An infected prosthetic hip. Is there a role for prophylactic antibiotics?
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Aged↗
Biomedical subjects
C T Dollery
Publications and source records attributed to C T Dollery.
The identity of IgE receptors (Fc epsilon RII) that mediate cellular activation of human macrophages: evidence against a role for CD23.
There is now compelling evidence that macrophages bind IgE, and are involved in several IgE-dependent responses. The CD23 antigen mediates a mitogenic response in "primed" B-lymphocytes, although its expression is not confined to B cells, and CD23 is inducably expressed in many cells including macrophages. CD23 is also known to bind IgE, a property that leads to inhibition of the mitogenic response in B cells. In the present review, the possibility that CD23 mediates IgE-dependent responses in macrophages has been re-examined, and it is proposed that the functional receptor for IgE on macrophages may be quite separate from the CD23 antigen.
Antigens, Differentiation, B-Lymphocyte↗
Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects.
The effects of a highly selective leukotriene D4 receptor antagonist, ICI 204.219, on allergen-induced bronchoconstriction and changes in airway reactivity were evaluated in a double-blind, placebo-controlled, crossover trial. Ten atopic subjects were selected for the study on the basis of an immediate fall in forced expiratory volume in 1 s (FEV1) of at least 15% and a least a doubling dose fall in their PC20-histamine (the concentration of histamine needed to reduce FEV1 by 20%) after antigen challenge. Baseline PC20-histamine was determined before the ingestion of a single oral 40 mg dose of ICI 204.219 or matched placebo. 2 h later subjects were challenged with aerosolised allergen; FEV1 was measured for the next 6 h then PC20-histamine was remeasured. Two subjects did not complete the study for reasons not related to the trial medication. ICI 204.219 significantly attenuated the early and late phase bronchoconstriction to inhaled allergen (mean treatment difference in area under the FEV1-time curves 2529 [95% Cl 1085-3972] delta %FEV1.min; p less than 0.005: and 3537 [528-6545] delta %FEV1.min; p less than 0.03) and suppressed the allergen-induced increase in non-specific bronchial reactivity (mean treatment difference 1.03 [0.34-1.71] doubling dilutions of histamine; p less than 0.01). These findings suggest that ICI 204.219 may be a disease-modifying agent in asthma. Further studies are under way to evaluate its clinical efficacy.
Administration, Inhalation↗
The effects of two centrally-acting anti-hypertensive drugs on the quality of life.
The objectives of this study were to compare the effects of two centrally-acting antihypertensive drugs on measures of quality of life in a three-month double-blind trial of hypertensive patients randomized to methyldopa (n = 79) or rilmenidine (n = 78). We studied men and women aged over 21 y attending eight hospital out-patient clinics in the United Kingdom. They had average diastolic blood pressures between 95 and 110 mm Hg and systolic pressures below 210 mm Hg after a 4-week placebo run-in period. The doses ranged from 1 to 2 mg daily of rilmenidine and 500 mg to 1 g of methyldopa. Hydrochlorothiazide (25 mg daily) was added after 8 weeks when the diastolic blood pressure remained at 90 mm Hg or more in 29% of patients on rilmenidine and 35% of those on methyldopa. Quality of life was assessed from self-completed questionnaires using standardized instruments. Both drugs reduced blood pressure, but at the end of the trial the fall in the methyldopa group (19.3/13.0 mm Hg) was significantly greater than in the rilmenidine group (13.2/10.0 mm Hg). Ten patients in the methyldopa group withdrew from the trial compared with three in the rilmenidine group, primarily because of adverse effects. In both groups there was a significant increase in the overall reporting of adverse effects. Reports of dry mouth increased on both drugs, and sleepiness on rilmenidine but not methyldopa. There was no significant difference between the drugs in the overall reporting of adverse effects or of individual adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization.
The Syst-Eur Trial is a concerted action of the European Community's Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure. To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10-40 mg/day), combined with enalapril (5-20 mg/day) and hydrochlorothiazide (12.5-25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and per-protocol comparison of the outcome in the 2 treatment groups. A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).
Aged↗
Assessment of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, with intravenous clonidine.
The activity of MK-467, a new peripherally acting alpha 2-antagonist, was assessed in volunteers by a randomized, double-blind, crossover design. One hour after administration of either 15 mg or 30 mg MK-467 or placebo, 200 micrograms clonidine was given intravenously and observations were made for a further 8 hours. Clonidine reduced plasma norepinephrine levels to 79% +/- 7% of that of control 1 hour after infusion, an effect that was antagonized by low-dose MK-467 (p less than 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of MK-467 (p less than 0.01), although there was no significant difference between the 3 study days in the maximal clonidine-induced decrease in systolic pressure, diastolic pressure, or heart rate. Clonidine induced a peak increase in mean blood glucose of 13%, which was antagonized by both doses of MK-467 (p less than 0.05). Plasma insulin was suppressed by clonidine from 72 +/- 14 to 47 +/- 7 IU.L-1, an effect antagonised by both doses of MK-467 (p less than 0.05 in each case). MK-467 had no effect on clonidine-induced increased drowsiness, xerostomia, or increase in growth hormone secretion, which is consistent with it being a peripherally acting specific alpha 2-antagonist. The small effect of MK-467 on clonidine-induced changes in plasma glucose and insulin suggests that peripheral alpha 2-adrenergic receptors play only a minor role in normal glucose homeostasis.
