Biomedical subjects
B E Schneider
Publications and source records attributed to B E Schneider.
Differences in the capacity of reovirus strains to induce apoptosis are determined by the viral attachment protein sigma 1.
Reoviruses are important models for studies of viral pathogenesis; however, the mechanisms by which these viruses produce cytopathic effects in infected cells have not been defined. In this report, we show that murine L929 (L) cells infected with prototype reovirus strains type 1 Lang (TIL) and type 3 Dearing (T3D) undergo apoptosis and that T3D induces apoptosis to a substantially greater extent than T1L. Using T1L x T3D reassortant viruses, we found that differences in the capacity of T1L and T3D to induce apoptosis are determined by the viral S1 gene segment, which encodes the viral attachment protein sigma 1 and the non-virion-associated protein sigma 1s. Apoptosis was induced by UV-inactivated, replication-incompetent reovirus virions, which do not contain sigma 1s and do not mediate its synthesis in infected cells. Additionally, T3D-induced apoptosis was inhibited by anti-reovirus monoclonal antibodies that inhibit T3D cell attachment and disassembly. These results indicate that sigma 1, rather than sigma 1s, is required for induction of apoptosis by the reovirus and suggest that interaction of virions with cell surface receptors is an essential step in this mechanism of cell killing.
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition.
The relationship between four pharmacologically distinct NMDA receptor subtypes, identified in radioligand binding studies, and the recently identified NMDA receptor subunits (NR1a-g, NR2A-D) has not been determined. In this report, we demonstrate that the anatomical distribution of the four NMDA receptor subtypes strikingly parallels the distribution of mRNA encoding NR2A-D subunits. The distribution of NR2A mRNA was very similar to that of "antagonist-preferring" NMDA receptors [defined by high-affinity 3H-2-carboxypiperazine-4-yl-propyl-1-phosphonic (3H-CPP) binding sites; correlation coefficient = 0.88]. Agonist-preferring NMDA receptors localized to brain regions expressing both NR2B mRNA and NR1- mRNA (NR1 splice variant lacking insert 1). NR2C mRNA was largely restricted to the cerebellar granule cell layer, a region that displays a unique pharmacological profile. NR2D mRNA localized exclusively to those diencephalic nuclei that have a fourth, distinct pharmacological profile (typified by the midline thalamic nuclei). The pharmacology of native NMDA receptors was compared to that of heteromeric NMDA receptors expressed in Xenopus oocytes (NR1/NR2A, NR1/NR2B, NR1/NR2C). The oocyte-expressed NR1/NR2A receptor displayed a higher affinity for antagonists and a slightly lower affinity for agonists than the NR1/NR2B receptor. These patterns are analogous to those found for radioligand binding to native receptors in the lateral thalamus and medial striatum, respectively. NMDA receptors in the lateral thalamus (with a high density of NR2A subunit mRNA) displayed higher affinity for antagonists and a lower affinity for agonists than did NMDA receptors of the medial striatum (a region rich in NR2B mRNA). Relative to the NR1/NR2A and NR1/NR2B receptors, oocyte-expressed NR1/NR2C receptors had a lower affinity specifically for both D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene) and homoquinolinate (HQ). This pattern was identical to that observed for cerebellar (NR2C-containing) versus forebrain (NR2A- and NR2B-containing) NMDA receptors. Taken together, the data in this report suggest that the four previously identified native NMDA receptor subtypes differ in their NR2 composition. Furthermore, the NR2 subunits significantly contribute to the anatomical and pharmacological diversity of NMDA receptor subtypes.
Reassessment of verbal and visual analog ratings in analgesic studies.
The relative performance of three analgesic rating scales--visual pain analog, verbal pain intensity, and verbal pain relief--was assessed in clinical trials with 1,497 patients and a variety of pain models. The scales correlated strongly with one another, with inconsistent and generally minimal differences in sensitivity. Overall, the verbal relief scale tended to be slightly more sensitive than the pain analog rating, which in turn showed a small advantage over the verbal pain intensity assessment. When the scores derived from the categorized ratings 1 hour after drug dosing (generally the time of peak effect) were analyzed, there was little difference whether a parametric or nonparametric approach was taken. When the cumulative measures of overall effect over 6 hours were considered, however, the nonparametric approach was decidedly more powerful. There was a similar pattern when the analog scores were analyzed. This unanticipated finding appears to be due to the cumulative measures (from all three scales) being more skewed toward the lower end of their respective ranges than are the 1-hour scores. A composite efficacy variable was defined, incorporating data from the three primary scales; this measure was found to be generally comparable in sensitivity to the individual scales and may be useful as a global summary of response. While our investigation provides evidence that any of the ratings considered will accurately reflect analgesic response, the verbal relief scale was the most sensitive and might be the best choice if a single measure is desired.
Recent methods for assessing effectiveness of antihypertensive agents.
