Clinical experience with moroctocog alfa (AF-CC) in younger paediatric patients with severe haemophilia A: Two open-label studies.

INTRODUCTION: The pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF-CC) have been demonstrated in haemophilia A patients aged ≥6 years. AIM: These studies aimed to further describe moroctocog alfa (AF-CC) experience in paediatric patients (<12 years) with severe haemophilia A (FVIII:C < 1%). METHODS: Two prospective, open-label studies enrolled patients aged <12 years: one study with 37 previously treated patients (PTPs) and another with 23 previously untreated patients (PUPs). All patients initially received 50 IU/kg of moroctocog alfa (AF-CC) to evaluate either recovery alone, or with other PK parameters (6 to <12 years) before continuing treatment for 100 exposure days (EDs) or 24 months. RESULTS: At baseline, mean (±SD) recovery ranged between 1.32 ± 0.65 (PUPs aged <2 years) and 2.13 ± 0.82 (PTPs aged 6 to <12 years). The mean (±SD) half-life was 9.12 ± 1.94 hours in PTPs aged 6 to <12 years. No new safety signals were detected in either study, 2 transient lower titre inhibitors occurred in PTPs while 8 inhibitors (3 low and 5 high titre) were detected in PUPs. Most bleeding episodes resolved with one infusion (94% [893/954]). The annualised bleeding rate (ABR) in the PTP study was 27.5 and 4.2 for patients reporting an on-demand and routine prophylaxis regimen at baseline, respectively. In the PUP study, the overall ABR was 5.9. CONCLUSION: Moroctocog alfa (AF-CC) had expected PK findings (lower recovery in young children compared with older children) along with being safe and efficacious in a population of young severe haemophilia A patients.

Evaluating lingual carcinoma for surgical management: what does volumetric measurement with MRI offer?

MRI plays a crucial but under utilized role in the surgical management of lingual squamous cell carcinoma (SCC). Measurement of three-dimensional tumour volume (TV) has the potential to guide management of clinically negative cervical lymph nodes and address deficiencies in current TNM staging criteria This work studied the value of MRI-measured TV as a predictor of 2 year disease-related survival (DRS) and disease-free survival (DFS), as well as occult cervical lymph node metastasis (OM) in lingual cancer. TV was determined by manually segmenting the tumour contour in each image slice and using the resulting pixel value to calculate the three-dimensional extent of disease. TV was also compared with the more established measure of tumour thickness (TT) Significant differences in DRS (χ²(1) = 7.7, Hazard ratio (HR) = 7.3, p = 0.005) and DFS (χ²(1) = 5.6, HR = 4.3, p = 0.02) at two years were found using a cut-off of 8 cm³. Similarly, a significant relationship between TV and occult cervical lymph node metastasis was discovered using a 3 cm³ cut-off (OR = 6.7, p = 0.02, Fisher's Exact Test).

The in vivo relationship between cross-sectional area and CT dose index in abdominal multidetector CT with automatic exposure control.

The relationship between patient cross-sectional area and both volume CT dose index (CTDI) and dose length product was explored for abdominal CT in vivo, using a 16 multidetector row CT (MDCT) scanner with automatic exposure control. During a year-long retrospective survey of patients with MDCT for symptoms of abdominal sepsis, cross-sectional areas were estimated using customised ellipses at the level of the middle of vertebra L3. The relationship between cross-sectional area and the exposure parameters was explored. Scans were performed using a LightSpeed 16 (GE Healthcare Medical Systems, Milwaukee, WI) operated with tube current modulation. From a survey of 94 patients it was found that the CTDI increased with the increase in patient cross-sectional area. The relationship was logarithmic rather than linear, with a least-squares fit to the data (R(2) = 0.80). For abdominal CT the cross-sectional area gave a measure of patient size based on the region of the body to be exposed. Exposure parameters increased with increasing cross-sectional area and the greater radiation exposure of larger patients was partly a consequence of their size. Given increasing obesity levels we believe that cross-sectional area and scan length should be added to future dose surveys, allowing patient size to be considered as a factor of relevance when examining population doses.

Justifying multidetector CT in abdominal sepsis: time for review?

The further development of multidetector row CT (MDCT) has led to changes in the application and examination technique, leading to a need to justify the level and frequency of radiation exposure associated with MDCT. A literature review of how the use of modern scanners has affected diagnosis was undertaken, followed by a year-long retrospective study of MDCT scans of patients presenting with symptoms of abdominal sepsis. The diagnostic accuracy of detecting causes of abdominal sepsis using this technology was sought. Scans were performed using a LightSpeed 16 system (GE Healthcare Medical Systems, Slough, UK and Milwaukee, WI). Clinical diagnoses were based upon surgical and histopathological findings, treatment outcome and follow-up scans. System dose parameters recorded were the dose-length product (DLP) and volume CT dose index. The literature on investigating suspected abdominal sepsis has not been updated significantly since the time of conventional CT. 94 patients were included in the study; causes of abdominal sepsis could be detected with a sensitivity of 0.95 and a specificity of 0.91. Repeat examination and cumulative exposure was a key finding. Patients with abscesses and acute pancreatitis had the highest number of scanner visits; patients with diverticular disease had the lowest number of visits, lowest cumulative DLP and shortest stay in hospital. Cumulative DLP was affected by scan length, number of scans and patient size. In conclusion, diagnostic accuracy data for MDCT scans using 16 slices confirm that CT remains a suitable modality for imaging abdominal sepsis but scope for dose constraint exists.

Drug interactions with clinafloxacin.

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.

Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites.

This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600 mg troglitazone for 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6 and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean tmax values of 2.7 to 2.9 hours. Mean Cmax and AUC(0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.

Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites.

The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC0-24 and Cl/F, the explanatory power of the overall model was weak (R2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.