Plasma concentrations of isosorbide dinitrate after administration of increasing doses of a sustained-release formulation to human subjects

Plasma concentrations of isosorbide dinitrate have been measured after administration of increasing doses in the range 20--100 mg as sustained-release tablets (Isoket retard) containing 20 mg to human subjects. Means of peak concentrations of 4.2 ng/ml, 13.1 ng/ml, 20.7 ng/ml, 36.8 ng/ml, and 34.9 ng/ml were measured after doses of 20 mg, 40 mg, 60 mg, 80 mg and 100 mg, respectively. In the plasma of individual subjects, peak concentrations of isosorbide dinitrate increased in proportion to the dose administered. Areas under the plasma isosorbide dinitrate concentration-time curves also increased in proportion to the dose administered. Bioavailability parameters were better correlated to the dose over the range 20--60 mg than over the range 20--100 mg.     

Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system

Human influenza vaccine reference strains are prepared as required when an antigenically new strain is recommended by WHO for inclusion in the vaccine. Currently, for influenza A, these strains are produced by a double infection of embryonated hens' eggs using the recommended strain and the laboratory strain PR8 which grows to high titre in eggs, in order to produce a high growth reassortant (HGR). HGRs are provided by WHO reference laboratories to the vaccine manufacturing industry which use them to prepare seed virus for vaccine production. The use of reverse genetics in preparing vaccine reference strains offers several advantages over the traditional method: (i) the reverse genetics approach is a direct rational approach compared with the potentially hit-or-miss traditional approach; (ii) reverse genetics will decontaminate a wild type virus that may have been derived in a non-validated system, e.g. a cell line not validated for vaccine purposes, or that may contain additional pathogens; (iii) at the plasmid stage, the HA can be engineered to remove pathogenic traits. The use of reverse genetics in deriving HGRs has been demonstrated by several laboratories, including its use in deriving a non-pathogenic reassortant strain from a highly pathogenic virus. In this report, we have advanced the use of reverse genetics by making use of a cell line acceptable for human vaccine production, by demonstrating directly the short time frame in which a reassortant virus can be derived, and by deriving a non-pathogenic pandemic vaccine reference virus in cells validated for vaccine production and under quality controlled conditions.     

On-line hemodiafiltration does not induce inflammatory response in end-stage renal disease patients: results from a multicenter cross-over study

BACKGROUND: On-line hemodiafiltration (HDF) represents the supreme blood purification modality for end-stage renal disease (ESRD) patients. Large-volume infusion of on-line prepared substitution fluid may, however, expose patients to inflammatory contaminants. As a result, on-line HDF might aggravate chronic inflammation, which correlates with malnutrition, cardiovascular disease, and mortality among ESRD patients. METHODS: In a multicenter cross-over study, 27 ESRD patients were randomly assigned to treatment with on-line HDF and low-flux hemodialysis (HD). After 6 months, patients were crossed to the other treatment modality, and treatment continued for another 6 months. Both on-line HDF and low-flux HD were conducted with polysulfone membranes and ultrapure dialysis fluid. Samples were drawn at the end of each treatment period. RESULTS: Inflammatory parameters were elevated in the study population when compared to healthy controls. Induction of interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor alpha (TNF-alpha) was comparable for on-line HDF and low-flux HD, and there was no intradialytic increase in cytokine production. As a result, interleukin-6 (IL-6) plasma levels did not differ significantly between the two treatment modalities. Similarly, no difference between on-line HDF and low-flux HD was observed for C-reactive protein (CRP) and albumin. Markers of endothelial cell activation (soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1) as well as the cardiovascular risk marker cardiac troponin T (cTnT) remained elevated compared to healthy subjects, but showed no difference between the two treatment modalities. CONCLUSIONS: On-line HDF, as the most effective renal replacement therapy, does not provoke inflammatory response and is both safe and highly biocompatible.     

