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Biomedical subjects

P Manley

Publications and source records attributed to P Manley.

At least 19 recordsLinked to original sources
PubMed2006

AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL.

Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50< 30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed.

Animals↗
PubMed2005

Unilateral limb enlargement in a dog with a malignant peripheral nerve sheath tumor.

A 3- to 4-month-old female Golden Retriever dog presented with right hind limb enlargement. Physical examination of the limb and radiographic findings initially included soft tissue swelling with elongation, bowing, and cortical irregularity of the femur and tibia. During a period of approximately 7 months, pathology in the limb progressed to include tarsal laxity, muscle atrophy, avulsion of the gastrocnemius muscle, and luxation of the patella. During surgical intervention to shorten the limb and repair the patellar luxation, a large soft tissue cyst was identified along the caudal aspect of the femur and stifle. The limb was later amputated, and a final diagnosis of malignant peripheral nerve sheath (PNS) tumor of the sciatic nerve and surrounding soft tissues was made. The unilateral limb enlargement in this dog appears to have been because of the development and progression of a malignant PNS tumor. The presentation and associated pathologic changes in the limb are unusual for canine PNS tumor but have similarities with neurofibromatosis in the limbs of humans.

Amputation, Surgical↗
PubMed2001

Tyrosine kinase inhibitors: from rational design to clinical trials.

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

Animals↗
PubMed2000

Atypical effect of minoxidil sulphate on guinea pig airways.

The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.

Adenosine Triphosphate↗
PubMed1998

Evidence for an allelic association between bipolar disorder and a Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3).

BACKGROUND: Disturbances in central nervous system Na+, K+ adenosine triphosphatase (ATPase) activity have previously been proposed as being involved in the pathophysiology of bipolar mood disorder. METHODS: We have examined one particular alpha subunit of this enzyme for allelic association in a sample of 85 Irish bipolar patients and 85 matched controls. RESULTS: There was evidence for an overall allelic association between the disease and a dinucleotide polymorphism within the ATP1A3 gene (p = .022). Subjects were then analyzed on the basis of a number of criteria, and the significance of the association increased when cases were divided based on the nature of the first episode. Patients who presented with a depressive episode first showed a significant association (p = .001) with this polymorphism. CONCLUSIONS: The results presented here provide preliminary evidence of an association between bipolar disorder and an alpha subunit of Na+, K+ ATPase, the expression of which predominates in the brain.

Adult↗
PubMed1997

Lack of evidence for a major locus for bipolar disorder in the pericentromeric region of chromosome 18 in Irish pedigrees.

Seven families, multiply affected by bipolar mood disorder, have been collected from the Irish population and have been genotyped with microsatellite markers from the pericentromeric region of chromosome 18, a region that has been implicated as a site for a susceptibility gene for this relative common psychiatric disorder. The families significantly excluded linkage of bipolar disorder to this region under various models. Although the data provided no evidence of linkage heterogeneity among families, the number of families investigated may be too small to exclude completely the possibility of linkage in a small number of families.

Adult↗
PubMed1996

Use of the Wagner apparatus to lengthen the antebrachium of a growing dog.

A six-month-old male golden retriever was presented with a shortened radius and ulna and valgus deformity of the carpus secondary to premature closure of the distal radial and ulnar physes. Osteotomies of the radius and ulna were performed and the antebrachium was lengthened over eight weeks using a Wagner apparatus. This external fixation distractor is used in humans for limb-lengthening procedures. In this case, it was used to correct the angular deformity and to lengthen the limb.

Animals↗
PubMed1996

Helicobacter pylori, gastritis and non-ulcer dyspepsia in Ethiopian patients.

The aim of this study is to find out the prevalence of Helicobacter pylori infection in patients with nonulcer dyspepsia (NUD) and asymptomatic controls and to see if there is an etiological association between gastritis, NUD and Helicobacter pylori. One hundred thirty six patients with NUD and 71 controls had six endoscopic biopsies from different sites of the gastric mucosa for histological diagnosis. Helicobacter pylori was looked for in all biopsy specimens utilizing half Gram, Giemsa and Gimenez staining techniques. Type B chronic gastritis was detected in 96% of the NUD cases and in 100% of the asymptomatic controls (P > 0.05). Helicobacter pylori was found in 82 (65%) patients with NUD and in 38 (56%) asymptomatic controls (P > 0.05). Type B chronic gastritis is almost universal in both NUD cases and asymptomatic controls. There is no difference in the prevalence of Helicobacter pylori infection between the two groups. The absence of Helicobacter pylori in a significant number of patients (36%) and controls (45%) with gastritis contradicts the etiological association between Helicobacter pylori and gastritis reported by others, suggesting that in Ethiopia there may be a chronic environmental gastritis which may not be helicobacter-related. There is no correlation between NUD and Type B gastritis, and between symptoms and Helicobacter pylori infection in this population.

Adolescent↗
PubMed1994

Ingrowth reduces implant-to-bone relative displacements in canine acetabular prostheses.

