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Congress in St. Gallen, Switzerland last year showed that treatment of people with high blood pressure in the US reduced deaths from cardiovascular disease by two thirds between 1950 and 1994. Without antihypertensive therapy, the study found, an estimated 86 000 excess premature deaths from cardiovascular disease and more than 800 000 hospitalizations for stroke and heart attacks would have occurred. Treatment of hypertension was highly cost effective, creating USD 10 in value for each dollar spent for American women, and a payback of USD 6 per dollar spent for treatment of American men with high blood pressure. To demonstrate the value of its medicines, Novartis conducts and supports extensive health economic research. The analysis is often based on large clinical trials but increasingly also "real-world" outcomes. A study involving Diovan, for example, analyzed claims data from a US pharmacy benefit manager showing treatment outcomes for more than 140 000 patients with hypertension. The study found that patients who received Diovan "in a usual care setting" had better compliance with therapy than people who received either amlodipine or lisinopril, two other antihypertensive medicines. According to the authors, the findings suggest that choice of Diovan for chronic drug management of hypertension "has the potential to affect patient drug-taking behavior and perhaps longer-term outcomes in a typical real-world setting." Moreover, in one of the clearest examples yet of the value of a pioneering medicine, Novartis broke new ground with Gleevec Glivec, an innovative treatment for people with chronic myeloid leukemia who were in an advanced stage of the disease, blast crisis or intolerant to interferon. After being designated an orphan drug, Glivec was.
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Variable regions of the external envelope glycoprotein of human immunodeficiency virus type 1 in chimpanzees infected with the virus and baboons immunized with a candidate recombinant vaccine. Journal of General Virology 73, 1099 1106. THmlART, C., FRANCOTTE, M., COHEN, J., COLLIGNON, C., DELERS, A., KUMMERT, S., MOLITOR, C., GILLES, D., ROELANTS, P., VAN WIJNENDAELE, F., DE WILDE, M. & BRUCK, C. 1989 ; . Several antigenic determinants exposed on the gp 120 moeity of HIV- 1 gp 160 are hidden on the mature gpl20. Journal of Immunology 143, 1832-1836. TOWBIN, H., STAEHELIN, T. & GORDON, J. 1979 ; . Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets : procedure and some applications. Proceedings of the National Academy of Sciences, U.S.A. 76, 435 b4354. VAHLNE, A., HORAL, P., ERIKSSON, K., JEANSSON, S., RYMO, L., HEDSTROM, K. G., CZERKINSKY, C., HOLMGREN, J. & SVENNERHOLM, B. 1991 ; . Immunizations of monkeys with synthetic peptides disclose conserved areas on gpl20 of human immunodeficiency virus type 1.
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Six months may exist in the hospital environment [37, 92].The results of these studies indicate that extensive air sampling, as well as typing of all recovered isolates may be necessary to link cases of invasive aspergillosis with environmental recovery of Aspergillus spp. Studies on the relation between airborne Aspergillus conidia and invasive aspergillosis have primarily focused on in-hospital exposure to Aspergillus conidia. However, since little is known on the incubation period of invasive aspergillosis, it may well be that patients become colonized outside the hospital, either before or after discharge, and that invasive aspergillosis is, at least partly, a community acquired disease. Arguments in favor of this hypothesis, comes from a study from Einsele et al. [97], were bone marrow transplant patients underwent a bronchoalveolar lavage in a screening procedure at the time of the transplantation. Seven out of 134 patients tested positive in the PCR for Aspergillus and five of them developed invasive aspergillosis during their immunosuppressive treatment after the transplantation. None of the patients with a negative PCR result developed invasive aspergillosis. This study suggests that preventive measures should not be aimed at the hospital environment only. Water The discovery of hospital water as a source of A. fumigatus and other filamentous fungi may suggest a new route for the transmission of invasive filamentous fungal infections. It might well be that conidia originating from water, become aerosolized during activities like showering. Subsequently, patients may inhale the aerosols containing Aspergillus conidia and become infected. Alternatively, conidia may be present on walls and floors of the bathroom, being disturbed by air flow changes which occur during showering. Initial studies indicate that there is an increase in conidial counts in the air in patient bathrooms over the day after multiple shower periods [51]. Anaissie et al. [98] showed that a gradient exists between patient bathrooms and patient rooms and hallways, with higher numbers of aerosolized conidia in the bathrooms. Furthermore, conidial air counts of Aspergillus spp. were increased during showering, suggesting that aerosolization occurs during showering. The clinical significance of these findings as yet remains unclear. To prove a wet route of transmission, molecular characterization of isolates recovered from water and patients is warranted. Preliminary results obtained by analysing various isolates by amplified fragment length polymorphism AFLP ; showed genotypic relatedness between clinical isolates recovered from three patients with isolates recovered from water [99]. Although preliminary, these results suggest that a wet route of transmission may exist. Besides this, anecdotal reports have linked invasive aspergillosis with aspiration of contaminated surface water in near-drowning patients [100, 101]. Other routes of transmission Although inhalation of airborne conidia is believed to be the primary route of acquiring Aspergillus infection, alternative modes of transmission may be present. Breeches in the skin and intravenous insertion sites, with or without the use of adhesive tapes and armboards, can serve as a port d'entre by disrupting the outer barrier integrity [102-104]. Contamination of wounds or the immature, thin skin in very low birth weight infants, by direct inoculation or from the surrounding air, has also been reported [105-107]. Recently, a cluster of cutaneous.
