Effect of fluvoxamine on the pharmokinetics of zolpidem: a two-treatment period study in healthy volunteers

1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed.     

Cancer epidemiology in Central, South and Eastern European countries

Aim

To collect cancer epidemiology data in South Eastern European countries as a basis for potential comparison of their performance in cancer care.

Methods

The South Eastern European Research Oncology Group (SEEROG) collected and analyzed epidemiological data on incidence and mortality that reflect cancer management in 8 countries – Croatia, Czech Republic, Hungary, Romania, Poland, Slovakia, and Serbia and Montenegro in the last 20-40 years.

Results

The most common cancer type in men in all countries was lung cancer, followed by colorectal and prostate cancer, with the exception of the Czech Republic, where prostate cancer and colorectal cancer were more common. The most frequent cancer in women was breast cancer followed by colorectal cancer, with the exceptions of Romania and Central Serbia where cervical cancer was the second most common. Cancer mortality data from the last 20-40 years revealed two different patterns in men. In Romania and in Serbia and Montenegro, there was a trend toward an increase, while in the other countries mortality was declining, after increasing for a number of years. In women, a steady decline was observed over many years in the Czech Republic, Hungary, and Slovakia, while in the other countries it remained unchanged.

Conclusions

There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors which provides a clear challenge to prevention. There are some differences in incidence and mortality that cannot be explained by exposure to known risk factors or treatment availabilities.On a global scale, cancer has become a major public health problem and an increasingly important contributor to the burden of disease. Based on the most recent available international data, there were an estimated 12.7 million new cancer cases, 7.6 million deaths from cancer, and 28 million persons alive with cancer within five years from the initial diagnosis (1-3). The most common cancers in the world were lung (1.61 million cases), breast (1.38 million), and colorectal cancer (1.24 million) (3). Because of its poor prognosis, lung cancer was also the most common cause of death (1.38 million), followed by gastric (737 000 deaths), and liver cancer (695 000 deaths) (1-4).Priority setting for cancer control and cancer services in any region needs to be based on knowledge of the cancer burden and the local mix of predominant cancer types (5). According to estimates of global cancer burden made by the International Agency for Research on Cancer (IARC), the incidence and mortality rates from many specific types of cancer and all cancers combined vary widely by geographic locality (6). Moreover, the IARC also estimated that over half of newly diagnosed cases and two-thirds of cancer deaths occur in low and medium-income countries (6). There are striking variations in the pattern of cancer by site from region to region (7). The large differences in incidence and mortality in different countries may reflect a combination of differences in prevalence of underlying risk factors, differences in host susceptibility, and/or variations in cancer detection, reporting, classification systems, treatment, and follow-up. Among European countries, wide differences in the quality of cancer care are observed, especially when comparison is made between “old” and “new” EU members or between developed and developing countries (8). Cancer survival is significantly lower in Eastern European countries, including the new Member States, than in the EU 15 (9-12). Transitional countries and middle income countries are frequently left forgotten “in between” and the cancer problem in these countries is among the worst and fastest growing (8).In this report, we provide an analysis, which we propose as a foundation for detailed evaluation of cancer care in selected Central, Southern and Eastern European countries, represented by members of the South Eastern European Research Oncology Group (SEEROG). Our epidemiological analysis indicates the scale of the problem of oncological care in individual countries and shows current trends in the incidence of particular cancers. Comparison of status of oncology between countries in Eastern, Southern, and Central European region has never been undertaken before and key barriers to deliver appropriate quality of care have not previously been identified.     

The Behavioural Assessment of the Dysexecutive Syndrome (BADS) in schizophrenia and its relation to functional outcomes

The purpose of this study was to establish further the validity of the Behavioural Assessment of the Dysexecutive Syndrome (BADS) in a population with schizophrenia. Specific objectives were: to examine the construct validity and sensitivity of the BADS in differentiating between adult inpatients during an acute episode of illness, adult outpatients in the chronic stages of illness, and healthy controls; and to examine the predictive validity of the BADS regarding functional outcomes within the chronic group. Participants were 30 inpatients during an acute episode of their illness; 31 outpatients in the chronic stage; and 93 healthy controls. Instruments included the BADS, the Neurobehavioral Cognitive Status Examination (Cognistat) and the Routine Task Inventory (RTI). Significant differences in BADS scores were found between participants with schizophrenia and healthy controls, and between both groups of patients, showing the chronic group to have more deficits in executive functions. In addition, within the chronic group the BADS was found to be a significant predictor of two of the RTI outcome areas, instrumental activities of daily living (IADL) and communication, beyond that accounted for by basic cognitive skills. These results support the validity of the BADS within the schizophrenic population, and highlight the importance of measuring executive functions for rehabilitation.     

