Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients.

BACKGROUND: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients, refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largest series of patients treated with caspofungin outside clinical trials. METHODS: Centres in Germany that were known to treat patients with invasive fungal infections were asked to fill out detailed questionnaires for all patients treated with caspofungin. No effort was made to influence the decision to use caspofungin. RESULTS: A total of 118 patients were evaluable (median age 48 years, interquartile range 38-58), out of which 41 (35%) suffered from acute leukaemia, 31 (26%) had allogeneic stem cell transplants, 16 (14%) lymphoma or myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression. One hundred and six patients were evaluable for efficacy out of which 68 (64%) patients achieved a complete or partial remission. A total of 81 out of 115 (70%) patients were alive 30 days after the end of caspofungin therapy. Response rates were similar in proven (20/32, 63%) and probable (27/46, 59%) infections, in neutropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractory to antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24). Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A, no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found. CONCLUSIONS: This open case study of severely ill patients with invasive fungal infections demonstrates both excellent efficacy and very low toxicity of caspofungin.

Formation of neutralizing antibodies after treatment with human calcitonin.

PURPOSE: Calcitonin is used for the treatment of Paget's disease of bone, hypercalcemia, and postmenopausal osteoporosis. The formation of antibodies against heterologous calcitonins, such as salmon calcitonin (sCT), has been described frequently. Neutralizing effects of these antibodies have been demonstrated in many cases. As far as antibody formation against human calcitonin (hCT) is concerned, only a single case has been reported in the literature; however, investigations concerning the biologic activity of the antibodies were not performed. We have now assessed the sera of 33 patients treated with hCT for postmenopausal osteoporosis for a period of at least 12 months to evaluate the occurrence of hCT-binding and hCT-neutralizing antibodies. PATIENTS AND METHODS: Binding antibodies were detected by incubation of patient sera with 125I-labeled hCT; neutralizing activity was assessed in an in vitro bioassay that measured the impairment of the hCT-induced cyclic adenosine monophosphate (cAMP) formation in the human breast cancer cell line T47D. RESULTS: Prior to hCT treatment, none of the patients showed evidence of the presence of either binding or neutralizing antibodies. During the course of treatment, binding antibodies occurred in a single patient. These antibodies had a neutralizing activity characterized by 15% impairment of cAMP formation after 6 months and 27% impairment after 12 months of treatment compared with pretreatment control values. The neutralizing effect observed in this particular patient was comparatively mild compared with the effects seen after the formation of neutralizing antibodies against sCT, so major clinical sequelae were not expected in this patient. This may be due to the lower antigenicity of hCT as compared with sCT. CONCLUSION: Although antibody formation against hCT is a rare phenomenon, we nonetheless recommend monitoring of postmenopausal osteoporosis patients treated with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment.

Neutralizing antibodies against calcitonin.

The use of calcitonin (CT) is established as a treatment of Paget's disease of bone and postmenopausal osteoporosis (PMO). Salmon calcitonin (sCT), which differs in 14 of the 32 amino acids from human calcitonin, has found a wider distribution world wide, although antibody formation against sCT has been reported in more than 70% of the patients on continuous sCT treatment. The clinical significance of these antibodies has been discussed controversially, because the occurrence of antibodies is not always associated with the development of secondary resistance. Using an in vitro bioassay, based on the CT-mediated increase of the cyclic AMP (cAMP) production of the human breast cancer cell line T 47 D we could identify a neutralizing activity against sCT in the serum of a subset of patients with formation of antibodies against sCT which was related to the development of secondary resistance. Antibody formation against human calcitonin (hCT) has been reported only once before. Binding and neutralizing antibodies were now observed in 1 of 33 patients with PMO treated with hCT. Due to a low neutralizing activity, clinical sequelae were not to be expected in this patient. The formation of neutralizing antibodies against calcitonin is common after treatment with salmon but a rare phenomenon after treatment with human calcitonin. We recommend monitoring of patients with postmenopausal osteoporosis and Paget's disease of bone on long term treatment with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment.

A new in vitro bioassay for human calcitonin: validation and comparison to the rat hypocalcemia bioassay.

The human breast cancer cell line T 47 D expresses calcitonin (CT) receptors that are coupled to adenylate cyclase and which reveal a dose-dependent cyclic AMP response to CT. We used this model to establish an in vitro bioassay for synthetic human CT (hCT) preparations to overcome some of the obstacles of the standard rat hypocalcemia in vivo bioassay. The detection limit of the in vitro bioassay was 1 x 10(-10) M hCT (EC 50: 8.7 pM +/- 26%) compared to 7.3 x 10(-9) M (EC 50: 7.2 microM +/- 32%) for the in vivo bioassay. The relative potencies of test preparations revealed a good correlation (r = 0.89) and several hCT-related substances produced comparable results when tested by the two methods. The standard deviations of precision and accuracy, however, were significantly smaller (P less than 0.05) for the in vitro bioassay. According to these data the T 47 D in vitro bioassay is more sensitive, superior in precision and accuracy, and comparable in specificity to the rat hypocalcemia bioassay.