Biomedical subjects

F M Cunningham

Publications and source records attributed to F M Cunningham.

At least 55 records · Page 3Linked to original sources

PubMed1995

Comparative pharmacodynamics of flunixin, ketoprofen and tolfenamic acid in calves.

The pharmacodynamics of the non-steroidal anti-inflammatory drugs flunixin, tolfenamic acid and ketoprofen were studied in calves after intravenous administration. An acute inflammatory reaction was induced in tissue cages by the intracaveal injection of the mild irritant carrageenan, and the inhibition of inflammatory mediators and enzymes was investigated. The substances measured in the exudate included the enzymes (active and total metalloproteases, serine and cysteine proteases, acid phosphatase [AP], lactate dehydrogenase [LDH] and beta-glucuronidase) and the eicosanoids (prostaglandin [PG]E2 and leukotriene [LT]B4). Studies were also made of inhibition of the synthesis of serum thromboxane (Tx)B2 ex vivo, of bradykinin-induced oedema in vivo and of the generation of superoxide anions (O2-) in vitro. None of the drugs affected the concentration of LTB4, or the activities of metalloproteases, cysteine and serine proteases, AP or LDH in the exudate. All the drugs inhibited the synthesis of serum TxB2 and exudate PGE2 and inhibited the release of beta-glucuronidase. They also decreased the oedematous response to intradermally injected bradykinin and inhibited the generation of O2- ions by neutrophils in vitro. These actions may contribute to the anti-inflammatory effects of the drugs and hence to their clinical efficacy.

Animals↗

PubMed1995

Actions of PAF receptor antagonists in horses with the allergic skin disease sweet itch.

Platelet activating factor (PAF) mimics the effects of Culicoides antigen by inducing oedema and inflammatory cell accumulation in the dermis of horses with the allergic skin disease, sweet itch. PAF could therefore contribute to antigen-induced inflammatory changes in these horses. We now report that intravenous administration of the PAF receptor antagonist WEB 2086 (3 mg kg-1), at a dose that inhibited the vascular and cellular responses to PAF in sweet itch horses, reduced Culicoides antigen-induced oedema at 1 h by 73% and at 8 h by 71% (p < 0.05). Neutrophil accumulation and eosinophil recruitment were not significantly reduced by WEB 2086 or a second hetrazepine PAF receptor antagonist WEB 2170 (0.1 mg kg-1). These findings suggest a key role for PAF in oedema formation, but not inflammatory cell accumulation, induced by Culicoides antigen in the skin of sweet itch horses.

Animals↗

PubMed1995

Platelet activating factor mimics antigen-induced cutaneous inflammatory responses in sweet itch horses.

Hypersensitivity responses to biting flies such as Culicoides are believed to be the cause of sweet itch, a seasonal intensely pruritic skin condition of horses. Little is known about the mediators released by antigen in the skin of affected horses. In the present study the cutaneous vascular and cellular responses to intradermally injected platelet activating factor (PAF) have been characterised in sweet itch cases during the active phase of the disease and compared with those of Culicoides antigen extract. Histamine was used as a positive control in vascular permeability studies. Responses were also examined in 4 of the 5 sweet itch cases during the inactive phase of the disease. Normal ponies were used as controls. PAF-induced increases in vascular permeability that were dose-related (0.001-1 micrograms per site) and of a similar magnitude in sweet itch and normal animals. Antigen (0.5-50 micrograms per site) also caused dose-related wheal formation in sweet itch cases during the active, but not the inactive, phase of the disease. This effect was biphasic, with maximal responses occurring at 1 and 8 h. An increase in vascular permeability occurred in normal ponies only after administration of the highest dose of antigen tested. Interestingly, histamine (0.02 micrograms per site) induced wheals were significantly smaller in the affected, compared with the normal, group, both during the active and inactive phases. PAF and antigen caused neutrophil accumulation in the skin of sweet itch and normal animals during both the active and inactive phases of the disease. Eosinophil recruitment was also observed but only in the affected group and, in the case of PAF, during the active, but not the inactive, phase. Antigen additionally caused the accumulation of mononuclear cells in the skin of sweet itch cases during the active phase, PAF induced a small increase in mononuclear cell numbers in these animals but the increase was not statistically significant. These findings demonstrate that PAF mimics the effects of Culicoides antigen during the active phase of the disease. Hence, PAF, like histamine, may play a role in the pathogenesis of antigen-induced responses in the skin of sweet itch horses.

