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Biomedical subjects

A Rees

Publications and source records attributed to A Rees.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dynamic sensory sensitivity and children's word decoding skills.

The relationship between sensory sensitivity and reading performance was examined to test the hypothesis that the orthographic and phonological skills engaged in visual word recognition are constrained by the ability to detect dynamic visual and auditory events. A test battery using sensory psychophysics, psychometric tests, and measures of component literacy skills was administered to 32 unselected 10-year-old primary school children. The results suggest that children's sensitivity to both dynamic auditory and visual stimuli are related to their literacy skills. Importantly, after controlling for intelligence and overall reading ability, visual motion sensitivity explained independent variance in orthographic skill but not phonological ability, and auditory FM sensitivity covaried with phonological skill but not orthographic skill. These results support the hypothesis that sensitivity at detecting dynamic stimuli influences normal children's reading skills. Vision and audition separately may affect the ability to extract orthographic and phonological information during reading.

Acoustic Stimulation↗
PubMed2000

A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320.

Thirty healthy HIV negative volunteers were randomised to receive 200 micrograms of rgp120W61D in either: 3D-MPL and QS21, with an oil and water emulsion (SBAS-2) (13); or 3D-MPL and QS21 (SBAS-1) (11); or alum (six). Immunizations were given at 0, 4 and 28 weeks and 23 (77%) participants completed the schedule. Adverse events were more frequent (P < 0.001) and more severe (P < 0.001) in the SBAS-2 group. Binding antibodies to the homologous rgp120W61D were detected after the first immunisation only in those receiving SBAS-1 and SBAS-2, were maximal after the third immunization in all three groups, and persisted to week 84 only in the novel adjuvant groups. These differences were significant (p = 0.02). Neutralising antibodies to TCLA-strains of HIV-1 were observed after the second immunization in all three groups, were maximal after the third immunization, but did not neutralise homologous or heterologous PBMC derived primary HIV-1 isolates. Proliferative T-cell responses to rgp120W61D were maximal after the second immunization and reached very high values in the SBAS-2 group. HIV-1 specific CD8+ MHC Class I restricted cytotoxic T-lymphocytes were not seen in a subset of participants tested at a single timepoint. SBAS-2 with rgp120W61D induced antibody titres as high as those seen in HIV infection, but the quality of the antibodies remained different in that there was no evidence of primary isolate neutralisation. Although cell-mediated immunity was enhanced by SBAS-2 in terms of lymphoproliferative responses, HIV-1 specific CD8+ cytotoxicity was not demonstrated.

AIDS Vaccines↗
PubMed2000

Human brain areas involved in the analysis of auditory movement.

This work tests the hypothesis that a network of areas involving bilateral premotor cortex and right parietal cortex subserves the analysis of sound movement. The components of this network have been examined at the level of individual subjects in a study where 720 fMRI scans were acquired per subject. Additionally, the effect of movement direction was investigated by varying this property systematically. Linear sound ramps that are perceived as movement toward one side of the head or the other were used in an experiment in which the principal contrast was between movement, and a stationary control stimulus made up of identical component interaural phase and amplitude cues. In a group analysis, the network of bifrontal and right parietal areas suggested by previous work was confirmed. The frontal activation included both dorsal premotor activity in the region of the frontal eye fields and discrete ventral premotor activation in an area corresponding to primate areas for multimodal spatial analysis and motor planning. The right parietal activation included both superior and inferior parietal cortex. Analysis of the individual data showed a similar pattern of activation in each subject, with the greatest variability within the right parietal area. The pattern of activation did not vary when the direction of movement was varied, suggesting that both directions of movement are represented in the network we have demonstrated.

Acoustic Stimulation↗
PubMed2000

Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide.

