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Biomedical subjects

J A Clegg

Publications and source records attributed to J A Clegg.

At least 19 recordsLinked to original sources
PubMed1999

Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy.

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.

Adenosine Monophosphate↗
PubMed1999

Regulation of the contact sensitivity response to urushiol with anti-urushiol monoclonal antibody ALG 991.

The objective of the studies was to demonstrate that the contact sensitivity (CS) response to poison ivy/oak could be downregulated following treatment with a monoclonal antibody (mAb) reacting with the allergen urushiol. Conjugation of urushiol and its synthetic analogue 3-n-pentadecylcatechol (PDC) to N-acetylcysteine yielded hydrosoluble derivatives which induced humoral immune responses in BALB/c mice. Hybridomas secreting monoclonal antibodies (mAbs) reacting with urushiol and PDC were generated by fusion of B lymphocytes from immunized mice with mouse myeloma P3NS0 cells. The specificity of mAb ALG 991 (IgM isotype) was defined by inhibition of antibody binding by PDC analogues. This demonstrated that mAb ALG 991 reacted with the catechol moiety of urushiol, the region of the allergen being critically important in the induction of contact dermatitis. The CS response to urushiol in BALB/c mice was suppressed by stimulation with mAb ALG 991 and the role of sensitized T cells, including suppressor T cells, has been considered. Suppression of CS was most effective with low doses (1 microg) of mAb incorporated into a vaccine with Freund's adjuvant. This treatment suppressed CS responses in BALB/c mice already sensitized to urushiol.

Allergens↗
PubMed1996

Striking the balance: a grounded theory analysis of staff perspectives.

Staff from four units for adults with profound learning disabilities described their relationship with a particular client during individual discussions. Issues arising from discussion were elaborated in subsequent individual and group meetings, evolving into an account of interactional aspects of professional care based on a core typology of relationships (Provider, Meaning-maker, Mutual and Companion). The process of this grounded theory analysis is exemplified. The analysis concludes with four propositions about staff-client relationships, and discussion of their implications for clinical services.

Adult↗
PubMed1995

Attachment and learning disability: a theoretical review informing three clinical interventions.

Attachment theory makes sense of two phenomena observed in some people with learning disabilities: it provides a reason for their limited exploration of the world, and it explains discontinuities in the pattern and intensity of their expressions of anger. Applying this framework to three enmeshed relationships occurring between an adult with learning disabilities and a member of care staff achieved at least partial resolution of their problems. Attachment theory's critics have set a number of challenges for its proponents, including emphasizing an interactional rather than a unidirectional approach to relationships; prioritizing social context; and understanding the attachment dynamic dimensionally rather than as a set of categories. The latter issue is pertinent for residential services: facilitating secure attachment relationships for distressed clients may be difficult for professionals, but partial assuagement of their attachment needs is a realistic clinical goal.

Adult↗
PubMed1995

Pharmacological profile of the novel P2T-purinoceptor antagonist, FPL 67085 in vitro and in the anaesthetized rat in vivo.

1. The role of endogenous ADP in platelet aggregation in vivo remains unclear due to the lack of suitable P2T-antagonist probes. This paper describes the potency, selectivity and specificity of the novel P 2T-purinoceptor antagonist, FPL 67085 (2-propylthio-D-beta,gamma-dichloromethylene ATP) both in vitro and in the anaesthetized rat in vivo. 2. FPL 67085 (3-30 nM) produced concentration-dependent rightward displacement of the concentration-effect (E/[A]) curve for ADP-induced aggregation of human washed platelets with no effect on ADP-independent aggregation at < or = 10 microM. 3. Logistic fitting of ADP E/[A] data indicated that the antagonist effect of FPL 67085 did not consistently accord with simple competition: in some preparations depression of the asymptote was seen. Schild analysis of data combined from all preparations, regardless of the antagonist profile observed, gave an apparent pKB of 8.9 (slope parameter 0.90). 4. The potency of FPL 67085 was unaffected by the P1-purinoceptor antagonist, 8-sulphophenyltheophylline, was similar (IC50 0.6-3.8 nM) in human and rat washed platelets or whole blood and, in rat blood, did not change following 2-30 min incubation at 37 degrees C. 5. FPL 67085 was a weak (pA50 approximately 4.2) partial agonist in tissues containing P2X- or P2Y-purinoceptors, indicating some 30,000 fold selectivity for the P2T-subtype. 6. In anaesthetized rats, intravenous infusion of FPL 67085 produced rapidly-reversible, dose-related inhibition of ADP-induced platelet aggregation measured ex vivo (ID50 1.3 micrograms kg-1 min-1) with no significant effect on haemodynamics or circulating cell counts. 7. Thus, FPL 67085 is a potent, specific and selective inhibitor of ADP-induced platelet aggregation both in vitro and in vivo. As such, it represents a novel pharmacological tool to define the role of endogenous ADP in thrombosis and the potential of P2T-purinoceptor antagonists as a novel class of infusible anti-thrombotic agents for acute use in man.

