European regulation on orphan medicinal products: 10 years of experience and future perspectives.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

[Noninvasive assessment of endothelial function in hemodialyzed hypertensive patients by laser Doppler flowmetry]. / Az endothelfunkció noninvazív vizsgálata dializált hypertoniás betegekben lézer Doppler-áramlásméréssel.

BACKGROUND: End stage renal disease and hypertension are associated with higher cardiovascular mortality. Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. The authors investigated the endothelium-dependent and -independent vasodilation in the forearm skin microcirculation and the plasma markers of endothelial damage in hypertensive hemodialysed patients and in normotensive control subjects. METHODS: Laser Doppler flowmetry with iontophoresis of acetylcholine and sodium nitroprusside and the postocclusive reactive hyperemia test was performed in 22 normal control subjects and in 21 hemodialysed patients with hypertension. Levels of endothelin-1, big-endothelin, and von Willebrand Factor were measured, as well. RESULTS: The average hyperemic response to the two doses of acetylcholine iontophoresis was 474 +/- 83%; 836 +/- 97% in the control subjects, and 160 +/- 26%; 360 +/- 67% in the hemodialysed patients group (p < 0.05). The vasodilation after the two doses of sodium nitroprusside was 381 +/- 60%, 782 +/- 81% in the control group and 186 +/- 42%; 379 +/- 63% in the dialysed patients group (p < 0.05 compared to control, respectively). The average peak flow during the postocclusive reactive hyperemia test was significantly lower in hemodialysed hypertensives (234 +/- 48%) compared to healthy control subjects (434 +/- 36%, p < 0.05). Levels of endothelin-1, big endothelin, von Willebrand Factor and von Willebrand Factor activity were significantly higher in the patient group compared to the control subjects. CONCLUSIONS: In hemodialysed hypertensive patients, both endothelium-dependent and -independent vasodilation are impaired. Markers of endothelial damage are elevated referring the progression of vascular disease.

Biomolecular cytokine therapy.

As for the chronicity of inflammatory-immune diseases, the medication of them needs to be longterm and thus, quite safe with respect to side effects due to drug actions. Therapy of these diseases includes steroid and non steroid anti-inflammatories given in monotherapy or in combination with cytotoxic antimetabolites. Longterm administration of these active substances cumulate in side effects, not to speak of the probability of developing unresponsiveness to the drug in use. In principle, the earlier the intervention, the better the outcome of medication in therapy. In harmony with this principle, biopharmacology focuses on specific targets in early (acute) phase of inflammatory-immune diseases. One of these targets is the proinflammatory cascade of cytokines (IL1beta, IL6, IL8, IL12, TNFalpha). Among them, the overproduction of tumor necrosis factor (TNFalpha) is suggested to orchestrate and escalate the disease phenotype. Hence, targeting of TNFa may restrict or stop the propagation of pathological reactions. TNFalpha in its excess can be captured at transcription, translation, secretion levels as well as in the extracellular soluble form. This latter approach is supported by clinical records emphasizing the use of recombinant antibodies and soluble receptors in trapping extra amounts of TNFalpha. This review serves as an illustration for the efficacy and safety of infliximab (antibody) and etanercept (soluble receptor) in the example of rheumatoid arthritis (RA).