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Biomedical subjects

P Lees

Publications and source records attributed to P Lees.

At least 109 records · Page 6Linked to original sources
PubMed1992

Effects of WEB 2086, an antagonist to the receptor for platelet-activating factor (PAF), on PAF-induced responses in the horse.

Platelet-activating factor (PAF) causes oedema and neutrophil accumulation when injected into the skin of normal horses. PAF is also known to induce aggregation of horse platelets in vitro. The selective PAF receptor antagonist WEB 2086 has now been used to determine whether these effects are mediated by PAF receptor activation. Addition of WEB 2086 to equine platelets in vitro inhibited PAF-induced aggregation in a competitive reversible manner (pA2 = 7.14). Inhibition of in vivo inflammatory responses to PAF occurred after local administration of WEB 2086: wheal formation induced by 0.1 micrograms PAF/site was reduced by 1-10 micrograms WEB 2086/site. PAF (1 micrograms/site)-induced neutrophil accumulation was also inhibited by co-administration of 10 micrograms WEB 2086/site. Systemic administration of WEB 2086 (3 mg/kg iv) to 4 normal ponies inhibited PAF-induced wheal formation and ex vivo platelet aggregation. At 30 min after drug administration the concentration of PAF required to produce a half maximal aggregation response was increased 496 +/- 137 fold. At 6 h the degree of inhibition was markedly reduced and responses had returned to pre-treatment values by 24 h. PAF-induced increases in cutaneous vascular permeability were also reduced by 80% as early as 30 min after iv administration of WEB 2086 in these animals, the inhibition persisting for at least 6 h. These results suggest that in vitro and in vivo responses to PAF in the horse are mediated via activation to PAF receptors. WEB 2086 will therefore be a useful agent for studying the role of PAF in the pathogenesis of equine inflammatory conditions.

Animals↗
PubMed1992

Inflammatory effects of platelet activating factor (PAF) in equine skin.

Intradermal administration of PAF (0.001-1 micrograms/site), but not lyso-PAF (10 micrograms/site), in the horse caused an increase in cutaneous vascular permeability which was maximal by 32 min. Responses to PAF and histamine were reduced by coadministration of the histamine 1 receptor antagonist chlorpheniramine, although only the inhibition of histamine-induced responses was dose-related and statistically significant. The cyclo-oxygenase inhibitor indomethacin was without effect on PAF-induced increases in vascular permeability. These findings suggest that the actions of PAF on equine skin microvasculature may be partly due to histamine release but not to prostanoid formation. Coadministration of prostaglandin (PG) E2 enhanced the oedematous responses to both PAF and histamine, although PGE2 failed to exert direct permeability-increasing activity. In addition, and in contrast to PAF and histamine, PGE2 increased cutaneous blood flow and skin surface temperature. PAF, but not lyso-PAF, also caused neutrophil infiltration into the skin which was maximal at 2 h. No significant effects on eosinophil or mononuclear cell numbers were apparent up to 24 h after injection of PAF. These results are consistent with the concept that PAF may be a mediator of inflammatory disorders of the skin in the horse.

Animals↗
PubMed1992

Influence of feeding schedule on the absorption of orally administered flunixin in the horse.

The effects of access to hay and of restricted feeding on the pharmacokinetics of flunixin administered orally to six healthy ponies were compared in a cross-over study. No access to feed for a few hours before and after flunixin administration resulted in rapid absorption with a mean peak plasma concentration of 2.84 +/- 0.28 micrograms/ml attained in an average time of 0.76 +/- 0.18 h, followed by an exponential decline in plasma concentration. A lower peak plasma concentration was obtained when ponies had free access to hay before and after drug dosing. The mean maximum concentration (Cmax) was 1.30 +/- 0.23 micrograms/ml and maximum time (tmax) was prolonged to a mean time of 7.66 +/- 1.74 h. Free access to hay reduced and delayed the peak plasma concentration resulting in two or three separate concentration peaks in some ponies. The mean area under the plasma concentration-time curve was not significantly different for the two feeding regimens.

Administration, Oral↗
PubMed1991

Late-stage mediators of the inflammatory response: identification of interleukin-1 and a casein-degrading enzyme in equine acute inflammatory exudates.

