Biomedical subjects

R A Robson

Publications and source records attributed to R A Robson.

At least 55 records · Page 3Linked to original sources

PubMed1993

Hemorheology and fistula function in home hemodialysis patients following erythropoietin treatment: a prospective placebo-controlled study.

The beneficial effect of correcting anemia in end stage renal failure using recombinant human erythropoietin (rHuEPO) is sometimes complicated by thrombosis of the arteriovenous fistula. This placebo-controlled study investigated the relationship between hemorheological changes caused by rHuEPO and alterations in fistula function and heparin requirements in home hemodialysis patients. Erythropoietin induced a rise in high shear rate blood viscosity, a determinant of blood flow in large vessels. Doppler assessment of brachial artery blood flows, tests of fistula function and heparin requirements were similar in the two patient groups. These findings indicate that rHuEPO treatment of renal anemia resulted in the expected rise in red blood cell mass and blood viscosity although these changes did not cause problems with arteriovenous access or alter fistula function in the short term.

Adult↗

PubMed1992

Membranous nephropathy: a 19 year prospective study in 51 patients.

AIM: to study prospectively patients presenting with membranous nephropathy. METHODS: the outcome of 51 patients (33 male; mean age 50.8 SD 17.7 years; 49 caucasian, two Maori), aged 14 years and over, with membranous nephropathy was studied prospectively. The patients were enrolled between 1 July 1972 and 30 June 1991. Patients with systemic lupus erythematosus were excluded. Membranous nephropathy was secondary to drug therapy in eight (gold 3, nonsteroidal antiinflammatory drug 3, penicillamine 1, captopril 1). All patients were hepatitis B surface antigen negative. The majority of patients did not receive immunosuppressive therapy. RESULTS: forty-seven (92%) presented with the nephrotic syndrome, eight (16%) with a plasma creatinine > or = 0.15 mmol/L and 28 (55%) with hypertension. The patients were followed for a mean of 5.4 years, the median being 3.9 years and range four months-19 years. The 10 year cumulative renal survival was estimated to be 78% and overall survival 66%. Six patients have entered a renal replacement programme and six have died of nonrenal causes. Of the remaining 39, eight have renal insufficiency, 27 hypertension and 22 proteinuria. Complete remission occurred in 17 (33%)-11 spontaneously, four following withdrawal of the offending drug and two after immunosuppressive therapy. Poor prognostic indicators at presentation included renal insufficiency, need for antihypertensive therapy, pathological stage IV on renal biopsy and older age. CONCLUSIONS: membranous nephropathy is an indolent disease with a good chance of spontaneous remission. In most patients immunosuppressive treatment appears unwarranted.

Adolescent↗

PubMed1992

A comparison of efficacy and tolerance of the short acting sedatives midazolam and zopiclone.

AIMS: To compare the efficacy and tolerance of midazolam, 15 mg and zopiclone 7.5 mg once daily for seven days in a prospective, double blind trial of 88 patients, aged 18 or over, with sleep disorders in general practice. METHODS: Efficacy was evaluated using the Leeds sleep evaluation questionnaire (LSEQ). Adverse reactions were recorded as volunteered. RESULTS: fifty-one patients completed all aspects of the trial without violation of the protocol. Patients taking zopiclone improved in all aspects of the Leeds questionnaire (p < 0.01). Patients taking midazolam improved in six out of 10 items (p < 0.01). Rebound insomnia was evident in the zopiclone group in five out of 10 items of the LSEQ. Rebound was not evident in the midazolam group. There were no significant differences between midazolam 15 mg, and zopiclone 7.5 mg, in comparison between groups. Thirty-eight patients suffered 49 adverse drug reactions and there were no differences between the groups. CONCLUSIONS: Zopiclone 7.5 mg daily improved more items on the LSEQ than midazolam 15 mg daily but was associated with significant rebound insomnia. Adverse reactions were frequent with both drugs.

Adolescent↗

PubMed1992

The effects of quinolones on xanthine pharmacokinetics.

