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Biomedical subjects

S R Walker

Publications and source records attributed to S R Walker.

At least 19 recordsLinked to original sources
PubMed1995

The value of information generated by long-term toxicity studies in the dog for the nonclinical safety assessment of pharmaceutical compounds.

Data on 117 pharmaceutical compounds in the CMR toxicology database have been analyzed to determine what new toxicological information was provided by the dog in chronic (6 months or longer) toxicity testing. For more than half of the 117 compounds, all salient effects in the dog were seen for the first time within 3 months. For just under one-third of the compounds, any effects that occurred for the first time beyond 3 months in the dog were also seen in studies in the rat. Only 13 of the 117 compounds showed new and possibly important effects in the chronic study. No particular therapeutic class nor any other single circumstance was implicated in these 13 cases. Types of late-onset findings in the dog occurring with more than 1 compound included nonspecific effects or hypertrophic/hyperplastic changes. There may be several reasons, pragmatic as well as scientific, why it can sometimes be desirable to carry out chronic repeat-dose studies of 6 months or longer in the dog. However, the results of this retrospective evaluation have demonstrated that in the large majority of cases analyzed, long-term toxicity studies in the dog provide relatively little qualitatively new toxicological information not already gained from a short-term (3 month) study in the dog in conjunction with short- and long-term studies in the rat.

Animals↗
PubMed1992

An international appraisal of the minimum duration of chronic animal toxicity studies.

1. There are international differences in regulatory guidelines for the appropriate duration of chronic, two species repeat-dose animal tests for new medicines intended for long-term use in man, ranging from 6 months in Europe to 12 months in Japan and the USA. 2. An adequate data base is necessary to support any challenge to the scientific rationale behind regulatory guidelines with regard to the design, duration and relevance of toxicity tests of new medicines. 3. The Centre for Medicines Research has established an international toxicology data base which has been expanded to enable a comparison of data obtained within 6 months, with information from longer periods, for 154 studies. 4. Although new findings were revealed after 6 months for 9/75 cases for which pathology data are available at 6 and 12 months or longer, and 21/80 with data at 1 or 3 (but not 6 months) and 12 months or longer, in no instance did these influence the decision to drop or further develop the compounds in question. 5. These data suggest that a 6-month period of dosing is all that is routinely required for evaluating the chronic toxic (excluding carcinogenic) potential of a new chemical entity intended for therapeutic use.

Animals↗
PubMed1991

An ASSEMBLER routine for on-line graphic display and averaging of data acquired on a personal microcomputer.

An ASSEMBLER routine is described for data acquisition and "on-line" averaging, artefact rejection and graphic display of data on a personal microcomputer (IBM compatible). The user determines the number of input channels, sampling frequency, number of samples, input range, stimulation frequency (epoch frequency) and the number of epochs to be acquired and averaged. Data from each epoch are scanned in search of saturating artefacts and will be added to previous epochs if none is found. Data are then graphically displayed as voltage versus time before acquiring next epoch. Display options can be defined by the user at run time by means of the keyboard and include: display of last epoch, display of the average, storage screen and refreshing screen after every epoch. High data transfer rates and program speed allows for high stimulation rates in the presence of on line graphic display. The computer then behaves as a multichannel digital oscilloscope with access to large memory buffers, disk storage, high averaging capabilities, artefact rejection and wide potential for data analysis. Its applications to the recording of magnetic and electric evoked responses are illustrated. The program is available from the authors.

Computer Graphics↗
PubMed1991

The need for a control animal pathology database: an international survey.

1. The sensitivity of long-term toxicity tests is impaired due to the 'background noise' of spontaneous lesions which are unrelated to treatment. 2. The need for a comprehensive source of computerized information concerning the occurrence and incidence of spontaneous lesions in control animals has been highlighted by initiatives in Europe and the USA. It is, however, essential to identify the potential users, and the type of information required for such a database to be of value. 3. This information has been acquired following an international survey of the pharmaceutical industry in Europe, Japan and the USA, including responses from 48 toxicologists and toxicopathologists representing 38 company groups. 4. Thirty-eight respondents indicated that they would use a historical control database that was regularly updated with the majority of respondents suggesting that they currently use external sources (Breeder's data, the literature, other companies) occasionally to acquire information on control animal pathology data. 5. The majority (94%) of the respondents indicated that a control animal database should contain information on both neoplastic and non-neoplastic lesions for use in evaluating long-term studies, in particular carcinogenicity studies. 6. The survey confirms the need for a historical control animal pathology database wider then those currently available.

Animals↗
PubMed1990

Harmonization of guidelines for toxicity testing of pharmaceuticals by 1992.