Interleukin-1 and a casein-degrading enzyme have been identified in an experimental system for studying acute inflammation in the horse. The levels of both the cytokine and the proteinase increased over the first 24 hours following initiation of the inflammatory response, and remained at high levels through to the last sample collected at 48 hours. This is in marked contrast to prostaglandin E2 concentrations which were low initially, peaked at four to eight hours and had returned to low levels by 12 to 24 hours. It is likely that interleukin-1 and various proteinases are involved in the later stages of the inflammatory response, such as the tissue remodelling associated with wound repair, and control of this cytokine may be important in the progression from acute to chronic inflammation.

Animals↗
PubMed1991

Isolation of equine peripheral blood mononuclear cells using Percoll.

The concentration of Percoll required for isolating equine peripheral blood mononuclear cells has been reinvestigated. A poor cell yield was obtained at the 60 per cent concentration already reported. It is recommended that workers specifically interested in high yields of mononuclear cells, for investigation of lymphocyte and monocyte functions, use a concentration of 65 per cent Percoll. However, workers wishing to isolate pure populations of equine neutrophils might consider a concentration of 70 per cent in the upper layer of Percoll used to retain the mononuclear cells.

Animals↗
PubMed1991

IL-1 alpha inhibits lymphocyte migration into a site of chronic inflammation.

The effects of murine recombinant IL-1 alpha (muIL-1 alpha) on lymphocyte migration in the mouse have been investigated. Continuous infusion of muIL-1 alpha had marked effects on patterns of lymphocyte migration into a site of chronic inflammation, inflammatory exudate and spleen; the numbers of lymphocytes migrating to the inflamed tissue and spleen were reduced in a dose-dependent manner. The number of lymphocytes in the blood of muIL-1 alpha-treated animals was increased in a dose-related manner. The decrease in numbers of lymphocytes present in the chronically inflamed site may either be due to a direct inhibitory action of muIL-1 alpha or reflect an increased rate of cell migration through the inflamed tissues accompanied by a more rapid return to the circulation. These findings suggest that IL-1 alpha may act not only as an inflammatory cytokine, but also as a modulator with anti-inflammatory activity during chronic inflammation.

Animals↗
PubMed1991

Antithrombotic actions of aspirin in the horse.

The antithrombotic effects of aspirin at two dose rates (4 mg/kg and 11 mg/kg bodyweight [bwt] were evaluated in normal, healthy ponies by measuring template bleeding time. Inhibition of platelet aggregation in response to adenosine diphosphate (ADP) and collagen was evaluated and cyclo-oxygenase activity was monitored by radioimmunoassay of thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2). TXB2 was measured in serum and platelet rich plasma. Bleeding time was prolonged significantly until 48 h after treatment at 12 mg/kg bwt and until 4 h at the lower dose rate. Synthesis of TXB2 and collagen induced aggregation were diminished for much greater periods with similar results at each of the dose rates. The prolonged effects of aspirin on platelet function occurred in spite of a very short plasma half-life of aspirin, because of its irreversible action on platelet cyclo-oxygenase. The results show that low dose aspirin has a potential role in antithrombotic therapy in horses although the relationship between skin bleeding time in normal horses and improvement of clinical conditions requires further research and evaluation in clinical trials. TXB2 measurement appears to overestimate the duration of antithrombotic effects of aspirin in vivo.

Adenosine Diphosphate↗
PubMed1991

Adverse conditions in vitro stimulate chondrocytes to produce prostaglandin E2 and stromelysin.

Chondrocytes subjected to adverse culture conditions in vitro are stimulated to produce the eicosanoid prostaglandin E2 (PGE2) and the neutral metalloproteinase stromelysin (proteoglycanase). This indicates the potential role of the chondrocyte in cartilage degeneration in equine clinical joint disease and suggests a mechanism which may be involved in the potentiation of the effects of other inflammatory mediators. Therefore, adverse conditions within the joint, such as decreased pH in an inflammatory focus and decreased access of nutrients to deeper layers of cartilage, might contribute to the activation of chondrocytes which leads to cartilage degradation.

Animals↗
PubMed1991

A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse.

