Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.     

Preteen children and illegal drugs

In this paper we report the results of research on the nature and extent of legal and illegal drug use among preteens and those factors associated with illegal drug use at this young age. The paper is based upon a survey of 2318 ten to twelve year olds in Glasgow and Newcastle. Overall around 30% of children reported having been exposed to illegal drugs and 3.9% had started to use illegal drugs. There was a significant difference in the level of illegal drug use between our two cities. In most cases the illegal drug use identified on the part of preteens related to cannabis although in a small number of instances children were using heroin, cocaine and LSD. On the basis of this research we estimate that around 60 children in the ten to twelve age range will have used heroin in Glasgow and around 34 pupils will have used the drug in Newcastle. Preteen drug use was significantly associated with frequent smoking and alcohol consumption, with preteens' involvement in a range of problem behaviours, and with family difficulties including the presence of someone else within the family using illegal drugs. The paper concludes by noting some of the challenges that are likely to be faced by services seeking to support children who are using illegal drugs by their preteens.     

The need for pharmaceutical care in the prevention of coronary heart disease: an exploratory study in acute myocardial infarction patients

AIM: To determine guideline-related pharmaceutical care issues for the prevention of coronary heart disease in hospitalised patients admitted for myocardial infarction (MI). METHODS: Consecutive patients admitted with a diagnosis of Q-wave MI to two large teaching hospitals were studied. Relevant patient medical and drug histories, co-morbidities and total cholesterol concentrations were recorded. Primary or secondary prevention treatment prior to admission was assessed using a data collection tool of 16 criteria developed from the Scottish Intercollegiate Guidelines Network (SIGN) guidelines. MAIN OUTCOME MEASURES: Frequency of adherence to defined clinical guideline criteria. RESULTS: There were 167 patients reviewed (mean age 65 years, 111 males), representing possible candidates for primary prevention (n = 98) or secondary prevention (n = 69) based on absence or presence of past history of coronary heart disease (CHD), respectively. Possible primary prevention candidates: eight guideline-based criteria were developed from the SIGN guideline. There were 85 (87%) patients with a total cholesterol concentration available on admission of whom 56 (66%) had a predicted CHD risk > or = 15% and 10 (12%) had CHD risk > or = 30%. Of those with CHD risk > or = 15% 6 (11%) had been receiving an anti-platelet agent and of those with CHD risk > or = 30% only 1 (10%) was recorded as taking a statin. Of known hypertensives with CHD risk > or = 15%, 21% (5/24) were not recorded as having received treatment. Secondary prevention candidates: a further eight guideline-based criteria were developed from the SIGN guidelines. There were 42/65 (65%) candidates for aspirin documented as receiving it. There were 22/47 (47%) of those who had a total cholesterol > or = 5 mmol/l and/or known history of hypercholesterolaemia receiving a statin (representing 76% of the known hypercholesterolaemic patients identified in the community). Of statin-treated patients with a cholesterol measured on admission, 44% (7/16) had cholesterol remaining > or = 5 mmol/l. Beta-blocker use was 27/62 (44%) and ACE inhibitors use was 11/31 (36%) of those eligible. Sublingual GTN was recorded in 36/69 (52%). CONCLUSION: The study has identified opportunities for improved pharmaceutical care in primary and secondary CHD prevention among those destined to suffer an MI. Candidates for secondary prevention are potentially identifiable from community pharmacy patient medication records from which the contribution of pharmacists in primary care might be targeted. The findings were obtained during a period of evolution of the evidence-base and so they establish a baseline for future work.     

The natural history of clinically unrecognized anal sphincter tears over 10 years after first vaginal delivery

OBJECTIVE: To estimate the influence of clinically unrecognized anal sphincter injuries detected by endoanal ultrasonography 3 months after first vaginal delivery on symptoms of anal incontinence over the subsequent 10-year period. METHODS: One-hundred fifty-six consecutive primigravid women were recruited, anal endosonography performed, and bowel habit predelivery characterized by means of a validated 24-point questionnaire. After excluding four women with a clinically recognized sphincter tear after delivery and 18 who delivered by cesarean, these procedures were repeated 3 months postpartum. The questionnaire was repeated at 5 and 10 years to estimate continence change over the decade after delivery. Logistic regression was used to examine the effect of clinically unrecognized sphincter tears on continence. RESULTS: After delivery, continence deteriorated from baseline in 37 (28%) women, eight of whom had anal sphincter tears. Continence did not deteriorate in 97 women, six of whom had anal sphincter tears. At 10 years, 59 (55%) of 107 contactable women had continence scores greater than zero, 23 of whom had deteriorated from baseline. There was a significant relationship between a sphincter tear that was symptomatic after delivery and continence deterioration sustained at 5 and 10 years (odds ratio 2.8 for change in continence score). However, no relationship was found over 10 years for those women who sustained a sphincter tear but whose continence did not deteriorate postpartum. CONCLUSION: Ultrasonographic anal sphincter defects without postpartum incontinence are not associated with deterioration in continence over the following decade. LEVEL OF EVIDENCE: II.     

Season modifies the relationship between bone and blood lead levels: the Normative Aging Study

Bone serves as a repository for 75% and 90-95% of lead in children and adults, respectively. Bone lead mobilization heightens during times of increased bone turnover, such as pregnancy, lactation, hyperthyroidism, and the rapid growth of childhood. Blood lead levels show seasonal periodicity. Children demonstrate peak blood lead levels in mid-summer and a secondary peak in late winter. Pregnant women demonstrate the highest mean blood lead levels in winter (January-March) and the lowest in summer (July-September). This fluctuation in blood lead levels may be related to seasonal patterns of environmental exposures, but it may also be partially related to the increased mobilization of bone lead stores during the winter months. We performed bone lead measurements using a K-x-ray fluorescent instrument to determine micrograms of lead per gram of bone mineral (parts per million) in middle-aged and elderly men who participated in the Normative Aging Study. We obtained measurements of blood and bone lead during the high sun exposure months of May-August (summer; n = 290); the intermediate sun exposure months of March, April, September, and October (spring/fall; n = 283); and the low sun exposure months of November-February (winter; n = 191). Mean blood lead concentrations were 5.8 microg/dl, 6.1 microg/dl, and 6.6 microg/dl for the summer, spring/fall, and winter, respectively. Mean patella (trabecular bone) lead concentrations were 34.3 microg/gm, 29.7 microg/gm, and 29.0 microg/gm for the summer, spring/fall, and winter time periods, respectively. In multivariate regression models, adjusted for age, smoking, alcohol ingestion, and dietary intake of iron and vitamin C, the authors found a strong interaction between season and bone lead level--with bone lead levels exerting an almost 2-fold greater influence on blood levels during the winter months than the summer months. The authors concluded that elevated blood lead levels in winter may be related to increased mobilization of endogenous bone lead stores, potentially from decreased exposure to sunlight, lower levels of activated vitamin D, and enhanced bone resorption.