Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study

Abstract

Objective:

Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes.     

Effects of Panax Ginseng Extract on the Benzo(a)Pyrene Metabolizing Enzyime System

ABSTRACT

Ethanol extract of Panax ginseng C. A. Meyer, which has been used for centuries as a tonic in Asian countries, exhibited a selective induction of epoxide hydratase and cytosolic glutathione transferase activity without the concurrent induction of aryl hydrocarbon hydroxylase activity. Thus, Panax ginseng appears to have the potential to alter the metabolic patterns of benzo(a)pyrene and its reactive metabolites.     

Centralized Pan-European survey on the under-treatment of hypercholesterolaemia (CEPHEUS): overall findings from eight countries

Abstract

Background:

Surveys evaluating plasma lipid goal attainment in patients with coronary heart disease have shown that hypercholesterolaemia is inadequately treated. Limited data account for the reasons behind this. The aim of the CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) survey was to evaluate the current use and efficacy of lipid-lowering drugs (LLD), and to identify possible patient/physician characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets recommended by the 2003 European guidelines (Third Joint Task Force).     

Therapist Rotation—A New Element in the Outpatient Treatment of Alcoholism

For nine years, the so-called “therapist rotation” has been a central part of OLITA, the Outpatient Longterm Intensive Therapy for Alcoholics. Thus far, the participation of several equally responsible therapists in the treatment of a patient has rarely been seen as a specific therapeutic approach. The present article analyzes the therapist rotation from a theoretical and clinical perspective. Articles concerned with the therapeutic alliance in the treatment of substance use disorders are reviewed. Furthermore, the literature on multiple psychotherapy, which may be seen as the precedent of the therapist rotation is surveyed. Based on the efficacy of multiple psychotherapy and the importance of the therapeutic alliance in the treatment of substance use disorders, the present work discusses the therapist rotation as an essential factor for the success of OLITA. It considers both potential advantages and disadvantages for patients and therapists and tries to identify conditions under which this approach appears to promote therapeutic interactions. Finally, the implementation of therapist rotation into OLITA is described, including the theoretical background of the program itself and the treatment procedure. New areas of application for the therapist rotation are discussed.     

The Significance of Isomerism and Stereospecificity to the Chemistry of Plant Teratogens

Abstract

Among the stereochemical relationships which may be relevant to the biological properties of four types of teratogenic plant alkaloids are: (a) rotational isomerism about the C-20, C-22 bond of 22,26-epiminocholestenes, (b) nitrogen inversion and/or preferential ring F opening of 22α-N spirosolanes, (c) conformational or configurational interconversions of solanidanes, and (d) atropisomerism of colchicine and its analogs.     

Sphingomyelinase of Bacillus Cereusas a Bacterial Hemolysin

Abstract

The enzymatic, toxic and molecular properties of sphingomyelinase from Bacillus cereuswere described in relation to other bacterial sphingomyelinases such as β-toxin of Staphylococcus aureus. The complete amino acid sequences of B. cereussphingomyelinase, determined from its chromosmal DNA, were examined in relation to other phospholipases C from B. cereusand Clostridium perfringens. The gene of B. cereussphingomyelinase codes 27 amino acid residues of signal peptide and 306 residues of mature protein. Both the genes of sphingomyelinase and phosphatidylcholine-hydrolyzing phospholipase C of B. cereusformed a gene cluster. According to the prediction of secondary structure of sphingomyelinase, almost half of the total amino acid residues might participate in loop or turn structure, while one-fifth and one-fourth of amino acid residues might be involved in α-helix and β-structure, respectively. The helical content determined by circular dichroism (CD) spectra indicated 0–5%. The enzyme specifically hydrolyzes sphingomyelin in the intact erythrocyte membranes as well as in the micelles and liposomes, causing the hemolysis of erythrocytes. The enzyme is specifically adsorbed onto the surface of membranes of erythrocytes and liposomes. The hydrolysis of sphingomyelin and the adsorptive properties were influenced by the divalent metal ions such as Mg²⁺, Ca²⁺and Mn²⁺. Selective modfication of amino acid residues in the molecule of sphingomyelinase suggested that acidic amino acid residues such as Asp and Glu would be involved in the catalytic center and adsorptive sites in the sphingomyelinase molecule. Also, the effects of membrane-perturbing agents were described.     

