PubMed Health⌕ Search

Biomedical subjects

A H Thomson

Publications and source records attributed to A H Thomson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Population pharmacokinetics of aminoglycoside antibiotics in patients with cystic fibrosis.

The population pharmacokinetics of gentamicin and tobramycin were investigated in a group of 51 young adults with cystic fibrosis. Their ages ranged from 14-35 years, weights from 38-82 kg, and 27 of the patients were female. None of the patients had renal impairment, but 3 patients were treated in the intensive therapy unit (ITU) during one of their courses of therapy. Data comprised 219 courses of therapy and 544 concentrations (mean: 11 per patient). Concentration-time data were analyzed using a nonlinear mixed-effects model package (NONMEM) and were best described by a one-compartment model. Factors identified as potentially influencing aminoglycoside pharmacokinetics were added in a stepwise fashion and the best model found that drug clearance and volume of distribution were related to body surface area and admission to ITU. The mean population estimates were a clearance of 2.89 L/hr/m2 and a volume of distribution of 9.21 L/m2 with a 60% increase in patients who were admitted to ITU. Interpatient variability in clearance and volume were 14% and 8%, respectively. The results suggested that a dose of 120 mg/m2 should achieve an average 1 hour postdose peak of 10 mg/L and trough of <1 mg/L and that higher doses might be required in ITU patients.

Adolescent↗
PubMed1999

Pharmacokinetics and dose requirements of vancomycin in neonates.

AIMS: To design and evaluate dosing guidelines for vancomycin based on data collected during routine use of the drug. METHODS: Following the observation that 66% of neonatal vancomycin trough concentrations were outside the target range, new dose guidelines were developed using a population pharmacokinetic approach. NONMEM (non-linear mixed effects model) was used to analyse dose histories and 347 concentration measurements collected during routine therapeutic drug monitoring in 59 neonates. RESULTS: Postconceptual ages in the patient group ranged from 26-45 weeks, weights from 0. 57-4.23 kg, and creatinine concentrations from 18-172 micromol/l. The population estimate of vancomycin clearance (l/h/kg) was 3. 56/creatinine concentration (micromol/l) with an interpatient coefficient of variation (CV) of 22% and volume of distribution 0.67 l/kg with a CV of 18%. Residual error was 4.5 mg/l. When the new recommendations on dosing were used prospectively in a separate group of neonates the proportion of acceptable troughs increased from 33% to 72%. CONCLUSIONS: The pharmacokinetics of vancomycin in neonates and young infants depend on weight and serum creatinine. Preliminary results from the new guidelines indicate an improvement on previous practice, but also an ongoing need to monitor concentrations.

Anti-Bacterial Agents↗
PubMed1999

Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee.

PK1 comprises doxorubicin covalently bound to N-(2-hydroxypropyl)methacrylamide copolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release. Radically altered plasma and tumor pharmacokinetics, compared to free doxorubicin, and significant activity in animal tumors have been demonstrated preclinically. We aimed to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers. Altogether, 100 cycles were administered (range, 20-320 mg/m2 doxorubicin-equivalent) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34-72 years). The maximum tolerated dose was 320 mg/m2, and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m2. Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t(1/2) of 1.8 h and an elimination t(1/2) averaging 93 h. 131I-labeled PK1 imaging suggests PK1 is taken up by some tumors. Responses (two partial and two minor responses) were seen in four patients with NSCLC, colorectal cancer, and anthracycline-resistant breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-related toxicity, and proof of principle that polymer-drug conjugation decreases doxorubicin dose-limiting toxicities. The recommended Phase II dose is 280 mg/m2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.

Adult↗
PubMed1998

Population pharmacokinetics of gentamicin in patients with cancer.

AIMS: The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients. METHODS: Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 micromol l(-1), 70 micromol l(-1) or 88.4 micromol l(-1) RESULTS: A two compartment model was fitted to the concentration-time curve. Two best models were obtained, one that related clearance to estimated creatinine clearance (minimum creatinine value 60 micromol l(-1)) and the other that related clearance to age, creatinine concentration and body surface area. Volume of the central compartment was influenced by body surface area and albumin concentration. For both models 90% of measured concentrations lay within the 95% confidence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL (1 h(-1))=0.88 x (1 + 0.043 x creatinine clearance) and central volume of distribution V1 (1)=8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.301 h(-1) and peripheral volume of distribution (V2) was 9.801. Coefficient of variation was 18.5% on clearance and 28.2% on Q. Residual error expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of clearance was 4.21 h(-1) and volume of distribution (Vss) was 24.61 (0.381 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h. CONCLUSIONS: In the context of published nomograms this analysis indicated that both the traditional approach and the new, 'once daily' approach should achieve satisfactory concentrations in cancer patients although serum concentration monitoring is required to confirm optimal dosing in individual patients.

