Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates.

PURPOSE: Vercirnon is a CCR9 chemokine receptor antagonist being developed for the treatment of Crohn's disease. As a variety of concomitant medications are often required for the treatment of Crohn's disease, it is important to characterise the drug interaction profile of vercirnon. To confirm the results of previous in vitro inhibition studies, this study assessed the in vivo effect of vercirnon on the activity of cytochrome P450 enzymes (CYP3A4, CYP2C19 and CYP2C8) and drug transport proteins (BCRP and OATP1B1) using probe substrates. METHODS: This was an open-label, single-sequence, repeat-dose study conducted in 24 healthy adult subjects. On days 1-4, subjects received probe substrates (midazolam, pioglitazone, omeprazole and rosuvastatin; in that order), followed by administration of vercirnon 500 mg twice daily (BID) on days 5-14. On days 11-14, in addition to vercirnon 500 mg BID, subjects also received probe substrates as on days 1-4. Blood samples were collected for pharmacokinetic analysis of probe substrates, vercirnon and two of its metabolites. RESULTS: Geometric least-squares mean ratios (90 % confidence interval) of area under the concentration-time curve from time zero to infinity for probe administered with vercirnon (test) compared with probe alone (reference) for midazolam, pioglitazone, omeprazole and rosuvastatin were 0.92 (0.85, 0.99), 1.01 (0.95, 1.07), 0.99 (0.76,1.31) and 0.98 (0.88, 1.09), respectively. CONCLUSIONS: Co-administration of probe substrates midazolam, pioglitazone, omeprazole, and rosuvastatin following repeat dosing of vercirnon 500 mg BID demonstrated vercirnon had no clinically significant effect on CYP3A4, CYP2C8, CYP2C19 enzyme activity or BCRP or OATP1B1 transporter activity.

Effectiveness of aromatherapy massage in the management of anxiety and depression in patients with cancer: a multicenter randomized controlled trial.

PURPOSE: To test the effectiveness of supplementing usual supportive care with aromatherapy massage in the management of anxiety and depression in cancer patients through a pragmatic two-arm randomized controlled trial in four United Kingdom cancer centers and a hospice. PATIENTS AND METHODS: Two hundred eighty-eight cancer patients, referred to complementary therapy services with clinical anxiety and/or depression, were allocated randomly to a course of aromatherapy massage or usual supportive care alone. RESULTS: Patients who received aromatherapy massage had no significant improvement in clinical anxiety and/or depression compared with those receiving usual care at 10 weeks postrandomization (odds ratio [OR], 1.3; 95% CI, 0.9 to 1.7; P = .1), but did at 6 weeks postrandomization (OR, 1.4; 95% CI, 1.1 to 1.9; P = .01). Patients receiving aromatherapy massage also described greater improvement in self-reported anxiety at both 6 and 10 weeks postrandomization (OR, 3.4; 95% CI, 0.2 to 6.7; P = .04 and OR, 3.4; 95% CI, 0.2 to 6.6; P = .04), respectively. CONCLUSION: Aromatherapy massage does not appear to confer benefit on cancer patients' anxiety and/or depression in the long-term, but is associated with clinically important benefit up to 2 weeks after the intervention.

Study comparing two types of screening provision for people with von Hippel-Lindau disease.

Patients diagnosed with von Hippel-Lindau disease (vHL) require life-long surveillance for this multi-system disease. It is therefore important to assess the comprehensiveness of screening provision, as well as identify what type of screening service is most likely to encourage regular patient attendance. This descriptive study reports on two types of screening service: single appointment One Stop (OS) clinics and multiple appointment Ad Hoc (AH) clinics. One hundred and seventeen vHL patients from eight regional genetics centres were approached to take part. Seventy-two (61.5%) returning a completed study questionnaire: fifty-four (75%) were screened at OS clinics and eighteen (25%) at AH clinics. Comprehensiveness of screening, attendance rates, patient ratings of quality of care and levels of psychological morbidity were compared between the two types of service. While levels of disease severity were similar in patients screened at OS and AH clinics, those seen at OS clinics were screened for twice as many site-specific vHL manifestations compared to those seen at AH clinics (P < 0.0001). More patients at OS clinics regularly attended their screening appointments compared to those at AH clinics (P = 0.0045). There was no difference in the quality of care reported by patients attending the two types of screening service and few problems were reported. Twenty-nine percent of respondents were categorised as clinically anxious and 13% as clinically depressed. These findings suggest that an optimum vHL screening service is one based on OS clinics offering regular comprehensive surveillance and psychological support.

