piperidines and ifoxetine

Ifoxetine (CGP 15 210 G) is a novel and unusual drug. It specifically and selectively blocks the 5-HT reuptake in the brain without affecting the 5-HT uptake processes in the periphery (blood platelets). In the first, open and explorative trials its tolerability and effectiveness were studied in 33 patients suffering from endogenous (n = 25) or other types of depressive disorders. In daily doses of 50 to maximally 300 mg mental condition considerably improved in 17 patients. As assessed by HAMD 7 patients out of 17 became asymptomatic (HAMD Score less than 10) whereas 10 other patients markedly improved (decrease in HAMD by greater than or equal to 50%) in the course of 3 to 4 weeks of treatment. Eleven patients improved only slightly, in 3 patients no particular change in condition could be observed and 2 patients deteriorated. This deterioration was due to psychotic decompensation after the second week of the treatment (75-100 mg/d). Apart from this, ifoxetine was well tolerated particularly at doses of 50-150 mg/day, which also appeared to be the optimal therapeutic range of doses. There were no changes in cardiovascular function or laboratory values and almost no somatic or other complaints of major concern. These preliminary results indicate that ifoxetine has antidepressant properties with possibly an advantageous side-effect profile, in comparison to other 5-HT uptake inhibitors.

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

A 14-year-old girl with multiple intra-abdominal tumors was diagnosed with stage III Burkitt's lymphoma. She achieved complete remission after multi-drug chemotherapy, but she relapsed after six courses. Autologous peripheral blood stem cells (PBSC) or allogeneic PBSC harvested from an HLA-identical sibling were insufficient, and her family did not agree to bone marrow collection from the sibling. Although the patient relapsed nine times (the relapses involved intra-abdominal organs or bone) during the following 4 years 7 months, treatment with rituximab monotherapy or in combination with ifosphamide, carboplastin, and etoposide, or local irradiation (33.8-40.0 Gy) to treat the bone metastases, proved effective, resulting in complete or partial remission. At the time of writing, the patient was in a 10th cycle of remission lasting 1 year 6 months and had not required transplantation. Thus, a chemotherapy regimen including rituximab might be effective for Burkitt's lymphoma in patients experiencing multiple relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Carboplatin; Etoposide; Female; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Piperidines; Remission Induction; Rituximab

A 47-year-old man had a retroperitoneal tumor measuring 18 cm in maximum diameter of the left kidney that was diagnosed with computed tomography (CT)-guided needle biopsy as small cell carcinoma. Microscopically, the tumor cells showed immunohistochemical reaction for neural cell adhesion molecule antibodies. This patient with advanced renal small cell carcinoma and multiple metastatic lesions was treated with the first-line combination chemotherapy of cisplatin, etoposide and ifosphamide, which showed a partial response of primary renal tumor and a complete response of liver metastasis, and with the second-line chemotherapy of cisplatin and irinotecan, which showed a complete response of Virchow's nodal metastasis. Thereafter, in spite of salvage chemotherapy of amurubicin hydrochloride for persistent and refractory renal small cell carcinoma, he died 32 months after the first presentation due to local progression. However, combination chemotherapy of these anticancer agents made his prognosis more favorable than we expected before treatment. The extrapulmonary small cell carcinomas are generally known to be more aggressive and malignant than the lung small cell carcinomas, and small cell carcinoma arising from the kidney is an extremely rare malignant neoplasm, with only 34 cases reported in the English or Japanese literature. The prognosis of renal small cell carcinomas is currently limited as compared with the lung small cell carcinomas, and therefore a cumulative investigation of a larger number of cases treated with multidisciplinary modalities including combination chemotherapy is necessary.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Cisplatin; Drug Administration Schedule; Etoposide; Humans; Irinotecan; Kidney Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Piperidines

Ifoxetine (CGP 15210 G; (+/-)-bis-[cis-3-hydroxy-4-(2,3-dimethyl-phenoxy)]-piperidine sulfate) prevented the depletion of serotonin (5-HT) induced by H 75/12 and p-chloromethamphetamine in the rat brain, and that caused by endogenously released dopamine after the combined administration of haloperidol and amfonelic acid in the rat striatum. These effects are typically caused by compounds that inhibit 5-HT reuptake. Unexpectedly, ifoxetine only weakly inhibited the uptake of radiolabelled 5-HT into rat brain synaptosomes in vitro or ex vivo, the human thrombocytes in vitro or into rat thrombocytes after pretreatment. The following, among the possible explanations for this apparent discrepancy, were considered and regarded as unlikely: the involvement of an active metabolite; the possibility that ifoxetine accumulates in the brain to an extent sufficient to cause in vivo uptake inhibition; a pharmacokinetic interaction with the depleting agents. The possibility that the depletor tests give false positives was also considered. However, ifoxetine lowered brain 5-hydroxyindoleacetic acid and reduced the accumulation of 5-hydroxytryptophan after central decarboxylase inhibition. This suggests that it also interferes with 5-HT metabolism in the absence of depleting agents, which means that it interacts in some way with serotonergic transmission. Ifoxetine displayed weak or no interactions with 5-HT1, 5-HT2, alpha 1-, alpha 2- and beta-noradrenoceptors, histamine H1, muscarinic acetylcholine, opiate, GABA A, and benzodiazepine receptors in vitro, and with dopamine and 5-HT2 receptors in vivo. It did not antagonize the noradrenaline (NA) depletion induced by H 77/77 in rat brain and only weakly interfered with the uptake of i.v. injected radiolabelled NA into the rat heart. This suggests that its interaction with the 5-HT system is specific. Due to its atypical properties, among which the rather weak potentiation of the neurological effects of 5-hydroxytryptophan is also important, ifoxetine may exhibit a therapeutic and/or side-effect profile which differs from that of classical 5-HT uptake inhibitors.

Topics: Animals; Blood Platelets; Brain Chemistry; Corpus Striatum; Haloperidol; In Vitro Techniques; Myocardium; Nalidixic Acid; Naphthyridines; Neurotransmitter Agents; Norepinephrine; Piperidines; Rats; Serotonin; Synaptosomes; Tryptophan; Tyramine; Tyrosine

The pharmacokinetics of CGP 15 210 G, a new 5-HT uptake inhibitor in poor and extensive metabolisers of debrisoquine, give indirect evidence of an association between its metabolism and polymorphic hydroxylation of the debrisoquine type.

Topics: Adult; Debrisoquin; Drug Evaluation; Female; Humans; Hydroxylation; Isoquinolines; Kinetics; Male; Phenotype; Piperidines; Polymorphism, Genetic; Serotonin