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Biomedical subjects

B G Miller

Publications and source records attributed to B G Miller.

At least 37 records · Page 2Linked to original sources

Crystallization of native and selenomethionyl yeast orotidine 5'-phosphate decarboxylase.

Crystals of the Saccharomyces cerevisiae pyrimidine biosynthetic enzyme orotidine 5'-phosphate decarboxylase (ODCase) were grown by the hanging-drop vapor-diffusion technique at 277 K using polyethylene glycol 4000 as the precipitant. Crystals of native and selenomethionyl ODCase diffract to less than 2.2 A and belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 90.1, b = 116.2, c = 117.0 A. Crystals of ODCase grown in the presence of the postulated transition-state analog inhibitor 6-hydroxyuridine 5'--phosphate (BMP) diffract to less than 2.5 A and belong to space group P2(1), with unit-cell parameters a = 79.9, b = 80.0, c = 98.2 A, beta = 108.6 degrees.

Crystallization↗

Activity of yeast orotidine-5'-phosphate decarboxylase in the absence of metals.

Yeast orotidine-5'-phosphate decarboxylase was recently shown to contain zinc and to be inhibited by zinc-complexing agents. When the gene for the yeast enzyme was expressed in Escherichia coli, the gene product was devoid of metal atoms but exhibited a specific activity and molecular mass similar to those of the enzyme obtained directly from yeast. This invalidates the hypothesis that zinc is involved in substrate decarboxylation. The zinc-free enzyme undergoes thermal inactivation at a somewhat lower temperature than does the zinc-containing enzyme isolated from yeast.

Escherichia coli↗

Relationships among metabolites influencing ovarian function in the dairy cow.

Time series analysis was used to evaluate relationships between the uptake of metabolites, ovarian blood flow, arterial LH concentrations, and the output of steroid hormones by the ovary. There were no significant correlations between cholesterol uptake and progesterone output; therefore, cholesterol uptake was not a factor that immediately limited progesterone output. Although no significant correlations were found between cholesterol and oxygen uptake, significant cross-correlations between the uptake of glucose and oxygen by the ovary at lag 0 indicated some immediate oxidation of glucose. This result strongly indicates that glucose is a major source of energy for the bovine ovary. Arterial LH concentrations had little influence on ovarian metabolism. The examination of interrelationships among factors that influence ovarian function was useful in identifying factors that can limit ovarian activity.

Animals↗

Biopersistence and durability of nine mineral fibre types in rat lungs over 12 months.

The study objectives were to assess the ability of intratracheal injection methods to discriminate between nine fibre types in respect of pulmonary biopersistence, and to provide approximate estimates of relative biopersistence and durability for a study of general relationships with biological and toxicological responses. The test fibres included six samples of size-selected fibre types specially prepared for research purposes, two commercially available fibres, and amosite. A 1 mg dose of each fibre type was administered to rats by intratracheal injection. The relative biopersistence of fibres in different size categories was assessed from the changes in mean lung burden, as determined by electron microscopy, at 3 days and 1, 6 and 12 months after injection. The ability of the test materials to resist dissolution was measured in a parallel series of simple in vitro acellular experiments at two pHs and in a continuous flow dissolution test. The observed differences in the persistence of fibres of differing length recovered from rat lungs were consistent with the current hypothesis that short fibres are cleared by cellular processes and long fibres by dissolution and disintegration. Differences in persistence of long (> 20 microns) fibres were correlated with measured rates of dissolution in vitro. Differences in persistence among those fibre types also studied by others workers were consistent with their findings after inhalation and intratracheal injection. Overall, the differences in the biopersistences of the test fibres following intratracheal injection were sufficient to enable an examination of the relationship of biopersistence with other biological and toxicological responses. Biopersistence was influenced by both fibre dimensions and solubility.

Air Pollutants, Occupational↗

Influence of fibre length, dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity.

