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Biomedical subjects

Andrew Hughes

Publications and source records attributed to Andrew Hughes.

15 recordsLinked to original sources
PubMed2006

A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers.

PURPOSE: AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t1/2 to be 1-3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (tmax), +/-6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity. RESULTS: Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807-S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807-S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK-PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249-T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose-response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively). CONCLUSIONS: The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.

Biomarkers↗
PubMed2006

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers.

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. Tmax occurred between 0.5-3.0 hours with a relatively short plasma half-life of 1-3 h. The coefficient of variation of exposures within a dose level ranged from 22-71% (AUC) to 16-63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438's action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.

Adult↗
PubMed2006

Absolute quantification of farnesylated Ras levels in complex samples using liquid chromatography fractionation combined with tryptic digestion and electrospray tandem mass spectrometry.

Farnesylation is the first posttranslational modification of H-Ras proteins, which can be blocked by farnesyl transferase inhibitors. We developed a sensitive and quantitative bioanalytical assay to determine the absolute amounts of farnesylated H-Ras in tumor cell lysates before and after administration of these compounds. Farnesylated H-Ras was isolated with reversed-phase liquid chromatography. Subsequently, the isolated fraction was digested with trypsin and analyzed with electrospray-tandem mass spectrometry. The farnesylated peptide consisting of cysteine-valine-leucine-serine (f-CVLS) proved to be a suitable signature peptide. Its deuterated analogue was used as internal standard for absolute quantification. With this method, we obtained a lower limit of quantification of 8pmol farnesylated H-Ras in cell lysates. We demonstrate that this method can be used to determine IC(50) values of farnesyl transferase inhibitors through absolute quantification of the amount of f-CVLS present after incubation with different concentrations of a farnesyl transferase inhibitor. The signature peptide approach combined with prefractionation may be used as a pharmacodynamic assay to determine dose-effect relationships of farnesyl transferase inhibitors in (pre)clinical studies.

Chromatography, Liquid↗
PubMed2005

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.

Aged↗
PubMed2005

Dopaminergic innervation of the human striatum in Parkinson's disease.

In Parkinson's disease (PD), dopaminergic input to the caudate nucleus and a band of putaminal tissue abutting the external globus pallidus seems well preserved on immunohistochemical staining for the dopamine transporter. Counting of dopaminergic terminals showed that terminal density in these regions in PD was the same as that in controls, which indicates that input is truly preserved and not a consequence of a compensatory upregulation of metabolism in a reduced pool of surviving terminals. When the branching pattern of dopaminergic axons coursing through the globus pallidus was examined, we found no evidence for increased axonal sprouting in PD that might have contributed to preservation of dopaminergic input to the putamen or caudate nucleus. Although terminal counting indicated that anatomic input was preserved to parts of the striatum, dopamine uptake site density in these regions was reduced significantly. This suggests that the impact of disease in these areas is more profound than was thought previously.

Aged↗
PubMed2004

Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS).

We assessed the inter-rater reliability of the 100-point International Cooperative Ataxia Rating Scale (ICARS). Three neurologists independently rated videotaped ICARS examinations of 22 subjects with genetically determined ataxias (spinocerebellar ataxia [SCA] Type 1 in 11; SCA Type 2 in 1; Friedreich's ataxia in 10) and 4 controls. Scores on live ICARS assessment had ranged from 0 to 7 for controls and 11 to 74 for ataxic subjects (clinically very mildly affected to wheelchair-bound). Inter-rater correlation was very high for the total score (Kendall's omega 0.994, 95% confidence interval, 0.988-0.997), and high to very high for each component subscore (0.791 for speech to 0.994 for posture/gait). All correlations were significant at P < 0.00001. The ICARS exhibits very high inter-rater reliability even without prior observer standardisation and is sensitive to a range of ataxia severities from very mild to severe.

Activities of Daily Living↗
PubMed2003

The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans.

