Neuropsychologic status in multiple sclerosis after treatment with glatiramer

BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.     

The effect of valproic acid on blood loss in patients with cerebral palsy

Valproic acid (VPA) is used in the treatment of seizure disorders often present in patients with cerebral palsy. The charts of 114 patients with cerebral palsy were reviewed to evaluate the effect of VPA on blood loss during spine surgery. Forty-one patients had seizure disorders. Of these, 18 were taking VPA as monotherapy (group III) and the remaining 23 patients were taking other antiseizure medications, including two taking VPA (group II). There was a significant increase in the number of patients with abnormal bleeding times and a significant difference (p < 0.001) in blood loss (ml/kg) in patients taking VPA as monotherapy (38.6 ml/kg vs. 30.0 ml/kg). There was also increased blood-product administration postoperatively in the VPA monotherapy patients. Physicians should be aware of this potential association between VPA use and increased blood loss. The routine laboratory tests of complete blood count, prothrombin time, and partial thromboplastin time will not adequately screen for the platelet-mediated effects of VPA.     

Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.     

Acetaminophen (paracetamol) levels in human tears.

This study was designed to measure acetaminophen (paracetamol) levels in tears, and to compare it to serum levels. Paracetamol levels were measured in 20 paired tears and serum samples from 10 healthy volunteers, 1 and 2 hours after ingesting 1.5 g paracetamol. Tears were collected using glass microcapillary tubes while stimulating the conjunctiva with a small sponge placed in the lower fornix. Blood samples were taken simultaneously. The samples were analyzed for paracetamol levels using homogeneous enzyme immunoassay. Tears and serum paracetamol levels 1 hour after ingestion were 16.3 microg/mL +/- 7.2 (mean +/- SD), and 21.4 microg/mL +/- 7.7 (mean +/- SD) respectively. Tears and serum levels 2 hours after ingestion were 14.4 microg/mL +/- 7.8 (mean +/- SD), and 17 microg/mL +/- 7.6 (mean +/- SD) respectively. Tears and serum paracetamol levels of all the 20 paired samples (1 h and 2 h after ingestion) were 15.35 microg/mL +/- 7.4, and 19.25 microg/mL +/- 7.8, respectively (mean +/- SD). There was a strong and highly significant correlation between paracetamol levels in serum and in tears 1 and 2 hours after ingestion (r = 0.8, p = 0.005, r = 0.85, p = 0.002 respectively). Mean +/- SD ratio of tears/serum paracetamol levels 1 hour and 2 hours after ingestion were 0.77 +/- 0.21 and 0.81 +/- 0.25 respectively. Delta tears (difference in mean levels at 1 and 2 hours) paracetamol levels is significantly correlated with delta serum levels (r = 0.7, p = 0.025). A reliable, convenient, and feasible noninvasive method is described for measuring paracetamol in tears. There is no information in the literature about tears paracetamol secretion, and little information of tears drugs concentration.     

Sedative antidepressants impair visual detection mechanisms in humans

The safety of sedative antidepressants is a topical issue in the treatment of depression, with driving impairment being of particular concern. We have recently completed a study with normal male volunteers comparing the actions of dothiepin (a traditional, sedating antidepressant) with those of fluvoxamine (one of the selective serotonin re-uptake-inhibiting SSRI class of newer antidepressants) on psychomotor functions relevant to driving. We set out to investigate whether these drugs impair visual selective attention (focused and divided) by employing the 'odd-ball' task. Subjects were required to respond to letters of the alphabet (T for target and other letters for non-targets) that were presented at the centre and/or periphery of the computer screen. The task has been shown to be useful in detecting differences between drugs in their effects on selective attention. Preliminary results show that dothiepin delayed responses to single targets compared with fluvoxamine and placebo. There was also preliminary evidence that it mainly affected response times to peripheral targets. Furthermore, there was preliminary evidence that both drugs delayed responses to central targets compared with placebo on the divided attention trials. Finally, response accuracy in detecting peripheral targets was greater under placebo compared with fluvoxamine and dothiepin. The impairment produced by dothiepin is presumably a consequence of the central blockade of cholinergic muscarinic or histaminergic H1 receptors. It could contribute to the reported association between the tricyclic class of antidepressants and road traffic accidents, and would be worth further investigation in depressed patients taking both classes of drug.     

Application of the Electrotopological State Index to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors

Purpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design. Methods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models. Results. Predictive models with correlation coefficients (r²) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r²) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis. Conclusions. E-state indices at C6, C3, C5, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.     

Dental examinations for quality control: peer review versus self-assessment.

This paper reports the dental care norms for restorative dentistry collected from examinations of 1,466 patients in 105 dental offices in Washington State during 1976. These results are part of a larger study, "Assessment of Care and Continuing Dental Education," being conducted by the University of Washington with the endorsement and cooperation of the Washington State Dental Association. Treatments in volunteer offices were evaluated either by colleagues (peer review) or by the practitioner himself (self-assessment). Two hundred twenty-four of 1,196 eligible dentists volunteered for the study. Patients from the practitioners' offices were randomly selected from office files by project staff. The study tests the proposition that, using standardized clinical evaluation procedures and comparable samples of treatment, dentists will be more critical of their own work than that of others. Results suggest a generally high level of care provided by volunteer practitioners and that self-assessments were significantly more critical than peer review.     

Screening for hypertension

A strategy for the control of hypertension in communities is presented as a staged program. Stage I consists of the evaluation and improvement of hypertension management in health care facilities. State II entails case-finding in health care facilities. Finally, Stage III involves targeted screening in the community. While isolated screening programs have been justly labeled irrational, such a sequential strategy represents a highly rational approach to the community control of hypertension.Dr. Gillum is with the Laboratory of Physiological Hygiene, University of Minnesota School of Public Health, Minneapolis, Minnesota 55455. Dr. Stason is with the Center for the Analysis of Health Practices, Harvard School of Public Health, Boston, Massachusetts 02115. Dr. Weinstein is with the John F. Kennedy School of Government, Harvard University, Cambridge, Massachusetts 02138. This work was supported in part by grant F32HL5018 from the National Institutes of Health. The Hypertension Screening Group of the 1974–75 Harvard School of Public Health Faculty Seminar on the Analysis of Health and Medical Practices provided an ongoing forum for the development of this work.     

Isoantigens A, B and H in urinary bladder carcinomas following radiotherapy

ABH tissue isoantigens were measured by the Specific Red Cell Adherence (SRCA) test in 66 surgical specimens of urinary bladder, including 53 transitional cell carcinomas, 2 squamous cell carcinomas and 11 controls. The SRCA test was strongly positive in 10 of 11 controls. ABH isoantigens were absent or equivocally present in 68 percent of noninvasive carcinomas (stage 0) and in 65 percent of invasive carcinomas. Clinical histories revealed that all patients with invasive carcinoma who had strongly positive SRCA test results had received prior radiotherapy to the bladder region. None of the patients with invasive bladder carcinoma with negative or weakly positive SRCA tests had been radiated. Histopathology of tumors in both groups was similar. Results of this retrospective study support the hypothesis that radiation may induce differentiation in tumors, possibly through an enhancement of Golgi apparatus function. The SRCA test should not be used as a predictor of the biological behavior of future recurrences in patients with bladder carcinoma who have received therapeutic radiation since radiation may produce "false positive" SRCA test results.