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J C Ritchie

Publications and source records attributed to J C Ritchie.

At least 73 records · Page 4Linked to original sources
PubMed1986

The metabolism of debrisoquine in man: (1) regioselectivity of hydroxylation and (2) aberrant oxidative metabolism in two sibling patients with carbimazole-induced agranulocytosis.

The regioselectivity of the metabolic hydroxylation of debrisoquine has been determined in 43 healthy British white volunteers and the priority was found to be in the order 4 greater than 7 greater than 6 greater than 5 greater than 8. The order of preference for hydroxylation position was independent of debrisoquine 4-hydroxylation phenotype. The extent of total aromatic hydroxylation varied widely between individuals and was largely independent of the extent of 4-hydroxylation, and thus of the influence of the DH/DL locus. Two sisters and their blood relations all excreted comparatively large amounts of the phenolic metabolites in their urine, indicating some genetic basis for the control of aromatic oxidation of debrisoquine in man. These same two sisters had previously developed agranulocytosis in association with carbimazole therapy.

Adolescent↗
PubMed1985

Plasma cortisol determination for the dexamethasone suppression test. Comparison of competitive protein-binding and commercial radioimmunoassay methods.

Quality control serum samples and postdexamethasone plasma pools were used to compare 16 commercial cortisol radioimmunoassay kits with the competitive protein-binding assay for plasma glucocorticoids that we used to standardize the dexamethasone suppression test (DST). Thirteen radioimmunoassays gave higher criterion values for the DST than those established using the competitive protein-binding assay. The range of radioimmunoassay criterion values was 4.34 to 8.70 mu mg/dL. Possible explanations are given for these findings, and their importance to the clinical utility of the DST are emphasized. Each laboratory should validate its own criterion cortisol value for depression based on local data, including appropriate control groups.

Depressive Disorder↗
PubMed1984

Comparison of plasma cortisol and corticosterone in the dexamethasone suppression test for melancholia.

The suppression of plasma corticosterone (B), measured by radioimmunoassay (RIA), was compared to simultaneous suppression of plasma cortisol (F), measured as total corticoids by a competitive protein binding (CPB) assay, in the overnight dexamethasone suppression test (DST). Baseline plasma B concentrations in 10 control subjects were 4.04 +/- 1.07 ng/ml (X +/- S.D.) at 0800 hr and 1.51 +/- 0.68 ng/ml at 1600 hr. Post-dexamethasone 1600 hr B levels in the controls were 0.46 +/- 0.29 ng/ml. An early escape of plasma B (greater than 1.2 ng/ml), like that of F (greater than 5 micrograms/dl), during the overnight 24 hr 1.0 mg dose DST was noted in patients with melancholia (endogenous depression). Half-hourly catheter samples in a normal subject stimulated to escape from dexamethasone suppression showed that in general, plasma B concentrations parallel plasma F concentrations over a 12 hr period. Repeated weekly DSTs on two patients with different psychiatric diagnoses resulted in B : F correlations of 0.74 and 0.60. Overall agreement between B- and F-DST outcomes in all categories tested at 1600 and 2300 hr was 93%; the agreement in the melancholic and non-endogenous depressed groups was 100%. Post-dexamethasone, both B and F were suppressed 55-60% below the criterion level in controls. In those patients who escaped from dexamethasone suppression, the percentage increase in plasma B above the criterion level was significantly greater (+55%) than the corresponding percentage change in plasma F. Most patients with borderline abnormal F-DSTs (3.5 - 4.9 micrograms/dl) exhibited clearly abnormal B-DSTs (greater than 1.2 ng/ml). We conclude that the use of dexamethasone suppression of plasma B (using 1.2 ng/ml as the abnormal criterion value) is an additional indicator of an abnormal DST in depressed patients.

Bipolar Disorder↗
PubMed1982

Spectral binding studies of the polymorphically metabolized drugs debrisoquine, sparteine and phenformin by cytochrome P-450 of normal and hydroxylation deficient rat strains.

The mechanisms of polymorphic drug hydroxylation of debrisoquine, sparteine and related drugs in vivo have been investigated using Cyt P-450 preparations of inbred rat strains as an in vitro model of the poor and extensive metabolizer phenotypes found in various rat strains and in man. Optical difference spectroscopy with debrisoquine, sparteine, phenformin and three other drugs (selected test compounds with proven or suspected hydroxylation polymorphisms in man) exhibited Type 1 binding in normal Sprague-Dawley, Fischer and Lewis Cyt P-450, whereas no Type I drug binding was found in the hydroxylation deficient DA rat liver Cyt P-450. Cyt P-450 content and Type II drug binding of metiamide was the same in normal and hydroxylation deficient rat liver microsomes. The pronounced Type I drug binding in extensive hydroxylation Cyt P-450 and the defective Type I binding in DA Cyt P-450 in vitro, therefore, closely parallels the polymorphic hydroxylation pattern of these test drugs found in the four rat strains studied in vivo. Consequently, missing binding properties of Cyt P-450 or of its micro-environment might represent the enzymatic defect underlying the genetically determined hydroxylation deficiency of polymorphically metabolized drugs in the poor metabolizer phenotype in the DA rat and, by inference, in man.

