Synthesis and antimalarial activity of new amino analogues of amodiaquine.

Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.

Reprimun--an antibiotic with large spectrum and immunomodulatory properties.

Reprimun contains an oxyminomethyl rifamycin-SV derivative as the active substance and has a large spectrum antibiotic activity, on Mycobacterium tuberculosis too. Reprimun also shows an inhibitory activity on viral and human lymphocyte reverse transcriptases, an antiproliferative effect on retrovirus, as well as a selective immunomodulator action at the level of TCD4+ lymphocyte. In animal, the toxicity tests demonstrated a good tolerance. In human subject, the drug is quite well tolerated: no severe adverse reactions were noted during and after its administration for 10-12 months. In man, Reprimun administration demonstrated a therapeutical effect in bacterial infections (tuberculosis included), sarcoidosis, immune thrombocytopenia, as well as in Kaposi's sarcoma. The drug is only for oral administration. It is well absorbed at the level of duodenum, achieving a repeated entero-hepatic circuit that provides a prolonged efficient concentration of Reprimun in blood serum. Like many other ansamycin derivatives, Reprimun can be given intermittently (e.g. twice or three times weekly). In case of antisarcoidosis therapy, Reprimun was applied with good results in 112 supervised cases, including 37 failures of a prior cortisone treatment its administration could be of a high benefit in HIV serum positive persons in which it can prevent both tuberculosis and HIV infection developments.

[AIDS and tuberculosis: the immunopathogenic processes]. / SIDA si tuberculoza: procese imunopatogene.

HIV infection is characterized by CD4+ lymphocyte depletion manifested through the loss of the immune response capacity. The resulting immunodeficit is expressed by the blocking of immune surveillance mechanisms and, thus, by the establishment of favourable conditions to the development of opportunistic infections and/or malignant processes. In tuberculosis, the immunodeficiency associated with HIV infection makes possible the evolution of a latent infection to a clinically manifest disease. Latent tuberculosis is characterized by the intracellular persistence of some metabolically inactive Tb bacillus forms which are incapable of multiplication. The conversion of these inactive into metabolically active forms capable of multiplication is usually neutralized by immunosurveillance mechanisms. The blocking of such mechanisms in case of CD4+ cell depletion will allow the multiplication of metabolically active Tb bacillus forms, and the development of a clinically manifest tuberculosis. CD4+ lymphocyte depletion is the result of facilitating antibodies and certain cytokines, and of some autoimmune processes which also affect the non-infected CD4+ cells. Therefore, it is necessary that Tb chemoprophylaxis in HIV infected subjects should also be addressed to the processes initiating the immune deficit, which include autoimmune mechanisms as well as those facilitating HIV infection.

[The importance of assessing angiotensin-converting activity in silicosis patients]. / Semnificatia evaluarii activitatii angiotensin-convertazice în serul bolnavilor cu silicoza.

The macrophage cells have an essential role in the pathogenesis of silicosis. After the endocytosis of silica grains, the lung macrophage demonstrates an active state, associated with high levels of lysosomal enzymes, expressed also in serum. A similar active state of macrophages is evident in sarcoid lung which manifests also an intensive serum activity of angiotensin-converting enzyme. The angiotensin-converting assay in the serum of 116 silicotic patients revealed over 60 per cent higher levels than in normals. Such increased levels were present more frequently among the patients with early studies of silicosis. In the same patients, the serum acid phosphatase activity, a marker of macrophage activity, and also serum lactate dehydrogenase activity, were higher than in normal individuals. On present evidence, it can be appreciated that increased serum levels of angiotensin-converting activity could be the expression of an active progressive state of silicosis.

[Serum enzyme tests in the diagnosis and follow-up of the evolution of sarcoidosis]. / Aportul unor teste enzimatice serice în diagnosticul si supravegherea evolutiei sarcoidozei.

Due to the diagnosis difficulties posed by sarcoidosis, new metabolic or biological tests were suggested for replacing and/or confirming the histopathological examination: determination of the serous levels of the angiotensin-convertase (ACS), lysozyme and acid phosphatase. For establishing the ACS diagnosis value, the enzyme serous level was determined in 117 sarcoidosis patients, histopathologically confirmed (62 with active sarcoidosis, 55 with chronic sarcoidosis) in comparison with 109 patients suffering from other chronic lung affections. The results obtained, statistically processed, showed that the ACS level in active sarcoidosis is increased in 97% of the patients and only in 8% of the patients non-suffering from sarcoidosis. In active sarcoidosis, the ACS level has a positive predicting value of 86.8% and a negative one of 98%. The serous activities of lysozyme and acid phosphatase are not significant in sarcoidosis diagnosis. Of 59 treated patients with active sarcoidosis, in 58 the ACS value became normal after the clinical-radiological remission, thus showing the prognosis value of the test.

[The advantages of Reprimum therapy in pulmonary sarcoidosis and other granulomatous diseases]. / Avantajele terapiei cu Reprimum în sarcoidoza pulmonara si alte boli granulomatoase.

In sarcoidosis and other granulomatous non-caseous diseases, the election treatment is immunosuppressive, mainly with cortisones that ensure more than 70% lasting remissions. Continuous use of cortisones for a long time (8-30 months) in high doses leads to serious side effects: gastric and intestinal ulcers, obesity, osteoporosis, suprarenal dysfunction, sensitivity to infections. Good results and elimination of the important side effects were obtained by treatment with Reprimum--a semisynthetic antibiotic with a wide spectrum and immunosuppressive properties--administered alone or with prednisone in small doses (15-20 mg once) in 6 weeks' series: 2 weeks--Reprimum 10/mg/kg daily +/- prednisone and for other 4 weeks--Reprimum 15 mg/kg twice a week +/- prednisone followed by two weeks' break. In 75 patients with histopathologically confirmed sarcoidosis (of whom 7-9.3% with outside-the-lung situs, too), the treatment with Reprimum gave: 94.7% lasting remission, only 5.3% failures, reduction of the treatment period to 6-12 months and the absence of any important side reaction. In other 37 sarcoidosis cases, failures of cortisone therapy (of which 11-30% relapses after 2-6 years), the treatment with Reprimum together with prednisone allowed recovery of 29 patients (78.4%). The same treatment with Reprimum, used in 22 patients with immunosuppressive treatment indication (dermatomyositis, Kaposi's syndrome, thrombocytopenias, nodose periarteritis, silicosis), of whom 18 (81.8%) were failures of the cortisone therapy, healed 20 of these cases (90.9%). Reprimum immunosuppressive property acts at the level of T4+ lymphocyte, involved in sarcoidosis pathogenesis. The functional blockage of T4+ lymphocyte can be also achieved by cyclosporine A.(ABSTRACT TRUNCATED AT 250 WORDS)

Advantages of treatment with Reprimun in sarcoidosis.

Favourable results were obtained by treatment with Reprimun alone or in association with low doses of Prednisone in 112 patients with sarcoidosis (59% with active sarcoidosis and 33% failures of a previous corticotherapy). Treatments were applied during 3-6 series each one of 6 weeks at intervals of 2 weeks between series. In comparison with the classical corticotherapy, treatment with Reprimun has better results, namely: absence of any major adverse reactions; reduction of the treatment period to 6-12 months (3-6 series); 95% lasting remissions in the sarcoidoses with initial treatment and 78% remissions in the case of failures of a previous corticotherapy.