We examined bone-to-implant relative displacement of acetabular prostheses acutely and after ingrowth in a canine model. Uncemented hemispherical acetabular cups with titanium mesh pads comprising approximately 26% of the surface of the cup were inserted in eight adult canine hemipelves ex vivo. The acetabular prostheses were fixed with 13 mm titanium screws. Zero, one, and two-screw configurations were tested, with the order of testing randomly assigned. A load simulating 1,000 cycles of canine gait as applied to the acetabular component, and relative displacements were measured at three locations between implant and bone to determine acute fixation. A repeated measures analysis of variance showed that two screws produced only 42% of the average relative displacement of one screw and 14% that of zero screws. Eight adult mixed-breed dogs then underwent unilateral total hip arthroplasty. All acetabula were biologically fixed with two cancellous screws. The results at 4 months showed significantly less relative displacement between the implant and bone than was measured in ex vivo implantations (p = 0.014). Bone ingrowth filled 20 +/- 6% (mean +/- SD) of the available space. The relative displacements of these implants were small in all cases (12 +/- 13 microns) and did not correlate with the amount of bone ingrowth. These data suggest that acetabular fixation with two screws can lead to bone ingrowth and reduced relative motion of the prosthesis under functional loading.

Acetabulum↗
PubMed1994

L-tryptophan and the eosinophilia-myalgia syndrome: a clinical and laboratory study.

Case notes of 202 patients who were prescribed a single brand of L-tryptophan (Optimax, manufactured by Merck) between January 1987 and December 1991 were examined. Fourteen patients' notes indicated that they had clinical or laboratory findings suggestive of a diagnosis of eosinophilia-myalgia syndrome (EMS). However, results of clinical examination and measurement of serum aldolase, total eosinophil count and antinuclear antibodies did not support the diagnosis of EMS in any of the 14 patients. Although a further study of 50 consecutive patients on L-tryptophan at the time of the investigation revealed that 5 had mild eosinophilia, none reached the criteria for EMS established by the US Centers for Disease Control and Prevention.

Antibodies, Antinuclear↗
PubMed1992

Principles of fracture fixation in growing animals.

Changes in bone structure and conformation can occur very rapidly in growing animals. Injury to the bones or articular surfaces warrant special consideration because of the potential devastating consequences of secondary growth deformities in the animal. Disturbance of normal growth plate activity, imperfect fixation of an articular fracture, and conformational defects in long bones may create lifelong problems for the animal.

Animals↗
PubMed1989

Acceptable loads and locomotor patterns selected in different carriage methods.

The purpose of this study was twofold: (1) to assess the reliability of both the psychophysical method in determining maximum acceptable loads (MAL) and the use of selected gait parameters in describing locomotor patterns; and (2) to describe and compare the locomotor patterns associated with a number of common load carriage strategies involving the hands and arms. A test-retest experimental design was utilized. Ten males performed five tasks comprising four load carriage conditions and one normal walking condition over a 10m walking distance. The MAL for each carriage task was determined using procedures modified from those described by Snook et al. (1970). Preferred walking speed was calculated from the time taken to cover a standardized portion of the walking distance. The other gait parameters-stride length, cadence and total and double support periods-were obtained using a footswitch technology as described by Wall et al. (1981). The results demonstrated that the procedures used in this study were reliable, in that no significant test-retest differences were found for any of the dependent variables (MAL and gait parameters). No significant differences in MAL were found between the carriage strategies involving two hands, but significantly less mass was chosen in the one-hand carriage condition. Only the two-handed arms-straight carriage condition resulted in significantly different preferred walking speeds. All load carriage conditions except the one-hand carriage condition resulted in significant changes in stride length and/or cadence when compared with normal walking. Only one condition, involving the heaviest MAL, resulting in significantly different total and double support periods when compared with normal walking. There appear to be discrepancies in the literature regarding the effects of load carriage on the various gait parameters. Specific task characteristics, such as the method of carriage, load mass, speed and walking medium, were discussed as potential contributors to the seemingly contradictory results. Subject characteristics, such as gender, age and occupation, may also be confounding factors.

Adult↗
PubMed1982

The dissociation of glucose oxidase by sodium n-dodecyl sulphate.

1. The enzymic activity of glucose oxidase was determined as a function of pH and sodium n-dodecyl sulphate (SDS) concentration. 2. Glucose oxidase is not deactivated by SDS at pH 6 even after prolonged incubation, but is deactivated at pH 4.3 and 3.65. 3. Sedimentation-rate analysis showed that glucose oxidase dissociates into its two subunits at pH 5 and below, and sedimentation-equilibrium experiments in the presence of SDS gave a subunit molecular weight of 73,500. 4. SDS binds to glucose oxidase in acid solutions; specific binding occurs ap pH 3.65, but at pH 6 only co-operative binding was observed. 5. Glucose oxidases in which some of the carboxy groups were blocked with glycine methyl ester were deactivated by SDS at pH 6.0; the rate of deactivation increased with the extent of esterification. 6. Deactivation of esterified glucose oxidases correlated with thermal analysis of the initial SDS interaction, the exothermicity of the interaction increasing with the extent of esterification. 7. The results show that carboxy groups confer resistance to deactivation by SDS on glucose oxidase by screening cationic residues and inhibiting specific interactions that facilitate dissociation into subunits.

Amino Acids↗