Administration, Oral↗
Clinical pharmacology of calcium antagonists.
There have been major advances in the understanding of the basic pharmacology of drugs acting upon voltage-dependent and receptor-activated calcium channels using patch-clamp techniques. The structure of the L channel is known and the (different) binding sites for various calcium antagonists have been identified using the methods of molecular biology. Although calcium slow-channel antagonists are very widely used in the treatment of hypertension, advances in the clinical pharmacology of angina and, to a lesser extent, cardiac arrhythmias, have not kept up with the basic research in molecular biology. All of the calcium antagonists in current use dilate arteries, and their therapeutic action largely depends on this property. There is evidence of differences in response between arteries and veins, and some degree of selectivity between vascular territories, but the goal of much more specific or localized vasodilation has not been achieved. The most prominent difference between the three main classes of antihypertensive drugs is the mild reflex increase of heart rate seen with the dihydropyridines and the bradycardia seen with verapamil. Most of the side effects of calcium antagonists are also based on vasodilatation, such as flushing and headache. The mild edema often seen with the dihydropyridines probably depends on the changes in capillary pressure brought about by arterial dilatation. Despite their undoubted efficacy as vasodilators, there are no studies thus far which allow any conclusions as to the long-term effect of calcium antagonists on the morbidity and mortality due to hypertension.
Calcium Channel Blockers↗
Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1.
1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.
6-Ketoprostaglandin F1 alpha↗
Inhaled PAF stimulates leukotriene and thromboxane A2 production in humans.
Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.
Administration, Inhalation↗
Thromboxane A2 biosynthesis in acute asthma and after antigen challenge.
Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma. We have examined the urinary excretion of a variety of products derived from thromboxane A2 (thromboxane B2, 2,3-dinor, and 11-dehydro-thromboxane B2) and prostacyclin (6-oxo-PGF1 alpha and 2,3-dinor-6-oxo-PGF1 alpha) using gas chromatography-mass spectrometry in patients admitted acutely to hospital with severe asthma and in atopic volunteers after bronchial antigen challenge. Urinary excretion of all thromboxane-derived products was markedly increased in a number of patients with severe acute asthma compared with that in a nonsmoking control population, in some cases approaching those previously described in myocardial infarction: TXB2, 31.6 +/- 12.0 versus 6.5 +/- 0.9; 2,3-dinor-TXB2, 79.0 +/- 19.2 versus 29.5 +/- 2.7; and 11-dehydro-TXB2, 234.3 +/- 65.3 versus 25.0 +/- 2.1 ng/mmol creatinine (p less than 0.001). Urinary prostacyclin-derived products were also significantly raised in acute asthma. In contrast, after inhaled allergen challenge in atopic volunteers, which caused significant bronchoconstriction, urinary excretion of thromboxane-derived products was not significantly elevated: TXB2, 5.6 +/- 1.1 versus 5.7 +/- 1.0; 2,3-dinor-TXB2, 41.2 +/- 12.5 versus 28.5 +/- 6.9; and 11-dehydro-TXB2, 69.8 +/- 17.6 versus 39.7 +/- 11.2 ng/mmol creatinine. In a separate experiment, less than 2% of exogenously administered TXB2 to the airway appeared as urinary thromboxane-derived products, suggesting that production of greater than or equal to 1 microgram of TXA2 in vivo would be required to increase urinary thromboxane excretion twofold.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Oral pharmacokinetics of fluazifop-butyl in human volunteers.
1. Fluazifop-butyl, the active ingredient of FUSILADE, a selective herbicide, was administered orally to three male volunteers at a dose level of 0.07 mg kg-1 body weight. Over a period of 6 d between 80 and 93% of the dose was excreted in urine as the metabolite fluazifop, the majority within the first 24 h. Peak plasma concentrations of fluazifop occurred 1-2.5 h after administration. 2. The elimination of fluazifop from plasma and urine can be described by a one-compartment pharmacokinetic model and the elimination half-life was estimated from blood and urine data to be within the range 9-37 h. Fluazifop was found to bind to serum proteins. 3. The study indicates that the amount of fluazifop-butyl absorbed in exposed persons can be assessed by measuring fluazifop concentrations in urine.
