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Biomedical subjects

J L Maddocks

Publications and source records attributed to J L Maddocks.

At least 37 records · Page 2Linked to original sources
PubMed1985

Skin cancer in renal transplant recipients is associated with increased concentrations of 6-thioguanine nucleotide in red blood cells.

Of 108 renal transplant recipients (53 men and 55 women) treated with azathioprine (0.8-2.9 mg/kg/day) and prednisolone (10 mg daily), 10 men had actinic keratoses, and five of these had squamous cell carcinoma, on light-exposed areas of skin. The time from transplantation to diagnosis of these skin lesions varied from 1.2 to 9.0 (mean 5.1) years. The concentration of the active azathioprine metabolite 6-thioguanine nucleotide was 120-425 (mean 276) pmol per 8 X 10(8) red blood cells in the transplant patients who developed skin lesions and 54-203 (mean 130) pmol per 8 X 10(8) red blood cells in a matched control group of renal transplant recipients. This difference was statistically significant (P = 0.005). There was no statistically significant difference between patients and controls in azathioprine dosage, clinical features of immunosuppression, sunlight exposure or infection with human papilloma virus. The association of raised 6-thioguanine nucleotide concentrations in red blood cells with actinic keratoses and malignant skin tumours in these patients supports chemical carcinogenesis as a possible cause.

Adult↗
PubMed1984

Disturbance of 6-mercaptopurine metabolism by cotrimoxazole in childhood lymphoblastic leukaemia.

The effect of cotrimoxazole on the utilization of 6-mercaptopurine (6MP) was studied in a group of children receiving remission maintenance treatment for lymphoblastic leukaemia (ALL). This was done by measuring the level of an active metabolite of 6MP, 6-thioguanine nucleotide (6TGN), and comparing it both with the drug dose and with subsequent neutropenia in the presence or absence of concurrent cotrimoxazole. In children who were not taken cotrimoxazole, the concentration of 6TGN showed a significant positive correlation with the dose and a significant negative correlation with the absolute neutrophil count 2 weeks later. In those who were taking the antibiotic both these relationships were lost. This suggests that cotrimoxazole can interfere with both the absorption and the cytotoxicity of 6MP and may, in turn, alter its antileukaemic effect.

Absorption↗
PubMed1984

Childhood lymphoblastic leukaemia: sex difference in 6-mercaptopurine utilization.

Twelve boys and 10 girls on similar long term remission maintenance treatment for lymphoblastic leukaemia had 79 random assays of their red cell 6 thioguanine nucleotide ( 6TGN ) concentrations performed as an index of cytotoxic activity generated by oral 6-mercaptopurine ( 6MP ). Correlation between the dose of 6MP and 6TGN was statistically significant in the girls (r = 0.58, P less than 0.001) but not in the boys (r = 0.15). Additionally, as a group the boys tolerated more 6MP (P less than 0.05), despite similar prescribing criteria, but this did not result in a higher mean 6TGN concentration or increased myelotoxicity. It appears that girls develop 6MP cytotoxicity at lower doses and more predictably than boys. If so, this may be relevant to the as yet unexplained but marked sex difference in prognosis apparent in some studies.

Adolescent↗
PubMed1984

Severe megaloblastic anaemia associated with abnormal azathioprine metabolism.

Severe anaemia is a rare, unexplained, side effect of azathioprine therapy. We report here such a case associated with a previously unreported abnormality in azathioprine metabolism. A 57 year old man on azathioprine therapy, for a presumed collagen vascular disease, developed severe megaloblastic anaemia. This resolved on cessation of azathioprine treatment. A very high concentration of an azathioprine metabolite, 6-thioguanine nucleotide, was found in the patient's red blood cells and this was confirmed by subsequent rechallenge with a single dose of 50 mg azathioprine.

Anemia, Macrocytic↗
PubMed1984

Azathioprine and 6-mercaptopurine (6-MP) suppress the human mixed lymphocyte reaction (MLR) by different mechanisms.

6-MP inhibitory effects on the MLR were reversed by AIC (46%), adenine (32%), hypoxanthine (89%), adenosine (86%) and inosine (93%). AIC, adenine, hypoxanthine and inosine had no effect on azathioprine inhibition of the MLR. Adenosine at 10 microM caused 29% reversal and had no effect at 100-400 microM on azathioprine inhibition of the MLR. Reversal of 6-MP suppression of the MLR was decreased with the delay of adenosine addition. Guanine, xanthine and guanosine caused no reversal of 6-MP or azathioprine inhibitory effects on the MLR. These results show that azathioprine and 6-MP suppress the MLR by different mechanisms.

Adenine↗
PubMed1984

Azathioprine metabolism in kidney transplant recipients.

Azathioprine metabolite concentrations were studied in 54 kidney transplant recipients. Thirty-seven of these patients were studied over a 6 month period to investigate the intrapatient variation in metabolite concentrations. All patients had stable functioning grafts and normal peripheral white blood cell counts. The metabolites measured were plasma 6-mercaptopurine and red blood cell 6-thioguanine nucleotide. There was no correlation between azathioprine dose and plasma 6-mercaptopurine concentration but there was a significant correlation between dose and red blood cell 6-thioguanine nucleotide concentration (rs = 0.41, P less than 0.005). The individual transplant recipient showed little variation in metabolite concentrations over several months. Using this group as a control we studied metabolite concentrations in patients with kidney transplants who developed leucopenia. Our preliminary findings indicate that elevated red cell 6-thioguanine nucleotide concentrations, above the control range, can be associated with bone marrow depression.