Caffeine, theobromine, and theophylline are among the most widely consumed compounds in beverages and in pharmaceutical preparations. These methylxanthine alkaloids are metabolized by similar pathways involving demethylation and hydroxylation that are predominantly cytochrome P-450 mediated. In vivo and in vitro evidence suggests that the cytochrome P-450 isozymes involved in the demethylation pathways are distinct from the cytochrome P-450 isozymes involved in the hydroxylation pathways. Although distinctions can be made between demethylation and hydroxylation pathways, the evidence suggests that these different cytochrome P-450 isozymes are under common regulatory control. Any drug inhibiting the family of cytochrome P-450 isozymes involved in the metabolism of the methylxanthines would, therefore, be expected to have a similar effect on theophylline, theobromine, and caffeine. A number of quinolones, including enoxacin, pipemidic acid, ciprofloxacin, norfloxacin, and pefloxacin, have been shown to reduce the clearance of theophylline, while lomefloxacin has no effect on theophylline or caffeine clearance. It has been hypothesized that only fluoroquinolones that form a 4-oxo-metabolite inhibit theophylline clearance. Lomefloxacin, which does not form a 4-oxo-metabolite, would therefore not be expected to inhibit the clearance of theophylline or caffeine. In contrast, ciprofloxacin, which does form a 4-oxo-metabolite, has been shown to reduce theophylline and caffeine clearances by about one third. Another hypothesis for the differences among quinolones suggests that quinolones that have a greater impact on theophylline clearances are more stereochemically similar to theophylline. Substitutions at position 8 on the quinolone nucleus (as in lomefloxacin) would result in stearic hindrance and decrease the structural similarity to theophylline.

4-Quinolones↗

PubMed1992

Comparison of ciprofloxacin with netilmicin for the treatment of acute pyelonephritis.

A prospective, randomised trial was undertaken to compare the efficacy of ciprofloxacin and netilmicin for the treatment of acute pyelonephritis. Forty-three patients were enrolled and 34 (29 women) completed the protocol. Fifteen of 17 patients treated with ciprofloxacin and 15 of 17 treated with netilmicin were cured. All patients were treated for five days. One patient relapsed after ciprofloxacin and another had a reinfection, while two relapsed after netilmicin. Five of six patients with a urinary tract abnormality were cured. Side effects were generally mild and rapidly reversible. Patients treated with ciprofloxacin spent a mean of 3.7 days in hospital compared with 5.3 days for those treated with netilmicin. The difference in duration of hospital stay was statistically significant (p less than 0.01). Both drugs proved highly effective and safe for the treatment of severe acute pyelonephritis.

Acute Disease↗

PubMed1992

The effect of celiprolol on glomerular filtration rate and renal blood flow in patients with chronic renal impairment and healthy volunteers.

A double-blind, placebo controlled study investigated the effects of celiprolol, 200 mg daily for 7 days, on glomerular filtration rate (GFR) and estimated renal blood flow (ERBF) in eight healthy volunteers and eight patients with chronic renal insufficiency. In healthy volunteers the mean difference in GFR was 4.8 ml min-1 (95% CI -8.2 to 17.7 ml min-1) and the mean difference in ERBF was 49.8 ml min-1 (95% CI -47.5 to 147 ml min-1) after celiprolol. In patients with chronic renal insufficiency the mean difference in GFR was -2.1 ml min-1 (95% CI -64.6 to 65.8 ml min-1). The study had sufficient power to detect a 15% change in GFR for normals and 10% for patients, and for ERBF, changes of 14% and 23% were detectable. Celiprolol at a dose of 200 mg daily for 7 days can be used in patients with chronic renal insufficiency without adversely affecting GFR or ERBF.

Adolescent↗

PubMed1991

Long term complications following renal transplantation.

The long term complications of renal transplantation were assessed in 36 patients who had lived for 10 or more years with a functioning renal transplant. Thirty-three patients were alive with a mean plasma creatinine of 0.13 mmol/L (SD 0.07). A 62 year old women died from a myocardial infarction 11 years after transplantation and two women developed chronic rejection and returned to dialysis after 17 years. Nineteen patients have required antihypertensive therapy, five have suffered ischaemic heart disease and two a cerebrovascular event. Malignancy has developed in 13 patients, with four having two or more organs involved. Skin cancers (9 squamous cell, 4 basal cell) were present in all 13 patients and recurred in six. The other malignancies included carcinoma of cervix (2), cervix and bladder (1) and thyroid (1). Three patients have required parathyroidectomy for autonomous hyperparathyroidism, two splenectomy for hypersplenism, and one bilateral hip replacement for avascular necrosis of the femoral heads. The development of hypertension, vascular disease and malignancy are the most important long term complications after renal transplantation. Strategies must be formulated to reduce the morbidity and mortality from these causes.

