DA8 Evaluating Health Outcomes and Pharmacoeconomic Literature

In 1997, the United States Pharmacopeia (USP) established an Ad Hoc Outcomes/Cost Effectiveness Advisory Panel to consider the development of specifications for compiling, indexing, and evaluating outcomes research/cost-effectiveness literature on a disease-specific basis. Such a resource could be used to support pharmaceutical therapy choice decision making by a variety of potential users. The USP had developed a protype health outcomes and pharmacoeconomic annotated registry of the literature on the disease state, congestive heart failure. Other organizations have established and are marketing pharmacoeconomic and health outcome literature registries, with two examples being the HEED database (OHE-IFPMA Database Ltd.) and the University of York NHS Centre for Reviews and Dissemination (DARE).
OBJECTIVE: To share experiences and to identify the needs of decision makers for outcome/pharmacoeconomic information and to discuss whether they are being met by currently available literature sources. Decision makers include health care practitioners, managed care organizations, third party payers, industry and governments.
WORKSHOP FORMAT: The USP congestive heart failure protype literature registry will be described and compared to currently available pharmacoeconomic/outcome databases. Participants will share their assessment of the currently available abstracting service/databases and determine if there is a role for further developments.
DESIRED OUTCOME: To determine if there is a need for a collaborative approach among interested parties to make relevant health outcome/pharmacoeconomic information more accessible to the drug therapy decision makers in a format that is "user friendly."     

Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.

A Spanish National PBPC Donor Registry has recently been established for short- and long-term safety data collection in normal donors receiving rhG-CSF. To date, 466 donors have been included in the Registry. Median (range) dose and duration of rhG-CSF administration was 10 microg/kg/day (4-20) and 5 days (4-8), respectively. Donors underwent a median of two aphereses (range, 1-5). Adverse effects consisted mainly of bone pain (90.2%), headache (16.9%) and fever (6. 1%), but no donor discontinued rhG-CSF prematurely due to toxicity. Side-effects were more frequent in donors receiving >10 microg/kg/day than in those with lower doses (82.8% vs 61.8%; P = 0. 004). A significant decrease between baseline and post-apheresis platelet counts was the most important analytical finding (229 x 10(9)/l vs 140 x 10(9)/l; P < 0.0001), with a progressive reduction in platelet count with each apheresis procedure. One donor developed pneumothorax that required hospitalization due to central venous line placement. The mean CD34+ cell dose collected was 6.9 x 10(6)/kg (range, 1.3-36), with only 14 donors (2.9%) not achieving a minimum target of CD34+ cells of 2 x 10(6)/kg. No definitive information about potential long-term side effects is yet available. However, we hope this National Registry will serve as a useful basis for better monitoring of the efficiency and side-effects of cytokine administration in healthy people.     

Exercise intolerance resulting from a muscle-restricted mutation in the mitochondrial tRNA(Leu (CUN)) gene.

BACKGROUND: Some patients presenting with isolated lifelong exercise intolerance and ragged-red fibres, harbour skeletal-muscle restricted mutations in their mitochondrial DNA. AIM: To identify the molecular defect in a patient presenting with lifelong exercise intolerance, ragged-red fibres and deficiencies of complexes III and IV in skeletal muscle. METHODS: The muscle biopsy was studied for activities of the respiratory chain, histochemical stains, and sequencing the tRNA genes of mitochondrial DNA. RESULTS: The patient had a heteroplasmic mutation in the tRNA(Leu (CUN)) gene of mitochondrial DNA (G12334A). Clinical and morphological data as well as restriction fragment length polymorphism (RFLP) and single-fibre polymerase chain reaction (PCR) analyses strongly indicate that this molecular defect is the primary cause of the myopathy. CONCLUSION: Mutations in any mitochondrial gene should be considered in the differential diagnosis of patients with lifelong exercise intolerance, even when the neurological examination is normal.     

A combination of a T cell-derived lymphokine differentiation-inducing activity and a physiologic concentration of retinoic acid induces HL-60 to differentiate to cells with functional chemotactic peptide receptors

The human acute promyelocytic leukemia cell line HL-60 is induced by retinoic acid (RA) and N,N-dimethylformamide (DMF) to differentiate into cells having many of the functional and morphologic characteristics of mature granulocytes. With normal human phagocytic cells there is both superoxide anion (O2-) production and chemotaxis in response to chemoattractants such as N-formyl-methionyl-leucyl- phenylalanine (FMLP). We have now found that although HL-60 cells induced with RA alone produce O2- in response to 12-0-tetradecanoyl- phorbol-13-acetate (TPA) they are deficient in FMLP-stimulated O2- production and chemotaxis. In contrast, HL-60 induced either with DMF or with a combination of 10 nmol/L RA and a T cell-derived lymphokine, differentiation-inducing activity (DIA), produce O2- and exhibit chemotaxis in response to FMLP. The basis for these results appears to be the concentration of cell surface chemotactic peptide receptors. Thus, untreated HL-60 and HL-60 induced with either RA alone or DIA alone do not have measurable levels of FMLP receptors, whereas HL-60 induced with a combination of RA and DIA has 5,400 receptors per cell. HL-60 induced with RA and DIA plus 1 mumol/L dexamethasone have 25,000 receptors per cell and have greater chemotactic activity than HL-60 induced with the combination of RA and DIA. Thus, differentiation of HL- 60 to cells with many properties of normal phagocytes can be induced in vitro by physiologic substances.     

光学活性的α-甲基丁酰基间苯三酚类化合物绝对构型与旋光方向的关系及其合成

合成了14个新化合物,其中有12个是(S)-(+)-α-甲基丁酰基间苯三酚类化合物。通过对新化合物旋光资料的研究和分析,找到了它们绝对构型与旋光方向的关系。该规律在测定光学活性的α-甲基丁酰基间苯三酚类化合物的绝对构型和开发研究该类药物上,均具有一定的实际应用价值。     

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.