A murine 6-day air-pouch model of inflammation has been developed and used to compare the patterns of acute and chronic inflammatory response to three irritants, carrageenan, dextran and zymosan, each injected into the cavity of the pre-formed pouch. The inflammation was assessed by measurement of exudate volume and numbers of infiltrating leucocytes over a 30-day time course. Histological changes in the inflamed air-pouch lining tissue were also investigated. The inflammatory response to carrageenan was acute with moderate exudate formation and cell numbers. Dextran produced a mild inflammatory reaction with low cell infiltration into exudate. In contrast, the inflammatory response to zymosan was greater in terms of cell migration, but smaller in terms of exudate volume and occurred later in the time course. Histological changes in the inflamed air-pouch tissue were also markedly different in response to the three irritants. Carrageenan induced a rapid, mainly polymorphonuclear leucocyte (PMN) infiltrate into the tissue and deposition of fibrin on the luminal surface. The response to dextran was characterized by a rapid resolution of the inflammatory response, with fewer leucocytes present in the lining and no fibrin deposition. In contrast, zymosan caused a marked but slower leucocyte influx, with greater numbers of monocytes, and clearance of the zymosan particles from the air-pouch lining by macrophages. This study indicates that by using different irritants to produce inflammation, it may be possible to dissect the roles played by various cells and inflammatory mediators during acute and chronic inflammation.

Animals↗
PubMed1990

Cephalexin in ponies: a preliminary investigation.

The administration of a single dose of the antibacterial agent cephalexin intramuscularly to six ponies at a dose rate of 7 mg/kg was well tolerated. No reactions at the injection site were apparent. It was absorbed rapidly and reached a mean peak plasma concentration of 6.77 micrograms/ml after a mean of 1.41 hours; plasma concentrations above 2.0 and 0.5 micrograms/ml were maintained for 3.8 and 9.8 hours, respectively.

Absorption↗
PubMed1990

A hospital quit-smoking consult service: clinical report and intervention guidelines.

A minimal-contact quit-smoking consult service was established to treat hospital inpatients and outpatients referred for behavioral smoking cessation treatment. Sixty-two consecutively referred patients were evaluated and triaged to one of three standardized quitting protocols: motivational counseling; standard behavioral abstinence counseling; or abstinence counseling plus nicotine fading. Consultations included personalized self-quit materials and planned telephone follow-up to enhance compliance. Triage differentiated patients with different levels of quitting readiness and nicotine dependence. Six months after treatment, 27% of patients had quit smoking (informant-verified). Predictors of quit attempts were shorter smoking history and lower nicotine dependence. Variables predicting cessation or substantial reductions in estimated daily nicotine intake included higher educational level, stronger beliefs in smoking health harms, higher trait anxiety, a greater desire to quit and quitting self-efficacy, and the recall of direct quitting advice from the referring physician. Results compare favorably with those of more intensive treatments with similar patient groups. Recommendations are presented for controlled follow-up research to explore promising findings in this clinical report.

Adult↗
PubMed1990

The characterisation of equine interleukin-1.

Equine interleukin-1 has been produced from peripheral blood monocytes by stimulation with E. coli lipopolysaccharide. Sephacryl S200 gel filtration revealed a molecular weight of 17-18 kD. Chromatofocusing of the 17-18 kD peak identified four active fractions. Two major peaks were detected at pH 6.7 and pH 7, with smaller peaks at pH 6.3 and pH 5.9. The pI 7 molecule is probably the equine form of IL-1 beta.

Animals↗
PubMed1990

Pharmacokinetics and dosage regimens of anti-inflammatory drugs.

The term anti-inflammatory drug, in its broadest sense, encompasses a number of very diverse compounds, ranging from steroids to non-steroidal anti-inflammatory drugs (NSAIDs) and from disease modifying agents (used in the treatment of canine rheumatoid arthritis) to chondroprotective agents (used in the treatment of osteoarthrosis and traumatic arthritis in the horse). For many of these drugs (eg, chondroprotective and disease modifying agents) the mode of action is unknown and even with steroids and NSAIDs there is no universal agreement on mechanism of action. It is therefore in many cases impossible to link pharmacokinetic data to a drug's pharmacodynamics, for example to an effect on a specific biochemical marker. Some agents, including corticosteroids, may have indirect modes of action, so that the pharmacodynamic half-life can be much longer than (and not clearly related to) the pharmacokinetic half-life. In other cases, clinical benefits may only become apparent after several weeks or even months. It can therefore be difficult or impossible to use classical pharmacokinetic approaches to set dosing intervals and dose rates for clinical use. To some extent, the position is more straightforward with NSAIDs. However, even with these drugs simple approaches are not possible and this paper will review briefly some of the studies undertaken in our laboratory which have attempted to utilize NSAID kinetics to set dosage schedules for clinical use.