Adult↗

PubMed1991

Antimicrobial effects of lomefloxacin in vitro.

The MIC of lomefloxacin was determined for 554 isolates from the urinary tract. Some of the more resistant strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa were studied in a dynamic in-vitro model in order to study dosing strategies. The model simulated, in Mueller-Hinton broth, the profile of plasma lomefloxacin concentrations in volunteers. Bacteria were exposed to a range of lomefloxacin concentration profiles achievable by oral dosing. The first dose of lomefloxacin was rapidly bactericidal in a dose-dependent manner for all strains. On re-exposure, a dose-dependent inhibitory effect was observed. Drug-resistant mutants were readily isolated from all bacteria tested on lomefloxacin-containing plates. These occurred at a high frequency in P. aeruginosa (10(-1)), but less frequently in K. pneumoniae (10(-3)). P. mirabilis (10(-5)), and E. coli (10(-6)). The number of resistant mutants isolated tended to be lower with use of higher drug concentrations. The results suggest that lomefloxacin dosing regimens ensuring maintenance of a high serum concentration: MIC ratio will result in maximal antibacterial effects and minimal problems with resistant strains.

4-Quinolones↗

PubMed1990

Wegener's granulomatosis with renal involvement: a 14 year experience.

Over a 14 year period 17 patients (nine men) with Wegener's granulomatosis and renal involvement had a renal biopsy. All patients had a necrotising glomerulonephritis and 15 had evidence of crescent formation in glomeruli. Fourteen patients were treated with both prednisone and cyclophosphamide and three with prednisone and azathioprine. The five year patient survival rate was 73% and the renal survival rate 68%.

Adult↗

PubMed1990

Single oral dose pharmacokinetics of erythromycin and roxithromycin and the effects of chronic dosing.

Roxithromycin is a semisynthetic macrolide antibiotic having similar in vitro antibacterial profile and potency to erythromycin but possibly greater in vivo potency. The single and multiple oral dose pharmacokinetics of roxithromycin and erythromycin were studied in 12 healthy volunteers. Plasma concentrations of the two compounds were measured by a sensitive and specific high-performance liquid chromatographic method using electrochemical detection. After single doses, roxithromycin 150 mg gave a Cmax 3.3-fold higher and an area under the curve (AUC) 16.2-fold higher than erythromycin 250 mg. The half-life for roxithromycin was 12.42 +/- 3.94 h compared with 1.53 +/- 0.42 h for erythromycin. On multiple dosing, the AUC over a dosing interval for erythromycin (250 mg, six hourly doses) was increased 2.3-fold compared with the single dose, whereas that for roxithromycin (150 mg, 12 hourly) was decreased by 25.4%. Because of these opposing changes during chronic dosing, the average plasma roxithromycin concentration over the dosing interval was 2.6-fold higher than that for erythromycin, which was a smaller excess than would have been predicted from the single dose data. The results suggest that roxithromycin exerts less inducing and inhibiting effects on human cytochrome P450 than erythromycin. Roxithromycin has a favorable pharmacokinetic profile suitable for twice daily dosing and may have a lower potential than erythromycin for cytochrome P450-mediated drug interactions.

Adolescent↗

PubMed1990

Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline.

Nine healthy male volunteers were studied to assess the interaction between theophylline and ciprofloxacin and to assess whether a similar interaction occurred with lomefloxacin, using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without lomefloxacin 400 mg 12 hourly or ciprofloxacin 500 mg 12 hourly for 7 days. Ciprofloxacin treatment lowered total theophylline clearance by 27%, owing to a decreased clearance via 1-, 3-demethylation and 8-hydroxylation. Lomefloxacin treatment did not alter theophylline clearance. Ciprofloxacin, at usual clinical doses, could cause a clinically significant interaction when co-administered with theophylline.

Adult↗

PubMed1990

The pharmacokinetics and pharmacodynamics of quinapril and quinaprilat in renal impairment.

