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Biomedical subjects

S R Walker

Publications and source records attributed to S R Walker.

At least 55 records · Page 3Linked to original sources
PubMed1989

Monoclonal antibodies specific for antigens expressed by rat type II alveolar epithelial and nonciliated bronchiolar cells.

Markers specific for various lung cells are useful for studies of cellular differentiation and function. We have produced monoclonal antibodies that bind to isolated rat type II alveolar epithelial cells in an ELISA. Two such antibodies, 2C1 and 3F9, specifically labeled type II cells and nonciliated bronchiolar cells by indirect immunofluorescence of rat lung. A third antibody, 2A3, recognized isolated type II cells by ELISA and immunofluorescence, but did not bind to sections of whole lung. Further immunofluorescence studies on adult rat tissue showed that neither 2C1 nor 3F9 labeled other lung cells or cells in kidney, small intestine, brain, or trachea. The antigen or antigens recognized by 2C1 and 3F9 was not detectable at day 15 of fetal lung gestation but was detectable by day 21. Immunofluorescence studies carried out on 0.5-microns frozen sections of lung tissue demonstrated that both 2C1 and 3F9 bound to cell surface antigens, which are expressed in a highly polarized fashion on the luminal surface of the alveolus and bronchiole. The rat cell line, L2, which displays some similarities to type II cells, did not display positive immunofluorescence to 2A3, 2C1, or 3F9. The antibodies 2C1 and 3F9 are distinct from and apparently more specific than previously described monoclonal antibodies raised to rat type II cells. Alveolar type II and nonciliated bronchiolar cells share several common features. Both cell types contain the surfactant apoprotein SP-A, proliferate in response to lung injury, develop in the late stages of gestation, take up and catabolize platelet-activating factor, contain high levels of cytochrome P-450, and can be induced to form tumors in response to chemical carcinogens. The recognition of highly specific surface antigen(s) on both nonciliated bronchiolar cells and type II cells demonstrates yet another characteristic shared by the two cell types.

Animals↗
PubMed1988

Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985).

1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1985 by seven UK-owned pharmaceutical companies. The majority (96.2%), were self-originated by the UK company or one of its overseas subsidiaries. 2 There was an increase in the number of NCEs investigated each year in man, doubling from an average of 12 per year up to 1980, to over 20 per year between 1981 and 1985. The majority of first drug evaluations in human volunteers were carried out in the UK (92.2%), in contrast to evaluation of new medicines in patients, where 42.9% were first tested outside the UK. 3 The majority of NCEs evaluated in man (78%), were in four therapeutic classes: anti-infectives (32%), anti-allergics (22%), drugs acting on the central nervous system (13%) and cardiovascular system agents (11%). 4 By the end of 1985, 49 (15.4%) of these NCEs had been marketed in the UK and 198 (62.0%) discontinued from further development. The main reasons for termination were inappropriate pharmacokinetics in man (39.4%), and lack of clinical efficacy (29.3%). 5 Average development times increased from less than 2 years between 1964 and 1965, to around 8 years in the 1980s with a consequent reduction in the effective patent life.

Chemistry, Pharmaceutical↗
PubMed1987

Incidence and size of erosions in the wrist and hand of rheumatoid patients: a quantitative microfocal radiographic study.

Quantitative macroradiographic examination of a group of early to moderately advanced rheumatoid patients showed the wrist and hand to have an average of 75 (SD 26) erosions out of 142 possible sites. Joint involvement was greatest in the wrist followed by the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints respectively. In the wrist erosion distribution was concentrated in the radiocarpal and medial carpometacarpal complex, in the hand it tended to be located at the second and third MCP and third PIP joints. No difference was observed in erosion number and area between the right and left extremities. The distribution of the lesions is discussed in relation to the intra-articular pressures on normal hand function. The similarity of erosion development, across the joints at the different regions of the hand, suggests the presence of factors other than mechanical pressure. In general, erosions were widespread, and the largest erosions occurred in the larger bones of the wrist and hand.

Adult↗
PubMed1987

The effect of substratum and serum on the lipid synthesis and morphology of alveolar type II cells in vitro.

To determine the effect of various culture conditions on the maintenance of lipid synthesis and morphology in alveolar type II cells, we cultured isolated adult rat alveolar type II cells on either plastic or denuded human amnionic basement membrane (ABM) in medium supplemented with either fetal bovine, porcine, horse, rat, or human serum. Lipid synthesis was assessed by incubation with [1-14C]acetate and determination of the distribution of radiolabel into individual lipid classes. Cells cultured on ABM incorporated significantly higher percentages of acetate into either phosphatidylcholine (PC) or phosphatidylglycerol (PG), and retained lamellar inclusions and a more characteristic cuboidal shape for longer periods than did cells cultured on plastic. Compared to other sera, cells cultured in the presence of rat serum incorporated the highest percentages of acetate into PC and saturated PC, had the best preservation of lamellar-body ultrastructure, and also appeared to contain more multivesicular bodies. The percent composition of linoleic acid, an essential fatty acid, was found to vary widely among the different sera. Supplementing media with linoleic acid resulted in a marked increase in acetate incorporation into saturated PC and a decreased incorporation into PG. We conclude that for maintenance of differentiated function of adult rat alveolar type II cells in primary culture (1) ABM is preferable to plastic as a culture substratum, (2) rat serum is preferable to fetal bovine serum as a serum supplement, and (3) the regulation of lipid synthesis by linoleic acid causes disparate effects on PG and saturated PC synthesis.

