Modification to improve efficiency of sampling schedules for BA/BE testing of FDC anti-tuberculosis drugs.

SETTING: The assessment of rifampicin (RMP) containing fixed-dose combination (FDC) formulations using in vivo bioequivalence testing is widely accepted. It would be advantageous for both the drug regulatory authorities and drug manufacturers, for optimum minimum blood testing time intervals that encompass all anti-tuberculosis active constituents in the FDC to be established. OBJECTIVE: To determine the optimum blood sampling schedule for testing novel FDC anti-tuberculosis drugs, isoniazid, RMP, pyrazinamide and ethambutol DESIGN: The results of 12 different single-dose, two-way cross-over designs are presented. The studies determined the bioavailability and bioequivalence of RMP-containing FDCs, and conformed with the requirements of the South African national drug regulatory authority for each of the active constituents. RESULTS: The pharmacokinetic parameters to determine bioavailability and the Hauschke method to determine bioequivalence revealed that a six-point time protocol, namely 0, 1, 2, 4, 6 and 8 h, provides a good approximation of the area under the curve, and that an 11-point time protocol of 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h provided information comparable to the conventional 15 time-points for FDCs containing up to four drugs. CONCLUSION: The findings provide concrete economic benefit and convenience for quality assurance testing of existing and novel FDCs.     

Alemtuzumab (CAMPATH 1H) Induction Therapy in Cadaveric Kidney Transplantation—Efficacy and Safety at Five Years

Alemtuzumab is a powerful lymphocyte depleting antibody currently being evaluated in solid organ transplantation. This paper describes 5-year results of a single center study of alemtuzumab as induction in renal transplantation. Thirty-three renal transplant recipients received 20 mg alemtuzumab on day 0 and 1, followed by half-dose cyclosporin monotherapy (trough concentration 75-125 ng/mL) from day 3. They were compared in a retrospective contemporaneous-controlled manner with 66 kidney transplant recipients transplanted in the same period and center who received conventional immunosuppression with cyclosporin, azathioprine and prednisolone. In the alemtuzumab group 12% of recipients died compared to 17% in the control group (p = 0.48); likewise graft loss was similar in both groups (21% vs. 26%, respectively, p = 0.58). Incidence of acute rejection was also comparable at 5 years (31.5% vs. 33.6%), although the pattern of rejection was different with 14% patients in the alemtuzumab group experiencing rejection over 1 year post-transplant compared to none in the control group. There was no significant difference between groups in terms of infection or serious adverse events. While acknowledging the limitations of a relatively small single-center study, results suggest that alemtuzumab induction allowed satisfactory long-term patient and graft survival equivalent to that seen with standard triple immunosuppression, while avoiding steroid therapy.     

Simultaneous prepubertal onset of panic disorder, night terrors, and somnambulism

Concurrent acute onset of night terrors, somnambulism, and spontaneous daytime panic attacks meeting the criteria for panic disorder is reported in a 10-year-old boy with a family history of panic disorder. Both the parasomnias and the panic disorder were fully responsive to therapeutic doses of imipramine. A second case of night terrors and infrequent full symptom panic attacks is noted in another 10-year-old boy whose mother has panic disorder with agoraphobia. The clinical resemblance and reported differences between night terrors and panic attacks are described. The absence of previous reports of this comorbidity is notable. It is hypothesized that night terror disorder and panic disorder involve a similar constitutional vulnerability to dysregulation of brainstem altering systems.     

Patient survival and local recurrence rate following radical prostatectomy for prostatic carcinoma

From 1970 to 1980, 153 patients with stages A2, B1 and B2 prostatic cancer and proved negative pelvic lymph nodes underwent radical prostatectomy (84 underwent radical perineal and 69 underwent radical retropubic prostatectomy). Seventeen patients were lost to followup. Of 136 patients who were followed for 5 years or until death 128 (94 per cent) were alive at 5 years, including 118 (87 per cent) who were without evidence of recurrence. Patients with microscopic invasion of the prostatic capsule have a better outcome at 5 years than those with microscopic involvement of the seminal vesicles. Only 46 of the patients could be assessed at 10 years or had died 6 to 10 years postoperatively. Results at 10 years are considered preliminary, since many more patients will reach the 10-year milestone within the next few years.     

Chewing gum,stress and health

Hollingworth described chewing gum as ‘a technique of relaxation’. Recent research has examined this issue and there is evidence that chewing gum can prevent the adverse effects of acute stress. There are also plausible biological mechanisms that could explain such effects. It is now important to examine chewing gum and chronic stress and the present study involved a survey of this topic. The survey covered the ‘stress process’, collecting data on exposure to stressful events, levels of perceived stress and health outcomes. Frequency of chewing gum was also recorded. Potential confounding factors (demographics, personality and health-related behaviours) were also recorded. The web-based survey was completed by a community sample of 2,248 full-time workers (68% female. Mean age: 35 years, range 18–74 years). Sixty-one per cent of the sample were gum chewers. The results showed that chewing gum was associated with lower levels of perceived stress (both at work and life in general). Gum chewers were also less likely to be depressed and to have seen their doctor for high blood pressure or high cholesterol. Chewing gum was associated with lower levels of alcohol consumption and with cigarette smoking. Gum chewers were also more likely to be neurotic extraverts. Those who chewed gum were also more likely to be exposed to negative factors at work. Logistic regression analyses showed that the effects of chewing gum on stress and health remained significant when these confounding factors were controlled for. These results suggest that chewing gum may be a simple way of preventing stress and the negative health outcomes that are often associated with it. Intervention studies are now required and the mechanisms underlying the effects reported here need further investigation. Copyright © 2009 John Wiley & Sons, Ltd.     

Lymph Node Dissection Impact on Staging and Survival of Extrahepatic Cholangiocarcinomas,Based on U.S. Population Data

Cholangiocarcinomas (CC) frequently demonstrate lymphatic spread. We investigated lymph node (LN) counts after resection of extrahepatic CC and survival based on the SEER 1973–2004 database. Out of 20,068 CC patients, 1,518 individuals were selected based on M0 stage and at least one LN examined. Primary cancer sites included gallbladder (29%), extrahepatic bile ducts (26%), and intrapancreatic/ampullary bile ducts (45%); 42% of patients were LN-positive. The median number of LNs examined was four (range 1–39). Median survival was 37 months for LN-negative and 16 months for LN-positive cancers. Multivariate prognostic variables were the number of positive LNs, primary site, age (all at p < 0.0001), gender (p = 0.002), size (p = 0.005), T category (p = 0.009), and total LN count (or number of negative LNs obtained, p = 0.01). The impact of total LN counts was seen in LN-negative (median survival, 1 vs 10 or more LNs examined: 27 vs 51 months, p = 0.002) and LN-positive disease (10 vs 22 months, p < 0.0001). Survival prediction of extrahepatic CCs is strongly influenced by total LN counts and numbers of negative LNs obtained. Although the resulting incremental benefit is small, dissection and examination of 10 or more LNs should be considered for curative intent resections.