ICI Pharmaceuticals Research Articles

Balancing Tricks and Mini-pigs: Steps along the Road to Propofol

Balancing Tricks and Mini-pigs: Steps along the Road to Propofol

Digital entrepreneurship

Digital entrepreneurship

Identification of the reactive metabolites of fenclozic acid in bile duct cannulated rats.

Fenclozic acid (Myalex) was developed by ICI pharmaceuticals in the 1960s for the treatment of rheumatoid arthritis and was a promising compound with a good preclinical safety profile and efficacy. While it did not show adverse hepatic effects in preclinical animal tests or initial studies in man [ Chalmers et al. Ann. Rheum. Dis. 1969 , 28 , 595 and Chalmers et al. Ann. Rheum. Dis. 1969 , 28 , 590 ], it was later withdrawn from clinical development. Hepatotoxicity was observed in humans at daily doses of 400 mg but was not replicated in any of the animal species tested. Rodrigues et al. [ Arch. Toxicol. 2013 , 87 , 1569 ] published a mechanistic investigation using modern in vitro assays/techniques in order to investigate the hepatotoxicity; however, only the covalent binding in rat, dog, and human microsomes was identified as a potential indicator for hepatoxicity. Metabolites associated with or responsible for covalent binding could not be detected, likely due to the low in vitro metabolic turnover of fenclozic acid in microsomes. Foulkes [ J. Pharmacol. Exp. Ther. 1970 , 172 , 115 ] investigated the in vivo metabolism of fenclozic acid which included a rat bile duct cannulated (BDC) study characterizing the biliary and urinary metabolites; however, no reactive metabolites were identified. This study aimed to reinvestigate the in vivo metabolism of fenclozic acid in rat, with a focus on identifying any reactive metabolites that could explain the in vitro covalent binding in microsomes observed across the species. Using modern analytical techniques, we were successful in identifying an epoxide reactive metabolite, which upon conjugation with glutathione (GSH), formed up to 16 GSH-related products including positional and diastereoisomers. Not including the GSH related conjugates, 7 additional metabolites were identified compared to these previous metabolism studies.

The adhesion of film coatings to tablet surfaces-measurement on biconvex tablets.

Journal Article The adhesion of film coatings to tablet surfaces-measurement on biconvex tablets Get access R C Rowe R C Rowe ICI Pharmaceuticals Division, Alderley Park, Cheshire, UK Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 29, Issue 1, September 1977, Pages 58–59, https://doi.org/10.1111/j.2042-7158.1977.tb11244.x Published: 12 April 2011 Article history Received: 26 August 1976 Published: 12 April 2011

The Measurement of the Rheological Properties of Wet Powder Masses

The Measurement of the Rheological Properties of Wet Powder Masses Get access PJ Harrison, PJ Harrison Pharmacy Dept., Chelsea College, Manresa Road, London SW3 6LX Search for other works by this author on: Oxford Academic Google Scholar JM Newton, JM Newton Pharmacy Dept., Chelsea College, Manresa Road, London SW3 6LX Search for other works by this author on: Oxford Academic Google Scholar RC Rowe RC Rowe ICI Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire SK10 2TG Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 33, Issue Supplement_1, December 1981, Page 24P, https://doi.org/10.1111/j.2042-7158.1981.tb11683.x Published: 12 April 2011

Peroxisomes Contain a Specific Phytanoyl-CoA/Pristanoyl-CoA Thioesterase Acting as a Novel Auxiliary Enzyme in α- and β-Oxidation of Methyl-branched Fatty Acids in Mouse

Phytanic acid and pristanic acid are derived from phytol, which enter the body via the diet. Phytanic acid contains a methyl group in position three and, therefore, cannot undergo beta-oxidation directly but instead must first undergo alpha-oxidation to pristanic acid, which then enters beta-oxidation. Both these pathways occur in peroxisomes, and in this study we have identified a novel peroxisomal acyl-CoA thioesterase named ACOT6, which we show is specifically involved in phytanic acid and pristanic acid metabolism. Sequence analysis of ACOT6 revealed a putative peroxisomal targeting signal at the C-terminal end, and cellular localization experiments verified it as a peroxisomal enzyme. Subcellular fractionation experiments showed that peroxisomes contain by far the highest phytanoyl-CoA/pristanoyl-CoA thioesterase activity in the cell, which could be almost completely immunoprecipitated using an ACOT6 antibody. Acot6 mRNA was mainly expressed in white adipose tissue and was co-expressed in tissues with Acox3 (the pristanoyl-CoA oxidase). Furthermore, Acot6 was identified as a target gene of the peroxisome proliferator-activated receptor alpha (PPARalpha) and is up-regulated in mouse liver in a PPARalpha-dependent manner.

