Cerebral ventricular enlargement in schizophrenia. A preliminary follow-up study.

Lateral cerebral ventricular enlargement is now known to occur in some schizophrenic patients. To determine whether ventriculomegaly in schizophrenia is a static vs progressive process, we conducted a follow-up computed tomographic brain scan study on 11 young male patients, three years after initial scans were obtained. No significant change was found in the mean ventricles-brain ratio of this small schizophrenic sample after three years. Four of 11 patients showed noticeable increases (greater than 50%) in individual ratio. Methodologic problems are discussed and the need for follow-up studies as a research strategy is emphasized.

Structural abnormalities in the frontal system in schizophrenia. A magnetic resonance imaging study.

Thirty-eight schizophrenics and 49 normal controls underwent magnetic resonance imaging. Midline sagittal cuts indicated that the schizophrenics had significantly smaller frontal lobes, as well as smaller cerebrums and craniums. The findings are consistent with some type of early developmental abnormality that might retard brain growth and therefore skull growth. These findings are confirmed on a smaller sample of patients on whom we have coronal cuts. Decreased cerebral and cranial size are associated with prominent negative symptoms, although decreased frontal size is not. Decreased cranial and cerebral size was also associated with impairment on some cognitive tests. These findings are consistent with the hypothesis that some schizophrenics may have a type of early developmental abnormality associated with prominent negative symptoms and cognitive impairment. Further, the results suggest that schizophrenics may have a type of structural frontal system impairment. Thus, they provide anatomic evidence for the "hypofrontality hypothesis."

Induced cytoskeletal changes in bovine pulmonary artery endothelial cells by resveratrol and the accompanying modified responses to arterial shear stress.

BACKGROUND: Atherosclerosis and coronary heart disease (CHD) are significant contributors to morbidity and mortality in developed countries. A noted exception is the low mortality of CHD in France, particularly the southwest region. This phenomenon, commonly referred to as the French paradox, may be associated with high consumption of red wine. We investigate whether the cardioprotective activity of red wine may involve the grape skin-derived polyphenol, resveratrol. We further test the possibility that resveratrol acts by modulating structural and functional changes in endothelial cells lining the blood vessel wall. RESULTS: Bovine pulmonary artery endothelial cells (BPAEC) were incubated with resveratrol, with and without concurrent exposure to simulated arterial shear stress. Resveratrol significantly affected proliferation and shape of BPAEC; growth was suppressed and cells became elongated, based on morphologic analysis of rhodamine-conjugated phalloidin stained F-actin by confocal microscopy. Using selective signaling inhibitors, we showed that the resveratrol-induced cellular phenotype was dependent on intracellular calcium and tyrosine kinase activities, and assembly of actin microfilaments and microtubules, but was unrelated to PKC activity. Exposure to simulated arterial flow revealed that, whereas controls cells easily detached from the culture support in a time-dependent manner, resulting in total cell loss after a 5 min challenge with simulated arterial flow conditions, a significant percentage of the treated cells remained attached to the cultured plastic coverslips under identical experimental conditions, suggesting that they adhered more strongly to the surface. Western blot analysis shows that whereas cells treated with 25 microM and 100 microM resveratrol had no change in total ERK1/2, treatment did result in an increase in phosphorylated ERK1/2, which probably involved stabilization of the active enzyme. An increase in nitric oxide synthase expression was detected as early as 6 h and persisted for up to 4 days of treatment. CONCLUSIONS: Results of our studies show that resveratrol interacts with endothelial cells in vitro to elicit morphological and structural changes; the observed changes support the interpretation that resveratrol acts as a cardioprotective agent.

Third-ventricle enlargement and neuropsychological deficit in schizophrenia.

Cerebral ventricular enlargement is present in a substantial subgroup of schizophrenic patients. Most, but not all studies examining neuropsychological performance and ventricular size in schizophrenics show more severe cognitive impairment in those patients with greatest ventricular enlargement. Inconsistencies in this literature have been attributed to different neuroimaging techniques, variation in patient characteristics across studies, and the variety of neuropsychological batteries used. In the present study, schizophrenic patients (n = 49 men, n = 23 women) and normal controls (n = 13 men, n = 18 women) underwent magnetic resonance (MR) imaging of the brain and extensive neuropsychological testing including measures of frontal and temporal lobe function. A complete coronal set of MR images was used to calculate volumetric estimates of lateral and third cerebral ventricles. Highly significant associations were found between cognitive deficits and third-ventricle volume, with measures of frontal functioning, attention, and concentration showing the most robust correlations. In contrast, neuropsychological performance was not highly associated with lateral ventricular size. These findings further support the pathophysiological relevance of ventricular enlargement in schizophrenia. More specifically, third, but not lateral, ventricular enlargement was associated with greater cognitive disturbance in this sample. Results are consistent with pathological involvement of periventricular diencephalic structures resulting in dysfunctional frontal and limbic processing in a subgroup of patients.