Clinically relevant graphic approaches to the assessment of patients' blood pressure responses to antihypertensive agents are reviewed and extended to include both statistical components and the effects of treatment-related patient discontinuations. Regression line fits of change in diastolic blood pressure (DBP) versus baseline diastolic blood pressure (BDBP) are used for multicenter comparisons of placebo, guanabenz, methyldopa, clonidine, propranolol, hydrochlorothiazide, and the combination of guanabenz plus hydrochlorothiazide. Orientations of the fitted lines can be contrasted to certain "ideal" response profiles and are particularly useful for comparative purposes. An additional graphic approach was developed to show overall "therapeutic" response rate categories, two of which account for patients discontinuing treatment because of nonresponse or adverse effects. This approach assesses antihypertensive effectiveness, "adjusted" for the effects of treatment-related patient withdrawal, thus addressing criticisms often raised in the evaluation of such agents. Although these methods are generally useful for comparing agents used in chronic disease therapy, further work is needed to extend these procedures to incorporate safety assessments and overall benefit-risk considerations in the selection of treatment modalities.
Long-term therapy of hypertension with guanabenz.
Guanabenz, a centrally acting antihypertensive (alpha-agonist) that does not induce secondary sodium retention or other metabolic disturbances, was evaluated for up to two years at 19 investigational sites. In 329 patients completing six months of therapy, the mean supine diastolic blood pressure (SDBP) fell from 101 to 90 mmHg (P less than 0.01). Clinically significant individual SDBP decreases occurred in 74% of the patients by week 2, and these reductions were maintained in 72% at six months. Mean weight was reduced 1.4 lb (P less than 0.01), and mean supine pulse rate was decreased 5 beats/min (P less than 0.01). The most frequent effective doses were 8 and 16 mg BID (range, 2 to 32 mg BID). Principal side effects, usually mild, were sedation (31%), dry mouth (24%), dizziness (6%), and weakness (6%). Postural hypotension, impotence, and abrupt discontinuation symptoms were rare or absent. There were no clinically significant drug-related laboratory changes other than a 10 mg/100 ml mean serum cholesterol decrease. Two hundred twenty-two patients completed one year of therapy, and 80 completed two years, with little change in any parameters other than improvement in mean SDBP to 85 mmHg and in individual response rate to 84%. These results suggest that guanabenz is safe and effective for initial and sole therapy of hypertension.
Comparative antihypertensive effects of guanabenz and methyldopa.
The effects of guanabenz acetate, a centrally acting alpha-adrenergic, non-sodium-retaining antihypertensive agent, were compared with those of methyldopa in 248 hypertensive outpatients during a one-year, double-blind, multi-center study. Mean supine diastolic blood pressure (SDBP) decreased from 102 to 91 mmHg (P less than 0.01) among 78 guanabenz-treated patients and from 101 to 92 mmHg (P less than 0.01) among 89 methyldopa-treated patients who completed six months of treatment. Clinically significant individual SDBP decreases occurred in 76% of the guanabenz-treated patients and in 63% of the methyldopa-treated patients (P less thn 0.05). Blood pressure remained unchanged during the second six months, with response of 82% and 60%, respectively, for guanabenz and methyldopa (P less than 0.05). Although drowsiness and dry mouth occurred more frequently with guanabenz, evidence of fluid retention, such as weight gain, edema, and congestive heart failure, was significantly more frequent with methyldopa than with guanabenz. Because it does not induce volume expansion, guanabenz, unlike methyldopa, may be useful as sole initial antihypertensive therapy.
Clinical effects of ethynyl estrogens, used with and without progestational agents, on bleeding patterns, weight, and blood pressure.
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Effects of placebo versus guanabenz on hypertensive out-patients.
The objectives of this study were two-fold: (1) 1 4-week multicentre, randomized, double-blind efficacy comparison of placebo and guanabenz acetate, a new centrally acting antihypertensive drug, in 168 hypertensive out-patients and (2) a more accurate determination of the incidence of drug-related, non-specific side-effects. Both treatment groups were comparable: 68% female, 63% black, mean age 53 years; 57% mild, 32% moderate, 11% moderately severe hypertensives. Seventy-six placebo patients completed 4 weeks and had a mean supine diastolic blood pressure (SDBP) decrease from 105 to 101 mm Hg (p < 0.01). Seventy-nine guanabenz patients completing 4 weeks had a mean SDBP decrease from 104 to 92 mm Hg (p < 0.01). All of the placebo responses and 10/12 mm Hg of the guanabenz response occurred during Week 1. Clinically significant individual SDBP decreases occurred in thirty-one (41%) placebo and fifty-five (70%) guanabenz-treated patients (p < 0.01). Mean daily guanabenz dose was 24 mg. Drug-related biochemical or electrocardiographic abnormalities were absent. Side-effects of sedation and dry mouth were recorded two and three times more frequently, respectively, in guanabenz as compared to placebo patients. Side-effects usually occurred within Week 1 and diminished in incidence thereafter. Consequently, in these patients it appeared that: (1) guanabenz was an effective, well-tolerated drug, (2) placebo effects on efficacy were significant, occurred early and remained stable, and (3) placebo and guanabenz side-effects were mainly sedation and dry mouth.