Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids

In an effort to determine the structural requirements for the significant antileukemic, cytotoxic, antitubulin, and antimitotic activity exhibited by the novel ansa macrolide, maytansine (1), four new C-3 ester and six new C-9 ether homologues were synthesized. The biological activities of these compounds were assayed and compared to the activities of previously reported, naturally occurring maytansinoids. From the data, it is apparent that presence of the C-3 ester is necessary for significant activity, and variations in the ester group are not accompanied by marked changes in activity. However, elimination of the ester group, as in maytansinol (7), maysine (8), normaysine (9), and maysenine (10), results in a significant decrease in biological activity. Blockage of the C-9 carbinolamide via etherification markedly reduces antileukemic and cytotoxic activity and slightly reduces antitubulin activity but has relatively little effect on antimitotic activity against sea urchin eggs. Thus, a free carbinolamide at C-9 is advantageous for optimal activity.     

Pharmacodynamics and population pharmacokinetics of enalapril and lisinopril

The di-acid metabolite of enalapril, enalaprilat, and its lysine analogue lisinopril are potent inhibitors of angiotensin converting enzyme (ACE); they do not contain sulphydryl groups. Both drugs can be assayed by high pressure liquid chromatography and by radioimmunoassay and plasma ACE inhibition remains stable under normal storage conditions. It is therefore possible to study their pharmacokinetics as well as their pharmacodynamic effects in man. Enalaprilat and lisinopril as well as ACE activity have been measured in blood taken during the course of two studies of the effects of these drugs on blood pressure and autonomic responsiveness. A population pharmacokinetic analysis approach applied to a few concentration-time data points in each of a relatively large number of subjects provided average population parameter estimates of the absorption rate constant, volume of distribution and clearance which correspond closely with the limited published data based on conventional pharmacokinetic approaches. It also provided estimates of pharmacodynamic parameters and the concentration of the drug required to produce a 50% ACE inhibition. Population drug concentration data obtained in the course of early clinical evaluations of new drugs may provide a rational basis for dosage regimens with improved efficacy and, in particular, reduced concentration-related toxic effects.     

Clinico-pathological findings in diarrhoea-negative haemolytic uraemic syndrome

This is a retrospective, national clinico-pathological study of past and current patients with haemolytic uraemic syndrome not associated with diarrhoea (D– HUS). Thirty-four patients were analysed and notified by members of the British Association for Paediatric Nephrology in 1998–1999. There was a 2:1 excess of males. Ten presented in infancy. The aetiology included 5 patients with complement abnormalities, 2 patients with complications of pneumococcal infection, and 2 with malignancies. Parental consanguinity was noted in 6 patients. Five children died, 9 developed chronic renal failure, and 10 end-stage renal failure. Only 7 made full recoveries. With a single exception, the pathological findings were unlike the previously reported glomerular thrombosis that is characteristic of diarrhoea-associated HUS, or HUS complicating verocytotoxin-producing Escherichia coli infection. Early and late glomerulopathy could be distinguished. Arteriolar and arterial disease was observed in 8 and 7 patients, respectively. Arterial disease correlated with a poor outcome. The pathology of D– HUS is of prognostic value, but this study was not powered to identify specific aetiological/pathological correlations.This paper was written on behalf of the British Association for Paediatric Nephrology     