1. The pharmacokinetics and pharmacodynamics of quinapril and its active metabolite quinaprilat were studied in 20 subjects with renal function varying from normal to severe renal failure, during the approach to and at steady-state, and for 72 h after cessation of quinapril 20 mg orally for 7 days. 2. The apparent oral plasma clearance of quinaprilat (dose of quinapril equivalent/AUC of quinaprilat) was directly related to creatinine clearance (CLCr). The predicted apparent oral clearance of quinaprilat was zero when CLCr was zero, suggesting minimal extrarenal elimination. 3. Peak and trough concentrations of quinaprilat, and its apparent elimination half-life, varied inversely with CLCr. 4. Trough concentrations of quinaprilat showed no accumulation between 2 and 7 days, even in severe renal impairment. 5. There was a weak relationship between the oral plasma clearance of quinapril and CLCr. 6. ACE inhibition was marked and prolonged in all subjects, with 50% inhibition at 2.7 +/- 1.9% ng ml-1 of quinaprilat. The time for which ACE inhibition was greater than 90% was related inversely to CLCr. 7. Aldosterone concentrations and plasma renin activity responded in a predictable way, but with no clear relationship To CLCr. 8. Atrial natriuretic peptide concentrations were not affected by quinapril administration. 9. Glomerular filtration rate, as measured by Tc99mDTPA clearance, was not affected by quinapril administration. 10. Blood pressure at steady-state decreased significantly in the subjects with hypertension. The changes in blood pressure were not related to renal function. 11. These results suggest that the dosage rate of quinapril may have to be altered in renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed1990

Disseminated prostatic carcinoma presenting with acute interstitial nephritis and microangiopathic haemolytic anaemia.

A 74-year-old man with metastatic prostatic carcinoma developed acute oliguric renal failure, a microangiopathic haemolytic anaemia and thrombocytopaenia. A renal biopsy showed an acute interstitial nephritis but no changes suggestive of the haemolytic uraemic syndrome. He recovered normal renal function after treatment with haemodialysis and prednisone 20 mg daily for five days. Previous assumptions about the renal lesion in patients with malignancy-associated microangiopathic haemolytic anaemia may need review.

Acute Disease↗

PubMed1990

Anemia and angiotensin-converting enzyme inhibition in renal transplant recipients.

The renin-angiotensin system has been shown to have an effect on erythropoietin synthesis and hemoglobin concentration. We present a retrospective study of stable renal transplant recipients who received an angiotensin-converting enzyme (ACE) inhibitor as treatment of hypertension. Fifteen patients were eligible, with a mean hemoglobin concentration of 130.7 +/- 22.7 g/L (SD). Within 6 months of ACE-inhibitor therapy, the mean hemoglobin had fallen significantly to 110.5 +/- 23.2 g/L (p less than 0.001). No parallel change in leukocyte or platelet counts was evident. Prospective studies are needed to clarify the effect of inhibition of the renin-angiotensin system on erythropoietin synthesis and release.

Anemia↗

PubMed1989

The pharmacokinetics of angiotensin converting enzyme inhibitors in patients with renal impairment.

The clearance of drugs excreted entirely unchanged by the kidneys is assumed to relate directly to renal function. The clearance of drugs which are entirely metabolized is usually not altered in patients with renal impairment, although there are examples of both increased and decreased metabolic clearance rates. The clearance of metabolites which are excreted unchanged through the kidneys is also directly related to renal function. The angiotensin converting enzyme (ACE) inhibitors enalapril, ramipril, cilazapril and quinapril are prodrugs that are rapidly converted to active metabolites which are excreted unchanged through the kidneys. Studies have consistently demonstrated reduction in the apparent oral clearance of the active metabolites, in proportion to the degree of impairment of renal function. In addition, for quinapril at least, the metabolic clearance of the parent drug is slightly reduced in renal impairment. The activity of captopril and lisinopril lies in the parent molecule itself. Lisinopril is excreted renally unchanged, while captopril is both metabolized and excreted renally unchanged. The duration of ACE inhibition after administration of any of the ACE inhibitors is prolonged in proportion to the degree of renal impairment. From these pharmacokinetic and pharmacodynamic properties, it follows that the dose rate of the ACE inhibitors should be reduced in direct proportion to the degree of reduction in renal function. Reducing the dose, rather than prolonging the dose interval, is more logical for compliance and for maintaining a consistent degree of ACE inhibition over 24 h.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies.