Cognitive impairment and cerebral structure by MRI in bipolar disorder.

The distinction between bipolar disorder and schizophrenia customarily follows examination of the clinical symptomatology and course of illness. The presence of cognitive impairment has been held to be uncommon in bipolar disorder and more likely in schizophrenia. This study explored neuropsychological function in 30 ambulatory outpatients with a DSM-III-R diagnosis of bipolar affective disorder (all of whom had been psychotic during manic episodes), comparing their performance with that of controls. These bipolar patients proved to have significant levels of diffusely represented cognitive impairment when compared with controls. Further, the degree of impairment was significantly correlated with reduction in midsagittal areas of brain structures measured on magnetic resonance imaging scans. The implications of these findings in relation to bipolar disorder are discussed.

Perinatal brain injury and cerebellar vermal lobules I-X in schizophrenia.

Several studies, including our own, have reported atrophy of the cerebellar vermis in some schizophrenic patients. A recent report by Courchesne et al (1988) of hypoplasia of a developmentally specific region of the cerebellar vermis in autism prompted us to hypothesize that the cerebellar "atrophy" in some schizophrenic patients may also have developmental origins. We measured the area of the vermal lobules in 30 male schizophrenics. Contrary to expectation, the patients as a group had consistently larger cerebellar structures than the controls. Patients with perinatal injury had smaller structures than the nonperinatally injured group, but these measures were still larger than in the control subjects. Patients without perinatal injury differed from controls, having larger lobules VI-VII (p less than 0.03). These preliminary findings tentatively suggest a role for developmental factors for cerebellar structures in schizophrenia. Further research is needed to clarify the cerebellar vermal changes observed in some schizophrenic patients.

A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia.

Two previous postmortem studies reported an increased thickness of the corpus callosum in schizophrenic patients compared to psychiatric controls. We report an in vivo study of the corpus callosum in schizophrenic patients (n = 38) and healthy controls (n = 41) using magnetic resonance (MR) brain imaging. A significant increase in mean callosal thickness was found in the middle and anterior, but not the posterior, parts of the callosal body. However, when the patients and controls were compared by gender and handedness, schizophrenic men were found not to differ from control men in callosal thickness, regardless of handedness, whereas schizophrenic women were found to have a highly significant increase in callosal middle and anterior thickness compared to control women. The data suggest that increased callosal thickness in schizophrenia is gender related, a factor that is not considered by postmortem studies. The implications of increased callosal dimensions in female schizophrenics are discussed.

Fluoride activates diradylglycerol and superoxide generation in human neutrophils via PLD/PA phosphohydrolase-dependent and -independent pathways.

In contrast to the rapid, ethanol-inhibited superoxide generation by the receptor-linked agonist formyl-methionyl-leucyl-phenylalanine (fMLP), fluoride-activated superoxide generation occurs after a prolonged lag, and as shown herein is relatively ethanol-insensitive. We have investigated fluoride-activation of diradylglycerol generation and phospholipase D activity. Fluoride induces a very large increase in diradylglycerol mass (both 1,2-diacylglycerol (DAG) and 1-O-alkyl,2-acylglycerol (EAG)), with kinetics similar to superoxide generation. Unlike fMLP-activated diglyceride generation which is completely inhibited by ethanol, that produced by fluoride is only partially (30%) blocked. When the phosphatidylcholine pool is 3H-prelabeled, fluoride activates both [3H]phosphatidic acid (PA) and [3H]diglyceride generation with similar kinetics. Partial inhibition of the production of these species by ethanol was seen, coincident with the appearance of [3H]phosphatidylethanol, indicating phospholipase D-dependent transphosphatidylation had occurred. The data are consistent with the fluoride activation of PA and diglyceride generation by both phospholipase D-dependent and -independent (presumably phospholipase C) mechanisms.

Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis.

BACKGROUND: Continued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. METHODS: All drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. RESULTS: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. CONCLUSIONS: Use of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.

Midsagittal cerebral anatomy by magnetic resonance imaging. The importance of slice position and thickness.

Several recent studies of psychiatric patients have relied upon magnetic resonance imaging (MRI) to demonstrate features of cerebral anatomy in the midsagittal plane. Methodologies have varied somewhat in relation to thickness and position of planes of view. Due to concerns over the effects of slice thickness and position on measurements, the authors used a multislice thin plane method to assess these effects in 143 individuals (34 controls, 58 schizophrenics, and 51 with bipolar or schizoaffective disorder). Substantial variance in area measurements attributable to slice position emerged, especially in ventricular, cerebral and cerebellar area. Of greater importance would be the demonstrated interaction of position with diagnosis and sex in measures of several regions. The implications of these findings for MRI studies are discussed.

