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Biomedical subjects

A D Pearson

Publications and source records attributed to A D Pearson.

At least 127 records · Page 7Linked to original sources
PubMed1993

Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children.

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each received a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plasma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performance thin layer chromatography method. During 3 days of continuous infusion, the plasma concentrations of parent drug decreased. This was accompanied by a continuous increase in dechloroethylated products in plasma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relatively minor route of elimination for parent drug and corresponded to < 25% of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. Comparison of metabolite recoveries in urine indicated a positive correlation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxicity was inversely correlated with glomerular filtration rate but not to parameters of ifosfamide metabolism. There was marked variation in levels of the carboxy metabolite, which could not be detected in the plasma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazaphosphorine cyclophosphamide. There appeared to be a higher clearance of ifosfamide in pediatric patients compared to adults. The significance of this, and of the variation in metabolism of ifosfamide, for clinical outcome remains to be established, but the increase in the dechloroethylation route of metabolism may be associated with an increased risk of toxicity.

Adolescent↗
PubMed1993

Analysis of multiple sugar probes in urine and plasma by high-performance anion-exchange chromatography with pulsed electrochemical detection. Application in the assessment of intestinal permeability in human immunodeficiency virus infection.

Mannitol, 3-O-methylglucose and lactulose administered orally are used to investigate small intestinal absorption pathways and mucosal integrity. Current methods of analysis include thin-layer chromatography, gas chromatography (GC) and enzymatic analysis, which require separate estimation of mono- and disaccharides and for GC, prior derivatization. We describe a high-pressure anion-exchange chromatographic method coupled with pulsed electrochemical detection allowing simultaneous measurement of all three sugars and its clinical application in monitoring intestinal damage in human immunodeficiency virus (HIV) infection. Sample preparation is simple and fast. All sugars are resolved within 10 min. Mean recovery is 93.3% for all sugars and the overall relative standard deviation is 4.2%. Intestinal permeability (lactulose/mannitol ratio) rises with disease progression to AIDS, indicating mucosal damage. The greatest increase in permeability is associated with chronic diarrhoea. The method is an ideal non-invasive test to assess gut mucosal damage in HIV infection.

3-O-Methylglucose↗
PubMed1993

Cytogenetic abnormalities in a disseminated medulloblastoma.

A 3-year-old girl developed central nervous system, bone and bone marrow metastases, and hypercalcaemia shortly after presentation with medulloblastoma. Cytogenetic studies of the involved bone marrow showed multiple abnormalities including iso(17q). This chromosome rearrangement has been reported in other cases of recurrent or disseminated medulloblastoma. More studies are required relating the karyotypes of medulloblastomas to long-term outcome to determine if the presence of iso(17q) is a prognostic factor in this malignancy.

Bone Neoplasms↗
PubMed1993

Low dose continuous infusion doxorubicin in children and young adults.

Ten patients (age range 3.2-26.3 yrs) with relapsed or resistant malignancies received a total of 20 courses of low dose continuous infusion doxorubicin (3 mg/m2/day for 28 days) delivered by portable Graseby infusion pumps via central venous catheters. Each patient received a median dose of 144 mg/m2 (range 87-261). Four patients responded to treatment (1 complete response (CR) and 3 partial response (PR)) and performance status improved in seven patients. Overall toxicity was minimal: WHO Grade 4 anaemia in 2/18 courses, Grade 4 neutropenia in 1/18, Grade 3-4 thrombocytopenia in 3/18, nausea and vomiting of Grades 2 and 4 in 4/20 and 1/20 respectively, and mucositis of Grades 2 and 4 in 2/20 courses each. Cardiac toxicity was assessed using echocardiography, and fractional shortening remained within normal limits in all patients. Low dose continuous infusion doxorubicin is a feasible, well tolerated, ambulatory therapy in children and may be an effective way of delivering doxorubicin with less toxicity, thus enabling the development of more dose intensive regimens.

Adolescent↗
PubMed1993

Prohibitive toxicity of a dose-intense regime for metastatic neuroblastoma containing ifosfamide, doxorubicin and cisplatin.

Three patients with stage 4 neuroblastoma were treated with a schedule comprising alternating modules of myelosuppressive (ifosfamide, etoposide, doxorubicin) and less myelosuppressive (vincristine, cisplatin) drugs given every 10 days regardless of the neutrophil count. A partial response was seen in two patients, and a very good partial response, in one patient. Extensive blood-component support was required. Non-haemopoietic toxicity was severe and led to treatment delays in two patients. Ifosfamide-related encephalopathy was seen in one patient and nephrotoxicity, in two patients. Mucositis was severe in two patients, may have contributed to the high rate of sepsis observed, and precluded the use of doxorubicin in one patient. As ifosfamide and doxorubicin were felt to be responsible for much of the toxicity, a subsequent schedule did not include these agents.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

21-day schedule oral etoposide in children--a feasibility study.