Animals↗
PubMed1986

The questionable value of long-term animal toxicity studies: a regulatory dilemma.

Recommendations for the minimum period of repeated dose administration to animals to support marketing authorization of pharmaceuticals vary from 6 months in the EEC to 18 months in Canada. The value of studies lasting longer than 6 months has not, however, been established. In order to enable retrospective analyses to be carried out, the Centre for Medicines Research has established a toxicology databank containing comprehensive data from repeated dose animal safety evaluation studies on 124 compounds, provided by 21 pharmaceutical companies in Europe (Lumley and Walker 1985a). There are 214 case studies (1 compound tested in 1 species for 1 or more time periods), and in 100 of these tests lasted for longer than 6 months. In 88 long-term studies comparable short-term data are available and these have been analysed to determine what new findings, if any, became apparent after 6 months. The data do not support the need for animal toxicity studies of longer than 6 months, apart from those designed to investigate carcinogenicity. Safety evaluation studies should be of value in predicting adverse drug reactions for man. Unless it can be established that these longer-term studies more accurately define potential target organ effects, the scientific rationale for conventional long-term studies must be questioned.

Animals↗
PubMed1986

A critical appraisal of the duration of chronic animal toxicity studies.

One method of assessing the contribution of studies of longer than 6 months to a safety evaluation program is to compare retrospectively the findings in toxicity tests carried out for 6 months or less with those observed after 6 months. The Centre for Medicines Research has therefore established a databank comprising animal toxicological data obtained from pharmaceutical companies in Europe. Twenty-one companies have provided data for 124 compounds (214 studies), including 88 studies of 65 compounds where comparable short-term (less than or equal to 6 months) and long-term (greater than 6 months) data are available. The results from the 88 studies show that, excluding the possibility of identifying carcinogens, tests of longer than 6 months have not added to the overall safety evaluation of these compounds.

Animals↗
PubMed1986

Trends in the development of new medicines by UK-owned pharmaceutical companies (1964-1980).

One hundred and ninety-seven new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1980 by the seven UK-owned pharmaceutical companies. Thirty-five of these NCEs have been marketed and 137 withdrawn from further research and development. There was an increase in the number of NCEs investigated each year, but this was counter-balanced by an increase in the number rejected. Development times increased from about 4.5 years in the 1960s to 9 years in the 1970s with an accompanying reduction in the effective patent life.

Drug Evaluation↗
PubMed1986

Quantitative microfocal radiography accurately detects joint changes in rheumatoid arthritis.

Microfocal radiography, producing x5 magnified images of the wrist and hands with a high spacial resolution (25 microns) in the film, permitted direct measurement of erosion area and joint space width in patients with rheumatoid arthritis. The magnitude of errors relating to direct measurement, repositioning the wrist and hand on successive x ray visits, repeated identification of erosions and their area calculation were assessed. The coefficients of variation for length and area measurements were 3.7% and 13% respectively, while the change in joint space width and erosion area in five patients over 18 months had average coefficients of variation of 12.7% and 42.0% respectively. The combined errors correspond approximately to the fifth percentile level for the total changes in size of these x ray features. The remaining alterations were due to the disease, which was markedly greater that that attributable to errors of measurement.

Arthritis, Rheumatoid↗
PubMed1986

Immunocytochemical localization of the major surfactant apoproteins in type II cells, Clara cells, and alveolar macrophages of rat lung.

The adsorptive properties of phospholipids of pulmonary surfactant are markedly influenced by the presence of three related proteins (26-38 KD, reduced) found in purified surfactant. Whether these proteins are pre-assembled with lipids before secretion is uncertain but would be expected for a lipoprotein secretion. We performed indirect immunocytochemistry on frozen thin sections of rat lung to identify cells and intracellular organelles that contain these proteins. The three proteins, purified from lavaged surfactant, were used to generate antisera in rabbits. Immunoblotting of rat surfactant showed that the IgG reacted with the three proteins and a 55-60 KD band which may be a polymer of the lower MW species. Specific gold labeling occurred over alveolar type II cells, bronchiolar Clara cells, alveolar macrophages, and tubular myelin. In type II cells labeling occurred in synthetic organelles and lamellar bodies, which contain surfactant lipids. Lamellar body labeling was increased fivefold by pre-treating tissue sections with a detergent. Multivesicular bodies and some small apical vesicles in type II cells were also labeled. Secondary lysosomes of alveolar macrophages were immunoreactive. Labeling in Clara cells exceeded that of type II cells, with prominent labeling in secretory granules, Golgi apparatus, and endoplasmic reticulum. These observations clarify the organelles and pathways utilized in the elaboration of surfactant. After synthesis, the proteins move, probably via multivesicular bodies, to lamellar bodies. Both lipids and proteins are present in tubular myelin. Immunologically identical or closely similar proteins are synthesized by Clara cells and secreted from granules which appear not to contain lipid. The role of these proteins in bronchiolar function is unknown.