A range of respirable man-made mineral fibres were tested for evidence of carcinogenicity by injection into the peritoneal cavity of male SPF Wistar rats; and differences in carcinogenicity were related to the dimensions and biopersistence of the injected fibres. The fibres tested included an amosite asbestos, a silicon carbide whisker, a special purpose glass microfibre, and a range of other man-made vitreous fibres (MMVFs) and refractory ceramic fibres (RCFs) from the TIMA fibre repository. The injected dose of each was designed as the estimated mass required to contain 10(9) fibres > 5 microns in length, as determined by optical microscopy. The numbers of long fibres (> 15 microns) contained in these doses ranged across fibres from 0.1 x 10(9) to 0.8 x 10(9) fibres; the number of long fibres thinner than 0.95 micron ranged from 0.015 x 10(9) to 0.4 x 10(9). The treatment groups contained between 18 and 24 animals. Animals were killed when they showed signs of debilitation. At autopsy, the diagnosis of mesothelioma was usually obvious macroscopically. Otherwise, histological examination of peritoneal organs was used to search for early tumour development. Judged by median survival time, four of the fibre types, in the doses administered, presented higher mesothelioma activity than amosite asbestos. The other fibres tested were less carcinogenic than the amosite. Only a ceramic material derived by extreme heating to simulate the effect of furnace or oven conditions, produced no mesotheliomas. Attempts were made, using regression models, to relate these differences to fibre dimensions and to measures of durability from separate experiments. The results pointed principally to a link with the injected numbers of fibres > 20 microns in length and with biopersistence in the rat lung of fibres longer than 5 microns. Improved quantification of the relative importance of fibre dimensions and biopersistence indices requires experimentation with a range of doses.

Animals↗

Influence of characteristics of inhaled fibres on development of tumours in the rat lung.

The objective was to examine and quantify the influence of fibre dimensions, persistence in the lung, and dissolution and cell toxicity in vitro, on the risks of developing lung tumours in rats. Data were brought together from the studies carried out at the IOM under the Colt Fibre Research Programme, and from studies carried out in Switzerland and the USA under the programme of the Thermal Insulation Manufacturers Association. In both studies, groups of rats were exposed by inhalation to a range of airborne fibres. At the end of their lives they were examined for the presence of benign and malignant lung tumours and mesothelioma. The studies differed in a number of details, but were combined on the basis of approximate equivalence of cumulative exposure to airborne fibres. Logistic regression models were used to relate differences in carcinogenicity to fibre characteristics; dimensions, persistence in the lung after intratracheal injection, dissolution rates from bench-top flow-through experiments, measures of inflammation, and other cell responses to fibres in vitro. Despite the small number of data points, the results suggested a primary influence of the airborne concentrations of the numbers of fibres thinner than 1 micron diameter and longer than 20 microns, and of the measured dissolution rate of the fibres. While these results are based on only a small number of fibre types, the statistical model fits the data reasonably well, and enables some cautious insights into the quantitative influences of dimensions and biopersistence. Results were broadly consistent with those from intraperitoneal injection studies of the same fibres, in that the responses were dependent on both the durability of the fibres and the numbers of long thin fibres. In vitro and in vivo cell responses did not predict significantly the risk of cancer following inhalation.

Air Pollutants, Occupational↗

Risks of silicosis in coalworkers exposed to unusual concentrations of respirable quartz.

OBJECTIVES: To describe the radiographic changes in coalworkers exposed to unusual concentrations of respirable quartz during the 1970s, and to relate these to exposure measurements. METHODS: Men who had worked at one Scottish colliery during the 1970s were invited to a health survey. Chest radiographs were taken from 547 subjects. Classifications of these films under the International Labour Organisation (ILO) 1980 scheme were related, by logistic regression, to existing data on individual men's exposures to respirable dust and quartz. RESULTS: Taking the median of the three readers' results on profusion of small opacities, 203 men (38%) showed progression of at least one profusion category on the 12 point scale, from the various 1970s surveys to the follow up in 1990-1. A total of 158 men (29%) had a profusion of at least 1/0, and 47 (8.6%) of at least 2/1 at the follow up survey. Large opacities were recorded as present by at least two readers for 14 (2.6%) of the men. Profusion of small opacities was strongly related to exposures experienced in the 1970s, and more strongly for quartz than for the non-quartz fraction of the dust. Estimates of risk are presented over the range of quartz exposures experienced. CONCLUSIONS: The quartz exposures experienced by some men at this colliery have caused considerable progression of radiographic abnormalities since exposure ended. The data accumulated offer opportunities for further more detailed analyses to inform debate on occupational limits for quartz exposures, both in collieries and in other industries where there is exposure to quartz in mixed dust.

Adult↗

Intraosseous patellar blood supply after medial parapatellar arthrotomy.