Neuropsychological correlates of negative, disorganized and psychotic symptoms in schizophrenia.

Recent studies suggest that three dimensions (negative, disorganized and psychotic) categorize schizophrenic symptoms. A developing literature indicates distinct cerebral correlates of each symptom cluster, but few investigations have determined their neuropsychological correlates. In the present study, the Schedules of Negative and Positive Symptoms measured symptom severity in 62 schizophrenics, and a subsequent principal components analysis revealed three symptom dimensions. Factor scores, age and parental socio-economic status were simultaneously entered into regression equations to explain variance across a broad neuropsychological test battery. Negative symptoms were associated with deficits involving intelligence, executive function, memory, sustained-attention and sensory-motor function, whereas disorganized symptoms correlated with decreased intelligence, attention-span and sensory-motor function. Psychotic symptoms were unrelated to deficits. These data are consistent with hypotheses that these three symptom dimensions have distinct neurobehavioral correlates.

Antisense oligonucleotides to c-fos and c-jun inhibit intimal thickening in a rat vein graft model.

BACKGROUND: C-fos and c-jun are 2 immediate early genes that have been implicated in the stimulation of vascular smooth muscle cell proliferation and migration. In previous experiments in our laboratory with a rat vein graft model a 2- to 3-fold increase of messenger RNA of c-fos and c-jun were noted 1 hour after vein graft perfusion. Because c-fos and c-jun are up-regulated after the perfusion of vein grafts, the purpose of this study was to delineate the temporal expression of c-fos and c-jun protein and to study the effect of antisense oligonucleotides (ASO) to c-fos and c-jun on intimal thickening observed in this model. METHODS: Sprague-Dawley rats underwent bilateral interposition femoral artery grafts with use of the superficial epigastric vein, which was harvested from 15 minutes up to 2 weeks and analyzed by Western blot for Fos and Jun protein. Additional rats underwent bypasses and at the time of the procedure 1 graft was treated with a pluronic gel containing an ASO to c-fos, c-jun, or sense and the contralateral side was treated with pluronic gel only. The vein grafts were harvested 2 weeks after the procedure and perfusion fixed. After longitudinal sectioning, the intimal and total wall thicknesses were measured in the perianastamotic and midgraft regions by a morphometric digitizing microscope and the statistics were analyzed by a paired Student's t test. RESULTS: Protein analysis by Western blot showed that c-fos levels rose quickly within 2 hours and leveled at 6 hours 40-fold above basal levels after vein graft perfusion. Similarly, c-jun levels rose 10-fold above basal levels after 15 minutes and peaked at 2 hours 120-fold above basal levels. The treatment of the vein grafts with these ASOs resulted in a reduction of about 30% in the thickness of the intimal layer and the total wall thickness in both the perianastomotic and the midgraft regions, which was statistically significant different from control veins. CONCLUSION: These results indicate a possible therapeutic role for ASO to immediate early genes in the treatment of vein graft intimal hyperplasia.

Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine.

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120-mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80-mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration-time curve extrapolated to infinity (AUC0-infinity), and a 2% decrease in elimination half-life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0-infinity and a 51 % increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.

Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin.

The objective of this study was to determine the effects of renal dysfunction on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, lambda z (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady-state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.

Pharmacokinetics of quinapril and its active metabolite quinaprilat during continuous ambulatory peritoneal dialysis.

The pharmacokinetics of quinapril, a novel angiotensin converting enzyme (ACE) inhibitor, and its active metabolite, quinaprilat, were determined following a single 20-mg oral dose of quinapril in six patients with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD). Overall, quinapril was well tolerated by these CAPD patients, with mild and transient side effects, not unexpected in this clinical setting, which included pruritus, headache, nausea, and cough. Blood pressure reduction was observed in four of six patients, with onset reliably two to four hours after dosing and duration up to 48 hours, associated with quinaprilat concentrations in plasma above 90 ng/mL for at least 33 hours postdose. Two patients experienced significant hypotension, systolic blood pressure below 90 mm Hg, which responded promptly to oral fluid administration and/or reduction in dialysate tonicity. The pharmacokinetic profile of quinapril in these CAPD patients was not significantly different from that previously observed in healthy subjects with normal renal function and in patients with moderate to severe renal dysfunction not yet requiring dialysis (RDND). The apparent elimination half-life of quinapril was approximately one hour, with negligible dialysate excretion. The pharmacokinetic profile of quinaprilat in these CAPD patients was similar to that previously observed in patients with RDND. The elimination half-life of quinaprilat was markedly prolonged when compared to that in healthy subjects and averaged 20 hours, with only a small amount of quinaprilat excreted in dialysate (mean = 2.6% of total dose).(ABSTRACT TRUNCATED AT 250 WORDS)

Erythromycin coadministration increases plasma atorvastatin concentrations.

