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R H Waring

Publications and source records attributed to R H Waring.

At least 73 records · Page 4Linked to original sources
PubMed1994

D-penicillamine metabolism in neurodegenerative diseases: an in vivo/in vitro sulphydryl methylation study.

1. D-Penicillamine (125 mg) was administered orally to control (healthy volunteers), Parkinson's and Motor Neurone Disease patients following an overnight fast. 2. Blood was collected at 08:00 h for the preparation of red blood cell membranes used in the in vitro S-methylation studies. Urine was collected from 08:00 to 16:00 h and analysed for D-penicillamine and its metabolites. 3. Metabolism occurred via S-methylation, N-acetylation and disulphide formation. Both the Parkinson's and Motor Neurone Disease patients excreted significantly higher median levels of S-methyl-D-penicillamine in the urine than the controls (177 and 209% more for the Parkinson's and Motor Neurone Disease patients respectively). 4. The in vitro and in vivo production of S-methyl-D-pencillamine was highly correlated in the control (rs = 0.936), Parkinson's (0.986) and Motor Neurone Disease (0.752) populations.

Adult↗
PubMed1993

The genetic basis of responses to drugs--a rheumatological perspective.

The wide individual variations seen in all metabolic pathways which have been examined largely explain differences in drug dose response and toxicity. In some cases, distinct sub-sets occur where the enzyme activity is markedly different from that in the rest of the population (genetic polymorphism). Studies on isolated enzymes and use of restriction fragment length polymorphisms have in some cases helped to elucidate the relevant molecular biology. However, the lack of certain concordance between genotype and phenotype has shown that many questions remain unanswered. As more information becomes available at the molecular level, it may be easier to gain an understanding of the endogenous biochemistry which underlies the human condition. Either genotyping or phenotyping may then be used to predict potential drug side-effects or clinical outcomes.

Anti-Inflammatory Agents↗
PubMed1992

Abnormal sulphur oxidation in systemic lupus erythematosus.

S-carboxy-L-methylcysteine was used to assess the activity of the S-oxidation pathway of sulphur metabolism in 35 patients with systemic lupus erythematosus (SLE); 25 (71%) showed impaired sulphoxidation and 21 (60%) produced virtually no sulphoxides, compared with 17 (36%) and 2 (4%), respectively, of 47 healthy controls. The substrate/product ratio of cysteine oxygenase (plasma cysteine/sulphate) was significantly higher in SLE patients than in controls (median [interquartile range] 362 [224-588] vs 65 [44-111]; p less than 0.00001). The alternative pathway of sulphur metabolism, S-methylation, catalysed by thiolmethyltransferase, was not impaired in the SLE patients. There is a biochemical difference in sulphur metabolism between SLE and rheumatoid arthritis, since both pathways are impaired in the latter disorder.

Adult↗
PubMed1992

Management of early inflammatory arthritis. Genetic factors predicting persistent disease: the role of defective enzyme systems.

In this chapter, we investigate the use of non-toxic 'probe drugs' to give information about basic biochemical pathways. We have examined the hypothesis that a major factor in RA is defective metabolism of sulphur-containing compounds. At least two pathways have been shown to be abnormal in RA. Generally, patients have reduced capacity to metabolize and detoxify thiol compounds by methylation, and have increased levels of plasma cysteine. They also have a lower capacity for S-oxidation of cysteine and its derivatives, with reduced amounts of plasma sulphate. The raised cysteine resulting from less effective metabolism may lead to reduced clearance of immune complexes and a raised inflammatory response in RA patients. Lower plasma sulphate, however, leads to defective tissue synthesis, and makes adequate repair of damaged joints less feasible. The co-existence of defects in these two interacting endogenous pathways serves to perpetuate the disease process, leading to chronic inflammation and tissue destruction. These enzyme defects have been shown to be predictive of persistent disease.

Acetaminophen↗
PubMed1991

Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease.

Enzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinson's disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.

Animals↗
PubMed1991

The effect of methimazole on thioamide bioactivation and toxicity.