Animals↗
PubMed1985

The value of chronic animal toxicology studies of pharmaceutical compounds: A retrospective analysis.

Extensive animal studies are carried out during the development of new medicines to assess toxicity and predict their safety for use in man. There are, however, differences of opinion concerning the nature of safety evaluation studies required prior to marketing. Any prospect of rationalizing the number and design of animal studies must stem from a reappraisal of conventional animal testing procedures and better use of available data on the toxicity of compounds previously investigated. The Centre for Medicines Research has therefore established a toxicology databank containing comprehensive data from repeated-dose animal safety evaluation studies provided by pharmaceutical companies. Thirteen companies within the United Kingdom have provided toxicological data for 32 pharmaceutical compounds studied in the rat, dog, or primate, resulting in 45 case studies for which both short-term (less than or equal to 6 months) and long-term (greater than 6 months) tests had been completed. A comprehensive analysis of these studies has been carried out to determine what new findings, if any, become apparent in studies after 6 months. The results do not support the need for animal toxicity studies of longer than 6 months duration, apart from those designed to investigate carcinogenicity.

Animals↗
PubMed1985

Identification of rat alveolar type II epithelial cells with a tannic acid and polychrome stain.

Alveolar type II epithelial cells are identified by the presence of characteristic lamellar inclusions visualized by transmission electron microscopy. We developed a tannic acid and polychrome stain that can visualize these intracellular inclusions in rat alveolar type II cells by light microscopy and that can be used for autoradiography. This method of staining and fixation provides more cellular detail than other methods that use light microscopy.

Animals↗
PubMed1985

A toxicology databank based on animal safety evaluation studies of pharmaceutical compounds.

Thirteen UK pharmaceutical companies have provided comprehensive toxicological data from repeated-dose animal safety evaluation studies of 74 pharmaceutical compounds. These data comprise a unique toxicology database and this paper describes its establishment including the problems encountered, its current size with over 35 000 data fields, its content and potential value for retrospective analyses. Increasing reliance on animal studies for predicting the safety of medicines in man necessitates a reappraisal of conventional animal testing procedures and better use of the considerable volume of data in the archives of regulatory authorities and pharmaceutical companies. This reappraisal may be achieved by the use of computer-based toxicology databanks.

Animals↗
PubMed1984

A comparative retrospective analysis of data from short- and long-term animal toxicity studies on 40 pharmaceutical compounds.

A comparative retrospective survey of data from chronic toxicity studies has been carried out on 40 pharmaceutical compounds based on comprehensive information from 19 pharmaceutical companies. The results showed that no new salient toxicological effects were observed in tests of more than 6 months duration excluding carcinogenicity studies. Since no additional information was identified by dosing animals continuously for 12-18 months, the value of prolonging chronic toxicity studies in animals beyond 6 months should be carefully reassessed.

Animals↗
PubMed1983

Acute toxicity of lead particulates on pulmonary alveolar macrophages. Ultrastructural and microanalytical studies.

Although it is well established that respiratory uptake of lead-containing particles plays a substantial role in the epidemiology of plumbism, relatively little is known about the role of the pulmonary alveolar macrophage in lead poisoning. An in vitro system was designed to investigate the effects of lead oxide particles of respirable size on the rabbit alveolar macrophage. The studies were concerned with the intracellular solubility of PbO and Pb3O4 and changes in fine structure attributable to lead toxicity. The distribution of phagocytosed lead and its intracellular reprecipitation complexes was established by electron microprobe analysis and secondary ion mass spectroscopy in conjunction with transmission electron microscopy, scanning electron microscopy, scanning transmission electron microscopy, and backscatter imaging. It was found that Pb3O4, PbO and PbO-coated particles were ingested by the rabbit alveolar macrophages and that each of these lead oxide compounds produced similar damage to the fine structure of the cell. Swelling of the mitochondria, nuclear membrane, and endoplasmic reticulum was common, as well as were characteristic reprecipitation complexes of lead, phosphorous, and calcium within the nuclear heterochromatin and cytoplasm of the cell. The precipitation complexes were not seen in cells incubated with the particles if phagocytosis was blocked by 0.22-microns, membrane filters. It was concluded that phagocytosis of these lead oxide particles was necessary to produce the cytopathic changes. It is suggested that solubilization of lead from the ingested particles in phagosomes of macrophages results in the liberation of intracellular lead with the resultant formation of reprecipitation complexes.

Animals↗