Adult↗
PubMed1984

Immune deficiency due to adenosine deaminase and purine nucleoside phosphorylase deficiency: a simple diagnostic test.

A simple method is described for diagnosing adenosine deaminase and purine nucleoside phosphorylase deficiency using urine. Cellulose thin layer chromatography of 1 microliter of urine from affected children was performed and deoxyadenosine and deoxyguanosine were easily detected by phosphorescence at the temperature of liquid nitrogen. This test is not expensive and can be done in any laboratory. It should be suitable for diagnostic screening in patients with immune deficiency.

Adenosine Deaminase↗
PubMed1983

Childhood leukaemia: a relationship between intracellular 6-mercaptopurine metabolites and neutropenia.

6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P less than 0.01; n = 90 and r = -0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 X 10(8) RBCs. The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Adolescent↗
PubMed1983

Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red blood cells.

An assay for 6-thioguanine (6-TG) nucleotide, a major metabolite of the cytotoxic drugs azathioprine, 6-mercaptopurine and 6-thioguanine in human red blood cells (RBCs) has been developed. The metabolite was not detected in RBCs when azathioprine or 6-mercaptopurine was incubated with whole blood in-vitro. The assay for intracellular 6-TG nucleotide is specific and requires 8 X 10(8) RBCs (100 microliters packed cells) for which the limit of sensitivity is 30 pmole 6-TG nucleotide. Pre-dose blood samples were obtained, 12 h after the last azathioprine dose, from 10 renal transplant recipients with stable functioning cadaver grafts on a total daily dose of 150 mg azathioprine. The mean 6-TG nucleotide concentration was 171 pmole/8 X 10(8) RBCs (s.d. = 84). The assay is also suitable for use in measuring 6-TG nucleotide in the RBCs of leukaemic children undergoing 6-mercaptopurine treatment.

Azathioprine↗
PubMed1982

Assay of an active metabolite of 6-thioguanine, 6-thioguanosine 5'-monophosphate, in human red blood cells.

A flow-fluorimetric, liquid chromatographic assay for 6-thioguanosine 5'-monophosphate (TGMP) in human red blood cells (RBCs) has been developed. This compound is an active metabolite of 6-thioguanine, 6-mercaptopurine and the immunosuppressant, azathioprine. The samples were prepared for chromatography by a novel isolation method which extracts the RBC constituents into an organic solvent and leaves the TGMP in the aqueous layer where it is oxidised to give a highly fluorescent species which is then separated by liquid chromatography. The method is sensitive to below 200 ng ml-1 in RBCs which is below the levels encountered following a therapeutic dose of 6-thioguanine or azathioprine. The assay is simple and rapid enough for routine use.

Azathioprine↗
PubMed1980

Assay of thioinosinic acid, an active metabolite of azathioprine, in human lymphocytes.

1 A specific assay for the measurement of thioinosinic acid, in human lymphocytes, has been developed with a sensitivity of 50 ng of thioinosinic acid per 5 x 10(6) lymphocytes. 2 Thioinosinic acid is precipitated from purified lymphocytes as the lanthanum salt. Acid hydrolysis results in the formation of 6-mercaptopurine which, when converted into its phenyl mercury derivative, can be easily extracted into toluene. Back-extraction of the toluene layer with 0.1N HCl regenerates 6-mercaptopurine which is then assayed fluorometrically. 3 Blood samples were taken from renal transplant recipients 3 h after an oral dose of 50 mg azathioprine. The results from 5 patients gave a range of 54 to 173 ng of thioinosinic acid per 5 x 10(6) lymphocytes, with a mean of 110 ng. 4 In an in vitro incubation of azathioprine, 1mM with fresh human blood, 160 and 180 ng of thioinosinic acid per 5 x 10(6) lymphocytes was formed after 0.5 h and 5 h respectively. 5 The assay is suitable for the study of the kinetics of thioinosinic acid formation in lymphocytes of patients with kidney transplants. It could also prove useful in the study of thioinosinic acid formation in leukaemia patients undergoing 6-mercaptopurine treatment.

Azathioprine↗
PubMed1980

Assay of 6-thioguanine in human plasma.

1. A fluorimetric method has been developed for measuring therapeutic concentrations of 6-thioguanine in human plasma. The drug was measured as an oxidized derivative, guanine 6-sulphonate. 2. 6-thioguanine was extracted from plasma by a novel procedure which isolated the drug from an interfering plasma components. This method involved the formation of the thioguanine phenyl mercury derivative in alkaline plasma and its extraction into toluene. The free drug was released by back-extraction into hydrochloric acid. 3. The assay is specific and shows a limit of sensitivity of 5 ng/ml. This was shown to be adequate for measuring plasma concentrations of 6-thioguanine after the administration of a 160 mg dose in a patient with leukaemia.

Chemical Phenomena↗