Talking about tamoxifen

Thank you for Andrew Herxheimer's thoughtful editorial.1 As the source for his reference to the deepening of the voice associated with tamoxifen use, 2 I feel I should add a personal note to the discussion. First, I wish to modify his statement slightly, to read: ‘The sometimes irreversible deepening of the singing voice that has been reported to occur with long-term use of tamoxifen for breast cancer is an example of a side effect that prescribers, manufacturers, and drug regulators seem to have considered trivial and have not investigated’ [my emphasis]. My own experience, of serious voice problems 2–3 weeks after starting to take 40 mg a day of tamoxifen in 1987, led me to enquire further of other women, in particular members of the charity Breast Cancer Care (then the Breast Care and Mastectomy Association). I found that similar problems had been reported to the then Director, Jinty Blanckenhagen, who had also notified the manufacturer, ICI Pharmaceuticals. However, this side-effect had not made it to the data sheet. So I conducted a small pilot study among readers of the BCMA newsletter, Network. I invited singers to write in if they had noticed any voice changes. Of the 10 who wrote in, seven had noticed changes similar to my own: mainly croakiness and a lowering of pitch. 2 To me this confirmed that my experience was not unique and I imagined that the drug company would wish to know about it. So early in 1992 I wrote to them, with copies to various other bodies such as the Committee on Safety of Medicines, as well as some eminent breast cancer specialists. The result astonished me. I was living in West Sussex at that time, and a senior member of the ICI medical team flew from Macclesfield to Gatwick, accompanied by another member of staff who seemed to have a Public Relations role, to see me in my home. It felt as if the object of this expensive exercise was to persuade me to shut up. This I did not do, but this particular side effect has still not been listed in the British National Formulary. The problem may be partly dose-related, and now the standard dose is 20 mg, not 40 mg. But I believe that the effect is real and that singers should know about it before embarking on tamoxifen treatment, which is only likely to benefit those with ER+ tumours. It is particularly important to mention it in any trials of tamoxifen for ‘prevention’.

Abstract of Current Literature

Summary: Orthopaedic surgeons in many major arthroplasty centres advocate the use of a prolonged surgical hand‐scrub prior to total joint replacement. In this study we evaluated the antimicrobial efficacy of a 5 compared with a 10 min scrub before both long (>90 min) and short (<90 min) operations for total hip arthroplasty. Surgical hand disinfection was performed on one occasion for 5 min and on a second for 10 min by 41 surgeons and theatre nurses using 4% chlorhexidine gluconate as a detergent formulation (‘Hibiscrub’, ICI Pharmaceuticals). None of the subjects had previously scrubbed on the day of each test. Bacterial colony counts on the fingers were measured using the method described by Rotter (vide infra) before scrubbing, immediately after scrubbing, and at the end of each operation. Our results showed that for arthroplasty procedures lasting less than 90 min (35 operations) a 5 min hand‐scrub was equally as effective as one of 10 min. However, following longer procedures (36 operations) colony counts were significantly higher on subjects who had scrubbed for 10 min than on those who only scrubbed for 5 (P < 0.05, Mann‐Whitney U‐Test). This study suggests that the practice of a prolonged scrub before total joint replacement does not have a scientific basis and that such a policy should be discontinued where it is still practised. ©1994 The Hospital Infection Society

Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures.