Animals↗

PubMed1995

Pharmacokinetics and pharmacodynamics of ketoprofen in calves applying PK/PD modelling.

The pharmacokinetics (PK) and pharmacodynamics (PD) of ketoprofen (KTP) were studied in calves following intravenous administration of the drug racemate at a dose rate of 3 mg/kg. To evaluate the anti-inflammatory properties of KTP, a model of acute inflammation, consisting of surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. No differences were observed between disposition curves of KTP enantiomers in plasma, exudate or transudate. This indicates that in calves KTP pharmacokinetics is not enantioselective. S(+)- and R(-)- KTP each had a short elimination half-life (t1/2 beta) of 0.42 +/- 0.08 h and 0.42 +/- 0.09 h, respectively. The volume of distribution (Vd) was low, values of 0.20 +/- 0.06 L/kg and 0.22 +/- 0.06 L/kg being obtained for R(-) and S(+)KTP, respectively. Body clearance (ClB) was high, correlating with the short elimination half-life, 0.33 +/- 0.03 L/kg/h [R(-)KTP] and 0.32 +/- 0.04 L/kg/h [S(+)-KTP]. KTP pharmacodynamics was evaluated by determining the effects on serum thromboxane (TxB2), exudate prostaglandin (PGE2), leukotriene (LTB4) and beta-glucuronidase (beta-glu) and bradykinin (BK)-induced oedematous swelling. Effect-concentration inter-relationships were analysed by PK/PD modelling. KTP did not affect exudate LTB4, but inhibition of the other variables was statistically significant. The mean EC50 values for inhibition of serum TxB2, exudate PGE2 and beta-glu and BK-induced swelling were 0.118, 0.086, 0.06 and 0.00029 microgram/mL, respectively. These data indicate that KTP exerted an inhibitory action, not only as expected, on eicosanoid (TxB2 and PGE2) synthesis but also on exudate beta-glu and BK-induced oedema. The EC50 values for these actions indicate that they are likely to contribute to the overall anti-inflammatory effects of KTP in calves. However, claims that KTP inhibits 5-lipoxygenase and thereby blocks the production of inflammatory mediators such as LTB4 were not substantiated. PK/PD modelling has proved to be a useful tool for analysing the in vivo pharmacodynamics of KTP and for providing new approaches to elucidating its mechanism(s) of action.

Animals↗

PubMed1995

Determination of pharmacokinetics and pharmacodynamics of flunixin in calves by use of pharmacokinetic/pharmacodynamic modeling.

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and beta-glucuronidase [beta-glu]), eicosanoid (prostaglandin E2 [PGE2], leukotriene B4, and serum thromboxane B2 [TXB2]) concentrations, and bradykinin (BK)-induced edema, were investigated. Flunixin had a long elimination half-life--6.87 +/- 0.49 hours--and volume of distribution was 2.11 +/- 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 +/- 0.03 L/kg/h. Flunixin exerted inhibitory effects on serum TXB2 and exudate PGE2 concentrations, beta-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗

PubMed1993

Early neutrophil but not eosinophil or platelet recruitment to the lungs of allergic horses following antigen exposure.

Previous studies have shown that bronchoalveolar lavage fluid from horses with allergic respiratory disease and showing clinical symptoms contains increased numbers of neutrophils. In some cases, the eosinophil count is also increased. In this study the time course of changes in lung function and the accumulation of radiolabelled leucocytes and platelets in the lungs of allergic and normal horses has been examined during a 7 hr allergen exposure. Antigen challenge had no effect on pleural pressure or the distribution of radiolabelled neutrophils, eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses, there was an increase in pleural pressure and neutrophil accumulation in the lungs, both of which were evident after 4-5 hr. However, during the 7 hr challenge period radiolabelled eosinophils were detected in the lungs of only 1/6 horses exhibiting an increase in pleural pressure and in 1/7 horses that failed to show a change in airway function despite a clinical history of allergic respiratory disease. Antigen challenge did not alter the distribution of radiolabelled platelets in the five allergic horses tested. These results demonstrate that increased pleural pressure is not accompanied by eosinophil or platelet accumulation in the lungs of horses with allergic respiratory disease following exposure to antigen. However, changes in airway function can be associated with neutrophil accumulation but can also take place in the absence of this cell recruitment. This raises the possibility that the presence of neutrophils in the lung is not a prerequisite for changes in lung function.