Total knee arthroplasty surgical exposure compromises blood flow to the patella. This reduction in blood flow may result in numerous patellar related complications. This study examined the intraosseous blood supply in normal patellas and those simulating total knee arthroplasty exposure. Fifteen anatomic specimen patellas were used. Ten undisturbed patellas were injected intravascularly with a colored perfusate via at least one geniculate artery, and five were subjected to a median parapatellar approach and a lateral release before injecting. Every patella was removed, embedded in epoxy, and sequentially milled. An orthogonal grid was used to position evident interosseous vessels, and each grid was normalized, allowing comparison among patellas. Perfused intrapatellar arteries formed an anastomotic network of penetrating and radiating arteries. Eighty percent of the interosseous blood supply was found in the central 50% of the undisturbed patellas. The surgically exposed patellas incurred a 75% decrease in total perfusion. There was no significant inflow from the periphery of the patella because the entire blood supply appeared to come from the anterior cortical perforating vessels. Damage to the central 50% of interosseous bone or anterior soft tissue cuff because of a central fixation post or anterior cruciate ligament graft increases the risk for segmental devascularization.

Aged↗

Formation of structural grafts from cancellous bone fragments.

Autogenous cancellous bone fragments can be compressed rapidly during surgery to create reproducible load-bearing grafts. Of the 32 grafts tested, 10 were constructed of composite cortical-cancellous bovine bone and 22 of cancellous human bone. Compressed composite bovine grafts and compressed human cancellous grafts supported average axial compressive loads of 2148 N and 960 N, respectively. Compared to iliac crest grafts, compression grafts may have better load-bearing capabilities and greater reproducibility. Potential applications include trauma, delayed unions, arthrodesis, and spinal fusions.

Aged↗

Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group.

Five fixed doses of the atypical antipsychotic "Seroquel" (quetiapine) were evaluated to delineate a dose-response relationship, as measured by changes from baseline in Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores, and to compare efficacy and tolerability opposite placebo and haloperidol. Three hundred sixty-one patients from 26 North American centers entered this double-blind, placebo-controlled trial with acute exacerbation of chronic schizophrenia (DSM-III-R). Patients who completed a single-blind, placebo washout phase were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol (12 mg daily), or placebo and evaluated weekly for 6 weeks. At end point, significant differences (p < 0.05, analysis of covariance) in adjusted mean changes from baseline were identified between the four highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Differences between quetiapine and haloperidol were not significant. Dose-response modeling showed significant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Notably, no significant safety concerns were identified as dose increased. Quetiapine was no different from placebo across the dose range studied regarding incidence of extrapyramidal symptoms or change in prolactin concentrations. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia. It is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day.

Acute Disease↗

Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.

BACKGROUND: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). METHODS: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. RESULTS: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. CONCLUSIONS: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

Adult↗

Assessment of human risks from exposure to low toxicity occupational dusts.

Recent animal studies have demonstrated three separate and distinct mechanisms by which low toxicity dusts can cause important chronic pulmonary effects; through overloading of clearance mechanisms, through increased toxicity associated with ultrafine particle size or by increasing the toxicity of known carcinogens in mixed exposures. The problem to be addressed is how the pathogenicity to man of various airborne dusts should be evaluated, when epidemiological evidence is often insufficient, and the reliability of extrapolation of quantitative risks from animals to man is not established. In this paper we examine the feasibility of evaluating the likely human risks of low toxicity dusts by: (1) semi-quantitative comparisons of the ability of various dusts, in animal studies, to cause overload of clearance and resulting inflammation and fibrosis; (2) postulating that these relativities apply quantitatively to human risks; and (3) estimating approximate human risks by comparisons with reference dusts for which adequate animal and human data are available. Such a decision-making framework appears feasible, provided: (1) comparable and quantitative methods are used consistently in animal studies for the measurement of impairment of clearance leading to overload and resulting inflammation and fibrosis; (2) the quantitative relationships between impairment of clearance leading to overload, and resulting inflammation and fibrosis, can be defined adequately in animals for various dusts; (3) the particle size distributions, including those in the ultrafine range, for dusts to which animals and/or humans are exposed, are taken into account (or are comparable); (4) at least two reference dusts with well-documented activities spanning the range of toxicity can be identified; and (5) the reliability of the predictions of human pathogenicity of a sample of other dusts is tested, in toxicological studies and by observation in humans. Some possible candidate reference and test dusts are identified.

Animals↗

Short-term studies of ovarian metabolism in the ewe.

