A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study.

BACKGROUND: Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines. PATIENTS AND METHODS: In part I, we used a 3+3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD. RESULTS: Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20mg/m(2) plus capecitabine 1000 mg/m(2) was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n=5), hand-foot syndrome (n=5), neutropenia (n=21), neutropenic infection (n=1), and neutropenic colitis (n=1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months. CONCLUSIONS: Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.

[Palliative sedation]. / Palliatieve sedatie.

Palliative sedation is the intentional lowering of the level of consciousness ofa patient in the last phase of life by means of the administration of sedatives. The objective of palliative sedation is to relieve severe physical or psychological suffering that is otherwise untreatable. Sedation is used in 12% of all patients dying in the Netherlands. Refractory delirium, dyspnoea or pain are the most common indications. If deep palliative sedation is used, the estimated life expectancy should be a few days to at most one week. Midazolam is used most often for continuous sedation, usually by subcutaneous infusion; if the response is insufficient, a combination of midazolam with levomepromazine or phenobarbital or monotreatment with propofol may be used. If continuous infusion is not desired or feasible, intermittent administration of midazolam, diazepam, lorazepam or chlorpromazine may be considered. Provided that it is used under the right circumstances, palliative sedation does not shorten life.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

BACKGROUND: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. METHODS: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. RESULTS: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). CONCLUSION: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

The experimental (in vitro) and clinical (in vivo) immunosuppressive effects of a rat IgG2b anti-human CD2 mAb, LO-CD2a/BTI-322.

BACKGROUND: CD2 is a cell surface glycoprotein expressed on most human T cells and natural killer (NK) cells, working as a cell adhesion and costimulatory molecule. The aim of this paper is to analyze the mechanism of action of a rat IgG2b anti-human CD2 monoclonal antibody (mAb) (LO-CD2a/BTI-322 mAb), which is a potent immunosuppressive agent and inducer of cell death. In vivo, this mAb is able to prevent or treat kidney allograft rejection. METHODS: The mechanisms by which the LO-CD2a/BTI-322 mAb is able to induce inhibition of cell activation and cell death were analyzed by mixed lymphocyte reactions and by flow cytometry. After in vivo treatment, levels of circulating mAb were measured by ELISA as well as anti-rat immunization and cytokine release. RESULTS: We show that the inhibition of cell activation induced by LO-CD2a/BTI-322 mAb after allogeneic or OKT3 stimulation is due to an Fcgamma receptor-dependent CD2 down-modulation and to T-cell depletion through an antibody-dependent cell-mediated cytotoxicity mechanism mediated by NK cells or activated monocytes. Peripheral T- and NK-cell depletion was observed after in vivo treatment with LO-CD2a/BTI322. Cytokine release (TNFalpha) was correlated with some side effects, but only after the first injection, and the effects were never severe or life threatening. CONCLUSION: The correlation between the in vitro and in vivo data suggests that T-cell depletion, especially of activated cells, and inhibition of cell activation after CD2 down-modulation are the main mechanisms of action of the LO-CD2a/BTI-322 mAb.

Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group.

BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

Technetium-99m L,L-ethylenedicysteine clearance and correlation with iodine-125 orthoiodohippurate for the determination of effective renal plasma flow.

Technetium-99m L,L-ethylenedicysteine (99mTc-L,L-EC) is a new renal tubular tracer that allows the determination of the effective renal plasma flow (ERPF). The aim of this study was to derive simplified methods for the estimation of 99mTc-L,L-EC clearance using one or two plasma samples after bolus injection. Fifty-nine multiple plasma dual-tracer samples (nine samples from 5 to 120 min after injection) were obtained after injection of kit-formulated 99mTc-L,L-EC and iodine-125 orthoiodohippurate (OIH). The studies were performed in 25 stable and 24 unstable transplant recipients, in five patients with renal insufficiency (four on chronic haemodialysis) and in five normal volunteers. This allowed a wide range of renal function values to be covered, with ERPF (estimated by OIH clearance) ranging from 25.4 to 604.0 ml/min. The reference 99mTc-L,L-EC clearance, as calculated from the multisample model, could be estimated from two samples at 15 and 90 min with an error of 11.3 ml/min and from one sample at 90 min with an error of 17.8 ml/min. Using appropriate linear regression analysis, ERPF could be estimated by the two- and one-sample 99mTc-L,L-EC clearance with an error of 24.2 and 22.8 ml/min, respectively. In conclusion, 99mTc-L,L-EC clearance can be accurately estimated by simplified one- or two-sample methods. Moreover, these methods can be used to estimate ERPF with an error that remains acceptable for clinical purposes.