Anti-human NADPH-cytochrome P-450 reductase inhibited all theophylline metabolic pathways confirming the involvement of cytochrome P-450 isozymes in the metabolism of theophylline. Tolbutamide, debrisoquine, mephenytoin, theobromine, phenylbutazone, sulphaphenazole and sulphinpyrazone did not inhibit theophylline metabolism by human liver microsomes. Verapamil and dextropropoxyphene were non-selective competitive inhibitors of theophylline metabolism. Cimetidine and caffeine selectively inhibited the two demethylations as Ki values for these two pathways were lower than for the 8-hydroxylation pathway. The effects of nifedipine, propranolol and alpha-naphthoflavone were atypical. The degree of inhibition by propranolol reached a plateau, which was greater for the two demethylations than for the 8-hydroxylation. Alpha-naphthoflavone (ANF) at low concentrations inhibited the demethylations to a greater extent than the 8-hydroxylation. At higher concentrations ANF activated all pathways, with this effect being most marked for the 8-hydroxylation. Nifedipine inhibited the theophylline demethylations but not the 8-hydroxylation. In some livers the 8-hydroxylation was markedly activated. The results confirm that there are at least two distinct cytochrome P-450 isozymes involved in theophylline metabolism, one isozyme being involved with the demethylations and a different isozyme involved in the 8-hydroxylation pathway. Preliminary correlation studies suggest that the human orthologue to the rabbit polycyclic hydrocarbon inducible P-450 Form 4 may be involved in the N-demethylations of theophylline.

Adult↗

PubMed1988

Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations.

Tolbutamide hydroxylation has been investigated in human liver microsomes. Anti-human liver NADPH-cytochrome P-450 reductase IgG inhibited hydroxytolbutamide formation and this metabolite was not formed when NADPH-generating system was omitted from microsomal incubations. Tolbutamide hydroxylation followed Michaelis-Menten kinetics, consistent with the involvement of a single form of cytochrome P-450 in this reaction. Mean apparent Km and Vmax values for hydroxytolbutamide formation were 120 +/- 41 microM and 0.273 +/- 0.066 nmol min-1 mg-1, respectively. A range of clinically used drugs and xenobiotics used as probes for cytochrome P-450 activity in laboratory animals was screened for inhibitory effects on hydroxytolbutamide formation. Caffeine, paraxanthine, theophylline, theobromine, debrisoquine, erythromycin, phenacetin, propranolol, aminopyrine, benzo(a)pyrene and 7-ethoxycoumarin were all found not to inhibit tolbutamide hydroxylation. In contrast, sulphaphenazole, phenylbutazone, nifedipine, verapamil, cimetidine, aniline, dextropropoxyphene and mephenytoin were competitive inhibitors of tolbutamide hydroxylation. The respective apparent Ki values for these compounds were 0.12 microM, 11 microM, 15 microM, 118 microM, 140 microM, 182 microM, 225 microM and 375 microM. Sulphinpyrazone inhibited tolbutamide hydroxylation with atypical kinetics. The in vitro data is in good agreement with in vivo drug interactions with tolbutamide. The data also confirm that tolbutamide hydroxylation is not associated with the cytochromes P-450 responsible for methylxanthine metabolism or with the form responsible for the polymorphic oxidation of debrisoquine.

Cytochrome P-450 Enzyme System↗

PubMed1988

Comparison of paracetamol metabolism in young adult and elderly males.

Paracetamol metabolism was compared in groups of young adult (mean age 20.8 years) and elderly (mean 79.3 years) males. Apparent oral clearance and half-life and partial metabolic clearances to the glucuronide and glutathione-derived conjugates of paracetamol were not significantly different between the two groups. However, the partial metabolic clearance to paracetamol sulphate was 23.1% lower and renal clearance of unchanged drug was 42.9% lower in the elderly compared to the young adults. Despite the decreased clearance by these pathways, reduction in paracetamol dosage should not be necessary in the elderly.

Acetaminophen↗