Determinants of the rate of nicotine metabolism and effects on smoking behavior.

BACKGROUND: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. METHODS: We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. RESULTS: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). CONCLUSION: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Informed decision making and prostate specific antigen (PSA) testing for prostate cancer: a randomised controlled trial exploring the impact of a brief patient decision aid on men's knowledge, attitudes and intention to be tested.

OBJECTIVE: To examine the impact of a brief patient decision aid (pDA) on men's knowledge, attitudes and intention to have a prostate specific antigen (PSA) test. To explore the important predictors of intention to be tested in men who received the brief pDA. METHODS: A brief pDA designed to facilitate informed decision-making for men considering PSA testing was developed for the NHS Prostate Cancer Risk Management Programme. Men aged 40-75 years selected from 11 General Practices in England and Wales were randomised to receive either a mailed copy of the brief pDA and a questionnaire (intervention group), or a questionnaire alone (control group). The questionnaire assessed knowledge, attitudes, perceived risk and intention to have a PSA test and, for the intervention group, their perceptions of the brief pDA. RESULTS: Nine hundred and ninety of the men who were eligible for the study returned completed questionnaires (response rate=54%). Men who received the brief pDA had significantly higher knowledge scores (p<0.0001) and less positive attitudes (p<0.0001) regarding PSA testing than men in the control group. There was no significant difference between the two groups in intention to be tested within the next 12 months. 87% of men found the brief pDA was easy to read, 94% considered it contained about the right amount of detail and 94% felt the information was presented in a balanced way. Multivariate analysis identified perceived risk (p<0.0001), perceived benefits of PSA testing (p<0.0001), knowledge (p=0.004), attitude (p=0.007) and age (p=0.01) as the most important independent predictors of intention to be tested amongst men in the intervention group. CONCLUSION: The brief pDA was shown to dramatically increase men's knowledge of the benefits and risks of the PSA test. Men who received the brief pDA were significantly less positive about the PSA test, although there was no difference between the two groups regarding their intention to be tested within the next year. PRACTICE IMPLICATIONS: This brief pDA could serve as an acceptable and low cost adjunct to counselling by the General Practitioner (GP), and should promote informed decision making regarding the PSA test. Further research is required to ascertain the utility of the decision aid during the consultation.

Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial.

A retrospective analysis of children with first relapse of acute lymphoblastic leukaemia (ALL), treated on the UKALL R2 protocol at four different hospitals, between June 1995 and December 2002 was performed. Of the 150 children 139 (93%) achieved a second complete remission. The overall survival (OS) and event-free survival (EFS) for the whole group was 56% and 47% respectively. The duration of first complete remission and immunophenotype, but not sites of relapse, were predictive for survival. Using the Berlin-Frankfürt-Münster risk stratification for relapsed ALL, the OS and EFS for standard, intermediate (IR) and high risk (HR) groups were 92% and 92%, 64% and 51%, and 14% and 15%, respectively; P < 0.0001 for both OS and EFS. In the IR group, those with a very early isolated central nervous system relapse also had a significantly worse outcome (P = 0.0001). Given the poor outcome of a second relapse, clear strategies are required to identify those in the IR group who will most benefit from stem cell transplantation (SCT). A higher proportion (16%) of induction failures in the HR group suggest the need for novel agents during this phase of treatment, but SCT was associated with a lower relapse rate and better outcome than those treated with chemotherapy alone.