A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours.

BACKGROUND: TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types. METHODS: Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay. RESULTS: 14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin. CONCLUSIONS: The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

Hsp90 inhibitors in the clinic.

Specific inhibitors of Hsp90 have recently entered human clinical trials. At the time of writing, trials have been initiated only in metastatic cancer, although a rationale exists for using these agents in a variety of human diseases where protein (mis)folding is involved in the disease pathophysiology. Hsp90 inhibitors offer a unique anti-cancer opportunity because they provide simultaneous combinatorial blockade of multiple oncogenic pathways. The first compound in this class, 17-AAG, has completed phase I trials and phase II trials are in progress. The toxicity has been manageable and evidence of possible clinical activity has been seen in metastatic melanoma, prostate cancer and multiple myeloma. Other inhibitors with improved properties are approaching clinical trials. This chapter presents an update of the current clinical trials using Hsp90 inhibitors, focussing on the areas that will be increasingly relevant in the next 5 years.

Low dose erythropoietin is effective in reducing transfusion requirements following allogeneic HSCT.

Blood transfusions are frequently required for several weeks after allogeneic transplantation due to inadequate erythropoiesis and defective erythropoietin production. Because red cell transfusion is not without complications in this setting, we sought to avoid them using recombinant human erythropoietin (rhEpo) therapy. We treated 53 patients following allogeneic transplantation for haematological malignancy, using rhEpo at a dose of 10 000 units subcutaneously twice weekly. The median time of commencement of rhEpo was 61 days post-transplant (range 19-465 days), and the median haemoglobin (Hb) concentration was 9.4 g dL(-1) (range 7.0-10.7 g dL(-1)). Thirty patients responded to rhEpo and required no further transfusion with a median rise in Hb after 2 weeks of therapy of 1.5 g (0.7-4.1 g dL(-1)). Erythropoietin (Epo) was discontinued at a median of 5 weeks (range 2-36), when the median Hb concentration was 12.3 g dL(-1) (range 10.0-14.3 g dL(-1)). Those patients who failed to respond to rhEpo frequently had additional reasons for anaemia including cytomegalovirus (CMV) reactivation and treatment, major ABO incompatibility, disease relapse, graft rejection or other transplant-related complications. We conclude that a short course of rhEpo is an effective treatment for anaemia arising following allogeneic hematopoietic cell transplantation, and can avoid the need for transfusion in this setting.

Oral magnesium and vitamin C supplements in asthma: a parallel group randomized placebo-controlled trial.

BACKGROUND: Epidemiological studies suggest that higher intakes of dietary vitamin C and magnesium may be associated with a reduced risk of asthma. OBJECTIVE: To determine whether vitamin C or magnesium supplements improve the clinical control of asthma in primary care patients. METHODS: A randomized, placebo-controlled, double-blind parallel group trial of 16 weeks supplementation with 1 g/day vitamin C, 450 mg/day magnesium chelate or matched placebo. Three hundred patients aged 18-60 years with physician-diagnosed asthma, controlled with at least one dose of an inhaled corticosteroid daily, were recruited from 24 primary care practices in Nottingham, UK. The main outcome measures were change in forced expiratory volume in 1 s, forced vital capacity, airway responsiveness to methacholine, mean morning and evening peak flow, symptom scores and bronchodilator use, both individually and as a combined summary statistic. RESULTS: There was no evidence of any beneficial effect of either supplement on any outcome measure of asthma control in the primary intention-to-treat analysis, or in an analysis restricted to participants who completed the study. CONCLUSIONS: Regular dietary supplementation with vitamin C or magnesium adds no clinical benefit to current standard therapy of asthma in primary care patients.

A review of methods of drug cost management in hospitals.

To stem the ever-increasing cost of health-care various strategies are being introduced by health authorities world-wide. Methods to control drug costs are reviewed with a particular emphasis on hospital-centred strategies and the role of the pharmacist. The literature suggests that no one single strategy is consistently successful and that better results are obtained by using a combination of strategies.

A multidisciplinary approach to hospital-based drug cost containment.

OBJECTIVE: To develop and implement a range of strategies to control rising drug expenditure in a teaching hospital. METHOD: A multidisciplinary team was established to survey drug use and to identify areas where drug wastage was occurring. Once target areas were identified, strategies were developed and implemented and drug expenditure monitored prospectively. RESULTS: Communication and education about optimum drug use, efficient drug handling and therapeutic drug substitution were identified as areas for action. Antibiotic prescribing, outpatient prescribing and expenditure on new drugs were identified as target areas for cost savings. Compared to previous years, the rate of increase in drug expenditure on antibiotics was reduced by over 5000 pound sterling, from a baseline of 552 278 pound sterling over the study period compared to an increase of 65 984 pound sterling for the previous corresponding period. CONCLUSION: We believe that despite the short-coming of the study, which adopted an open design without a control group, it demonstrates that effective cost-containment strategies can be implemented by multidisciplinary teams if they are given sufficient support by senior management.