The ovarian uptake of metabolites in anaesthetised ewes was determined. In both studies, catheters were inserted into the ovarian vein and femoral artery, and Transonic flow transducers were placed around the ovarian arterio-venous plexus. Arterio-venous differences in glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate (3-OHB), acetate, cholesterol and progesterone and oestradiol-17 beta levels were determined every 10 min over a 3.5 h period. In study one, glucose uptake was significant in three sheep, and one sheep only had a significant uptake of FFA. Ovarian 3-OHB uptake was significant in two sheep. significant uptake of acetate or cholesterol was identified in one sheep. Progesterone secretion was significant in three sheep and two sheep had significant progesterone uptake. In study 2, glucose uptake was significant in four sheep and lactate release was significant in the same sheep. There was uptake of FFA and 3-OHB, cholesterol, and acetate in each of three different sheep. Oestradiol-17 beta output was significant for sheep in oestrus and prooestrus. While the effects of gonadotrophin-releasing hormone (GnRH) treatment were confounded by time spent under anaesthesia, exogenous GnRH appeared to have no significant effect on the uptake of most metabolites and steroid hormone outputs. The metabolic requirements for energy and precursors for progesterone was small. Glucose was the major source of energy for the ovary and appears to be metabolised through anaerobic pathways, as indicated by significant lactate output.

Acetates↗

An evaluation of transovarian uptake of metabolites using arterio-venous difference methods in dairy cattle.

Arterio-venous (A-V) difference techniques were used in cattle to examine ovarian energy metabolism, cholesterol uptake and steroid hormone outputs. Catheters were inserted into the ovarian vein and facial artery, and Transonic flow transducers were placed around the ovarian A-V plexus. Further, in some cows, the effects of a challenge with GnRH were examined. Glucose uptake and lactate output were significant in most individual cows. Nonesterified fatty acids (NEFA) uptake were not significant in any cow in dioestrus. Ovarian uptake of beta-Hydroxy-butyrate (3-OHB) was significant in 4 cows in dioestrus. Cholesterol uptake was significant in only 1 cow. Oxygen uptake was significant in all cows at all stages of the oestrous cycle. All cows had significant output of progesterone and oestradiol-17 beta. These data show that the bovine ovary utilises significant amounts of glucose, and Respiratory quotient (RQ) estimates demonstrated that glucose was the primary fuel used by the ovary. The significant output of lactate suggested that anaerobic pathways were mainly used for glucose oxidation. The observed uptakes of 3-OHB indicated that the ovary utilises 3-OHB as a source of energy. Cholesterol uptake was not a rate-limiting factor for steroid hormone production in the ovary. Despite the high metabolic rate in the luteal ovary, the small difference in PO2 between arterial and ovarian venous blood indicated that the ovary consumes only a small proportion of available oxygen. GnRH had no significant effect on the uptake of metabolites and energy metabolism, but it increased OBF and the output of progesterone and oestradiol-17 beta. The use of A-V methods to determine the metabolic needs of the ovary is useful in understanding the means by which nutrition can influence fertility.

Analysis of Variance↗

Effect of weaning in the pig on ileal ion transport measured in vitro.

Early weaning in pigs results in small intestinal malabsorption and an increased susceptibility to E. coli infections. This is closely associated with villus shortening and crypt hyperplasia of the small intestine. The present study compared piglets either weaned at 3 weeks of age onto a high soya diet (n = 12) or an egg-based diet (n = 12) with piglets that remained on the sow (n = 12). Prior to weaning, care was taken to ensure that piglets only had access to sows milk. Serum anti-soya IgG was measured 7 days after weaning and sections of the mid-ileum excised and fixed for determination of crypt depth and villus height. Four pieces of 'stripped' mucosa were mounted in Ussing chambers in Krebs-phosphate Ringer (with indomethacin) for determination of short circuit current (SCC) and unidirectional fluxes of Na22 and Cl36, half in mucosa-serosa (MS), and half in serosa-mucosa (SM) direction. After basal measurements of absorptive capacity of Na, supramaximal doses of prostaglandin E2 (PGE2) and theophylline were added to measure the intestinal secretory capacity for Cl. Anti-soya IgG was elevated in the group weaned onto soya when compared either with the group weaned onto egg or the unweaned group. All intestinal transport and histological parameters were similar in both the weaned groups, although some were different from the unweaned. The SCC (equal to Na absorption) and the villus height were reduced two-thirds by weaning, whereas crypt depth and Cl secretion were similar in all groups. It is suggested that weaning per se is causal for the observed changes in intestinal transport and morphology, but they are not influenced by whether the weaning diet is soya or egg based.

