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Biomedical subjects

P Beale

Publications and source records attributed to P Beale.

15 recordsLinked to original sources
PubMed1998

Metabolism, excretion and pharmacokinetics of a single dose of [14C]-raltitrexed in cancer patients.

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase and has recently been licensed in Europe for use in the treatment of advanced colorectal carcinoma. This study evaluated the metabolism, excretion and pharmacokinetics after a single dose of 3.0 mg/m2 [14C]-raltitrexed in patients with advanced solid malignancies not amenable to curative therapy. From April 1994 to July 1995, nine patients (six men and three women) were recruited into the study. Pharmacokinetics analysis was performed during the first cycle of treatment in all patients and, in two patients, limited sampling was done prior to and during the second cycle of treatment. The mean observed peak plasma concentration (Cmax) was 700.6 ng/ml and the median time (tmax) to reach maximal raltitrexed concentrations was 15 min after the initiation of the infusion. After reaching Cmax the drug declined in a triexponential manner with a terminal half-life of 257 h. The AUC0-infinity as predicted by the pharmacokinetic model was 2341.7 ng h ml(-1). Clearance was 41.3 ml/min, of which renal clearance accounted for 50-60%. Urinary collection for the measurement of radiolabeled drug revealed that renal excretion extrapolated to infinity accounted for 40% of the total radioactive dose. Faecal excretion accounted for only 3% of the dose when samples were collected to day 5 in the first six patients. Collection was extended to 10 days in the last three patients and faecal elimination accounted for 14% in these patients. Raltitrexed measurements prior to subsequent doses suggest that there was no accumulation of the drug with repeated administration. Low levels of radioactivity measured in the red cell pellets on days 15, 22 and 29 are likely to represent drug retained by newly forming red cells at the time of dosing. Examination of the urine revealed that the drug was excreted unchanged. The toxicities seen were in line with those encountered in previous studies. Grade 3 and 4 thrombocytopenia occurred in three patients and grade 3 neutropenia occurred in two patients.

Adult↗
PubMed1998

Phase I study of oral JM216 given twice daily.

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV)] is an oral platinum complex that is currently in phase II trials in ovarian cancer and lung cancer on a daily-times-5 schedule. This trial examined an alternative schedule of two doses given 12 h apart, which may be better tolerated by patients. A total of 19 patients were given 50 cycles of treatment at doses ranging from 150 to 350 mg/m2 b.i.d. The study was stopped before the MTD was reached due to non-linear pharmacokinetics. Toxicity was similar to that encountered in previous phase I studies, with nausea, vomiting and diarrhoea being seen at all dose levels, although this was generally mild and short-lived, and grade 3 and 4 myelosuppression being seen at dose levels ranging from 250 to 350 mg/m2. There was no nephro-, oto-, or neurotoxicity, but one patient had an allergic reaction at 300 mg/m2 on the fifth and sixth cycles. No response was seen, but two patients with mesothelioma had stable disease and received six cycles. There was considerable interpatient variability in plasma pharmacokinetics at all dose levels. There was no relationship between dose and AUC (dose 1 and dose 2) or Cmax after dose 1. In a limited number of patients the first dose was given in the morning rather than in the evening, apparently resulting in lower AUC, Cmax and Tmax values at the 250-mg/m2 dose level, but this was not seen in one patient at 300 mg/m2. This study confirms that the pharmacokinetics of JM216 is non-linear and highly variable due to saturable absorption and that the daily times 5 schedule is the optimal schedule for further phase II trials.

Adult↗
PubMed1998

Mediastinal lipoma in children.

Mediastinal masses are uncommonly encountered in childhood. These tumours are often interesting because of the varied mediastinal tissues from which they arise. Despite extensive investigations, a large percentage of these lesions remain undiagnosed prior to operation. We describe two rare cases of mediastinal lipoma. The first was incidentally diagnosed whereas the second patient presented with respiratory symptoms. The definitive diagnosis was established at surgery, which was curative.

Child↗
PubMed1998

Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694).

This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) after a single intravenous dose of 3.0 mg m(-2), comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.

Adult↗
PubMed1997

Applications of S-layers.

The wealth of information existing on the general principle of S-layers has revealed a broad application potential. The most relevant features exploited in applied S-layer research are: (i) pores passing through S-layers show identical size and morphology and are in the range of ultrafiltration membranes; (ii) functional groups on the surface and in the pores are aligned in well-defined positions and orientations and accessible for binding functional molecules in very precise fashion; (iii) isolated S-layer subunits from many organisms are capable of recrystallizing as closed monolayers onto solid supports at the air-water interface, on lipid monolayers or onto the surface of liposomes. Particularly their repetitive physicochemical properties down to the subnanometer scale make S-layers unique structures for functionalization of surfaces and interfaces down to the ultimate resolution limit. The following review focuses on selected applications in biotechnology, diagnostics, vaccine development, biomimetic membranes, supramolecular engineering and nanotechnology. Despite progress in the characterization of S-layers and the exploitation of S-layers for the applications described in this chapter, it is clear that the field lags behind others (e.g. enzyme engineering) in applying recent advances in protein engineering. Genetic modification and targeted chemical modification would allow several possibilities including the manipulation of pore permeation properties, the introduction of switches to open and close the pores, and the covalent attachment to surfaces or other macromolecules through defined sites on the S-layer protein. The application of protein engineering to S-layers will require the development of straightforward expression systems, the development of simple assays for assembly and function that are suitable for the rapid screening of numerous mutants and the acquisition of structural information at atomic resolution. Attention should be given to these areas in the coming years.