Low-dose filgrastim significantly enhances neutrophil recovery following autologous peripheral-blood stem-cell transplantation in patients with lymphoproliferative disorders: evidence for clinical and economic benefit.

PURPOSE: To assess the clinical and economic benefit of low-dose (50 microg/m2) filgrastim after peripheral blood stem-cell transplantation (PBSCT) in a randomized, placebo-controlled double-blinded study. PATIENTS AND METHODS: Thirty-eight patients with lymphoproliferative disorders were randomized to receive low-dose filgrastim (19 patients) or placebo (19 patients) beginning on the first day after stem-cell reinfusion and continuing until absolute neutrophil count (ANC) was greater than 0.5 x 10(9)/L. All patients received greater than 2.5 x 10(6) CD34+ cells/kg, which was mobilized with chemotherapy and filgrastim 300 microg from the fifth day. An economic analysis was performed based on the outcome in the two groups. RESULTS: Neutrophil engraftment was significantly more rapid in patients who received filgrastim with a median number of days until ANC was greater that 0.5 x 10(9)/L of 10 (9 to 13) versus 14 (9 to 19; P < .0001). The time to reach an ANC greater than 1 x 109/L was 12 (9 to 14) versus 16 days (10 to 25; P < .0001). The total number of patients who required intravenous antibiotic therapy was lower in the filgrastim-treated group (68%) compared with the placebo group (89%); also, the median number of days with fever and the duration of antibiotic therapy were shorter, although these differences did not reach statistical significance. However, although only three of 19 (16%) patients who received filgrastim required amphotericin, 11 of 19 (58%) who received placebo did require it, and amphotericin usage was significantly less in the filgrastim group (P = .029). Finally, in-patient stay was significantly shortened in those who received filgrastim from 16 (13 to 23) to 13 days (11 to 18; P = .0003). CONCLUSION: Low-dose filgrastim significantly reduces neutrophil engraftment time post-PBSCT and also reduces in-patient stay and costs, which makes it economically viable for patients who are undergoing high-dose chemotherapy.

Inhibition of neuronal high voltage-activated calcium channels by insect peptides: a comparison with the actions of omega-conotoxin GVIA.

The whole cell variant of the patch clamp technique was used to investigate the actions of two novel insect peptides on high voltage-activated Ca2+ currents in cultured dorsal root ganglion (DRG) neurones. The insect peptides (PMP-D2 and PMP-C) were isolated originally from insect brains and fat bodies, and have been found to have similar three-dimensional structures to the N-type Ca2+ channel inhibitor omega-conotoxin GVIA (omega-CgTx GVIA). High voltage-activated Ca2+ currents were activated from a holding potential of -90 mV by depolarizing step commands to 0 mV. Extracellular application of synthetic PMP-D2 or PMP-C (1 microM) attenuated high voltage-activated Ca2+ currents. The effects of PMP-C were strongly dependent on the frequency of current activation, but inhibition was apparent and reached a steady state after 20 steps when currents were evoked for 30 msec at 0.1 Hz. The actions of the two insect peptides overlapped both with each other and with omega-CgTx GVIA, suggesting that N-type Ca2+ current was predominantly sensitive to these peptides. Low voltage-activated T-type current and 1,4-dihydropyridine sensitive L-type Ca2+ currents were insensitive to 1 microM PMP-D2 and PMP-C, which indicates a degree of selectivity. The presence of a fucose group on PMP-C abolished the ability of this peptide to attenuate high voltage-activated Ca2+ currents, which may reflect a mechanism by which peptide function could be regulated in insects. The electrophysiological data are supported by studies on 45Ca2+ influx into rat cerebrocortical synaptosomes. Both PMP-D2 (10 microM), PMP-C (10 microM) and omega-CgTx GVIA (1 microM) attenuated a proportion of 45Ca2+ influx into the synaptosomes, but additive effects of these peptides were not observed. We conclude that these naturally occurring peptides obtained from invertebrate preparations have inhibitory effects on N-type Ca2+ channels. Although the peptides have related three-dimensional structures, they have distinct amino acid sequences and appear to have different mechanisms of action to produce inhibition of mammalian neuronal high voltage-activated Ca2+ channels.