Cyclosporin A (CsA) is an immunosuppressive drug widely used in the prevention of organ allograft rejection. It has a narrow therapeutic range and, therefore, careful monitoring of CsA whole blood trough levels is essential. Low blood levels can result in rejection episodes with potential graft loss, and high CsA levels are associated with nephrotoxicity sometimes leading to chronic graft dysfunction (1). Therefore, drugs interfering with CsA blood levels are of special interest for both patients and physicians. St. John's wort (Hypericum perforatum) is an herbal drug extract with an unknown mechanism of action. It is used for different indications, including mild and moderate depression, dysthymia, anxiety, restlessness, and psychosomatic disorders. Its antidepressive activity has been proven in different clinical trials (23). Because St. John's wort is sold without prescription, and because of several reports in the tabloids, it is used increasingly, often without the knowledge of the treating physician. No side effects, with the exception of the rare occurrence of photosensibilization, nor interactions with other drugs are reported in the literature or by the manufacturers. We report the interaction of St. John's wort with CsA in recipients of kidney transplants. To date, 30 patients with kidney grafts and whose CsA levels dropped significantly after the use of St. John's wort have been observed at our institution. No other drugs were changed concomitantly, making another drug interaction highly unlikely. After initiation of therapy with St. John's wort, a drop in CsA whole blood trough levels by a mean of 47% (range 33–62%) was observed. In turn, CsA dosage had to be gradually increased by a mean of 46% (range 15% − 115%). With discontinuation of St. John's wort, CsA blood levels increased markedly by a mean of 187% (range 84–292%), allowing the gradual decrease of CsA to doses given before St. John's wort treatment was initiated. An exemplary patient is shown in the Figure 1Figure 1: CsA whole blood trough levels and daily CsA dosage. Example of a representative patient. Y1-axis: CsA whole blood trough level (ng/ml). Y2-axis: Daily dosage of CsA (mg/day). X-axis: Days after the transplant.. Although the mechanism of this drug interaction is currently unknown, three possible mechanisms are conceivable. First, the absorption of CsA could be decreased by St. John's Wort. We further investigated the absorption of CsA when taken concomitantly with St. John's wort. Since we found normal CsA whole blood trough levels 2, 4, and 6 hr after CsA uptake, this mechanism is unlikely (data not shown). Second, St. John's wort can induce cytochrome P-450 in the liver and/or small intestine, as shown for many drugs interacting with CsA (4). A third possible explanation would be the induction of the drug transporter P-glycoprotein in the small intestine, resulting in an increased export of CsA from the blood to the lumen of the intestine (5). Currently, it is impossible to define which of the latter two mechanisms is responsible for our finding. We are now in the process of uncover the possible mechanism. In conclusion, we have shown that St. John's Wort significantly affects CsA blood levels. Because uncontrolled reductions of CsA blood levels caused by St. John's Wort bear an unpredictable risk particularly for life sustaining organs such as the heart, liver or lung, caution should be taken with the administration of St. John's Wort in patients with transplants. Th. Breidenbach1 V. Kliem M. Burg J. Radermacher M. W. Hoffmann J. Klempnauer
5538 Background: Response rates (RR) up to 50% were found with PCw in platinum resistant EOC. We compared the efficacy of first-line PCw induction therapy to PC3w. Methods: 270 patients (pts) with FIGO stage II-IV, Performance status (PS) 0–2 were randomly assigned to 3 x PC3w (P 175mg/m2 with either cisplatin [Cis] 75mg/m 2 or carboplatin [Car] AUC 6) or 6 x PCw (P 90mg/m2 with either Cis 70mg/m 2 or Car AUC 4, day 1,8,15 and day 29,36,43) followed by up to 6 cycles PC3w in both arms. Pts were stratified for FIGO stage, PS, tumor size and center. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were RR and toxicity. A total of 225 events were needed to detect a 10–13% absolute difference in PFS/OS with a power of 84% (one-sided). Results: 267 pts (134 TC-3w and 133 TCw) were eligible (3 pts wrong tumor type). Pt characteristics were well balanced; median age 58 years, serous 62%, residual disease >1cm 66%, FIGO stage II 7%, III 64%, IV 29%. Median dose-intensity for PC3w was: P 58(47–58) and Cis 25(22.5–25) mg/m 2 /w, Car 2(1.6–2) AUC/w, for PCw: P 60(36–60) and Cis 44.7(30–44.7) mg/m 2 /w and for Car 2.7(1,6–2,7) AUC/w. After a median follow-up of 39 months (m) (range 0.03 - 93.3m) 206 pts (77%) had progressed and 164 pts (61%) had died. Median PFS was 18m for TC3w and 19m for TCw, 5-year PFS was 20% and 18%, respectively (logrank test: p = 0.63). Median OS was 44m for TC3w and 45m for TCw, 5-year OS was 36% and 37%, respectively (logrank test: p = 0.87). RR after induction therapy in 176 pts with measurable disease was 72% for TC3w and 74% for TCw (p = 0.68). TCw was well tolerated. Grade 3/4 toxicity for TC3w vs. TCw was respectively, platelets 1.75% vs.1.55% (ns), WBC 5.5% vs. 8.7 (p = <0.0001), granulocytes 16.7% vs. 11.7% (p = <0.001) and delay 3% vs. 9% of the cycles. TCw induced less grade 2/3 muscular and joint pain (TC3w 6.3% and 3.5% vs. TCw 0.3% and 0.8% of the cycles) and less neurotoxicity (TC3w 6% vs. 1.6% of the pts in TCw). The other toxicities were similar in frequency and severity in both arms. Conclusions: TCw was well tolerated and had less granulocytopenia, neurotoxicity, and muscular and joint pain but did not yield benefit in terms of OS, PFS or RR. No significant financial relationships to disclose.
The study was designed to determine the efficacy of a two-drug and three-drug combination chemotherapy regimen for patients with advanced epithelial ovarian carcinoma resistant to alkylating monotherapy. Patients were randomized to receive either Adriamycin (doxorubicin) and cis-diamminedichloroplatinum(II) (AP) repeated every 3 weeks, or AP plus hexamethylmelamine (HAP) repeated every 5 weeks. Forty-five patients were evaluable for response and 49 for survival. No significant differences were found between the treatment groups as to response rate, progression-free survival, and survival. A remission was achieved in 20% of the patients and stable disease in another 20%. Median progression-free survival of all patients was only 4 months (median survival, 6 months). All patients showed progressive disease within 13 months after the onset of chemotherapy. Patients responding to treatment and those with an interval of more than 2 years between the initial diagnosis and cancer recurrence, experienced prolonged survival. Two conclusions can be drawn from the results of this study; neither of the regimens is superior to the other, and the effect of both in alkylator-resistant patients with ovarian cancer are meager. In studies on salvage chemotherapy, to the contrary, these combinations induced remissions in more than 40% of the patients. This difference in response rate might be due to differences between the prognostic factors of the patient populations. Better results are to be expected when these drugs are used in initial drug programs for previously untreated patients.