In the past there has been considerable disagreement between various regulatory authorities regarding the type and design of animal tests that should be required before a new medicine can be used ethically and safely in the clinic. However, regulatory variations have largely been removed within politically and geographically similar regions (e.g., the U.S.A., the European Community, the Nordic countries) and there now appears to be a consensus regarding the value of harmonizing international requirements. In order to assist the process of harmonization, a detailed table of preclinical toxicity requirements in the U.S.A., Canada, Japan, and the European Community for each test (acute, subacute, chronic, carcinogenicity, mutagenicity, reproduction) has been compiled. This has been circulated to the relevant regulatory authorities to ensure that it accurately reflects current requirements. The major differences between authorities were found to be the duration of chronic, repeated-dose tests and the design of reproduction studies. International pharmaceutical companies were asked to complete a questionnaire, indicating how they design their preclinical testing program to comply with varying regulatory requirements. Most of the respondent companies indicated that chronic tests of longer than 6 months were conducted solely to comply with some regulatory requirements. Many companies repeat reproduction studies in order to comply with Japanese requirements. This emphasizes the need to harmonize these guidelines and discussions are currently underway to attempt to develop protocols acceptable to the FDA, the EC, and the Japanese Ministry of Health and Welfare.

Animals↗
PubMed1989

Distribution of rabbit mucosal glycoprotein throughout urinary tract.

The mucin layer covering the transitional epithelium of the bladder is thought to be an anti-adherence substance for bacteria. We describe the use of an immunoperoxidase staining technique to demonstrate the presence of glycoprotein lining the urothelium of both the upper and lower urinary tracts of the rabbit. Antisera against this glycoprotein (GP1) were raised in Swiss-Webster mice. The genitourinary tracts of male and female NZW rabbits were removed and sequentially treated with mouse anti-GP1 sera, biotin-labelled anti-mouse IgG, and an avidin-biotinylated horseradish peroxidase complex. The results demonstrated that an antigenically similar (or identical) glycoprotein covers the distal renal tubules and urothelium of the renal pelvis, ureters, bladder, and urethra, suggesting that it may function as an antibacterial defense mechanism throughout the urinary tract.

Animals↗
PubMed1989

Novel medicines marketed in the UK (1960-87).

1. A total of six hundred and eighty three new chemical entities (NCEs), were marketed in the UK between 1960 and 1987. The number of NCEs introduced annually onto the UK market declined to an average of 20 per year in 1964 and subsequently to only 7 in 1985. 2. Average development times have increased fourfold since 1960 to a peak value of 13 years in 1984. The concomitant decline in effective patent life has resulted in a mean effective patent life of less than 10 years since the mid 1960s and no more than 6 years since the early 1980s, except for the cohort marketed in 1987. 3. The largest contribution to total development time was made by the clinical phase. For NCEs marketed in the mid 1960s it was 3.3 years increasing to a peak of almost 8 years in the early 1980s, and representing on average two-thirds of research and development time. 4. Between 1960 and the early 1970s total development time for central nervous system (CNS) agents, cardiovascular products and anti-infectives had doubled to 9, 8 and 7.3 years respectively. By the 1980s it was averaging 13 years for CNS agents and was 54% and 28% longer than for anti-infectives and cardiovascular compounds respectively.

Drug Industry↗
PubMed1989

Erosion number and area progression in the wrists and hands of rheumatoid patients: a quantitative microfocal radiographic study.

Microfocal radiography has been used to evaluate the relation between erosion number and erosion area in the hands and wrists of 51 patients with early to moderately advanced rheumatoid arthritis. The hands of these patients showed different patterns of erosion progression, in terms of the relation between changes in number and area, and included those showing a decrease in one or both of the erosion parameters. The mean number of erosions in the group increased between the first and second visits. By the third visit (a mean of 48 months from the onset of symptoms) the mean number of erosions in the wrist and hand of the group had approached a constant value of 75 erosions. Over the same period the mean erosion area of the group continued to increase. Measurement of changes in erosion area is a more sensitive indicator of erosion progression than erosion number, both within the group and in individual patients.

Arthritis, Rheumatoid↗
PubMed1989

Properties of isolated nonciliated bronchiolar cells from mouse lung.

Nonciliated bronchiolar cells (Clara cells) are thought to provide important respiratory secretions in the small airways and to have other metabolic functions. In mice, nonciliated bronchiolar cells have been the subject of special investigation because tumors of these cells can be specifically induced by chemical carcinogens. A method for isolating nonciliated bronchiolar cells from mice has been reported. However, we have developed a method to isolate these cells from the lungs of BDF1 mice with approximately 80% purity. Cells were identified by electron microscopy, nitroblue tetrazolium dye reduction in the presence of NADPH, immunocytochemical staining of cytochrome P450 isozymes, and mitochondrial staining with rhodamine 123. The isolated cells were examined in culture for synthesis and secretion of proteins and phospholipids. Protein synthesis and secretion were examined in cells labeled with [34S]methionine for 16 h. Fresh medium was added to washed cells and the cells were incubated for an additional 3h. The secreted proteins were precipitated with 10% trichloroacetic acid. Molecular weights of the most prominent radiolabeled secreted proteins were 6, 36, 43, and 45 kDa. Phospholipid synthesis and secretion were examined in cells labeled with [14C]acetate and 32P. Less than 1% of the radioactive lipids was found in the medium, and secretion of lipid was not stimulated by terbutaline or tetradecanoylphorbol acetate compounds, which stimulate phospholipid secretion by type II cells. These data support the hypothesis that nonciliated bronchiolar cells synthesize and secrete proteins but do not secrete phospholipids in any appreciable amount.

Animals↗
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↗