The hepatotoxicity induced by administration of ethionamide and thionicotinamide (TNA) was shown to be decreased by pre-administration of methimazole (MMI). Pre-administration of MMI was also shown to decrease the levels of excretion of TNA S-oxide. This indicates that thioamide S-oxidation, mediated by the flavin-containing mono-oxygenase, may be linked to the initiation of hepatotoxicity induced by these thioamides. SK&F-525-A, the cytochrome P-450 inhibitor, did not affect either thioamide-induced toxicity or levels of excretion of TNA S-oxide; however, the role of the P-450 isoenzymes cannot be totally ruled out.

Animals↗
PubMed1991

The fate of monochlorobenzanilides in the rat.

The fate of the three isomeric benzoic acid-substituted monochlorobenzanilides has been studied in the rat after their oral administration. The excretory profile of all three isomers was similar with over half of the dose being excreted in the 0-24 hour urine and between 83-87% being recovered during the three days following administration. The most prominent route of metabolism was that of 4'-hydroxylation on the unsubstituted aniline moiety followed by glucuronic acid conjugation.

Administration, Oral↗
PubMed1991

The metabolism of thionicotinamide in the rat.

The metabolism of the thioamide, thionicotinamide, in the male Wistar rat is described. Thionicotinamide was shown to be metabolised to inorganic sulphate, thionicotinamide S-oxide and also N1-methylnicotinamide, which arises from N-methylation of nicotinamide via desulphuration of the parent thioamide. At 24 hours from dosing about 35% of the dose had been excreted as inorganic sulphate and 20.5% as the S-oxide metabolite. Three metabolites, detected by their fluorescence under UV light, have not been positively identified but are postulated to be pyridones, resulting from ring oxidation, by analogy with other thioamides. S-Oxidation is an important metabolic pathway as it may give rise to toxic intermediates.

Administration, Oral↗
PubMed1991

Metabolism of low-dose paracetamol in patients with rheumatoid arthritis.

1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with rheumatoid arthritis (RA) and to age-matched healthy controls and to hospital controls. 2. At this dose level, patients with RA excreted decreased amounts of paracetamol sulphate (controls means 11.3 +/- 5.1, 10.6 +/- 5.9; RA mean 3.02 +/- 3.7). This difference is statistically significant (P less than 0.001). 3. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6 +/- 12.1, 5.3 +/- 10.7 in controls but 2.1 +/- 2.7 in RA patients (P less than 0.001). 4. Patients with RA appear to have less capacity for excreting paracetamol as non-toxic conjugates and may be more susceptible to paracetamol toxicity, especially on chronic dosage.

Acetaminophen↗
PubMed1991

Reduced thiol methyl transferase activity in red blood cell membranes from patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) have a reduced capacity for S-oxidation and formation of drug sulfate conjugates. We investigated S-methylation catalyzed by thiol methyl transferase (TMT) (E.C. 2.1.1.9) as an alternative pathway for metabolism of aliphatic compounds. TMT activity was measured in vitro using red blood cell membrane preparations from 120 patients with RA and 35 controls. Mean values for controls were 10.1 +/- 3 units/mg protein and for RA 3.7 +/- 3 units/mg protein (p less than 0.05). TMT activity was not related to the acute phase response or to drug administration. However, patients with RA with higher TMT activity tended to have higher rheumatoid factor levels. This evidence is consistent with a generalized disturbance of sulfur metabolism in rheumatoid disease.

Aged↗
PubMed1990

Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease.

Elevated plasma cysteine to sulphate ratios were found in patients with Motor neurone disease (MND), Parkinson's disease (PD) and Alzheimer's disease (AD). Cysteine and sulphate were measured by colourimetric methods. Following recent discovery of a defect in sulphoxidation and sulphation of xenobiotics in these diseases, this finding confirms that endogenous sulphur metabolism is disturbed. The mean cysteine:sulphate ratios (x 10(3] in fasting early morning plasma were 506, 521 and 477 for MND, PD and AD whereas it was 96 for normal controls (P less than 0.001). This excess of cysteine thiol groups may interfere with neural protein function. The deficiency of sulphate ions may lead to reduced xenobiotic detoxification.

Adult↗