Sulphonylurea hypoglycaemic agents.
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Aged↗
Biomedical subjects
D A Joyce
Publications and source records attributed to D A Joyce.
Differentiation of the U-937 promonocytic cell line induced by phorbol myristate acetate or retinoic acid: effect of aurothiomalate.
Tissue macrophages, which participate in chronic synovial inflammation, differentiate from haemopoietic precursors in bone marrow and subsequently in tissue. During this process, they acquire attributes which are essential for their function in inflammation. Modulation of this process may represent a means of regulating inflammatory competence of macrophages in inflammatory joint disease. The action of aurothiomalate (ATM), an anti-rheumatic gold compound, on the differentiation of a promonocytic cell line (U937) was, therefore, examined in in vitro systems. U937 cells exposed to retinoic acid (RA) for 4 days or to phorbol myristate acetate (PMA) for 2 days acquired characteristics of macrophages, including the capacity to produce superoxide (O2-), responsiveness to formyl-methionyl-leucyl-phenylalanine (fMLP) and reduced proliferation. The activity of transglutaminase also increased in RA-exposed cultures. The effect of ATM exposure on acquisition of these characteristics was small and differed between RA- and PMA-stimulated cells.
Cell Differentiation↗
In vitro mechanism of oxidation of D-penicillamine in plasma.
D-Penicillamine (P-SH) added to plasma in-vitro is transformed rapidly to low molecular weight (LMW) disulfides and smaller amounts of D-penicillamine:protein conjugate. The P-SH loss through transformation is accompanied by a quantitatively similar decline in the total sulfhydryl group concentration in plasma solutions. Therefore, P-SH disappearance is predominantly through oxidation, rather than thioldisulfide interchange with plasma disulfides. The rate of P-SH transformation is dependent on the albumin concentration. It is not influenced, however, by the concentration of reduced sulfhydryl groups on plasma protein, since transformation occurs at an unattenuated rate in solutions of sulfhydryl-blocked plasma protein. D-Penicillamine:protein disulfides, therefore, are not important intermediates in P-SH oxidation in vitro. Trace amounts of transitional metals bind loosely to plasma albumin in vivo. The rate of P-SH oxidation in albumin solutions from which transitional metals have been removed is a mean of 68% of the rate in untreated solutions. Restoring [Cu2+] in treated albumin solutions to physiological levels restores the rate of P-SH oxidation. The rate of P-SH disappearance from albumin solutions correlates with [Cu2+] over a range of albumin concentrations. Catalysis of P-SH oxidation by physiological concentrations of albumin-associated Cu2+ therefore contributes to the disappearance of P-SH from plasma in vitro. A similar phenomenon may occur in vivo.
Albumins↗
Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid.
A double blind, placebo controlled trial examined the effects of folinic acid on the efficacy and toxicity of methotrexate in 27 patients with rheumatoid arthritis. Clinical and laboratory indices of disease activity worsened significantly in the 13 patients treated with folinic acid after four weeks of treatment, but not in the 14 patients treated with placebo. Exacerbation of rheumatoid arthritis led to withdrawal of the test drug in seven of the patients treated with folinic acid but in none of those treated with placebo. It is concluded that excerbation of rheumatoid arthritis is likely when folinic acid is given shortly after the weekly dose of methotrexate.
Arthritis, Rheumatoid↗
D-penicillamine metabolism: the role of transformation in blood plasma.
The transformation of D-penicillamine (D-pen) was studied in orally- and intravenously-dosed rats and in human plasma in vitro. In each case, low molecular weight (LMW) metabolites (previously identified as disulphides) and a mixed disulphide between D-pen and albumin (D-pen-protein) formed. The rates of D-pen elimination, other than through protein conjugation, were comparable in the rat groups to the rate of oxidation to LMW metabolites in vitro. The rates of transformation to D-pen-protein were also comparable in the in vitro preparations and in orally-treated rats. These qualitative and quantitative similarities suggest blood plasma may be an important site of transformation in vivo. Extracellular oxidation of D-pen may be linked to its antirheumatic action, either through reduction of oxygen species or through formation of D-pen-protein disulphides at surfaces of mononuclear leukocytes.
Administration, Oral↗
D-penicillamine.
D-Pen represents an effective treatment for a proportion of patients with RA and PSS. Its status in the treatment of juvenile RA is uncertain. The best results will be obtained by a skillful, careful physician maintaining careful surveillance for toxicity. Neither the mode of action nor the mechanisms of toxicity are well understood in RA. Consequently, safer and more effective analogues of D-pen have not been produced.