Actinomycetales↗

PubMed1993

Duration of antigen-induced hyperresponsiveness in horses with allergic respiratory disease and possible links with early airway obstruction.

Antigen-induced airway hyperresponsiveness in allergic horses has previously been demonstrated when clinical signs of acute airway obstruction were apparent, as a consequence of exposure of animals to hay and straw for variable periods of time, and repeat measurements of hyperresponsiveness have been made no earlier than 1 week after challenge. In the present study airway responsiveness to methacholine has been measured in normal horses and allergic horses in clinical remission before and 24, 48 and 72 h after a hay and straw challenge of fixed, short, duration (7 h). Correlations between early increases in interpleural pressure and hyperresponsiveness have also been investigated. As in other studies, the mean airway responsiveness of groups of normal and allergic horses in clinical remission was not significantly different. The responsiveness to methacholine of allergic, but not normal, horses was increased after antigen challenge and was significantly greater than that of normal horses at 48 and 72 h after challenge (log PD8 cm: -0.77 +/- 0.28 vs. 0.27 +/- 0.14 at 48 h and -0.6 +/- 0.25 vs. 044 +/- 01 at 72 h; P < 0.05). There was also a significant correlation between interpleural pressure at the end of the 7-h challenge in allergic horses and the increase in responsiveness to methacholine at 24, 48 and 72 h. These results demonstrate that antigen induces an increase in airway responsiveness in allergic horses that persists for up to 3 days and which may be linked to the initial increase in interpleural pressure.

Airway Obstruction↗

PubMed1993

A comparison of the actions of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse.

The effects of the selective platelet activating factor (PAF) receptor antagonist WEB 2170 on PAF-induced responses in equine cells and tissues have been examined and compared with those of WEB 2086. In initial experiments WEB 2170 was shown to inhibit in vitro platelet aggregation in a dose-dependent, competitive reversible manner (pA2 = 7.21). Co-administration of the antagonists with either PAF or histamine also inhibited PAF, but not histamine, induced wheal formation and PAF-induced neutrophil accumulation in vivo in equine skin. Intravenous (i.v.) administration of both drugs at a dose of 0.1 mg/kg blocked PAF-induced ex vivo platelet aggregation. The inhibition produced by WEB 2170 was greater and, at 30 min, this drug also reduced the slope and maximal response. Wheal formation in the skin was significantly inhibited for up to 6 h by WEB 2170 administered i.v., the reduction being more prolonged than that obtained with WEB 2086. Neutrophil accumulation in the skin was also significantly reduced for up to 24 h by WEB 2170, whilst no significant inhibition was produced by WEB 2086. These results demonstrate that WEB 2170, like WEB 2086, is an effective antagonist of PAF in the horse. Moreover, when given i.v., WEB 2170 appears to be a more potent PAF inhibitor than WEB 2086.

Animals↗

PubMed1992

Platelet activating factor is a mediator of equine neutrophil and eosinophil migration in vitro.

Platelet activating factor (PAF) is known to be a chemoattractant for equine neutrophils in vivo and in vitro. In this study the in vitro migratory response of equine eosinophils and neutrophils to PAF has been examined and compared with that to leukotriene (LT)B4. PAF (10(-8) to 10(-5) M), but not lyso-PAF (10(-6) M), caused dose related migration of both equine eosinophils and neutrophils, maximal responses occurring at 10(-6) M. Responses to PAF were inhibited by the receptor antagonist WEB 2086. LTB4 (10(-8) to 10(-6) M) also induced migration of both cell types, although the maximum effect was observed with a 10-fold lower concentration. Moreover, the maximum response of equine eosinophils to LTB4 was significantly greater than to PAF. It is concluded that LTB4 and PAF, if released in vivo at sites of allergic or inflammatory reactions, could mediate the recruitment of leucocytes to the involved tissue.

