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B Nunn

Publications and source records attributed to B Nunn.

At least 19 recordsLinked to original sources
PubMed1988

Isolation, identification and pharmacokinetic properties of human tissue-type plasminogen activator species: possible localisation of a clearance recognition site.

Purified preparations of recombinant tissue-type plasminogen activator (t-PA) from the recombinant Bowes melanoma cell line TRBM6 were shown to contain multiple species of plasminogen activator. Using a combination of chromatography on Sephadex G25, Sephadex G75 and Heparin Sepharose CL6B we have isolated two fibrinolytically active species, which, under non-reduced SDS PAGE, have apparent Mr = 38,000 and 56,000. Double immunodiffusion studies indicated that both species were closely related to both the t-PA B chain and t-PA itself. N-terminal sequencing identified the Mr = 38,000 species as ala160- t-PA (essentially delta FGKI t-PA) and the Mr = 56,000 species as ser1-tyr2-gln3-glyx-cys51 t-PA (delta F t-PA), the latter probably produced by alternative splicing of the t-PA gene. The pharmacokinetic properties of N,N dimethyl-4-aminobenzoyl (DAB) derivatives of these activators and native t-PA were determined in the guinea pig. Whereas DAB----delta F t-PA showed a similar, rapid plasma disappearance profile to that of DAB----t-PA, DAB----delta FGKI t-PA was cleared significantly slower. These results suggest that a rapid clearance recognition site resides on either the growth factor or kringle 1, or both, domains of t-PA.

Acylation↗
PubMed1988

Slow clearance of acylated, hybrid thrombolytic enzymes.

Two hybrid plasminogen activators, plasmin A-chain/t-PA B-chain and plasmin A-chain/u-PA B-chain have been synthesized and purified in sufficient yield to permit measurement of clearance in small laboratory animals. Each hybrid enzyme was reversibly acylated at the active centre to allow the pharmacokinetic profile to be followed using an activity-based method without interference from plasma inhibitors. The acylated plasmin/u-PA hybrid had a clearance half-life (t1/2) in guinea pigs of approximately 80 min, whereas acyl u-PA had a t1/2 of 3 min. The pharmacokinetic profile of the acylated plasmin/t-PA hybrid was measured in guinea pigs, rats and rabbits; the half-lives in all three species were 60-80 min compared to half-lives of acylated, native t-PA that were in the range 0.5-1.0 min. Thus, plasmin A-chain-containing, acylated hybrid enzymes are cleared some 30- to 100-fold more slowly than the acylated parent activators.

Acylation↗
PubMed1985

An investigation of the involvement of platelet activating factor in the non-histamine immediate hypersensitivity reaction in the rat peritoneal cavity.

Synthetic PAF-acether injected intraperitoneally (i.p.) into sham-sensitized rats, caused dose-dependent extravasation of plasma proteins into the peritoneal fluids. Platelet aggregating activity was detected in the peritoneal fluids. In rats that had been passively sensitized for a non-histamine mediated immediate hypersensitivity reaction, antigen challenge caused extravasation of plasma proteins into the peritoneal fluids. No platelet aggregating activity was detected in these fluids. PAF is unlikely to be the mediator of extravasation in the non-histamine mediated immediate hypersensitivity reaction in the rat.

Animals↗
PubMed1985

Inhibitors of blood platelet aggregation. Effects of some 1,2-benzisothiazol-3-ones on platelet responsiveness to adenosine diphosphate and collagen.

A series of substituted 1,2-benzisothiazol-3-ones was synthesized, and the compounds were tested for ability to inhibit platelet aggregation induced by adenosine diphosphate and collagen in rats and guinea pigs ex vivo. Alkyl substituents at the 2-position bearing a basic group were necessary for ex vivo activity. Several of the compounds were potent inhibitors of adenosine diphosphate induced first-phase aggregation, but adverse toxicological findings terminated their further development. Preliminary studies suggested that inhibition of aggregation was not attributable to inhibition of prostanoid synthesis or to raised levels of cyclic 3',5'-adenosine monophosphate.

Adenosine Diphosphate↗
PubMed1985

Effect of temocillin and moxalactam on platelet responsiveness and bleeding time in normal volunteers.

