Multiple-dose pharmacokinetics of efavirenz with and without the use of rifampicin in HIV-positive patients

Rifampicin (RIF) decreases serum concentrations of several antiretroviral drugs. We carried out a prospective, comparative study to define efavirenz (EFV) pharmacokinetics in 16 cases and 13 controls. Cases were HIV and tuberculosis (TB) co-infected adults assuming RIF 600 mg once daily and EFV 800 mg once daily. Patients on EFV at standard 600 mg dose without RIF were taken as controls. EFV levels in plasma were assayed by high-performance liquid chromatography (HLPC) predose (C(trough)) and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 18, 22 and 24 hours post-dose, and pharmacokinetic parameters were determined by non-compartmental methods. Among cases, 81% were males, mean age was 37 years, 50% were Caucasians, mean weight was 64 kg, mean CD4 cell counts and log HIV RNA copies were 160/microl and 5.2 /microl, respectively. Cases had a significantly higher Cl/F/kg if compared with controls (0.269 +/- 0.12 versus 0.167 + 0.05 L/h/kg, p<0.01). Otherwise, dose-dependent pharmacokinetic parameters of EFV were similar between cases and controls. Interindividual variability was consistently higher among TB cases compared to controls for all considered parameters. All cases completed combined treatment and no increased EFV toxicity was observed. These results suggest that a dose of 800 mg of EFV in association with rifampicin may be appropriate for patients of weight > 60 kg in Europe. Therapeutic drug monitoring may be beneficial for patients on combination therapy with RIF.     

Motor cortex stimulation for ALS: A double blind placebo-controlled study

Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS) of the brain may produce a modest slowing of disease progression in amyotrophic lateral sclerosis (ALS). The present study was designed to test the hypothesis that rTMS given as continuous theta burst stimulation (cTBS), repeated monthly for one year, would affect ALS progression. We performed a double blind, placebo-controlled trial. Twenty patients with ALS were randomly allocated to blinded real or placebo stimulation. cTBS of the motor cortex was performed for five consecutive days every month for one year. Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R). Treatment was well tolerated. There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation. ALSFRS-R mean scores declined from 32.0 (SD 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation. Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease.     

Analytical and pharmacological aspects of therapeutic drug monitoring of mTOR inhibitors

Mammalian Target Of Rapamycin (mTOR) inhibitors represent a new class of immunosuppressant drugs extensively used for the prevention and the treatment of graft rejection in organ transplant recipients. Their current use is due to referred low nephrotoxic effects, particularly important in kidney transplanted and/or patients with renal failure. The most representative drugs of such class are Sirolimus (Siro) and Everolimus (Rad). Both drugs show a narrow therapeutic window, therefore, monitoring of whole-blood drug levels is recommended in order to optimize the therapy. Among the available assays, Liquid Chromatography coupled with UltraViolet or Electrospray Tandem Mass Spectrometry methods (LC/UV or LC/ESI-MSMS) are the most accurate and specific ones. A reliable alternative is represented by immunoassays, which offer the opportunity to minimize sample pre-treatment, thus reducing the time between drawing blood sample and measuring the drug concentration, an important aspect in high-throughput analyses. Despite this, a limitation in the use of immunoassays for therapeutic drug monitoring is the lower specifity compared with the chromatographic methods when analysing structurally-related drugs. New insights to optimize mTOR inhibitors regimens seem to be offered by the evaluation of CYP450 3A activity by using the probe drug approach. To such purpose, there are a number of major probe drugs used for in vivo studies including: midazolam, cortisol, lidocaine, nifedipine, dextromethorphan, erythromycin, dapsone and alfentanil. The aim of the present paper is to report the most recent knowledge concerning this issue, supplying a critical and comprehensive review for whom are involved both in the clinical and analytical areas.     

Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor

We demonstrate that CD161 is a highly up-regulated gene in human interleukin (IL) 17 T helper cell (Th17) clones and that all IL-17–producing cells are contained in the CD161⁺ fraction of CD4⁺ T cells present in the circulation or in inflamed tissues, although they are not CD1-restricted natural killer T cells. More importantly, we show that all IL-17–producing cells originate from CD161⁺ naive CD4⁺ T cells of umbilical cord blood, as well as of the postnatal thymus, in response to the combined activity of IL-1β and IL-23. These findings implicate CD161 as a novel surface marker for human Th17 cells and demonstrate the exclusive origin of these cells from a CD161⁺CD4⁺ T cell progenitor.     