The intravenous, short-acting general anesthetic propofol was applied to three-dimensional (aggregating) cell cultures of fetal rat telencephalon. Both the clinically used formulation (Disoprivan, ICI Pharmaceuticals, Cheshire, England) and the pure form (2,6-diisopropylphenol) were tested at two different periods of brain development: immature brain cell cultures prior to synaptogenesis and at the time of intense synapses and myelin formation. At both time periods and for clinically relevant concentrations and time of exposure (i.e., concentrations > or = 2.0 micrograms/ml for 8 hr), propofol caused a significant decrease of glutamic acid decarboxylase activity. This effect persisted after removal of the drug, suggesting irreversible structural changes in GABAergic neurons. The gamma-aminobutyric acid type A (GABAA) blocking agents bicuculline and picrotoxin partially attenuated the neurotoxic effect of propofol in cultures treated at the more mature phase of development. This protective effect was not observed in the immature brain cells. The present data suggest that propofol may cause irreversible lesions to GABAergic neurons when given at a critical phase of brain development. In contrast, glial cells and myelin appeared resistant even to high doses of propofol.

Tomudex (ZD1694): from concept to care, a programme in rational drug discovery.

Folate-based anticancer drugs with specificity for thymidylate synthase (TS) have come of age. Ideas nurtured in the early 1970s led to the first-generation of antifolates with TS and dihydrofolate reductase (DHFR) inhibitory activities. Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR). CB3717 had significant clinical activity but its development had to be abandoned because its low aqueous solubility led to occasional nephrotoxicity. Collaborative laboratory studies between the ICR and ICI Pharmaceuticals (later to become Zeneca Pharmaceuticals) led to the discovery of ZD1694 (Tomudex), the first antifolate to be licensed for the treatment of cancer (UK 1995) in nearly 40 years and the first new drug for colorectal cancer in about 35 years. Tomudex belongs to a class of compounds that use the reduced-folate carrier (RFC) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase (FPGS). This paper reviews the underlying philosophies, and the milestones reached during the development of Tomudex.

Evaluation of the optimal hand-scrub duration prior to total hip arthroplasty

Orthopaedic surgeons in many major arthroplasty centres advocate the use of a prolonged surgical hand-scrub prior to total joint replacement. In this study we evaluated the antimicrobial efficacy of a 5 compared with a 10 min scrub before both long (>90 min) and short (< 90 min) operations for total hip arthroplasty. Surgical hand disinfection was performed on one occasion for 5 min and on a second for 10 mm by 41 surgeons and theatre nurses using 4% chlorhexidine gluconate as a detergent formulation (‘Hibiscrub’, ICI Pharmaceuticals). None of the subjects had previously scrubbed on the day of each test. Bacterial colony counts on the fingers were measured using the method described by Rotter (vide infra) before scrubbing, immediately after scrubbing, and at the end of each operation. Our results showed that for arthroplasty procedures lasting less than 90 min (35 operations) a 5 min hand-scrub was equally as effective as one of 10 min. However, following longer procedures (36 operations) colony counts were significantly higher on subjects who had scrubbed for 10 min than on those who only scrubbed for 5 (P < 0·05, Mann-Whitney U-Test). This study suggests that the practice of a prolonged scrub before total joint replacement does not have a scientific basis and that such a policy should be discontinued where it is still practised.

Editorial

INTRODUCTION The last decade has seen the emergence of a new class of pharmacological agents termed pure antioestrogens (Wakeling 1991, 1993). These compounds, which were originally developed by ICI Pharmaceuticals Division in the UK, bind to the oestrogen receptor (ER) (Wilson et al. 1990, Wakeling et al. 1991). Figure 1 shows the structures of ICI 164384, the lead compound, and ICI 182780, which are 7α long chain analogues of oestradiol. Both the ER binding affinity and potency of ICI 182780 are greater than those observed for ICI 164384 due to the replacement of the amide function with a sulphoxide group and the fluorination of the terminal chain (Wakeling et al. 1991). Such differences, nevertheless, do not alter the intrinsic biological behaviour of the drugs, which are identical to other more recently developed steroidal and non-steroidal pure antioestrogens (Von Angerer et al. 1990, Day et al. 1991, Claussner et al. 1992,

Tubeless anesthetic technique for optimal carbon dioxide laser surgery of the larynx

Purpose: To evaluate the operative conditions and safety of a tubeless technique of anesthesia for carbon dioxide laser surgery of the larynx. Materials and Methods: This prospective study evaluated 78 consecutive procedures in 72 adult patients undergoing carbon dioxide laser microlaryngeal surgery. Anesthesia was maintained by an intravenous infusion of Propofol (ICI Pharmaceuticals, Cheshire, UK) while the patient breasthed spontaneously without endotracheal intubation. Results: The operative conditions were optimal in 76 of the 78 procedures providing a clear uninterrupted view of the larynx with no combustible material in the surgical field. Conclusions: This series shows the technique described to be safe without risk of combustion and provides and unobstructed view to the larynx.