Animals↗

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↗

PubMed1990

Pharmacologic and clinical effects of lonapalene (RS 43179), a 5-lipoxygenase inhibitor, in psoriasis.

The pharmacologic and clinical effects of the 5-lipoxygenase inhibitor, lonapalene, have been determined in a double-blind, placebo-controlled, topical study in ten volunteers with psoriasis. A statistically significant clinical improvement was seen in lesions treated with 2% lonapalene ointment as compared with vehicle-treated sites. Although there was a statistically significant reduction in the levels of material similar or identical to the chemoattractant arachidonate 5-lipoxygenase product, leukotriene B4, in skin chamber fluid samples from lonapalene versus vehicle treated lesions, no significant reduction in arachidonic acid or 12-hydroxy-5,8,10,14-eicosatetraenoic acid was seen. The reduction in leukotriene B4 equivalents occurred before significant clinical improvement in lesions was seen. This and the selectivity of the pharmacologic response suggest that the therapeutic effect of topical lonapalene in psoriasis might be related to inhibition of leukotriene B4 synthesis. These results support the view that 5-lipoxygenase inhibitors may be useful in the treatment of psoriasis, and that leukotriene B4 is a relevant mediator of the pathology of this disease.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1989

Effect of dithranol treatment on arachidonic acid and its lipoxygenase products in psoriasis.

The concentrations of arachidonic acid and its lipoxygenase metabolites were measured in exudates from lesional psoriatic skin during treatment with 0.25% dithranol (anthralin) applied topically for 10 days. Dithranol caused a reduction in the concentration of arachidonic acid at 10 days (167 +/- 42 and 358 +/- 55 ng ml-1 treated and control sites respectively, p less than 0.05) concurrent with clinical improvement of the lesions. Neither 12-hydroxyeicosatetraenoic acid nor leukotriene B4 concentrations were significantly affected. These results do not support the view that lipoxygenase products are of major importance in the pathogenesis of psoriasis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1988

Neutrophil chemoattractant and IL-1-like activity in samples from psoriatic skin lesions. Further characterization.

The IL-1-like neutrophil chemoattractant activity previously reported by us to be present in the stratum corneum of psoriatic skin lesions has now been characterized further. Aqueous extracts of stratum corneum samples from psoriatic lesions and from the heels of normal volunteers were ultrafiltered to yield 10- to 30-kDa fractions. The ultrafiltered psoriatic preparations consistently contained greater neutrophil chemokinetic activity than the normal heel preparations, but in contrast the latter contained markedly greater IL-1 activity than the former. Successive chromatographic purification of psoriatic lesional stratum corneum extracts showed that the neutrophil chemokinetic material previously reported to co-elute with IL-1 activity on reversed phase HPLC, but to be distinct from C5a des arg, could now be separated by anion exchange HPLC into at least four different chemokinetic compounds that were also resolved from the IL-1 activity. The reversed phase HPLC-purified chemokinetic material from psoriatic stratum corneum was also active in a neutrophil chemotaxis assay. These findings show that samples from psoriatic skin lesions contain a group of novel 10- to 30-kDa neutrophil chemoattractant compounds that are distinct from both C5a des arg and IL-1. The contrasting neutrophil chemokinetic and IL-1 activities in psoriatic lesional and normal heel stratum corneum preparations support the finding that the two activities are produced by different compounds. These neutrophil chemoattractant and IL-1-like compounds may be of pathogenic importance in inflammatory skin disease.

Adolescent↗

PubMed1988

Actions of platelet activating factor (PAF) homologues and their combinations on neutrophil chemokinesis and cutaneous inflammatory responses in man.