Delirium Tremens

The varied clinical manifestations and management of 14 male patients with delirium tremens (DT) have been studied. Eight patients were initially hospitalised for diseases unrelated to ethanol abuse i.e. 2 each for gun shot wound, myocardial infarction and stroke, and one each for pneumonia and gastroenteritis. One patient was going through withdrawal because of prodrome of viral hepatitis before he was hospitalised for uncontrolled agitation and delirium. Two known cases of mild essential hypertension on dietary therapy reported for agitation, abnormal behaviour, a single episode of tonic clonic seizure and hypertensive encephalopathy as they could not/did not get alcohol for 3 days. Three patients presented denovo with DT without concomitant illness. The other features besides delirium and hallucinations were tremulousness in 10, tachycardia in 12, fever in 3, diaphoresis in 2 and tonic clonic seizures in 4 patients. The symptoms fluctuated markedly at short intervals and 2 patients did not have any features of sympathetic overactivity. Altered hepatic biochemical parameters and ketonuria with normal blood sugar were noted in 4 and one patients respectively. Other biochemical parameters including serum electrolytes were normal. CT scan brain done for 5 patients revealed subdural haematoma in one. Cerebro spinal fluid (CSF) and EEG findings were noncontributory. All made good recovery with heavy doses of intravenous vitamin B complex, glucose and oral benzodiazepine. Short course of haloperidol was used in 2 patients. Two patients developed pancreatitis during follow up. All patients made complete recovery, and 8 patients have been followed for 8 to 12 months without relapse. The reason for hospitalisation in such cases is often unrelated to alcohol abuse; hence a detailed history of alcoholism is mandatory to identify those at risk as well as for prompt treatment and decreasing the mortality.Key Words: Alcohol withdrawal, Concomitant illnesses, Delirium, Precipitating events     

Portfolio assessment in medical students' final examinations

The introduction of an outcome-based approach to education at Dundee Medical School in Scotland instigated a search for assessment methods that would appropriately assess the students' achievements in terms of the learning outcomes. Portfolio assessment has been developed for this purpose and has been adopted for the summative assessment of students in their final examination in Dundee. The contents of the portfolio and the assessment process have been defined and the first cohort of students to be assessed in this way has been studied. The evaluation of the approach demonstrated strong staff support. Students were also positive although with some reservations. It is concluded that portfolio assessment is a powerful approach to assessing a range of curriculum outcomes not easily assessed by other methods and is worthy of inclusion in the assessor's toolkit.     

Should the pre-sedation Glasgow Coma Scale value be used when calculating Acute Physiology and Chronic Health Evaluation scores for sedated patients? Scottish Intensive Care Society Audit Group

OBJECTIVE: To assess the effect on the performance of Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III of two different approaches to scoring the Glasgow Coma Scale (GCS) in sedated patients. The first approach was to assume that the GCS score was normal, and the second was to use the GCS value recorded before the patient was sedated. DESIGN: Prospective cohort study over 2 yrs. SETTING: Twenty-two general adult intensive care units in Scotland. PATIENTS: 13,291 consecutive admissions to the participating intensive care units. MEASUREMENTS AND MAIN RESULTS: After exclusion of patients according to standard, predefined criteria, the Acute Physiology and Chronic Health Evaluation II and III systems were used to calculate the probability of hospital mortality for patients included in the study. In patients whose GCS scores could not be assessed accurately during the first 24 hrs, the APACHE II and III predictions were calculated twice: first, assuming that the GCS score was normal; and second, substituting the GCS score recorded before sedation. This generated two different databases for each system, and the predictions for both were compared with the observed hospital mortality rate. The effect of the two different approaches to the GCS on the performance of both APACHE II and APACHE III was assessed using measures of discrimination (area under the receiver operating characteristic curve) and goodness of fit (calibration curves and the Hosmer-Lemeshow statistic). Analysis was undertaken for both the entire cohort and for the group of patients whose APACHE scores were altered. There was a wide variation in the number of patients who had their scores altered between participating units. There were also differences between diagnostic groups. Overall, however, 50% of the patients were sedated and 22% had their scores altered. Using the presedation GCS score increased the discrimination of both APACHE II and APACHE III. The calibration of APACHE III was also improved but that of APACHE II deteriorated. The calibration improved, however, in those patients with altered scores, suggesting that the overall deterioration is attributable to other limitations in the fit of the model to these data. Although changes had the greatest effect in patients with a neurologic or trauma diagnosis, the changes were important in most diagnostic groups. CONCLUSIONS: The GCS is an important component of both APACHE II and APACHE III. It should be assessed directly whenever possible. When patients are sedated, using the GCS score recorded before sedation is preferable to the assumption of normality. The variations between different units and different diagnostic groups highlight the possible effects of case mix on the performance of prognostic scoring systems.