A specific radioimmunoassay for the measurement of ICI 200,880, an elastase inhibitor, in human serum

ICI 200,880, 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl- l-valyl- l-proline-1( RS)-(1-trifluoroacetyl-2-methylpropyl)amide ( I), is a human neutrophil elastase inhibitor in development by ICI Pharmaceuticals Group. A specific and sensitive radioimmunoassay has been developed for this compound in human serum. An hydroxysuccinimide ester analogue of ICI 200,880 was coupled to the lysine residues of bovine serum albumin, characterized by gel electrophoresis and injected into rabbits to stimulate antibody formation; a highly specific, high titre antibody was obtained. An 125I-diiodinated 4-hydroxy-phenyl derivative of ICI 200,880 was utilized as the radiolabelled antigen. Satisfactory zero and non-specific binding were achieved with a 2-h pre-incubation of ICI 200,880 and antiserum at 37°C, followed by the addition of radiolabelled antigen and a second 2-h incubation. Separation of bound and free radiolabel was achieved by employing PEG-goat anti-rabbit IgG separant. Sensitivity of 25 pg ml −1 ICI 200,880 in human serum was achieved ( n = 12), with quantitative recovery of 106%, inter-assay precision of 6.3% and an average relative binding statistically different than that of pooled human serum. Serum quality control samples spiked at 600 and 100 pg ml −1 ICI 200,880 averaged 104% recovery over 6 validation days, with intra-assay precision of 12.8% RSD and inter-assay precision of 9.2% RSD ( n = 24). Cross-reactivity of the ICI 200,880 antibody to three known metabolites and several analogues was negligible. Over 1200 clinical samples following aerosol administration of ICI 200,880 have been analysed by this procedure. After maximum exposure ranging from 0.3 to 32 mg ICI 200,880, mean peak levels from 0.08 to 20.5 ng ml −1 were measured, respectively, with compound detected generally up to 16 h post-dose.

Daily scrub with chlorhexidine reduces skin colonization by antibiotic-resistant Staphylococcus epidermidis

The aim of this study was to establish whether long-term use of chlorhexidine would prevent skin colonization by antibiotic-resistant Staphylococcus epidermidis. Ten nurses, working on a ward for haematological disorders, volunteered to participate in the test. They washed one arm every morning for three weeks with chlorhexidine gluconate, (‘Hibiscrub’ ICI Pharmaceuticals). The other arm served as a negative control. Samples from the antecubital fossa of both arms were taken two to three times a week during the wash period and two weeks thereafter, giving a total of 216 samples. The appearance of resistant S. epidermidis with different antibiograms was analysed. During the wash period the total bacterial counts and the counts of the resistant S. epidermidis strains on the test arm were both about one-tenth of those on the control arm, a significant difference ( P < 0·05). Moreover, there were significantly fewer resistant S. epidermidis on the test arm, 1·3 per sample, than on the control arm, 2·5 per sample ( P < 0·01). Most of the resistant S. epidermidis were only found once or a few times on the same site, after which they disappeared, though a few persisted on the skin even during ‘Hibiscrub’ washing. In an agar dilution test, chlorhexidine minimum inhibitory concentrations (MICs) of persisting strains were the same as for strains disappearing from the skin following ‘Hibiscrub’ washing, 1·0 or 2·0 mg 1 −1, but somewhat higher than MICs of strains isolated from healthy carriers outside the hospital whose MICs were 0·5 mg 1 −1. The relative contribution to the skin counts by those S. epidermidis strains found only occasionally were compared with those found repeatedly but no difference in reduction was found between these categories during ‘Hibiscrub’ washing.