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Imatinib mesylate STI571; Gleevec ; is a potent tyrosine kinase inhibitor with selectivity against c-abl and bcr abl, as well as c-kit and platelet-derived growth factor receptor PDGF-R ; .1, 2 Significant activity has been demonstrated in patients with Philadelphia chromosome Ph ; positive chronic myeloid leukemia CML ; after failure of interferon-alpha IFN- ; therapy. The standard dose recommended for chronic-phase CML is 400 mg daily. With these doses, more than 90% of patients treated in chronic-phase CML after IFN- failure achieve a complete hematologic response CHR ; , 3, 4 and 60% achieve a major cytogenetic CG ; response, which is complete in 40%.3, 4 After a median follow-up of 18 months, 90% of patients have not transformed to the accelerated or blastic phase. As significant as these responses are, most patients still do not achieve a complete CG response, and 8% have lost their major CG response.3 Achievement of a complete CG response has been associated with 10-year survival rates of 70% to 85%5-8 with IFN- based therapy. Thus, achievement of a complete CG remission is the most important short-term objective of CML therapy. Furthermore, molecular remissions have been rare among patients treated with standard-dose imatinib.9 Data from imatinib trials suggest that higher doses of imatinib may be more effective. The initial dose-finding phase 1 trial reported a clear relationship between dose and response.10 Complete hematologic responses were achieved in 98% of patients treated at daily doses of 300 mg or higher, compared with 56% in patients treated with 200 or 250 mg daily, and lower responses at doses of less than 200 mg daily. Cytogenetic response occurred in 29 54% ; of 54 patients treated at 300 mg d or higher, while only 2 patients treated at lower doses had such a response.10 In the phase 2 studies, patients in accelerated phase were treated with a daily starting dose of either 400 mg or 600 mg.11 The higher dose induced higher response rates and longer response durations and survival compared with the lower dose. In the chronic-phase trials, imatinib dose escalation to 800 mg daily in patients not responding to 400 mg recaptured CHR in 2 of patients and improved cytogenetic response to a major one in 40%. Finally, amplification of the BCR ABL gene or overexpression of its protein product is one of the known mechanisms of resistance.12-15 In this study we investigated the efficacy and toxicity profile of high-dose imatinib in patients with CML after IFN- failure. We observed a high rate of major and complete cytogenetic responses and, more important, a high rate of complete molecular remission and glucagon.
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. 6.1 Chronic Myeloid Leukemia The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash Table 2 for newly diagnosed CML, Table 3 for other CML patients ; . Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec. [see Dosage and Administration 2.10 ; ] The frequency of severe superficial edema was 1.5%-6%. A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies where the dose was 600 mg day ; , and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec treated patients are shown in Tables 2 and 3. Table 2 Adverse Reactions Reported in Newly Diagnosed CML Clinical Trial 10% of Gleevec treated patients ; 1 ; All Grades CTC Grades 3 4.
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Of Molecular Biology of Cancer, 2Department of Molecular and Medical Biophysics, 3Department of Molecular Cancerogenesis, Medical University of Ld, Ld, Poland * e-mail: Justyna Jakubowska jjakubowska poczta. onet STI571 imatinib; Gleevec ; developed as the molecularly targeted therapy is a potent and selective inhibitor of Bcr-Abl and is a first-line drug for the treatment of newly diagnosed CML patients. Although highly active in early stages of CML, STI571 seems unable to eradicate the malignant progenitors and several patients develop drug resistance after long-time use. Combination of STI571 with doxorubicin DOX ; was investigated to determine optimal concentrations of both drugs which could enhance the pro-apoptotic activity of STI571 in apoptosis reluctant cell line K562, derived from blast crisis CML patient. Analysis of cell proliferation has shown that STI571 and DOX exerted synergistic or additive effects on K562 cells depending on the concentrations used in the study. Examination of cell cycle indicated that DOX induced G2 M arrest whereas dependence on concentrations of STI571 was observed when DOX was combined with different concentrations of STI571. The antiproliferative activities were mainly due to the effect on cellular differentiation when STI571 in the range of 100250 nM was combined with 40 nM DOX and apoptosis when STI571 used in combinations was in the range of 250800 nM. Both processes were accompanied by m dissipation. A low concentration of STI571 in combination with low concentration of DOX might be an alternative approach to high concentration of STI571 currently used in clinics. This therapeutic strategy might decrease the probability of STI571 resistance development and side effects caused by higher doses of DOX, and therefore increase the efficacy of chemotherapy against CML and goldenseal.
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Came much more intimate with my beans than usual. But labor of the hands, even when pursued to the verge of drudgery, is perhaps never the worst form of idleness. It has a constant and imperishable moral, and to the scholar it yields a classic result. A very agricola laboriosus was I to travellers bound westward through Lincoln and Wayland to nobody knows where; they sitting at their ease in gigs, with elbows on knees, and reins loosely hanging in festoons; I the home-staying, laborious native of the soil. But soon my homestead was out of their sight and thought. It was the only open and cultivated field for a great distance on either side of the road, so they made the most of it; and sometimes the man in the field heard more of travellers' gossip and comment than was meant for his ear: "Beans so late! peas so late!" -- for I continued to plant when others had begun to hoe -- the ministerial husbandman had not suspected it. "Corn, my boy, for fodder; corn for fodder." "Does he live there?" asks the black bonnet of the gray coat; and the hard-featured farmer reins up his grateful dobbin to inquire what you are doing where he sees no manure in the furrow, and recommends a little chip dirt, or any little waste stuff, or it may be ashes or plaster. But here were two acres and a half of furrows, and only a hoe for cart and two hands to draw it -- there being an aversion to other carts and horses -- and chip dirt far away. Fellow-travellers as they rattled by compared it aloud with the fields which they had passed, so that I came to know how I stood in the agricultural world. This was and gleevec.
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