The inflammatory actions of synthetic C16:0 and C18:0 platelet activating factor (PAF) homologues, both alone and in combination, have been compared in an in vitro human neutrophil chemokinesis assay and by intradermal injection in human skin. In the chemokinesis assay, the maximum distance moved by neutrophils in the presence of C18:0 PAF was significantly greater than that seen with the C16:0 compound. A mixture of C16:0 and C18:0 PAFs in a ratio of 1:9 appeared to be more active than in a ratio of 3:1. Intradermal injection of the C16:0 and C18:0 PAF homologues induced dose-dependent increases in weal volume and flare area responses which were not significantly different. Combination of these phospholipids in a ratio of 3:1 or 1:9 of C16:0:C18:0 did not significantly alter the dose response curves. Thus, changes in the chain length of the alkyl substituent of synthetic PAF homologues and combination of these homologues, in ratios found in vivo or formed by leukocytes in vitro, did not alter the cutaneous inflammatory responses to PAF in man. The C18:0 homologue was, however, more active as a human neutrophil chemoattractant in vitro.

Chemotaxis, Leukocyte↗

PubMed1988

Psoriatic skin lesions contain a novel lipid neutrophil chemokinetic compound which is distinct from known chemoattractant eicosanoids.

1. Lipid extracts of scale from the lesions of the skin disease psoriasis were purified by high performance liquid chromatography (h.p.l.c.). Assay of fractions by an agarose microdroplet method showed the presence of a novel neutrophil chemokinetic compound which possessed the chromatographic properties of a monohydroxy fatty acid, yet was distinct from the chemoattractant eicosanoid, 12-hydroxyeicosatetraenoic acid, previously isolated in psoriasis. 2. The novel, material, termed compound X, was also detected in fractions collected on h.p.l.c. of extracts of chamber fluid samples obtained from abraded psoriatic lesions, but was not detectable in samples from clinically normal skin. 3. Comparison of the straight and reversed phase h.p.l.c. retention times of compound X with those of a range of standard monohydroxy fatty acids, together with further analysis by gas chromatography-mass spectrometry and assay of selected standards for neutrophil chemokinetic activity, failed to reveal the structural identity of compound X. 4. The finding of a further compound in psoriatic lesions, which stimulates neutrophil movement, highlights the complexity of inflammatory mediator production in this disease.

Adult↗

PubMed1988

Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12-hydroxy-5,8,10,14-eicosatetraenoic acid.

1. The chemotactic activity of 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(R)-HETE), 12(S)-HETE and leukotriene B4 (LTB4) for human mixed peripheral blood lymphocytes has been assessed in a 48-well microchemotaxis assay. Responses to the standard lymphocyte chemoattractants, zymosan-activated plasma, casein and N-formyl-methionyl-leucyl-phenylalanine (fMLP) were also measured. 2. 12(R)-HETE was shown to be chemotactic for lymphocytes over the range 5 x 10(-7) to 5 x 10(-5) M. In contrast, negligible chemotactic responses to 12(S)-HETE were obtained. 3. LTB4 was 200 times more potent than 12(R)-HETE as a lymphocyte chemoattractant, although maximal responses to the two agonists were similar. 4. 12(R)-HETE and LTB4, which are present in extracts of samples from the skin lesions of psoriasis, may be, at least in part, responsible for the lymphocyte infiltrate which is a characteristic feature of this disease.

Cell Movement↗

PubMed1987

12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid is a chemoattractant for human polymorphonuclear leucocytes in vitro.

Increased amounts of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) are found in the lesional skin of patients with the skin disease psoriasis when compared to clinically normal skin. Stereochemical analysis has recently shown that the 12-HETE present in lesional psoriatic scale is the (R), and not the (S) hydroxyl enantiomer, produced by platelets. Since the chemoattractant activity of 12(R)-HETE has not previously been described, the (R) and (S) hydroxyl enantiomers of 12-HETE have now been synthesised and their chemokinetic activity compared in vitro. 12(R)-HETE, was more potent than 12(S)-HETE as a chemokinetic agent for human polymorphonuclear leucocytes but 2000 times less potent than leukotriene B4. In contrast to results obtained with the 12-HETE enantiomers, the chemoattractant compound 5(S)-HETE was found to be more potent than the 5(R) hydroxyl enantiomer. Thus, the configuration of the hydroxyl group appears to be of importance to the chemokinetic activity of the HETEs, and the increased potency of the 12(R) enantiomer may enhance its significance as a mediator of inflammation in psoriasis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