Adolescent↗
PubMed1998

An audit of therapeutic drug monitoring service provision by laboratories participating in an external quality assessment scheme.

Therapeutic drug monitoring services were investigated in a questionnaire sent to all subscribers to the United Kingdom National External Quality Assessment Scheme for Therapeutic Drug Assays. Questions were posed on assay availability and use, target ranges, and reporting procedures for digoxin, lithium, phenytoin, phenobarbitone, carbamazepine, theophylline, and valproic acid. One hundred fifty-seven laboratories replied and, except for lithium, 45% reported in mass units, 34% in molar units, and 22% a mixture of mass and molar units. Target ranges for lithium, digoxin, carbamazepine, and phenobarbitone were highly variable but ranges for phenytoin, theophylline, and valproic acid were more consistent. Immunoassay was the most popular methodology although high-performance liquid chromatography was commonly used for anticonvulsants. Paper copies of results were provided by 93% of laboratories, 40% reported by telephone, 12% by fax, and 28% by computer. Additional data, mainly dose, time of last dose, and duration of therapy were requested by 55% to 67% of laboratories. Grades of staff authorizing results ranged from nurses to senior consultants, and collaboration with pharmacists occurred in 26% of laboratories. Most laboratories provided a daily analytical service and 73% offered a 24-hour emergency service. This audit unexpectedly identified use of a wide range of target concentrations, particularly for digoxin and lithium.

Drug Monitoring↗
PubMed1998

Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis.

BACKGROUND: Disease severity in patients with cystic fibrosis shows marked variability. Attempts to explain this phenotypic heterogeneity on the basis of CFTR genotype have had limited success. A study was undertaken to test the hypothesis that naturally occurring variants of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the detoxifying enzyme glutathione S-transferase M1 (GSTM1) could influence disease severity in cystic fibrosis. METHODS: Fifty-three children with cystic fibrosis were studied. To allow for the effect of age, all clinical details were collected during the eighth year of age. The subjects were divided into groups, both according to the presence or absence of the TNF2 TNF-alpha -308 promoter polymorphism (n = 20), and by homozygosity for the null allele of GSTM1 (n = 26). RESULTS: Percentage predicted forced expiratory volume in one second (FEV1) and weight z scores were significantly lower in the TNF2 group (mean difference (95% confidence intervals) for FEV1 11.6% (1.7 to 21.5) and 0.59 (0.06 to 1.12) for weight z score). The Chrispin-Norman chest radiographic score was significantly higher and the Shwachman score was significantly lower in patients homozygous for the GSTM1 null allele. CONCLUSIONS: Two independent genetic factors have been identified which appear to influence disease severity in cystic fibrosis. These results support the contention that inflammation in cystic fibrosis contributes to tissue damage. Isolation of further such factors may lead to identification of patients at risk of more severe disease and allow targeted aggressive therapy in this group.

Alleles↗
PubMed1996

Methotrexate removal during haemodialysis in a patient with advanced laryngeal carcinoma.

A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.

Antimetabolites, Antineoplastic↗
PubMed1996

Antimicrobial practice. Development of guidelines for gentamicin dosing.

The performance of dosage guidelines for starting gentamicin therapy was evaluated prospectively in 50 patients with suspected or proven Gram-negative septicaemia and the results were compared with results from similar group of 50 patients for whom the guidelines were not followed. Peak concentrations were significantly higher when the guidelines were followed (7.2 (+/- 1.9) mg/L vs 5.7 (+/- 1.8) mg/L) but there was no difference in trough concentrations. Fifty-eight per cent of patients had both peak and trough concentrations within the target range (peak > 5 mg/L, trough < 2 mg/L) when doses were decided empirically; this increased to 96% when the guidelines were followed. However, use of the guidelines achieved peaks of > 7 mg/L in only 56% of patients. A revised protocol with higher doses given less frequently was therefore developed and a prospective assessment of its performance indicated that satisfactory concentrations were obtained in 96% of patients.

Anti-Bacterial Agents↗
PubMed1996

Population pharmacokinetics of caffeine in neonates and young infants.

The population pharmacokinetics of caffeine were investigated in 60 neonates and young infants using data collected during routine therapeutic drug monitoring. Clearance was influenced by body weight and postnatal age, and increased in the presence of dexamethasone. No clinical factors were identified that influenced volume of distribution. The population pharmacokinetic parameter estimates were then tested prospectively in a further 20 neonates. Although they produced unbiased results, the dexamethasone effect could not be identified. A final analysis using all 80 patients found clearance (L/day) = 0.14 x weight (kg) + 0.0024 x postnatal age (days) (+/- 20%) and volume of distribution = 0.82 L (+/- 24%). Simulations based on these results indicated that the current dosage guidelines of 20 mg/kg loading dose of caffeine citrate followed by a 5 mg/kg/day maintenance dose should achieve concentrations within the traditional target range in > 70% of neonates.

