Biomedical subjects
Publications and source records attributed to J R Trounce.
The previously unrecorded association of superficial bullous pyoderma and IgG-producing multiple myeloma is described. A rapid response of the cutaneous manifestations was achieved by treatment of the malignant paraproteinaemia.
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1 Prizidilol hydrochloride (SK&F 92657) is a new compound which causes both arteriolar dilatation and beta-adrenoceptor blockade. The effect of a single oral dose on the responses of heart rate and blood pressure to isoprenaline infusion has been studied in healthy volunteers. 2 Isoprenaline heart rate dose-response curves showed parallel shifts to the right after oral prizidilol, indicating antagonism by this compound at beta-adrenoceptors in the heart. 3 Isoprenaline dose-response curves for decreases in diastolic blood pressure also showed shifts to the right after oral prizidilol, providing evidence of beta-adrenoceptor antagonism by this drug in peripheral resistance vessels. 4 The peak effect of a 40 mg dose of propranolol was greater than that of a 200 mg dose of prizidilol but both drugs caused persistent beta-adrenoceptor blockade for at least 7 h after ingestion.
Isobutyloxycarbonyl derivatives of the polyamines, spermidine, spermine and putrescine in 1 ml plasma were analysed on a mixed phase, 1.5% SE-30, 0.15% FFAP, column by temperature-programmed gas chromatography using a nitrogen-sensitive glass bead detector. Levels in 60 normal subjects (mean +/- 2- S.D.) were 0.13 +/- 0.08 mumol/l for spermidine, 0.02 +/- 0.04 for spermine and less than or equal to 0.18 for putrescine. Elevated spermidine levels were found pre-treatment in only 20% of patients with advanced metastatic cancer, reflecting the lack of sensitivity of polyamines as markers for malignant disease. However, serial studies in 26 patients undergoing remission induction chemotherapy showed that a significant rise in plasma spermidine within 48 h correlated with subsequent clinical response (p less than 0.001). Tumour response to chemotherapy can be predicted by the assay of plasma polyamines.
Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0-51 ml . min-1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21 +/- 2.33 (SD) h whilst that in renal failure was 10.15 +/- 1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6 +/- 10.9 ml . kg-1h-1 which was significantly larger than in renal failure where it was 48.8 +/- 10.9 ml . kg-1h-1. Vd beta, Vdss and Vc were not significantly different between the two groups. A linear relationship exists between beta, the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t1/2 in normal patients was 8.33 +/- 2.0 h, whilst in the renal failure group it was 13.37 +/- 4.23 h. Total alkylating activity as measured by the nitrobenzyl-pyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.
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1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.
A simple gas chromatographic assay utilising alkali flame ionisation detection is described for the estimation of cyclophosphamide as its trifluoroacetate derivative from plasma. Examination of five patients following intravenous cyclophosphamide gave values of 8.9 h (SD 2.7) for the half-life and 0.061 liters/h/kg (SD 0.011) for whole-body clearance of the drug.
1. A rapid intravenous bolus injection of 4.0 g Magnapen (which contains 2.0 g of ampicillin and 2.0 g of flucloxacillin) was to seven patients undergoing total hip replacement immediatly before induction of general anesthesia. Postoperatively the patients patients received 2.0 g Magnapen by intramuscular injection every 6 h for up to 72 h until removal of the wound drains. 2. The plasma, bone, hip capsule and drain fluid concentrations of ampicillin and flucloxacillin were measured by a differential small plate microbiological assay method using Sarcina lutea and a penicillinase producing Staph. aureus Russell as the test organisms. 3. The mean +/- s.e. mean concentrations of ampicillin after this regimen were 4222.2 +/- 285.0 microgram/ml (plasma), 65.6 +/- 1.3 microgram (g (hip capsule), 19.1 +/- 3.8 microgram/g (cancellous bone), and 211.1 +/- 65.6 microgram/g (ground up bone) respectively. 4. The mean +/- s.e. mean flucloxacillin concentrations after this regime were 137.2 +/- 28.4 microgram/ml (plasma), 61.8 +/- 15.0 microgram/g (hip capsule), 47.1 +/- 9.5 microgram/g (cancellous bone) and 139.4 +/- 21.8 microgram/g (ground up bone) respectively. 5. An intravenous bolus injection of Magnepen (4.0 g), given immediately before induction of general anaesthesia, provides concentrations of ampicillin and flucloxacillin in plasma, hip capsule, cancellous and ground up bone, and drain fluid that exceed the MICs of these antibiotics against Staph. aureus and E. coli. 6. The plasma, hip capsule, cancellous and ground up bone concentrations of ampicillin after this dose of Magnapen do not, however, exceed the MICs of the Gram negative anaerobes that sometimes cause postoperative wound infections in these patients.
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