D-penicillamine induced suppression of B cell function: in vivo effect of D-penicillamine

We assessed the immunoglobulin secretory capacity of circulating B lymphocytes in 9 patients with classical rheumatoid arthritis (RA) before and after treatment with D-penicillamine. Peripheral blood lymphocytes (PBL) from patients with RA spontaneously synthesized more IgG and IgA than normals. The secretory rate of rheumatoid PBL could not be induced by the polyclonal activator, pokeweed mitogen (PWM). The presence of D-penicillamine in cultures significantly suppressed PWM stimulated immunoglobulin synthesis of control PBL but did not inhibit synthesis of mitogen stimulated RA PBL. After D-penicillamine therapy for 3 months immunoglobulin synthesis by PBL from patients with RA was reduced with or without PWM. The T mu:T gamma ratio was also decreased after therapy. These results support the hypothesis that D-penicillamine selectively impairs helper T cells in vivo, preventing the T dependent expansion and activation of B cells characteristic of RA.     

The localization of a histamine H2-receptor adenylate cyclase system in canine parietal cells and its inhibition by prostaglandins

A method is described for the preparation of parietal cell-enriched suspensions from dog gastric mucosa. Histamine and E type prostaglandins produce an elevation of cyclic AMP concentration in mixed cell preparations. Parietal cell-rich fractions respond to histamine but only weakly to prostaglandins whilst in fractions virtually free from parietal cells the converse is observed. Prostaglandins which are good antisecretory agents, PGE₁, PGE₂ and 16,16 dimethyl PGE₂ are potent inhibitors of the histamine elevation of cyclic AMP in parietal cell-rich fractions, whilst PGF₂ shows 1% of their potency. The experiments described support the view that histamine stimulates gastric acid secretion by excitation of an H₂-receptor adenylate cyclase system in the plasma membrane of the parietal cell and that acid secretory inhibition by prostaglandins is a result of inhibition of that system.     

Latinos and electroconvulsive therapy: implications for treatment, research, and reform in Texas and beyond

No literature exists concerning the implications of using electroconvulsive therapy (ECT) in the treatment of Latinos. Given the large and increasing Latino population in the United States, the contentious history of ECT, and the possible differences in language and cultural vantage point between the typical ECT provider and Latino client, this paucity of research is worrisome. This article identifies a number of potential problems involved in multiculturally untrained service providers treating Latinos with ECT, including invalid diagnoses, an incomplete knowledge of the strengths and resiliencies of the client, and the use of ECT rather than culturally appropriate interventions. Also discussed are Latino cultural beliefs and practices salient to mental health service providers, some of the recent mandates for multiculturally informed service provision in mental health, ideas for the constructive modification of the diagnostic and treatment protocols currently guiding the use of ECT with Latinos, and needed research relevant to the issues raised.     

Screening mammography participation and invitational strategy: the Quebec Breast Cancer Screening Program, 1998-2000

In the Quebec Breast Cancer Screening Program, a personalized letter signed by a regional program physician is sent to every woman in the province 50 to 69 years of age, inviting her to have a screening mammogram. A reminder letter is also frequently sent. The aim of this study was to evaluate the influence of this screening invitational strategy on rates of participation. The population studied was comprised of 684,028 women in Quebec aged 50-69. The baseline (expected) monthly mammography screening rate was estimated from the rate of screening mammograms recorded between the date a woman became eligible for screening and the mailing date of her personalized invitational letter; the observed monthly mammography screening rate was calculated after the mailing of the letter. Compared to baseline (expected) screening rates, observed rates were substantially increased (p<.05). The ratios of observed to expected rates were respectively 3.05 and 2.23 in the second and fourth months, respectively, after the letter mailing, coinciding with the mailing of the initial and reminder letters. In the twelve months after the mailing, the ratio of observed to expected rates was 1.68 (95% CI: 1.67-1.69). Twelve months following the mailing, 30 percent of the women who were letter recipients had undergone a screening mammography, compared to an expected cumulative probability of 20 percent for women not receiving a letter. The strength of this effect was similar to one seen in randomised controlled trials.