Administration, Oral↗
PubMed1994

Evaluation of a Bayesian approach to the pharmacokinetic interpretation of cyclosporin concentrations in renal allograft recipients.

The utility of a Bayesian parameter estimation program in the interpretation of cyclosporin concentrations was investigated in a group of 32 patients following renal transplantation. The program was evaluated by comparing concentrations predicted from individual estimates of pharmacokinetic parameters with measured concentrations. A one-compartment model incorporating an exponential, time-related change in clearance was used for data collected in the first 4 weeks after transplantation, and predictions of concentrations measured during weeks 5-14 were made using three schemes: a changing clearance model using all data from week 1 onward; a changing clearance model using data from week 4 onward; and a nonchanging clearance model using data from week 4 onward. Results demonstrated that predictions made by the Bayesian program were unreliable during the first 4 weeks of therapy, but that there was a progressive improvement as time after transplantation increased. The changing clearance model was superior to the constant clearance model and its performance was not compromised by including data from the first 4 weeks of therapy. Although the Bayesian approach may help with the interpretation of blood cyclosporin concentrations during maintenance therapy, the large variability in the pharmacokinetics of orally administered cyclosporin limits the usefulness of the approach in the early weeks following transplantation.

Adult↗
PubMed1994

Hirschsprung's disease associated with a deletion of chromosome 10 (q11.2q21.2): a further link with the neurocristopathies?

We report a patient with total colonic aganglionosis in association with a deletion of part of the long arm of chromosome 10: (del(10)(q11.2q21.2)). This deletion includes the ret proto-oncogene, which has recently been implicated in multiple endocrine neoplasia type 2A (MEN 2A). The possible links between Hirschsprung's disease and the neurocristopathies and the aetiological role of abnormalities of neural crest development in these conditions are discussed.

Cephalometry↗
PubMed1993

Value of theophylline treatment in patients handicapped by chronic obstructive lung disease.

BACKGROUND: It is still not certain whether it is worth using theophylline in addition to inhaled bronchodilators and corticosteroids to treat obstructive airways disease. This trial was designed to test whether the addition of prescribed theophylline in doses sufficient for sustained optimal steady state plasma concentrations would produce any detectable additional advantage in spirometric or functional variables in these handicapped patients. METHODS: A randomised, double blind, placebo controlled, crossover study of added theophylline treatment was aimed at steady state plasma concentrations of 10 and 17 mg/l, the dose being calculated individually by Bayesian parameter estimation and maintained for six weeks along with the patient's previously prescribed bronchodilators and steroids. Of 20 patients sequentially recruited, 15 provided data that could be analysed. All had chronic obstructive lung disease with a mean forced expiratory volume in the first second (FEV1) up to about 30% of the predicted value and gave no history of being treated with theophylline. The protocol included spirometry, whole body plethysmography, and treadmill exercise. Measurements also included steady state plasma theophylline concentrations and trapped gas volume. Quality of life was assessed by an established questionnaire method covering breathlessness in everyday activities, fatigue, emotional function, and control over the disease. RESULTS: Both target plasma concentrations were achieved. Improvements in peak flow (PEF; mean 20%), trapped gas volumes (38%), two stage vital capacity (15%), distances walked (48%), breathlessness in everyday activities (32%), and fatigue (18%) were found at the higher plasma concentration only. FEV1, forced vital capacity (FVC), emotional function, and control did not change. CONCLUSION: Theophylline treatment with sustained steady state concentrations about 17 mg/l provides worthwhile objective and subjective further benefits for patients handicapped by chronic obstructive lung disease when it is added to bronchodilators and corticosteroids.

Adrenal Cortex Hormones↗
PubMed1992

Bayesian estimation of streptomycin pharmacokinetics.

Streptomycin dose requirements were determined in an 83-year-old man with renal impairment who was being treated for miliary tuberculosis. Concentration measurements were interpreted using a Bayesian parameter estimation program. Estimated creatinine clearance (1.1 L/h) was used as a starting value for streptomycin clearance, and volume was initially assumed to be 0.3 L/kg. Bayesian estimates of clearance were close to the starting value and declined from 1.4 L/h to 0.9 L/h during the course of therapy. Volume was higher than the initial estimate (0.4-0.5 L/kg), possibly due to the patient having a low albumin and being underweight. Satisfactory concentrations were maintained for several weeks with doses of 500 mg every 36-48 h.

Aged↗