BACKGROUND & AIMS: Central sensitization, an activity-dependent increase in spinal cord neuronal excitability, has been shown to contribute to esophageal pain hypersensitivity. Prostaglandin E2 (PGE(2)) is a mediator in both peripheral and central sensitization, in part via the prostaglandin E2 receptor-1 (EP-1), and may be a potential target for treating visceral pain. The purpose of this study was to determine whether acid-induced pain hypersensitivity within the non-acid-exposed esophagus (secondary hyperalgesia) is mediated by PGE(2) activation of the EP-1 receptor. METHODS: Twelve healthy male subjects participated in a randomized, placebo-controlled crossover study. Upper esophageal pain thresholds (PTs) to electrical stimulation were determined, and either the EP-1 antagonist ZD6416 or a placebo was orally administered. One-hour after dosing, acid or saline (0.15 mol/L) was infused into the lower esophagus for 30 minutes. Upper esophageal PT was monitored for 120 minutes after infusion. RESULTS: Except in 1 subject (who was excluded), the pH in the upper esophagus remained above 5 throughout all studies. In 8 subjects, ZD6416 attenuated the reduction in PT in the upper esophagus normally induced by acid infusion into the lower esophagus (area under curve [AUC]: -11.9 +/- 2.5 and 6.4 +/- 6.7 for placebo and ZD6416, respectively; P < 0.01). After saline infusion, the effects of ZD6416 and placebo were similar (AUC: 9.9 +/- 6 and 4.1 +/- 2, respectively; P = 0.8). Three subjects had no reduction in PT to acid infusion with placebo and were excluded at post hoc analysis. CONCLUSIONS: The attenuation of secondary esophageal hyperalgesia by ZD6416 suggests that PGE(2), via the EP-1 receptor, contributes to human visceral pain hypersensitivity.

Acids↗
PubMed2003

A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.

PURPOSE: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. EXPERIMENTAL DESIGN: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day. RESULTS: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels. CONCLUSIONS: The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.

Adult↗
PubMed2002

Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain.

The reproducibility and tolerability of intradermal (i.d.) administration of capsaicin as a method for eliciting human pain was assessed in healthy male volunteers (n = 12). The primary endpoints for assessing pain were spontaneous pain response and areas of allodynia, pinprick hyperalgesia and neurogenic inflammation. These were recorded before, immediately after, and at regular intervals following each of four doses (250 microg) of capsaicin (two per trial day). Within- and between-subject variability to the technique was assessed by measuring the maximum recorded values (max), time to maximum value (t(max)) and area under the curve (AUC(0-1 h)) of each of the endpoints. Tolerability to the technique was addressed by recording adverse events. Reproducibility of the i.d. capsaicin model was demonstrated for each type of capsaicin-induced pain. Following each dose, the magnitude and profile of response and overall AUC values were similar for each parameter although some decrease in pinprick hyperalgesia was observed over time. For spontaneous pain, evidence of a period effect was observed in mean AUC data, with values increasing following the second dose of each trial day. This effect was confounded by the possibility of an arm effect, with the non-dominant arm appearing to be more sensitive to pain than the dominant arm. The data were not sufficient to confirm the existence of these effects. Between-subject variability and within-day, within-subject variability accounted for most of the variability observed in the trial. By optimising study design to eliminate these sources of variability, it was estimated that spontaneous pain and the area of allodynia would be the least variable endpoints. A positive correlation was found between the area of allodynia and area of pinprick hyperalgesia (r(2) = 0.835). Overall, the model was well tolerated with no reports of adverse events. We conclude that the tolerability profile, and variability of i.d. capsaicin-induced pain is acceptable for pharmacological profiling of novel anti-nociceptive agents, with limited number of subjects.

Analysis of Variance↗
PubMed2002

Descriptors of breathlessness in patients with cancer and other cardiorespiratory diseases.

The objective of this study was to examine the relationship between descriptors of breathlessness and its underlying cause in patients with lung cancer and cardiopulmonary diseases to see whether descriptors might be used to help determine the cause of breathlessness, particularly in patients with lung cancer. We studied 131 patients with primary or secondary lung cancer, whose breathlessness was attributed to tumor mass, pleural effusion, lung collapse, metastases, pleural thickening or lymphangitis carcinomatosis, and 130 patients with breathlessness attributed to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease or cardiac failure. Patients selected statements (descriptors) that described the quality of their breathlessness from a 15-item questionnaire and the relationship between the descriptors and the attributed cause of breathlessness was evaluated by cluster analysis. All patient groups were characterized by more than one cluster and several clusters were shared between groups. Specific sets of clusters were associated with breathlessness due to asthma, COPD and cardiac failure, and to cancer causing collapse, metastases or pleural thickening. The association of different sets of clusters with the different diagnostic groups suggests that patients are describing qualitatively different experiences of breathlessness, but the relationship does not appear to be sufficiently robust for the questionnaire to aid differential diagnosis.