The effects of temocillin and moxalactam on platelet responsiveness and bleeding time were examined in healthy male volunteers. In the first study, moxalactam (4 g intravenously every 12 h) was given to six subjects; template bleeding times were at least doubled in five subjects 12 to 14 h after 7 doses (P = 0.008) and in all six subjects 12 to 14 h after 13 doses (P = 0.004). ADP-induced primary aggregation was approximately halved after 7 (P = 0.026) and 13 doses (P = 0.008), and there was a markedly increased tendency toward disaggregation. Collagen-induced aggregation was also halved, but the effect only reached statistical significance after 13 doses (P = 0.008). There was essentially no effect on primary aggregation in response to the thromboxane receptor agonist U46619 or to platelet activating factor. Temocillin (4 g intravenously every 12 h) was given to eight subjects, three of whom had participated in the moxalactam study 8 weeks earlier. Temocillin had no significant effect on template bleeding time 12 to 14 h after 7 or 13 doses. However, in four subjects, the endpoint may have been less abrupt. There was no significant effect on ADP-induced primary aggregation or responsiveness to collagen. Even after 13 doses of temocillin, secondary aggregation in response to normal concentrations of ADP was demonstrable in the platelet-rich plasma of all eight subjects. Neither antibiotic had any effect on prothrombin times. Thus, with methodology that readily detected the effects of moxalactam on hemostasis, we were unable to demonstrate any unequivocal deleterious effects of temocillin at its maximum recommended dose. Temocillin may therefore be particularly useful for the treatment of many gram-negative infections in patients at increased risk of clinical bleeding.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

A brief neuropsychological screening procedure that assesses left and right hemispheric function.

Assessed the utility of two brief neuropsychological tests in screening patients referred to a neuropsychological consulting service. Forty-three cortically impaired and 19 neurologically intact Ss completed the Cognitive Capacity Screening Exam (CCSE) and the Memory-for-Designs (MFD). The results of these tests analyzed individually and in combination were compared with the Ss' neurological reports. The analysis revealed that the combined system was significantly better than either single test in accurately detecting neuropathology. A closer look at the data suggests that the MFD was superior in identifying unilateral, right hemispheric damaged patients, while the CCSE was superior in identifying Ss with unilateral, left hemispheric damage. Results are discussed with reference to the difficulty in using single screening tests for detecting deficits that result from unilateral cortical dysfunction.

Brain Damage, Chronic↗
PubMed1984

Spouse contracting to increase antabuse compliance in alcoholic veterans.

Developed and evaluated a home-based contracting program to determine its effect on the compliance rates of discharged alcohol patients to a disulfiram (antabuse) regimen. The three comparison groups included (a) no contract/no recording; (b) contract/recording; and (c) contract/recording plus instructions for positive reinforcement. Twenty-five patients who had been treated in a behaviorally oriented inpatient alcohol dependence treatment program and who lived with a significant other (i.e., spouse, sibling, parent) participated in the study. At the end of the 3-month period for which the disulfiram was prescribed, those Ss who were involved in contracting and recording reached criterion more frequently than those who were in the minimal treatment group. Furthermore, 84% of this S sample were abstinent at the 3-month follow-up according to collateral reports. The discussion centers on the use of home-based contracting as an inexpensive alternative to other, more costly disulfiram programs. Additional methods for obtaining measures of reliability on self-report of disulfiram usage also are discussed.

Adult↗
PubMed1983

Total and selective desensitisation of human platelets to synthetic platelet activating factor (PAF): evidence that extracellular PAF does not mediate collagen-induced aggregation.

A technique is described that renders human platelets totally insensitive to synthetic PAF. The procedure involves gently mixing human citrated platelet-rich plasma (PRP) with 0.1 microM PAF at room temperature. After 3-5 min, a further addition of 0.1 microM PAF is made, followed 3-5 min later by 1 microM PAF. Preparations so treated did not aggregate in response to 50 microM PAF whereas control PRP always responded to 0.05 microM PAF. The selectivity of the desensitisation procedure depended on the presence of aspirin. In the absence of aspirin, collagen-induced aggregation was slightly inhibited, but so too was primary aggregation in response to ADP and the thromboxane receptor agonist, U46619. When PRP was pretreated with aspirin to prevent any secondary aggregation during the desensitisation procedure, collagen-induced aggregation and primary aggregation in response to ADP were essentially unchanged by total desensitisation to PAF. It is concluded that endogenous PAF acting extracellularly does not mediate or help to mediate collagen-induced aggregation in human citrated PRP.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1983

Further evidence against the validity of using an ADP-removing enzyme system (CP/CPK) for demonstrating the role of secreted ADP in platelet activation.