Arthritis, Juvenile↗
D-penicillamine and D-penicillamine-protein disulphide in plasma and synovial fluid of patients with rheumatoid arthritis.
1. The plasma pharmacokinetics of D-penicillamine (D-pen) and D-penicillamine-albumin disulphide (D-pen-alb) were examined over a dosage interval in six patients with rheumatoid arthritis. In two of these, 24 h synovial fluid profiles of D-pen and D-pen-alb were also obtained. 2. D-pen was undetectable in plasma at the beginning of the study. The peak concentration (5.4 +/- 1.2 microM) occurred at between 45 min and 2 h and the mean elimination half-life was 0.6 h. D-pen-alb, however, was present at a mean plasma concentration of 19.1 microM prior to dosage, peaked at 26.2 microM and was eliminated with a half-life of 40 h. 3. D-pen concentrations in synovial fluid rose more slowly and peaked lower than in plasma. D-pen-alb was present in synovial fluid of the patients at 50.1% and 83.6%, respectively, of the simultaneous plasma concentration prior to dosage. Concentrations varied during the study interval, corresponding to changes in plasma concentrations. 4. These results demonstrate that D-pen forms stable conjugates with protein in treated patients. The presence of D-pen-alb in relatively high concentrations throughout the dosage interval contrasts with the low concentrations and rapid elimination of D-pen. Both D-pen and D-pen-alb were also shown to be present at the putative site of drug action (the inflamed synovial joint) in concentrations lower than those in plasma.
Adult↗
D-penicillamine pharmacokinetics and pharmacodynamics in man.
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Humans↗
Pharmacokinetics of intravitreal injection. Assessment of a gentamicin model by ocular dialysis.
Intravitreal drug administration is the treatment of choice for bacterial endophtalmitis, but improved knowledge of vitreal pharmacokinetics is essential for the development of optimal antibiotic regimes. We used our recently developed sampling device to estimate vitreal gentamicin concentrations for up to 30 hr after an intravitreal bolus injection of gentamicin. The device is based on the principle of dialysis, whereby a constant flow rate of dialysate through a loop of dialysis fiber in the vitreous attains a gentamicin concentration proportional to the intravitreal gentamicin level around the fiber. The dialysate is continuously recovered and the collected samples then assayed for gentamicin. Normal cat eyes and those with induced bacterial endophthalmitis formed the two groups tested. Concentration-time data fitted well to an open single compartment pharmacokinetic model that incorporated the processes of transfer of drug from the injection site to the sampling site (a function of diffusion within the vitreous), and the elimination from the sampling site (a function of elimination from the vitreous). The initial phase of transfer between the injection and sampling site was rapid and rates were comparable in the two groups. Elimination rate constants were uniformly greater in infected eyes than in controls (0.107 hr-1 compared to 0.055 hr-1). Aqueous humor gentamicin concentrations in control eyes varied between 3 and 6 times those found in fellow infected eyes at the end of each experiment. Accelerated elimination of gentamicin from the vitreous body of eyes with endophthalmitis may be explained by increased permeability of the blood-retinal barrier.
Animals↗
Assay for D-penicillamine-protein conjugate in human plasma utilising chemical reduction followed by high-performance liquid chromatography with gold/mercury electrochemical detection.
D-Penicillamine (D-pen), a thiol with antirheumatic activity, forms a mixed disulphide with albumin in vivo. This conjugate is important in the pharmacokinetics and possibly the mode of action of D-pen. An assay was devised for D-pen-albumin disulphide, based on separation from plasma by acid precipitation followed by quantitative reduction with sodium borohydride in an anoxic environment. The liberated D-pen was then assayed by high-performance liquid chromatography with gold/mercury electrochemical detection. The assay was sensitive to 1.2-microM D-pen-albumin disulphide (signal-to-noise ratio greater than 2), absolute recovery was 92.7% and intra-assay coefficient of variation was 4.6% in human plasma. This technique also may be useful for quantitating protein conjugates of other thiols.
Arthritis, Rheumatoid↗
D-penicillamine pharmacokinetics and action.
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Animals↗
D-penicillamine metabolism in an in-vivo model of inflamed synovium.