Slaframine and Swainsonine,Mycotoxins from Rhizoctonia Leguminicola

Abstract

The mold, Rhizoctonia leguminicola, parasitizes certain legumes, e.g. red clover, in wide areas of the U.S. Consumption of such moldy forage may cause several syndromes of varying severity including excessive salivation, lacrimation, diarrhea, and even death. 1-Acetoxy-6-aminooctahydroindolizine (slaframine, SF) a parasympathomimetic, and 1,2,8-trihydroxyoctahydroindolizine (swainsonine, SW) a potent a-mannosidase inhibitor, are produced in pure R. leguminicola cultures and were also isolated directly from moldy red clover hay which had caused a severe slobbers outbreak. SW when compared with locoweed was found to produce similar effects on tissue glycosidases and oligosaccharides of the pig indicating that SW is the principal toxin responsible for the induction of locoism. Our research presently focuses on aspects of SW as a mycotoxin e.g. the possibility that SW may enter the human food chain via milk from diary cattle consuming moldy forage is being considered. Additionally we are interested in the biogenesis of SF and SW from lysine in R. leguminicola enzyme systems and if such pathways of secondary nitrogen metabolism are subject to conventional regulatory mechanisms of microbial pathways.     

Studies on Glutathione S-Transferases of Aspergillus Flavus Group in Relation to Aflatoxin Production

Abstract

Aflatoxin synthesis in the mycelia of Aspergillus is positively correlated with the activity of cellular glutathione (GSH) S-transferases (Saxena, Manju, Mukerji, K.G., Raj, H.G. 1988, Biochem. J. 254, 567-570). This finding is further extended to the action of inducer and inhibitor of aflatoxin synthesis upon A. flavus GSH S-transferase. Phenobarbitone (PB) a known inducer of aflatoxin formation increases GST activity in toxigenic strain alone as compared to non-toxigenic strains. Tinaderm (Tolnaftate) an antifungal drug specifically inhibit aflatoxin synthesis. Tinaderm - treated A. flavus mycelium was found to have significantly diminished GSH S-transferase activity coupled with reduce levels of aflatoxin. These observations point out clearly that theendogenous aflatoxin is the main factor effecting specific induction of A. flavus GSH S-transferase. The inducing effect of aflatoxin appears to be different from phenobarbital pattern of induction of GSH S-transferase. In this connection, a direct interaction of aflatoxin with A. flavus genome similar to the action of TCDD is suggested.     

Aflatoxin Related Occupational Hazards Among Rice Mill Workers

Abstract

Present study has been designed to find out the airborne mycoflora of the work environment of rice mills where workers are occupationally exposed to these environmental flora with a special reference to isolation and identification of aflatoxin positive Aspergillus strain from the work environment. The study covered altogether three rice mills located at Bawla town in Ahmedabad district (India). Of all the isolates, 27.39 were Aspergillus of which 6.64; were A. flavus. Quantitative evaluation showed the maximum number of isolates recovered from work place (P<0.01) in comparison to office (control). Strains of A. flavus were subcultured onto various qualitative media for identification of toxigenic strain, but none of the strains showed positive result indicating that all the eight strains were non-toxigenic.     

The Direct Actinc α-Fibrin(Ogen)Olytic Enzymes from Snake Venoms

Abstract

A variety of α-fibrin(ogen)olytic enzymes have been found in snake venoms. More than 15 α-fibrin(ogen)ases have been isolated and characterized. Most work has been done with the venom of snakes belonging to a few species from the Agkistrodon, Crotalus, Trimeresurus, Bothrops, and Vipera. Only one α-fibrin(ogen)olytic enzyme is characterized from Elapidae snake venoms. The enzymatic properties of these proteinases are described in relation to action on fibrinogen, fibrin, and casein. The fibrinolytic enzymes act directly on fibrin and do not activate plasminogen. The proteolytic activity of these metalloproteinases is inhibited by EDTA. Most thoroughly investigated snake venom fibrinolytic enzymes are fibrolase from Agkistrodon contortrix contortrix venom, atroxase from Crotalus atrox venom and cerastase from Cerastes cerastes venom. Antibodies to fibrolase were prepared and their cross-reactions with other fibrinolytic components from several snake venoms have been detected. These antibodies were successfully used for purification of fibrolase from crude southern copperhead venom. Fibrolase and atroxase have no hemorrhagic activity, and they effectively solubilize artificial thrombi. Research in this area has a chance to provide new therapeutic agents for dissolving thrombi.     

Statin plus ezetimibe treatment in clinical practice: the SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) monitoring of clinical practice study

ABSTRACT

Background: Poor results from lipid-lowering therapy are mainly due to inadequate dosing and increased adverse effects with high-dose statin monotherapy or drug combinations.

Objectives: The SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) study evaluated the effectiveness of either ezetimibe (EZE) 10?mg as monotherapy or co-administered with on-going statin treatment (S?+?EZE) in clinical practice.

