Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers.

In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun.

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80-0.94) or missed the criterion only marginally (90% confidence interval of c (max) 0.75-0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules.

Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients.

OBJECTIVE: A meta-analysis of 3 major German studies conducted between 1989 and 1994 with cyclosporine in severe psoriasis was performed to allow an integrated evaluation of the efficacy and tolerability of cyclosporine in this indication. DESIGN AND SETTING: All 3 studies were prospective, randomized, parallel group studies. The studies were conducted in 61 dermatologic centers in Germany. PATIENTS AND INTERVENTIONS: The studies involved 597 patients with severe plaque type psoriasis. Treatment consisted of cyclosporine (at a dosage of 1.25, 2.5 or 5 mg/kg/day), etretinate (at a mean daily dose of 0.53 mg/kg/day) or placebo in a total of 756 treatment cycles with a maximum duration of 12 weeks. MAIN OUTCOME MEASURES: The main outcome measures were the psoriasis area and severity index (PASI) and serum creatinine level. RESULTS: The meta-analysis revealed that cyclosporine given in a dosage of 2.5 and 5 mg/kg/day was significantly superior to etretinate. In addition cyclosporine 1.25 mg/kg/day proved to be significantly more effective than placebo. An increase in serum creatinine level that required intervention occurred in 3.4% of cyclosporine treatment cycles. CONCLUSION: Cyclosporine is highly effective and well tolerated in the short term treatment of severe psoriasis.

Comparison of three tropisetron-containing antiemetic regimens in the prophylaxis of acute and delayed chemotherapy-induced emesis and nausea.

There is still controversy as to what constitutes the optimal therapy for acute and delayed chemotherapy-induced emesis and nausea. We conducted a three-armed randomized multi-centre study in 193 chemotherapy-naive patients receiving highly emetogenic chemotherapy inducing both acute and delayed symptoms (cisplatin > or = 50 mg/m2, carboplatin > or = 300 mg/m2, cyclophosphamide > or = 750 mg/m2, ifosfamide > or = 1.5 g/m2 on day 1). Group A: 1 x 5 mg tropisetron i.v. on day 1 + 2, then 10 mg p.o. (oral dose now recommended: 5 mg); group B: tropisetron as for A+dexamethasone, 20 mg i.v., on days 1 + 2, then 4 mg i.v./p.o.; group C: tropisetron as for A+metoclopramide, 20 mg i.v. +2 x 10 mg p.o. on day 1, then 3 x 10 mg p.o. Treatment was continued for at least 2 days after the end of chemotherapy. Tropisetron+dexamethasone was significantly superior to tropisetron alone both for acute (P = 0.0064) and delayed (P = 0.0053) emesis. Complete control of acute and delayed emesis (nausea) was achieved in 80% (75%) and 53% (46%) in group A, 97% (90%) and 80% (58%) in group B, and 86% (80%) and 49% (45%) in group C. Patients completely asymptomatic during the whole cycle accounted for 26% of those in group A, 49% in group B and 28% in group C. The most frequent adverse events were constipation (16.6%), headache (7.3%) and tiredness (7.3%). Once-daily tropisetron+dexamethasone over several days is well tolerated and is a simple means of achieving further significant improvement in the efficacy of tropisetron against acute and delayed symptoms.

Chemotherapy-induced severe thrombocytopenia in gynecologic oncology and its treatment with interleukin-3.

Six patients suffering from various gynecologic malignancies developed severe thrombocytopenia (WHO IV) after normal-dose chemotherapy. All patients were treated with platelet transfusions but the results on hematopoietic recovery were not satisfactory. Therefore treatment with a new hematopoietic substance (rh interleukin-3) was initiated. All patients received a dosage of 5 mu g/kg/bw daily s.c. up to 10 days depending on the response of platelet counts. In two women, who had suffered from severe hemorrhage (epistaxis resp. ankle joint hematoma), symptoms disappeared after approximately three days of rhIL-3 use. Whereas platelet transfusions were ineffective in all patients, IL-3 led to a significant increase of the platelet count after 3-5 days of application. Side-effects were mild, when seen in one case, where G-CSF was given at the same time. Our experience supports the idea of using new growth factors like rhIL-3 to cure chemotherapy-induced myelosuppression, such as severe thrombocytopenia.

Pharmacokinetics of the 5HT3 receptor antagonist tropisetron in children.