Animals↗
PubMed1982

Population studies of polymorphism in drug oxidation and its relevance to carcinogenesis.

Metabolic oxidation plays a central role in both the detoxication and chemical activation of many environmental procarcinogens. A plethora of in vitro data suggests that metabolic activation and subsequent DNA covalent binding of such substances vary widely between individuals. The need for a simple test in vivo of human variability in metabolic oxidation is apparent, not only to help understand the variation in disposition of many drugs and other chemicals, but also as an aid to predicting individual cancer risk from metabolically activated procarcinogens. Current methodology has failed to provide such information for a number of reasons, which are discussed. A genetic polymorphism affecting the metabolic disposition and biological effects of a number of drugs is described. Persons can be phenotyped as either extensive or poor metabolizers, using the drug debrisoquine. The measured variable, urinary 'metabolic ratio', which is distributed across these two phenotypes with values of 0.1 to 200, gives a clear indication of the metabolic behaviour of many drugs and, possibly therefore, of certain procarcinogens. Accordingly, two groups of cancer patients were investigated with debrisoquine, namely Nigerians with hepatocellular and related tumours and white smokers with bronchial carcinoma in the United Kingdom. These preliminary studies are suggestive of a phenotype component in relative cancer risk, poor metabolizers appearing to be less vulnerable. Animal model data seem to confirm a relationship between aflatoxin B1 metabolism and DNA binding and polymorphic debrisoquine oxidation. It is concluded that the biological consequences of ingesting exogenous chemicals may be better understood from studies of discrete, genetically determined steps in their interaction with living systems.

Animals↗
PubMed1980

Toxicological implications of polymorphic drug metabolism.

The occurrence of genetic polymorphisms of drug metabolism means that populations contain subgroups (phenotypes) that differ sharply in their abilities to effect a number of metabolic reactions. Because of this, major interphenotype differences occur in responsiveness to drugs and toxic substances. The well established genetic polymorphisms of acetylation and hydrolysis illustrate the important association that exists between phenotype and propensity to develop toxic and exaggerated responses to some substances. Recently, for metabolic oxidation, a new genetic polymorphism of drug metabolism has been described and it promises to provide a better understanding of inter-individual variability in the metabolic handling of, and responsiveness to, drugs and toxic substances. The following effects of the polymorphism are described here: (a) its influence in determining variable presystemic metabolism and hence systemic drug availability; (b) its role in determining alternative toxic pathways of metabolism in individuals who have a genetically determined impairment of oxidative capacity and (c) its influence on the development of agranulocytosis associated with metiamide administration.

Alleles↗
PubMed1979

Connective tissue activation. XIV. Composition and actions of a human platelet autacoid mediator.

Connective tissue activating peptide-III (CTAP-III) isolated from human platelets is a potent mitogen for human connective tissue cells in culture in addition to stimulating glycosaminoglycan synthesis, glucose consumption, and lactate formation. The amino acid composition of apparently homogeneous CTAP-III was determined, confirming the presence of two disulfide links and providing a calculated molecular weight of 11,633 daltons. Comparison of the mitogenic activity of serum and plasma-serum suggests that CTAP-III is a major mitogenic component of human serum. Seventeen strains of human connective tissue cells (synovial, cartilage, dermal and thyroid) incorporated [3H]-thymidine at up to 30 times control at levels under the influence of microgram quantities of CTAP-III and caused detectable increases in thymidine incorporation at levels as low as 10-29 ng/ml. Prostaglandin E1 (0.01 microgram/ml) and dibutyryl cyclic AMP (25 microgram/ml) potentiated the glycosaminoglycan stimulating effect of CTAP-III, but not its mitogenic effect. Cycloheximide and actinomycin D blocked the biologic actions of CTAP-III. Cortisol and penicillamine had little effect on the mitogenic activity of CTAP-III, whereas antirheumatic agents such as acetylsalicylic acid and phenylbutazone opposed the mitogenic activity when added to cultures at clinically relevant concentrations. A weak antiheparin factor secreted by platelets, low affinity platelet factor 4 (LA-PF4), was shown to be similar to CTAP-III in biologic actions, electrophoretic mobility, amino acid composition, and antigenic determinants.

Amino Acids↗
PubMed1977

Connective tissue activation. XI. Stimulation of glycosaminoglycan and DNA formation by a platelet factor.

This report describes a small basic protein found in human platelets which stimulates hyaluronic acid formation, glucose uptake, and lactate formation in several types of human connective tissue cells. In addition, it stimulates in incorporation of [3H] methyl thymidine into DNA in human synovial cell cultures. This platelet factor (connective tissue activating peptide-II, CTAP-III) clearly differs form CTAP-I, found in human lymphocytes, and may play a role as a mediator of the inflammatory process.

Blood Platelets↗
PubMed1977

Measurement of urinary and serous-fluid glycosaminoglycans and urinary hydroxyproline.

Although analytic measurements of connective tissue components in biological fluids would frequently be useful in diagnosis and/or management of many inflammatory, neoplastic and metabolic diseases, such information is often unavailable due to the methodologic problems posed by these natural products. This report outlines relatively simple procedures leading to the colorimetric measurement of glycosaminoglycans in urine and other body fluids and to measurement of hydroxyproline in urine. Normal values and potential applications are presented.

Ascitic Fluid↗