Bacteria↗
PubMed1994

Gulf illness.

Explore the source record for details and available documents.

Humans↗
PubMed1991

Making the IT (information technology) jigsaw fit.

Providers will need good information systems to survive in the internal market. In the first of the Journal's regular special features on computing (to appear in the last week of every month) we examine the strategic issues facing hospital managers investing in information technology, and look at two very different approaches to harnessing IT--one of which is a sophisticated hospital management package, the other a rough and ready early warning system.

Computer Communication Networks↗
PubMed1991

Management of severe hypertension in childhood Takayasu's arteritis.

Six children presented with severe hypertension caused by Takayasu's arteritis (TA), of whom four had bilateral renal artery narrowing and two coarctation syndrome. Two presented with hypertensive encephalopathy and four with congestive cardiac failure. All had a strongly positive skin reactions to purified protein derivative of mycobacterium tuberculosis. Bilateral renal arterial bypass grafts performed in two children resulted in prolonged normalization of their blood pressures, but the grafts clotted 12-18 months later. Primary renal autotransplantation was unsuccessful in two children, one with bilateral renal arterial narrowing and iliac vessel involvement and one with a long coarctation. Secondary renal autotransplantation was successful in a third child with localized aortitis. A successful aortic patch graft was performed in one child with coarctation of the aorta. Angiotensin-converting-enzyme inhibitors should be used with caution in treating the hypertension caused by TA, since bilateral renal arterial narrowing is common and their administration may result in renal insufficiency. The long-term prognosis is guarded in severely hypertensive children with extensive vascular disease due to TA.

Adolescent↗
PubMed1986

Small and asymptomatic hepatocellular carcinoma detected by alpha-fetoprotein screening in black hepatitis B carriers. A report of 2 cases.

Two patients in whom asymptomatic and small hepatocellular carcinomas (HCC) were detected by alpha-fetoprotein (AFP) screening are reported. Both patients were hepatitis B surface antigen-positive. In the first patient, the tumour grew slowly and was resected more than 2 years after a significant elevation in serum AFP levels had been first detected and 13 months after hepatic angiography confirmed the presence of a vascular tumour. In the second patient, a small encapsulated HCC was diagnosed by AFP screening and hepatic imaging. The clinical course in these 2 patients illustrates that small, asymptomatic and encapsulated HCCs do occur in southern African black hepatitis B carriers. Regular screening of patients at risk may be justified.

Adult↗
PubMed1984

Hypertension as the major problem of idiopathic arterial calcification of infancy.

We describe two infants with severe hypertension associated with idiopathic arterial calcification of infancy. In both children, blood pressure control was refractory to aggressive antihypertensive therapy. There was radiologic and laboratory evidence of renovascular disease requiring the use of specific renin antagonists and later nephrectomy, resulting in moderate improvement of hypertension. Although on occasion there is a familial incidence, in the vast majority of cases the diagnosis hinges on a high index of suspicion.

Arteries↗
PubMed1983

The treatment of end-stage renal disease at the Johannesburg Hospital: a 17-year experience. Part II. The role of transplantation.

Experience with 525 kidney transplants performed at the Johannesburg Hospital from 1966 to 1982 is reviewed. The 1-year graft survival rates for HLA-identical related living donor (RLD) transplants, haplo-identical RLD transplants, and first and subsequent transplants from cadaver donors (CDs) are 95%, 72%, 59% and 52% respectively. One-year patient survival figures for all RLD and all CD transplants are 93% and 78% respectively. There is a slower but steady attrition in both graft and patient survival over the next 10-15 years which is the same for all patients irrespective of donor source. Infection and myocardial infarction remain the major causes of mortality and morbidity. Mortality in the 1st year after transplantation has been reduced dramatically in the last 5 years of the programme. This has coincided with the introduction of a policy of routine pretransplant blood transfusion and a less aggressive approach to the treatment of severe and recurrent rejection episodes. However, the incidence of irreversible graft rejection in the 1st year has remained the same. These results, although gratifying in a broad context, leave no room for complacency. The induction of a state of specific tolerance towards the grafted organ remains the ultimate goal in clinical transplantation.

Actuarial Analysis↗