Design and methods: A total of 1053 dyslipidaemic patients (52% men, age 60.3 years, 42.9% with CHD, 32.0% with diabetes mellitus and 69.6% with hypertension) were enrolled. The majority (n?=?986; 93.6%) were treated with EZE as ‘add-on’ to their already prescribed statin, the rest only received EZE (n?=?67).

Main outcome measures: Baseline lipid levels were compared with those obtained 16 weeks after initiating treatment.

Results: Total (TC) and low density lipoprotein cholesterol (LDL-C), as well as triglycerides (TG) decreased significantly with S?+?EZE (by 25.3%, 31.4% and 28.9%, respectively; p?<?0.0001 for all comparisons), while monotherapy with EZE resulted in a decrease of 20.8% for TC (?p?<?0.0001), 28.0% for LDL-C (?p?<?0.0001) and 28.8% for TG (?p?=?0.016). At the end of the study 43.9% of patients achieved target TC (<?5.0?mmol/L for primary prevention and <?4.5?mmol/L for secondary prevention), 50.5% target LDL-C (<?3.0?mmol/L for primary prevention and <?2.5?mmol/L for secondary prevention) and 61.6% target TG (<?2.0?mmol/L). The overall incidence of adverse effects during the treatment period, and probably related to EZE use, was low (n?=?6, 0.6% of patients).

Conclusions: (1) S?+?EZE combination therapy was effective and safe irrespective of the statin used, (2) the S?+?EZE combination resulted in significantly more patients reaching their recommended target lipid levels and (3) the lipid-lowering efficacy of EZE in monotherapy as well as of the S?+?EZE combination was related to initial lipid values. The much greater decrease of TG than expected could be, at least in part, due to better control/compliance regarding diet and drug treatment during the study and adherence to the need for an overnight fast before sampling.     

Comparative Study of Ceftazidime and Cefamandole in the Treatment of Patients with Infections of Skin and Soft Tissues

Abstract

Ceftazidime (Fortaz, Glaxo, Inc.) and cefamandole were compared in a randomized, prospective study of patients with infections of skin and soft tissue and/or septicemia. Infections caused by gram-positive and gram-negative bacteria were evaluated. Ceftazidime 1 gram IV every 8 hours was used in 20 patients and cefamandole 1 gram IV every 6 hours was used in 15 patients. If bacteria were not sensitive to the agent provided and if laboratory data confirmed resistance to cefamandole and susceptibility to ceftazidime, treatment was changed to ceftazidime. Bacteriological eradication of the initial pathogens and clinical improvement or cure occurred in all patients treated in each treatment group. There were no statistically significant differences (p > 0.05) between the two groups. Four patients originally placed on cefamandole were changed to ceftazidime therapy due to in vitro bacterial resistance. Each of these patients responded favorably with bacteriological eradication and clinical cure. Site of infection, age, sex and concurrent disorder were not determinants of clinical response. One patient experienced phlebitis during ceftazidime therapy; however, the infection continued to respond to IM administration of ceftazidime. Ceftazidime is safe and clinically effective in the treatment of patients with skin and soft tissue infections. It has advantages over cefamandole in the treatment of infections caused by resistant Proteus sp., E. coli, and Pseudomonas sp. Addition of a pure anti-staphylococcal agent to ceftazidime was unnecessary.     

Efficacy,safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study

ABSTRACT

Objective: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).

Methods: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50–85 years were randomized to rivastigmine capsules (3–12?mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.

Trial registration: NCT00099216.

Results: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p?≤?0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (≥?75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine–placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.

Conclusion: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.     

Surface Lipids of Seeds Support Both Aspergillus Parasiticus Growth and Aflatoxin Production

Abstract

Seed surface lipids (SSL) play a key role in supporting aflatoxin (AFT) output in oily and starchy seeds following infection with Aspergillus parasiticus. On oily seeds, fungal growth and AFT production occur when the levels of SSL are higher than 0.15% of total oil content of seeds, with a ratio between triglycerides and free fatty acids (TG/FFA) of SSL > 1. If FFA prevail over TG, growth can be inhibited because of the toxicity towards Aspergillus of unsaturated FFA of SSL. Defatted meals of sunflower seeds support a reduced AFT biosynthesis. On starchy seeds, A. parasiticus proliferates in the germ region, the area richest in lipids.     

Developmental Effects Associated with Exposure to Xylene: A Review

ABSTRACT

Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all of the above mentioned effects, with the exception of cleft palate. The o^- and p^- isomers appeared more hazardous to offspring than did the m-isomer. Malformations (i.e., cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to exposure to xylene has yet to be presented.     

