Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized,placebo‐controlled trials

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial‐onset seizures (POS). Methods: Two identical, randomized, placebo‐controlled, double‐blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy‐refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8‐week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12‐week double‐blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double‐blind phase compared with the prospective baseline phase. Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment‐emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence. Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial‐onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well‐tolerated in both studies.     

Synchrotron X‐ray analyses demonstrate phosphate‐bound gadolinium in skin in nephrogenic systemic fibrosis

Background Nephrogenic systemic fibrosis (NSF) is an incurable, debilitating disease found exclusively in patients with decreased kidney function and comprises a fibrosing disorder of the skin and systemic tissues. The disease is associated with exposure to gadolinium (Gd)‐based contrast agents (GBCA) used in magnetic resonance imaging (MRI). Tissue samples from many patients with NSF contain micron‐sized insoluble Gd‐containing deposits. However, the precise composition and chemical nature of these particles is unclear. Objectives To clarify the precise chemical structure of the Gd‐containing deposits in NSF tissues. Methods Autopsy skin tissues from a patient with NSF were examined in situ using synchrotron X‐ray fluorescence (SXRF) microscopy and extended X‐ray absorption fine structure (EXAFS) spectroscopy and in correlation with light microscopy and the results of scanning electron microscopy/energy dispersive spectroscopy analyses. Results The insoluble Gd deposits were shown to contain Gd no longer coordinated by GBCA chelator molecules but rather in a sodium calcium phosphate material. SXRF microscopy shows a clear correlation between Gd, Ca and P. EXAFS spectroscopy shows a very different spectrum from the GBCAs, with Gd–P distances at 3·11 Å and 3·72 Å as well as Gd–Gd distances at an average of 4·05 Å, consistent with a GdPO₄ structure. Conclusions This is the first direct evidence for the chemical release of Gd from GBCA in human tissue. This supports the physical–chemical, clinical and epidemiological data indicating a link between stability and dose of GBCA to the development of NSF.     

A randomized,double-blind comparison of single-dose and divided multiple-dose dolasetron for cisplatin-induced emesis

 Purpose: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. Methods: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin (≥80 mg/m²) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. Results: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P=0.034) longer median time to the first emetic episode (10.1 h vs >24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. Conclusions: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration. Received: 31 March 1995/Accepted: 20 October 1995     

Measurement and prediction of medication compliance in problem drinkers

BACKGROUND: A variety of methods have been used to measure medication compliance. Although electronic monitoring has been considered to be the best method, it has some potential for error and its high cost may limit its feasibility. This study examined the concordance of data on medication compliance that was obtained by using an electronic monitoring system (Medication Event Monitoring System, or MEMS), daily diary reports, and tablet counts. METHODS: Subjects were 150 problem drinkers participating in a pharmacotherapy trial. Subjects were randomly assigned to receive naltrexone 50 mg (n = 75) or placebo (n = 75) and to receive either daily (n = 72) or targeted (n = 78) medication administration. Comparisons between methods were conducted at the aggregate and individual daily levels, and the association between compliance and three alcohol-related outcomes was evaluated. RESULTS: Daily diaries showed good day-to-day concordance with MEMS and a higher correlation with MEMS than did tablet counts. However, high-compliance subjects did no better than low-compliance subjects on any of three alcohol-related outcome measures. CONCLUSIONS: Compliance measurement using a daily diary method yielded results that are comparable to those obtained with electronic monitoring, which served as a criterion measure. In contrast, tablet counts provided data that were less concordant with the criterion measure. The unique nature of the study sample (i.e., the majority of subjects were not committed to a goal of abstinence), combined with the targeted approach to treatment, may explain the lack of association between compliance and alcohol-related outcomes. Further research should aim to ascertain the factors affecting the relationship between compliance and outcomes.     

Motor cortex stimulation for enhancement of recovery after stroke: case report

We present a case report of a 65-year-old patient who had a subcortical infarct and a right spastic hemiparesis that occurred 19 months before being treated with an investigational therapy consisting of low frequency subthreshold epidural motor cortex electrical stimulation delivered during structured occupational therapy repeated daily for three weeks. Before treatment the patient's affected arm rested in a flexion posture and he was unable to flex or extend the fingers. After three weeks of treatment, the resting tone of his arm had improved and he was able to grasp a pen and write letters. The Fugl-Meyer motor scale score improved from 36 to 46 and this improvement was sustained for four weeks after the conclusion of rehabilitation therapy. This is the first patient to be entered into a randomized clinical feasibility and safety study assessing functional improvement in stroke patients treated with epidural cortical stimulation concurrent with occupational therapy (an investigational therapy).     