The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0-infinity) increased by 37.7% and 32.5%, respectively. Mean terminal half-life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first-pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P-glycoprotein-mediated intestinal or biliary secretion.

Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients on chronic hemodialysis.

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end-stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20-mg oral dose of quinapril 4 hours before a 4-hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half-life of 1.7 hours. Quinapril was extensively de-esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half-life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr less than 29 mL/min) not yet requiring hemodialysis (RDND).

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients with various degrees of renal function.

Single- and multiple-dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, were determined after oral administration of 20 mg quinapril HCl on day 1 and days 4 through 10 in 17 normotensive subjects with various degrees of renal function. Blood and urine samples were collected over 72- and 24-hour periods, respectively, after the first single dose and last multiple dose for measurement of quinapril and quinaprilat concentrations. The renal clearance of quinapril and quinaprilat decreased with increasing renal insufficiency but did not result in significant changes in quinapril pharmacokinetics in patients with renal impairment. In contrast, quinaprilat maximum plasma concentration, trough and peak steady-state plasma concentrations, area under the plasma concentration-time curve, and half-life increased significantly with increasing renal insufficiency. The disposition of quinapril and quinaprilat was unchanged from single to multiple doses. Small changes in the pharmacokinetic disposition of quinapril, together with a decreased rate of quinaprilat elimination, resulted in increased quinaprilat plasma concentrations following administration of both single and multiple quinapril doses to normotensive patients with renal impairment. Thus, quinapril dosage adjustment may be required in some patients with renal impairment.

Pharmacodynamics and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an HMG-CoA reductase inhibitor.

The objective of this study is to determine the relationships between plasma atorvastatin concentrations, LDL (low-density lipoprotein) cholesterol reduction, and atorvastatin dose; the earliest time at which lipid levels change when atorvastatin treatment is initiated or discontinued; and alterations in LDL particle composition. Twenty-four subjects with elevated LDL-cholesterol were treated with escalating daily doses of 5, 20, and 80 mg atorvastatin for 6 weeks each. Serial plasma lipid and lipoprotein analyses were performed during the initiation and discontinuation of atorvastatin therapy, as well as at steady state. LDL-apolipoprotein B and LDL-cholesterol were measured directly after ultracentrifugation, and LDL-cholesterol also was estimated by the method of Friedewald. Steady-state atorvastatin pharmacokinetic parameters were estimated on the last day of each dosing period. LDL-cholesterol (Friedewald) reductions of 34%, 43%, and 57% were produced by atorvastatin doses of 5, 20, and 80 mg, respectively. The mean dose-response relationship was log linear, and almost all individual dose-response curves paralleled the mean curve. LDL-apolipoprotein B reductions were slightly less than those of LDL-cholesterol. Atorvastatin area under the curve (AUC(0-24) values increased proportionally with dose, while values of Cmax (maximum concentration) increased more than proportionally, and Cmin (minimum concentration) increased less than proportionally. Following initiation of dosing, statistically significant decreases in total cholesterol, LDL-cholesterol (beta quant), and LDL-apolipoprotein B were observed within 24 hours and in LDL-C (Friedewald) within 72 hours. Following discontinuation of drug dosing, statistically significant increases were observed in total cholesterol and LDL-cholesterol (Friedewald) within 48 hours and in LDL-cholesterol (beta quant) and LDL-apolipoprotein B within 72 hours. At each dose, an individual's LDL-cholesterol response was not correlated with AUC(0-24). In conclusion, atorvastatin produces marked LDL-cholesterol reductions, the mean dose-response relationship is log linear, almost all individual dose-response curves parallel the mean dose-response curve, onset and cessation of action are rapid, the estimated and measured LDL-cholesterol are the same, LDL-cholesterol and LDL-Apo B reductions are similar, and plasma concentrations are not correlated with LDL-cholesterol reduction at a given dose.

Gender differences in schizophrenia on MRI brain scans.

There are many reports of clinical and biological gender differences in schizophrenia. Gender differences in structural brain abnormalities in schizophrenia have been reported on both computed tomographic (CT) and magnetic resonance imaging (MRI) scans. We present here a new MRI study of cerebral structures in schizophrenia. On the basis of previous findings, we hypothesized that schizophrenic males are more likely than females to show smaller brains and larger ventricles compared to their control counterparts. Our results indicated that the opposite was true: schizophrenic females, but not schizophrenic males, had smaller craniums and brains and larger lateral and third ventricles on MRI scans. The possible significance and implications of these data are discussed.