Animals↗
PubMed1990

The curled catheter: dependable device for percutaneous peritoneal access.

The curled peritoneal dialysis catheter is theoretically less prone to catheter migration and drainage failure. It also allows percutaneous placement, rather than surgical placement exclusively, whenever desired or necessary. Review of 213 curled-catheter placements, 134 (63%) percutaneous and 79 (37%) surgical, over the last 4 years, shows that the probability of continuing catheter function by life-table analysis was 88% at one year, 71% at 2 years, and 61% at three years, with no difference comparing percutaneous to surgical placement. Among the 213 total cases, nearly 50% of all catheters were still functioning at last follow up, and 38 catheters (17.8%) have been lost in total, attributed to infectious complications in 24 cases (tunnel-exit infection alone in 5, peritonitis alone in 11, combined infection in 8), refractory drain failure in 9 cases (early drain failure in 4, late drain failure in 5), recurrent late subcutaneous dialysate leaking in 3 cases, and peri-catheter hernia in 2 cases. Among other complications, the incidence of early drain failure (7.0%), and late drain failure (4.2%), compare favorably to reports describing other devices or other placement methods having comparable size of reported experience. Analyzing our own percutaneous and surgical placements separately, there were no differences in the respective frequencies of early drain failure, late drain failure, late subcutaneous dialysate leaking, outer cuff extrusion, required hernia repair, peritonitis or tunnel-exit infection. Only early external dialysate leaking was more frequent using percutaneous placement methods (21.6% vs. 10.1%; p less than 0.05), although no catheters were lost due to early external leaking.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

Action of dexamethasone in an equine model of acute non-immune inflammation.

In a crossover study in seven New Forest ponies the actions of dexamethasone, at a dose rate of 0.06 mg kg-1 administered intravenously, were compared with those of a placebo treatment. Dexamethasone exerted expected effects on plasma and inflammatory exudate concentrations of cortisol and on blood glucose concentration and circulating leucocyte numbers, but it failed to affect exudate concentrations of the eicosanoids, prostaglandin E2, thromboxane B2, 6-keto-PGF1 alpha and leukotriene B4. These findings do not support the hypothesis that the anti-inflammatory actions of dexamethasone in the horse are mediated by inhibition of phospholipase A2.

Animals↗
PubMed1989

Flunixin pharmacokinetics and serum thromboxane inhibition in the dog.

Flunixin meglumine administered orally to beagle dogs at doses of 0.55, 1.10 or 1.65 mg/kg bodyweight was rapidly absorbed to produce maximum mean plasma concentrations of 2.40 +/- 0.70, 4.57 +/- 1.12 and 7.42 +/- 2.07 micrograms/ml, respectively. Thereafter, the plasma concentrations of flunixin fell rapidly to values less than 0.10 micrograms/ml from 24 hours after drug administration at all dosage levels. The maximum mean inhibition of serum thromboxane B2 was 91.5 per cent after the lowest dose of flunixin and 98.8 per cent for both the intermediate and high dose rates. At plasma concentrations of flunixin above 2 micrograms/ml there was more than 90 per cent inhibition of thromboxane.

Administration, Oral↗
PubMed1989

Lymphocyte kinetics in a murine model of chronic inflammation.

A modification of the air pouch system [1], has been developed to investigate the role of lymphocytes in an inmmunologically driven model of chronic inflammation. Radiolabelled spleen and lymph node mononuclear cells from mice presensitised with Bordatella pertussis vaccine (BPV) were infused intravenously into mice also presensitised with BPV and challenged with BPV into 6 day old air pouches. Cell migration was monitored by gamma counting of tissues sampled 4 hours after infusion. The percentage increase in counts obtained in air pouch tissue compared to control skin, over a time course of 30 days, reached a peak at 10 days after BPV challenge. Vessels with features of high endothelial venules, and clusters of lymphocytes have been demonstrated histologically and immunohistochemically in air pouch tissue at this time.

Animals↗