Potent monomeric and dimeric cyclic peptide very late antigen-4 (VLA-4) inhibitors have been designed based on a tetrapeptide (Ile-Leu-Asp-Val) sequence present in a 25-amino acid peptide (CS-1) reported in the literature. The peptides, synthesized by the SPPS techniques, were evaluated in the in vitro cell adhesion assays and in the in vivo inflammation models. The N- to C-terminal cyclic peptides such as cyclo(Ile-Leu-Asp-Val-NH-(CH2)2-S-(CH2)2-CO) (28) and cyclo(MeIle-Leu-Asp-Val-D-Ala-D-Ala) (31), monomeric and dimeric peptides containing piperazine (Pip) or homopiperazine (hPip) residues as linking groups, e.g. cyclo(MeIle-Leu-Asp-Val-Pip-CH2CO-NH-(CH2)2-S-CH2-CO) (49) and cyclo(MeIle-Leu-Asp-Val hPip-CH2CO-MeIle-Leu-Asp-Val-hPip-CH2CO) (58) and cyclic peptides containing an amide bond between the side chain amino group of an amino acid such as Lys and the C-terminal Val carboxyl group, e.g. Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) (62) and beta-Ala-cyclo(D-Lys-D-Leu-Leu-Asp-Val) (68) were more potent than CS-1 in inhibiting the adhesion of the VLA-4-expressing MOLT-4 cells to fibronectin. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule- 1-expressing Chinese hamster ovary cells (LFA-1) and ADP-induced platelet aggregation (GPIIb/IIIa). A number of the more potent compounds inhibited ovalbumin-induced delayed type hypersensitivity in mice and some were 100-300 times more potent (ED50 = 0.003-0.009 mg/kg/day, s.c.) than CS-1. Two peptides, Ac-cyclo(D-Lys D-Ile-Leu-Asp-Val) (62) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) (55), were formulated in poly(DL-lactide-co-glycolide) depots and the release profile was investigated in vitro over a 30-day period.

Amino Acid Sequence↗
PubMed2000

Potent cyclic peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation.

Additional structure-activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X = 2-4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Phe) (20), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(DL-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nM, respectively, and did not show any significant effect against other integrins (IC50 > 300 microM). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1-10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3-10 mg/kg. The peptide was released from some formulations over a period of 10-20 days. ZD7349 is currently undergoing pre-clinical investigation.

Animals↗
PubMed2000

Mechanism, localization and cure of atrial arrhythmias occurring after a new intraoperative endocardial radiofrequency ablation procedure for atrial fibrillation.

OBJECTIVES: The purpose of this study was to test a new pattern of radiofrequency ablation for atrial fibrillation (AFib) intended to optimize atrial activation, and to demonstrate the usefulness of catheter techniques for mapping and ablation of postoperative atrial arrhythmias. BACKGROUND: Linear radiofrequency lesions have been used to cure AFib, but the optimal pattern of lesions is unknown and postoperative tachyarrhythmias are common. METHODS: A radial pattern of linear radiofrequency lesions (Star) was made using an endocardial open surgical approach in 25 patients. Postoperative arrhythmias were induced and characterized during electrophysiological studies in 15 patients. RESULTS: The AFib was abolished in most patients (91%), but atrial flutter (AFlut) occurred in 96% of patients postoperatively. At postoperative electrophysiological studies, 37 flutter morphologies were studied in 15 patients (46% spontaneous, cycle length [CL] 223 +/- 25 ms). Seven mechanisms (lesions discontinuity, n = 6; focal mechanism, n = 1) of AFlut were characterized in six patients. In these cases, flutter was abolished using further catheter radiofrequency ablation. In the remaining cases, flutter was usually localized to an area involving the interatrial septum, but no critical isthmus was identified for ablation. After 16 +/-10 months, 15 patients (65%) were asymptomatic with (n = 3) or without (n = 12) antiarrhythmic medications. Eight (35%) patients had persistent arrhythmias. Postoperative atrial electrical activation was near physiological. CONCLUSIONS: The AFib maybe abolished using a radial pattern of linear endocardial radiofrequency lesions, but postoperative AFlut is common even when lesions are made under optimal conditions. Endocardial mapping techniques can be used to characterize the flutter mechanisms, thus enabling subsequent successful catheter ablation.

Adolescent↗
PubMed2000

Identification and monitoring of disordered water balance: bioelectrical impedance analysis as an alternative to the target weight procedure.

Many psychiatric patients present with disorders of water balance manifested by polydipsia or polyuria. Multiple frequency bioelectrical impedance analysis (MFBIA) was investigated as a suitable method for the assessment of body water in such patients. Whole body bioelectrical impedance, total body water and extracellular water and serum sodium were measured in 10 chronic psychiatric inpatients with polydipsia. Fluid volumes predicted by MFBIA correlated significantly (P < 0.002) with those obtained by reference methods but the relatively high limits of agreement (2.2 L) suggest that the method is not yet sufficiently accurate for random screening purposes. However, owing to the simplicity and non-invasive nature of the technique, it warrants further investigation and development, particularly for routine patient monitoring.

