Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.

First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

[Cancer in Israel: mass mediated reality vs. real reality].

BACKGROUND: Cancer, being a terminal and often incurable disease, is a source of fear and concern for human beings. One of the most important sources of medical information in general, and cancer specifically, is the mass media. The media can shape beliefs regarding health and influence people's decision-making. The main hypothesis guiding this study, based on the theoretical framework of cultivation research, is that there will be considerable differences between media coverage and medical data regarding cancer in the Israeli population. METHOD: A systematic content analysis was applied to test this hypothesis, examining all the press reports (650 articles) published during the year 2000 in three of Israel's most popular daily newspapers--"Yedioth Ahronot", "Maariv" and "Haaretz". Data from the Israeli Ministry of Health was used for comparison with media reports to the population in terms of the types of cancer reported, the emphasis on death in the context of the disease, reports concerning treatment, and the age of cancer patients. RESULTS: The findings of the study are in accordance with the main hypothesis and show that the media's portrayal of cancer does not always reflect the medical reality regarding the above mentioned aspects. Several possible explanations are proposed in analyzing these findings, focusing mainly on the nature of news making and media selection, as well as on the impact of various interest groups such as pharmaceutical companies, hospitals. laboratories, oncology departments, and various organizations trying to promote awareness and raise funds for research. CONCLUSION: The findings of this study enhance a wide range of research in different areas of human knowledge that have documented processes of constructing "mass-mediated realities", but in the case of a fatal disease, the findings may have acute implications.

Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia.

OBJECTIVE: To assess the crossreactivity of glucosamine sulfate, used for treatment of degenerative joint disease with antibodies induced in heparin-induced thrombocytopenia (HIT). BACKGROUND: HIT is a severe adverse effect of heparin therapy induced by an immunological mechanism. The antibodies in HIT are induced by a complex of heparin and, in most cases, platelet factor 4. Hereby generation of the antigen is not strictly dependent on heparin. Heparin can be substituted by a variety of polysulfated carbohydrates. In vitro and in vivo crossreactivity of HIT antibodies has been demonstrated for a chemically polysulfated chondroitin-like substance (Arteparon, Luitpoldwerke, Munich, Germany), formerly used for chondroprotection. Another drug widely used in the treatment of degenerative joint disease is glucosamine sulfate. Glucosamine is a building block of glycosaminoglycans, of which heparin is the clinically most important. Many patients with degenerative joint disease use glucosamine sulfate. This group is also at the highest risk to develop HIT following joint replacement surgery. METHODS: We examined the interactions of glucosamine sulfate (DONA 200-S, Opfermann, Wiehl, Germany) with platelets and antibodies of patients with HIT in and without the presence of heparin. Sera of 5 HIT patients and platelets of 4 healthy donors were used. The binding of HIT antibodies to PF4/glucosamine sulfate complexes was assessed by an ELISA. RESULTS: HIT antibodies did not activate platelets in the presence of glucosamine sulfate in a serotonin-release assay. Preincubation with glucosamine sulfate did not inhibit platelet activation by HIT antibodies in the presence of heparin (0.2 IU/ml). Antibodies bonded to PF4/heparin but not to PF4/glucosamine sulfate complexes. CONCLUSIONS: In contrast to sulfated glycosaminoglycans, there is no evidence for an immunological crossreactivity of HIT antibodies between heparin and glucosamine sulfate.

t(5;14)(q33-34;q11), a new recurring cytogenetic abnormality in childhood acute leukemia.

A novel translocation, t(5;14)(q33-34;q11), was identified in the leukemic cells of four children presenting with acute lymphoblastic leukemia (ALL). The patients were 14 months, 2 years, 10 years, and 12 years old; each presented with one or more features of bulky disease, including lymphadenopathy, organomegaly or a mediastinal mass. The leukemic blasts were B lineage in two cases and T lineage in two cases. The patients with B-lineage ALL remain in continuous remission at 22 and 19 months following diagnosis. One patient with T-lineage ALL relapsed 6 months after diagnosis. The other patient with T-lineage ALL developed acute myelocytic leukemia (AML) 17 months after diagnosis; t(5;14)(q33-34;q11) was present in both the lymphoblasts at diagnosis and the myeloblasts at relapse, consistent with a lineage switch from ALL to AML. Rearrangement of the T-cell receptor delta chain (TCRD) gene at 14q11 was demonstrated in the three cases studied, suggesting its involvement in the pathogenesis of these leukemias by alteration of the structure or expression of an unidentified gene(s) on the long arm of chromosome 5.