thus may have potential use as a specific algicide.

Duration of immunosuppression caused by a vaccine strain of infectious bursal disease virus.

The depression of response of Brucella abortus strain 19 caused by an infectious bursal disease vaccine virus given to chicks at one day old was shown to persist for four weeks. Histological examination of the bursa of Fabricius showed a gradual repopulation by bursal lymphocytes, after initial damage, concomitant with the development of a humoral response.

Cognitive function in patients with multiple sclerosis.

The performance of patients with multiple sclerosis on selected psychological tests was examined to ascertain the usefulness of such examinations to diagnosis. Cognitive impairment was studied in relationship to disease-related factors, physician's identification of cerebral involvement, and psychological adjustment. The results indicate that half the subjects exhibited cognitive impairment. Levels of neurologic involvement, physical impairment, and depression were not predictive of cognitive impairment. Of the subjects who were judged on neurological examination to have intact mentation, half were actually impaired. Impaired cognitive functioning, which is often not detected through routine examination, may occur early in the disease. These deficits may represent manifestations of otherwise undetectable plaques in the subcortical white matter.

Psychological profiles in patients with multiple sclerosis. A preliminary investigation.

Most psychological and psychiatric studies of patients with multiple sclerosis (MS) have failed to take into account the varying demographic and disease-related factors that may be expected to play a role in patients' adjustment to this disease. We describe the psychological response of patients to MS as a function of age, sex, educational level, disease state, length of disease, physical disability, manual dexterity, and abstract reasoning. Several resulting response patterns are discussed.