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.

I . This communication reports the action of bovine thrombin on ovine, bovine and human growth hormones. Thrombin cleavage was shown to be restricted to a single homologous peptide bond in all three growth hormones (at sequence positions 133 -134 of the ovine and bovine hormones).2. Ovine growth hormone was the most sensitive to the action of thrombin, bovine growth hormone was attacked to a relatively less extent, and human growth hormone was the most resistant to the enzyme.3. After reduction and carbamidomethylation of the disulfide bonds in thrombin modified ovine growth hormone, the two fragments (residues 1 -133 and 134-191) were isolated. The large NH,-terminal thrombin fragment of the hormone (residues 1 -133) was found to be inactive in the rat tibia test, whereas a tryptic fragment (residues 96-133) isolated in an independent way gave measurable responses.After the first isolation of growth hormone from bovine pituitary glands [I], our knowledge of the chemistry of pituitary growth hormones has steadily grown. Complete primary structures (191 amino acids) of human [2-41, ovine [5] and bovine growth hormones [6-81 have been elucidated, revealing a 65 homology between the structures of human and ovine growth hormones [3] and only a single sequence difference between the ovine and bovine hormones [7 -81.

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).

The effect of tamoxifen (TAM) on the serum levels of sexual hormones and on the sex hormone-binding globulin (SHBG) was investigated in 30 postmenopausal patients with advanced breast cancer. To study the ‘prolactin reserve capacity’ of the pituitary gland, thyrotrophin-releasing hormone (TRH) and sulpiride-induced prolactin release were measured prior to TAM treatment, then in the 2nd and 8th week of the therapy. The TRH (400 μg i.v.)-induced prolactin secretion was significantly suppressed by TAM after an 8-week treatment, but only in responding cases. Maximal prolactin stimulation occurred at the 15th min after TRH injection, being equal to 5,600 ± 800 mlU/l in cancer patients, and decreasing to 2,400 ± 150 mlU/l after 8 weeks. TAM did not suppress the sulpiride-inducable prolactin release either in responders or in nonrespon-ders.

It is well known that administration of a single injection of testosterone propionate to newborn female rats results in permanent anovulatory sterility. After puberty these animals show permanent vaginal cornification and their ovaries contain follicles but no corpora lutea (Barraclough, 1961). One of the most important lesions in these rats seems to be a blockade of the pre-ovulatory discharge of luteinizing hormone releasing factor (LH-RF) from the median eminence.Porcine LH-RF has been shown to be a decapeptide, pyro Glu-His-Trp-Ser-Tyr\x=req-\ Gly-Leu-Arg-Pro-Gly(NH2), and when this polypeptide was synthesized it was found to have follicle-stimulating hormone releasing factor activity as well (Matsuo, Matsuo, Baba, Nair, Arimura & Schally, 1971). In the present experiments we posed the question of whether a subcutaneous injection of synthetic LH-RF could induce ovulation in androgen-sterilized female rats, and if so, whether this would be a dose-dependent effect.Albino rats of the Sprague\p=m-\Dawley strain kept in light-controlled quarters were used. On the morning of the 3rd day after birth female rats were given 10, 50, 100 or 1000/¿g testosterone propionate, subcutaneously. Two weeks before autopsy vaginal smears were taken and only rats showing persistent cornification of the vaginal mucosa were used. The LH-RF decapeptide was synthesized in our laboratory by a conventional fragment condensation method. Its homogeneity was examined by thin-layer chromatography and electrophoresis. The amino acid composition, amino acid sequence and optical rotation ([a]ff = -49°, in 1 % acetic acid) of the