Brief motivational intervention and alcohol expectancy challenge with heavy drinking college students: a randomized factorial study

This study is the first reported test of the unique and combined effects of Brief Motivational Intervention (BMI) and Alcohol Expectancy Challenge (AEC) with heavy drinking college students. Three hundred and thirty-five participants were randomly assigned in a 2x2 factorial design to either: BMI, AEC, BMI and AEC, and assessment only conditions. Follow-ups occurred at 1, 3, and 6 months. Unconditional latent curve analyses suggested that alcohol use (Q-F), heavy episodic drinking, and alcohol problems were best modeled as quadratic effects. BMI produced significant decreases in Q-F, heavy drinking, and problems, while AEC produced significant decreases in Q-F and heavy drinking. There was no evidence of an additive effect of combining the interventions. Intervention effects decayed somewhat for BMI and completely for AEC over 6 months. Multi-group analyses suggested similar intervention effects for men and women. BMI effects on alcohol problems were mediated by perceived norms. These findings extend previous research with BMI and AEC but do not support their utility as a combined preventive intervention to reduce collegiate alcohol abuse.     

Explosive-aggressive behavior related to bilateral subthalamic stimulation

We describe a patient with Parkinson's Disease who underwent bilateral subthalamic nucleus deep brain stimulation and later presented with episodes of aggressive behavior disorder with disturbed impulse control and an inability to control anger likely related to the deep brain stimulation "switch-on stimulation". We hypothesize that increasing voltage intensity could influence neighboring passing fibers coming from basal limbic system that are involved in the regulation of affect and emotional behavior. We suggest investigating these neuropsychological disturbances considering their influence on quality of life after surgery.     

Postoperative infections in cytoreductive surgery with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis

BACKGROUND: Peritoneal carcinomatosis is a common evolution of many abdominal and pelvic malignancies. Over the last decade novel therapeutic approaches have emerged combining cytoreductive surgery with perioperative intraperitoneal chemotherapy. Aim of our study was to assess frequency, sites, and organisms of postoperative infections in this surgery and to evaluate associated risk factors and clinical outcome. METHODS: Retrospective study of postoperative infection in 30 patients undergoing combined cytoreductive surgery and hypertermic intraoperative chemotherapy in an oncologic surgery in Rome, between June 2001 and December 2004. RESULTS: Twenty-nine postoperative infections were recorded in 11 patients (36.7%; 2.6 infections per patient), including 13 surgical site infections, 8 clinical sepsis, 6 bloodstream infections, and 2 pneumonias. At multivariate analysis, total peritonectomy was found as independent variable associated to postoperative infection. Mortality rates were 36.4% and 5% among patients with and without postoperative infections, respectively (P = 0.04). Four of the 5 patients with invasive candidosis died. CONCLUSIONS: Peritonectomy procedures have an high risk of postoperative infections, prolonged hospital stay, and high morbidity and mortality. The increasing role of this surgery for the treatment of peritoneal carcinomatosis should strengthen the need for a careful evaluation of possible risk factors for postoperative infections, including the role of colonizing organisms.     

Qualitative research: mapping an ongoing journey

In this personal essay, the author argues for a language-centered approach to qualitative research, with a focus on reconstructing the practices of those we study as reflexively constitutive of our social world.     

Cognitive rehabilitation for early post-surgery inpatients affected by primary brain tumor: a randomized, controlled trial

Cognitive impairment is one of the most common neurological disorders in neuro-oncological patients and exerts a deep negative impact on quality of life interfering with familiar, social and career-related activities. To test the effectiveness of early cognitive rehabilitation treatment for inpatients affected by primary brain tumors. Out of 109 consecutive patients enrolled in the study, 58 patients were randomly assigned to a rehabilitation group or to a control group. The rehabilitation consisted of 16 one-hour individual sessions of therapist-guided cognitive training, spread over 4 weeks, combining computer exercises and metacognitive training. Patients in the control group received usual care without cognitive training. All patients were evaluated by means of a comprehensive neuropsychological battery at the admission (T0) and after 4 weeks (T1). Patients in the rehabilitation group showed a significant improvement of cognitive functions. In particular, the domains that benefited most from the training were visual attention and verbal memory. The control group exhibited only a slightly, not statistically relevant, enhancement of cognitive performances. Cognitive rehabilitation for neuro-oncological inpatients resulted in a significant enhancement of cognitive performances after the training, also providing a foundation for early administration. Future research should be aimed to clarify the patients’ characteristics that predict neuropsychological improvement, to identify the most effective elements in rehabilitative programs and to study the effects of treatment extension to everyday life.