Oxidation to disulphides is the chief metabolic transformation of D-penicillamine (D-pen) in patients with rheumatoid arthritis. Oxidation also occurs in many biological fluids in-vitro. Reduction of oxygen species may accompany the oxidation of D-pen under appropriate conditions and may mediate the anti-rheumatic action of D-pen. The transformation of D-pen therefore was examined in an in-vivo model of inflamed synovium. Subcutaneous air-pouches of groups of rats were treated with saline, 10% serum or 10% zymosan activated serum (ZAS). The transformation of D-pen to low molecular weight (LMW) metabolites and protein conjugates within the pouch was then assessed. The concentrations of total protein were significantly higher in the serum and ZAS-treated groups than in the saline-treated group and the inflammatory cell counts were significantly higher in the ZAS-treated group than in either of the other groups, as expected. D-pen oxidised rapidly to LMW metabolites and smaller amounts of D-pen-protein conjugate (D-pen-protein) in the air pouches of all animals. The rates of oxidation to LMW metabolites were greater in the ZAS-treated animals than the saline-treated group (p less than 0.005). The concentrations of D-pen-protein conjugate were also greater for the serum-treated and ZAS-treated animals than for the saline controls (p less than 0.005 in each case) at all times. Oxidation of D-pen therefore occurs at this site of inflammation and is influenced by local conditions. This may be important to understanding the forms in which D-pen exists in inflamed synovial joints and the way it may exert its antirheumatic activity.
Animals↗
Hygiene and hatchability of duck eggs--a field study.
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Animals↗
Hatchery problems--a field report.
A long term investigational, advisory and monitoring exercise with a major hatchery emphasised the multi-disciplinary approach adopted by the Agricultural Development and Advisory Service (ADAS) to raise the performance of the many aspects of chick production. These included an investigation of egg handling techniques from nest box to hatcher; the adoption by the hatchery of plastic setter trays; an improvement to incubator environment; an improvement in the overall hatchery hygiene programme and the introduction of a regular monitoring programme based on the examination of hatchery fluff. Collectively these improvements led to an improvement of approximately 10 per cent in hatchability over a two year period.
Animals↗
The pharmacokinetics of albumin conjugates of D-penicillamine in humans.
D-penicillamine (D-PEN) is incompletely recovered during short-term balance studies, despite rapid elimination of D-PEN and its low molecular weight metabolites. Urinary excretion of metabolites of D-PEN also persists long after cessation of chronic therapy. A study was performed to determine whether the formation and later breakdown of a stable disulfide between D-PEN and plasma albumin could explain these aspects of D-PEN pharmacokinetics. Five human volunteers received D-penicillamine, 250 mg orally, daily for 21 days. Plasma concentration-time profiles for D-PEN and D-PEN-albumin disulfide (D-PEN-albumin) were determined during the first day and pre-dose concentrations were measured on five further occasions. The pharmacokinetics of D-PEN on the first day were similar to those reported previously. No D-PEN was found in any of the pre-dose specimens. The concentration of D-PEN-albumin rose rapidly during the first day, with an estimated 8.6% of the bioavailable D-PEN being transformed to D-PEN-albumin. Pseudo-steady-state concentrations of D-PEN-albumin were achieved in three subjects at between 14 and 21 days. The mean trough concentration of D-PEN-albumin at 21 days (19.5 microM) exceeded the peak concentration of D-PEN (during the first day) by 5.7-fold. The terminal elimination half-life of D-PEN-albumin was 1.65 +/- 0.29 days, which compared with an elimination half-life of 59 +/- 8.4 min for D-PEN.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The pharmacokinetics of albumin conjugates of D-penicillamine in rats.
A protein conjugate that forms during the metabolism of D-penicillamine (D-PEN) in rats is electrophoretically indistinguishable from the (D-PEN-albumin) mixed disulfide that forms during the oxidation of D-PEN in plasma in vitro. Both the conjugate formed in vivo and the mixed disulfide synthesized in vitro are eliminated slowly in rats, with half-lives of 5.33 +/- 0.25 days and 3.48 +/- 0.42 days, respectively. These half-lives approximate or exceed the half-lives of radioiodinated plasma protein in the animals. The stability of the D-PEN-albumin conjugate contrasts with the rapid elimination of D-PEN itself and probably explains delayed elimination of D-PEN-containing disulfides in humans. Stable modification of tissue proteins by D-PEN may also be involved in the mode of action of D-PEN in rheumatoid arthritis.
Albumins↗