Adenosine Diphosphate↗
PubMed1994

Epistemology and learning disabilities: invited commentary on Hastings and Remington.

The effect on service provision of describing a variety of actions as challenging behaviour is discussed: it is suggested that studying stereotyped, aggressive and self-injurious acts in their own right has yielded more useful psychological debate, and ignoring such conceptual thinking leads to implicit theorizing where assumptions go unquestioned. Evidence for the relevance of staff actions on different topographies of client responses is critically reviewed, alongside discussion of the authors' rhetoric. The importance of adjusting language and frameworks to make room for alternative conceptualizations is discussed. The article concludes by recommending that research into staff attitudes and actions will be better served by reflexive methods and reporting which emphasize mutuality.

Humans↗
PubMed1993

Suppression of antibody responses to ricin A chain (RTA) by monoclonal anti-RTA antibodies.

Balb/c mice treated with an immunotoxin constructed by conjugation of murine monoclonal antibody 791T/36 via a disulfide linker to ricin A chain generate a pronounced antibody response to peptide epitopes on ricin A chain. Monoclonal anti-RTA antibodies which recognize peptide epitopes have been developed and these have been used to down-regulate anti-RTA antibody responses in 791T/36-RTA immunotoxin-treated Balb/c mice. Of the five MAB tests, two (608/7 and 596/134) proved most effective, inhibiting anti-RTA antibody formation by up to 73%. MAB treatment was effective when initiated up to 3 days after immunotoxin treatment. Pharmacokinetic studies with 791T/36-RTA have shown that the immunotoxin is rapidly eliminated from the circulation, with no more than 4% remaining in blood after 24 hr. It is proposed that the down-regulation of anti-RTA antibodies is effected by MAB interfering with antigen processing.

Animals↗
PubMed1993

Putting people first: a social constructionist approach to learning disability.

Moving from an individual to a social focus will allow clinical psychologists working with people who have learning disabilities to address a wider range of difficulties experienced by this client group. Social constructionist theory may be a useful framework to facilitate such an approach, and is intellectually compatible with changes occurring in other related disciplines. Research relevant to this perspective is reviewed under four subheadings proposed by Doise. Implications for clinical practice are discussed by reference to two case studies.

Adult↗
PubMed1991

Friendship among adults who have developmental disabilities.

The difference between people with developmental disabilities who did and did not have peer-group friends was investigated by interviewing 36 adults attending day centers. Those with a friend were significantly more likely to describe themselves positively on all dimensions. Results showed that people without a peer-group friend were similar to lonely people without disabilities on two of the three factors explored. Qualitative analysis of subjects' descriptions of their friends suggested that most of the people interviewed had relatively shallow relationships.

Adult↗
PubMed1990

A phase I/II study of trichosanthin treatment of HIV disease.

Trichosanthin, a ribosomal inhibitor protein, blocks HIV replication in lymphocytes and macrophages. This agent was used to treat 51 patients with advanced HIV disease in a dose-escalation study in which three injections were administered over a 9-21-day period in a dose range of 10-30 micrograms/kg per injection. The maximum tolerated dose was estimated to be 30 micrograms/kg. Reversible but severe fatigue and myalgias were the major dose-limiting side-effects; mild leucocytosis and elevations in serum transaminases were noted and were reversible. Non-dose-related reversible mental status changes were seen in six patients and were considered to be associated with the drug. This was usually manifest as dementia, but progressed to coma in two patients. This reversed, but the sequelae resulted in death in one patient. Decreases in serum p24 antigen levels were noted 1 month after the first infusion in 10 of 18 patients who entered the study with elevated levels; one converted to negative. Values usually remained low to the end of the study period (2 months). In those patients with CD4+ cell levels greater than 50 x 10(6) cells/l significant decreases in sedimentation rate and increases in CD4+ cell numbers were also noted. These changes were found at all dose levels but only in patients receiving three infusions.

Adult↗
PubMed1988

Biodistribution and tumour localization of a methotrexate-monoclonal-antibody 791T/36 conjugate in nude mice with human tumour xenografts.

The blood kinetics and tumour localization of a conjugate of methotrexate (MTX) and MAb 791T/36 were examined in nude mice with human tumour xenografts. The antibody moiety of the conjugate was detected by labelling with 125I and the drug moiety was assayed using a radioimmunoassay for methotrexate. After radioiodination, the drug moiety was co-precipitable with the radiolabel when TCA or rabbit anti-mouse IgG antiserum was used. Following i.v. injection, serum kinetics of both the antibody and the drug moieties of the conjugate were essentially similar, and the integrity of serum-borne conjugate was confirmed by the co-precipitation of radiolabel and drug. The radiolabelled antibody moiety of the conjugate localized in tumour xenografts, with 5-7% of the injected dose being present per gram of tissue within 6 hr of injection, and the levels were maintained for up to 4 days. Analysis of tumour levels of the MTX moiety showed a progressive uptake over the 4-day observation period with up to 4% of the injected dose being present per gram of tumour when the experiment was terminated. Parallel studies with free MTX showed rapid clearance from the blood and a maximum of 0.35% of the dose/g of tumour 30 min after injection. Control immunoglobulin conjugated to MTX did not show tumour localization of either the antibody or the drug moieties. These studies confirm that in vivo MTX remains bound to antibody in this type of drug antibody conjugate and demonstrate site-specific targeting of this therapeutic agent.