A pharmacokinetic study in children was performed to assess whether the pharmacokinetic profile of tropisetron in pediatric patients in similar to that in adults. In three pediatric centers, three dosages were tested in two age groups during chemotherapy (Group A, 3-6 years, 2, 5, or 20 mg/m2; group B, 7-15 years, 2, 5, or 20 mg). Children received tropisetron intravenously (course 1) or orally (course 2) before the start of chemotherapy. Blood samples were drawn over 24 hours. Tropisetron treatment continued for up to 6 days at the same daily dose, administered orally. Data were available for 45 patients after intravenous and for 38 patients after oral administration. 82% of course 1 patients and 72% of course 2 patients had no emesis on day 1. Headache occurred in eight patients and abdominal symptoms in three patients. Terminal half-life (5.3-6.6 hours), tmax (1.4-1.5 hours), and absolute bioavailability (41-42%) were identical in both age groups and comparable to those in adults. Because of a smaller volume of distribution, group A children showed a higher Cmax/dose (P < .001) and a higher area under curve (AUC) dose (P < .05) than adults. All parameters were independent of the dose administered. In conclusion, the elimination and absolute bioavailability of tropisetron in children are similar to those in adults. Because of its age-dependent volume of distribution, tropisetron should be administered once a day according to the body surface area in children below 10 years of age.

Dose comparison of tropisetron (Navoban) 5 mg and 10 mg orally in the prophylaxis of dacarbazine-induced nausea and emesis.

In this double-blind, randomized trial performed at five study centers, the prophylactic, antiemetic effect of two different dosages of tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland) was investigated in dacarbazine-treated patients with melanoma. Patients received tropisetron 5 mg or 10 mg orally (as one capsule) once daily (minimum 3 days) on each day of chemotherapy. No significant differences were found in the effects of tropisetron 5 mg and 10 mg. During the first 24 hours, total control of vomiting was seen in 93% and 98% of patients receiving tropisetron 5 mg and 10 mg, respectively. Total control of nausea was achieved in 84% and 80% of patients receiving tropisetron at these dosages. Over days 2 to 7 of chemotherapy, total control of vomiting and nausea remained high. Patients reported that quality of life remained good throughout chemotherapy, as did mood; only a small decrease in food intake occurred. Tropisetron was well tolerated. Constipation was the most common adverse event, occurring in 13% of patients. Headache (4%), diarrhea (4%), and anorexia (2%) also were observed.

Prevention of chemotherapy-induced nausea and vomiting by tropisetron (Navoban) alone or in combination with other antiemetic agents.

We report an open, three-armed, multicenter study being carried out to assess the optimum treatment for acute and delayed emesis and nausea in patients undergoing highly emetogenic chemotherapy. Eighty-seven patients were randomized to receive tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland), tropisetron plus dexamethasone, or tropisetron plus metoclopramide during chemotherapy. Tropisetron in combination with dexamethasone produced the best control of both acute and delayed emesis. Acute vomiting was prevented in 69% of patients by tropisetron monotherapy, and the addition of dexamethasone significantly increased the total control of vomiting to 92% (P < .01). Similarly for delayed vomiting, total control of emesis was seen in approximately 70% of patients on tropisetron alone during days 2 and 3; this control rate increased to almost 90% with combined tropisetron/ dexamethasone treatment. In all patients receiving cisplatin, the tropisetron/dexamethasone combination produced total control of acute emesis. The tropisetron and dexamethasone combination also provided the best control of acute and delayed nausea. Tropisetron produced total control of acute nausea in 69% of patients. The addition of dexamethasone increased this control rate to 81%. Similarly for delayed nausea, on days 2 and 3 of treatment, dexamethasone plus tropisetron provided total control of nausea in more than 80% of patients compared with a control rate of more than 60% achieved using tropisetron. The combination of tropisetron and metoclopramide did not improve significantly on the control of nausea and vomiting achieved using tropisetron alone. Evaluation of quality of life events by patients indicated no appreciable change in their mental or physical condition during chemotherapy, irrespective of antiemetic therapy. In the tropisetron and tropisetron plus metoclopramide treatment groups, a decreased food intake was observed due to delayed nausea while the addition of dexamethasone prevented loss of appetite. The antiemetic treatments were similarly well tolerated. The most common adverse events were constipation (15%) and tiredness (7%).