To determine the feasibility and toxicity of prolonged oral etoposide in children, 22 patients with relapsed or refractory disease were commenced on etoposide 50-100 mgs/m2 per day for 21 days. A second course was administered after full blood count recovery, followed by disease reassessment. In total, 72 courses were evaluable for toxicity, with 10% of completed courses complicated by febrile neutropenia. 15 patients were evaluable for response, with 1 partial response, 10 stable disease and 4 progressive disease. This schedule was well tolerated with acceptable toxicity when doses of less than 80 mg/m2/day were administered and warrants further evaluation.

Administration, Oral↗
PubMed1993

p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis.

Primitive neuroectodermal tumours (PNET's) or medulloblastomas are common primary brain tumours of childhood. Current treatment protocols achieve 50-60% cures. However, it has proved difficult to develop better treatment for the remaining patients because prognostic factors are not established. We have investigated the prognostic value of p53 protein expression in 87 PNET's using immunohistochemistry with DO-7 and CM-1 antibodies on biopsy paraffin sections. Eight patients (9%) had intensely reactive tumour cell nuclei, and a significantly reduced survival (P = 0.002); only one survives and this with a recurrent tumour 50 months following diagnosis. Sixty eight per cent of patients had faintly reactive tumour cell nuclei, a reduced survival up to 4 years but a long term survival not significantly different (P = 0.41) from 23% of patients with p53 negative PNET's; the 10 year survival rates were 37% and 40%, respectively. Males had a reduced survival (P = 0.04) with a 2-fold relative risk of death compared to females. Multivariate analysis showed that intense overexpression of p53 protein identifies a group of PNET patients with a 7-fold relative risk of death compared to all other cases, irrespective of sex. This marked difference suggests the involvement of p53 in the pathogenesis of PNET's which have a particularly poor response to treatment, and should help to develop new therapies for this group of patients.

Adolescent↗
PubMed1993

Colonization of broiler chickens by waterborne Campylobacter jejuni.

Chickens on a broiler farm in southern England were found to be colonized with Campylobacter jejuni of a single serotype, Lior 1 Penner 4. The farm was the sole supplier of a local slaughterhouse associated with a campylobacter outbreak in 1984 caused by this serotype. The serotype persisted on the farm for at least 18 months after the outbreak; its prevalence in the human population served by the farm remained high until it disappeared from the farm in 1986. The possible sources and routes of transmission of C. jejuni to the broilers on the farm were investigated. The results showed that vertical transmission, feed, litter, small mammals, and environmental or airborne cross-contamination between sheds or successive crops could be excluded as persistent sources of C. jejuni. The predominant source of C. jejuni on the farm was shown to be the water supply. Direct microscopy and fluorescent antibody methods revealed presumptive campylobacters throughout the farm's water system. Campylobacter-free chickens raised in an animal house and given water from the farm supply became colonized with the serotype of C. jejuni endemic on the farm (Lior 1 Penner 4). An intervention program based on water chlorination, shed drinking system cleaning and disinfection, and withdrawal of furazolidone from feed reduced the proportion of birds colonized with campylobacter from 81 to 7% and was associated with a 1,000- to 10,000-fold reduction in campylobacters recoverable from the carcasses. Two months after the end of the intervention program colonization of the birds returned to high levels (84%), indicating that there was a temporal association between intervention and reduced colonization with C. jejuni. Investigations continue to establish the general applicability of these findings.

Animal Feed↗
PubMed1993

Ifosfamide, mesna, and nephrotoxicity in children.

PURPOSE: With the increasing use of ifosfamide in pediatric malignancies, nephrotoxicity has emerged as a potentially serious adverse effect, which may be dose-limiting or may cause severe chronic morbidity, including glomerular impairment and/or Fanconi's syndrome. The purpose of this review was (1) to improve the documentation of ifosfamide nephrotoxicity in children, and (2) to consider the possible causative role of ifosfamide metabolites. DESIGN: (1) A grading system was developed that allowed documentation of the nature and severity of published reports of ifosfamide-induced nephrotoxicity, and evaluation of patient and treatment-related risk factors. (2) The relationship between the pharmacology of ifosfamide/mesna and nephrotoxicity was investigated by examination of published data, especially that concerning the quantitative differences in the metabolism of ifosfamide and its nonnephrotoxic structural isomer, cyclophosphamide. RESULTS: (1) Examination of 16 published reports (with assessable data from 40 children) demonstrated that ifosfamide-induced nephrotoxicity was associated with a wide range of patient ages and ifosfamide cumulative doses given by different administration schedules. (2) Chloroacetaldehyde, a major metabolite of ifosfamide only, may be at least partly responsible for the renal toxicity of this drug. Although mesna may be capable of detoxifying the toxic metabolite(s), delivery to the renal tubule may not be sufficient to provide adequate protection of tubular glutathione from depletion by the metabolite(s), which results in a failure to prevent nephrotoxicity. CONCLUSION: Increased understanding of the interindividual variability in the extent and nature of ifosfamide metabolism, which may be a major determinant of susceptibility to renal damage, may lead to improved use of the drug with less nephrotoxicity.