HPLC-microparticle enzyme immunoassay specific for tacrolimus in whole blood of hepatic and renal transplant patients.

Tacrolimus is a relatively new immunosuppressant used in organ transplantation to prevent graft rejection. However, its use is not devoid of side effects, making it important to maintain blood concentrations within therapeutic ranges. Several analytical methods are currently available for routine drug monitoring. However, these methods are based on use of the same monoclonal antibody, which also cross-reacts with some metabolites, resulting in overestimation of some blood concentrations. Even though this antibody appears appropriate for therapeutic drug monitoring, no reference method measures only the parent drug, mainly because of the poor absorptivity of tacrolimus in ultraviolet light. We have developed a method displaying an increased specificity towards the unchanged drug, using conventional equipment available in most clinical laboratories. After chromatographic separation of the blood extract, the tacrolimus fraction is analyzed by an automated microparticle enzyme immunoassay (MEIA) performed on the IMx analyzer (Abbott Labs.). This method is linear from 0 to 40 micrograms/L, yields CVs from 8.5% to 18.2%, and has a detection limit of 5 micrograms/L. Tacrolimus concentrations obtained by HPLC-MEIA in hepatic and renal transplant patients are from 47.5% to 18.8% lower than those obtained by MEIA, according to liver function tests and metabolite accumulation, even though no significant differences were observed between the methods for drug-free blood samples supplemented with known amounts of tacrolimus.

Measurement of the vasoconstrictive substances endothelin, angiotensin II, and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults.

In a rat model, the left kidney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro-Collins (EC) solution (n = 12) or University of Wisconsin (UW) solution (n = 6) for 10 min. Each kidney was then harvested and stored at 4 degrees C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A-II), thromboxane (B2) (TxB2), and prostaglandin I2 (PGI2). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64 +/- 0.3 pg/ml vs 0.82 +/- 0.1 pg/ml (P < or = 0.009); A-II 20.8 +/- 6.2 pg/ml vs 7.75 + 2.3 pg/ml (P < or = 0.007); TxB2 100.8 +/- 17.7 pg/ml vs 40.1 +/- 11.7 pg/ml (P < or = 0.04); PGI2 638.3 +/- 41.1 pg/ml vs 318.3 +/- 36.4 pg/ml (P < or = 0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB2 and prostacyclins during the 24-48 h period. In the UW solution, basal levels of ET and A-II were lower than those in EC solution, but similarly increased after initial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of regulating cholesterol biosynthesis on breath isoprene excretion in men.

Isoprene is a normal constituent of human breath and may be derived from the cholesterol synthetic pathway. Acute and chronic lovastatin and a cholesterol-supplemented diet were used to determine whether a mechanistic link exists between isoprene and cholesterol biosynthesis in vivo in humans. The acute effects of lovastatin, a competitive inhibitor of the rate-limiting step of cholesterol biosynthesis, on breath isoprene excretion was determined by administering a single 20, 40 or 80 mg dose of this drug to five healthy male subjects at 8 p.m. and measuring their breath isoprene levels every 4 h for one 24 h cycle before and after treatment. When compared to the baseline cycle, all three doses of lovastatin significantly reduced breath isoprene levels at 6 and 10 h post-drug treatment. Chronic lovastatin therapy (40 mg b.i.d. for 6 wk) reduced 6 a.m. breath isoprene levels (time of maximum baseline value) by 27 +/- 9% (SEM) and cholesterol synthesis measured in freshly isolated mononuclear leukocytes (ML) by 12 +/- 6%. A cholesterol-supplemented diet (1070 mg, total) ingested for 6 wk reduced breath isoprene excretion and ML sterol synthesis by 16 +/- 5 and 19 +/- 4%, respectively. The parallel decreases in isoprene excretion and cholesterol synthesis caused by these pharmacologic and dietary means suggest that breath isoprene is derived from the cholesterol synthesis pathway.

