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Biomedical subjects

J L Maddocks

Publications and source records attributed to J L Maddocks.

At least 19 recordsLinked to original sources
PubMed1991

Application of new fluorescent thiol reagent to diagnosis of homocystinuria.

A new fluorescent thiol reagent, dansyl-aminophenylmercuric acetate (DAPMA), was applied to the diagnosis of homocystinuria, a disorder which can be associated with vascular disease at an early age. DAPMA was added to urine containing metabisulphite and the resulting fluorescent derivatives were extracted on a cyclohexyl silica column and separated by thin-layer chromatography. 102 coded samples were tested. The derivative of homocysteine was easily identified in samples from 4 children with homocystinuria but was absent from all samples from normal subjects and patients with unrelated disorders. Other thiols (cysteine, acetylcysteine, mercaptolactate, thiosulphate, and thiocyanate) were also identified in urine from healthy fasting subjects.

Child↗
PubMed1988

Adenine phosphoribosyltransferase deficiency: a simple diagnostic test.

1. A simple method for diagnosing adenine phosphoribosyltransferase (APRT) deficiency using urine is described. 2. T.l.c. of 1 microliter urine from a child with APRT deficiency was performed and adenine was easily detected by its brilliant blue phosphorescence at liquid nitrogen temperature. 3. Four physicochemical characteristics of adenine were recorded: RF value, and the colour, decay time and pH sensitivity of phosphorescence. 4. Adenine was not detected in the urine of 116 subjects used as controls. These included healthy individuals and patients with inherited metabolic disorders, diseases of purine metabolism and of the kidney and urinary tract. Some of them were taking a variety of drugs including purine derivatives. 5. The test correctly diagnosed three cases of APRT deficiency out of 10 urine samples tested blind.

Adenine↗
PubMed1988

Blue rubber bleb naevus disease: an uncommon cause of gastrointestinal tract bleeding.

A 23 year old woman presented with facial pain, a right parotid tumour and iron deficiency anaemia. She had several cutaneous venous swellings and tumours with a similar appearance were found in the large bowel. Histological examination of the parotid tumour and angiography of the skin and gut lesions confirmed that they were venous in origin. The aetiology, classification, and complications of disorders of the venous system and the importance of using a tourniquet to examine the peripheral veins is discussed.

Adult↗
PubMed1987

Metabolism of azathioprine to 6-thioguanine nucleotides in patients with pemphigus vulgaris.

Azathioprine metabolism, to red cell 6-thioguanine nucleotides (6TGN), was studied in four patients with pemphigus vulgaris. Throughout treatment blood samples were taken for red cell 6TGN assay and differential white cell counts. Metabolite steady-state occurred in three patients in 2, 2 and 4 months respectively. In the fourth patient red cell 6TGN concentrations increased slowly over 3 years. There was a significant negative correlation between 6TGN concentrations and the white blood cell count (rs = -0.92, P less than 0.0005) in this patient.

Adult↗
PubMed1986

The effect of folate supplements on 6-mercaptopurine remission maintenance therapy in childhood leukaemia.

The effect of folic acid supplements on 6-mercaptopurine remission maintenance therapy in lymphoblastic leukaemia (ALL) was investigated in a retrospective longitudinal study of 10 children. Red cell concentrations of 6-thioguanine nucleotide, a cytotoxic metabolite of 6-mercaptopurine, were measured and the peripheral neutrophil count was used as an index of myelosuppression. During the control period of the study there were significant correlations between 6-mercaptopurine dose and 6-thioguanine nucleotide concentration (rs = 0.59, P less than 0.0005) and between 6-thioguanine nucleotide concentration and the peripheral neutrophil count at 14 days (rs = 0.58, P less than 0.0005). These relationships were absent when the same children were subsequently taking folate supplements. Also when taking folate supplements the children tolerated significantly more 6-mercaptopurine (P less than 0.005) for a significantly longer time (P less than 0.005) before neutropenia developed. There was no significant difference in red cell 6-thioguanine nucleotide concentration in the absence and presence of folate supplements. These findings suggest that folate supplements may interfere with remission maintenance therapy in ALL.

Adolescent↗
PubMed1986

Does 2-mercaptoethane sulphonate (mesna) prevent cyclophosphamide and azathioprine induced immunosuppression? In vitro studies.