Child↗
PubMed1993

Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group.

PURPOSE: The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail. PATIENTS AND METHODS: Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil (51Cr-EDTA). RESULTS: Carboplatin pharmacokinetics in children were best described in most patients (16 of 22) by a two-compartment model. The dose-normalized area under the plasma carboplatin concentration versus time curve (AUC) ranged from 3.1 to 9.6 mg/mL.min/400 mg/m2 and there was only a weak linear relationship between carboplatin dose and AUC (R2 = .31). There was a significant relationship between absolute carboplatin and 51Cr-EDTA clearances (R2 = .56), but the relationship was weaker (R2 = .28) when both clearances were normalized for body surface area. Carboplatin plasma clearance was predicted by the equation: clearance = GFR (mL/min) + 0.36 x body weight (BW; kg), and a modified form of the adult carboplatin dose formula is proposed: dose (mg) = target AUC x (GFR [mL/min] + [0.36 x BW(kg)]). Two further equations were developed that use the 51Cr-EDTA half-life (t1/2) to calculate the GFR and these may reduce errors resulting from inaccurate measurement of the volume of distribution for 51Cr-EDTA. In patients treated with single-agent carboplatin or carboplatin plus vincristine, there was a significant sigmoidal relationship between AUC and thrombocytopenia (R2 = .56). CONCLUSION: GFR-based carboplatin dosing in children should be feasible and will be evaluated prospectively.

Adolescent↗
PubMed1993

Simultaneous quantification of mannitol, 3-O-methyl glucose, and lactulose in urine by HPLC with pulsed electrochemical detection, for use in studies of intestinal permeability.

The percentage of an oral dose of mannitol, 3-O-methyl glucose, and lactulose excreted in urine is used in noninvasive investigation of active and passive intestinal mucosal transport. We developed a high-pressure liquid-chromatographic method involving anion exchange and pulsed electrochemical detection that allows the simultaneous determination of all three sugar probes in urine. Sample preparation is simple: diluting, mixing with internal standard (melibiose), and desalting. With use of a Dionex 250 x 40 mm Carbopac PA-1 column and elution with an isocratic mixture of 120 mmol/L NaOH and 0.5 mmol/L zinc acetate, all sugars were resolved within 10 min. The standard curve of the method is linear to the following concentrations: mannitol 125 mg/L, 3-O-methyl glucose 300 mg/L, and lactulose 40 mg/L. The minimal detectable concentration of lactulose is 0.4 mg/L. Analytical recovery of the sugars is between 89.0% and 99.5%. The precision of estimation (CV) ranges from 1.76% to 5.6% overall. Reference intervals were established from results for 28 healthy children. The method is adaptable for the study of carbohydrates at low concentrations in other biological fluids.

3-O-Methylglucose↗
PubMed1993

Prognostic importance of histological and immunopathological assessment of skin and rectal biopsies in patients with GVHD.

Skin and rectal biopsies from patients with GVHD were examined histologically and immunopathologically before and after treatment for the disease. The patients were divided into two groups: those showing a good response to treatment and those showing a poor or no response. The aims of the study were to assess the possibility of predicting the response to treatment and to compare good and poor responders after treatment. The results show that there are no features on either skin or rectal biopsy that could identify those patients with early GVHD who would respond to treatment. Following treatment with steroids there was no change histologically in the grading of the skin biopsy whereas the rectal biopsy showed improvement in six of nine good responders and no improvement in the poor responders. There was an increase in infiltrating lymphocytes in both the skin and rectum of patients showing a poor response and this is most likely due to the ongoing immune reaction. The pre-treatment biopsy did not show any features that would predict this development and was therefore of no prognostic value. However, examination of skin and rectal biopsies may aid in determining whether patients are responding to the treatment given for GVHD.

Adolescent↗
PubMed1992

The surveillance and control of campylobacter infection.

Campylobacter jejuni and C. coli are the most commonly reported bacterial causes of enteritis in man in the United Kingdom. The reported incidence of campylobacter infection varies with place and time. Its epidemiology differs from that of salmonella: campylobacters do not multiply on food, secondary spread is rare, and infections peak at the end of May (salmonellas peak in July). Known sources of infection include poultry, milk, water, pets and other domestic animals. Campylobacters are widespread in the environment, and in domestic and wild birds and mammals. About 10% of infections reported in the UK are acquired abroad. The application of preventive measures can be effective in reducing the incidence of infection and its not inconsiderable financial burden.

Adolescent↗