Association of galactose-1-phosphate uridyltransferase activity and N314D genotype with the risk of ovarian cancer

Deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme results in accumulation of galactose and its metabolites in the ovary (Am J Epidemiol 1989;130:904-10). Galactose may raise gonadotropin levels, resulting in proliferation of ovarian epithelium. In 1993-1999, the authors conducted a population-based case-control study of ovarian cancer in Hawaii and Los Angeles, California, to examine the hypothesis that reduced GALT activity is associated with an increased risk of ovarian cancer. A total of 239 ovarian cancer cases and 244 population controls were interviewed. A blood sample was collected to measure levels of GALT and to assay for the N314D (A940G) polymorphism of the GALT gene. Covariate-adjusted mean GALT activity was similar between cases (23.8 micro mol per hour/g hemoglobin (Hb)) and controls (23.7 micro mol per hour/g Hb) (p = 0.83). No evidence was found for a dose-response relation between the odds ratios for ovarian cancer and GALT activity or the ratio of lactose intake to GALT activity. The risk associated with the presence of at least one variant Asp314 allele was 0.77 (95% confidence interval: 0.42, 1.41). This study did not support the hypothesis that reduced galactose metabolism is a risk factor for ovarian cancer, although increased GALT activity attenuated the inverse association of oral contraceptive pill use with risk.     

Motor recovery and cortical reorganization after constraint-induced movement therapy in stroke patients: a preliminary study

Constraint-induced movement therapy (CIMT) is a physical rehabilitation regime that has been previously shown to improve motor function in chronic hemiparetic stroke patients. However, the neural mechanisms supporting rehabilitation-induced motor recovery are poorly understood. The goal of this study was to assess motor cortical reorganization after CIMT using functional magnetic resonance imaging (fMRI). In a repeated-measures design, 4 incompletely recovered chronic stroke patients treated with CIMT underwent motor function testing and fMRI. Five age-matched normal subjects were also imaged. A laterality index (LI) was determined from the fMRI data, reflecting the distribution of activation in motor cortices contralateral compared with ipsilateral to the moving hand. Pre-intervention fMRI showed a lower LI during affected hand movement of stroke patients (LI = 0.23+/-0.07) compared to controls (LI unaffected patient hand = 0.65+/-0.10; LI dominant normal hand = 0.65+/-0.11; LI nondominant normal hand = 0.69+/-0.11; P < 0.05) due to trends toward increased ipsilateral motor cortical activation. Motor function testing showed that patients made significant gains in functional use of the stroke-affected upper extremity (detected by the Motor Activity Log) and significant reductions in motor impairment (detected by the Fugl-Meyer Stroke Scale and the Wolf Motor Function Test) immediately after CIMT, and these effects persisted at 6-month follow-up. The behavioral effects of CIMT were associated with a trend toward a reduced LI from pre-intervention to immediately post-intervention (LI = -0.01+/-0.06, P = 0.077) and 6 months post-intervention (LI = -0.03+/-0.15). Stroke-affected hand movement was not accompanied by mirror movements during fMRI, and electromyographic measures of mirror recruitment under simulated fMRI conditions were not correlated with LI values. These data provide preliminary evidence that gains in motor function produced by CIMT in chronic stroke patients may be associated with a shift in laterality of motor cortical activation toward the undamaged hemisphere.     

Characteristics of visits to licensed acupuncturists,chiropractors, massage therapists,and naturopathic physicians

BACKGROUND: Despite growing popularity of complementary and alternative medical (CAM) therapies, little is known about the patients seen by CAM practitioners. Our objective was to describe the patients and problems seen by CAM practitioners. METHODS: We collected data on 20 consecutive visits to randomly sampled licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians practicing in Arizona, Connecticut, Massachusetts, and Washington. Data were collected on patient demographics, smoking status, referral source, reasons for visit, concurrent medical care, payment source, and visit duration. Comparative data for conventional physicians were drawn from the National Ambulatory Medical Care Survey. RESULTS: In each profession, at least 99 practitioners collected data on more than 1,800 visits. More than 80% of visits to CAM providers were by young and middle-aged adults, and roughly two thirds were by women. Children comprised 10% of visits to naturopathic physicians but only 1% to 4% of all visits to other CAM providers. At least two thirds of visits resulted from self-referrals, and only 4% to 12% of visits were from conventional physician referrals. Chiropractors and massage therapists primarily saw musculoskeletal problems, while acupuncturists and naturopathic physicians saw a broader range of conditions. Visits to acupuncturists and massage therapists lasted about 60 minutes compared with 40 minutes for naturopathic physicians and less than 20 minutes for chiropractors. Most visits to chiropractors and naturopathic physicians, but less than one third of visits to acupuncturists and massage therapists, were covered by insurance. CONCLUSIONS: This information will help inform discussions of the roles CAM practitioners will play in the health care system of the future.