Aged↗
PubMed2002

Using anti-muscarinic drugs in the management of death rattle: evidence-based guidelines for palliative care.

The management of 'death rattle' was reviewed by a task group on behalf of the Association for Palliative Medicine's Science Committee. Evidence was searched for the effectiveness of various anti-muscarinic drugs in drying oropharyngeal and bronchial secretions in dying patients. Clinical guidelines were constructed based on evidence from volunteer and clinical studies. Death rattle occurs in half of all dying patients and some response occurs in around 80% of treated patients. Clinical studies demonstrate that subcutaneous hyoscine hydrobromide 400 microg is more effective at improving symptoms at 30 min than glycopyrronium 200 microg by the same route. Volunteer studies demonstrate that intramuscular glycopyrronium 400 microg is as effective in drying secretions at 30 min as a dose of 200 microg given intravenously. Duration of response is shortest for hyoscine butylbromide (1 h) and longest for glycopyrronium (more than 6 h). There is insufficient evidence to support the use of one drug over another in a continuous infusion and prescribers should base decisions on different characteristics of each anti-muscarinic drug.

Bronchi↗
PubMedDate not supplied

Observation of snakebite victims: is twelve hours still necessary?

OBJECTIVE: To determine the period of observation required to exclude elapid envenoming following presentation with suspected or definite snakebite in South-east Queensland. METHODS: Two part case series of patients presenting with a snakebite to a regional hospital in South-east Queensland. A snakebite assessment protocol was established for a prospective phase with the same data collection tool used for retrospective cases. The time of onset of clinical features, and abnormal investigations consistent with envenoming were recorded for each feature. 'Time zero' was set at the time of removal of effective first aid or, time of presentation in the absence of effective first aid. RESULTS: A total of 360 presentations of snakebite were identified with envenoming diagnosed in 34 cases (9%). Seventy-three percent of clinical features and investigation abnormalities were present at, or before, time zero with 95% present within 6 h. All abnormalities, which commenced beyond 6 h, occurred in patients where the diagnosis of envenoming had already been established. CONCLUSIONS: Six hours of assessment appears adequate to exclude elapid envenoming in asymptomatic patients in South-east Queensland. Evidence in the literature of delayed onset of envenoming in completely asymptomatic patients is difficult to find.

Animals↗
PubMedDate not supplied

Evidence-based assessment: evaluation of the formocresol versus ferric sulfate primary molar pulpotomy.

PURPOSE: Formocresol and ferric sulfate were evaluated as pulpotomy medicaments using evidence-based dentistry principles. Formocresol has been challenged as a potential carcinogen and mutagen, leading to consideration of ferric sulfate. METHODS: The PICOT statement was: (P) In human carious primary molars with reversible coronal pulpitis, (I) does a pulpotomy performed with ferric sulfate, (C) compared with formocresol, (O) result in dinical/radiographic success, (T) in time periods up to exfoliation? Relevant papers (N=894) were identified from databases and inclusion criteria were applied; 94 papers remained (randomized clinical trials [RCTs]=7; clinical trials [CTs]=28; case-control studies=14; opinions, cohort, and cross-sectional studies=4; reviews=22; irretrievable papers=19). Three RCTs and 10 CTs (total teeth: formocresol=753; ferric sulfate=90) were meta-analyzed; 1 RCT and 1 CT were tested for homogeneity (odds ratios; 95% confidence intervals); 3 RCTs and 10 CTs were examined by student's t test. RESULTS: Clinical data indicated ferric sulfate was significantly more successful than formocresol (OR=1.95; CI=1.01-3.80). Radiographic data indicated no difference between medicaments (OR=0.90; CI=0.58-1.39). Medicaments did not differ with t-tests of clinical (P>.10) and radiographic (P>.50) data. CONCLUSIONS: This evidence-based assessment concluded that, in human carious primary molars with reversible coronal pulpitis, pulpotomies performed with either formocresol or ferric sulfate are likely to have similar clinical/radiographic success.

Child, Preschool↗