Risk factors for the development of food allergy

Both genetic and environmental factors seem to predispose to the development of food allergy. A most notable factor is diet, particularly during infancy. Possible other factors include maternal diet during pregnancy and lactation, birth by cesarean section, exposure to tobacco smoke, multivitamin supplementation, and intake of antacids. It is important to identify and control such risk factors to reduce the development of food allergy.     

Preliminary evaluation of the Web Initiative for Surgical Education (WISE-MD)

BACKGROUND: Major changes in health care delivery and financing have negatively impacted students' experience during the surgery clerkship, particularly their exposure to physicians' decision-making processes and to the continuity of patient care. In response to these dilemmas in surgical education, we have developed the Web Initiative for Surgical Education (WISE-MD), a comprehensive surgery clerkship curriculum delivered through multimedia teaching modules and designed to enhance exposure to surgical disease and clinical reasoning. METHODS: As part of the process of creating WISE-MD, we conducted preliminary studies to assess the impact of this computer-assisted approach on students' knowledge, clinical reasoning, and satisfaction. RESULTS: Compared to students who did not view the modules, early data show a trend toward improved knowledge and an improvement in clinical reasoning for students who used the WISE-MD modules. This effect was specific to the clinical content area addressed in the module seen by the students. Most students felt the module was superior to traditional teaching methods and enhanced their understanding of surgical technique and anatomy. CONCLUSIONS: WISE-MD, a theory-driven example of a concerted technology-based approach to surgical education, has the potential to address the myriad problems of today's clinical learning environment.     

Is there a role for endoscopic ultrasonography in evaluation of the left liver in colorectal liver metastasis patients selected for right hepatectomy

Background  

Meticulous assessment of the left liver for patients scheduled for right hepatectomy is essential. Endoscopic ultrasonography (EUS) is frequently used for the locoregional staging or biopsy of pancreatic tumours and has shown some value in the evaluation of the left liver.     

SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells

Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 (bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC50 of approximately 250 nmol/L, which was also the IC50 for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of beta-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130Cas), with an IC50 similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer.     

High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency

Common variable immunodeficiency (CVID) is characterized by low levels of immune globulins and lack of antibody. Mutations in transmembrane activator and calcium-modulating cyclophilin ligand (TACI), are found in 8-10%, associated with autoimmunity and splenomegaly. Some patients with mutations had increased serum levels of TACI. Because of this, and the prevalence of autoimmunity, splenomegaly, and lymphadenopathy, we quantitated levels of TACI ligands, a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and TACI in serum of 77 patients. CVID subjects had markedly increased serum levels of BAFF (p<0.0001), APRIL (p<0.0001), and TACI (p=0.001) but there was no relationship between levels and autoimmunity, lymphadenopathy, splenomegaly, B cell numbers, or mutations in TACI. Peripheral blood mononuclear cells of CVID subjects had increased levels of BAFF mRNA. We conclude that increased constitutive production and/or underlying immuno-regulatory or inflammatory conditions lead to enhanced release of ligands; however, the biological result remains unclear.     

Gallbladder dysfunction in diabetes mellitus

To further elucidate the mechanism of impaired gallbladder emptying in diabetics with and without neuropathy, gallbladder function was assessed by ultrasonography following a medium-chain triglyceride (lipomul, 1.5 mg/kg) infusion into the duodenum and compared to that during intravenous infusion of cholecystokinin in diabetic women. Results were compared with five healthy control women. Mean (±sd) maximal percent gallbladder volume in diabetics following lipomul was reduced to 49±8% and after intravenous cholecystokinin to 47±9%, which was less than those in controls, 21±9% and 24±6%, respectively, but not significantly different. Further analysis of gallbladder emptying to lipomul differentiated two subgroups of diabetics: one subgroup (N=5) had emptying comparable to controls (responders), while the other (N=5) had very modest emptying (nonresponders). Two of the patients in the latter group had normal gallbladder emptying during exogenous cholecystokinin and their response would be compatible with visceral neuropathy. Blood levels of cholecystokinin, measured by bioassay, following lipomul and exogenous cholecystokinin were similar in controls and diabetics. Presence of diabetic neuropathy did not correlate with impaired gallbladder emptying. Follow up at 6 and 12 months of the three nonresponder diabetics revealed that no gallstones had developed and that two of them became responders to exogenous cholecystokinin. We conclude that: (1) following lipomul, about 50% of diabetics in this study have impaired gallbladder emptying, which is not strictly correlated with diabetic neuropathy; (2) this was not due to abnormal cholecystokinin release; (3) in diabetic patients with impaired gallbladder emptying another abnormality may be present in the gallbladder; and (4) impaired gallbladder contraction may not lead to gallstone formation in one-year follow-up.