Christopher James

Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry.

We studied the variability in doxorubicin pharmacokinetics in 27 patients, all of whom had normal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography (HPLC). The relationship of doxorubicin clearance (dose/AUC) with biochemical tests (AST, bilirubin, alkaline phosphatase, albumin, creatinine) and physical characteristics (age, gender, height, weight, tumour type) was investigated. The 6 men had a significantly higher doxorubicin clearance than did the 21 women (median values, 59 and 27 lh−1 m−2, respectively;P=0.002). Doxorubicin clearance was significantly lower in patients with breast cancer than in those with other tumours (median values, 26 and 53 lh−1 m−2, respectively;P=0.0008). The other biochemical and physical parameters did not correlate with doxorubicin clearance. However, in multivariate analysis, gender was the only factor predicting doxorubicin clearance (r2=40%). The ratio of the AUCs for doxorubicinol and doxorubicin (R) was higher in the men than in the women (median values, 0.62 and 0.36, respectively;P=0.03). We conclude that gender may be an important determinant of doxorubicin clearance in patients with normal liver biochemistry.

Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests

We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests (AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not be optimal.

Biliary elimination of cyclophosphamide in man

SummaryA 72-year-old male with a lymphoma and obstructive jaundice received 900 mg cyclophosphamide IV as a part of a chemotherapeutic regimen whilst external biliary drainage was in progress. Plasma, urinary, and biliary pharmacokinetics of cyclophosphamide and nitrobenzylpyridine (NBP)-alkylating metabolites were studied. In 32 h 891 ml bile was collected, and this contained unchanged cyclophosphamide and NBP-alkylating material. Despite fluctuations in biliary flow, estimates of the half-life of cyclophosphamide from plasma, urine, and bile were similar. Good correlation existed between plasma and biliary cyclophosphamide concentrations after the initial plasma had been completed. The ratio of bile to plasma concentrations was 0.7 and showed no time dependence, as evidenced by a lack of hysteresis in the correlation curve. Of the administered dose, 3.5% was excreted as unchanged cyclophosphamide in the bile over 32 h. NBP-alkylating activity was found in bile up to 25 h but not after this time, despite the presence of unchanged cyclophosphamide in plasma. NBP-alkylating material was not found in the bile when it could not be detected in plasma, and vice versa.

The influence of cimetidine on debrisoquine 4-hydroxylation in extensive metabolizers.

SummaryWe have studied the effect of cimetidine (800 mg·day−1) administration for three days on debrisoquine 4-hydroxylation in nine healthy extensive metabolizers.The debrisoquine metabolic ratio was significantly increased (p<0.01), but the new ratios remained in the extensive metabolizer range (<12.6).These data suggest that pre-treatment with cimetidine in usual therapeutic doses will impair debrisoquine 4-hydroxylation, but not enough to alter the apparent oxidation phenotype.

Ifosfamide plasma clearance in relation to polymorphic debrisoquine oxidation

SummaryIfosfamide (IF) pharmacokinetics and the plasma (NBP)-alkylating activity were determined in 33 patients with different tumours after the administration of IF as single-agent chemotherapy. All subjects had been phenotyped for debrisoquine oxidation. There is a lack of correlation between the debrisoquine metabolic ratio (DMR) and either the total plasma clearance of IF (CLIF) or the AUC of the plasma NBP-alkylating activity.

Operative Surgery Vivas for the MRCS: Amputation (below knee)

What are the indications for limb amputation? Which is the commonest in the UK? Lower limb ischaemia secondary to atherosclerosis and/or diabetes is by far the commonest indication for amputation in the UK Trauma which is the commonest indication in the Third World Infection Malignancy Congenital deformity What types of lower limb amputation do you know? Hip disarticulation or hindquarter amputation Transfemoral or above knee amputation (AKA) Through knee amputation Transtibial or below knee amputation (BKA) Through ankle or Symes amputation Partial foot amputations What pre-operative measures should be taken? This is an entirely multidisciplinary process. All the members of the team (physiotherapy, occupational therapy (OT), rehabilitation specialist, prosthetic specialist, nursing staff, psychologists as well as the surgeon) must be involved and if possible meet the patient prior to surgery. The level of amputation must be decided upon. This depends on the patients “rehabilitation potential”, degree of tissue compromise, and severity and pattern of the vascular disease. Finally a careful anaesthetic assessment is made, bearing in mind that these patients may have atherosclerosis affecting their renal, coronary and cerebral vasculture as well as other co-morbid factors such as hypertension and diabetes. They may even be heavy smokers with associated pulmonary compromise. Name two common techniques used for a BKA Long posterior flap (the Burgess and Romano technique) Skew flap How do you perform a BKA? Position This is supine with the affected leg in a knee-flexed position.

Operative Surgery Vivas for the MRCS: Frontmatter

This is a comprehensive study manual for the operative surgery section of the MRCS examination. This unique text is set to the level of a basic surgical examination and the material is discussed in easy to access, simple and informative manner. The A–Z format means topics appear at random, mirroring the nature of the examination. For each operative procedure the basic principles, applied anatomy, indications and complications are discussed alongside an overview of technique. Frequently asked examination questions and practical tips for giving the fullest answer for the most marks are also included. Care has been taken to ensure compatibility with all UK syllabuses, and inclusion of material required for equivalent examinations internationally. This manual is an excellent source of information for use during personal study and self-testing, and as a teaching aid.

Operative Surgery Vivas for the MRCS: Contents

This is a comprehensive study manual for the operative surgery section of the MRCS examination. This unique text is set to the level of a basic surgical examination and the material is discussed in easy to access, simple and informative manner. The A–Z format means topics appear at random, mirroring the nature of the examination. For each operative procedure the basic principles, applied anatomy, indications and complications are discussed alongside an overview of technique. Frequently asked examination questions and practical tips for giving the fullest answer for the most marks are also included. Care has been taken to ensure compatibility with all UK syllabuses, and inclusion of material required for equivalent examinations internationally. This manual is an excellent source of information for use during personal study and self-testing, and as a teaching aid.

Operative Surgery Vivas for the MRCS

This is a comprehensive study manual for the operative surgery section of the MRCS examination. This unique text is set to the level of a basic surgical examination and the material is discussed in easy to access, simple and informative manner. The A–Z format means topics appear at random, mirroring the nature of the examination. For each operative procedure the basic principles, applied anatomy, indications and complications are discussed alongside an overview of technique. Frequently asked examination questions and practical tips for giving the fullest answer for the most marks are also included. Care has been taken to ensure compatibility with all UK syllabuses, and inclusion of material required for equivalent examinations internationally. This manual is an excellent source of information for use during personal study and self-testing, and as a teaching aid.