Adult↗
PubMed2000

Long-term results after aortic valve replacement in patients with congestive heart failure. Homografts vs prosthetic valves.

OBJECTIVES: The aim of this study was to assess the influence of valve substitute (homograft vs prosthetic valve) on the long-term survival and late valve-related complication rates following aortic valve replacement in patients with aortic valve disease and congestive heart failure. BACKGROUND: The effect of choice of valve substitute on outcome after aortic valve replacement in patients with pre-operative heart failure is unknown. The superior haemodynamic profile of homografts may be of particular benefit. METHODS: We retrospectively analysed pre-operative, operative and follow-up data on 518 adults in functional classes III and IV, who, over the 25 years 1969-1993, had their initial aortic valve replacement at Harefield hospital. Follow-up conducted during 1996 to April 1997 and totalling 4439 patient-years was 96.1% complete. Using multivariate analysis, independent risk factors for different complications and mortality were defined. RESULTS: Overall 5-, 10- and 20-year survival was 80+/-2%, 62+/-2% and 30+/-3%, respectively, with no significant difference between valve types. However, homografts (n=381) independently reduced the rate of serious complications and cardiac death, whereas mechanical valves were an independent adverse risk factor for late mortality. The rates of anticoagulant-related bleeding and thromboembolism were increased by mechanical valves, whereas primary tissue failure was the main complication of homografts. CONCLUSIONS: Long-term outcome of homograft aortic valve replacement in patients with congestive heart failure is acceptable, with a reduced rate of serious complications and cardiac death. Further improvements would be expected if the rate of primary tissue failure could be reduced.

Adolescent↗
PubMed2000

The spectrum of hearing loss due to mitochondrial DNA defects.

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of neurological disease. Although hearing impairment is common in patients with mtDNA defects, the spectrum and pathophysiology of the hearing loss is not well characterized. We therefore studied the relationship between cochlear and brainstem auditory function in 23 patients harbouring a range of different mtDNA mutations. Based upon the pure tone audiogram, patients fell into three distinct groups: (i) normal hearing, (ii) mild to moderate predominantly high frequency hearing loss, and (iii) severe or profound hearing loss at all frequencies. Within this study group only certain genetic defects were associated with hearing loss, and for individuals harbouring the A3243G point mutation, the severity of the hearing loss correlated with the percentage level of mutated mtDNA (mutation load) in skeletal muscle. The 10 patients who had a moderate hearing loss or less had normal brainstem auditory evoked responses and MRI, but it was not possible to interpret the brainstem auditory evoked responses in 13 patients with severe hearing loss. Otoacoustic emissions were absent in patients with a moderate or more severe hearing loss. These findings are consistent with a predominantly cochlear origin for the hearing deficit, which is determined by the precise genetic defect and the percentage mutation load.

Adult↗
PubMed2000

Effect of atrial radiofrequency ablation designed to cure atrial fibrillation on atrial mechanical function.

INTRODUCTION: The effects of linear radiofrequency lesions in the atria for cure of atrial fibrillation on atrial contraction have not previously been quantified. METHODS AND RESULTS: Atrial function was measured before and 30 +/- 24 days after a biatrial ablation procedure designed to cure atrial fibrillation in eight dogs and after a sham procedure in three dogs. Atrial mechanical function was assessed using Doppler diastolic blood flow velocities, atrial systolic pressure wave amplitude, and assessment of atrial contribution to cardiac output estimated by comparison of AV sequential pacing to ventricular pacing at the same heart rate. The mitral Doppler A/E velocity ratio was 1.03 +/- 0.45 before and 0.72 +/- 0.43 after ablation (P = 0.048). The tricuspid A/E ratio was 0.88 +/- 0.17 before and 0.71 +/- 0.12 after ablation (P = 0.04). The estimated atrial contribution to cardiac output was 18% +/- 9% before and 5% +/- 4% after ablation (P < 0.01). The left atrial systolic pressure wave amplitude was 2.8 +/- 1.5 mmHg before and 1.7 +/- 1.0 mmHg after ablation (P = 0.1). These changes were not observed in control dogs. Lesions covered 25% +/- 6% of the atrial endocardial surface. CONCLUSION: Multiple linear radiofrequency lesions in the atria designed to cure atrial fibrillation may impair atrial contractility. Reduced atrial function is partly due to loss of atrial myocardial mass, but regional delays in atrial activation and splinting of the atria by scarring also may contribute.

