Olanzapine compared to lithium in mania: a double-blind randomized controlled trial

Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.     

Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.     

Value of a radionuclide limb blood flow technique in the assessment of percutaneous balloon and dynamic angioplasty

In a prospective study, a radionuclide technique was used to evaluate the limb blood flow (LBF) changes in 30 patients undergoing dynamic (n=15) or balloon (n=15) angioplasty for arterial occlusions or stenoses, respectively. The results were compared with Doppler Ankle Brachial Index (DABI) and treadmill exercise tests. Whilst LBF values (ml of blood flow per 100 ml of limb volume per min) were significantly lower in limbs with arterial occlusion than stenosis (4.5±0.46 and 6.4±0.74, respectively; P<0.05), DABI provided no discrimination. Immediately after balloon angioplasty, there was a fall in DABI, from 0.60±0.05 to 0.47±0.04 (P<0.05), which rose 24 h later to 0.73±0.02 (P<0.01). Following dynamic angioplasty, DABI improved from 0.60±0.05 to 0.66±0.02 (P<0.05). At 3 weeks, the LBF improved from 4.6±0.66 to 11.1±0.53 (P<0.001) following dynamic angioplasty and from 6.2±0.68 to 8.53±0.81 (P<0.001) following balloon angioplasty. Normal LBF (> 10 ml/100 ml per min) was achieved in 80% of patients who underwent successful dynamic angioplasty but in only 36% of the balloon group (P<0.05, ²-test). Reproducibility of repeated LBF measurements in control limbs was superior to that of DABI. This was indicated by a lower coefficient of variation, 13.8% compared with 25.2%, and a higher correlation coefficient, r=0.79 compared with 0.27. Treadmill exercise tests were invalid or impossible in 30% of all occasions. There was a good correlation between the improvement in maximum walking distance on the treadmill and that in LBF (r=0.84, P<0.05). In conclusion, measurement of LBF using radionuclide technique is a potentially valuable method for the assessment of patients undergoing percutaneous angioplasty. LBF results are reproducible and correlate well with the improvement in walking ability, which cannot always be assessed objectively. Offprint requests to: A.A. Gehani     

Dual effect of lovastatin and simvastatin on LDL-macrophage interaction.

Lovastatin and simvastatin which are very potent cellular cholesterol biosynthesis inhibitors, significantly affect the plasma lipoprotein concentration. After incubation of plasma with 14C-labelled compounds, radioactivity was found in all lipoprotein fractions but mainly (40%) in high density lipoprotein (HDL), and in the lipoprotein-deficient plasma fraction (20-30%). Drug-treated lipoproteins showed reduced electrophoretic mobility on cellulose acetate in comparison with control lipoproteins. The lovastatin-treated low density lipoprotein (LDL) displayed 28% increased fluidity in comparison with control LDL. The immunoreactivity of drug-treated LDL with monoclonal antibody directed towards the LDL receptor binding domains (B1B6) was significantly less than that of control LDL, suggesting reduced binding to the LDL receptor. When drug-treated LDL was incubated with J-774 A.1 macrophage-like cell line, its binding (at 4 degrees C) was 28% less than that of control LDL, whereas a substantial increase in the cellular cholesterol esterification rate (by 83% with lovastatin and by 67% with simvastatin) was noted. Similarly, the degradation of lovastatin and simvastatin-treated LDL by macrophages was 87-89% greater than that of control LDL. The "apparent Vmax" for the macrophage degradation of lovastatin-treated LDL was 70% greater than that for control LDL. Thus, both drugs may have a dual effect on the macrophage uptake of LDL; they may increase the number of LDL receptors on the cell surface, but they may also reduce the affinity of LDL for its receptor, the former being the major effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cost sharing in health insurance on disability days

We assess how cost sharing for medical services affects restricted activity days (RADs) and work loss disability days (WLDs), using data from a controlled experiment. We grouped the experimental insurance plans into four categories, one providing free care and the other three requiring varying amounts of cost sharing. RADs per person per year decreased by one to two days with greater cost sharing, with the strongest effects among those of average or poor health status, especially the non-poor. Unlike RADs, WLDs showed no systematic differences by plan.     

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.     

Relationship of mammographic parenchymal patterns to breast cancer risk factors and smoking in Alaska Native women.

The purpose is to determine breast cancer risk factors and correlates of mammographic parenchymal patterns among Alaska Native women. A retrospective review was performed of mammograms and mammogram records among 528 sequential screening mammogram examinations performed in Anchorage, Alaska. Mammogram density was classified by American College of Radiology (Breast Imaging Reporting and Data System) density patterns 1-4 (fat-->dense) and by percent density. Clinical data, including risk factors, ethnic group (Indian, Aleut, or Eskimo), and smoking status were obtained. Results were analyzed by univariate and multivariate analyses. Of 528 women, 164 were Indian, 155 were Aleut, and 209 were Eskimo. Mean age at first birth was lower and parity higher compared with published data in white women. Breast cancer risk factors were similar across ethnic groups. In multivariate analysis, patient age, parity, hormone replacement therapy, hysterectomy, and history of biopsy were associated, and smoking was not associated with density scores. Aleut and Indian women were less likely to have high-density mammograms than were Eskimo women (P = 0.0448). No significant differences were found between ethnic group for conventional breast cancer risk factors. Mammogram density was associated with age at screening, parity, hormone replacement therapy, hysterectomy, history of biopsy, and ethnicity but not smoking status. Eskimo women had higher mammogram density than Aleuts or Indians.     