Administration, Oral↗
Gastrinoma syndrome in multiple endocrine neoplasia.
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Gastrinoma↗
Cerebral mass lesions in patients with AIDS.
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Acquired Immunodeficiency Syndrome↗
Life threatening thrombocytopenia in sarcoidosis.
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Adult↗
Leukotriene C4 elimination and metabolism in man.
Three doses of radiolabeled leukotriene C4 (0.2 to 15 muCi) were infused into three subjects to investigate its metabolism and routes of elimination during 4 days. Between 12% and 20% of the infused dose was recovered in the urine within 24 hours, of which a substantial and relatively constant proportion (4.1% to 6.3% total dose) appeared as leukotriene E4 (LTE4), mainly in the first 4 hours. Polar omega-oxidation products, N-acetyl LTE4, and tritiated water were also present. Fecal elimination accounted for a further 30% to 40% of the infused dose. In the absence of altered metabolism or biliary excretion, urinary LTE4 may be a useful measure of whole body production of the cysteinyl leukotrienes.
Adult↗
Increased production of cysteinyl leukotrienes in hepatorenal syndrome.
The cysteinyl leukotrienes C4 and D4 are potent renal vasoconstrictors which may modulate glomerular function in vivo, and may therefore be important in the pathogenesis of hepatorenal syndrome. Urinary leukotriene E4, the major metabolite of leukotrienes C4 and D4, was elevated in patients with hepatorenal syndrome (17.8 ng/h) when compared with normal controls (5.1 ng/h) or subjects with renal failure alone (1.9 ng/h). Urinary leukotriene E4 was also elevated in subjects with decompensated liver disease (cirrhosis with ascites 28.6 ng/h, severe hepatocellular dysfunction 57.5 ng/h), but normal in compensated liver disease (6.7 ng/h). In the early stages of hepatorenal syndrome, leukotriene E4 excretion rate was up to 100-fold higher (560 ng/h) than in normals, and fell in parallel with creatinine clearance, indicative of the glomerular filtration rate-dependent renal excretion. Following correction for creatinine clearance, leukotriene E4, excretion was considerably higher in hepatorenal syndrome (54.1 pg/ml creatinine clearance) compared with normals (1.0 pg/ml creatinine clearance), chronic renal failure (3.2 pg/ml creatinine clearance), decompensated liver disease (ascites 7.7 pg/ml creatinine clearance, and severe hepatocellular dysfunction 11.0 pg/ml creatinine clearance), and compensated liver disease (1.9 pg/ml creatinine clearance). To interpret the significance of these findings, we determined renal clearance and endogenous metabolism of the cysteinyl leukotrienes by infusion of [3H]leukotriene C4 into a single subject with hepato-renal syndrome and two control subjects. Renal clearance of leukotriene E4, was reduced in hepatorenal syndrome (2.4 ml/min) compared with controls (greater than 17 ml/min) which together with the increased excretion rate of leukotriene E4 demonstrates that there is increased cysteinyl leukotriene production in hepatorenal syndrome. This may be one of the factors involved in its pathogenesis.
Adolescent↗
Autoradiographic localization of atrial natriuretic peptide receptor subtypes in rat kidney.
The distribution of atrial natriuretic peptide (ANP) clearance receptors in rat kidney was investigated by in vitro autoradiography using des[Gln18,Ser19,Gly20,Leu21,Gly22]-ANP-(4- 23) (C-ANP) and 125I-Tyr0-ANP-(5-25) as relatively specific ligands of this receptor. Alpha-125I-ANP (100 pM) bound reversibly but with high affinity to glomeruli, outer medullary vasa recta bundles, and inner medulla. C-ANP (10 microM) inhibited greater than 60% of this glomerular binding but did not inhibit the binding of alpha-125I-ANP to medullary tissues. Alpha-125I-ANP also bound reversibly to the renal arteries up to the glomerulus. This arterial binding was only partly inhibited by 10 microM C-ANP. In the presence of 10 microM C-ANP, increasing concentrations of alpha-125I-ANP bound to a residue of glomerular sites with apparent dissociation constants of 0.82 +/- 0.16 to 2.73 +/- 1.20 nM at different cortical levels. 125I-Tyr0-ANP-(5-25) bound significantly to glomeruli and intrarenal arteries but not to vasa recta bundles or inner medulla. This glomerular binding also occurred with nanomolar dissociation constants. It was completely inhibited by 1 microM alpha-ANP and 10 microM C-ANP, but not by unrelated peptides such as gastrin. These results suggest that renal ANP clearance receptors are restricted in vivo to the glomeruli and renal arterial system of the rat.
Animals↗
Urinary N tau-methylimidazole acetic acid excretion in respiratory disease.
N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.
Adult↗