Olanzapine: a critical review of recent literature

The purpose of this review is to critically review the current literature on olanzapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of mood disorders and schizophrenia. New information continues to emerge on the impact of olanzapine on schizophrenia and on aspects of the course of mood disorders. There are also continued efforts to understand, predict and manage the side-effect risk with olanzapine.     

Fish drug analysis—Phish-pharm: A searchable database of pharmacokinetics data in fish

Information about drug residues and pharmacokinetic parameters in aquatic species is relatively sparse. In addition, it is difficult to rapidly compare data between studies due to differences in experimental conditions, such as water temperatures and salinity. To facilitate the study of aquatic species drug metabolism, we constructed a Fish Drug/Chemical Analysis Phish-Pharm (FDA-PP) database. This database consists of more than 400 articles that include data from 90 species (64 genera) of fish. Data fields include genus, species, water temperatures, the average animal weight, sample types analyzed, drug (or chemical) name, dosage, route of administration, metabolites identified, method of analysis, protein binding, clearance, volume of distribution in a central compartment (Vc) or volume of distribution at steady-state (Vd), and drug half-lives (t((1/2))). Additional fields list the citation, authors, title, and Internet links. The document will be periodically updated, and users are invited to submit additional data. Updates will be announced in future issues of The AAPS Journal. This database will be a valuable resource to investigators of drug metabolism in aquatic species as well as government and private organizations involved in the drug approval process for aquatic species.     

A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads

This was a 12-month extension of a randomized, investigator-blinded, multicenter, 8-week trial with triple combination (TC) cream in facial melasma. A total of 585 patients were enrolled in the study and 569 patients received study medication. Three hundred eighty-nine patients completed 6 months of treatment and 327 patients completed 12 months of treatment. TC cream demonstrated a favorable safety profile: only 14 patients (2.5%) discontinued the study due to treatment-related adverse events (AEs). The 2 cases of skin atrophy were mild and did not lead to withdrawal. From the 23 cases of mild telangiectasia, only 2 resulted in discontinuation. All others were transient. Results confirmed those of a previous smaller study, with both physicians and patients reporting clinically significant improvements in melasma. By month 12, 80% of patients had lesions completely cleared or nearly cleared. Once daily application of TC cream applied intermittently over a long period is a safe, tolerable, and effective treatment for moderate to severe melasma of the face.     

Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial

BACKGROUND: Imatinib inhibits the c-kit tyrosine kinase, which, accounts for its activity in gastrointestinal stromal tumors. The presence of c-kit protein expression in small cell lung carcinoma (SCLC) tumor specimens, as well as in vitro data supporting the role of c-kit in autocrine and paracrine growth stimulation specifically in SCLC, provided a rationale for studying imatinib in this disease. The authors conducted a Phase II single-institution study of imatinib in patients with recurrent SCLC whose tumor specimens expressed c-kit protein. METHODS: Patients with progressive SCLC after one or two previous chemotherapy regimens consented to have their tumor specimens screened by immunoperoxidase stain (CD117, Dako Corporation, Carpinteria, CA) for c-kit protein expression. If present, individuals were then eligible for treatment with an imatinib dose of 400 mg orally twice daily (total, 800 mg per day). RESULTS: The presence of c-kit protein was assessable in 36 of 39 (92%) tumor samples. Twenty-eight (78%) tumor samples had immunohistochemical staining for c-kit protein. Twelve patients were enrolled in the treatment portion of the current study. No responses were observed, and all patients had disease progression by Week 4. Edema, fatigue, nausea, and electrolyte abnormalities were the primary toxicities. CONCLUSIONS: Imatinib did not have antitumor activity against SCLC, even with c-kit protein present in tumor specimens. The dismal prognosis for these patients with progressive SCLC emphasized the urgent need for continued studies of new therapies in this population.     