Comparison of Efficacy of Ginger with Various Antimotion Sickness Drugs

Abstract

Ginger and several other medications were compared with scopolamine and d-amphetamine for effectiveness in prevention of motion sickness. Methods: Double-blind techniques were used. The subjects were given the medications two hours before they were rotated in a chair making head movements until a synptun total short of vomiting was reached. Standardized N.A.S.A. techniques were used for speed of rotation and end-point of motion sickness. Results: The three doses of ginger were all at the placebo level of efficacy. Amitriptyline, ethopropazine and trihexyphenidyl increased the tolerated head movements but the increase was not statistically significant. Significant levels of protection were produced by dimenhydrinate, promethazine, scopolmine and d-amphetamine. Protection was further increased by combination of these latter drugs with d-amphetamine. Efficacy was greatest as the dose was increased. Conclusions: The medication of choice in this study was scopolamine 0.6 mg with d-amphetamine 10 mg. This combination provided good protection with acceptable side effects.     

Doxorubicin conjugated with a trastuzumab epitope and an MMP-2 sensitive peptide linker for the treatment of HER2-positive breast cancer

HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic YCDGFYACYMDV-NH₂ (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDYCDGFYACYMDV-NH₂, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX via a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP-DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as in vitro model systems and nude mice with BT474 xenografts as an in vivo model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower in vitro IC₅₀, and its in vivo extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K–AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals.     

Mutagenicity Evaluation of Azaperone in the Salmonella/Microsome Test

ABSTRACT

Azaperone was evaluated for its mutagenic potential by the Salmonella/microsome test. No mutagenic activity towards six S. typhimurium strains could be evidenced with azaperone at doses up to 2,000 µg/plate, either without or with metabolic activation at usual test conditions. Higher concentrations of liver post-mitochondrial fraction from Aroclor 1254 (ARO)-pretreated rats did not reveal any increase in the number of revertants towards S. typhimurium strains TA1537, TA1538 and TA98. Moreover, a plate-incorporation test with liver post-mitochondrial fractions from mice pretreated with phenobarbital (PB) and a liquid preincubation test with liver post-mitochondrial fractions from rats pretreated with ARO also failed to reveal any mutagenic action of azaperone towards S. typhimurium strain TA98. Thus, none of the tests used provided any indication of azaperone having a mutagenic action.     

Preparation and Characterization of Metoprolol Controlled-Release Solid Dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE_8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.     

From a Theoretical Framework of Human Exposure and Dose Assessment to Computational System Implementation: The Modeling ENvironment for TOtal Risk Studies (MENTOR)

Georgopoulos and Lioy (1994) Georgopoulos, P. G. and Lioy, P. J. 1994. Conceptual and theoretical aspects of human exposure and dose assessment. J. Expo. Anal. Environ. Epidemiol, 4: 253–285. [CSA] [Google Scholar] presented a theoretical framework for exposure analysis, incorporating multiple levels of empirical and mechanistic information while characterizing/reducing uncertainties. The present review summarizes efforts towards implementing that framework, through the development of a mechanistic source-to-dose Modeling ENvironment for TOtal Risks studies (MENTOR), a computational toolbox that provides various modeling and data analysis tools to facilitate assessment of cumulative and aggregate (multipathway) exposures to contaminant mixtures.

MENTOR adopts a “Person Oriented Modeling” (POM) approach that can be applied to either specific individuals or to populations/subpopulations of interest; the latter is accomplished by defining samples of “virtual” individuals that statistically reproduce the physiological, demographic, etc., attributes of the populations studied. MENTOR implementations currently incorporate and expand USEPA's SHEDS (Stochastic Human Exposure and Dose Simulation) approach and consider multiple exposure routes (inhalation, food, drinking water intake; non-dietary ingestion; dermal absorption). Typically, simulations involve: (1) characterizing background levels of contaminants by combining model predictions and measurement studies; (2) characterizing multimedia levels and temporal profiles of contaminants in various residential and occupational microenvironments; (3) selecting sample populations that statistically reproduce essential demographics (age, gender, race, occupation, education) of relevant population units (e.g., census tracts); (4) developing activity event sequences for each member of the sample by matching attributes to entries of USEPA's Consolidated Human Activity Database (CHAD); (5) calculating intake rates for the sample population members, reflecting physiological attributes and activities pursued; (6) combining intake rates from multiple routes to assess exposures; (7) estimating target tissue doses with physiologically based dosimetry/toxicokinetic modeling.