Interferon-induced depression: prevalence and management.

BACKGROUND: Interferon-induced depression ranges from 0 to 50%. Interferon schedule and a history of psychiatric illnesses are not enough to predict who will develop symptoms and who will not. AIMS: To assess the prevalence of depression during interferon therapy; to test whether Minnesota Multiphasic Personality Inventory is useful in clinical practice for the early identification of patients at risk of depression; whether and how the depression can be cured. PATIENTS: One hundred and eighty-five patients treated with interferon and ribavirin for chronic hepatitis C. METHODS: Before therapy, all patients underwent a Minnesota Multiphasic Personality Inventory and a clinical examination, specifically for the identification of depressive symptoms. RESULTS: Thirty-one patients developed a psychiatric disorder, 11 of them requiring treatment with anti-depressant drugs. Among the 18 patients with Minnesota Multiphasic Personality Inventory positive tests, 16 developed a psychiatric disorder, 8 of them a severe disorder (sensitivity of 0.58; 0.73 for severe disorders). Among the 154 who did not develop psychiatric side effects, 152 had a negative Minnesota Multiphasic Personality Inventory (specificity: 0.99). Severe psychiatric disorders were successfully treated with anti-depressant drugs. CONCLUSIONS: Psychiatric side effects are easy to see during interferon therapy. A psychiatric evaluation should be considered on all patients before treatment. If depression develops, it should be treated aggressively, and selective serotonin re-uptake inhibitors are the anti-depressants of choice.

New biosynthetic anthracyclines related to barminomycins incorporating barbiturates in their moiety.

Three new anthracyclines, FCE 21424 (2), FCE 24366 (3) and FCE 24367 (4), were isolated from culture broths of Streptomyces peucetius and its mutant strains after addition of sodium barbiturates during the fermentation. Structural assignment, achieved through spectroscopic and degradative studies, that the new anthracyclines had a common barminomycin-like structure incorporating different barbiturate moieties. The new anthracyclines were found to display outstanding cytotoxicity and remarkable potency "in vivo" against P388 ascitic leukemia.

Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.

Improved synthesis and antitumor activity of 1-deazaadenosine.

A more convenient synthetic route to 1-deazaadenosine (1) by reduction of the new nucleoside 7-nitro-3-beta-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (6) is reported. Compound 6 was obtained by reaction of 7-nitroimidazo-[4,5-b]pyridine with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose in the presence of stannic chloride followed by treatment with methanolic ammonia. 1-Deazaadenosine (1) showed good activity in vitro as inhibitor of HeLa, KB, P388, and L1210 leukemia cell line growth, with ID50 values ranging from 0.34 microM (KB) to 1.8 microM (P388). The nitro derivative 6 demonstrated moderate activity against the same cell lines.

Chemical and biological characterization of 4'-iodo-4'-deoxydoxorubicin.

4'-Iodo-4'-deoxydoxorubicin is a doxorubicin (DXR) analogue with greater lipophilicity and reduced basicity of the amino group. In vitro 4'-iodo-4'-deoxydoxorubicin is more cytotoxic than DXR against a panel of human and murine cell lines and is characterized by a higher and faster uptake. In vivo, the spectrum of activity of 4'-iodo-4'-deoxydoxorubicin is comparable to that of DXR, but the new compound has higher activity against murine P388 leukemia resistant to DXR and against pulmonary metastases from Lewis lung carcinoma. Moreover, the new analogue exhibits antitumor activity also after p.o. administration and shows no cardiotoxicity in experimental systems.

DNA polymerases and DNA topoisomerases as targets for the development of anticancer drugs.

Studies of a variety of compounds designed as derivatives of prototype active molecules aphidicolin and doxorubicin are reported. So far none of the aphidicolin simpler analogues is as active as the parental molecule. Ten anthracycline analogues, characterized for their cytotoxicity, antitumor activity and inhibition of the relaxing activity of purified human DNA topoisomerase II can be divided into five groups. The majority of the tested compounds shows properties very similar to those of doxorubicin. Epirubicin shows extremely high inhibitory activity toward the relaxing property of topoisomerase II but its antitumor activity and cytotoxicity are similar to those of the former group. The third group includes a compound with extremely high cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity. The fourth group is represented by a compound which shows a cytotoxicity typical of anthracyclines and good antitumor activity but which has no specific inhibitory activity on topoisomerase II. A fifth group includes a totally inactive compound. Our results suggest that the inhibition of human DNA topoisomerase II is only partially correlated with antitumor activity.