The effect of 2-mercaptoethane sulphonate (mesna) on the inhibition of the human MLR by 4-hydroxycyclophosphamide or azathioprine was studied. 4-Hydroxycyclophosphamide (34 microM) completely inhibited the MLR and this inhibition was unaffected by 122 microM of 2-mercaptoethane sulphonate or its disulphide. At high concentrations (mM) 2-mercaptoethane sulphonate inhibited the MLR reaching 85% at 24 mM. 2-Mercaptoethane sulphonate (15-122 microM) had no effect on azathioprine (36 microM) inhibition. The results of these in vitro studies suggest that 2-mercaptoethane sulphonate does not interfere with cyclophosphamide or azathioprine induced suppression of cellular immunity.

Azathioprine↗
PubMed1985

High-performance liquid chromatographic assay of 6-methylthioguanine, a major metabolite of 6-thioguanine, in urine.

A flow-fluorimetric high-performance liquid chromatographic assay for 6-methylthioguanine in urine has been developed. This compound is a major catabolite of 6-thioguanine, an important drug in cancer chemotherapy. The metabolite was extracted from alkaline urine with ethyl acetate which was injected onto a reversed-phase high-performance liquid chromatographic system for separation and detection. The method is simple, rapid and sensitive to below 500 ng ml-1 which is below the levels encountered following a therapeutic dose of 6-thioguanine. Another metabolite was chromatographically separated from 6-methylthioguanine and partially characterised.

Biotransformation↗
PubMed1985

Strength of the human mixed lymphocyte reaction (MLR) and its suppression by azathioprine or 6-mercaptopurine.

Azathioprine (36 microM) had a significantly (P less than 0.00003) greater inhibitory effect on human MLR responses below 20,000 counts/min than on responses above 20,000 counts/min. In contrast, 6-mercaptopurine (100 microM) had a similar suppressive effect on MLR responses below and above 20,000 counts/min suggesting it has a different mode of action to azathioprine.

Azathioprine↗
PubMed1985

Lack of inhibition of purine nucleoside phosphorylase and adenosine deaminase in patients treated with azathioprine.

Deficiency of the purine salvage enzymes purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) are known causes of immunodeficiency. Evidence for inhibition of these enzymes was sought in 16 patients on azathioprine therapy by testing for deoxyguanosine (PNP deficiency) and deoxyadenosine (ADA deficiency) in urine using a novel phosphorescence method. These abnormal nucleosides were not found in urine of azathioprine treated patients or in 30 normal controls but were easily detected in urine from proven cases of PNP and ADA deficiency suggesting lack of in vivo inhibition of PNP and ADA by azathioprine.

Adenosine Deaminase Inhibitors↗
PubMed1985

Effect of interleukin-2 on the inhibition of the human mixed lymphocyte reaction (MLR) by azathioprine.

The effect of interleukin-2 on the response of the human MLR to azathioprine was studied. Azathioprine (36 microM) inhibited the MLR by 86% and interleukin-2 (25%) stimulated the MLR by 99%. Only partial relief (16%) of azathioprine (36 microM) inhibition was found in the interleukin-2 treated MLR compared with azathioprine treatment alone. However, [3H]-thymidine incorporation by azathioprine (36 microM) + interleukin-2 treated MLR was 4.3 times greater than that exposed to azathioprine alone. As the residual number of immunocompetent cells after drug exposure is pathologically more important than the fraction suppressed, this result may be of clinical relevance. These results show that the major mode of action of azathioprine is not the inhibition of interleukin-2 production.

Azathioprine↗
PubMed1985

Azathioprine suppresses the mixed lymphocyte reaction of patients with Lesch-Nyhan syndrome.

The mixed lymphocyte reaction of Lesch-Nyhan patients (HGPRT deficient) was used to study the immunosuppressive effects of azathioprine and 6-mercaptopurine (6-MP). Mitogen stimulated lymphocytes of these patients are highly resistant to azathioprine and 6-MP. When both stimulator and responder lymphocytes in the MLR were HGPRT deficient, azathioprine (36 microM) was much more inhibitory than 6-MP (100 microM). Azathioprine produced inhibition of 98.2% and 78.5% compared with the values of 63.9% and 30.6% for 6-MP. The difference in inhibitory activity between azathioprine and 6-MP was reduced when normal stimulator lymphocytes were cultured with HGPRT deficient responder lymphocytes in the MLR. These results provide very strong evidence that the nucleotide metabolites of azathioprine and 6-MP are unnecessary for immunosuppression. They also suggest that azathioprine and 6-MP interfere with antigenic triggering of the MLR.

Adolescent↗
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↗