The ADP-removing enzyme system creatine phosphate-creatine phosphokinase (CP/CPK) selectively inhibited primary aggregation in response to the thromboxane receptor agonist, U46619, in mouse aspirin-treated platelet-rich plasma. Inhibition by CP/CPK has become accepted as evidence for mediation by secreted ADP, yet primary aggregation is not usually attributed to secreted ADP. Hence these results throw doubt on the assumed mechanism by which CP/CPK inhibits aggregation. The possibility that such inhibition was due to removal of extracellular ADP released prior to platelet stimulation and exerting a potentiating influence was investigated. Ths explanation appeared unlikely as further additions of creatine phosphokinase to platelet-rich plasma preincubated with CP/CPK caused further inhibition of primary aggregation. Moreover, low concentrations of CP/CPK that reduced responsiveness to U46619 had no effect on collagen-induced aggregation, which ADP is known to potentiate. The evidence presented is consistent with CP/CPK exerting a direct inhibitory effect on platelet membranes and so inhibiting a facet of platelet aggregation not mediated by secreted ADP. These data support the conclusion of a previous study (Huang, E.M. and Detwiler, T.C., J. Lab. Clin. Med.,95, 59-68, 1980) that inhibition by CP/CPK cannot be taken as evidence for the involvement of secreted ADP.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Effect of nabumetone (BRL 14777), a new anti-inflammatory drug, on human platelet reactivity ex vivo: comparison with naproxen.

The effect of nabumetone (BRL 14777) on human platelet reactivity ex vivo was compared with that of naproxen at equitherapeutic doses in the same six subjects. Nabumetone had only a weak and equivocal effect on collagen-induced and second phase aggregation in response to adenosine diphosphate and adrenaline. After nabumetone, platelets fully aggregated in response to sodium arachidonate, though approximately twice as much was needed as on control occasions. Sodium arachidonate was unable to elicit a full aggregation response after naproxen. These results suggest that nabumetone may cause less interference with haemostasis than other non-steroidal anti-inflammatory drugs.

Adenosine Diphosphate↗
PubMed1981

Some characteristics of mouse platelet aggregation and a comparison of the activity of a range of compounds in mouse and human platelet-rich plasma in vitro.

Collegan-induced platelet aggregation in mouse citrated platelet-rich (PRP) was associated with 5-hydroxytryptamine (5-HT) release and degranulation. Adenosine 5'-diphosphate (ADP) induced monophasic and reversible aggregation with no degranulation. Mouse platelets gave no response to adrenaline but changed shape and sometimes aggregated in response to 5-HT. Both amines potentiated the effect of ADP. The respective potencies of prostaglandin E1, papaverine, VK 774, BL 3459 and adenosine as inhibitors of ADP-induced aggregation were similar in mous and human PRP. Although ticlopidine had similar activity in the two species, aspirin and flurbiprofen were considerably less potent in mouse than human PRP as inhibitors of collagen-induced aggregation. It is suggested that collagen-induced aggregation of mouse platelets in vitro occurs by a mechanism largely independent of arachidonic acid metabolites.

Adenosine Diphosphate↗
PubMed1980

Effect of sulphinpyrazone on human platelet aggregation, 5-hydroxytryptamine release and adhesion ex vivo: comparison with naproxen.

1 The effects of single doses of naproxen and sulphinpyrazone and of 4 and 8 days treatment with sulphinpyrazone on human platelet responsiveness were compared. 2 A single dose of sulphinpyrazone had no effect whereas a single dose of naproxen caused a five-fold depression in responsiveness to collagen. 3 Repeated administration of sulphinpyrazone led to a weak and equivocal inhibitory effect on collagen-induced aggregation, second phase aggregation in response to ADP and adhesion to collagen. There was no effect on ADP-induced first phase aggregation, adrenaline-induced second phase aggregation or platelet retention in glass bead columns. 4 It is concluded that the anti-aggregant activity of sulphinpyrazone is too weak to be a major factor in its reported effect on the incidence of cardiac death.

Adenosine Diphosphate↗
PubMed1979

Collagen-induced platelet aggregation:--evidence against the essential role of platelet adenosine diphosphate.

The hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 microM ADP, were not inhibited by 500 microM adenosine, a concentration that greatly reduced the effect of 300 microM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

Adenosine↗