Animals↗
PubMed1988

Biodistribution of a monoclonal antibody-methotrexate conjugate (791T/36-MTX) in patients with colorectal cancer.

The monoclonal antibody (MAb) 791T/36 which has previously been shown to localise in colorectal cancer has been conjugated to methotrexate (MTX) for potential use as a chemotherapeutic agent in malignant disease. To examine its biodistribution and tumour localisation, 16 patients with primary colorectal cancer were injected intravenously with 131I-labelled 791T/36-MTX conjugate and imaged using a gamma camera after 48-72 hr. Serial blood samples were taken to determine the levels of circulating conjugate and samples of tumour and normal colon were assayed for uptake of radioactivity. Whole body biodistribution, visualised by gamma scintigraphy, and blood clearance of both the antibody and drug moieties of 791T/36-MTX were similar to that previously found with unconjugated antibody. Assays of tissue radioactivity showed positive tumour uptake of drug-antibody conjugate (T:NT greater than 1.9:1) in 13/15 primary tumour specimens (median T:NT = 2.9:1). These studies indicate that 791T/36-MTX conjugates may have potential in the treatment of metastatic colorectal carcinoma.

Aged↗
PubMed1987

Biodistribution and tumour localization of radiolabelled monoclonal antibody during continuous infusion in nude mice with human tumour xenografts.

The distribution in athymic nude mice of radiolabelled monoclonal antibody 791T/36 has been assessed during continuous infusion from subcutaneously implanted Alzet Osmotic Minipumps. During prolonged administration (up to 15 days) blood levels continued to rise. At 15 days, distribution of radiolabel was virtually identical to that seen after a single parenteral dose. Blood levels were in good agreement to those expected from whole body levels indicating satisfactory entry of antibody into the vascular compartment. Gel filtration chromatography of osmotic minipump contents and circulating radiolabel showed that the antibody had retained its structural integrity. In mice with human tumour xenografts examined a 5-day infusion of a mixture of 131I-791T/36 antibody and 125I-control IgG2b, blood levels of both radiolabels were comparable to those expected from whole body levels and there was effective tumour localization of the antibody to 2.5 times that of control IgG. These studies have demonstrated that prolonged administration of monoclonal antibody is feasible, that antibody enters the vascular compartment satisfactorily and that it can then localize in tumour deposits.

Animals↗
PubMed1987

An investigation of sex-linked differences to the toxic and to the pharmacological actions of difenacoum: studies in mice and rats.

We have investigated the actions of the coumarin anticoagulant, difenacoum, in male and female rats and mice. In our first experiment difenacoum (0.5 mg kg-1) killed 50% of male mice within 9 days of its administration, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 h after administration of difenacoum (0.4 mg kg-1 i.p.), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 h after difenacoum, the PCA in male rats was significantly (P less than 0.05) lower than in female rats. PCA began to recover over the subsequent 48 h in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concentrations of difenacoum 24 h after its administration were the same in both sexes. The concentration of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 +/- 18.6 ng (g liver)-1 (male), and 29.4 +/- 5.4 ng (g liver)-1 (females) in control rats, but 24 h after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Hydroxycoumarins↗
PubMed1987

Comparative biodistribution of methotrexate and monoclonal antibody-methotrexate complexes in mice.

The biodistribution of radiolabelled methotrexate and immune complexes of methotrexate and a murine monoclonal anti-methotrexate antibody has been compared in mice. Complexes formed in-vitro with the antibody, but not with control immunoglobulin. The complexes were, characteristically, acid labile. In-vivo, blood levels, organ distribution and whole body catabolism of methotrexate in immune complexes were similar to those of free antibody, and markedly different from those of free drug. These findings suggest the feasibility of prolonging the survival of drugs and altering in-vivo distribution using complexes with monoclonal antibodies.

Animals↗
PubMed1985

Vaccination against Schistosoma mansoni with purified surface antigens.

Two surface antigens were isolated from young or adult schistosomes by affinity chromatography with monoclonal antibodies. Vaccination with an antigen having a molecular weight of 155,000 gave partial protection against challenge in some batches of mice and in a group of cynomolgus monkeys. Vaccination with an antigen having a molecular weight of 53,000 gave similar levels of protection in mice. The results demonstrate that protection can be obtained with single antigens, but the precise requirements for reproducible vaccination are as yet unknown.

Animals↗