Post-dural puncture headache in young patients. A comparative study between the use of 0.52 mm (25-gauge) and 0.33 mm (29-gauge) spinal needles.

In a prospective study of 80 patients under 40 years of age, given spinal anaesthesia through either a 0.52 mm (25-gauge) needle or a 0.33 mm (29-gauge) needle, the incidence of post-dural puncture headache and backache was compared. There were no headaches in the 0.33 mm needle group, while in the 0.52 mm needle group an incidence of 25% was found. The incidence of backache was the same in both groups. The technique of performing spinal anaesthesia was evaluated and concluded to be slightly more difficult with a 0.33 mm needle, as estimated by the number of redirections of the needle needed to obtain cerebrospinal fluid. There were no differences between the two needles with respect to obtaining adequate spinal anaesthesia and spread of blockade.

[Role of thromboxanes in hepatic ischemia]. / Rôle des thromboxanes dans l'ischémie hépatique.

Thromboxanes and prostacyclins are two prostanoids that may play an important part in the hepatic lesions induced by ischemia. In order to study this hypothesis, we have compared the survival rate of rats submitted to a 90-minute warm ischemia by giving them agents inhibiting the synthesis of thromboxanes and/or exogenic PGI2. Simultaneously, we have measured the rate of production of TxA2 and PGI2 by the hepatic tissue after 90-minute ischemia and after 30-minute reperfusion. Our results suggest that the decrease in the thromboxane level is a deciding factor of improvement in the tolerance of the liver to ischemia. The drug that allows achieving the best survival rate and the greatest decrease in the thromboxane levels is Imidazole.

Atrial natriuretic factor, arachidonic acid metabolites and acute renal ischemia: experimental protocol in the rat.

The effects of an atrial natriuretic factor (ANF) infusion upon the production of the arachidonic acid metabolites (thromboxane B2, TxB2; 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha, PGI2, or prostaglandins E2, PGE2) were investigated after acute renal ischemia in the rat. This experimental protocol included a right nephrectomy and a 45-min left renal artery occlusion. Fifteen minutes after declamping, blood samples were collected from the left renal venous effluent for the assay of plasmatic prostanoid concentrations. Three experimental groups were studied: group I (n = 9) sham, no ischemia-group II (n = 9) control group, 45 min of left renal ischemia, followed by a 15-min revascularization, and group III (n = 10) ANF group, a similar ischemic protocol to that in group II was used but, after declamping, synthetic Atriopeptin III was infused (0.5 micrograms/kg/min) during the 15-min of vascular reflow. Fifteen minutes after declamping, TxB2 secretion significantly increased after ischemia in the control and ANF groups: TxB2: 210 +/- 22.4 pg/ml (control group) and 234.8 +/- 25.1 pg/ml (ANF group) versus 135.8 +/- 17.8 pg/ml (sham group) (p less than 0.05 and 0.01, respectively). On the other hand, the 6-keto-PGF1 alpha plasma levels were significantly higher after ischemia in the ANF group (221 +/- 34 pg/ml) in comparison with the sham (124 +/- 24.1 pg/ml) or with the control group (116.7 +/- 12.5 pg/ml). The calculated TxB2/6-keto-PGF1 alpha ratio was therefore higher in the control group, 1.93 +/- 0.27, than in physiological conditions (sham group), 1.2 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)