Animals↗

Respiratory health effects of opencast coalmining: a cross sectional study of current workers.

OBJECTIVE: To identify whether there is evidence of pneumoconiosis and other respiratory health effects associated with exposure to respirable mixed dust and quartz in United Kingdom opencast coalmines. METHODS: A cross sectional study of current workers (1224 men, 25 women) was carried out at nine large and medium sized opencast sites in England, Scotland, and Wales. To characterise a range of occupational groups within the industry, full shift measurements of personal exposures to respirable dust and quartz were taken. Up to three surveys were carried out at each site, covering all four seasons. For the purposes of comparisons with health indices these groups were further condensed into five broad combined occupational groups. Full sized chest radiographs, respiratory symptoms, occupational history questionnaires, and simple spirometry were used to characterise the respiratory health of the workforce. Logistic or multiple regression techniques were used to examine relations between indices of exposure and respiratory health. RESULTS: None of the group geometric mean dust concentrations, based on 626 valid dust samples, exceeded 1 mg.m-3, and 99% of all quartz concentrations were below 0.4 mg.m-3, the current maximum exposure limit. The highest quartz concentrations were experienced by the rock drilling team and drivers of bulldozers (used to move earth and stone from layers of coal). There were clear differences in mean respirable dust and quartz concentrations between occupational groups. These were consistent across the different sites, but depended in part on the day of measurement. The variations between sites were not much greater than between days, suggesting that differences between sites were at least partly explained by differences in conditions at the time of the measurements. The prevalence of radiographic small opacities profusion category > or = 1/0, based on the median of three readings, was 4.4%. Five men had category 2 pneumoconiosis and two men (including one of these five) had progressive massive fibrosis category A. From regression analyses, the relative risk of attaining a profusion of category > or = 0/1 was estimated to be doubled for every 10 years worked in the dustiest, preproduction opencast jobs, after allowing for age, smoking, and site effects. Risk was not associated with time worked in any other occupation within the industry, nor with previous employment in underground mining or other dusty jobs. Symptoms of chronic bronchitis were present in 13% of the men. Frequency of chronic bronchitis was influenced by years worked in dusty jobs outside opencast mining, but not by time spent in occupations within the industry. Asthmatic symptoms were reported by 5% of the workforce, close to the mean frequency found in adult men. No positive associations were found between asthma and occupational exposures. Lung function on average was close to predicted value and showed no relation to time worked in opencast occupations. CONCLUSIONS: Frequency of (mostly mild) chest radiographic abnormalities is associated with working in the dustier, preproduction jobs in the industry. Although some of these mild abnormalities may be non-occupational (due to aging or smoking), the association with exposure indicates a small risk of pneumoconiosis in these men, and the need to monitor and control exposures, particularly in the high risk occupations.

Adolescent↗

Short-term inhalation and in vitro tests as predictors of fiber pathogenicity.

A wide range of fiber types was tested in two in vitro assays: toxicity to A549 epithelial cells, as detachment from substrate, and the production of the proinflammatory cytokine tumor necrosis factor (TNF) by rat alveolar macrophages. Three of the fibers were also studied in vivo, using short-term inhalation followed by a) bronchoalveolar lavage to assess the inflammatory response and b) measurement of cell proliferation in terminal bronchioles and alveolar ducts, using incorporation of bromodeoxyuridine (BrdU). The amount of TNF produced by macrophages in vitro depended on the fiber type, with the man-made vitreous fibers, and refractory ceramic fibers being least stimulatory and silicon carbide (SiC) whiskers providing the greatest stimulation. In the epithelial detachment assay there were dose-dependent differences in the toxicity of the various fibers, with long amosite being the most toxic. However, there was no clear relationship to known chronic pathogenicity. Fibers studied by short-term inhalation produced some inflammation, but there was no clear discrimination between the responses to code 100/475 glass fibers and the more pathogenic amosite and SiC. However, measurements of BrdU uptake into lung cells showed that amosite and SiC produced a greater reaction than code 100/475, which itself caused no more proliferation than that seen in untreated lungs. These results mirror the pathogenicity ranking of the fibers in long-term experiments. In conclusion, the only test to show potential as a predictive measure of pathogenicity was that of cell proliferation in lungs after brief inhalation exposure (BrdU assay). We believe that this assay should be validated with a wider range of fibers, doses, and time points.

Administration, Inhalation↗

ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group.

ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic.

Acute Disease↗