P. Diehl, E. Fluck, and H. Gunther (Eds) M. Rudin (Guest Ed.). NMR: Basic principles and progress. Volume 27. in vivo magnetic resonance spectroscopy II: Localization and spectral editing. Springer, Berlin, 1992, ISBN 3‐540‐55022‐4, DM 168.00 (hard cover)

Magnetic Resonance in ChemistryVolume 31, Issue 4 p. 426-426 Book Review P. Diehl, E. Fluck, and H. Gunther (Eds) M. Rudin (Guest Ed.). NMR: Basic principles and progress. Volume 27. in vivo magnetic resonance spectroscopy II: Localization and spectral editing. Springer, Berlin, 1992, ISBN 3-540-55022-4, DM 168.00 (hard cover) John C. Waterton, John C. Waterton ICI Pharmaceuticals, Alderley Park, CheshireSearch for more papers by this author John C. Waterton, John C. Waterton ICI Pharmaceuticals, Alderley Park, CheshireSearch for more papers by this author First published: April 1993 https://doi.org/10.1002/mrc.1260310425AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume31, Issue4April 1993Pages 426-426 RelatedInformation

Antiandrogenic drugs.

Prostate cancer is the most frequent cancer diagnosed in American men today. Currently, about half of all patients with newly diagnosed prostate cancer present with metastatic diseases. Antiandrogenic drugs, or more appropriately androgen-receptor antagonists, represent a group of compounds that currently have played a limited role in the treatment of metastatic prostate cancer. Their method of action is primarily one of blocking androgens at their receptor sites in target tissues. They generally are classified as steroidal or nonsteroidal compounds. Cyproterone acetate and megestrol acetate are synthetic steroidal antiandrogenic drugs that, not only compete with testosterone and dihydrotestosterone for androgen receptors, but also have progestational activity and reduce pituitary luteinizing hormone and subsequently plasma testosterone. Nonsteroidal antiandrogenic agents (flutamide, Casodex [ICI Pharmaceuticals, England], and nilutamide) block cellular binding of androgens only, and there is no reduction of testosterone levels. Antiandrogenics have been used in numerous trials both in Europe and the United States. This group of compounds have been used as monotherapy and in combination therapy, ie, with orchiectomy or with LHRH agonists. Currently, antiandrogens are used primarily in conjunction with conventional medical or surgical castration to achieve maximal androgen deprivation; however, ongoing clinical studies are comparing these compounds alone against standard hormonal therapy. It seems probable that antiandrogens will play an expanding role in the treatment of metastatic prostate cancer as well as having a role in the treatment of prostate cancer.

Letter to the editor

Rapid Communications in Mass SpectrometryVolume 6, Issue 11 p. 719-720 Letter to the Editor Letter to the editor E. Clayton, E. Clayton ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorR. H. Bateman, Corresponding Author R. H. Bateman VG Analytical, Floats Road, Wythenshawe, Manchester, UKVG Analytical, Floats Road, Wythenshawe, Manchester, UKSearch for more papers by this author E. Clayton, E. Clayton ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorR. H. Bateman, Corresponding Author R. H. Bateman VG Analytical, Floats Road, Wythenshawe, Manchester, UKVG Analytical, Floats Road, Wythenshawe, Manchester, UKSearch for more papers by this author First published: November 1992 https://doi.org/10.1002/rcm.1290061118Citations: 26AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume6, Issue11November 1992Pages 719-720 RelatedInformation

Armor: ICI's Automated Tracking System for Adverse Events from Clinical Trials

An important responsibility of a pharmaceutical company is proper and effective management of reports of adverse events for patients receiving their drugs. In this regard, there are ethical as well as regulatory considerations. Because of the time frame in which certain adverse event reports from clinical trials must be filed with the Food and Drug Administration, ICI Pharmaceuticals Group has developed a computerized data base system with monitoring and reporting capabilities. The system described is menu-driven for user-friendly data input, and automated for efficient production and distribution of reports. Under optimal conditions, the appropriate data can be entered and reviewed in 1 day and the report distributed the next day.

Diprivan — ICI pharmaceuticals UK

Diprivan — ICI pharmaceuticals UK