Estimated impact of the Prostate Cancer Prevention Trial on population mortality

BACKGROUND: The potential public health impact of the recently completed Prostate Cancer Prevention Trial (PCPT) is debated. The results indicated that the period prevalence of prostate cancer was reduced by 24.8% due to finasteride, whereas an increase in the rate of high-grade tumors (Gleason score 8-10) among men who were diagnosed with cancer also was found (5.0% in the PCPT placebo arm vs. 11.9% in the PCPT finasteride arm). Whether the increased Gleason score was valid or was a histologic artifact is under investigation. METHODS: The authors estimated the number of person-years saved assuming a 24.8% reduction in the incidence of prostate cancer for 5 years among United States males age > or = 55 years. Scenarios for different proportions of patients with high-grade Gleason scores also were considered. RESULTS: With a 24.8% reduction in the number of men with newly diagnosed prostate cancer, the authors estimated that 316,760 person-years would be saved due to finasteride in the United States. An absolute increase of 6.9% in the proportion of men with high-grade tumors in the United States cancer population (corresponding to the difference between the rates on the placebo and finasteride arms of the PCPT) would reduce the number of person-years saved to 262,567. For each absolute increase of 5% in the proportion of patients with high-grade tumors, the number of person-years saved would be reduced by approximately 39,000. CONCLUSIONS: The results of the PCPT may have a major impact on population mortality from prostate cancer if they are applied clinically. The potential detrimental effects of an increased rate of patients who have prostate cancer with high-grade Gleason scores would be outweighed by a reduction in incidence.     

A population-based study of lung carcinoma in Pennsylvania: comparison of Veterans Administration and civilian populations

BACKGROUND: Lung carcinoma remains the major cause of cancer death in North America and is even more common among military veterans. The objective of this study was to determine whether there were differences in the characteristics and survival of Pennsylvania patients with lung carcinoma in the Veterans Administration (VA) hospital system compared with patients in the rest of the state. METHODS: The Pennsylvania Cancer Registry was used to identify all patients who were diagnosed with lung carcinoma in the State of Pennsylvania from 1995 to 1999. Patients who were treated within the Veterans Administration Health Care Network were identified by hospital code. Survival from the date of diagnosis of lung carcinoma was determined by using the Pennsylvania state mortality files from 1995 to 2001. RESULTS: From 1995 to 1999, 48,994 patients were newly diagnosed with lung carcinoma in Pennsylvania (41.2% women), including 856 patients in the VA system (6 women). The current analysis was restricted to male patients (n = 28,798 men). There was no major difference in age of VA patients compared with non-VA patients, and the proportions of patients who had localized or regional stage disease were similar (49% of VA patients vs. 48% of non-VA patients). The proportion of black patients was much higher in the VA population (23%) compared with the non-VA population (9%). The median survival was 6.3 months for VA patients compared with 7.9 months for patients in the rest of the state, and the 5-year overall survival rate was 12% for VA patients compared with 15% for patients in the rest of the state. When survival was analyzed according to race, there was a significant difference in the age-adjusted survival of white patients in the VA system compared with patients in the rest of the state (P = 0.0007), but no significant difference was observed among black patients (P = 0.92). CONCLUSIONS: The overall survival of VA patients with lung carcinoma in Pennsylvania was inferior to that of patients in the remainder of the state and this was due primarily to differences in survival among the white patients. Further investigation will be necessary to determine whether this disparity was caused by differences in socioeconomic status or comorbidities or whether there are systematic differences in the diagnosis, staging, or treatment of lung carcinoma between VA patients and civilian patients.     

Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma

BACKGROUND: Surgical resection for large (> 10 cm) hepatocellular carcinoma (HCC) is believed by many to be ineffective. The objective of the current study was to review the outcome of partial hepatectomy in patients with large HCC. METHODS: Between 1985 and 2002, 193 consecutive patients who underwent partial hepatectomy for HCC were identified from a prospective database. The 82 patients with tumors > 10 cm were compared with the remaining 111 patients with < or = 10 cm tumors. Clinicopathologic features were analyzed and prognostic factors were evaluated by univariate and multivariate analysis. RESULTS: The 5-year overall survival for patients with large HCC was 33% with a median of 32 months. Patients with < or = 10 cm tumors had similar survival. Furthermore, there was no significant difference between the groups in operative mortality (2% in large HCC vs. 6%) or recurrence rate. In patients with large HCC, vascular invasion by tumor and intraoperative blood loss > 2 liters predicted overall survival on multivariate analysis. CONCLUSIONS: Partial hepatectomy is safe for patients with large HCC. In selected patients with large tumors, resection achieves similar overall survival and recurrence-free survival to that of patients with smaller tumors. Minimizing intraoperative blood loss appears to be critical for favorable long-term outcome in patients with large HCC.     

Meeting report: Structural determination of environmentally responsive proteins

The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein-protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health.