Adenoid Cystic Carcinoma of the Salivary Glands: A Review of 10 Years

A retrospective analysis was performed of 50 patients with adenoid cystic carcinoma who were seen in the Department of Radiation Oncology, University of Witwatersrand, Johannesburg, South Africa, in the past 10 years. There were 25 men and 25 women with a mean age of 52 years (age range, 21 to 88 years). Five patients had metastatic disease, and 17 had neural invasion. Thirty-four patients had surgery (11, complete; 23, microscopic residual). Sixteen patients had radiotherapy as initial management. The disease-free survival was 26%, overall survival was 29%, and local control was 30% at 10 years. Most recurrences occurred in the first 3 years. Nine patients had metastasis following treatment. The mean survival after metastasis was 15 months. Seven prognostic variables were analyzed using the log-rank test. There was no impact of age, site, type of salivary gland (major vs. minor), tumor stage, node positivity, or neural invasion on disease-free survival, overall survival, or local control. Extent of surgical resection (complete vs. microscopic residual) had a significant impact on disease-free survival and local control (P < 0.05) but no impact on overall survival (P > 0.05) because of the slow-growing nature of these tumors. Similarly, patients who had microscopic residual after surgery and were treated with radiotherapy did better than those who had biopsy and radiotherapy, although this was not significant statistically (P > 0.05). Thus, whenever possible, every attempt must be made to remove all microscopic tumor by surgery. Addition of postoperative radiotherapy with high-energy photons did not improve the locoregional control or survival in our series. There is a place for neutrons in the treatment of adenoid cystic carcinomas in advanced cases of inoperable or recurrent tumors, as a review of literature shows.     

Measuring underuse of necessary care among elderly Medicare beneficiaries using inpatient and outpatient claims

CONTEXT: Continuing changes in the health care delivery system make it essential to monitor underuse of needed care, even for relatively well-insured populations. Traditional approaches to measuring underuse have relied on patient surveys and chart reviews, which are expensive, or simple single-condition claims-based indicators, which are not clinically convincing. OBJECTIVE: To develop a comprehensive, low-cost system for measuring underuse of necessary care among elderly patients using inpatient and outpatient Medicare claims. DESIGN: A 7-member, multispecialty expert physician panel was assembled and used a modified Delphi method to develop clinically detailed underuse indicators likely to be associated with avoidable poor outcomes for 15 common acute and chronic medical and surgical conditions. An automated system was developed to calculate the indicators using administrative data. SETTING AND SUBJECTS: A total of 345,253 randomly selected elderly US Medicare beneficiaries in 1994-1996. MAIN OUTCOME MEASURES: Proportion of beneficiaries receiving care, stratified by indicators of necessary care (n = 40, including 3 for preventive care), and avoidable outcomes (n = 6). RESULTS: For 16 of 40 necessary care indicators (including preventive care indicators), beneficiaries received the indicated care less than two thirds of the time. Of all indicators, African Americans scored significantly worse than whites on 16 and better on 2; residents of poverty areas scored significantly lower than nonresidents on 17 and higher on 1; residents of federally defined Health Professional Shortage Areas scored significantly lower than nonresidents on 16 and higher on none (P<.05 for all). CONCLUSIONS: This claims-based method detected substantial underuse problems likely to result in negative outcomes in elderly populations. Significantly more underuse problems were detected in populations known to receive less-than-average medical care. The method can serve as a reliable, valid tool for monitoring trends in underuse of needed care for older patients and for comparing care across health care plans and geographic areas based on claims data. JAMA. 2000;284:2325-2333.     

Using Vignettes to Compare the Quality of Clinical Care Variation in Economically Divergent Countries

Objective. To determine whether clinical vignettes can measure variations in the quality of clinical care in two economically divergent countries.
Data Source/Study Setting. Primary data collected between February 1997 and February 1998 at two Veterans Affairs facilities in the United States and four government-run outpatient facilities in Macedonia.
Study Design. Randomly selected, eligible Macedonian and U.S. physicians (>97 percent participation rate) completed vignettes for four common outpatient conditions. Responses were judged against a master list of explicit quality criteria and scored as percent correct.
Data Collection/ Extraction. An ANOVA model and two-tailed t-tests were used to compare overall scores by case, study site, and country.
Principal Findings. The mean score for U.S. physicians was 67 percent (+/−11 percent) compared to 48 percent (+/−11 percent) for Macedonian physicians. The quality of clinical practice, which emphasizes basic skills, varied greatly in both sites, but more so in Macedonia. However, the top Macedonian physicians in all sites approached or—in one case—exceeded the median score in the U.S. sites.
Conclusions. Vignettes are a useful method for making cross-national comparisons of the quality of care provided in very different settings. The vignette measurements revealed that some physicians in Macedonia performed at a standard comparable to that of their counterparts in the United States, despite the disparity of the two health systems. We infer that in poorer countries, policy that promotes improvements in the quality of clinical practice—not just structural inputs—could lead to rapid improvements in health.