Animals↗
PubMed2000

Monaural and binaural detection of sinusoidal phase modulation of a 500-Hz tone.

The detectability of phase modulation was measured for three subjects in two-alternative temporal forced-choice experiments. In experiment 1, the detectability of sinusoidal phase modulation in a 1500-ms burst of an 80-dB (SPL), 500-Hz sinusoidal carrier presented to the left ear (monaural condition) was measured. The experiment was repeated with an 80-dB, 500-Hz static (unmodulated) tone at the right ear (dichotic condition). At a modulation rate of 1 Hz, subjects were an order of magnitude more sensitive to phase modulation in the dichotic condition than in the monaural condition. The dichotic advantage decreased monotonically with increasing modulation rate. Subjects ceased to detect movement in the dichotic stimulus above 10 Hz, but a dichotic advantage remained up to a modulation rate of 40 Hz. Thus, although sound movement detection is sluggish, detection of internal phase modulation is not. In experiment 2, thresholds for detecting 2-Hz phase modulation were measured in the dichotic condition as a function of the level of the pure tone in the right ear. The dichotic advantage persisted even when the level of the pure tone was reduced by 50 dB or more. The findings demonstrate a large dichotic advantage which persists to high modulation rates and which depends very little on interaural level differences.

Adult↗
PubMed2000

Secondary prevention of hypercholesterolaemia: results of an audit conducted in South Wales.

OBJECTIVE: To audit the standards of secondary prevention of coronary heart disease in postmyocardial infarction patients. DESIGN: Follow up audit, one year after acute admission with myocardial infarction. SETTING: University Hospital. SUBJECTS: For the initial admission, 153 patients were audited, with 84 patients contacted one year later. Demographic data, treatment status, and cholesterol levels were analysed both on admission and at follow up. INTERVENTIONS: Total cholesterol was checked at the audit time either in the hospital or in the doctor's surgery. MAIN OUTCOME MEASURES: Statin doses and cholesterol levels. RESULTS: Ninety six per cent of patients had their lipid profile performed on admission. Eighty three per cent of the patients with total cholesterol >/= 5 mmol/l were discharged from the hospital on lipid lowering medication. Forty five per cent of the subjects who were followed up had cholesterol levels >/= 5 mmol/l at 1 year. There was a disproportionate use of low doses of statins (lower than those shown in effective trials: simvastatin 20 to 40 mg, pravastatin 40 mg) with a third of all patients on medication not achieving the targets at one year. CONCLUSION: There was a major improvement in the proportion of patients started on treatment compared with figures reported by previous studies. However, the titration of the statin doses to achieve the targets is still unsatisfactory.

Aged↗
PubMed2000

The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency.

OBJECTIVES: Controversy persists with regard to the atherogenic risk associated with adult growth hormone deficiency (GHD). Endothelial dysfunction and enhanced oxidative stress are early features of atherogenesis. Therefore, we have studied the effect of three months of low dose GH replacement therapy (0.03IU/kg/day) on these parameters in GHD adults. SUBJECTS AND METHODS: Eight hypopituitary GHD adults (4 male, 4 female), who were receiving conventional hormone replacement therapy, were studied before and after 3 months of GH replacement (0.03IU/kg/day). All observations obtained were compared with similar measurements made in 8 matched control subjects. All study subjects were non-smokers, normotensive and gave no personal or family history of premature vascular disease. Endothelial function was assessed using a specialised vessel wall tracking system to measure endothelium-dependent, flow-mediated, brachial artery dilatation (FMD). Measurements were repeated following glyceryl-trinitrate (GTN) (endothelium-independent dilatation). Oxidative stress was assessed by directly measuring lipid-derived free radicals in venous blood by electron paramagnetic resonance spectroscopy. Fasting lipids, insulin, plasma glucose and IGF-I were also measured at baseline and following GH replacement. RESULTS: FMD, expressed as a percentage change from resting base-line diameter, was significantly impaired in the pre-treatment GHD patients compared with controls (3.1+/-2.1% vs 6.1+/-0.9%, P<0. 001; means+/-s.d.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1+/-2.1% vs 6. 5+/-1.9%, P<0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36+/-0.09 vs 0.11+/-0.12, P<0.05) and fell significantly following GH therapy (0.23+/-0.03 vs 0.36+/-0.09, P<0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9+/-18.8 vs 13.9+/-6.7mu/l, P<0.05) and IGF-I concentrations lower (10.8+/-4.7 vs 20.2+/-6.3nmol/l, P<0.05) in the pre-treatment GHD subjects. After treatment there were no changes in insulin concentration, although IGF-I levels were normalised (10. 8+/-2.3 vs 23.6+/-11.4nmol/l, P<0.05). CONCLUSIONS: Endothelial dysfunction and enhanced oxidative stress are features of adult GHD. This study suggests plausible mechanisms underlying any proatherogenic tendency in adult GHD and demonstrates improvement of these factors following GH replacement.

Adult↗
PubMed1999

Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?

Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.

Acoustic Stimulation↗
PubMed1999

Molecular diversity and its analysis.

We have recently developed a novel strategy for the rational design of compounds. This 'in silico screening' approach is based on the design and screening of virtual combinatorial libraries. Screening is performed using defined rules derived from a comprehensive description of active and inactive molecules in a relevant learning set. This strategy allows the development of potential ligands without the necessity of any knowledge of the 3D-structure of the target receptor. Key to the success of such methods is the quality of the information being processed, in particular, the diversity of the data in the context of the molecular population in the libraries concerned. Here, we review the problem of data diversity, its definition and its analysis using a new software tool, named Diverser.

Journal Article↗
PubMed1999

Psychotherapy in two-plus-one sessions: outcomes of a randomized controlled trial of cognitive-behavioral and psychodynamic-interpersonal therapy for subsyndromal depression.

A total of 116 clients with a range of subsyndromal depression received 3 therapy sessions: 2 sessions 1 week apart followed by a 3rd session 3 months later (the 2 + 1 model). Clients were stratified for severity on the Beck Depression Inventory (BDI) as stressed, subclinical, or low-level clinically depressed. In a 2 x 2 design, they received either cognitive-behavioral (CB) or psychodynamic-interpersonal (PI) therapy, either immediately or after a 4-week delay. An initial advantage for the immediate condition disappeared once the delayed-condition clients received treatment. Improvement rates at the end of treatment were 67% (stressed), 72% (subclinical), and 65% (low-level clinically depressed). There were no significant differences between CB and PI treatment methods, with the exception at 1-year follow-up, when the BDI showed a significant advantage for CB. Implications for designing very brief planned interventions are discussed.

Adult↗
PubMed1999

Anti-inflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion.

1. Small, N- to C-terminal cyclized peptides containing the leucyl-aspartyl-valine (LDV) motif from fibronectin connecting segment-1 (CS-1) have been investigated for their effects on the adhesion of human T-lymphoblastic leukaemia cells (MOLT-4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)-4 (alpha4beta1, CD49d/CD29). 2. Cyclo(-isoleucyl-leucyl-aspartyl-valyl-aminohexanoyl-) (c(ILDV-NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6+/-0.44 microM) than the 25-amino acid linear CS-1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV-NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV-NH(CH2)2CO), was inactive at 100 microM. 3. c(ILDV-NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA-5 (alpha5,beta1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule-1 (LFA-1, alphabeta2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule-1) at concentrations up to 300 microM. 4. c(ILDV-NH(CH2)5CO) inhibited ovalbumin delayed-type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini-pumps (0.1-10 mg kg(-1) day(-1)). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg(-1) i.v.) directed against the alpha4 integrin subunit. 5. c(ILDV-NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1-10 mg kg(-1)). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post-dose (10 mg kg(-1)). 6. Small molecule VLA-4 inhibitors derived from c(ILDV-NH(CH2)5CO) may be useful as anti-inflammatory agents.

Amino Acid Sequence↗